ES2711949T3 - Treatment of addiction and impulse control disorders using PDE7 inhibitors - Google Patents

Abstract

Composition comprising (a) a phosphodiesterase 7 (PDE7) inhibitor which is a selective PDE7 inhibitor for which the lower of the IC50 to inhibit the activity of PDE7A and the IC50 to inhibit the activity of PDE7B is less than a tenth of the IC50 having the agent to inhibit the activity of any other PDE enzyme of the PDE1-6 and PDE8-11 enzyme families; and (b) a dopaminergic agent for use in the treatment of an addiction that is an addiction to an addictive substance or that is the practice of compulsive behavior associated with a primary impulse control disorder or an obsessive-compulsive disorder.

Description

DESCRIPTION

Treatment of addiction and impulse control disorders using PDE7 inhibitors

Declaration regarding the sequence listing

The sequence listing associated with the present application is provided in text format instead of a hard copy and is therefore incorporated by reference into the specification. The name of the text file containing the sequence listing is NE_1_0172_SequenceListingFinal_ST25; and it has been sent through the EFS website together with the presentation of the descriptive report.

I. Field of the invention

The present disclosure is directed to the prevention and treatment of substance and behavioral addictions using inhibitors of phosphodiesterase 7 (PDE7) in combination with dopaminergic agents.

II. Background of the invention

The World Health Organization (WHO) defines addiction to substances as the use of a substance repeatedly, despite knowing and experiencing its harmful effects. Substance addiction is a chronic, relapsing disease characterized by a loss of control over the use of drugs, compulsive drug seeking and craving for a substance, use that persists despite negative consequences and physical and / or psychological dependence on the substance. substance. Substance addition usually follows a cycle of tolerance, abstinence, compulsive drug-taking behavior, drug-seeking behavior, practice of addictive behavior and relapse. Substance abuse and addiction are public health problems with significant social and economic impact on both the addict and the society, playing an important role in violent crime and the spread of infectious diseases. Addictive substances include alcohol, caferna, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-type opioid agonists such as heroma, phencyclidine and phencyclidine-like compounds, sedative drugs such as benzodiazepines and barbiturates and psychostimulants such as cocama , amphetamines and amphetamine-related drugs such as dextroamphetamine and methylamphetamine.

Alcohol is one of the most commonly abused substances globally. Additionally, alcoholism leads to serious liver and cardiovascular disease and generates dependence, resulting in serious mental disorders, social problems and adverse consequences that include the division of families, tragic accidents and the reduction of work performance. According to WHO, alcohol consumption is responsible for 20-30% of esophageal and liver cancer, liver cirrhosis, homicides, epilepsy and car accidents worldwide. Globally, alcohol abuse leads to approximately 1.8 million deaths per year. Compulsive behavior towards the consumption of alcohol is a main symptom of the disorder. In recent years several approaches have been investigated to help alcoholic patients not only to control alcohol consumption but also alcohol cravings and relapse (Monti et al., J Stud Alcohol 54: 235-45 (1993); Volpicelli et al. , Arch Gen Psychiatry 49: 876-880 (1992); and O'Brien Science 278: 66-70 (1997)).

Medications such as naltrexone, acamprosate, ondansetron, disulfiram, gamma hydroxybutyrate (GHB) and topiramate tested to determine their potential therapeutic effect on alcohol abuse belong to several classes (Volpicelli et al., 1992; O'Brien et al., 1997). . Few of these pharmacotherapeutic products, such as naltrexone, acamprosate and disulfiram, have been shown to have a certain utility and have been approved for the treatment of alcoholism. Among these drugs, the non-selective opioid antagonist natrexone is currently considered the best pharmacological option. However, despite some promising results, none of these drugs, including naltrexone, has sufficient efficacy in alcoholism and the prognosis is still bad.

Nicotine is one of the most widely used addictive drugs, and nicotine abuse is the most common form of substance abuse. The WHO estimates that there are 1250 million smokers worldwide, representing one third of the global population over 15 years of age. The WHO also estimates that 5 million deaths occur each year as a direct consequence of the use of tobacco, making nicotine abuse the largest single cause of preventable death worldwide. In industrialized countries, 70-90% of cases of lung cancer, 56 80% of chronic respiratory disease and 22% of cardiovascular disease are attributed to smoking. Cigarette smoking is associated with 430,000 deaths annually in the United States alone and is estimated to cost the state $ 80 billion a year in health care costs. The use of tobacco causes one third of all cancers, including cancer of the lung, mouth, pharynx, larynx, esophagus, cervix, kidney, ureter and bladder. Overall death rates from cancer are twice as high among smokers than among non-smokers. Smoking also causes lung diseases such as chronic bronchitis and emphysema; aggravates asthma symptoms; and increases the risk of heart disease, including stroke, heart attack, vascular disease and aneurysm. An estimate of 20% of deaths from heart disease are attributable to smoking. Pregnant women who smoke are at greater risk than nonsmokers of premature birth, miscarriage and children with low birth weight.

The use of nicotine results in higher levels of the neurotransmitter dopamine, which activates the reward pathways to regulate pleasure sensations and mediate the desire to consume nicotine. The symptoms associated with nicotine withdrawal include cravings, irritability, anger, hostility, aggression, fatigue, depression and cognitive decline, which leads the addict to seek more nicotine. The environmental conditioning factors and exposure to stress represent additional factors that motivate the use of nicotine in smokers. The repeated use of nicotine results in the development of tolerance, which requires higher doses of nicotine to produce the same initial stimulation.

Most therapies developed for nicotine addiction have shown only moderate success in the prevention of relapse, which leads to a high failure rate in attempts to quit smoking. Treatments include the use of nicotine replacement products, antidepressants, antihypertensives and behavioral therapy.

The National Institute on Drug Abuse estimates that 72 million Americans, roughly a third of the population, have tested marijuana. The acute effects of marijuana use include memory and learning problems, altered perceptions, difficulty in solving problems, loss of coordination, and increased heart rate. Long-term abuse can cause the same respiratory problems seen in tobacco smokers, such as daily cough, phlegm production, increased risk of lung infections and an increased likelihood of developing cancer of the head, neck and lungs. Depression, anxiety and work-related problems have been associated with the use of marijuana. The long-term use of marijuana can result in compulsive use of addiction that interferes with daily activities. The craving and symptoms of withdrawal, such as irritability, increased aggression, insomnia and anxiety make it difficult for addicts to stop using marijuana. There are no pharmaceutical treatments available for the treatment of marijuana addiction and relapse.

According to the WHO, an estimated 13 million people abuse opioids worldwide, including 9 million addicts to the heroma. More than 25% of people who abuse opioids die from suicide, homicide or an infectious disease, such as HIV and hepatitis, in a period of 10-20 years from the start of the addiction. Tolerance and physical dependence can develop within two to three days. Although the abuse and addiction to opioid agents is a known phenomenon, there has been a further worsening of this problem in recent years (Compton and Volkow, Drug Alcohol Depend 83 Supl 1: S4-7 (2006A) and Compton and Volkow, Drug Alcohol Dependent 81 (2): 103-7 (2006B)). Epidemiological studies of young people in the United States in 2003 indicated that opioid analgesics were among the most frequently abused illegal drugs among high school students (12th year), only after marijuana (Delva et al., Am J Public Health 95 (4): 696-702 (2005)). Also, in recent years there has been a marked increase in the use of opioid drugs in the United States and an even greater increase in problems associated with such use. This increase in use and problems is particularly worrisome because it seems to represent an expanded route to opioid addiction (Siegal et al., Am Fam Physician 67: 942-945 (2003)).

According to recent epidemiological data, 4.7% (that is, 11.0 million) of residents of households in the United States over twelve years of age abused a medically opioid in 2002 and 13.7% of these people ( say, 1.5 million) met the criteria for an opioid use disorder DSM-IV (Psychiatric Association of the United States, Diagnostic and Statistical Manual of Mental Disorders, fourth edition. (1994); Substance Abuse Services Administration and Mental Health, Mortality Data from the Drug Abuse Warning Network, 2002, (2004)). As reviewed recently by Compton and Volkow, the annual incidence of opioid analgesic abuse from 628,000 initiated in 1990 to 2.4 million initiated in 2001 (Substance Abuse and Mental Health Services Administration, Overview of Findings from the 2002 National Survey on Drug Use and Health, (2003); Substance Abuse and Mental Health Services Administration, Emergency Department Trends from the Drug Abuse Warning Network, Final Estimates 1995-2002, (2003)). One of the reasons that encourage the expansion of opioid addiction is the increase in the use of analgesics secondary to medical prescription. The short-term use of opioid medications is rarely associated with addiction. On the contrary, prolonged treatments with these agents have been associated with the development of addiction in up to 18% of patients.

The objectives for the treatment of opiate addiction, such as other types of substance addictions, are to stop opioid use while minimizing painful abstinence symptoms and avoiding relapse. Current treatments involve replacing the addictive drug with a substitution of an agonist or mixed agonist / antagonist of the opioid receptors. An alternative approach consists of the use of an opioid receptor antagonist to block the effect of the agonist. Antagonists provide no relief from pain or other symptoms of withdrawal; rather, they can precipitate abstinence and their therapeutic use has been associated with increased accidental overdosage of opioid agonists and increased lethality. The use of agonists with a lower affinity for the receptors results in less severe abstinence symptoms, but can lead to a dependence on the substitute opiaceum. In addition, many replacement therapies take 3-6 months, which allows time for addicts to stop treatment in half.

Psychostimulants, such as cocama and amphetamines, cause temporary euphoria, increased alertness and increase of the physical capacity in human beings. These substances first increase the transmission of dopamine, but the use of long-term drugs results in a reduction in dopamine activity, which leads to deregulation of the brain's reward system and dysphoria. The WHO estimates that 33 million people in the world abuse amphetamines.

The chronic abuse of cocama can result in hyperstimulation, tachycardia, hypertension, mydriasis, muscle fasciculations, insomnia, extreme nervousness, hallucinations, paranoia, aggressive behavior and depression. Overdose of cocama can lead to tremors, seizures, delirium and death resulting from cardiac arrhythmias and cardiovascular failure. It has been shown that desipramine, amantadine, and bromocriptine reduce the symptoms of cocaine abstinence.

Amphetamine withdrawal symptoms include EEG changes, fatigue and mental depression. Tolerance develops over time and can be associated with tachycardia, auditory and visual hallucinations, delirium, anxiety reactions, paranoid psychosis, exhaustion, confusion, memory loss and prolonged depression with suicidal tendencies. Current treatments for amphetamine addiction include phenothiazines, haloperidol and chlorpromazine for hallucinations, but the potential side effects of these drugs include postural hypotension and severe extrapyramidal motor disorders. Subjects who are addicted to psychostimulants will sometimes experience psychological abstinence as well as physiological withdrawal, making the relapse potentially more likely.

In the past, treatment for substance addiction has focused on behavioral therapy, but it is difficult to break the dependence on many of these highly addictive substances. In particular, addictions to alcohol, cocama and heroma are considered chronic, relapsing disorders. In addition, the simultaneous abuse of multiple substances, such as nicotine, heroma, cocama and alcohol, is common.

The chronic, long-term nature of many addictions and the high rates of recurrence present a considerable challenge for the treatment of drug and alcohol addiction, so that the understanding of the neurobiological basis of relapse has emerged as a central problem in the investigation of addiction. Emotional and environmental factors (conditioning factors) have been listed among the main causes of relapse. For example, it is known that specific stress conditions such as loss of work and economic difficulties, or predictive stimuli of the presence of alcohol previously associated with their use such as a preferred wine bottle and a bar type environment, can greatly facilitate measured the relapse in alcoholics previously detoxified.

The increasing incidence of obesity in the United States, Europe and other westernized societies is also indicative of the prevalence of addictive behavior to food. Unlike normal eating behaviors, addiction to food is maladaptive behavior, which makes people who eat in response to addiction rather than hunger feel worse instead of better. Overeating a food addict is also persistent and habitual, eating an excessive amount of food regularly, and often eating excessive amounts of unhealthy foods. Food addiction not only leads to obesity, but it can also lead, paradoxically, to malnutrition. There are several similarities between food addiction and drug substance addiction, including effects on mood, external signals that cause addictive behavior, expectations, moderation, ambivalence and attribution.

There are two theoretical positions to explain the persistence of addictive behavior and vulnerability to relapse associated with drug and alcohol addiction, homeostatic hypotheses and conditioning hypothesis.

Homeostatic hypotheses relate the risk of relapse with neuroadaptive changes and alteration of neuroendocrine homeostasis that is believed to underlie the anxiety, ammonic dysregulation and somatic symptoms that accompany abstinence and that may persist for considerable periods of time during what has been called the "prolonged abstinence" phase. This point of view, therefore, implies relief of the discomfort and the negative effect as a motivating basis of the relapse.

Conditioning hypotheses are based on observations that relapse is frequently associated with exposure to environmental stimuli related to the drug. This view maintains that specific environmental stimuli that have been associated with reward actions of a drug by means of classical conditioning can induce subjective states that trigger the resumption of drug use. The homeostatic and conditioning hypotheses are not mutually exclusive. In fact, homeostatic and conditioning factors are likely to exert additive effects because exposure to environmental stimuli related to the drug may increase the vulnerability to relapse transmitted by homeostatic alterations.

Clearly, there is a need in the art for new methods to treat and prevent addiction and the recurrent use of addictive agents. The present invention covers these needs by providing useful pharmaceutical methods and combinations in the treatment and prevention of addiction and recurrence.

III. Summary of the invention

The present invention provides a method for treating or preventing an addiction by determining that a subject has an addiction or is at risk of developing an addiction and then administering an inhibitor of a phosphodiesterase 7 (PDE7) effective for the subject for the treatment or prevention of The addiction.

In one aspect of the invention, the subject is addicted to an addictive agent. Examples of addictive agents include alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants. In one embodiment, the addictive agent is alcohol. In another embodiment, the addictive agent is nicotine. In a further embodiment, the addictive agent is an opioid, for example, morphine, methadone, fentanyl, sufentanil, codema, oxicodema and heroma. In a further embodiment, the addictive agent is a psychostimulant, for example, cocama, amphetamine or an amphetamine derivative. In another embodiment, the addictive agent is cocama.

In one aspect of the invention, the subject is addicted to an addictive or compulsive behavior or suffers from a pulse control disorder. In another aspect of the invention, the subject suffers from a primary impulse control disorder, i.e., a pulse control disorder in which the disorder is a primary disorder rather than a disorder that is iatrogenic (secondary to medical treatment) or that is secondary to another disease or primary disorder. Addictive or compulsive behaviors that are control disorders of primary impulses include the following: compulsive overacting, ludopathy, pathological use of electronic devices, pathological use of electronic video games, pathological use of electronic communication devices, pathological use of mobile phones, addiction to pornography, sex addiction, compulsive spending, anorexia, bulimia, intermittent explosive disorder, kleptomania, piromama, tricotilomama, excessive compulsive exercise and excessive compulsive work. In another embodiment, the addictive or compulsive behavior is a food addiction. In another embodiment, the addictive or compulsive behavior is compulsive overacting. In another aspect of the invention, the addictive or compulsive behavior is an obsessive-compulsive disorder.

In one aspect of the invention, the PDE7 inhibitory agents for the treatment of addiction are selected from the following disclosed herein: formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2 , compound 3 and compound 4.

In one aspect of the invention, the PDE7 inhibitory agent has an IC ⁵⁰ for inhibiting PDE7A and / or PDE7B activity of less than about 1 pM. In one embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ for inhibiting PDE7A and / or PDE7B activity of less than about 100 nM. In another embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE1B activity of more than 5 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and IC ⁵⁰ to inhibit PDE7B activity. In another embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE10 activity of more than 5 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and IC ⁵⁰ to inhibit PDE7B activity. In a further embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE3 activity of more than 10 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and / or IC ⁵⁰ to inhibit PDE7B activity. In another embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ for inhibiting the activity of PDE3 and PDE4 of more than 10 times the lowest of the IC ⁵⁰ to inhibit the activity of PDE7A and the IC ⁵⁰ to inhibit the activity of PDE7B. In a further embodiment, the PDE7 inhibitory agent has an IC50 to inhibit the activity of PDE 4 and PDE 8 of more than 10 times the lowest of the IC ⁵⁰ to inhibit the activity of PDE7A and the IC ⁵⁰ to inhibit the activity of PDE7B . In another embodiment, the PDE7 agent has an IC ⁵⁰ to inhibit the activity of PDE1, PDE2, PDE3, PDE 4, PDE 8, PDE10 and PDE11 of more than 10 times the lowest of IC ⁵⁰ to inhibit the activity of PDE7A and IC ⁵⁰ to inhibit the activity of PDE7B. In a further embodiment, the PDE7 inhibitory agent is a selective inhibitor of PDE7 for which the lower of the IC ⁵⁰ for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than one-tenth of the IC ⁵⁰ which has the agent to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11. In another embodiment, the PDE7 inhibitory agent is a highly selective inhibitor of PDE7 for which the lower of the IC ⁵⁰ for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than fifty-fifty of the IC ⁵⁰ which has the agent to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11. In a further embodiment, the PDE7 inhibitory agent has a molecular weight of less than about 450 g / mol. In another embodiment, the PDE7 inhibitory agent is capable of crossing the blood-brain barrier.

The present invention provides a method for treating or preventing an addiction by determining that a subject has an addiction or is at risk of developing an addiction and then administering a chemical compound that inhibits the activity of PDE7 and a dopaminergic agent. The chemical compound has the following characteristics: (i) an IC ⁵⁰ for inhibiting the activity of PDE7A and / or PDE7B of less than about 1 pM; and (ii) an IC ⁵⁰ to inhibit PDE 3 of more than 10 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and / or IC ⁵⁰ to inhibit PDE7B activity.

In one embodiment, the chemical compound has an IC ⁵⁰ for inhibiting PDE7A and / or PDE7B activity of less than about 100 nM. In another embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE1B activity of more than 5 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and IC ⁵⁰ to inhibit the activity of PDE7B. In another embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE10 activity of more than 5 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and IC ⁵⁰ to inhibit PDE7B activity. In another embodiment, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE4 activity of more than 10 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and IC ⁵⁰ to inhibit PDE7B activity. In a further embodiment, the PDE7 inhibitor has an IC ⁵⁰ to inhibit PDE8 activity of more than 10 times the lowest of IC ⁵⁰ to inhibit PDE7A activity and IC ⁵⁰ to inhibit PDE7B activity. In another embodiment, the PDE7 agent has an IC ⁵⁰ to inhibit the activity of PDE1, PDE2, PDE3, PDE 4, PDE 8, PDE10 and PDE11 of more than 10 times the lowest of IC ⁵⁰ to inhibit the activity of PDE7A and IC50 to inhibit PDE7B activity. In a further embodiment the PDE7 inhibitor agent is a selective PDE7 inhibitor for the lower IC 50 for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than one tenth of the CI ⁵⁰ it has the agent to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11. In another embodiment, the PDE7 inhibitory agent is a highly selective inhibitor of PDE7 for which the lower of the IC ⁵⁰ for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than fifty-fifty of the IC ⁵⁰ which has the agent to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11. In a further embodiment, the PDE7 inhibitory agent has a molecular weight of less than about 450 g / mol. In another embodiment, the PDE7 inhibitory agent is capable of crossing the blood-brain barrier.

In one aspect of the invention, the subject is addicted to an addictive agent. Examples of addictive agents include alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants. In one embodiment, the addictive agent is alcohol. In another embodiment, the addictive agent is nicotine. In a further embodiment, the addictive agent is an opioid, for example, morphine, methadone, fentanyl, sufentanil and heroma. In a further embodiment, the addictive agent is a psychostimulant, for example, cocama, amphetamine or an amphetamine derivative. In another embodiment, the addictive agent is cocama.

In one aspect of the invention, the subject treated with a PDE7 inhibitor is addicted to an addictive or compulsive behavior or suffers from a pulse control disorder. In another aspect of the invention, the subject suffers from a primary impulse control disorder, i.e., a pulse control disorder in which the disorder is a primary disorder rather than a disorder that is iatrogenic (secondary to medical treatment) or that is secondary to another disease or primary disorder. Addictive or compulsive behaviors that are control disorders of primary impulses include the following: compulsive overactive, ludopaffa, pathological use of electronic devices, pathological use of electronic video games, pathological use of electronic communication devices, pathological use of mobile phones, addiction to pornography, sex addiction, compulsive spending, anorexia, bulimia, intermittent explosive disorder, kleptomania, piromama, tricotilomama, excessive compulsive exercise and excessive compulsive work. In another embodiment, the subject suffers from food addiction. In another embodiment, the addictive or compulsive behavior is compulsive overacting. In another aspect of the invention, the subject to be treated according to the present invention has an obsessive-compulsive disorder.

The present invention provides a composition for use in the treatment or prevention of an addiction, which comprises providing a subject having an addiction, an inhibitor of a phosphodiesterase 7 (PDE7) and dopaminergic agents.

Exemplary dopaminergic agents include, for example, levodopa (also referred to as "L-dopa"), carbidopa, and dopamine receptor agonists and precursors such as bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, rotigotine, and quinagolide, as well as phenoldopam, which is selective for the dopamine D1 receptor.

In one aspect, the subject is addicted to an addictive agent, for example, alcohol, nicotine, marijuana, a marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate and a psychostimulant. In one embodiment, the addictive agent is alcohol and the additional therapeutic agent is an opioid antagonist, such as naltrexone, or a mixed opioid partial antagonist / agonist, such as buprenorphine. In another embodiment, the subject is addicted to a psychostimulant such as cocama, amphetamine, an amphetamine derivative or methamphetamine and the additional therapeutic agent is an antidepressant, such as bupropion. In a further embodiment, the subject is addicted to nicotine and the additional therapeutic agent is an antidepressant, such as bupropion.

In another aspect, the subject is addicted to an addictive or compulsive behavior, such as a primary impulse control disorder, including, for example, ludopaffa, compulsive overactive, pathological use of electronic devices, pathological use of electronic video games, pathological use of electronic communication devices, mobile phone pathological use, addiction to pornography, sex addiction, compulsive spending, anorexia, bulimia, intermittent explosive disorder, kleptomania, piromama, tricotilomama, excessive compulsive exercise and excessive compulsive work. In one embodiment, the addictive or compulsive behavior is compulsive overactive and the additional therapeutic agent is topiramate. In another aspect of the invention, the subject to be treated according to the present invention has an obsessive-compulsive disorder.

The present invention provides a method for preventing the recurrent use of an addictive agent or the practice of an addictive or compulsive behavior, treating a subject who has experienced a period of abstinence, or limited or limited use, of the addictive agent or the addictive behavior or compulsive by administering an inhibitor PDE7 to the subject. The present invention also provides a method of preventing recidivism of addictive or compulsive behavior associated with a primary impulse control disorder, treating a subject who has experienced a period of remission, or limited or limited use, of addictive behavior or compulsive associated with the primary impulse control disorder by administering a PDE7 inhibitor to the subject. The present invention also provides a method of preventing the relapse of an addictive or compulsive behavior associated with an obsessive-compulsive disorder, treating a subject who has experienced a period of remission, or limited or reduced practice, of the associated addictive or compulsive behavior. with obsessive-compulsive disorder by administering a PDE7 inhibitor and a dopaminergic agent to the subject. Additional therapeutic agents that contribute to the relapse prevention effect can be administered with the PDE7 inhibitor. This treatment can be administered to subjects who have previously been treated with a different anti-addiction treatment that is no longer used.

In one aspect, the use of relapsing addictive agents such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants is prevented by the administration of PDE7 inhibitors. In a preferred embodiment, the recurrent use of cocama, amphetamine or methamphetamine is prevented.

In another aspect, the relapse of an addictive or compulsive behavior, in particular addictive or compulsive behavior associated with a primary impulse control disorder, is prevented by the administration of PDE7 inhibitors. In a preferred embodiment, the following behaviors are prevented: compulsive overacting, ludopaffa, pathological use of electronic devices, pathological use of electronic videogames, pathological use of electronic communication devices, pathological use of mobile telephones, addiction to pornography, sex addiction, compulsive spending, anorexia, bulimia, intermittent explosive disorder, kleptomania, piromama, tricotilomama, excessive compulsive exercise and excessive compulsive work. In one embodiment, the addictive or compulsive behavior is compulsive overactive that has been induced by tension. In another embodiment, the subject is treated to prevent the relapse of an addictive or compulsive behavior associated with an obsessive-compulsive disorder.

The present invention provides a pharmaceutical composition that includes a PDE7 inhibitor and a dopaminergic agent, wherein both the PDE7 inhibitor and the dopaminergic agent contribute to the treatment or effective prevention of an addiction. Unitary dosages of the pharmaceutical composition are also provided.

In one aspect of the invention, the subject is addicted to an addictive agent. Examples of addictive agents include alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, cocama and other psychostimulants. In one embodiment, the addictive agent is alcohol. In another embodiment, the addictive agent is nicotine. In a further embodiment, the addictive agent is an opioid, for example, morphine, methadone, fentanyl, sufentanil and heroma. In a further embodiment, the addictive agent is a psychostimulant, for example, cocama, amphetamine or an amphetamine derivative. In a preferred embodiment, the addictive agent is cocama.

In one aspect of the invention, the subject is addicted to an addictive or compulsive behavior or suffers from a pulse control disorder. In another aspect of the invention, the subject suffers from a primary impulse control disorder, i.e., a pulse control disorder in which the disorder is a primary disorder rather than a disorder that is iatrogenic (secondary to medical treatment) or that is secondary to another disease or primary disorder. Addictive or compulsive behaviors that are control disorders of primary impulses include the following: compulsive overactive, ludopaffa, pathological use of electronic devices, pathological use of electronic video games, pathological use of electronic communication devices, pathological use of mobile phones, addiction to pornography, sex addiction, compulsive spending, anorexia, bulimia, intermittent explosive disorder, kleptomania, piromama, tricotilomama, excessive compulsive exercise and excessive compulsive work. In a preferred embodiment, the addictive or compulsive behavior is compulsive overacting. In another aspect of the invention, the subject to be treated according to the present invention has an obsessive-compulsive disorder. The additional therapeutic agent of the pharmaceutical composition is a dopaminergic agent.

In one aspect, the subject is addicted to an addictive agent, for example, alcohol, nicotine, marijuana, a marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate and a psychostimulant. In one embodiment, the addictive agent is alcohol and the additional therapeutic agent is an opioid antagonist, such as naltrexone, or a mixed opioid partial antagonist / agonist, such as buprenorphine. In another embodiment, the addictive agent is nicotine and the additional therapeutic agent is varenicline. In another embodiment, the subject is addicted to a psychostimulant such as cocama, amphetamine, an amphetamine derivative or methamphetamine and the additional therapeutic agent is an antidepressant, such as bupropion. In a further embodiment, the subject is addicted to nicotine and the additional therapeutic agent is an antidepressant, such as bupropion. In another embodiment, the subject is addicted to more than one addictive agent and the additional therapeutic agent is an opioid antagonist, such as naltrexone, or a mixed opioid partial antagonist / agonist, such as buprenorphine.

The present invention provides a kit for the treatment or prevention of an addiction. The kit includes a first container containing an p DE7 inhibitor and a second container containing a dopaminergic agent. Both the PDE7 inhibitor and the therapeutic agent contribute to the treatment or effective prevention of an addiction.

In one aspect, the subject is addicted to an addictive agent, for example, alcohol, nicotine, marijuana, a marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate and a psychostimulant. In one embodiment, the addictive agent is alcohol and the additional therapeutic agent is an opioid antagonist, such as naltrexone, or a mixed opioid partial antagonist / agonist, such as buprenorphine. In another embodiment, the subject is addicted to a psychostimulant such as cocama, amphetamine, an amphetamine derivative or methamphetamine and the additional therapeutic agent is an antidepressant, such as bupropion. In a further embodiment, the subject is addicted to nicotine and the additional therapeutic agent is an antidepressant, such as bupropion. In another embodiment, the subject is addicted to more than one addictive agent and the additional therapeutic agent is an opioid antagonist, such as naltrexone, or a mixed opioid partial antagonist / agonist, such as buprenorphine.

In another aspect of the invention, a subject at risk of addiction to an addictive substance is administered the addictive substance in combination with a PDE7 inhibitor. For example, a subject to whom an opioid antagonist is administered for the relief of acute or chronic pain is administered an opioid agonist in combination with a PDE7 inhibitor so as to provide non-addictive or less addictive analgesia. Examples of addictive agents that can be administered in combination with a PDE7 inhibitor, such as a fixed dose combination or as a kit, include benzodiazepines, barbiturates and analgesic drugs including alfentanil, allylprodine, alphaprodin, anileridin, benzylmorphine, becitramide, buprenorphine, butorphanol. , clonitazene, codema, cyclazocine, desomorphine, dextromoramide, dezocin, diampromide, dihydrocodema, dihydromorphine, dimenoxadol, dimetheptanol, dimethylthiambutene, dioxafethyl butyrate, dipipanone, eptazocine, ethoheptacine, ethylmethylthiambutene, ethylmorphine, fentanyl of etonitazene, heroma, hydrocodone, hydromorphone, hydroxypetidine , isomethadone, ketobemidone, levalphorne, levorphanol, levofenacillmorphan, lofenanthyl, meperidine, meptacinol, methozoin, methadone, metopon, morphine, myrofine, nalbuphine, narcema, nicomorphine, norlevorphanol, normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, OXYCONTIN®, oxymorphone, papaveretum, pentazocine, fena doxone, fenomorphane, phenazocine, phenoperidine, piminodine, piritramide, propy- lecine, promedol, properidin, propiram, propoxyphene sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing and mixed p-agonists / antagonists.

In some embodiments, for any of the methods and compositions described herein, the following PDE7 inhibitors are used: formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35 formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3 and compound 4.

In another embodiment of the invention, a PDE7 inhibitor is provided to a subject who is addicted or is at risk of becoming addicted to an addictive substance to reduce the subject's motivation to seek or acquire the addictive substance.

IV. Brief description of the drawings

In the following, the present invention will be described in greater detail, by way of example, with reference to the accompanying drawings in which:

FIGURE 1 demonstrates the effect of OMS 182056, a PDE7 inhibitor, on the self-administration of cocama by rats.

FIGURE 2 demonstrates the effect of OMS 181869, a PDE7 inhibitor, on the self-administration of cocama by rats.

FIGURE 3 demonstrates the effect of OMS 182401, a PDE7 inhibitor, on the self-administration of cocama by rats.

FIGURE 4 demonstrates the effect of SKF82958, a dopamine D1 agonist, on the self-administration of cocama by rats.

FIGURE 5 demonstrates the effect of OMS 182056, a PDE7 inhibitor, in the lever-actuated response not reinforced by rats.

FIGURE 6 demonstrates the effect of SKF82958, a dopamine agonist D1, on the lever-actuated response not reinforced by rats.

FIGURE 7 demonstrates the chronic effect of OMS182401, a PDE7 inhibitor, on the self-administration of cocama in rats.

FIGURE 8 demonstrates the effect of OMS 182056, a PDE7 inhibitor, on rat-lever response on the first day of extinction after cocama addiction.

FIGURE 9 demonstrates the effect of OMS 182056, a PDE7 inhibitor, on yohimbine-induced relapse to cocama search by rats.

FIGURE 10 demonstrates the effect of OMS182401, a PDE7 inhibitor, on yohimbine-induced relapse to cocama search by rats.

FIGURE 11 demonstrates the effect of OMS 182056, a PDE7 inhibitor, on signal-induced relapse to rat cocama research.

FIGURE 12 demonstrates the effect of OMS182401, a PDE7 inhibitor, on signal-induced relapse to cocama search by rats.

FIGURE 13 demonstrates the effect of OMS 182056, a PDE7 inhibitor, on relapse induced by cocaine stimulation by rats.

FIGURE 14 demonstrates the effect of SKF82958, a dopamine D1 agonist, on relapse induced by cocaine stimulation by rats.

FIGURE 15 demonstrates the effect of OMS182401, a PDE7 inhibitor, on self-administration of nicotine in rats using a short access model.

FIGURE 16 demonstrates the effect of OMS182401, a PDE7 inhibitor, on self-administration of nicotine in rats using a long access model.

FIGURE 17 demonstrates the effect of OMS182399, a PDE7 inhibitor, on self-administration of nicotine in rats using a short access model.

FIGS. 18A and 18B demonstrate that the PDE7 inhibitors OMS 182399 and OMS 182401, respectively, have no effect on self-administration of food.

FIGURES 19A-19C demonstrate the effect of OMS182401, a PDE7 inhibitor, on the motivation of nicotine-addicted mice to acquire nicotine in a progressive self-administration relationship study.

FIGURE 20 demonstrates the effect of OMS182401, a PDE7 inhibitor, the first day of extinction of nicotine self-administration.

FIGURE 21 demonstrates the effect of OMS182401, a PDE7 inhibitor, on the signal-induced restoration of nicotine search behavior.

FIGURE 22 demonstrates the effect of OMS182401, a PDE7 inhibitor, on yohimbine-induced reestablishment of nicotine search behavior.

FIGURES 23A-23D demonstrate the effect of OMS182401, a PDE7 inhibitor, on stress-induced compulsive overeating by rats. FIGURE 23A shows the results for control animals, which do not fear tension or undergo dietary restriction. FIGURE 23B shows the results for experimental animals that do not fear tension and underwent dietary restriction. FIGURE 23C shows the results for experimental animals that are stressed and not subjected to dietary restriction. FIGURE 23D shows the results for experimental animals that are stressed and subjected to dietary restriction.

FIGURES 24A-24D demonstrate the effect of OMS 182056, a PDE7 inhibitor, on stress-induced compulsive overeating by rats. FIGURE 24A shows the results for control animals, which did not have stress or undergo dietary restriction. FIGURE 24B shows the results for experimental animals that do not fear tension and underwent dietary restriction. FIGURE 24C shows the results for experimental animals that are stressed and not subjected to dietary restriction. FIGURE 24D shows the results for experimental animals that are stressed and subjected to dietary restriction.

FIGURES 25A-25D demonstrate the effect of topiramate, as a comparator, on compulsive overactive stress induced by rats. FIGURE 25A shows the results for control animals, which do not fear tension or undergo dietary restriction. FIGURE 25B shows the results for experimental animals that are not stressed and subjected to dietary restriction. FIGURE 25C shows the results for experimental animals that are stressed and not subjected to dietary restriction. FIGURE 25D shows the results for experimental animals that are stressed and subjected to dietary restriction.

FIGURE 26 demonstrates the effect of the OMS182399 PDE7 inhibitor on yohimbine-induced relapse for search for food in a model of food addiction.

FIGURES 27 and 28 demonstrate the effect of OMS182399, a PDE7 inhibitor, on the release of basal or nicotine induced dopamine, respectively, in the nucleus and accumbens of Wistar rats by an in vivo microdialysis study .

FIGURES 29A-29B demonstrate that 0MS182401, a PDE7 inhibitor, inhibits the spontaneous activity of dopaminergic ventral tegmental area (VTA) neurons and potentiates the inhibitory effect of SKF82958, a dopamine D1 agonist.

FIGURE 30 demonstrates the effect of the PDE7 inhibitor OMS182401 on the release of VTA GABA.

FIGURE 31 demonstrates that the OMS 182401 PDE7 inhibitor inhibits the activation of dopaminergic VTA neurons by nicotine and acts synergistically with the dopamine agonist D1 SKF82958.

FIGURE 32 demonstrates the effect of direct administration of the PDE7 inhibitor WHO 182401 in rat VTA.

FIGURE 33 demonstrates that the OMS182399 PDE7 inhibitor blocks dose-dependently the morphine-induced excitation of dopamine VTA cells.

FIGURE 34 demonstrates that acute application of the PDE7 inhibitor OMS182399 blocks dose-dependent excitation of ethanol-induced dopamine VTA cells.

FIGURE 35 shows that the acute application of the PDE7 inhibitor OMS182399 reverses dose-dependent excitation of cocama-induced dopamine VTA cells.

FIGURE 36 demonstrates that the OMS182401 PDE7 inhibitor enhances the activity of the dopamine agonist D1 SKF82958 in a model of open field activity.

V. Detailed description of the preferred embodiment

The present invention is based on the surprising discovery by the present inventors that selective inhibitors of the nucleotide phosphodiesterase type 7 (PDE7) together with dopaminergic agents cause a surprising reduction of the relapse of the addiction. Using rat models, the reductions were demonstrated in subjects addicted to addictive agents and in subjects who showed compulsive behaviors. A. Methods to treat and prevent addictions using PDE7 inhibitors or inhibitors

Thus, the present invention includes methods for treating or preventing an addiction, comprising administering one or more PDE7 inhibitors to a subject having an addiction or at risk of developing an addiction. In various embodiments, the subject is addicted to an addictive agent or behavior, including, but not limited to, any of the addictive agents and behaviors described herein. The subject may be physically or physiologically dependent on the substance or behavior; the subject can be psychologically dependent; or the subject can be both physically and psychologically dependent. The subject may be addicted to one or more of an addictive agent or behavior.

As used herein, unless the context dictates otherwise, "treating", and similar words such as "treatment", "treating", etc., is an approach to obtaining beneficial or desired results, including and preferably Classical results The treatment may optionally involve the reduction or alleviation of a disease or condition, (e.g., addiction or use or recurrent behavior) or the retardation of the progression of the disease or condition (e.g., addiction or use or relapsing behavior).

As used herein, unless the context indicates otherwise, "prevent", and similar words such as "prevention," "preventing," etc., is an approach to prevent the occurrence or recurrence of a disease or disease. condition, (eg, addiction or use or recurrent behavior) or prevent the onset or recurrence of the symptoms of a disease or condition, or optionally an approach to delay the onset or recurrence of a disease or condition or delay the onset or recurrence of the symptoms of a disease or condition.

As used herein, the term "PDE7" is used generically to refer to all translation products encoded by transcripts of one or both of these two genes: PDE7A and / or PDE7B. As used herein, the term "PDE7 inhibitory agent" or "PDE7 inhibitor" refers to an agent, such as a chemical compound, a peptide or a nucleic acid molecule, that inhibits or blocks directly or indirectly the phosphodiesterase activity of PDE7A, PDE7B or PDE7A and PDE7B. In some cases, the agent can bind or interact directly with PDE7 protein. An agent that binds with PDE7 can act to inhibit or block the activation of PDE7 by any suitable means, such as by inhibiting the binding of cAMP or substrate ligand with PDE7. In other cases, the PDE7 inhibitory agent can inhibit PDE7 activity indirectly, such as by reducing the expression of the PDE7 protein. In some cases, the PDE7 inhibitory agent can inhibit PDE7 activity by altering the cellular distribution of PDE7, for example, by interfering with the association between PDE7 and an intracellular anchor protein.

As used herein, the term "dopaminergic agent" refers to an agent that acts to enhance or replicate dopamine-mediated effects in the central nervous system, including dopamine (if a clinically effective method of delivery should be developed), dopamine precursors, such as levodopa (L-dopa), dopamine cofactors, inhibitors of dopamine metabolizing enzymes, other dopamine receptor agonists and precursor compounds that are converted metabolically into a dopamine receptor agonist, as well as inhibitors of the reuptake of dopamine and facilitators of the release of dopamine.

As used herein, the term "dopamine receptor agonists" refers to any molecule that causes the activation of one or more of the subtypes of the dopamine receptor family.

As used herein, the term "mammalian subject" includes all mammals, including without limitation humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs and rodents.

In general, a subject is provided with an effective amount of a PDE7 inhibitor. As used herein, an "effective amount" or a "therapeutically effective amount" of a substance, e.g., a PDE7 inhibitor, is sufficient to affect a desired biological or psychological effect, such as beneficial results. , including clinical results. For example, in the context of the treatment of addiction using the methods of the present invention, an effective amount of a PDE7 inhibitor is sufficient to cause the subject to reduce or stop the use of an addictive agent. In the case of addictive behavior, an effective amount of a PDE7 inhibitor is sufficient to cause the subject to reduce or stop the addictive behavior.

In one embodiment, a therapeutically effective dose is an amount of PDE7 inhibitory agent sufficient to inhibit the enzymatic activity of PDE7 in a neuronal cell. In another embodiment of the methods of the invention, a therapeutically effective dose is an amount of inhibitory agent of PDE7 sufficient to inhibit the enzymatic activity of PDE7 in striated neurons or nucleus accumbens. The determination of an effective dose of a PDE7 inhibitory agent sufficient to cross a cell membrane and inhibit the enzymatic activity of PDE7 in a cell can be determined using a cellular assay for inhibition of PDE7, as described in Smith SJ et al., Molecular Pharmacology 66 (6): 1679-1689 (2004), incorporated by reference herein. The determination of an effective dose of a PDE7 inhibitory agent sufficient to inhibit the enzymatic activity of PDE7 in the striatum can be determined using an assay to measure the effect of a PDE7 inhibitor on cAMP levels in the striatum, such as is described in Siuciak JA et al., Neuropharmacology 51: 386-396 (2006).

According to certain embodiments of the present invention, a subject is provided with a PDE7 inhibitor alone, while, in other embodiments, a subject is provided with a PDE7 inhibitor in combination with an additional therapeutic agent. It is understood that the effective amount of one or both of a PDE7 inhibitor and an additional therapeutic agent may be different when given alone than when provided in combination. For example, when the PDE7 inhibitor and the additional therapeutic agent act synergistically, then a minor amount of the PDE7 inhibitor, a minor amount of the additional therapeutic agent or minor amounts of the PDE7 inhibitor or the additional therapeutic agent may be necessary for achieve the same therapeutic effect that provides the PDE7 inhibitor or the additional therapeutic agent alone. In other embodiments, the same amount of the PDE7 inhibitor and the additional therapeutic agent are used to provide an enhanced therapeutic effect relative to the therapeutic effect provided by the PDE7 inhibitor or the additional therapeutic agent alone.

According to certain embodiments of the present invention, a subject is provided with a PDE7 inhibitor in combination with an addictive therapeutic agent, determining the dosage of the addictive therapeutic agent to achieve the desired therapeutic effect and determining the dosage of the PDE7 inhibitor to eliminate or reduce the potential for addiction to the addictive therapeutic agent.

The subject can be any animal, including a mammal, and, particularly, a human being.

In one aspect of the invention, it is first determined or diagnosed that the subject has an addiction, or is at risk of developing an addiction, by diagnostic testing, observation or analysis by a healthcare provider. An effective amount of a PDE7 inhibitor, or an effective amount of a PDE7 inhibitor and an additional therapeutic agent, are then provided to the subject for the treatment or prevention of addiction. In another aspect of the invention, it is first determined or diagnosed that the subject has an addiction, or is at risk of developing an addiction, by diagnostic testing, observation or analysis by an assistance provider. doctor, but has not been diagnosed or determined that the subject has diabetes or another insulin disorder. An effective amount of a PDE7 inhibitor, or an effective amount of a PDE7 inhibitor and an additional therapeutic agent, are then provided to the subject for the treatment or prevention of addiction. The dosage of the PDE7 inhibitor, or the PDE7 inhibitor and the additional therapeutic agent, can be determined specifically by the medical practitioner for the treatment or prevention of addiction rather than any other disorder or disease.

In particular embodiments, the subject suffers from or is at risk of becoming addicted to any physically addictive agent or addictive or compulsive behavior, including, for example, any of those described below. In particular embodiments, the subject is addicted to alcohol, cocama, nicotine, marijuana, an opiate or other opioid agonist or methamphetamine or other psychostimulant, or phencyclidine and phencyclidine derivatives. In another embodiment, the subject suffers from a primary impulse control disorder. In yet another embodiment, the subject suffers from obsessive-compulsive disorder. In another embodiment, the subject has a history of multiple diets and is at risk of compulsive overacting.

In particular embodiments, it is considered that a subject is at risk of having addiction or relapse from the use of an addictive agent or practices addictive behavior when the subject has been previously addicted to the same addictive agent or addictive or compulsive behavior or a different one. In a certain embodiment, it is considered that the subject is at risk of being addicted or recaptures the use of an addictive agent or practices addictive behavior when the subject is psychologically addicted to an addictive agent or addictive or compulsive behavior, even if the subject is already he is not physically addicted. In one embodiment, the subject suffers from food addiction. In other embodiments, the addictive behavior is compulsive overactive. Subjects at risk of compulsive overeating usually have at least one of the following in their history: recurrent dietary restrictions or yo-yo diets, eating in response to environmental stress, preference for highly appetizing and highly caloric food, eating after satisfying and eating even the discomfort. In another embodiment, the subject suffers from a primary impulse control disorder.

In certain embodiments, the subject is addicted to or is at risk of becoming addicted to a therapeutic agent provided to the patient to treat a disease or disorder, for example, an analgesic drug. In a related embodiment, the subject may be at risk of abusing an addictive therapeutic agent, such as an analgesic drug. It is understood that the abuse of a therapeutic agent, in certain embodiments, indicates the use of the agent for a reason other than or in addition to its prescribed use. In such a situation, both an addictive therapeutic agent and a PDE7 inhibitor may be provided to a subject, alone or in combination with an additional therapeutic agent. For example, an opioid agonist and a PDE7 inhibitor can be provided to a subject suffering from pain, or at risk for pain, both to provide analgesia and to prevent or treat opioid agonist addiction.

In various embodiments, the subject is provided with the PDE7 inhibitor at the same time the subject is using an addictive agent, after the subject has stopped using an addictive agent or before the subject begins to use an addictive agent.

Addictive agents and impulse control disorders

The term "addiction" is used to describe a recurrent compulsion by an individual to perform some specific activity, despite consequences that are detrimental to the health, mental state or social life of the individual. The term is often reserved for drug addictions, but it is applied to other compulsions, such as ludopaffa and compulsive overacting. Factors that have been suggested as causes of addiction include genetic, biological / pharmacological and social factors.

The medical community now makes a theoretical distinction between care between physical or physiological dependence (characterized by symptoms of withdrawal) and psychological dependence (sometimes called simply addiction). The addiction is now called in a restricted form "compulsive, uncontrolled use". If the patient or another person suffers no harm, or is not causing any harm, then it can be considered compulsive, but according to some definitions it is not classified as "addiction". In practice, the two types of addiction (physiological dependence and psychological dependence) are not always easy to distinguish. Addictions often have both physical and psychological components.

"Physical dependence" (or "pharmacological dependency") refers to a state resulting from the usual use of a drug, where negative physical withdrawal symptoms result from abrupt arrest. Examples of addictive agents for which a user may develop physical dependence include nicotine, opioids, barbiturates, benzodiazepines, alcohol, i.e., efflic alcohol, GHB and methaqualone.

It is not believed that stimulants that are habitually abused, such as drugs from the cocama or amphetamine classes, cause significant physical dependence. However, its potential for extreme psychological addiction may persuade the user to consume amounts that become physically harmful, but no abstinence effects have been observed with danger to life.

As used herein, "addictive agent (s)" includes each and every agent to which a subject may become addicted, either physically or psychologically, or both. As noted above, addiction includes addiction to chemical entities, such as drugs, as well as behavioral addiction, as in impulse control disorders.

Addictive agents include addictive recreational drugs, as well as addictive medications. Examples of addictive agents include, but are not limited to, alcohol, for example, ethyl alcohol, gamma hydroxybutyrate (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-type opioid agonists such as heroma, phencyclidine and phencyclidine-like compounds, sedative sommifiers such as benzodiazepines, methaqualone, mecloqualone, etaqualone and barbiturates and psychostimulants such as cocama, amphetamines and amphetamine-related drugs such as dextroamphetamine and methylamphetamine. Other examples include LSD, psilocybin, ecstasy and other hallucinogens. Examples of addictive medicaments include, for example, benzodiazepines, barbiturates and analgesic drugs including alfentanil, allylprodine, alphaprodin, anileridin, benzylmorphine, becitramide, buprenorphine, butorphanol, clonitazene, codema, cyclazocine, desomorphine, dextromoramide, dezocin, diampromide, dihydrocodema, dihydromorphine. , dimenoxadol, dimefeptanol, dimethiltiambutene, dioxafetil butyrate, dipipanone, eptazocine, ethoheptacine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroma, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levalorphan, levorphanol, levofenacillurene, lofenanthyl, meperidine, meptacinol, metazocine , methadone, metopon, morphine, mirofin, nalbuphine, narcema, nicomorphine, norlevorphanol, normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxytoxin, oxymorphone, papaveretum, pentazocine, fenadoxone, fenomorphan, phenazocine, phenoperidine, piminodine, piritramide, prophetine, promedol, pr operidine, propiram, sufentanil of propoxyphene, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed p-agonists / antagonists, and the like.

In certain embodiments, a subject can be addicted to an opioid agonist. The terms "opioid agonist", "opioid" and "opiate" are used interchangeably herein and are used to designate a group of drugs that have, to varying degrees, properties of the opium or morphine type. Its main use is for analgesia. These agents work by binding to opioid receptors, which are found mainly in the central nervous system and the gastrointestinal tract. Opiates are also addictive agents. Opiates include alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, betahydroxy 3-methylfentanyl, becitramide, carfentanil, clonitazene, codema, desomorphine, dextromoramide, diacetylmorphine (heroma), diampromide, dihydrocodema, dihydroetorphine, dihydromorphine, dimenoxadol, dimetheptanol, dimethylthiambutone , dioxafetilbutirato, dipipanona, eptazocina, etoheptacina, ethylmetiltiambuteno, etilmorfina, etonitaceno, etorfina, fentanilo, hidrocodona, hidromorfona, hydroxypetidina, isomethadone, ketobemidona, LMM, levorfanol, levofenacilmorfano, lofentanilo, meperidina, metapon, metazocina, methadone, acetate of metadilo, metopon , morphine, myrofin, narcema, nicomorphine, norlevorphanol, normetadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaverine, fenadoxone, fenomorphan, phenoperidine, piminodine, piritramide, propytine, promedol, properidin, propoxyphene, remifentanil, sufentanil, tebama, tildina and tramadol.

Opiates of natural origin include codema, morphine, noscapine, papaverine and tebama. Semi-synthetic opioids include diacetylmorphine, hydrocodone, hydromorphone, levorphanol, metapon, nalorphine, naloxone, naltrexone, oxycodone, oxymorphone and tramadol. Synthetic opioids include ethoheptazine, fentanyl, levorphanol, meperidine, methadone, phenazocine, propoxyphene, and sufentanil.

Three general classifications of opiates are phenanthrenes, phenylheptylamines and phenylpiperidines. Examples of phenanthrenes include codema, etorpine, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone. Examples of phenylheptylamines include dimeheptanol, dimenoxadol, dipipanone, isomethadone, methadone, methadyl acetate and propoxyphene. Examples of phenylpiperidines include alfentanil, alphaprodine, beta-promedol, carfentanil, fentanyl, lofentanil, meperidine, properidin and sufentanil.

Specific psychostimulants include, by way of example, amphetamine, cocama, dextroamphetamine, methamphetamine, pemoline, Ritalin, Adderall and methylenedioxymethamphetamine.

As noted above, the addiction includes addiction to behaviors, for example, food addiction, compulsive overactive disorder, ludopathy, pathological use of electronic devices, for example, BlackBerry®, pathological use of electronic video games, pathological use of devices of electronic communication, pathological use of mobile phones, addiction to pornography, sex addiction, obsessive-compulsive disorder, compulsive spending, intermittent explosive disorder, kleptomania, piromama, tricotilomama, excessive compulsive exercise and excessive compulsive work.

In one aspect of the invention, a subject treated with a PDE7 inhibitor suffers from food addiction or compulsive overactive disorder, often with secondary health problems such as obesity due to excessive consumption of food and / or malnutrition due to excessive consumption. of foods that are high in fat and / or sugar and low in vitamins and minerals.

As used herein, "compulsive overactive disorder" or "compulsive overactive" include at least one of the following episodic symptoms: eating large amounts of food, eating even when is sated, eat fast, feel that eating behavior is out of control, eat substantial amounts of food when not hungry, frequent diets possibly without weight loss, eat alone, feel depressed or disgusted about their eating habits, eat in response to tension. Compulsive overactive disorder is distinguished from other types of eating disorders, including food addiction, bulimia, and overeating-purging smdromes. Unlike the bulimia and smdromes of overeating-purging, a subject who suffers from compulsive overactive disorder and food-type behavior is that subjects suffering from compulsive overactive disorder and food-type behavior do not undertake compensatory behavior for mitigate the excessive consumption of lime.

A set of scientific literature is being accumulated that supports the characterization of certain types of problematic feeding behaviors such as addictions, since compulsive overeating and chronic over-feeding share many characteristics with addictive behaviors (for example, reduced control, continued use of despite negative consequences). Despite similarities, the disorder of compulsive overeating and food addiction can represent particular but overlapping conditions. Gearhardt, AN, et al., Binge Eating Disorder and Food Addiction, Curr. Drug Abuse Rev, 4: 201-207 (2011).

As used herein, the term "food addiction" refers to a regular, persistent and habitual pattern of overeating characterized by craving and searching for highly caloric foods, overfeeding in response to stimuli other than hunger, reduced control over the consumption of food, continued consumption despite negative consequences and reduced capacity to reduce and abstain from the consumption of an excess of food. Food addiction is a chronic relapsing disorder that usually follows a cycle of overfeeding, tolerance, abstinence, behavior of high calorie food search and relapse (beginning of overfeeding after a period of abstinence).

A natural preference has been developed for highly tasty foods rich in fat and carbohydrate for evolutionary reasons due to the high caloric contribution associated with such foods. Although it is indisputable that feeding behavior is regulated by homeostatic mechanisms, feeding and overfeeding are also regulated by emotional, affective and learning processes. Polivy, et al., "Food restriction and binge eating: a study of a former prisoner of war," J Abnorm Psychol 103: 409-411 (1994). In this respect, there are several points in common between excessive feeding and drug abuse (reward, reinforcement, effects on the state of mind, external control of appetite for signals, stress-induced motivation). Evidence is accumulating that excessive consumption of certain foods under specific conditions produces behaviors and changes in the brain that resemble an addiction-type state. Gold, et al., "Overeating, binge eating, and eating disorders as addictions," Psychiatr Ann 33: 112-116 (2003); Kenny, et al., "Common cellular and molecular mechanisms in obesity and drug addiction," Nat Rev Neurosci 12: 638-651 (2011); Pelchat, et al., "Images of desire: food-craving activation during fMRI," Neuroimage 23: 1486-1493 (2004); Avena, et al., "Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake," Neurosci Biobehav Rev 32: 20-39 (2008); Ifland, et al., "Refined food addiction: a classic substance use disorder," Med Hypotheses 72: 518-526 (2009); Gearhardt, et al., "Food addiction: an examination of the diagnostic criteria for dependence," J Addict Med 3: 1-7 (2011).

Pharmacological addiction can be characterized by a progressive increase in the use of drugs, development of tolerance, abstinence after abrupt cessation of its use and recurrent relapse, and similar phenomena have been described for high fat and high sucrose foods. For example, rats fed a highly palatable sucrose solution experience opiate-type withdrawal symptoms after sucrose withdrawal. Cross-sensitization between sucrose and drugs of abuse has also been described. Avena, et al., "Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake," Neurosci Biobehav Rev 32: 20-39 (2008); Avena, et al., "Dysregulation of brain reward systems in eating disorders: Neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa," Neuropharmacology (Epub before printing) (November 27, 2011). On the other hand, it has been well documented that psychological tension and dysphoric ammonic states play an important role in facilitating overeating as well as excessive drug use, and contribute to the high rate of recurrence typical of both disorders. Corwin, et al., "Feeling and reward: perspective from three mouse models of binge eating," Physiol Behav 104: 87-97 (2011); Ghitza, et al., "The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF1 receptors," Neuropsychopharmacology 31 (10): 2188-2196 (2006); Mizes, et al., "Bulimia: A review of its symptomatology and treatment," Adv. Behav. Res. Ther. 7: 91-142 (1985); Crowther, et al., "The role of daily hassles in binge eating," Int J Eat Disord 29: 449-454 (2001); Herman, et al., "Anxiety, Restraint, and Eating Behavior," J Abnorm Psychol 84: 66-72 (1975).

It has also been shown that exposure to environmental conditioning stimuli plays a critical role in the induction of the imperative need for drugs in obese patients who meet the criteria for food addiction. Gearhardt, et al., "Food addiction: an examination of the diagnostic criteria for dependence," J Addict Med 3: 1 7 (2011). Consistent with studies in humans, in laboratory animals it has been shown that exposure to environmental conditioning factors and stress exposure (ie, yohimbine) are similarly effective in inducing the re-establishment of drug behaviors. abuse and for highly tasty food. Cifani, et al., "Preclinical model of binge-eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate and midazolam," Psychopharmacology 204: 113-25 (2009); Cifani, et al., "Pre-exposure to environmental cues predictive of food availability elicits hypothalamic-pituitary-adrenal axis activation and Increased operant responding for food in female rats, "Addict Biol. 14 (4): 397-407 (September 2009); Pickens, et al., " Effect of fenfluramine on reinstatement of food seeking in female and male rats: implications for The predictive validity of the reinstatement model, "Psychopharmacology (Berl) 221 (2): 341-353 (May 2012.) It has also been proposed that neural systems that motivate and reinforce drug abuse underlie behaviors associated with compulsive drug seeking. Food and excessive consumption of food Johnson, et al., "Dopamine D2 receptors in addiction like reward dysfunction and compulsive eating in obese rats," Nat Neurosci 13: 635-641 (2010); Hoebel, et al., "Brain neurotransmitters In Food and Drug Reward, "Am J Clin Nutr 42 (5 Suppl): 1133-1150 (1985); Volkow, et al., " How can drug addiction help us understand obesity? "Nat Neurosci 8: 555-560 (2005) ); Corwin, et al., "Feeling and reward: perspective from three mouse models of binge eating," Physiol Behav 104: 87-97 (2011); Gearhardt, et al., "Neural correlates of food addiction," Arch Gen Psychiatry 68: 808-816 (2011); Wang, et al., "Enhanced striatal dopamine release during food stimulation during binge eating disorder," Obesity 19 (8): 1601-1608 (August 2011). For example, some studies suggest that as in drug addicts, there may be an altered regulation of striated dopamine (DA) in patients with bulimia nervosa.

Recently, interest in the concept of food addiction has received greater attention, largely due to the similarities between behavioral indicators of addiction and compulsive overactive disorder (BED). Compulsive overactive episodes in humans are characterized by the compulsive, not homeostatic, consumption of an unusually large amount of highly palatable food in a short period of time. Even if they are not hungry, subjects eat more quickly than normal until they feel uncomfortably full. As described in the DMS-IV-TR (Psychiatric Association of the United States, "Diagnostic and statistic manual of mental disorders," Washington, DC. (2000)), these episodes are accompanied by a subjective sense of loss of control over feeding and are associated with the feeling of anguish, disgust, depression, guilt about overfeeding and eating alone due to embarrassment.

BED, first described by Stunkard, "Eating Patterns and Obesity," Psychiatry Q 33: 284-295 (1959), is probably the most prevalent eating disorder. Hudson, et al., "The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication," Biol Psychiatry 61: 348-58 (2007). It is characterized by repeated episodes of compulsive overeating in the absence of compensatory behavior to avoid weight gain. The diagnostic criteria for BED in DSM-IV-TR include that compulsive overactive episodes should appear at least 2 days a week for six months. BED is associated with significant medical and psychiatric comorbidity. Javaras, et al., "Co-occurrence of binge eating disorder with psychiatric and medical disorders," J Clin Psychiatry 269: 266-273 (2008); Grucza, et al., "Prevalence and correlates of binge eating disorder in a community sample," Compr Psychiatry 48: 124-131 (2007). It is estimated that compulsive overactivation afflicts approximately 5% of the adult population of the United States at some time during their lives (Foulds, et al., "The biology of binge eating," Appetite 52: 545-553 (2009)) and that contributes to aggravate obesity and associated pathologies. Hudson, et al., "The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication," Biol Psychiatry 61: 348-58 (2007); Yanovski, "Binge eating disorder and obesity in 2003: could be treating an eating disorder with a positive effect on the obesity epidemic?" Int J EatDisord 34 Suppl: S117-S1120 (2003).

A large body of evidence suggests that dieting, tension, and negative affective states represent important triggers for compulsive overactivation in patients with BED or bulimia nervosa. Wardle, et al., "Stress, dietary restraint and food intake," J Psychosom Res 48: 195-202 (2000); Freeman, et al., "Daily stress, coping, and dietary restraint in binge eating," Int J Eat Disord 36: 204-212 (2004). In fact, there are habitual periods of diet in the histories of people who eat compulsively, although the hunger itself does not seem to be enough to induce compulsive overactive in the absence of tension and negative affective state. Polivy, et al., "Food restriction and binge eating: a study of former prisoner of war," J Abnorm Psychol 103: 409-411 (1994); Waters, et al., "Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa," Int J Eat Disord 29: 17-22 (2001). Considerable evidence suggests that compulsive overeating may be caused by a particular interaction between diet and tension; therefore, environmental stress and a history of specific dietary restrictions may be responsible for their precipitation and maintenance. Stice, et al. "Subtyping binge eating-disordered women along with dieting and negative affect dimensions," Int J Eat Disord 30: 11-27 (2001); Crowther, et al., "The role of daily hassles in binge eating," Int J Eat Disord 29: 449-454 (2001). Consequently, recurrent food restrictions are uniformly the strongest predictor of overeating in response to stress. Wardle, et al., "Stress, dietary restraint and food intake," J Psychosom Res 48: 195-202 (2000).

Although a subject can be addicted to a single addictive agent or behavior, the subject is often addicted to two or more addictive agents or behaviors. The addiction to two or more addictive agents or addictive behaviors is called poliadiction.

B. Methods of treatment and prevention of addiction and impulse control disorders using inhibitor or inhibitors of PDE7 in combination with other therapeutic agents

The PDE7 inhibitors can be used effectively in combination with one or more additional therapeutic agents to treat or prevent the addiction, including the addiction to one or more of the addictive agents described herein and compulsive or addictive behavior. Accordingly, the present invention includes methods for treating or preventing an addiction, comprising administering to a subject addicted to an addictive agent one or more PDE7 inhibitors and one or more additional therapeutic agents, wherein each of the PDE7 inhibitor (s) and the therapeutic agent (s) contribute to the treatment or effective prevention of the addiction. In one embodiment, a PDE7 inhibitor and an additional therapeutic agent is provided or administered to a subject. In another embodiment, a subject is addicted to two or more addictive agents.

The PDE7 inhibitor and the additional therapeutic agent can be administered at the same time (i.e., simultaneously) or they can be administered one before the other (ie, sequentially). In general, both the PDE7 inhibitor and the additional therapeutic agent are present in the subject at the same time for a period of time and at levels sufficient to provide a therapeutic benefit to the subject, i.e., in the treatment or prevention of an addiction or the prevention of a recurrent use (or restoration) of an addictive agent or compulsive or addictive behavior. The PDE7 inhibitor and the additional therapeutic agent can be administered by the same or different routes of administration. Usually, the PDE7 inhibitor and the additional therapeutic agent are each provided to a subject according to a conventional route of administration of a commercially available pharmaceutical composition or other. In one embodiment, the PDE7 inhibitor and the additional therapeutic agent are co-administered using a composition comprising both agents.

The additional therapeutic agent provided in combination with a PDE7 inhibitor can be any therapeutic agent that contributes to an aspect of effective treatment or prevention of addiction. For example, the additional therapeutic agent may be a drug used to treat an addiction or a drug used to alleviate side effects associated with psychological withdrawal from an addictive agent. In addition, the additional therapeutic agent can be any drug that affects the neurotransmission of serotonin in the brain, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin reuptake inhibitors and norepinephrine (SNRI) as described below, and serotonin agonists such as sumatriptan, ergonovine, dihydroergotamine and buspirone. In certain embodiments, the additional therapeutic agent is an opioid antagonist, including mixed opioid agonist / partial antagonists, an antidepressant, an antiepileptic, an antiemetic, a dopaminergic agent such as a dopamine D1 receptor agonist, an antagonist of the release factor of corticotropin 1 (CRF-1), a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A / 2C antagonist such as mianserin, mirtazapine, and ketanserin, or a cannabinoid receptor-1 (CB1) antagonist, including , but without limitation, the therapeutic agents specifically described herein.

In one embodiment, the addictive agent is alcohol and the additional therapeutic agent is an opioid antagonist or a partial opioid antagonist / agonist. In a particular embodiment, the opioid antagonist is naltrexone. In another embodiment, the mixed opioid partial / antagonist agonist is buprenorphine.

In one embodiment, the addictive agent is alcohol and the additional therapeutic agent is topiramate or levetiracetam.

In one embodiment, the addictive agent is nicotine and the additional therapeutic agent is an antidepressant. In a particular embodiment, the antidepressant is bupropion.

In one embodiment, the addictive agent is cocama and the additional therapeutic agent is buprenorphine.

In one embodiment, the addictive agent is a psychostimulant and the additional therapeutic agent is an antidepressant. In a particular embodiment, the antidepressant is bupropion.

In one embodiment, the addictive behavior is compulsive overactive and the additional therapeutic agent is an antidepressant or antiepileptic. In a particular embodiment, the antidepressant is sibutramine. In another particular embodiment, the antidepressant is fluoxetine. In a particular embodiment, the antiepileptic is topiramate.

In one embodiment, the addictive agent is nicotine and the additional therapeutic agent is an antiepileptic. In a particular embodiment, the antiepileptic is levetiracetam. In another particular embodiment, the antiepileptic agent is naltrexone.

In one embodiment, the subject is addicted to two or more addictive agents and the additional therapeutic agent is an opioid antagonist or a mixed opioid partial / antagonist agonist. In a particular embodiment, the mixed opioid partial / antagonist agonist is buprenorphine.

In one embodiment, the subject is addicted to both nicotine and alcohol, and the additional therapeutic agent is an antiepileptic. In a particular embodiment, the antiepileptic is naltrexone.

For the treatment of alcohol addiction, combinations to be administered according to the present invention include a PDE7 inhibitor and an opioid agonist or a mixed opioid partial antagonist / antagonist, a PDE7 inhibitor and an antidepressant, a PDE7 inhibitor and an antagonist / inverse agonist of the CB1 receptor, a PDE7 inhibitor and varenicline, an inhibitor of PDE7 and acamprosate and a PDE7 inhibitor and disulfiram.

For the treatment of a psychostimulant addiction, combinations to be administered according to the present invention include, for example, a PDE7 inhibitor and an antidepressant or a PDE7 inhibitor and a partial opioid agonist / antagonist, for example, buprenorphine.

For the treatment of nicotine addiction, combinations to be administered according to the present invention include, for example, a PDE7 inhibitor and an antidepressant, a PDE7 inhibitor and nicotine (as a replacement, in an oral, transcutaneous or another conventional), a PDE7 inhibitor and an opioid antagonist, a PDE7 inhibitor and an antagonist / inverse agonist of the CB1 receptor, and a PDE7 inhibitor and varenicline. In one embodiment, an addictive agent, such as nicotine and a PDE7 inhibitor are administered together using a transdermal patch delivery system. In another aspect of the invention, a kit that includes multiple transdermal patches, including nicotine dosages at decreasing levels and dosages of a PDE7 inhibitor at constant or decreasing levels, is provided for sequential use by a subject addicted to nicotine for move the subject away from his addiction to nicotine.

For the treatment of the politoxicomama, combinations to be administered according to the present invention include, for example, a PDE7 inhibitor and an opioid agonist or a mixed opioid partial antagonist / antagonist.

For the treatment of gambling addiction, combinations to be administered according to the present invention include, for example, a PDE7 inhibitor and an antidepressant or a PDE7 inhibitor and an agent that affects the neurotransmission of dopamine, for example, a direct or indirect dopamine antagonist.

The effective amount of one or both of a PDE7 inhibitor and an additional therapeutic agent can be reduced when administered in combination as compared to when one is provided alone. For example, when the PDE7 inhibitor and the additional therapeutic agent act additively or synergistically, then a minor amount of the PDE7 inhibitor, a minor amount of the additional therapeutic agent or minor amounts of the PDE7 inhibitor or the additional therapeutic agent may be necessary to achieve the same therapeutic effect provided by the PDE7 inhibitor or the additional therapeutic agent alone.

1. Opioid antagonists

An opioid antagonist acts on one or more opioid receptors. At least three types of opioid receptors, mu, kappa, and delta opioid receptors have been reported, and opioid antagonists are generally classified by their effects on opioid receptors. Opioid antagonists can antagonize central receptors, peripheral receptors or both. Naloxone and naltrexone are commonly used opioid antagonist drugs that are competitive because they bind opioid receptors with greater affinity than agonists, but do not activate receptors. This effectively blocks the receptor, preventing the body from responding to opiates and endorphins.

Many opioid antagonists are not pure antagonists but also produce some weak opioid partial agonist effects, and may produce analgesic effects when administered in high doses to individuals not exposed to opioids. Examples of such compounds include nalorphine and levalorphan. However, the analgesic effects of these drugs are limited and tend to be accompanied by dysphoria, most likely due to the action of the kappa opioid receptor. Since it induces opioid withdrawal effects in people who take, or have previously used, complete opioid agonists, these drugs are considered to be antagonists.

Naloxone is an example of an opioid antagonist that has no partial agonist effect. Instead, it is a weak inverse agonist in mu opioid receptors and is used to treat opioid overdoses.

Specific examples of opioid antagonists which can be used according to the invention include alvimopan, binaltorphimine, buprenorphine, cyclazocine, cyclorphan, cypridimine, dinicotinate, beta-fungaltrexamine, levalorphan, methylnaltrexone, nalbuphine, nalide, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate, naloxone. , naloxonacin, naltrendol, naltrexone, naltrindol, oxilorphan and pentazocine.

2. Antidepressants

Antidepressants are drugs used to treat depression. The three neurotransmitters thought to be involved in depression are serotonin, dopamine and noradrenaline. Certain types of antidepressants increase the levels of one or more of these neurotransmitters in the brain by blocking their reabsorption.

Several different classes of antidepressants have been identified, including selective serotonin reuptake inhibitors (SSRIs), tridic and tetracyclic serotonin and noradrenaline reuptake inhibitors (SNRI), norepinephrine reuptake inhibitors (NRIs), reuptake inhibitors of noradrenaline and dopamine (IRND), azaspirones, monoamine oxidase inhibitors (MAOIs) and atypical antidepressants.

SSRIs include, for example, cericlamin, citalopram, clomipramine, cyanodotiepine, dapoxetine, duloxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, imipramine, indalpin, indeloxacin, litoxetine, lofepramine, mianserin, milnacipran, mirtazapine, nefazadone, nortriptyline, paroxetine. , sertraline, sibutramine, tomoxetine, trazodone, venlafaxine and zimeldine.

Amitriptyline, amoxapine, butriptiline, clomipramine, demexiptiline, desipramine, dibenzepine, dimethacrine, dotiepin, Doxepin, imipramine, iprindol, lofepramina, maprotilina, melitraceno, metapramina, mianserina, mirtazpina, nortriptilina, propicepina, protriptilina, quinupramina, setiptilina, tianeptin and trimipramina are all tridclicos and tetradclicos antidepressants.

The SNRIs include, for example, amoxapine, atomoxetine, bicifadine, desipramine, desvenlafaxine, duloxetine, maprotiline, milnacipran, nefazodone, reboxetine, sibutramine and venlafaxine.

Nisoxetine, nortriptyline, reboxetine, talsupram and tomoxetine are all examples of IRN.

NRIs include, for example, bupropion, hydroxybupropion and tesofensin.

Azaspirones include, for example, buspirone, gepirone, ipsapirone, tandospirone and thiapirone. Buspirone is an anxiolytic (partial agonist in 5-HT1 autoreceptors) that can be provided with an antidepressant such as an SSRI.

Specific MAOIs include, for example, amiflamin, brofaromine, clorgyline, alpha-ethyltriptamine, iproclocid, iproniacid, isocarboxacid, mebanacin, moclobemide, nialamide, pargyline, phenelzine, fenipracin, pirlindol, safracin, selegiline, toloxatone and tranlcypromine.

The atypical antidepressants include, for example, amesergide, amineptine, benacticin, bupropion, clozapine, phezolamine, levoprothiline, lithium, medifoxamine, mianserin, minaprine, olanzapine, oxafloxane, oxytriptan, rolipram, tenyloxacin, tofenacin, trazodone, tryptophan and viloxacin.

3. Antiepileptics

Anticonvulsants, also called antiepileptic drugs (AEDs) are a diverse group of drugs used in the prevention of the onset of epileptic seizures and bipolar disorders. AEDs suppress the rapid and excessive firing of neurons that initiates an attack and / or prevents the spread of the attack in the brain and offer protection against possible excitotoxic effects that can result in brain damage. Many anticonvulsants block sodium channels, calcium channels, AMPA receptors or NMDA receptors.

Anti-epileptic agents include, but are not limited to, benzodiazepines, barbiturates, valproates, GABA agents, iminostilibenos, hydathocysts, NMDA antagonists, sodium channel blockers, and succinamides.

Benzodiazepines include, for example, alprazolam, chlordiazepoxide, colzacepate, clobazam, clonazepam, diazepam, halazapam, lorazepam, oxazepam and prazepam.

Barbiturates used as antiepileptics include, for example, amobarbital, mepobarbital, methylphenobarbital, pentobarbital, phenobarbital and primidone.

Valprolates used as antiepileptics include, for example, sodium valproate, valproic acid, semisodic valproate and valpromide.

Antiepileptic GABA agents include, for example, gabapentin, losigamone, pregabalin, retigabine, rufinamide and vigabatrin.

Carbamazepine and oxcarbazepine are examples of iminostilbenes.

Hydatoms include, for example, sodium phosphomenoma, mefenomenoma and sodium phenthoma.

Nm d A antagonists such as harkoseramide are used as antiepileptics.

Sodium channel blockers such as lamotrigine are also anti-epileptic agents.

Succinimides include, for example, ethosuximide, methsuximide and phensuximide.

Other antiepileptic drugs include acetazolamide, briveracetam, CBD cannabis derivative, clomethiazole edisilate, divalproex sodium, felbamate, isovaleramide, lacosamide, lamotrigine, levetiracetam, methanesulfonamide, talampanel, tiagabine, topiramate, safinamide, seletracetam, soretolide, stiripentol, sultiam, valrocemide and zonisamide

4. Antiemetics

Antiemetics are effective drugs against vomiting and nausea. Antiemetics are commonly used to treat motion sickness and the side effects of opioid analgesics, general anesthetics, and chemotherapy.

Classifications of antiemetics include, for example, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, histamine receptor antagonists, dopamine receptor antagonists, muscarmic receptor antagonists, acetylcholine receptor antagonists, cannabinoid receptor antagonists, Ifmbic system inhibitors, NK-1 receptor antagonists, corticosteroids, tachykinin antagonists, agonists GABA, cannabinoids, benzodiazepines, anticholinergics and substance P inhibitors.

Antagonists of the 5-HT3 receptor include, for example, alosetron, azasetron, bemesetron, cilansetron, dolasetron, granisetron, indisetron, itasetron, ondansetron, palonosetron, propisetron, ramosetron, renzapride, tropisetron and zatosetron.

Corticosteroid antiemetics include dexamethasone and methylprednisolone.

Inhibitors of the limbic system include alprazolam, lorazepam, and midazolam.

Dopamine receptor antagonists include diphenhydramine, dronabinol, haloperidol, metoclopramide and prochlorperazine.

Antagonists of the NK-1 receptor used as an antiemetic include aprepitant and morpholine and an example of a GABA agonist is propofol.

Tietilperazine is a type of histamine receptor antagonist.

Antagonists or cannabinoid receptor agonists used as antiemetics include dronabinol, nabilone, rimonabant, tanarabout and tetrahydrocannabinol.

Examples of other antiemetics include acetyleucine, monoethanolamine, alizapride, benzquinamide, bietanautine, bromopride, bucycin, chlorpromazine, clebopride, cyclicine, dimenhydrinate, dipheniodol, domperidone, dranisetron, mecillin, metaltal, metopyamine, oxypendyl, pipamazine, piprinhydrinate, scopolamine, thioproperzame and trimethobenzamide.

5. Cannabinoid receptor antagonists

Cannabinoid receptors are a class of the superfamily of receptors coupled to protein G. Their ligands are known as cannabinoids. There are currently two known subtypes, CB1 that is expressed mainly in the brain, but also in the lungs, the hugado and the kidney, and CB2, which is expressed mainly in the immune system and in hematopoietic cells. It is also believed that there are new cannabinoid receptors, that is, not CB1 and not CB2, which are expressed in endothelial cells and in the CNS. Cannabinoid receptor antagonists may be selective for the CB1 or CB2 receptor. The present invention contemplates the use of one or both of the CB1 and CB2 receptor antagonists.

Addictive agents (eg, alcohol, opiates, Delta (9) -tetrahydrocannabinol (Delta (9) -THC) and psychostimulants, including nicotine) induce a variety of chronically recurrent disorders interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems and virtually all drugs that are abused elevate dopamine levels in nucleus accumbens. The cannabinoid receptors 1 (CB1) are expressed in this brain reward circuit and modulate the dopamine-releasing effects of Delta (9) -THC and nicotine.

Rimonabant (SR141716), a CB1 receptor antagonist, blocks both dopamine releasing and differentiating and rewarding effects of Delta (9) -THC in animals. Although blockade of the CB1 receptor is generally ineffective in reducing the self-administration of cocama in rodents and primates, it reduces the reestablishment of search behavior for extinct cocama produced by conditioned stimuli associated with cocama and injections of cocaine stimulation. Similarly, blockade of the CB1 receptor is effective in reducing the nicotine search behavior induced by re-exposure to nicotine-associated stimuli. In human clinical trials, rimonabant was shown to block the subjective effects of Delta (9) -THC in humans and prevents relapse in smoking for ex-smokers.

Other examples of CB1 cannabinoid receptor antagonists include SR141716A (rimonabant), rosanabant, taranabant and CP-945598.

6. Dopaminergic agents

Drug addiction is a chronic, relapsing disease characterized by a loss of control over the use of drugs, compulsive drug seeking and craving for a substance, use that persists despite negative consequences and physical and / or psychological dependence on the substance. A fundamental role in the pathogenesis of addiction has been attributed to dopamine. Dopamine, in fact, has permeated the natural history of drug addiction at all levels, from its involvement in the modeling of the individual response to factors of vulnerability (ie, genetic, environmental and stress) to its role in the mechanism of action of drugs of abuse.

The mesocortical-dopamine system is originated in the ventral tegmental area (VTA), which projects prominently to the nucleus accumbens (NAc) and the prefrontal cortex (PFC). It is a common defining characteristic of all the addictive drugs that at least initially stimulate the transmission of dopamine in the terminal areas of the mesolfmbic system and in particular in the nucleus cortex NAc. Nestler, EJ, "Is there a common molecular pathway for addiction?" Nat Neurosci 8: 1445-1449 (2005); Pierce, RC, et al., "The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?" Neurosci Biobehav Rev 30: 215-238 (2006). Brain imaging studies have extended these observations to humans. Drevets, WC, et al., "Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria," Biol Psychiatry 49:81 96 (2001); Brody AL, et al., "Smoking-induced ventral striatum dopamine release," Am J Psychiatry 161: 1211-1218 (2004). It is believed that the release of dopamine from these projections plays an important role in the mediation of drug reward, reinforcement and in the induction of addictive compulsive behavior. Although dopamine is involved in predisposition and in the early stages of the development of drug addiction, this condition, once established, is associated with long-term changes related to chronic exposure to drugs themselves.

These changes are collectively indicated as "neuroadaptive" and are believed to be the substrate of behavioral sensitization, a long-lasting increase in sensitivity to the behavioral stimulatory properties of drugs and changes in the basal measurement of the hedonic state (hedonic alostasis) . Berridge KC, et al., "What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience?" Brain Res Rev 28: 309-369 (1998); Koob, GF, et al., "Neurobiological mechanisms for opponent motivational processes in addiction," Philos Trans R Soc Land B Biol Sci. 363: 3113-3123 (2008). Neuroadaptations also occur in the dopamine system, where a relative reduction in the basal level of dopamine transmission activity in ventral striated areas and a reduction in dopamine D2 receptor levels have been documented. Volkow, ND, et al., "Dopamine in drug abuse and addiction: results from imaging studies and treatment implications," Mol Psychiatry 9: 557-569 (2004); Volkow, ND, et al., "Dopamine in drug abuse and addiction: results from imaging studies and treatment implications," Arch Neurol 64: 1575-1579 (2007); Fehr, C., et al., "Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse," Am J Psychiatry 165: 507-514 (2008).

The most common mechanism by which drugs of abuse result in neurotransmission of dopamine is by modulating the presynaptic Y-aminobutmone (GABA) activity of VTA. Luscher, C., et al., "The mechanistic classification of addictive drugs," PLoS Med 3: e437 (2006). In the VTA, the GABA neurons act as local inhibitory interneurons that perform a tonic control in corticomesolfimic dopamine cells. The reduction of GABA neurotransmission leads to a net disinhibition of dopamine neurons and increased dopamine release in terminal areas such as NAc and CPF.

A prototypical example of this mechanism is offered by opiates that upon activation of opioid receptors located in presynaptic GABA cells lead to a marked inhibition of GABAergic neurotransmission resulting in disinhibition of VTA dopaminergic cells. Johnson, SW, et al., "Opioids excite dopamine neurons by hyperpolarization of local interneurons," J Neurosci 12: 483-488 (1992). Cannabis derivatives appear to increase the rate of VTA dopamine firing with a similar mechanism but through the selective activation of cannabinoid receptor 1 (CB1R) located in presynaptic GABA neurons. In addition, nicotine increases the neurotransmission of dopamine but through a complex interaction of actions of nicotimic receptors in GABA and in glutamatergic contributions to dopamine neurons. Luscher C, et al., The mechanistic classification of addictive drugs, PLoS Med. 3 (11): e437 (2006). In fact, nicotine, through nAChR containing p2 reduces the release of presynaptic GABA leading to a prolonged disinhibition of dopamine, acting at the same time in nAChR homomers containing a7, which are expressed mainly in synaptic terminals of excitatory glutamatergic afferents in dopamine neurons in the VTA, facilitating the release of glutamate. This effect may also contribute to the release of nicotine-induced dopamine. Also, recent evidence suggests that nicotine directly modulates the release of dopamine in the NAc. Ethanol and benzodiazepines also appear to stimulate dopamine neurotransmission of VTA through the inhibition of presynaptic GABA activity by modulation of specific GABA-A receptor subunits.

Psychostimulants, as derivatives of amphetamine and cocama, comprise the only class of addictive drugs that act directly on dopaminergic terminals by inhibiting the mechanisms of dopamine reuptake or by facilitating the release of dopamine from synapses. Through these mechanisms, extracellular dopamine levels increase in terminal areas (ie, NAc and MPF) of the brain's dopamine system. More notably, however, dopamine terminals are also present in the VTA where receptors of type D1 and D2 are expressed in bodies of dopaminergic cells (autoreceptors) as well as in presynaptic glutamatergic and GABAergic neurons. The direct application of cocama in the VTA results in a reduction or an increase (depending on the dose) of the dopamine firing rate, an effect that could potentially be mediated by D1 receptors located in presynaptic cells of GABA and glutamate, respectively. . Therefore presynaptic modulation of VTA DA activity may also play a role in regulating the addictive properties of psychostimulants. Brodie, MS, et al., "Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action," Naunyn Schmiedebergs Arch Pharmacol 342: 660-665 (1990); Bonci, A., et al., "Increased probability of GABA release during withdrawal from morphine," J Neurosci 17: 796-803 (1997).

Accordingly, in the present invention the additional therapeutic agent administered in combination, simultaneously or sequentially with a PDE7 inhibitor is a dopaminergic agent for treating a patient suffering from an addiction or a compulsive disorder. In another embodiment of the invention, the PDE7 inhibitor is administered in combination, simultaneously or sequentially with a dopamine receptor agonist to treat a patient suffering from an addiction or a pulse control disorder. In another embodiment of the invention, the PDE7 inhibitor is administered in combination, simultaneously or sequentially with a dopamine D1 receptor agonist (i.e., a dopamine receptor agonist of subtype D1) to treat a patient suffering from an addiction or impulse control disorder.

Exemplary dopaminergic agents suitable for administration in conjunction with PDE7 inhibitors include, for example, levodopa (also referred to as "L-dopa"), carbidopa, and dopamine receptor agonists and precursors such as bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, rotigotine and quinagolide, as well as fenoldopam, which is selective for the dopamine D1 receptor.

Suitable dosages of D1 receptor agonists for administration in conjunction with a PDE7 inhibitor according to the present invention may be determined by medical practitioners but may be, for example, in the range of 0.1 mg to 1,000 mg daily or biweekly , or from 0.25 mg to 100 mg daily or biweekly.

C. Methods of treatment and prevention of relapse

Recurrent use, or recovery, refers to the process of returning to the use of alcohol or another addictive agent or engaging in addictive behavior after a period of abstinence from, or limited or limited use of, an addictive agent or practice of an addictive behavior In certain situations, the recurrent use of an addictive agent refers to the return to the use of an addictive agent by a subject who has experienced physical abstinence from the addictive agent. Typically, the subject will have experienced physical abstinence from the addictive agent during a period of no use or limited or limited use of the addictive agent. In one embodiment, recurrent use occurs in a subject who has previously experienced a treatment regimen with an effective amount of an anti-addictive agent to reduce or eliminate the use of an addictive agent, but who no longer uses an effective amount of the anti-addictive agent. Anti-addiction agents include each and every one of the agents used to treat or prevent the symptoms of addiction or abstinence.

Alcoholism, like many other addictions, is a chronic relapsing disorder characterized by high rates of recurrence. Two important factors that trigger recurrent behavior are stress and environmental conditioning experiences (O'Brien et al., 1997; Monti et al., 1993; Shaham et al., 1995), which probably facilitate relapse in search of alcohol through defined cerebral mechanisms. For example, the activation of the mesolimbic dopamine system by an opioid-dependent mechanism (or by direct alterations in the transmission of dopamine in the basolateral nucleus of airngdala) seems to mediate the effect of drug-associated signals (Liu and Wiess 2002; Ciccocioppo). et al., 2001), and, extrahipotalamic CRF in the nucleus of the terminal terminal bed and middle raphe nucleus probably mediates the stress-induced restoration of drug-seeking behavior (Erb et al 1998; Shaham et al., 1995; Le et al., 2000).

Several sets of evidence suggest that the molecular mechanisms underlying the relapse to addiction are common in different classes of drugs of abuse. Drug cravings and loss of control over the drug use behavior associated with relapse are directly influenced by stress and environmental conditioning stimuli; the two main factors that affect the resumption of drug use.

Chronic drug abuse produces neuroadaptive changes not only in systems involved in the acute booster effects of ethanol, but also in other systems of motivation, notably mechanisms regulating brain tension. Stress has an established role in the initiation and maintenance of drug abuse and is an important determinant of relapse in abstinent individuals. (Brown, et al., J Studies Alcohol 56: 538 (1995); Marlatt, Relapse prevention: introduction and overview of the model, in Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors, Guilford, London, (1985); McKay, et al., Drug Alcohol Dep., 38, 35, (1995); and Wallace, J Subst Abuse Treat, 6:95, (1989)). The significance of stress in drug-seeking behavior has also been documented extensively in the animal literature. Physical, social and emotional tension may facilitate the acquisition or increase of self-administration of cocama, heroma and ethanol in rodents and non-human primates. (Goeders and Guerin, Psychopharmacology, 114, 63, (1994), Haney, et al., Brain Res., 698, 46, (1995), Ramsey and Van Ree, Brain Res., 608, 216, (1993); Ahmed and Koob, Psychopharmacology, 132, 289, (1997), Shaham and Stewart, Psychopharmacology 119: 334 (1995), Nash and Maickel, Prog Neuropsychopharmacol Biol Psychiatry, 12, 653, (1988), Mollenauer, et al., Pharmacol Biochem. Behav., 46, 35, (1993); Blanchard, et al., Pharmacol. Biochem. Behav.

28, 437, (1987) and Higley, et al., Proc. Natl. Acad. Sci. USA, 88, 7261, (1991)). It has also been shown that stress stimuli induce the reestablishment of cocama, heroma and ethanol search behavior in drug-free animals after extinction and these findings provide experimental support for a stress role in relapse. (Ahmed and Koob (1997), Shaham, Psychopharmacology, 111,477, (1993), and Shaham and Stewart (1995)).

Traditionally, it has been believed that drug-seeking behavior related to stress is mediated through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, more and more evidence suggests that the non-neuroendocrine corticotropin releasing factor (FLC) system in the central nucleus of airngdala (CeA) can play a significant independent role in the regulation of addictive behavior associated with stress. CeA is rich in CRF immunoreactive cell bodies, terminals and receptors, and this neuronal CRF system has been implicated in the mediation of behavioral and emotional responses to stress stimuli. (Dunn and Berridge, Brain Res Brain Res Rev, 15, 71, (1990); and Koob et al., Semin Neurosci 6: 221 (1994)). For example, immobilization tension raises extracellular CRF levels in CeA while intra-CeA injection of CRF receptor antagonist, CRF9-41 a-helical, reduces behavioral signals anxiety produced by social and environmental stressors (Merali et al., J. Neurosci., 18, 4758, (1998), Merlo Pich et al., J. Neurosci., 15, 5439, (1995), Heinrichs et al., Brain Res., 581, 190 (1992). ); Swiergiel et al., Brain Res, 623, 229 (1993)). Anxiety and tension-type symptoms are central to drug and alcohol withdrawal symptoms. Considering the evidence of a role in CRF neurons in CeA in the regulation of emotional and anxiety effects of stress, it is likely that the anxiety and tension-type consequences of abstinence from drugs of abuse can be mediated by the CRF system in the CeA too.

Changes in the regulation of the activity of the CRF system in CeA may represent a neuro-adaptive mechanism responsible for the development of dependence and compulsive drug-seeking behavior.

The data analyzed above identify neuroadaptive changes in brain circuits and alterations in tension systems as an important element in the behavior of compulsive drug seeking and drug dependence. Another important factor in the long-term addictive potential of drugs of abuse is the conditioning of their reward actions with specific environmental stimuli. Environmental signals repeatedly associated with the subjective effects of drugs of abuse including alcohol can induce drug cravings or induce automatic behavioral responses (Miller and Gold 1994; Tiffany and Carter 1998) that can ultimately lead to relapse. (Childress et al., Conditioned craving and arousal in cocaine addiction: A preliminary report, in NIDA Research Monograph 81, (1988), Ehrman et al., Psychopharmacology, 107, 523, (1992); Monti et al., J Stud Alcohol 54: 235-45 (1993), Pomerleau et al., Addict. Behav., 8, 1, (1983), Stormark et al., Addict. Behav., 20, 571, (1995), Miller and Gold Ann Clin Psychiatry, 6, 99, (1994); and Tiffany and Carter, J Psychopharmacol., 12, 23, (1998)). The responses learned to stimuli related to the drug can, therefore, contribute in a critical way to the high rates of relapse associated with cocaine and other drug addiction.

Data from operational response restoration models developed to investigate drug-seeking behavior associated with exposure to drug-related environmental signals in rats indicate that differentiating predictors of cocama, ethanol, and heroma availability reliably induce strong recovery of behavior from Search for drugs extinguished in the absence of additional drug availability. (Weiss et al., Proc. Natl. Acad. Sci. USA, 97, 4321, (2000), Katner et al., Neuropsychopharmacology, 20, 471, (1999), Katner and Weiss, Alcohol Clin Exp Res. 23: 1751 (1999); and Gracy et al., Pharmacol. Biochem. Behav., 65, 489, (2000)). The effects of restoration of response of these stimuli show remarkable resistance to extinction with repeated exposure and, in the case of cocama, can still be observed after several months of forced abstinence. Additionally, in the case of ethanol, it was discovered that drug-seeking behavior induced by predictive differentiators of ethanol was enhanced in P rats with genetic preference for alcohol compared with rats with no preference for alcohol (NP) and Wistar not selected. (Weiss and Ciccocioppo, Soc. Neurosci. Abstr., 25, 1081, (1999)). This observation demonstrates that the genetic predisposition toward increased ethanol consumption is also reflected by a greater susceptibility to the motivating effects of ethanol signals (ie, enhanced drug search under conditions in which the behavior is not directly reinforced by ethanol in itself). Together, these findings support the hypothesis that learned responses to drug-related stimuli are a significant factor in long-term vulnerability to relapse.

In humans, the risk of relapse involves multiple determinants that probably interact. For example, exposure to drug signals may increase the vulnerability to relapse transmitted by prolonged withdrawal symptoms resulting from neuroadaptive changes in dependent individuals. There may also be interactive effects that aggravate the risk of relapse between stress-inducing effects and drug-related signals. Recent work addressing these problems has confirmed that additive interactions can in fact be demonstrated between the effects of reestablishing the response of signals associated with ethanol and stress, and that these effects are enhanced in rats with a history of ethanol dependence. (Liu and Weiss, Soc. Neurosci, Abstr 26, 786 (2000)).

In experimental laboratories, reestablishment of drug search is obtained with the administration of the adrenergic receptor antagonist a-2 yohimbine, which, by increasing the firing and release of norepinephrine cells in the brain, acts as a pharmacological stressor. Stress by electrical shock in the foot and yohimbine-induced reestablishment of drug-seeking behaviors represent both valid experimental models for investigating stress-induced alcohol relapse (Lee et al., Neuropsychopharmacology 29: 686-93 (2004)). Le et al., Psychopharmacology 150: 317-24 (2000)).

As shown in the appended examples, PDE7 inhibitors significantly reduce the recurrent stress-induced use of an addictive agent (Example 1). These data indicate, therefore, that PDE7 inhibitors have anti-relapse properties.

Interestingly, several reports have shown that the non-selective opioid receptor antagonist naltrexone reduces the imperative need for drinking induced by the presentation of alcohol signals in human alcoholics (Monti et al., 1993, mentioned above) and reduces the efficacy of a Alcohol signal to restore the response extinguished in a lever trial paired with drugs in rats (Katner et al., 1999, mentioned above). However, naltrexone does not reduce the relapsing behavior induced by tension ((Le AD Psychopharmacology 1998).

In a related embodiment, the invention includes a method of treating preventing or preventing the recurrent use of an addictive agent or the practice of addictive or compulsive behavior, comprising administering an effective amount of a PDE7 inhibitor to a subject that has previously reduced or eliminated the use of an addictive agent or the practice of addictive or compulsive behavior in response to exposure to an effective amount of another antiadictive treatment, in which the subject is no longer exposed to an effective amount of anti-addiction treatment. The antiadictive treatment can be an anti-addictive drug or it can be a non-pharmacological therapy such as counseling, psychotherapy or hypnotherapy. Recurrent use can be triggered by stress.

In certain embodiments, the subject is no longer exposed to an effective amount of an anti-addictive agent because the subject has become tolerant to the agent, so that the blood plasma concentration of the antidictive agent that was previously effective in the treatment of the addiction is no longer effective. In other embodiments, the subject is no longer exposed to an effective amount of an anti-addictive agent because the subject is now exposed to a lower blood plasma concentration of the anti-addictive agent and this concentration in minor blood plasma is not effective.

In certain embodiments of the methods of the present invention, the subject has experienced a period of abstinence, or limited or limited use, of the addictive agent or practices of addictive or compulsive behavior. The period of abstinence or limited or limited use can be, for example, at least 24 hours, at least 48 hours, at least 3 days, at least 5 days, at least a week, at least 2 weeks, at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 9 months, at least one year, at least 2 years or at least 5 years.

In another embodiment, the present invention includes a method for treating or preventing the recurrent use of an addictive agent, comprising providing a PDE7 inhibitor and an opioid antagonist to a subject who has experienced physiological withdrawal from the addictive agent.

In a further embodiment, the present invention includes a method of treating or preventing the recurrent use of an addictive agent, comprising administering a PDE7 inhibitor and a CB1 antagonist, for example, disulfiram, topiramate, levetiracetam, SSRI or wavesetron, a a subject who has experienced physiological abstinence from the addictive agent.

In particular embodiments, recurrent use is triggered by stress, an environmental conditioning factor, or both.

Although the methods of the present invention can be practiced in subjects addicted to a single addictive agent, they can also be used in subjects addicted to two or more addictive agents. Similarly, although these methods can be used to prevent the recurrent use of the addictive agent from which the subject has experienced abstinence, they can also be adapted to prevent the recurrent use or initiation of use of an addictive agent other than that the subject has experienced abstinence. physiological

D. Pharmaceutical compositions, administration routes, dosage unit forms, kits

The present invention has established the efficacy of the use of combinations of a PDE7 inhibitor, in combination with one or more additional therapeutic agents, such as opioid antagonists, antidepressants, antiepileptics, antiemetics and CB1 receptor antagonists. Thus, the present invention further includes compositions comprising one or more PDE7 inhibitors and one or more additional therapeutic agents, such as opioid antagonists, mixed opioid partial agonists / antagonists, antidepressants, antiepileptics, antiemetics, CRF1 receptor antagonists and antagonists. of the CB1 receiver.

In particular embodiments, the composition comprises a PDE7 inhibitor and an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is an opioid antagonist or a mixed opioid partial agonist / antagonist. In one embodiment, the opioid antagonist is naltrexone. In another embodiment, the mixed opioid partial / antagonist agonist is buprenorphine. In certain embodiments, the additional therapeutic agent is an antidepressant. In a particular embodiment, the antidepressant is bupropion. In certain embodiments, the additional therapeutic agent is an antiepileptic, an antiemetic or an opioid antagonist or an agonist partial / mixed opioid antagonist.

The compositions of the present invention can be administered to a subject as a pharmaceutical composition or formulation. In particular embodiments, the pharmaceutical compositions of the present invention may be in any form that allows the composition to be administered to a subject. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical administration routes include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal and intranasal. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, epidural, intrasternal injection, or infusion techniques.

The pharmaceutical compositions used according to the present invention comprise a PDE7 inhibitor, another therapeutic agent and a pharmaceutically acceptable diluent, excipient or vehicle. "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro, 1985). For example, sterile saline solution and phosphate buffered saline at physiological pH can be used. Preservatives, stabilizers, colorants and even flavoring agents can be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid, and hydroxybenzoic acid esters can be added as preservatives. Id. At 1449. In addition, antioxidants and suspending agents can be used. Id.

The pharmaceutical compositions of the invention are formulated in general so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a subject. The compositions that will be administered to a subject can take the form of one or more dosage units, where for example, a tablet, a capsule or a wafer can be a unit dosage unit, and a container comprising a combination of agents according to the present invention in aerosol form may contain a plurality of dosage units.

In particular embodiments, the composition comprising a PDE7 inhibitor and another therapeutic agent is administered in one or more doses of a tablet formulation, usually for oral administration. The tablet formulation can be, for example, an immediate release formulation, a controlled release formulation or an extended release formulation. In one embodiment, a tablet formulation comprises an effective amount of a composition comprising a PDE7 inhibitor and another therapeutic agent. In particular embodiments, a tablet comprises about 1, 5, 10, 20, 30, 50, 100, 150, 200, 250 or 300 mg of a PDE7 inhibitor and about 1, 5, 10, 20, 30, 50100, 150 , 200, 250 or 300 mg of another therapeutic agent.

The present invention also includes dosage unit forms of pharmaceutical compositions comprising a PDE7 inhibitor and another therapeutic agent. Each unit dosage form comprises a therapeutically effective amount of a pharmaceutical composition of the present invention, when used in the recommended amount. For example, a unit dosage forms can include a therapeutically effective amount in a single tablet or a unit dosage forms can include a therapeutically effective amount in two or more tablets, so that the prescribed amount comprises a therapeutically effective amount.

In particular embodiments, a PDE7 inhibitor is provided to a subject in an amount in the range of 0.1 1000 mgMa, 1-1000 mg / day, 10-100 mg Ma or 25-50 mg Ma. In one embodiment, pioglitazone is provided to a patient at about 30 mgMa.

Certain combinations of PDE7 inhibitors and other therapeutic agents may not be readily adaptable to coformulation. For example, one of the agents may be more susceptible to intravenous administration, while another agent may be more susceptible to oral administration. Or, the serum half-life of the two agents may be such that one should be administered more frequently than the other. Accordingly, the present invention contemplates kits comprising one or more unit dosage forms of a PDE7 inhibitor and one or more unit dosage forms of another therapeutic agent, so that the two unit dosage forms can be provided to a subject of a therapeutically effective way.

In one embodiment, the present invention includes a kit comprising unit dosage forms of a PDE7 inhibitor and unit dosage forms of nicotine. In one embodiment, the unit dosage forms of nicotine comprise a plurality of different forms of unit dosage of nicotine, wherein the different forms of nicotine dosage represent a decreasing amount that can be taken one after the other during a period of time, to overcome addiction and abstinence from nicotine. Dosage unit dosage forms of nicotine may be present, for example, in the form of a transdermal patch, gumdrop or lozenge.

E. PDE7 proteins and inhibitory agents

Nucleic acid phosphodiesterase type 7 (PDE7) is identified as a single family based on its primary amino acid sequence and defined enzymatic activity. PDE genes identified as PDE7 (PDE7A and PDE7B) encode cAMP-specific PDEs. The biochemical and pharmacological characterization of PDE7 shows a specific ^{high-affinity cAMP PDE (Km = 0.2} | j ^{M) that is not affected by cGMP or selective inhibitors} of other PDEs. The PDE7 enzyme selectively decomposes cAMP and is characterized as an enzyme that is not inhibited by rolipram, a selective inhibitor of PDE4, which is a PDE family specific for cAMP. Two subtypes have been identified in the PDE7 family, PDE7A (Michael, T., et al., J Biol. Chem. 268 (17): 12925-12932, 1993; Han, P., et al., J Biol. Chem. 272 (26): 16152-16157, 1997) and PDE7B (U.S. Patent No. 6,146,876; Gardner, C., et al., Biochem. Biophys., Res. Commun. 272 (1): 186-192, 2000; and Saski, T., et al., Biochem. Biophys., Res. Commun. 271 (3): 575-583, 2000). The two gene products show 70% identity in their C-terminal catalytic domains (Hetman JM, et al., PNAS 97 (1): 472-476 (2000).

PDE7A has three splice variants (PDE7A1, PDE7A2 and PDE7A3); these variants are generated by alternative splicing at both the N and C ends (Bloom, T.J., and J.A. Beavo, Proc. Natl. Acad. Sci. USA.

93: 14188-14192, 1996). The nucleotide sequence of PDE7A, variant 1 of the transcript, is accessible in public databases by the registration number NM_002603. The human PDE7A1 protein (SEQ ID NO: 2, encoded by SEQ ID NO: 1) has 456 amino acids and migrates to an apparent molecular weight of 53-55 kDa in reduced SDS-PAGE.

The nucleotide sequence of PDE7A, variant 2 of the transcript, is accessible in public databases by the registration number NM_002604. The human PDE7A2 protein (SEQ ID NO: 4, encoded by Se Q ID NO: 3) has 424 amino acids.

The PDE7A protein has a region of approximately 270 amino acids at the carboxyl terminal end that shows significant similarity (-23% homology) with the analog regions of other PDEs that hydrolyze cAMP. This region acts as the catalytic domain. The amino-terminal region of this protein is divergent from that of other PDEs and supposedly mediates the unique regulatory and distinguishing properties of this family of enzymes.

The human PDE7B protein sequence is accessible in public databases by registration number NM_018945, provided as SEQ ID NO: 6, encoded by SEQ ID NO: 5. Three PDE7B splice variants have been reported: PDE7B1, PDE7B2 and PDE7B3. PDE7B is published in WO 01/62904, U.S. Patent No. 6,146,876.

Both PDE7B2 and PDE7B3 possess particular N-terminal sequences. The human PDE7B gene products have an apparent molecular weight of 53-55 kDa in reduced SDS-PAGE (Sasaki, T., Kotera, J., Omori, K., Biochemical J. 361: 211-220, 2002). As in PDE7A, PDE7B has a significantly conserved region of approximately 270 amino acids common to all PDEs at the carboxyl terminus, which acts as the catalytic domain. Similar to the PDE7A protein, the amino terminal region of the PDE7B protein is divergent and presumably explains the distinctive and regulatory properties of the individual PDE families. The PDE7B protein shows homology to other cAMP-dependent PDEs (23%) in the catalytic domain. The polypeptide PDE7B is 61% homologous to PDE7A, according to WO 2004/044196.

PDE7 is also localized in a particular way in maritime subjects in relation to other PDE families. PDE7A expression has been detected in the majority of tissues analyzed, including the brain, heart, kidney, skeletal muscle, spleen and uterus (Bloom, et al., PNAS 93: 14188, 1996). In the brain, PDE7A is widely distributed in both neuronal and non-neuronal cell populations (Miro, et al., Synapse 40: 201, 2001). The broad expression of PDE7A in the brain, including the basal ganglia and the substantia nigra, provides a theoretical basis for a role of PDE7A in brain functions.

In the practice of the methods of the invention, representative PDE7 inhibitory agents that inhibit the phosphodiesterase activity of PDE7 include: molecules that bind PDE7 and inhibit the enzymatic activity of PDE7 (such as small inhibitory molecules or blocking peptides that are bind with PDE7 and reduce the enzymatic activity) and molecules that reduce the expression of PDE7 at the transcriptional and / or translational level (such as PDE7 antisense nucleic acid molecules, PDE7 specific RNAi molecules and PDE7 ribozymes), avoiding this way that PDE7 cleaves cAMP. The PDE7 inhibitory agents can be used alone as primary therapy or in combination with other therapeutic products (such as dopamine receptor agonists) as an adjuvant therapy to enhance the therapeutic benefits, as discussed above.

The inhibition of PDE7 is characterized by at least one of the following changes that occurs as a consequence of the administration of a PDE7 inhibitory agent according to the methods of the invention: the inhibition of the PDE7-dependent enzymatic cleavage of the phosphodiester bond 3 'in cAMP to form 5'-adenosine monophosphate (5'-AMP), a reduction in the level of gene or protein expression of PDE7, measured, for example, by analysis of gene expression (e.g., RT-PCR analysis) or protein analysis (eg, Western blotting).

In some embodiments, a PDE7 inhibitory agent is a molecule or composition that inhibits the expression of PDE7A, PDE7B or both PDE7A and PDE7B, such as an antisense nucleotide or small inhibitor (e.g., siRNA) that specifically hybridizes with cellular mRNA and / or genomic DNA corresponding to the gene or genes of the PDE7 target to inhibit its transcription and / or translation, or a ribozyme that specifically excises the mRNA of a PDE7 target.

Potency of PDE7 inhibitors

In one embodiment, a PDE7 inhibitory agent useful in the methods of the invention is a compound that is sufficiently potent to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B or PDE7A and PDE7B) at an IC ^{50 <1} | j ^{M, preferably less than or about 0.1 jM. In one embodiment, the PDE7 inhibitory agent is} sufficiently potent to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B or PDE7A and PDE7B) at an IC ⁵⁰ of about 0.1 to about 500 nM. In one embodiment, the PDE7 inhibitory agent is potent for inhibiting the enzymatic activity of PDE7 (PDE7A, PDE7B or PDE7A and PDE7B) at an IC ⁵⁰ of about 1 to about 100 nM.

Representative methods for determining IC ⁵⁰ for a PDE7 inhibitor agent (PDE7A or PDE7B) are also well known in the art, such as the scintillation proximity assay (SPA) disclosed in Bardelle et al., Anal Biochem 15: 275 ( 2): 148-55 (1999).

Selective inhibitors of PDE7A or PDE7B

In one embodiment, the PDE7 inhibitor useful in the method of the invention is a PDE7A inhibitor. In one embodiment, the PDE7A inhibitory agent is potent for inhibiting the enzymatic activity of PDE7A at an IC ⁵⁰ of about 0.1 to about 500 nM. In one embodiment, the PDE7A inhibitor has an IC ⁵⁰ of about 1 to about 100 nM. A suitable assay for determining IC ⁵⁰ for a PDE7A inhibitor uses recombinant human PDE7A2 enzymes expressed in a baculovmco system. This test method is a modification of the SPA assay indicated by Bardelle et al mentioned above.

In some embodiments, the PDE7 inhibitor shows selective isozyme activity against PDE7A. A selective PDE7A inhibitory agent reduces PDE7A activity at least two times more than PDE7B activity, more preferably at least 10 times, at least 20 times, at least 50 times or at least 100 times. In some embodiments, the PDE7A inhibitory agent is an inhibitory agent that is at least 10 times (such as at least 20 times, or at least 50 times or at least 100 times) more selective to inhibit PDE 7A activity than for the enzymatic activity of any other PDE (PDE1-6, 7B and 8-11).

In one embodiment, the PDE7B inhibitor has an IC ⁵⁰ of about 0.1 to about 500 nM. In one embodiment, the PDE7B inhibitory agent is sufficiently potent to inhibit the enzymatic activity of PDE7B at an IC ⁵⁰ of about 0.1 to about 500 nM. In one embodiment, the PDE7B inhibitor has an IC ⁵⁰ of about 1 to about 100 nM. Methods for determining IC ⁵⁰ for a PDE7B inhibitor are also well known in the art, such as the assays disclosed in Bardelle et al., Mentioned above.

In some embodiments, the PDE7 inhibitor shows selective isozyme activity against PDE7B. A PDE7B selective inhibitory agent reduces the activity of PDE7B at least twice as much as the PDE7A activity, more preferably at least 10 times, at least 20 times, at least 50 times or at least 100 times. In some embodiments, the PDE7B inhibitory agent is an inhibitory agent that is at least 10 times (such as at least 20 times, or at least 50 times or at least 100 times) more selective to inhibit PDE7B activity than for activity. Enzymatic of any other PDE (PDE1-6, 7A and 8-11).

Selectivity of PDE7 compared to other PDEs

In some embodiments, the PDE7 inhibitor has an IC ⁵⁰ for inhibiting PDE1B activity more than 5 times (such as at least 10 times, at least 20 times, or at least 50 or at least 100 times) the smallest IC ⁵⁰ to inhibit the activity of PDE7A and IC ⁵⁰ to inhibit PDE7B activity. In other words, the PDE7 inhibitor is more potent (5 times, 10 times, 20 times, 50 times or 100 times) in the inhibition of PDE7A or PDE7B activity (the PDE7A or PDE7B isozyme on which the inhibitor of PDE7 has the greatest effect), than in the inhibition of PDE1B activity. For the purposes of the present specification, by way of example, this property can be indicated even more simply as that the PDE7 inhibitor is more potent (5 times, 10 times, 20 times, 50 times or 100 times) in the inhibition of PDE7 activity than in the inhibition of PDE1B activity.

Double inhibition of both PDE7 and PDE1B may confer additional benefit in the treatment of movement disorders based on a report that deletion of the gene for PDE1B in mice stimulates dopamine metabolism and sensitizes animals to the effects of dopamine agonists (Siuciak, et al., Neuropharmacology 53 (1): 113-23 (2007)).

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE10 activity more than 5 times (such as at least 10 times, at least 20 times, at least 50 or at least 100 times) the smallest of the IC ⁵⁰ to inhibit the activity of PDE7A and IC ⁵⁰ to inhibit PDE7B activity. Double inhibition of both PDE7 and PDE10 may confer additional benefit in the treatment of movement disorders based on a report that selective PDE10 inhibitors cause an increase in cAMP levels in the striatum (Siuciak JA et al., Neuropharmacology 51 (2): 386-96 (2006)).

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE3 activity more than 10 times (such as at least 20 times, at least 50 or at least 100 times) the lower of IC ⁵⁰ to inhibit activity of PDE7A and IC ⁵⁰ to inhibit PDE7B activity. This is because the administration of selective PDE3 inhibitors to patients with cardiac insufficiency has been shown to increase their mortality rate (Packer M. et al., N Engl J Med. 325 (21): 1468-75 (1991)). ).

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE4 activity more than 10 times (such as at least 20 times, at least 50 or at least 100 times) the lower of IC ⁵⁰ to inhibit activity of PDE7A and IC50 to inhibit PDE7B activity. This is because the suppression of one of the PDE4 genes in mice has been shown to lead to cardiomyopathy (Lehnart SE et al., Cell 123 (1): 25-35 (2005)).

In some embodiments, the PDE7 inhibitory agent has an effective semi-maximal dose ("ED ⁵⁰ ") in an in vivo assay of PDE4 inhibition (eg, sedation or inhibition of TNF alpha levels after endotoxin treatment) of more than 10 times (at least 20 times, at least 50 times or at least 100 times) the lowest of the ED ⁵⁰ in an in vivo assay of the inhibition of PDE7A and PDE7B (eg, prevention of cocaine relapse) or another psychostimulant addiction). According to said embodiments, it has been determined that some compounds having double inhibitory activity of PDE4 / PDE7 possess higher selectivity against PDE7 than PDE4 in vivo, compared to the selectivity of PDE4 / PDE7 of the compound as determined in an in vitro assay. .

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ for inhibiting PDE3 activity and PDE4 activity more than 10 times (such as at least 20 times, at least 50 or at least 100 times) the smallest of the IC ⁵⁰ to inhibit the activity of PDE7A and the IC50 to inhibit the activity of PDE7B.

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit PDE8 activity more than 10 times (such as at least 20 times, at least 50 or at least 100 times) the lowest of IC ⁵⁰ to inhibit activity of Pd E7A and IC ⁵⁰ to inhibit PDE7B activity.

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ for inhibiting PDE4 activity and PDE8 activity more than 10 times (such as at least 20 times, at least 50 or at least 100 times) the lowest of the IC ⁵⁰ to inhibit the activity of PDE7A and IC ⁵⁰ to inhibit PDE7B activity. In accordance with this embodiment, it is known that PDE families that specifically hydrolyze / preferably cAMP include PDE4, PDE7 and PDE8.

In some embodiments, the PDE7 inhibitory agent has an IC ⁵⁰ to inhibit the activity of PDE1, PDE2, PDE3, PDE4 and PDE8, PDE10 and PDE11 of more than 10 times the lowest of C ¹⁵⁰ to inhibit the activity of PDE7A and the IC50 to inhibit the activity of PDE7B. According to this embodiment, it is known that PDE families that specifically hydrolyze / preferably cAMP include PDE4, PDE7, and PDE8 and the families of PDE1, PDE2, PDE3, PDE10 and PDE11 show substantial activity both against cAMP and against cGMP.

In some embodiments, the PDE inhibitory agent is a selective PDE7 inhibitor for which the lower of the IC ⁵⁰ for inhibiting the activity of PDE7A and the IC50 for inhibiting the activity of PDE7B is less than one tenth (such as a twentieth, a fifty or one hundredth) of the IC ⁵⁰ that has the agent to inhibit any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11.

A selective PDE7 inhibitor can be identified, for example, by comparing the ability of an agent to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B or PDE7a and PDE7B) with its ability to inhibit PDE enzymes from the other PDE families. For example, an agent can be assayed for its ability to inhibit PDE7 activity as well as PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE8, PDE9, PDE10 and PDE11. The ratio of IC ⁵⁰ inhibition for each of the PDE isozymes (1-6 and 8-11) with respect to inhibition of IC ⁵⁰ of PDE7 (ie, the most sensitive of PDE7A or PDE7B) can be determined by a conventional in vitro, in vivo or ex vivo assay , such as those described herein.

In some embodiments, a PDE7 inhibitor is selective for PDE7 and substantially inactive against other PDEs (eg, PDE1, PDE2, PDE3, PDE4 and PDE8, PDE10 and PDE11) due to the direction of the PDE7 inhibitor to one or more target tissues. , such as the brain and / or skeletal muscle. As described herein, PDE7 is uniquely localized in marine subjects in relation to other PDE families. In the brain, PDE7A is widely distributed in both neuronal and non-neuronal cell populations, including the basal ganglia and the substantia nigra (Miro et al., Synapse 40: 201,2001). PDE7B is expressed in the brain in the striatum (Reyes-Irisarri et al., Neuroscience 132: 1173, 2005).

Types of PDE7 inhibitors

The PDE7 inhibitory agent can be any type of agent, including, but not limited to, a chemical compound, a protein or a polypeptide, a peptidomimetic, a nucleic acid molecule or a ribozyme. In some embodiments, the PDE7 inhibitory agents are small molecule inhibitors that include natural and synthetic substances having a low molecular weight (ie, less than about 450 g / mol), such as, for example, peptides, peptidomimetics and inhibitors. non-peptide drugs such as chemical compounds.

Chemical compounds:

PDE7 inhibitors useful in the methods of the invention include agents that are administered via a conventional route (eg, oral, intramuscular, subcutaneous, transdermal, trans-oral, intravenous, etc.) to the bloodstream and are ultimately transported through of the vascular system through the blood-brain barrier to inhibit PDE7 in the brain. Consequently, for these methods of administration, PDE7 inhibitors have the ability to cross the blood-brain barrier. PDE inhibitors described below that have the ability to cross the blood-brain barrier (for example, those having a molecular weight less than about 450 g / mol and which are sufficiently lipophilic) are useful in the methods of the invention when the inhibitors are they administer via a route that ultimately transports the inhibitors to the brain in the bloodstream.

Below is a description of exemplary PDE7 inhibitors useful in the methods of the invention.

In one embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in EP 1454 897, WO 2003/053975 and US 20050148604, each expressly incorporated herein. by reference in its entirety. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The substituents for the above compounds are defined as follows:

A represents N or CR ⁴ ,

B represents a hydrogen atom or a halogen atom,

Ri represents optionally substituted C ^3-7 cycloalkyl or tert-butyl,

R ² represents hydrogen, methyl or ethyl,

R ³ represents an atom of hydrogen, nitro, cyano or halogen, NR ⁵ R ⁶ , C (= X) R 7, SO ² NR ⁵ R ⁶ , ORs, NR ⁸ CONR ⁵ R ⁶ , NR ⁸ SO ² R ⁹ , NR ⁸ CO ² R ⁹ , a heteroaryl group, optionally substituted C ^1-3 alkyl, optionally substituted C ^1-6 alkenyl or optionally substituted saturated or unsaturated heterocycloalkyl,

R ⁴ represents hydrogen or C ^1-3 alkoxy substituted, if desired, by one or more fluorine atoms,

R ⁵ and R 6 are the same or different and represent a hydrogen atom, optionally substituted C ^1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted acyl or, together with the hydrogen atom to which they are attached, form acetidinyl, pyrrolidinyl, piperidinyl , morpholino, thiomorpholino, piperazinyl or homopiperazinyl, each of these groups being optionally substituted by optionally substituted C ^1-4 alkyl, OH, C ^1-3 alkoxy, CO ² H, NR ⁵ R ⁶ , an oxo group, NR ⁹ COR ⁷ , or C (= O) R7,

R ⁷ represents optionally substituted C ^1-6 alkyl, OH, OR8, or NR ⁵ R ⁶ ,

R8 represents hydrogen, an optionally substituted C ^1-6 alkyl group or optionally substituted heterocycloalkyl,

R ⁹ represents an optionally substituted C ^1-6 alkyl group, and X represents O, S or NH.

With respect to the above compounds, "optionally substituted" refers to a linear, branched or optionally substituted alkyl group such as methyl, ethyl, propyl or cyclohexyl; a hydroxyl group; a cyano group; a group alkoxy such as methoxy or ethoxy; an optionally substituted amino group such as amino, methylamino or dimethylamino; an optionally substituted acyl group such as acetyl or propionyl; a carboxyl group; an optionally substituted aryl group such as phenyl or naphthyl; an optionally substituted heteroaryl group such as pyridinyl, thiazolyl, imidazolyl or pyrazole; an optionally substituted saturated or unsaturated heterocycloalkyl group such as piperazinyl or morphonyl; an optionally substituted carbamoflo group; an optionally substituted amido group; a halogen atom, such as chlorine, fluorine or bromine; a nitro group; an optionally substituted sulfone group; an optionally substituted sulfonylamido group; an oxo group; a urea group; and an optionally substituted linear, branched or cyclic alkenyl group such as ethenyl, propenyl or cyclohexenyl.

Examples of the heteroaryl group such as R ³ include a 5- to 7-membered monodilic heteroaryl group having from 2 to 8 carbon atoms and containing from 1 to 4 heteroatoms consisting of oxygen atoms, nitrogen atoms or sulfur atoms, and a polydilic heteroaryl group comprising two or more said identical or different monodilic compounds fused together, examples of the monodilic and polycyclic heteroaryl groups being pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyridyl, pyrazyl, indolyl, quinolyl, isoquinolyl and tetrazolyl.

In one embodiment, a PDE7 inhibitor useful in the invention has the formula:

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

In another embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula:

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The preparation of the above compounds is described in EP 1454 897, WO 2003/053975 and US 20050148604.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 2002/0198198, WO 2002/076953, WO 2002/074754, WO document. 2006/092691, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4623-4626 and Bioorganic & Medicinal Chemistry Letters 14 (2004) 4627-4631, each expressly incorporated herein by reference in its entirety. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The substituents for the above compounds are defined as follows:

(a) Xi, X ² , X ³ , and X ⁴ are the same or different and are selected from:

N, provided that no more than two of the groups Xi, X ² , X ³ , and X ⁴ represent simultaneously a nitrogen atom, or, C-Ri, in which Ri is selected from:

Qi, or

lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted by one or more Q ² groups;

the group X ⁵ -R ⁵ in which,

X ⁵ is selected from:

a simple link,

lower alkylene, lower alkenylene or lower alkynylene; optionally interrupted with io 2 heteroatoms chosen from O, S, S (= O), SO ² or N, the carbon atoms of these groups being unsubstituted or substituted by one or several groups, identical or different, selected from SR6, OR6 , NR ⁶ R ⁷ , = O, = S or = NR 6 in which R 6 and R ⁷ are the same or different and are selected from hydrogen or lower alkyl, and,

R ⁵ is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C (= O) or with i, 2 or 3 heteroatoms chosen from O, S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with C (= O) or with i, 2 or 3 heteroatoms chosen from O, S, S (= O), SO ² or N, or a bidclic group, these groups being unsubstituted or substituted with one or more groups selected from Q ³ , heteroaryl or lower alkyl optionally substituted with Q ³ ;

in which Qi, Q ² , and Q ³ are the same or different and are selected from:

hydrogen, halogen, CN, NO ² , SO ³ H, P (= O) (OH) ² , OR ² , OC (= O) R ² , C (= O) OR ² , SR ² , S (= O) R ² , NR ³ R ⁴ , QR ² , Q-NR ³ R ⁴ , NR ² -Q-NR ³ R ⁴ , or NR ³ -QR ² where Q is selected from C (= NR), C (= O), C (= S) or SO ² , R is selected from hydrogen or lower alkyl, and R ² , R ³ , and R ⁴ are the same or different and are selected from:

hydrogen, lower alkyl optionally interrupted with C (= O), (CH ² ) n-aryl, (CH ² ) n-heteroaryl, (CH ² ) n-cycloalkyl optionally interrupted with C (= O) or with 2 selected heteroatoms between O, S, S (= O), SO ² or N, where n is an integer selected from 0, i, 2, 3 or 4; these groups being unsubstituted or substituted with one or more groups selected from lower alkyl, halogen, CN, CH ³ , SO ³ H, SO ² CH ³ , CF ³ , C (= O) NHSO ² CH ³ , ORa, COORa, C (= O) Ra, NRaR7, C (= O) NR6R7, or SO2NRaR7, wherein Ra and R ⁷ are identical or different and are selected from hydrogen or optionally substituted with one or two groups selected from oR, COOR or NRR8 lower alkyl those that R and R8 are hydrogen or lower alkyl, and,

Ra and R ⁷ , and / or, R ³ and R ⁴ , together with the nitrogen atom to which they are bound, can form a 4 to 8 membered heterodical ring, which may contain one or two heteroatoms selected from O, S, S (= O), SO ² , or N, and that may be substituted with,

a 4 to 8 membered heterodical ring, which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or, a lower alkyl optionally substituted with OR ', NR'R ", C (= O) NR'R "or COOR 'in which R' and R" are the same or different and are selected from H, lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl, and R ' and R ", together with the nitrogen atom to which they are bound, can form a 4 to 8 membered heterodical ring, which may contain one or two heteroatoms selected from O, S or N; or,

(b) X is O, S or NR ⁹ , wherein R ⁹ is selected from hydrogen, CN, OH, NH ² , lower alkyl, lower alkenyl

3i

or lower alkynyl, these groups being unsubstituted or substituted by cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S , S (= O), SO ² or N, aryl, heteroaryl, OR ¹⁰ , or NR ¹⁰ R ¹¹ in which R ¹⁰ and R ¹¹ are the same or different and are selected from hydrogen or lower alkyl;

(c) Y is selected from O, S or NR ¹² , wherein R ¹² is selected from hydrogen, CN, OH, NH ² , lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted by cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S (= O), SO ² or N, aryl, heteroaryl, OR ¹⁰ , or NR ¹⁰ R ¹¹ wherein R ¹⁰ and R ¹¹ are the same or different and are selected from hydrogen or lower alkyl; (d) Z is selected from CH-NO ² , O, S or NR ¹³ in which R ¹³ is selected from hydrogen, CN, OH, NH ² , aryl, heteroaryl, cycloalkyl optionally interrupted with one or more heteroatoms chosen from O , S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with one or more heteroatoms chosen from O, S, S (= O), SO ² or N, C (= O) R 14, C (= O ) NR14R15, OR ¹⁴ , or, lower alkyl, unsubstituted or substituted with one or more groups which are the same or different and which are selected OR ¹⁴ or NR ¹⁴ R ¹⁵ ;

R ¹⁴ and R ^{15 being} independently selected from hydrogen or lower alkyl, or, R ¹⁴ and R ¹⁵ , together with the nitrogen atom to which they are bound, can form a 4 to 8 membered heterodic ring which may contain one or two heteroatoms chosen between O, S or N and which may be substituted with a lower alkyl; (e) Z ¹ is selected from H, CH ³ , or NR ¹⁶ R ¹⁷ in which R ¹⁶ and R ¹⁷ are the same or different and are selected from hydrogen, CN, aryl, heteroaryl, cycloalkyl optionally interrupted with one or more heteroatoms chosen from O, S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with one or more heteroatoms chosen from O, S, S (= O), SO ² or N, C (= O) R 14, C (= O) NR ¹⁴ R ¹⁵ OR ¹⁴ , or, lower alkyl unsubstituted or substituted with one or more groups selected from OR ¹⁴ or NR ¹⁴ R ¹⁵ ,

R ¹⁴ and R ^{15 being} independently chosen from hydrogen or lower alkyl, and, R ¹⁴ and R ¹⁵ , and / or, R ¹⁶ and R ¹⁷ , together with the nitrogen atom to which they are bound, can form a 4 to 4 heterodic ring 8 members which may contain one or two heteroatoms chosen from O, S or N and which may be substituted with a lower alkyl;

(f) A is a cycle selected from:

in which

A ¹ , A ² , A ³ , A ⁴ , A ⁵ , and A6 are the same or different and are selected from O, S, C, C (= O), SO, SO ² , or NR ¹⁸ in which R ¹⁸ is selected from hydrogen, aryl, heteroaryl, cycloalkyl optionally interrupted with one or more heteroatoms chosen from O, S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with one or more heteroatoms chosen from O, S, S ( = O), SO ² or N, unsubstituted or substituted alkyl with aryl, heteroaryl, cycloalkyl optionally interrupted with one or more heteroatoms chosen from O, S, S (= O), SO ² or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S (= O), SO ² or N, CN, NR ¹⁹ R ²⁰ , C (= O) NR ¹⁹ R ²⁰ , OR ¹⁹ , C (= O) R ^{19 or} C (= O) OR ¹⁹ wherein R ¹⁹ and R ²⁰ are identical or different and are selected from hydrogen or lower alkyl;

* represents the carbon atom that is shared between cycle A and the main chain cycle containing X and / or Y; each carbon atom of cycle A is not substituted or substituted with 1 or 2 identical or different groups selected from lower alkyl optionally substituted with OR ²¹ , NR ²¹ R ²² , COOR ²¹ , or CONR ²¹ R ²² , lower haloalkyl, CN, F, = O, SO ² NR ¹⁹ R ²⁰ , OR ¹⁹ , SR ¹⁹ , C (= O) OR19, C (= O) NR19R20, or NR ¹⁹ R ²⁰ in which R ¹⁹ and R ²⁰ are identical or different and selected from hydrogen or lower alkyl optionally substituted with OR ²¹ , NR ²¹ R ²² , COOR ²¹ , or CONR ²¹ R ²² , wherein R ²¹ and R ²² are identical or different and are selected from hydrogen or lower alkyl, and, R ¹⁹ and R ²⁰ , and / or, R ²¹ and R ²² , together with the nitrogen atom to which they are bound, can form a 4 to 8 membered heterodic ring;

two atoms of cycle A, which are not adjacent, can be linked by a chain of 2, 3 or 4 carbon atoms that can be interrupted with 1 heteroatom chosen from O, S or N; provided that no more than two of the groups A ¹ , A ² , A ³ , A ⁴ , A ⁵ , and A6 simultaneously represent a heteroatom; Y

its tautomeric forms, its racemic forms, its isomers and its pharmaceutically acceptable derivatives.

With respect to the above compounds, halogen includes fluorine, chlorine, bromine and iodine. Preferred halogens are F and Cl. The lower alkyl includes simple and branched carbon chains having from 1 to 6 carbon atoms. Examples of said alkyl groups include methyl, ethyl, isopropyl and fer-butyl. The lower alkenyl includes simple and branched hydrocarbon radicals having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups are alkenyl ethenyl, 3-buten-1-yl, 2-ethenylbutyl and 3-hexen-1-yl. The lower alkynyl includes simple and branched hydrocarbon radicals having from 2 to 6 carbon atoms and at least one triple bond.

Examples of such alkynyl groups are ethynyl, 3-butyne-1-yl, propynyl, 2-butyne-1-yl and 3-pentyne-1-yl. The lower haloalkyl includes a lower alkyl as defined above, substituted with one or more halogens. An example of haloalkyl is trifluoromethyl. It is understood that aryl refers to an aromatic carbocycle containing between 6 and 10 carbon atoms. An example of an aryl group is phenyl. Heteroaryl includes aromatic rings having from 5 to 10 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S and N. Representative heteroaryl groups have 1, 2, 3 or 4 heteroatoms in an aromatic ring of 5 or 6 members. Examples of such tetrazole, pyridyl and thienyl groups are examples. The representative cycloalkyl contains from 3 to 8 carbon atoms. Examples of such cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups are examples. The term "interrupted" means that in a main chain, a carbon atom is replaced by a heteroatom or a group as defined herein. For example, in "cycloalkyl or cycloalkenyl optionally interrupted with C (== O) or with 1 heteroatom selected from O, S, S (== O), SO ² or N", the term "interrupted" means that C (= = O) or a heteroatom can replace a ring carbon atom. Examples of such groups are morpholine or piperazine. The cycloalkenyl includes 3- to 10-membered cycloalkyl containing at least one double bond. Heterocyclic rings include heteroaryl as defined above and cycloalkyl or cycloalkenyl, as defined above, interrupted with 1, 2 or 3 heteroatoms chosen from O, S, S (== O), SO ² or N. The bidclic substituents they refer to two rings, which are the same or different and which are selected from aryl, heterodic, cycloalkyl or cycloalkenyl ring, fused together to form bidclic substituents. An example of a bicyclic substituent is indolyl.

In one embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula:

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The preparation of the above compounds is described in US 2002/0198198, WO 2002/076953, WO 2002/074754, WO 2006/092691, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4623-4626 and Bioorganic & Medicinal Chemistry Letters 14 (2004) 4627-4631.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in EP 1 193 261, WO 2002/28847, US 20030045557, United States Patent No. 7,122. .565, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607-4613 and Bioorganic & Medicinal Chemistry Letters 14 (2004) 4615-4621. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

And it's S or O;

Ri is C ¹ -C ¹⁰ alkyl , C ² -C ¹⁰ alkynyl, C ² -C ^10, cycloalkyl, cycloalkenyl, heterocycle, aryl or a group poliddico; each optionally substituted with one or more identical or different X ¹ -R ⁴ groups, in which Xi is a single bond, lower alkylene, C ² -C ⁶ alkenylene, cycloalkylene, arylene or divalent heterocycle, and R ⁴ is:

(1) H, = O, NO ² , CN, halogen, lower haloalkyl, lower alkyl, carboxylic acid bioisoster;

(2) COOR ⁵ , C (= O) R 5, C (= S) R 5, SO ² R ⁵ , SOR ⁵ , SO ³ R ⁵ , SR ⁵ , OR ⁵ ;

(3) C (= O) NR7R8, C (= S) NR7R8, C (= CH-NO2) NR7R8, C (= N-CN) NR7R8, C (= N-SO2NH2) NR7R8, C (= NR7) NHR8 , C (= n R7) R8, C (= NRg) NHR8, C (= NRg) R8, SO ² NR ⁷ R ⁸ , or NR ⁷ R ⁸ , where R ⁷ and R 8 are the same or different and are selected from among OH, R ⁵ , Ra, C (= O) NR5Ra, C (= O) R5, SO ² R ⁵ , C (= NRg) NHR ¹⁰ , C (= NRg) R ¹⁰ , C (= CH-NO ² ) NRgR ¹⁰ , C (= N-SO ² NH ² ) NRgR ¹⁰ , C (= N-CN) NRgR ¹⁰ , or C (= S) NRgR ¹ o;

R ² is lower alkyl, alkenyl C ² -C ¹⁰ alkynyl, C ² -C ^10, cycloalkyl, cycloalkenyl, heterocycle, aryl; each optionally substituted with one or more groups which are the same or different and which are selected from:

(1) H, carboxylic acid bioisoster, lower haloalkyl, halogen,

(2) COOR ⁵ , OR ⁵ , SO ² R ⁵ ,

(3) SO ² NR ¹¹ R ¹² , C (= O) NRnR ¹² , NR ¹¹ R ¹² , where R ¹¹ and R ¹² are the same or different and are selected from OH, R ⁵ , Ra, C (= O) NR5Ra, C (= O) R5, SO ² R ⁵ , C (= S) NRgR ¹⁰ , C (= CH-NO ² ) NRgR ¹⁰ , C (= N-CN) NRgR ¹⁰ , C (= N-SO ² NH ² ) NRgR ¹⁰ , C (= NRg) NHR ¹⁰ , or C (= NRg) R ¹ o;

R ³ is X ² -R ³ wherein X ² is optionally substituted with one single bond or, a group selected from ^C1 - ^C4 alkylene, alkenylene C ² -Ca, alkynylene C ² -Ca, each one or more Groups that are the same or different and that are selected from:

(1) H, C ¹ -C ³ alkyl, C ³ -C ⁴ cycloalkyl, aryl, heterocycle, = O, CN,

(2) OR5, = NR5; or

(3) NR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are the same or different and are selected from R ⁵ , Ra, C (= O) NR ⁵ R a, C (= O) R ⁵ , SO ² R ⁵ , C (= S) NRgR ¹⁰ , C (= CH-NO ² ) NRgR ¹⁰ , C (= NRg) NHR ¹⁰ , or C (= NRg) R ¹ o;

R '3 is cycloalkyl, cycloalkenyl, aryl, heterocycle or a polydial group; each optionally substituted with one or more groups X ³ -R ¹⁷ wherein X ³ is a single bond, lower alkylene, C ² -C al alkenylene, C ² -C alkynylene, cycloalkylene, arylene, divalent heterocycle or a divalent polydial group, and, R ¹⁷ is:

(1) H, = O, NO ² , CN, lower haloalkyl, halogen, carboxylic acid bioisoster, cycloalkyl,

(2) COOR ⁵ , C (= O) R 5, C (= S) R 5, SO ² R ⁵ , SOR ⁵ , SO ³ R ⁵ , SR ⁵ , OR ⁵ ;

(3) C (= O) NR15R1a, C (= S) NR15R1a, C (= N-CN) NR15R1a, C (= N-SO2NH2) NR15R1a, C (= CH-NO2) NR15R1a, SO2NR15R1a, C (= NR15 ) NHR1a, C (= NR15) R1a, C (= NRg) NHR ¹ a, C (= NRg) R ¹ a, or NR15R1a where R ¹⁵ and R ¹ a are the same or different and are selected from OH, R ⁵ , Ra, C (= O) NR5Ra, C (= O) R5, SO ² R ⁵ , C (= S) NRgR ¹⁰ , C (= CH-NO ² ) NRgR ¹⁰ , C (= N-CN) NRgR ¹⁰ , C (= N-SO ² NH ² ) NRgR ¹⁰ , C (= NRg) NHR ¹⁰ or C (= NRg) R ¹⁰ ,

(4) heterocycle optionally substituted with one or more R5 groups;

wherein R ⁵ and Ra are the same or different and are selected from OH, lower alkyl, C ² -C alkenyl, C ² -Ca alkynyl, X 4 -cycloalkyl, X 4 -cycloalkenyl, X 4 -aryl, X 4-heterocycle or X ⁴ -group polycyclic, wherein X ⁴ is a single bond, lower alkylene or C ² -C al alkenylene; each optionally substituted with one or more groups which are the same or different and selected from halogen, = O, COOR ²⁰ , CN, OR ²⁰ , O-lower alkyl optionally substituted with OR ²⁰ , C (= O) -lower alkyl, haloalkyl lower,

wherein X ⁵ is a single bond or lower alkylene and R ¹⁸ , R ^, and R ²⁰ , are the same or different and are selected from H or lower alkyl;

X6-heterocycle, X6-aryl, X6-cycloalkyl, X6-cycloalkenyl or X6-polycyclic group, wherein X6 is a single bond or lower alkylene, these groups being optionally substituted with one or more groups, identical or different, selected between halogens, COOR ²¹ , OR ²¹ , or (CH ² ) nNR ² i R ²² in which n is 0, 1 or 2 and R ²¹ and R ²² are the same or different and are selected from H or lower alkyl;

R ⁹ is selected from H, CN, OH, lower alkyl, O-lower alkyl, aryl, heterocycle, SO ² NH ² , or

wherein X ⁵ is a single bond or lower alkylene and R ¹⁸ and R ¹⁹ are the same or different and are selected from H or lower alkyl;

R ¹⁰ is selected from hydrogen, lower alkyl, cyclopropyl or heterocycle; or its pharmaceutically acceptable derivatives.

With respect to the above compounds, aryl refers to an unsaturated carbocycle, which exclusively comprises carbon atoms in the dical structure, which number is between 5 and 10, including phenyl, naphthyl or tetrahydronaphthyl. "Heterocycle" refers to an unsaturated or saturated monocycle containing 1 to 7 carbon atoms in the organic structure and at least one heteroatom in the organic structure, such as nitrogen, oxygen or sulfur, preferably 1 to 4 heteroatoms, identical or different , selected between nitrogen, sulfur and oxygen atoms. Suitable heterocycles include morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, pyrimidinyl, 2- and 3-furanyl, 2- and 3-thienyl, 2-pyridyl, 2- and 3-pyranyl, hydroxypyridyl, pyrazolyl, isoxazolyl, tetrazole, imidazole, triazole. , and similar. The polydilic groups include at least two cycles, identical or different, selected from aryl, heterocycle, cycloalkyl, cycloalkenyl groups fused together to form said polydyl group such as 2- and 3-benzothienyl, 2- and 3-benzofuranyl, 2-indolyl , 2- and 3-quinolinyl, acridinyl, quinazolinyl, indolyl benzo [1,3] dioxolyl and 9-thioxantanyl. The bidlic groups refer to two cycles, which are the same or different and which are chosen from aryl, heterocycle, cycloalkyl or cycloalkenyl, fused together to form said bidclic groups. Halogen refers to fluorine, chlorine, bromine or iodine. "Lower alkyl" refers to an alkyl that is linear or branched and contains from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, fer-butyl, isobutyl, n-butyl, pentyl, hexyl, and the like. "Alkenyl" refers to a chain of linear or branched unsaturated carbon atoms, having one or more double bonds, preferably one or two double bonds. Alkynyl refers to a chain of linear or branched unsaturated carbon atoms, comprising one or more triple bonds, preferably one or two triple bonds. "Lower haloalkyl" refers to a lower alkyl substituted with one or more halogens; Preferred lower haloalkyl groups include perhaloalkyl groups such as CF ³ . Cycloalkyl refers to saturated monocarbocycle containing from 3 to 10 carbon atoms; including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkenyl refers to unsaturated monocarbocycle containing from 3 to 10 carbon atoms. Examples of suitable cycloalkenyl are 3-cyclohexene and 3-cycloheptene. The carboxylic acid bioisostero has the classic meaning; are usual carboxylic acid bioisosterers tetrazol-5-yl, C (= O) N (H) OH, isoxazol-3-yl, hydroxythiadiazolyl, sulfonamido, sulfonylcarboxamido, phosphonic acid, phosphonamido, phosphinic acid, sulfonic acids, acyl sulfonamido, mercaptoazole , acyl cyanamides.

In one embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula:

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The preparation of the above compounds is described in EP 1 193 261, WO 02/28847, US 20030045557, U.S. Patent No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607 4613 and Bioorganic & Medicinal Chemistry Letters 14 (2004) 4615-4621.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2004/111054, US 20060128728 and US 20070270419, each expressly incorporated herein by reference in its entirety. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The substituents for the above compounds are defined as follows:

Ri is a substituted or unsubstituted C ^3-8 cycloalkyl or substituted ferc-butyl group;

R ² is a hydrogen atom or C ^1-3 alkyl group;

R ³ is a group: NR ⁵ R ⁶ , C (= O) R 7, or S (O) or ^-2 R ⁸ ;

R ⁴ is a hydrogen atom or C ^1-3 alkoxy group which is unsubstituted or substituted by one or more fluorine atoms;

R ⁵ and R 6 are, identical or different from each other, a hydrogen atom, substituted or unsubstituted C ^1-6 alkyl group, substituted or unsubstituted acyl group, substituted or unsubstituted heterocycloalkyl group and substituted or unsubstituted heterocycloalkyl ring formed with a nitrogen atom that binds to R ⁵ and R6;

R ⁷ is a group: OR ⁹ or NR ⁵ R ⁶ ;

R8 is a hydrogen atom, a halogen atom, a group: NR ⁵ R ⁶ , substituted or unsubstituted C ^1-6 alkyl group or substituted or unsubstituted aryl group;

R ⁹ is a hydrogen atom or substituted or unsubstituted C ^1-6 alkyl group;

or pharmaceutically acceptable salts or solvates thereof.

With respect to the above compounds, the expression "C ¹ -C ³ alkyl group" includes a straight or branched chain alkyl group having from 1 to 3 carbon atoms. The term "C ³ -C ⁸ cycloalkyl group" includes a cycloalkyl group having from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The term "heterocycloalkyl group" is a 3 to 7 membered heterodical group containing the same or different 1 to 4 heteroatoms such as oxygen, nitrogen or sulfur atoms, and examples may include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl and azetidinyl. The expression "C ¹ -C ³ alkoxy group" means alkoxy group having from 1 to 3 carbon atoms. The term "acyl group" means acyl group having from 1 to 8 carbon atoms. The expression "aryl group" is a phenyl, naphthyl, biphenyl group having 6 to 12 carbon atoms and the expression "heteroaryl group" is a 5- or 7-membered monodilic or polydial group containing from 2 to 8 carbon atoms. carbon and the same or different 1 to 4 heteroatoms such as oxygen, nitrogen, sulfur atom (s). Examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl pyridazinyl and pyrimidinyl. Examples of "substituted or unsubstituted C ¹ -C ⁶ alkyl group" include hydroxyl group and halogen atom, and examples of suitable substituent of "substituted or unsubstituted acyl group" include halogen atom and nitro group. In addition, examples of suitable substituent of "substituted or unsubstituted aryl group" include C ¹ -C ³ alkyl, halogen atom, amino group, acyl group, amide group, hydroxyl group, acylamino group, carboxyl group and sulfonyl group. Examples of suitable substituent of "substituted or unsubstituted C ³ -C ⁸ cycloalkyl group" C ¹ -C ³ alkyl, hydroxyl group and oxo group, and examples of suitable substituent of "substituted or unsubstituted heterocycloalkyl group" may include group carboxyl, acyl group, alkoxy group, amino group, alkylamino group, acylamino group, hydroxyl group, oxo group, ethylenedioxy group, methyl group, ethyl group and hydroxyethyl group.

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The preparation of the above compounds is described in WO 2004/111054, US 20060128728 and US 20070270419.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,903,109, US 20040082578, WO 2003/088963 and US 20060154949. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

(a) R ¹ is selected from the group consisting of:

(i) COR ⁵ , wherein R ⁵ is selected from H, optionally substituted straight or branched chain C ^1-8 alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl are selected from alkoxy C ^1-8, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy or NR ²⁰ R ²¹ wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, C ^1-8 straight or branched chain alkenyl , C ^3-7, benzyl or aryl;

(ii) COOR6, wherein R6 is selected from H, optionally substituted straight or branched chain C ^1-8 alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy or NR ²⁰ R ²¹ wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkyl C ^1-8 straight or branched chain alkenyl , C ^3-7, benzyl or aryl;

(iii) cyano;

(iv) a lactone or lactam formed with R ⁴ ;

(v) CONR ⁷ R ⁸ wherein R ⁷ and R8 are independently selected from H, C ^1-8 straight or branched chain alkenyl , C ^3-7, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl; or R ⁷ and R 8 taken together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group;

(vi) a carboxylic or bioisostero ester of carboxylic acid including optionally substituted heteroaryl groups;

(b) R ² is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ^3-7 cycloalkyl, optionally substituted heterocyclyl, wherein the heterocyclyl is 1,3-dioxolane or furan, or R ² is

(c) R ³ is from one to four groups independently selected from the group consisting of:

(i) hydrogen, halo, straight or branched chain Ci-8 alkyl, arylalkyl, C ^3-7 cycloalkyl, C ^1-8 alkoxy, cyano, C ^1-4 carboalkoxy, trifluoromethyl, C ^1-8 alkylsulfonyl, halogen, nitro , hydroxy, trifluoromethoxy, C ^1-8 carboxylate, aryl, heteroaryl and heterocyclyl;

(ii) NR ¹⁰ R ¹¹ wherein R ¹⁰ and R ¹¹ are independently selected from H, straight or branched chain C ^1-8 alkyl, arylalkyl, C ^3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, or heterocyclyl, or R tornadoes ¹⁰ and R ¹¹ together with the nitrogen they are attached form a heterocyclyl or heteroaryl group;

(iii) NR ¹² COR ¹³ wherein R ¹² is selected from hydrogen or alkyl and R ¹³ is selected from hydrogen, alkyl, substituted alkyl, C ^1-3 alkoxy, carboxyalkyl, R ³ or R ³¹ N (CH 2) p, R ³ or R ³¹ NCO (CH 2) p, aryl, arylalkyl, heteroaryl, or heterocyclyl, or R ¹² and R ¹³ taken together with the carbonyl group form a heterocyclyl group containing carbonyl, wherein R ³⁰ and R ³¹ are independently selected from H, OH, alkyl and alkoxy, and p is a number 1-6 whole, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;

(d) R ⁴ is selected from the group consisting of (i) hydrogen, (ii) straight or branched chain C ^1-3 alkyl, (iii) benzyl, and

(iv) NR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are independently selected from hydrogen and C ^1-6 alkyl; wherein the benzyl and C ^1-3 alkyl groups are optionally substituted with one or more groups selected from C ^3-7 cycloalkyl, C ^1-8 alkoxy, cyano, C ^1-4 carboalkoxy, trifluoromethyl, C ^1-8 alkylsulfonyl, halogen , nitro, hydroxy, trifluoromethoxy, C ^1-8 carboxylate, amino, NR ¹³ R ¹⁴ , aryl and heteroaryl; Y

(e) X is selected from S and O;

and pharmaceutically acceptable salts, esters and prodrug forms thereof.

In an alternative embodiment, R ¹ , R ³ , and R ⁴ are as above and R ² is NR ¹⁵ R ¹⁶ , where R ¹⁵ and R ¹⁶ are independently selected from hydrogen, straight or branched chain C ^1-8 alkyl, arylalkyl , C ^3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R ¹⁵ and R ¹⁶ taken together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group.

With respect to the above compounds, "alkyl" refers to straight chain, distal and branched alkyl. The alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C ¹ -C ⁸ alkoxy C ¹ -C ⁸ alkylthio C ¹ -C ⁸ alkyl C ¹ -C ⁸ -amino, di (C ¹ -C ⁸ alkyl) amino, (mono-, di-, tri- and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ¹ -C ⁸ alkyl -CO-O -, C ¹ -C ⁸ alkyl -CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl (C ¹ -C ⁸ ) alkyl, heterocyclyl and heteroaryl. The term "bioisostero" is defined as "groups or molecules that have chemical and physical properties that produce similar biological properties in general". (Burger's Medicinal Chemistry and Drug Discovery, ME Wolff, ed. Fifth Edition, Vol. 1, 1995, Pag. 785). The term "acyl", as used herein, whether used alone or as part of a substituent group, means an organic radical having from 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid per removal of the hydroxyl group. "Aryl" or "Ar," whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl, and the like. The aromatic radical carbodclico may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C ¹ -C ⁸ alkoxy C ¹ -C ⁸ alkylthio C ¹ -C ⁸ , C ¹ -C ⁸ alkyl-amino, di (C ¹ -C ⁸ alkyl) amino, (mono-, di-, tri- and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C-alkyl ¹ -C ⁸ -CO-O-, C ¹ -C ⁸ alkyl -CO-NH- or carboxamide. Exemplary aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. The term "heteroaryl" refers to a cyclic, completely unsaturated radical having from five to ten atoms in the ring of which, an atom of the ring is selected from S, O, and N; 0-2 atoms in the ring are additional heteroatoms independently selected from S, O, and N; and the other atoms of the ring are carbon. The radical can be attached to the rest of the molecule by any of the atoms in the ring. The terms "heterocycle", "heterodyl", and "heterocyclyl" refer to a fully or partially saturated, optionally substituted, cyclic group, which is, for example, a monodic 4- to 7-membered ring system, of 7 to 11 members bidlic, or 10 to 15 tridical, having at least one heteroatom in at least one ring containing carbon atoms. Each ring of the heterodyl group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. Nitrogen atoms may optionally be quaternized. The heterodic group can be attached to any heteroatom or carbon atom.

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The preparation of the above compounds is described in U.S. Patent No. 6,903,109, US 20040082578, WO 2003/088963 and US 20060154949.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,958,328, WO 2002/085894 and US 20030212089. These inhibitors of PDE7 have the same formula as those described above (e.g., U.S. Patent No. 6,903,109), except that R ¹ is not a carboxylic ester or a biosy isher of carboxylic acid. The preparation of these compounds is described in U.S. Patent No. 6,958,328, US 20030212089 and WO 2002/085894.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2006/004040 and EP 1775298. In one embodiment, the PDE7 inhibitors useful in the methods of invention have the formula:

The substituents for the above compounds are defined as follows:

Ri is a substituted or unsubstituted C ^3-8 alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group (for example, cyclohexyl, cycloheptyl or tetrahydropyranyl);

R ² is a hydrogen atom or substituted or unsubstituted C ^1-3 alkyl group (eg, methyl);

R ³ is a hydrogen atom, substituted or unsubstituted C ^1-3 alkyl group, or a halogen atom; Y

R ⁴ is substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group or a group CONR ⁵ R ⁶ , or CO ² R ⁷ , wherein R ⁵ and R 6 are, same or different from each other, a hydrogen atom; C ^1-6 alkyl group which may be substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, a group NR ⁷ COR ⁸ , COR8, NR ⁹ R ¹⁰ ; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom linking R ⁵ and R 6;

wherein R ⁷ is a hydrogen atom or substituted or unsubstituted C ^1-3 alkyl group;

wherein R 8 is a substituted or unsubstituted heterocycloalkyl group, or an OH, OR ⁷ , or NR ⁹ R ^{10 group} ;

wherein R ⁹ and R ¹⁰ are, same or different from each other, a hydrogen atom; C ^1-3 alkyl group substituted or unsubstituted, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl; an SO ² R ⁷ group, or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom linking R 5 and R 6;

or pharmaceutically acceptable salts or solvates thereof.

With respect to the above compounds, the expression "cycloalkyl group" means cycloalkyl group having from 3 to 8 carbon atoms. The term "heterocycloalkyl group" may be a 3- to 7-membered mono- or poly-cyclic heterodic group containing the same or different 1 to 4 heteroatoms such as oxygen, nitrogen or sulfur atoms, and examples may include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl, hexahydropyrrolidinyl, octahydroindolidinyl, octahydroquinolidinyl, octahydroindolyl and oxo derivatives thereof. The term "aryl group" may be an aromatic hydrocarbon group, which consists of a monobenzene ring, or a benzene ring or a condensed benzene, such as phenyl, naphthyl, biphenyl, and the like; and dichloric or tridical group, which consists of benzene ring condensed with cycloalkyl or heterodicic ring, such as 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indoline, coumarone and the like. The term "heteroaryl group" can be a 5- to 7-membered heteroaryl group or polydial heteroaryl group, and having from 2 to 8 carbon atoms with 1 to 4 heteroatoms such as oxygen, nitrogen, sulfur atoms, wherein the polydilic heteroaryl group has ring system fused by the same or different monodilic heteroaryl or benzene ring to each other; or polydilic group consisting of heteroaryl group fused with cycloalkyl ring or heterocycloalkyl. Examples of suitable substituent of the present invention may include linear, branched or cyclic C ¹ -C ⁸ alkyl group, which may be substituted by one or more methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl, trifluoromethyl, C ¹ -C ³ alkoxy, halogen atom and hydroxyl group; hydroxyl group; cyano group; substituted or unsubstituted alkoxy group, such as methoxy, ethoxy group; amino group which can be substituted by C ¹ -C ⁶ alkyl group or acyl group such as amino, methylamino, ethylamino, dimethylamino, acylamino and the like; carboxylic group; ester group substituted or unsubstituted; Phosphate group; sulfonic group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; saturated or unsaturated heterocycloalkyl group which may be substituted; carbamoflo group substituted or unsubstituted; substituted or unsubstituted amide group; substituted or unsubstituted thioamide group; halogen atom; nitro group; sulfon substituted or unsubstituted group; substituted or unsubstituted sulfonyl amide group; oxo group; Urea substituted or unsubstituted group; linear, branched chain or cyclic alkenyl group such as ethenyl, propenyl, cyclohexenyl and the like.

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

Ċ

The preparation of the above compounds is described in EP 1775298 and WO 2006/004040.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in the disclosed WO 2004/111053 and US 20060128707, In one embodiment, the PDE7 inhibitors useful in the methods of invention have the formulas:

The substituents for the above compounds are defined as follows:

A is N or CR ⁴ ;

B is N or CH;

R ¹ is a C ^3-8 cycloalkyl or substituted or unsubstituted fer- cyl butyl group;

R ² is a hydrogen atom or C ^1-6 alkyl group;

R ³ is a hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; C ¹ -C 6 alkyl group substituted or unsubstituted; C ^2-6 substituted or unsubstituted alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; one group: NR ⁵ R ⁶ , C (O) R 7, SO ² R ⁷ , OR ⁸ , NR ⁸ COR ⁷ , NR ⁸ SO ² R ⁷ ;

R ⁴ is a hydrogen atom or C ^1-3 alkoxy group which is unsubstituted or substituted by one or more fluorine atoms; R ⁵ and R 6 are, same or different from each other, a hydrogen atom; C ^1-6 alkyl group substituted or unsubstituted; substituted or unsubstituted acyl group; or substituted or unsubstituted heterocycloalkyl group;

R ⁷ is a hydrogen atom; C ^1-6 alkyl group substituted or unsubstituted; substituted or unsubstituted heterocycloalkyl group; OH; OR8 or NR ⁵ R ⁶ ;

R8 is a hydrogen atom, substituted or unsubstituted Ci-6 alkyl group; or substituted or unsubstituted heterocycloalkyl group;

or pharmaceutically acceptable salts or solvates thereof.

With respect to the above compounds, the expression "C ¹ -C ⁶ alkyl group" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, and the expression "C ² -C ⁶ alkenyl group" refers to a straight or branched chain alkenyl group having from 2 to 6 carbon atoms. The term "cycloalkyl group" refers to a cycloalkyl group having from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "heterocycloalkyl group" is a 3 to 7 membered heterodical group containing the same or different 1 to 4 heteroatoms such as oxygen, nitrogen or sulfur atoms, and examples may include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, acetydinyl and homopiperazinyl. The term "heteroaryl group" is a 5- or 7-membered monodilic or polydilic group thereof containing from 2 to 8 carbon atoms and the same or different 1 to 4 heteroatoms such as oxygen, nitrogen or sulfur atoms. Examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl and pyrimidinyl. The "halogen atom" includes fluorine, chlorine, bromine and iodine. Examples of the suitable substituent of "substituted or unsubstituted C ¹ -C ⁶ alkyl group", "substituted or unsubstituted C ³ -C ⁸ cycloalkyl group", "substituted or unsubstituted alkenyl group", "substituted or unsubstituted heterocycloalkyl group""and" substituted or unsubstituted acyl group "include a straight or branched chain alkyl group, or substituted or unsubstituted, such as methyl, ethyl, propyl, isopropyl, n-butyl, fer-butyl, substituted or unsubstituted cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; hydroxyl group; cyano group; alkoxy group such as methoxy and ethoxy; substituted or unsubstituted amino group such as amino, methylamino, ethylamino and dimethylamino; substituted or unsubstituted acyl group such as acetyl and propionyl; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; carbamoMo group substituted or unsubstituted; substituted or unsubstituted amide group; halogen atom; nitro group; sulfon substituted or unsubstituted group; oxo group; Urea group; a straight or branched chain, or cyclic group which is substituted or unsubstituted such as ethenyl, propenyl and cyclohexenyl.

In other embodiments, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The preparation of the above compounds is described in US 20060128707 and WO 2004/111053.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,617,357, US 20020156064 and Molecular Pharmacology, 66; 1679- 1689, 2004. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ri is NRaRb where Ra and Rb are independently H or Ci-6 alkyl, or represents a 5- to 7-membered ring comprised of carbon or carbon and one or more heteroatoms selected from O, N or S;

R ² is H, Ci-8 alkyl, Ci-3-Ar alkyl, C 1-3 alkyl-C ^3-6 cycloalkyl, C ^2-8 alkenyl, C ^2-4 alkenyl, or C ^2-4 alkenyl-C ³ cycloalkyl ^-6 , wherein Ar is substituted or unsubstituted phenyl;

R ³ is NO ² , halo, CN, C (O) OR 7, CORi, or NR a R b where R a and R b are independently H or C ^1-6 alkyl; R ⁴ is H, C ^1-6 Oalkyl, halo, C (O) NRaRb, C (O) OR 7, C ^1-8 alkyl, OCHF ² , CH ² OR ⁸ , O-alkyl C i ^-3 -Ar or CH ² NHC (O ) CH3; R ⁵ is H, halo or alkyl;

R6 is C ^1-8 alkyl, C ^1-4 alkyl or halo;

R ⁷ is hydrogen or an ester or amide-forming group;

R 8 is hydrogen or C ^1-6 alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula:

The preparation of the above compounds is described in U.S. Patent No. 6,617,357, US 20020156064 and Molecular Pharmacology, 66: 1679-1689, 2004.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,852,720, EP 1348 433 and WO 2003/082277. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R ¹ is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, said groups being optionally substituted by one or more groups, identical or different, independently selected from one another among halogen, trifluoromethyl, nitro, cyano, oxo, NR ⁴ R ⁵ , CO ² R ⁴ , CONR ⁴ R ⁵ , OR ⁴ , S (O) nR ⁴ , S (O) nNR ⁴ R ⁵ , tetrazolyl and (C ¹ -C ⁶ ) alkyl which is optionally substituted by 1 to 3 groups, identical or different, independently selected from each other between OR ⁴ , NR ⁴ R ⁵ , and CO ² R ⁴ ; wherein n is an integer from 0 to 2 inclusive, R ⁴ and R ⁵ are identical or different and independently of each other are a hydrogen atom or a group of formula X ¹ -Ra, wherein X ¹ is a single bond or an alkylene group (C ¹ -C ⁶ ) and Ra is a group selected from (C ¹ -C ⁶ ) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,

R ² is a group selected from alkyl ^(C1 - ^C6), alkenyl ^(C2 - ^C6), alkynyl ^(C2 - ^C6), aryl and cycloalkyl, R ³ is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by one or more groups, identical or different, independently selected from each other among halogen, nitro, cyano, trifluoromethyl, oxo, (C ¹ -C ⁶ ) alkyl, OR ⁶ , NR ⁶ R ⁷ , COR6, CO ² R ⁶ , CONHOH, CONR ⁶ R ⁷ , S (O) mR6, S (O) mNR6R7, NR ⁶ COR ⁷ , NR ⁶ SO ² R ⁷ , N (SO2R7) 2, NR ⁶ CONR ⁷ R ⁸ , C (= NCN) NR6R7, NR8C (= NCN) NR6R7, and tetrazolyl optionally substituted with a (C ¹ -C ⁴ ) alkyl, where m is an integer from 0 to 2 inclusive, R 6 and R 7 are identical or different and independently of one another are a hydrogen atom or a group of formula X ² Rb, wherein X ² is a single bond or an alkylene group (C ¹ -C ⁶ ), R b is a group selected from alkyl (C ¹ - C ⁶ ), cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, independently selected from each other from hydroxy, ^(C1 - ^C6) alkyl, (C ¹ -C ^6), amino, mono (C ¹ being -C ⁶ ), dialkylamino (C ¹ -C ⁶ ) (each alkylamino being identical or different, independently of one another), carboxy, alkoxycarbonyl (C ¹ -C ⁶ ), and benzyl, and R 8 represents a hydrogen atom or a alkyl group (C ¹ -C ⁶ );

a racemic form thereof, an isomer thereof, an N-oxide thereof or an acidic or pharmaceutically acceptable basic salt thereof.

The preparation of the above compounds is described in U.S. Patent No. 6,852,720, EP 1348433 and WO 2003/082277.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,753,340, US 20030191167, EP 1348 701 and WO 2003 / 082839. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R ¹ a is a group selected from hydrogen, alkyl (C ¹ -C ⁶ ) and arylalkyl (C ¹ -C ⁶ ),

R ¹ b is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by one or more groups, identical or different, independently selected from each other among halogen, trifluoromethyl, nitro, cyano, oxo, NR ⁴ R ⁵ , CO ² R ⁴ , CONR ⁴ R ⁵ , OR ⁴ , S (O) nR ⁴ , S (O) nNR ⁴ R ⁵ , tetrazolyl and (C ¹ -C ⁶ ) alkyl which is optionally substituted by 1 to 3 groups, identical or different , independently selected from each other between OR ⁴ , NR ⁴ R ⁵ , and CO ² R ⁴ , where n is an integer from 0 to 2 inclusive, R ⁴ and R ⁵ are identical or different and independently of one another are a hydrogen atom or a group of formula X ¹ -Ra, wherein X ¹ is a single bond or an alkylene group (C ¹ -C ⁶ ) and Ra is a group selected from (C ¹ -C ⁶ ) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,

R ² is a group selected from alkyl ^(C1 - ^C6), alkenyl ^(C2 - ^C6), alkynyl ^(C2 - ^C6), aryl and cycloalkyl, R ³ is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by one or more groups, identical or different, independently selected from each other among halogen, nitro, cyano, trifluoromethyl, oxo, (C ¹ -C ⁶ ) alkyl, OR ⁶ , NR ⁶ R ⁷ , COR6, CO ² R ⁶ , CONHOH, CONR ⁶ R ⁷ , S (O) mR6, S (O) mNR6R7, NR ⁶ COR ⁷ , NR ⁶ SO ² R ⁷ , N (SO2R7) 2, NR ⁶ CONR ⁷ R ⁸ , C (= N-CN) NR6R7, NRsC (= N-CN) NR6R7, and tetrazolyl optionally substituted with an alkyl (C ¹ -C ⁴ ), wherein m is an integer from 0 to 2 inclusive, R 6 and R ⁷ are identical or different and independently of one another are a hydrogen atom or a group of formula X ² Rb, wherein X ² is a single bond or an alkylene group (C ¹ -C ⁶ ), Rb is a group selected from alkyl (C ¹ -C ⁶ ), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, independently selected from each other from hydroxy, ^(C1 - ^C6) alkyl, (C ¹ -C ^6), amino, mono (C ¹ -C ⁶ ), dialkylamino (C ¹ -C ⁶ ) (each alkylamino being identical or different, independently from each other), carboxy, alkoxycarbonyl (C ¹ -C ⁶ ), and benzyl, and Rs is a hydrogen atom or a alkyl group (C ¹ -C ⁶ ), or

a racemic form thereof, an isomer thereof, an N-oxide thereof or an acidic or pharmaceutically acceptable basic salt thereof.

The preparation of these compounds is described in U.S. Patent No. 6,753,340, US 20030191167, EP 1348701 and WO 2003/082839.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,849,638, US 20030119829 and WO 2002/088138. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R ¹ and R ² are independently selected from the group consisting of hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-7 carbon atoms , fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various atoms of halogen to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1, 2 heteroatoms selected from N, S and O, saturated heteroaryl 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms , alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and R ⁴ -R ⁵ , or R ¹ and R ² combine to form, together with the nitrogen atom to which they are attached, a 5-7 membered saturated ring which may contain additional 1-2 heteroatoms selected from the group consisting of in NH, NR8, S and O, or combine to form, together with the nitrogen atom to which they are attached, a saturated ring of 5-7 members which may contain 1-2 additional heteroatoms selected from the group consisting of N, S and O,

wherein said saturated or unsaturated ring can be substituted with 1-2 substituents selected from the group consisting of OH, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-7 carbon atoms, fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, halogen, haloalkyl of 1-2 carbon atoms and various halogen atoms up to the level perhalo, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, and R ⁹ -R ¹⁰ ; or

R ¹ and R ² combine to form, together with the nitrogen atom to which they are attached, an 8-10 membered bidclic saturated ring;

R ³ is selected from the group consisting of NH, S, S (= O) ² , and O;

R ⁴ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, C (= C), S (= O) ² , and C (= O) )OR;

R ⁵ is selected from hydrogen, Oh, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1 -6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms and heteroaryl of 4-11 atoms of carbon and 1-2 heteroatoms selected from N, S and O, saturated heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 atoms d carbon and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various atoms of halogen to the level of perhalo, aryl of 6-12 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-7 carbon atoms, fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and NR ⁶ R ⁷ , R6 and ^R7 are independently selected from hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms, or R6 and ^R7 combine together with the nitrogen atom to which they are attached to form a 5-7 membered unsaturated ring which may contain 1-2 additional heteroatoms selected from N, S and O or to form a 5-7 membered saturated ring which may contain 1 2 additional heteroatoms selected from NH , S and O; Rs is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, R ¹¹ -R ¹² , cycloalkyl of 3-7 carbon atoms, fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms , alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various atoms of halogen to the level of perhalo, haloalkoxy of 1-6 carbon atoms and several halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, saturated heteroaryl of 4-11 carbon atoms and 1 -2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms ono, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various atoms of halogen to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;

R ⁹ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms,

R ¹⁰ is selected from OH, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6 -12 carbon or heteroaryl atoms of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and saturated heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 atoms of carbon carbon and various halogen atoms to the level of perhalo, haloalkoxy of 1-6 carbon atoms and several atoms of halogen to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N , S and O;

R ¹¹ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms; and R ¹² is selected from cycloalkyl of 3-7 carbon atoms, fully saturated heterocycle of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and several halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and saturated heteroaryl of 4-11 carbon atoms and 1 2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 atoms of carbon, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 atoms of carbon carbon and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1 -2 heteroatoms selected from N, S and O; and pharmaceutically acceptable salts thereof.

The preparation of these compounds is described in U.S. Patent No. 6,849,638, US 20030119829 and WO 2002/088138.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 2005222138 and WO 2003/064389. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R ¹ and R ² are each independently, (1) hydrogen atom or (2) C ^1-8 alkyl, or

R ¹ and R ² can be taken together with the carbon atom to which they are bound to form Cyc1,

wherein R ¹ and R ² do not represent hydrogen atom at the same time;

Z is (1) CR ³ R ⁴ , (2) O, (3) S or (4) a bond;

R ³ and R ⁴ are each independently, (1) hydrogen atom, (2) C ^1-8 alkyl, (3) C ^1-8 alkoxy or (4) hydroxy, or R ³ and R ⁴ may be taken together with the carbon atom to which they are bound to form Cyc1 or C (O);

R ⁵ and R 6 are each independently, (1) hydrogen atom or (2) C ^1-8 alkyl, or

R ⁵ and R 6 can be taken together with the carbon atom to which they are attached to form Cyc 1;

Cyc1, which is represented by R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R 6 is, each independently, (1) C ^3-10 cycloalkyl, or (2) 3-10 membered monodilic hetero ring comprising 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, and Cyc1 can be substituted with R ¹⁰ ;

R ¹⁰ is (1) C ^1-8 alkyl, (2) C ^1-8 alkoxy, (3) hydroxy, (4) COOR ¹¹ , (5) oxo, (6) SO ² R ¹² , or (7) COR ¹³ ;

R ¹¹ is hydrogen atom or C ^1-8 alkyl;

R ¹² and R ¹³ are (1) C ^1-8 alkyl, or (2) phenyl which may be substituted with C ^1-8 alkyl;

R ⁷ and R 8 are each independently, (1) hydrogen atom, (2) C ^1-8 alkyl, (3) C ^1-8 alkoxy, (4) hydroxy, (5) cyano, (6) halogen atom , (7) COOR ¹⁴ , (8) CONR ¹⁵ R ¹⁶ , (9) Cyc2, (10) C ^2-8 alkenyl, (11) C ^2-8 alkynyl, (12) NR ⁵¹ R ⁵² , (13) nitro , (14) formyl, (15) C ^2-8 acyl, (16) C ^1-8 alkyl substituted with hydroxy, C ^1-8 alkoxy, Cyc2, NR ⁵¹ R ⁵² , or NR53-Cyc2, (17) NR ⁵⁴ COR ⁵⁵ , (18) NR ⁵⁶ SO ² R ⁵⁷ , (19) SO ² NR ⁵⁸ R ⁵⁹ , (20) C ^2-8 alkenyl substituted with COOR ¹⁴ , (21) CH = No H, (22) C ¹ alkylene ^-8 -NR ⁶⁰ - (C ^1-8 alkylene) -R ^61, (23) C ^1-8 alkylthio, (24) C ^1-8 alkyl substituted with 1-3 halogen atoms, (25) substituted C ^{1- 8} substituted with 1-3 halogen atoms, (26) C ^1-8 alkoxy substituted with Cyc2, (27) O-Cyc2, (28) OSO ² R ⁶⁵ , or (29) CH = N-ORw;

R ¹⁴ is hydrogen atom or C ^1-8 alkyl;

R ¹⁵ and R ¹⁶ are each independently hydrogen atom or C ^1-8 alkyl;

R ⁵¹ and R ⁵² , R ⁵⁸ and R ⁵⁹ are each independently, hydrogen atom or C ^1-8 alkyl;

R ⁵³ , R ⁵⁴ , R ⁵⁶ , and R ⁶⁰ are each independently, hydrogen atom or C ^1-8 alkyl;

R ⁵⁵ is hydrogen atom, C ^1-8 alkyl or C ^1-8 alkoxy; R ⁵⁷ is C ^1-8 alkyl;

R6i is NR ⁶² R ⁶³ or hydroxy;

R ⁶² and R63 are each independently, hydrogen atom or Ci-s alkyl;

R65 is Ci-s alkyl;

R ¹³⁷ is Ci-s alkyl;

(hereinafter abbreviated as ring) is Cyc2 wherein the carbonyl-binding group is carbon;

R ⁷ , Rs, and Cyc 2 represented by ring are each independently, (1) carboarillo C ^3-15 mono, bi or tricfclico (fused or spiro), or (2) hetero ring of 3-15 members mono, bi or tricfclico ( fused or spiro) comprising 1-4 heteroatoms selected from oxygen, nitrogen and sulfur;

Cyc2 can be substituted with 1-5 of R ¹⁷ or R ¹⁷ ;

R ¹⁷ is (1) C ^1-8 alkyl, (2) C ^2-8 alkenyl, (3) C ^2-8 alkynyl, (4) C ^1-8 alkoxy, (5) alkylthio C ^1-8 , (6) ) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) carboxy, (11) formyl, (12) cyano, (13) NR ¹⁸ R ¹⁹ , (14) phenyl, phenoxy or phenylthio, which can be substituted with 1-5 of R ²⁰ , (15) C ^1-8 alkyl, C ^2-8 alkenyl, C ^1-8 alkoxy or C ^1-8 alkylthio, which can be substituted with 1-5 of R ²¹ (16) OCOR ²² , (17) CONR ²³ R ²⁴ , (18) SO ² NR ²⁵ R ²⁶ (19) COOR ²⁷ , (20) COCOOR ²⁸ , (21) COR ²⁹ , (22) COCOR ³⁰ , (23) NR ³¹ COR ³² , (24) SO ² R ³³ , (25) NR ³⁴ SO ² R ³⁵ , or (26) SOR64;

R ¹⁸ and R ¹⁹ , R ³¹ and R ³⁴ are each independently, hydrogen atom or C ^1-8 alkyl;

R ²⁰ and R ²¹ are C ^1-8 alkyl, C ^1-8 alkoxy, hydroxy, halogen atom, nitro or COOR ^36;

R ²² and R64 are each independently C ^1-8 alkyl;

R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are each independently hydrogen atom, C ^1-8 alkyl or phenyl;

R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³² , R ³³ and R ³⁵ are (1) C ^1-8 alkyl, (2) C ^2-8 alkenyl, (3) C ^1-8 alkyl substituted with 1 -5 of R ³⁷ , (4) diphenylmethyl, (5) triphenylmethyl, (6) Cyc3, (7) C ^1-8 alkyl or C ^2-8 alkenyl substituted with Cyc3, (8) C ^1-8 alkyl substituted with O -Cyc3, S-Cyc3 or SO2-Cyc3;

R ³⁶ is hydrogen atom or C ^1-8 alkyl;

R ³⁷ is C ^1-8 alkoxy, C ^1-8 alkylthio, benzyloxy, halogen atom, nitro or COOR ^38;

R ³⁸ is hydrogen atom, C ^1-8 alkyl or C ^2-8 alkenyl;

Cyc3 is (1) C ^3-15 carboaryl mono, bi or tridic (fused or spiro), or (2) hetero ring of 3-15 mono, bi or tridicic (fused or spiro) members comprising 1-4 heteroatoms selected from oxygen , nitrogen and sulfur;

Cyc3 can be substituted with 1-5 of R ³⁹ ;

R ³⁹ is (1) C ^1-8 alkyl, (2) C ^2-8 alkenyl, (3) C ^2-8 alkynyl, (4) C ^1-8 alkoxy, (5) alkylthio C ^1-8 , (6) ) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (13) C ^1-8 alkyl, C ^1-8 alkoxy or C ^1-8 alkylthio substituted with 1-5 of R ⁴⁰ , (14) phenyl, phenoxy, phenylthio, phenylsulfonyl or benzoflo which can be substituted with 1-5 of R ⁴¹ , (15) OCOR ⁴² , (16) SO ² R ⁴³ , (17) NR ⁴⁴ COR ⁴⁵ , (18) SO ² NR ⁴⁶ R ⁴⁷ , (19) COOR ⁴⁸ , or (20) NR ⁴⁹ R ⁵⁰ ;

R ⁴⁰ is halogen atom;

R ⁴¹ is C ^1-8 alkyl, C ^1-8 alkoxy, halogen atom or nitro;

R ⁴² , R ⁴³ and R ⁴⁵ are C ^1-8 alkyl;

R ⁴⁴ and R ⁴⁸ are hydrogen atom or C ^1-8 alkyl;

R ⁴⁶ and R ⁴⁷ , R ⁴⁹ and R ⁵⁰ are each independently, hydrogen atom or C ^1-8 alkyl;

R ¹⁷ is (1) SH, (2) NR66CHO, (3) Cyc5, (4) C ^1-8 alkyl, C ^2-8 alkenyl or C ^2-8 alkynyl substituted with Cyc 5, (5) CO- (NH-) amino acid residue -CO) n-OH, (6) NR ⁶⁷ CONR ⁶⁸ R ⁶⁹ , (7) CONR ⁷⁰ NR ⁷¹ R ⁷² , (8) CONR ⁷³ OR ⁷⁴ , (9) CONR ⁷⁵ COR ⁷⁶ ,

(10) C (S) NR77R78, (11) CONR79C (S) COOR80, (12) NR ⁸¹ COCOOR ⁸² , (13) NR83COOR84, (14) CONR85C (S) R86, (15) OCOR87, (16) SOR88, (17) CONR ⁸⁹ R ⁹⁰ . (18) SO ² NR ⁹¹ R ⁹² , (19) COOR ⁹³ , (20) COCOOR ⁹⁴ , (21) COR ⁹⁵ , (22) COCOR ⁹⁶ , (23) NR ⁹⁷ COR ⁹⁸ , (24) SO ² R ⁹⁹ , (25) NR ¹⁰⁰ SO ² R ¹⁰¹ , or (26) NR ¹⁰² R ¹⁰³ ;

n is an integer of 1 or 2;

R ⁶⁶ , R ⁷³ , R ⁷⁵ , R ⁷⁷ , R ⁷⁹ , R ⁸¹ , R 83, R 85, R ⁹⁷ , R ¹⁰⁰ and R ¹⁰² are hydrogen atom or C ^1-8 alkyl;

R67 R68, R ⁷⁰ and R ⁷¹ are each independently hydrogen or C atom ^1-8 alkyl; R89 and R ⁹¹ are (1) hydrogen atom,

(2) C ^1-8 alkyl, (3) phenyl or (4) C ^1-8 alkyl substituted with cyano or C ^1-8 alkoxy;

R ¹⁰³ is Cyc6;

R69, R ⁷² , R ⁷⁴ , R ⁷⁶ , R ⁷⁸ , R ⁸⁰ , R ⁸² , R ⁸⁴ , R ⁸⁶ , R ⁸⁷ , R 88, R ⁹⁰ and R ⁹² are (1) hydrogen atom, (2) C ^1-8 alkyl, (3) C ^2-8 alkenyl, (4) C ^2-8 alkynyl, (5) C ^1-8 alkyl substituted with 1-5 of R ¹⁰⁴ , (6) diphenylmethyl, (7) triphenylmethyl, (8) Cyc6, (9) C ^1-8 alkyl or C ^2-8 alkenyl substituted with Cyc6, or (10) C ^1-8 alkyl substituted with O-Cyc6, S-Cyc6 or SO ² -Cyc ⁶ ; R ¹⁰⁴ is (1) C ^1-8 alkoxy, (2) C ^1-8 alkylthio, (3) benzyloxy, (4) halogen atom, (5) nitro, (6) COOR ¹⁰⁵ , (7) cyano, ( 8) NR ¹⁰⁶ R ¹⁰⁷ , (9) N ¹⁰⁸ COR ¹⁰⁹ , (10) hydroxy, (11) SH, (12) SO ³ H, (13) S (O) OH, (14) OSO ³ H, (15 C ^2-8 alkenyloxy, (16) C ^2-8 alkynyloxy, (17) COR ¹¹⁰ , (18) SO ² R ¹¹¹ , or (19) C ^1-8 alkoxy or C ^1-8 alkylthio substituted with hydroxy; R ¹⁰⁵ is an atom of hydrogen, Ci-8 alkyl or C ^2-8 alkenyl;

R ¹⁰⁶ and R ¹⁰⁷ are each independently, hydrogen atom or C ^1-8 alkyl;

R ¹⁰⁸ is hydrogen atom or C ^1-8 alkyl;

R ¹⁰⁹ and R ¹¹¹ are C ^1-8 alkyl;

R ¹¹⁰ is C ^1-8 alkyl, or halogen atom;

R ⁹³ , R ⁹⁴ , R ⁹⁵ , R ⁹⁶ , R ⁹⁸ , R ⁹⁹ and R ¹⁰¹ are (1) C ^2-8 alkynyl, (2) C ^1-8 alkyl substituted with R ¹²⁸ which may be substituted with 1-4 R ²⁹ , (3) Cyc8, (4) C ^1-8 alkyl or C ^2-8 alkenyl substituted with Cyc8, or (5) C ^1-8 alkyl substituted with O-Cyc8, S-Cyc8 or SO ² -Cyc ⁸ ; R ¹²⁸ is (1) cyano, (2) NR ¹⁰⁶ R ¹⁰⁷ , (3) NR ¹⁰⁸ COR ¹⁰⁹ , (4) hydroxy, (5) SH, (6) SO ³ H, (7) S (O) OH, (8) ³ H OSO, (9) C ^2-8 alkenyloxy, (10) C ^2-8 alkynyloxy, (11) COR ¹¹⁰ , (12) SO ² R ¹¹¹ , or (13) C ^1-8 alkoxy or alkylthio C ^1-8 substituted with hydroxy;

R ¹²⁹ has the same meaning as R ¹⁰⁴ ;

Cyc5 and Cyc6 can be substituted with 1-5 of R ¹¹² ;

R ¹¹² is (1) C ^1-8 alkyl, (2) C ^2-8 alkenyl, (3) C ^2-8 alkynyl, (4) C ^1-8 alkoxy, (5) alkylthio C ^1-8 , (6) ) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (13) C ^1-8 alkyl, C ^1-8 alkoxy or C ^1-8 alkylthio substituted with 1-5 of R ¹¹³ , (14) phenyl, phenoxy, phenylthio or benzoflo, which may be substituted with 1-5 of R ¹¹⁴ , (15) COR ¹¹⁵ , (16) SO ² R ¹¹⁶ , (17) NR ¹¹⁷ COR ¹¹⁸ , (18) SO ² NR ¹¹⁹ R ¹²⁰ , (19) COOR ¹²¹ , (20) NR ¹²² R ¹²³ , (21) COR ¹²⁴ , (22) C ⁰ NR ¹²⁵ R ¹²⁶ , (23 ) Sh, (24) C ^1-8 alkyl substituted with hydroxy or NR127-benzoflo or (25) Cyc7;

R ¹¹³ is halogen atom;

R ¹¹⁴ is C ^1-8 alkyl, C ^1-8 alkoxy, halogen atom or nitro;

R115, R1 ¹⁶ and R ¹¹⁸ are C ^1-8 alkyl;

R ¹¹⁷ , R ¹²¹ , R ¹²⁴ and R ¹²⁷ are hydrogen atom or C ^1-8 alkyl;

R 1 ¹⁹ and R ¹²⁰ , R ¹²² and R ¹²³ , R ¹²⁵ and R ¹²⁶ are each independently, hydrogen atom or C ^1-8 alkyl;

Cyc7 can be substituted with 1-5 groups selected from (1) C ^1-8 alkyl, (2) C ^1-8 alkoxy, (3) halogen atom or (4) nitro;

Cyc8 can be substituted with R ¹³⁰ , and can be further substituted with 1-4 of R ¹³¹ ;

R ¹³⁰ is (1) COR ¹²⁴ , (2) CONR ¹²⁵ R ¹²⁶ , (3) SH, (4) C ^1-8 alkyl substituted with hydroxy or NR127-benzoflo or (5) Cyc7; R ¹³¹ has the same meaning as R ¹¹² ;

Cyc5, Cyc6, Cyc7 and Cyc8 are (1) carbohydrate C ^3-15 mono, bi or tridic (fused or spiro), or (2) heteroarillo of 3 15 members mono, bi or tridclico (fused or spiro) comprising 1- 4 heteroatoms selected from 1-4 of oxygen, nitrogen or sulfur;

wherein when R ¹⁷ is Cyc5, Cyc5 is not phenyl substituted with 1-5 can selected from C ^1-8 alkyl, C ^1-8 alkoxy, hydroxy, halogen atom, nitro, COOH or COO (alkyl C ^{1- 8} );

wherein Cyc7 is not phenyl;

Cyc4 is (1) C ^5-7 monodilic carboanillo, or (2) 5-7 membered monodilic hetero ring comprising 1-2 heteroatoms selected from oxygen, nitrogen and sulfur; (abbreviated as discontinuous line a hereinafter in the present document); and (abbreviated as discontinuous line b hereinafter in the present document); are (1) a link or (2) a double bond;

R ⁹ (1) absent or (2) is hydrogen atom;

where

(1) when the discontinuous line a is a bond, the discontinuous line b is a double bond, and R ⁹ is absent, (2) when the discontinuous line is a double bond, the discontinuous line b is a bond, and R ⁹ is hydrogen atom and R6 is absent, and

(3) 2- (3,3-dimethyl-3,4-dihydro- (2H) -isoquinolin-1-ylidene) -1-phenylethan-1-one is excluded, or a pharmacologically acceptable salt thereof.

The preparation of these compounds is described in US 2005222138 and WO 2003/064389.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2003/057149. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

(1) X is selected from halogen and NR ¹ R ² ,

(2) And it is selected between NR ³ , S and O, with the proviso that Y is not S when X is Cl,

(3) Ri and R ² are independently selected from hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2 8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-7 carbon atoms, polycycloalkyl of 5-9 carbon atoms, heterocycloalkyl of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkoxy from 1-6 carbon atoms and various halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, saturated heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and R ⁴ R ⁵ , or R ¹ and R ² combine to form, together with the nitrogen atom to which they are attached, a 5-7 membered bidclic saturated ring, optionally containing 1-2 additional heteroatoms selected from the group consisting of NH, NR6, S, and O, or combine to form, together with the nitrogen atom to which they are attached, a 6-10 membered fused polydilic saturated ring, optionally containing 1-2 additional heteroatoms selected from the group consisting of NH, NR6, S and O, or combine to form, together with the nitrogen to which they are attached, a 5-7 membered bidclic ring unsaturated, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, S, and O, wherein said saturated monodic ring, saturated ring, or polydial unsaturated ring may be substituted with 1-2 substituents selected from the group consisting of OH, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-7 carbon atoms , heterocycloalkyl of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, halogen, haloalkyl of 1-2 carbon atoms and various halogen atoms up to the level of perhalo, alkoxy of 1-6 atoms of carbon carbon, haloalkoxy of 1 6 carbon atoms and various halogen atoms up to the level of perhalo, and R ⁷ R ⁸ ,

(4) R ³ is selected from hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-7 carbon atoms and heteroaryl of 4- 11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon or heteroaryl atoms of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,

(5) R ⁴ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, C (= O), S (= O) ² , and C (= O) OR,

(6) R ⁵ is selected from hydrogen, OH, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, thioxy of 1-8 carbon atoms, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1 -6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6- 12 carbon or heteroaryl atoms of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, saturated heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which can be to be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halo Octane, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-7 carbon atoms, heterocycloalkyl of 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, and NR ⁹ R ¹⁰ ,

(7) R ⁶ and R ⁷ is independently selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms,

(8) R8 is selected from OH, aryl of 6-12 carbon atoms, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various atoms of halogen to the level of perhalo, haloalkoxy of 1-6 carbon atoms and various halogen atoms to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and saturated heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and Or, which may be substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms and various halogen atoms up to the level of perhalo, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 hete roatomos selected among N, S and O;

(9) R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl from 1-8 carbon atoms, alkenyl from 2-8 carbon atoms and alkynyl of 2-8 carbon atoms, or Rg and R ¹⁰ are combined together with the nitrogen atom to which they are attached to form a 5-7 member unsaturated ring that can contain 1-2 heteroatoms additional selected from N, S and O or to form a 5-7 membered saturated ring that may contain 1-2 additional heteroatoms selected from NH, NR ¹¹ ; S and O;

(10) R ¹ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms, and pharmaceutically acceptable salts thereof.

The preparation of these compounds is described in WO 2003/057149.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 20030092721, U.S. Patent No. 7,022,849, documents w O 2002/102315 and US 2006116516. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

Substituents for the above compounds are defined as follows: R ¹ is H or alkyl;

R ² is (a) heteroaryl or heterocycle, any of which may be optionally substituted with one to three groups T1, T2, T3; or (b) aryl fused to a heteroaryl ring or heterocycle wherein the combined ring system can be optionally substituted with one to three groups T1, T2, T3;

L is (a) OR ⁴ , C (O) R 4, C (O) OR ⁴ , SR ⁴ , NR ³ R ⁴ , C (O) NR ³ R ⁴ , NR ³ SO 2 R 4b, halogen, nitro or haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocycle or cycloalkyl, any of which may be optionally substituted with one to three groups T1a, T2a and / or T3a;

Y ¹ , Y ² and Y ³ are independently (a) hydrogen, halo or -OR4a; or (b) alkyl, alkenyl or alkynyl, any of which can be optionally substituted with one to three groups T1 b, T2b and / or T3b;

R ³ and R ⁴ are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl, any of which may be optionally substituted with one to three groups T1a, T2a and / or T3a; or

R ³ and R ⁴ together with the nitrogen atom to which they are attached can be combined to form a 4- to 8-membered heterocycle ring optionally substituted with one to three T 1 a, T 2 a and / or T 3 a groups;

R 4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocycle, (heterocycle) alkyl, cycloalkyl or (cycloalkyl) alkyl, any of which may be optionally substituted with one to three T 1b groups , T2b and / or T3b;

R4b is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl, any of which may be optionally substituted with one to three T groups 1a, T2a and / or T3a; Z is N or CH;

T1-1b, T2-2b and T3-3b are each independently;

(1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl; (ii) a group (i) that is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is independently replaced by one or more of the following groups (2) to (13) of the definition of T1-1b, T2-2b and T3-3b;

(2) -OH or -OT6;

(3) -SH or -ST6;

(4) -C (O) tH, -C (O) tT6 or -O-C (O) T6, where t is 1 or 2;

(5) -SO ³ H, -S (O) tT 6 or S (O) t N (T 9) T 6;

(6) halo;

(7) cyano;

(8) nitro;

(9) -T4-NT7T8;

(10) -T4-N (T9) -T5-NT7T8;

(11) -T4-N (T10) -T5-T6;

(12) -T4-N (T10) -T5-H; Y

( ^{1 3} ) oxo;

T4 and T5 are each independently a single bond, T11S (O) tT12-, T11C (O) T12-, T11C (S) T12, T11OT12, T11ST12, T11OC (O) T12, T11C (O) OT12, T11C (= NT9a) T12 or T11C (O) C (O) T12;

T7, T8, T9, T9a and T10 are:

(1) each independently hydrogen or a group provided in the definition of T6, or

(2) T7 and T8 may together be alkylene or alkenylene, by completing a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T1-1b, T2-2b and T3-3b, or

(3) T7 or T8, together with T9, may be alkylene or alkenylene by completing a saturated or unsaturated ring of 3 to 8 members together with the nitrogen atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T1-1b, T2-2b and T3-3b, or

(4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached can be combined to form a group N = CT13Tl4 where T13 and T14 are each independently H or a group provided in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene or alkynylene.

The preparation of these compounds is described in US 20030092721, U.S. Patent No. 7,022,849, WO 2002/102315 and US 2006116516.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,838,559, U.S.

20030100571 and WO 2002/102314. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

Y

The substituents for the above compounds are defined as follows:

R ¹ is H or alkyl;

R ² is (a) heteroaryl or heterocycle, any of which may be optionally substituted with one to three groups T1, T2, T3; (b) aryl substituted with one to three groups T1, T2, T3 provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl ring or heterocycle wherein the combined ring system can be optionally substituted with one to three groups T1, T2, T3;

Y is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, (aryl) alkyl or (heteroaryl) alkyl any of which may be optionally substituted with one to three T groups 1a, T2a, T3a;

J is (a) hydrogen, halo, or OR ⁴ , or (b) alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or, cycloalkyl any of which may be optionally substituted with one to three groups T 1b, T2b, T3b ;

Z is (a) OR ⁴ , SR ⁴ , NR ³ R ⁴ , NR ³ SO ² R ^{4 a} halogen, nitro, haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocycle or cycloalkyl, any of which can be optionally substituted with one to three groups T1c, T2c, T3c; R ³ is H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl any of which may be optionally substituted independently when permitted by the Valencia with one to three groups T 1c, T2c, T3c;

R ⁴ is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl any of which can be optionally substituted independently when Valencia allows it with one to three groups T1d, T2d or T3d; or

R ³ and R ⁴ together with the nitrogen atom to which they are attached can be combined to form a 4- to ^8- membered heterocycle ring optionally substituted with one to three T ¹ c, T ² co or T 3c groups;

R ⁴ a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocycle, (heterocycle) alkyl, cycloalkyl or (cycloalkyl) alkyl any of which may be optionally substituted with one to three T1d groups , T2d or T3d; T1, T1a, T1b, T1c, T1d, T2, T2a, T2b, T2c, T2d, T3, T3a, T3b, T3c and T3d (abbreviated hereinafter as T1-1d, T2-2d and T3-3d ) are independently

(1) Hydrogen or T ⁶ , where T ⁶ is

(a) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl or ( heteroaryl) alkyl; (b) a group (a) that is itself substituted by one or more of the same or different groups (a); or (c) a group (a) or (b) which is independently replaced by one or more (preferably from 1 to 3) of the following groups (2) to (13) of the definition of T 1-1d, T2- 2d and T3-3d,

(2) OH or OT ⁶ ,

(3) SH or ST ⁶ ,

(4) C (O) tH, C (O) tT ⁶ or OC (O) T ⁶ , where t is 1 or 2;

(5) SO3H, S (O) tT ⁶ or S (O) tN (T9) T6,

( ⁶ ) halo,

(7) cyano,

( ⁸ ) nitro,

(9) T4NT7 T ⁸ ,

(10) T4N (T9) -T5NT7 T ⁸ ,

(11) T4N (T10) -T5-T6,

(12) T4N (T10) -T5H,

(13) oxo,

T4 and T5 are each independently a single bond, T11-S (O) t-T12, T11-C (O) -T12, T11-C (S) -T12, T11-O-T12, -T11S-T12 , -T11OC (O) -T12, -T11-C (O) O-T12, -T11C (= NT9a) -T12 or T11-C (O) -C (O) -T12;

T7, T ⁸ , T9, T9a and T10 are

(1) each independently hydrogen or a group provided in the definition of T ⁶ , or

(2) T7 and T ⁸ may be alkylene together or alkenylene, completing a saturated or unsaturated 3 to ⁸ members together with the carbon to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T1-1d, T2-2d and T3-3d, or

(3) T7 or T ^8, together with T9 can be alkylene or alkenylene completing a saturated or unsaturated 3 to ⁸ members together with the nitrogen atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T 1-1d, T2-2d and T3-3d, or

(4) T7 and T ⁸ or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group N = T14 CT13 where

T13 and T14 are each independently H or a group provided in the definition of T ⁶ ; Y

T11 and T12 are each independently a single bond, alkylene, alkenylene or alkynylene.

The preparation of these compounds is described in U.S. Patent No. 6,838,559, U.S.

20030100571 and WO 2002/102314.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 7,087,614, U.S.

20030162802 and WO 2002/102313. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

Substituents for the above compounds are described below.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ria is hydrogen or alkyl; R ² a is

W is S; X ¹ is alkoxy; and X ² is alkyl;

Z * is halogen, haloalkyl, oxazolyl, NR3aR4a, C (O) -N (H) -alkylene-COOH, or phenyl which is unsubstituted or substituted with heteroaryl, COtH or COtT6;

R3a is hydrogen or alkyl;

R 4a is unsubstituted or substituted alkyl, alkoxy, (heteroaryl) alkyl, unsubstituted or substituted heterocycle, (heterocycle) unsubstituted or substituted alkyl or (aryl) alkyl wherein the aryl group is substituted with one or two T 1 groups and / or T2 and / or further substituted with a group T3; or R3a and R4a together with the nitrogen atom to which they are attached combine to form an unsubstituted or substituted heterocycle ring;

R5a is an unsubstituted or substituted (heteroaryl) alkyl, or (aryl) alkyl wherein the aryl group is substituted with one or two T1 and / or T2 groups and / or further substituted with a T3 group; or R5a and R6a together with the nitrogen atom to which they are attached combine to form an unsubstituted or substituted heterocycle ring; R6a is hydrogen or alkyl; J * is hydrogen or alkyl; T1 and T2 are independently alkoxy, alkoxycarbonyl, heteroaryl, SO ³ H or sO ² R ⁸ where R 8a is alkyl, amino, alkylamino or dialkylamino; or T1 and T2 together with the aryl ring to which they are attached combine to form a bi-ring; T3 is H, alkyl, halo, haloalkyl or cyano; t is 1 or 2; and T6 is alkyl, haloalkyl, cycloalkyl, alkoxy or heteroaryl.

The preparation of these compounds is described in U.S. Patent No. 7,087,614, U.S.

20030162802 and WO 2002/102313.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 20030104974, WO 2002/088080 and WO 2002/088079. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

Y

The substituents for the above compounds are defined as follows:

Ri is H or alkyl; R ² is optionally substituted heteroaryl or 4-substituted aryl; R ³ is hydrogen or alkyl; R ⁴ is alkyl, (aryl) alkyl optionally substituted, (heteroaryl) alkyl optionally substituted, heterocycle optionally substituted, or (heterocycle) alkyl optionally substituted; or R ³ and R ⁴ together with the nitrogen atom to which they are attached can be combined to form an optionally substituted heterocycle ring; R ⁵ is optionally substituted alkyl, (aryl) alkyl or optionally substituted (heteroaryl) alkyl; and R6 is hydrogen or alkyl.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

wherein Ria is H or alkyl; R ² a is optionally substituted heteroaryl; Z is halogen, alkyl, substituted alkyl, haloalkyl or NR3aR4a; R3a is hydrogen or alkyl; R4a is optionally substituted alkyl, (heteroaryl) alkyl, optionally substituted heterocycle, (heterocycle) optionally substituted alkyl or (aryl) alkyl wherein the aryl group is substituted with one or two T1 and / or T2 groups and optionally further substituted with a group T3; or R3a and R4a together with the nitrogen atom to which they are attached can be combined to form an optionally substituted heterocycle ring; R5a is (aryl) alkyl wherein the aryl group is substituted with one or two groups T1 and T2 and optionally further substituted with a group T3; R6a is hydrogen or alkyl; R7a is hydrogen or alkyl; T1 and T2 are independently alkoxy, alkoxycarbonyl, heteroaryl or SO ² R ⁸ where R 8a is alkyl, amino, alkylamino or dialkylamino; or T1 and T2 together with the atoms to which they are attached can be combined to form a ring (for example, benzodioxole); t 3 is H, alkyl, halo, haloalkyl or cyano.

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

wherein R ¹ b is H or alkyl; R ² b is optionally substituted heteroaryl; R3b is H or alkyl; R 4b is (aryl) alkyl optionally substituted; R5b is H, alkyl or C (O) (CH ² ) vOYR ⁶ b, where Y is a bond or C (O), R6b is hydrogen or alkyl, and v is an integer from 0 to 2; J ¹ and J ² are independently optionally substituted C ^1-13 alkylene, provided that J ¹ and J ² are not both greater than C ² alkylene; X ⁴ and X ⁵ are optional substituents attached to any available carbon atom in one or both of J ¹ and J ² , independently selected from hydrogen, OR ⁷ , NR ⁸ R ⁹ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl; R7 is hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C (O) alkyl, C (O) substituted alkyl, C (O) cycloalkyl, C (O) substituted cycloalkyl, C (O) aryl, C (O) substituted aryl, C (O) O-alkyl, C (O) O-substituted alkyl, C (O) heterocycloalkyl, C (O) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl; and R8 and ^R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C (O) alkyl, C (O) substituted alkyl, C (O) cycloalkyl, C ( O) substituted cycloalkyl, C (O) aryl, C (O) substituted aryl, C (O) Oalkyl, C (O) O substituted alkyl, C (O) heterocycloalkyl, C (O) heteroaryl, S (O) ² alkyl, S (O) ² substituted alkyl, S (O) ² cycloalkyl, S (O) ² substituted cycloalkyl, S (O) ² aryl, S (O) ² substituted aryl, S (O) ² heterocycloalkyl, S (O) ² heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl, or R8 and ^R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl ring or optionally substituted heteroaryl.

In a further related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

wherein R ¹ c is H or alkyl; R ² c is optionally substituted heteroaryl; R3c is H or alkyl; R 4c is (aryl) alkyl optionally substituted; and X ⁴ and X ⁵ are optional substituents attached to any available carbon atom in one or both of Ji and J ² , independently selected from hydrogen, OR ⁷ , NR ⁸ R ⁹ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl.

The preparation of these compounds is described in US 20030104974, WO 2002/088080 and WO 2002/088079.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 20030092908 and WO 2002/087513. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ri is hydrogen or alkyl;

R ² is (a) heteroaryl or heterocycle, any of which may be optionally substituted with one to three groups T1, T2, T3; (b) aryl substituted with one to three groups T1, T2, T3 provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl ring or heterocycle wherein the combined ring system can be optionally substituted with one to three groups T1, T2, T3;

Z is NR ³ R ⁴ , NR ³ SO ² R 4a, OR ⁴ , SR ⁴ , haloalkyl or halogen;

R ³ and R ⁴ are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl any of which may be optionally substituted independently when the valence allows it with one to three groups T 1a, T2a or T3a; or

R ³ and R ⁴ can be taken together with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl ring optionally substituted independently when the valence allows with one to three T a, T 2 a or T 3 a groups;

R 4a is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl any of which may be optionally substituted independently when the valence permits with one to three groups T ia, T2a or T3a;

R3b and R4b are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocycle or (heterocycle) alkyl;

R5 is

(1) hydrogen or cyano;

(2) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl, any of which may be optionally substituted independently when permitted the valence with one to three groups T 1b, T2b or T3b; or

(3) C (O) R6, C (O) OR6, C (O) -C (O) OR or SO ² R ⁶ a;

R6 is H, alkyl, alkenyl, NR3bR4b, heterocycle, (heterocycle) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, (aryloxy) alkyl, (NR3bR4b) alkyl, heteroaryl, aryl or (aryl) alkyl, any of which it can be optionally substituted independently when the valence allows with one to three groups T 1b, T2b or T3b;

R6a is alkyl, alkenyl, NR3bR4b, heterocycle, (heterocycle) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, (aryloxy) alkyl, (NR3bR4b) alkyl, heteroaryl, aryl or (aryl) alkyl, any of which can be optionally substituted independently when Valencia allows with one to three T 1b, T2b or T3b groups;

Ji and J ² are independently optionally substituted C ^1-3 alkylene, provided that J ¹ and J ² are not both greater than C ² alkylene; Y

T1-1b, T2-2b and T3-3b are each independently

(I) hydrogen or T6, where T6 is (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl;

(ii) a group (i) that is itself substituted by one or more of the same or different groups (i); or (iii) a group (1) or (ii) that is independently replaced by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T l-lb, T2-2b and T3-3b,

(2) OH or OT6,

(3) SH or ST6,

(4) C (O) tH, C (O) tT6 or OC (O) T6, where t is 1 or 2,

(5) SO ³ H, S (O) tT6 or S (O) tN (T9) T6,

(6) halo,

(7) cyano,

(8) nitro,

(9) T4-NT7T8,

(10) T4-N (T9) -T5-NT7T8,

(I I) T4-N (T10) -T5-T6,

(12) T4-N (T10) -T5H,

( ^{1 3} ) oxo,

T4 and T5 are each independently (1) a single bond, (2) T11-S (O) t-T12, (3) T11-C (O) -T12, (4) T11-C (S) -T12 , (5) -T11-O-T12, (6) T11-S-T12, (7) T11-OC (O) -T12, (8) T11-C (O) -O-T12, (9) T11 -C (= NT9a) -T12 or (10) T11-C (O) -C (O) -T12,

T7, T8, T9, T9a and T10,

(1) are each independently hydrogen or a group provided in the definition of T6, or

(2) T7 and T8 may together be alkylene or alkenylene, by completing a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T1-1b, T2-2b and T3-3b, or

(3) T7 or T8, together with T9, may be alkylene or alkenylene by completing a saturated or unsaturated ring of 3 to 8 members together with the nitrogen atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T1-1b, T2-2b and T3-3b, or

(4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached can be combined to form a group N = CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6; Y

T11 and T12 are each independently a single bond, alkylene, alkenylene or alkynylene.

The preparation of these compounds is described in US 20030092908 and WO 2002/087513.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 20040127707 and WO 2002/085906. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ri is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,

R ² is fluorine, bromine or chlorine,

R ³ and R ⁴ are both hydrogen or together they form an additional bond,

R ⁵ is R6, CmH2m-R7, CnH ² nC (O) R ^8, CH (Rg) ^2, CpH2p-Y-Aryl1, ^R12 or ^R26, where

R6 alkyl 1-8C, cycloalkyl 3-10C, cycloalkyl 3-7C-methyl, alkenyl 3-7C, alkynyl 3-7C, phenyl-alkenyl 3-4C, polycycloalkyl 7-10C, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolinyl, quinolinyl, indanyl, indazolyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, N-methylpiperidyl, tetrahydropyranyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 1,3,4-trimethyl- 1H-pyrazolo [3,4-b] pyridin-6-yl, 3-thiophen-2-yl [1,2,4] thiadiazol-5-yl, 1,1-dioxido-tetrahydrothiophen-3-i-1, 1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4- (4-yl-but-1-oxy) benzoic acid, or a phenyl radical unsubstituted or substituted with R ⁶¹ and / or R ⁶² , where

R ⁶¹ is hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, halogen, carboxyl, hydroxycarbonylalkyl 1-4C, alkoxy 1-4C-carbonyl, hydroxyalkyl 1-4C, amino, mono- or dialkyl 1-4C-amino , alkyl 1-4C-carbonylamino, aminocarbonyl, mono- or dialkyl 1-4C-aminocarbonyl, aminosulfonyl, mono- or dialkyl 1-4C-aminosulfonyl, 4-methylphenylsulfonamido, imidazolyl; tetrazol-5-yl, 2- (1-4C-alkyl) tetrazol-5-yl or 2-benzyltetrazol-5-yl and

R ⁶² is 1-4C alkyl, 1-4C alkoxy, nitro or halogen,

R ⁷ is hydroxyl, halogen, cyano, nitro, nitroxy (O-NO ² ), carboxyl, carboxyphenyloxy, phenoxy, alkoxy 1-4C, cycloalkoxy 3-7C, cycloalkyl 3-7C-methoxy, alkyl 1-4C-carbonyl, alkyl 1-4C-carbonyloxy, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or dialkyl-1-4C-aminocarbonyl, amino, mono- or dialkyl-4-C-amino, or a piperidyl, piperazinyl radical, pyrrolidinyl or morpholinyl unsubstituted or substituted with R ⁷¹ and / or R ⁷² , wherein R ⁷¹ is hydroxyl, C 1-4 alkyl, hydroxyalkyl 1-4C or alkoxy 1-4C-carbonyl, and

R ⁷² is 1-4C alkyl, carboxyl, aminocarbonyl or 1-4C-carbonyl alkoxy,

R8 is a phenyl, naphthyl, phenanthrenyl or anthracenyl radical unsubstituted or substituted by R ⁸¹ and / or R ⁸² , wherein R ⁸¹ is hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, carboxyl, aminocarbonyl, mono- or dialkyl 1-4C-aminocarbonyl, alkyl 1-4C-carbonyloxy, alkoxy 1-4C-carbonyl, amino, mono- or dialkyl 1-4C-amino, alkyl 1-4C carbonylamino or alkoxy 1-4C which is completely or predominantly substituted by fluorine, and

R ⁸² is hydroxyl, halogen, 1-4C alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,

R ⁹ is CqH ² q-phenyl,

And it is a bond or O (oxygen),

aryl ¹ is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinolinyl, isoquinolyl, quinolyl, coumarinyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, a 2- (1-4C-alkyl) -thiazol-4-yl radical, or a phenyl radical substituted by R ¹⁰ and / or R ¹¹ , wherein

R ¹⁰ is hydroxyl, halogen, nitro, cyano, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, carboxyl, hydroxycarbonylalkyl 1-4C, alkyl 1-4C-carbonyloxy, alkoxy 1-4C-carbonyl, amino, mono or dialkyl. -4C-amino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or dialkyl-1-4C-aminocarbonyl, imidazolyl or tetrazolyl, and R ¹¹ is hydroxyl, halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy,

m is an integer from 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, q is an integer from 0 to 2,

R ¹² is a radical of formula (a)

wherein R ¹³ is S (O) 2-R 14, S (O) 2- (CH 2) r-R 15, (CH 2) s S (O) 2 R 16, C (O) R 17, C (O) - (CH ² ) R R ¹⁸ , (CH 2) s C (O) -R 19, Hetaryl 1, Arib or Arib-C 1-4 alkyl, R ¹⁴ is C 1-4 alkyl, 5-dimethylaminonaphthalin-1-yl, N (R ² o) R ²¹ , phenyl or phenyl substituted by R ²² and / or R ²³ , R ¹⁵ is N (R ² o) R ²¹ , R ¹⁶ is N (R ² o) R ²¹ ,

R ¹⁷ is 1-4C alkyl, hydroxycarbonylalkyl 1-4C, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl, 2-oxo-imidazolidin-1-yl or N (R ² or) R ²¹ , R ¹⁸ is N (R ² o) R ²¹ , R ¹⁹ is N (R ² o) R ²¹ , phenyl, phenyl substituted by R ²² and / or R ²³ , and / or R ²⁴ , R ²⁰ and R ²¹ are independently from each other hydrogen, 1-7C alkyl, 3-7C cycloalkyl, 3-7C-methyl or phenyl cycloalkyl, or R ² o and R ²¹ together and including the nitrogen atom with which they bind, form a ring of 4 -morpholinyl, 1-pyrrolidinyl ring, 1-piperidinyl ring, 1-hexahydroazepine ring or 1-piperazinyl ring of formula (b)

wherein R ²⁵ is pyrid-4-yl, pyrid4-ylmethyl, alkyl 1-4C-dimethylamino, dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl, R ²² is halogen , nitro, cyano, carboxyl, 1-4C alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-carbonyl, amino, mono- or dialkyl-4-C-amino, aminocarbonyl-1-4C-carbonylamino or mono- or dialkyl-1-alkyl. -4C-aminocarbonyl, R ²³ is halogen, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy, R ²⁴ is halogen,

Hetaryl ¹ is pyrimidin-2-yl, thieno- [2,3-d] pyrimidin-4-yl, 1-methyl-1H-pyrazolo- [3,4-d] pyrimidin-4-yl, thiazolyl, imidazolyl or furanyl , Aryl ² is pyridyl, phenyl or phenyl substituted by R ²² and / or R ²³ , Aryl 3 is pyridyl, phenyl, phenyl substituted by R ²² and / or R ²³ , 2-oxo-2 H -chromen-7-yl or 4- (1,2,3-thiadiazol-4-yl) phenyl,

r is an integer from 1 to 4, s is an integer from 1 to 4,

R ²⁶ is a radical of formula (c)

wherein R ²⁷ is C (O) R ²⁸ , (CH 2) t C (O) R 29, (CH 2) u R 30, Aryl ⁴ , Hetaryl ² , phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl, R ²⁸ hydrogen, alkyl 1-4C, OR ³¹ , furanyl, indolyl, phenyl, pyridyl, phenyl substituted by R ³⁴ and / or R ³⁵ or pyridyl substituted by R ³⁶ and / or R ³⁷ , R ²⁹ is N (R32) R33, R ³⁰ is N (R32) R33, tetrahydrofuranyl or pyridinyl, R ³¹ is C 1-4 alkyl, R ³² is hydrogen, C 1-4 alkyl, 3-7C cycloalkyl or 3-7C-cycloalkylmethyl, R ³³ is hydrogen, alkyl 1 -4C, 3-7C cycloalkyl or 3-7C-methylcycloalkyl, or

R ³² and R ³³ together and including the nitrogen atom with which they bind, form a 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-hexahydroazepinyl ring,

Aryl4 is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R ³⁴ and / or R ³⁵ , pyridyl substituted by R ³⁶ and / or R ³⁷ , R ³⁴ is halogen, nitro, C 1-4 alkyl, trifluoromethyl or C 1-4 alkoxy, R ³⁵ is halogen or C 1-4 alkyl, R ³⁶ is halogen, nitro, C 1-4 alkyl, trifluoromethyl or C 1-4 alkoxy, R ³⁷ is halogen or C 1-4 alkyl,

Hetaryl ² is indole-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-i-1,3-phenyl-1 , 2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,

t is an integer from 1 to 4, u is an integer from 1 to 4, v is an integer from 1 to 2, X is -C (O) - or -S (O) ² -, and the salts of these compounds.

The preparation of these compounds is described in US 20040127707 and WO 2002/085906.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,818,651, US 20040044212 and WO 2002/040450. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R ¹ denotes hydrogen and R ² denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R ¹ indicates hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano, and R ² indicates hydrogen, R 'and R "indicate both hydrogen or together represent a bond, and Ar represents a phenyl radical of the formulas IIa, IIb or IIc

wherein R ³ denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or dialkyl-1-4C-aminocarbonyl,

R ⁴ represents C ^1-4 alkyl, naphthalenyl, 5-dimethylaminonaphthalen-1-yl, phenylene-2-yl, 3,5-dimethylisoxazol-4-yl, 5-chloro-3-methyl-benzo [b] thiophen-2-yl, 6-chloro-imidazo [2,1b] -thiazol-5-yl, or represents a phenyl or thiophene radical which is unsubstituted or is substituted by one or more identical or different radicals selected from the group halogen, cyano, alkyl 1- 4C, trifluoromethyl, 1-4C-alkoxy which is completely or mainly substituted by fluorine, alkoxy 1-4C, alkyl 1-4C-carbonylamino, 1-4C-alkoxycarbonyl, phenylsulfonyl or isoxazolyl, or

a hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof.

The preparation of these compounds is described in U.S. Patent No. 6,818,651, US 20040044212 and WO 2002/040450.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2002/040449. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ri denotes hydrogen and R ² denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or Ri indicates hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R ² indicates hydrogen,

R 'and R "indicate both hydrogen or together represent a bond,

R ³ denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or dialkyl-1-4C-aminocarbonyl and R ⁴ indicates C (O) -X-R5, N (H) -C (O) -R6 or N (H) -C (O) -N (H) -R ² , wherein

X indicates 0 or N (H),

R ⁵ denotes hydrogen, 1-4C alkyl, 3-7C-methylcycloalkyl, 6,6-dimethylbicyclo [3,3, I] hept-2-yl, 3-7C alkynyl, alkyl 1-4C-carbonyl-alkyl 1- 4C, aminocarbonylalkyl 1-4C, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, morpholine 4-yl-et-2-yl, morpholin-4-yl-et-1-yl, 2-benzo [1,3] dioxol-4-yl-et-1-yl, chroman-4-yl, 1 -methoxycarbonyl-2-indol-3-yl-et-1-yl, 1,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-et-1-yl, 1-methoxycarbonyl-2-thiazole -2-yl-et-1-yl or 4-methylthiazol-5-yl-et-2-yl, or represents a benzyl-, phenyl-et-1-yl or 1-methoxycarbonyl-2-phenyl-et radical -2-ilo which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl,

R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-et-1-yl, 1-acetylpiperidin-4-yl, Ar 1 or Ar 2 -CH = CH-, where Ar 1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3- phenoxyphenyl, indol5-yl, 2-methylpyridin-5-yl, quinolin-6-yl 2-benzothiazol-6-yl, Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indole-3 -yl, 3-trifluoromethylphenyl, 3-methoxyphenyl or pyridin-3-yl,

R ⁷ represents alkyl 1-4C, alkenyl 3-7C, cycloalkyl 3-7C, 1-ethoxycarbonyl-2-phenyl-et-1-yl, thiophen-2-yle-1-yl or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, C 1-4 alkyl, trifluoromethyl, C 1-4 alkylthio, C 1-4 alkoxy, C 1-4 alkoxy which is completely or predominantly substituted by fluorine, C 1-4 alkylcarbonyl and phenoxy, or

a salt of it.

The preparation of these compounds is described in WO 2002/040449.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2001/098274. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

W, X, Y and Z, which may be the same or different, each represents a nitrogen atom or a C group (R5)

[wherein R ⁵ is a hydrogen atom or halogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO ² or -CN] group provided that two or more of W, X, Y and Z are C groups (R 5 );

Ri, R ² and R ³ , which may be the same or different, each is an atom or group -Li (Alki) rL ² (Ra) s where Li and L ² , which may be the same or different, are each a covalent bond or an atom or connecting group, r is zero or the whole number 1, Alki is an aliphatic or heteroaliphatic chain, s is a whole number 1, 2 or 3 and R6 is a hydrogen atom or halogen or a selected group of alkyl, -OR ⁷ [where R ⁷ is a hydrogen atom or an optionally substituted alkyl group], -SR ⁷ , NR ⁷ R ⁸ [where R ⁸ is as defined for R ⁷ and may be the same or different] , -NO ² , CN, CO ² R ⁷ , SO ³ H, S (O) R 7, SO ² R ⁷ , OCO ² R ⁷ , CONR ⁷ R ⁸ , OCONR ⁷ R ⁸ , CSNR ⁷ R ⁸ , OCR ⁷ , N (R7) COR8, N (R7) CSR8, S (O) NR7R8, SO ² NR ⁷ R ^8, N (P7) SO2R8, N (R7) CON (R8) (R9) [where R ⁹ is a hydrogen atom hydrogen or an optionally substituted alkyl group], N (R7) Cs N (R8) (R9), N (R7) SO2N (R8) (R9), C (R7) = NO (R8), cycloaliphatic, heterocycloaliphatic, aryl group or heteroaryl]; provided that one or more of Ri, R ² , or R ³ is a substituent other than a hydrogen atom;

R ⁴ represents a phenyl, 1- or 2-naphthyl, pyridyl, pyrimidinyl, pyridazinyl or optionally substituted pyrazinyl group; and the salts, solvates, hydrates and N-oxides thereof.

The preparation of these compounds is described in WO 2001/098274.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2001/074786. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R ¹ represents an aryl or heteroaryl group;

A, B, P and E, which may be the same or different, each represents a nitrogen atom or a C (R ² ) group [wherein R ² is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy group , haloalkoxy, hydroxy, -NO ² or -CN] provided that two or more of A, B, D and E are C (R ² ) groups; X represents an oxygen or sulfur atom or a group N (R3) wherein R ³ is a hydrogen atom or an alkyl group;

Q, R, S and T, which may be the same or different, each represent a nitrogen atom or a C group (R4)

[wherein R ⁴ is an atom or group -L 1 (Alki) r L ² (R 5) s wherein L ¹ and L ² , which may be the same or different, are each a covalent bond or an atom or linking group, r is zero or the whole number 1, Alkyl is an aliphatic or heteroaliphatic chain, s is an integer 1, 2 or 3 and R ⁵ is a hydrogen atom or halogen or a group selected from alkyl, ORa [where Ra is an atom of hydrogen or an optionally substituted alkyl group], SRa, NRaR7 [where R ⁷ is as defined for Ra and can be the same or different], NO ² , CN, CO ² Ra, SO ³ H, S (O) Ra , SO ² Ra, OCO ² Ra, CONRaR7, OCONRaR7, CSNR ⁷ R ⁷ , OCRa, OCORa, N (Ra) COR7, N (Ra) CSR7, S (O) NRaR7, SO2NRaR7, N (Ra) SO2R7; N (Ra) CON (R7) (R8) [where R8 is a hydrogen atom or an optionally substituted alkyl group], N (Ra) CSN (R7) (R8), N (Ra) sO2N (R7) (R8) , C (Ra) = NO (R7), cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group) provided that two or more of Q, R, S and T are C (R4) groups; and the salts, solvates, hydrates and N-oxides thereof.

The preparation of these compounds is described in WO 2001 / 07478a.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2000/08230. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

to ^two

X-Y-Z represents NR4-C = N or N = C-NR4;

Ri represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocycloalkyl;

R ² represents OR ⁸ , NR ⁸ R ⁹ , SR ¹³ , alkyl or CF ³ ;

R ³ represents halogen, alkyl, CF ³ or OR 8;

R ⁴ , which can be linked with X or Z, is a rest selected from

wherein the union is by any position in the saturated ring, provided that the joint is not in a position adjacent to V, and the saturated ring may be substituted in any position with one or more R6; A, B, D and E are the same or different and each one represents CLR ⁵ , N or NO;

V represents O, S, NR ⁷ or C (L1mRi4) (L2nRi4);

Q and W are the same or different and each represents CLnR5 or N;

T represents O, S or NR ⁷ ;

L1 and L2 are the same or different and each represents C (R) 5) 2;

m and n are the same or different and each represents 0, 1, 2, 3, 4 or 5;

the R ⁵ are the same or different and each represents H, halogen, alkyl, cycloalkyl, OR ⁸ , NR ⁸ R ⁹ , CO ² R ¹⁰ , CONR ¹¹ R ¹² , CONHOH, SO ² NR ¹¹ R ¹² , SON ¹¹ R ¹² , COR ¹³ , SO ² R ¹³ , SOR 13, SR 13, CF 3, NO 2 or CN;

R6 represents H, alkyl, cycloalkyl, OR8, NR ⁸ R ⁹ , CO ² R ¹⁰ , CONR ¹¹ R ¹² , SO ² NR ¹¹ R ¹² , SON ¹¹ R ¹² , COR ¹³ , SO ² R ¹³ , SOR ¹³ , SR ¹³ , CF 3 , CN u = O;

R ⁷ represents H or alkyl;

R8 represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocycloalkyl;

R ⁹ represents R8 or alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylsulfonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulfonyl, heteroarylalkylcarbonyl, heteroarylalkoxycarbonyl, heteroarylsulfonyl, heterocycloalkylcarbonyl, heterocycloalkoxycarbonyl or heterocycloalkylsulfonyl; or

NR ⁸ R ⁹ represents a heterodilic ring such as morpholine;

R ¹⁰ represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocycloalkyl;

R ¹¹ and R ¹² are the same or different and are each R 8, or NR ¹¹ R ¹² represents a heterodic ring such as morpholine;

R ¹³ represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocycloalkyl;

the R ¹⁴ are the same or different and each is selected from H, alkyl, cycloalkyl, OR8, NR ⁸ R ⁹ , CO ² R ¹⁰ , CONR ¹¹ R ¹² , CONHOH, SO ² NR ¹¹ R ¹² , SON ¹¹ R ¹² , COR ¹³ , SO ² R ¹³ , SOR ¹³ , SR ¹³ , CF ³ , NO ² and CN, provided that when both m and n represent 0, if one R ¹⁴ is OR8, NR ⁸ R ⁹ or SR ¹³ , the other does not is OR8, NR ⁸ R ⁹ or SR ¹³ ; and R ¹⁵ represents H, alkyl or F; or

a pharmaceutically acceptable salt thereof.

The preparation of these compounds is described in WO 2000/068230.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 20040106631, EP 1400244 and WO 2004/026818. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

m is 1, 2 or 3; Ri is methyl, chlorine, bromine or fluorine; R ² is -Q ¹ -Q ² -Q ³ -Q 4 or alkyl (Ci-Ca), said alkyl (Ci-Ca) is substituted with one to three OR ⁴ , COOR ⁴ , NR ⁴ R ⁵ , NRC (= O) R 4, C (= O) NR4R5 or SO ² NR ⁴ R ⁵ ;

R ⁴ is alkyl (Ci-Ca) substituted with one to three F, CN, S (= O) Ra, SO ³ H, SO ² Ra, SR ⁷ , C (= O) -NH-SO 2 -CH 3, C ( = O) R7, NR'C (= O) R7, NR'SO ² Ra, C (= O) NR7R8, OC (= O) NR7R8 or SO ² NR ⁷ R ⁸ ;

R ⁵ is H or alkyl (Ci-Ca) optionally substituted by one to three F, CN, S (= O) Ra, SO ³ H, SO ² Ra, SR ⁷ , C (= O) -NH-SO ² - CH ³ , C (= O) R 7, NK'C (= O) R 7, NR'SO ² Ra, C (= O) NR ⁷ R ⁸ , OC (= O) NR ⁷ R ⁸ or SO ² NR ⁷ R ⁸ ; or said alkyl (Ci-Ca) is

(1) substituted with one to three OC (= O) R4a, SR4a, S (= O) R3, C (= NRg) R4a, C (= NRg) -NR4aR5a, NR-C (= NRg) -NR4aR5a, NRCOOR4a , NR-C (= O) NR4aR5a, NR-SO2-NR4aR5a, NR-C (= NRg) -R4a or NR-SO ² -R ^3; Y

(2) optionally substituted with one or two OR4a, COOR4a, C (= O) -R4a, NR4aR5a, NRC (= O) R4a, C (= O) NR4R5a or sO2NR4aR5a;

Rg is H, CN, OH, OCH ³ , SO ² CH ³ , SO ² NH ² or alkyl (Ci-Ca); and R ³ is alkyl (Ci-Ca) optionally substituted with one to three F, CN, S (= O) Ra, SO ³ H, SO ² Ra, C (= O) -NH-SO 2 -CH 3, OR ⁷ , SR ⁷ , COOR ⁷ , C (= O) R7, OC (= O) NR7R8, NR ⁷ R ⁸ , NR'C (= O) R7, NR'SO ² Ra, C (= O) NR7R8 or SO ² NR ⁷ R ⁸ ;

R4a and R5a are the same or different and are H or alkyl (Ci-Ca) optionally substituted with one to three F, CN, S (= O) Ra, SO ³ H, SO ² Ra, C (= O) -NH- SO2-CH3, OR ⁷ , SR ⁷ , COOR ⁷ , C (= O) R7, OC (= O) NR7R8, NR ⁷ R ⁸ , NR'C (= O) R7, NR'SO ² Ra, C (= O) NR7R8 or SO ² NR ⁷ R ⁸ ;

Q1 is a single bond or alkylene (Ci-Ca); Q2 is a saturated heterocyclyl of 4 aa members comprising one or two O or N; Q3 is alkylene (Ci-Ca); Q 4 is a 4- to 8-membered heterocyclyl, aromatic or non-aromatic, comprising 1 to 4 O, S, S (= O), SO ² or N, said heterocyclyl being optionally substituted with one to three OR, NRR ', -CN or alkyl (Ci-Ca); R is H or alkyl (Ci-Ca);

Ra is alkyl (Ci-Ca) optionally substituted with one or two OR ';

R ⁷ and R 8 are the same or different and are H or alkyl (Ci-Ca) optionally substituted with one or two OR ';

Rg is H, CN, OH, OCH ³ , SO ² CH ³ , SO ² NH ² or alkyl (Ci-Ca);

R 'is H or alkyl (Ci-Ca); and R "is H or alkyl (Ci-Ca);

provided that (i) the Q2 atom bound to Q1 is a carbon atom; and (2) the Q4 atom bound to Q3 is a carbon atom;

or a racemic, isomeric, pharmaceutically acceptable derivative thereof.

The preparation of these compounds is described in US 2004010aa31, EP 1 400 244 and WO 2004 / 02a818.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Pat. Nos. 93 a.a09 and U.S. 20040249148. In one embodiment, PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ri represents aryl (Ca-Ci ⁰ ), which is optionally substituted identically or differently by radicals selected from the group consisting of halogen, formyl, carbamoflo, cyano, hydroxyl, trifluoromethyl,

a4

trifluoromethoxy, nitro, alkyl (Ci-Ca) or alkoxy (Ci-Ca), and optionally by a radical of the formula SO ² NR ⁵ R ⁶ , wherein R ⁵ and Ra independently of one another indicate hydrogen or alkyl (Ci- Ca), or NR5Ra denotes 4- to 8-membered heterocyclyl, linked by a nitrogen atom, optionally substituted identically or differently by radicals selected from the group consisting of oxo, halogen, alkyl (Ci-Ca) and acyl (Ci-). AC),

R ² represents a saturated or partially unsaturated hydrocarbon radical having from 1 to 10 carbon atoms,

R ³ represents methyl or ethyl,

A represents O, S or NR ⁷ , wherein R ⁷ denotes hydrogen or alkyl (Ci-Ca) optionally substituted by alkoxy (Ci-C3),

E represents a bond or alkanediyl (Ci-C3),

R ⁴ represents aryl (Ca-Cio) or heteroaryl of 5 to 10 members, where aryl and heteroaryl are optionally substituted identically or differently by radicals selected from the group consisting of halogen, formyl, carboxyl, carbamoflo, -SO ³ H, aminosulfonyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, nitro, alkyl (Ci-Ca), alkoxy (Ci-Ca), i, 3-dioxapropan-i, 3-diyl, alkylthio (Ci-Ca), alkylsulfinyl (Ci-Ca) ) and alkylsulfonyl (Ci-Ca), -NR ⁸ R ⁹ and heteroaryl or phenyl of 5 aa members, optionally substituted with methyl,

wherein R 8 and R ⁹ , independently of one another, denote hydrogen, alkyl (Ci-Ca) or acyl (Ci-Ca), or salt thereof.

The preparation of these compounds is described in U.S. Pat. No. a.93a.a09 and US 20040249i48.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 200a / 092a92. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

Y

where n is an integer from i to 4 and where there are stereocenters, each center can be independently R or S.

to 5

The preparation of these compounds is described in WO 2006/092692.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 2006229306 and WO 2004/065391. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

Ri and R ²

(1) independently represent:

(a) a hydrogen atom;

(b) a group selected from alkyl, alkenyl or alkynyl groups, wherein each alkyl, alkenyl and alkynyl group is optionally substituted independently by one or more substituents selected from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, hydroxycarbonyl groups , alkoxycarbonyl, mono and dialkylaminoacyl, oxo, amino and mono- and dialkylamino; or

(c) a group of formula (CH ² ) nR ⁶ , wherein n is an integer from 0 to 4 and R 6 represents a cycloalkyl or cycloalkenyl group;

(2) Ri and R ² form, together with the nitrogen atom to which they are attached, a ring of 3 to 8 members comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, said ring being saturated or unsaturated and optionally substituted by one or more substituents selected from halogen atoms, alkyl, hydroxy, alkoxy, acyl, hydroxycarbonyl, alkoxycarbonyl, alkylenedioxy, amino, mono and dialkylamino, mono and dialkylaminoacyl, nitro, cyano and trifluoromethyl groups;

R ³ is a group of formula (CH ² ) nG 'wherein n is an integer from 0 to 4 and G represents a monodilic or bi- cylic aryl or heteroaryl group comprising from zero to four heteroatoms, said group being optionally substituted by one or more substituents selected from:

(1) halogen atoms;

(2) alkyl and alkylene groups, wherein each alkyl and alkylene group is optionally substituted independently by one or more substituents selected from halogen atoms; Y

(3) phenyl, hydroxy, hydroxyalkyl, alkoxy, alkylenedioxy, aryloxy, alkylthio, amino, mono or dialkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, cyano, difluoromethoxy and trifluoromethoxy groups;

R ⁴ represents a hydrogen atom, an alkyl or aryl group.

The preparation of these compounds is described in US 2006229306 and WO 2004/065391.

Other compounds useful in the methods of the invention include imidazopyridine derivatives (WO 2001/34601), dihydropurine derivatives (WO 2000/68203), pyrrole derivatives (WO 2001/32618), benzothiopyranoimidazolone derivatives (DE 19950647 ), heterodilic compounds (WO 2002/87519), guanine derivatives (Bioorg, Med. Chem. Lett., 11: 1081-1083, 2001) and benzothienothiadiazine derivatives (Eur. J. Med. Chem. 36: 333, 2001). ).

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2008/130619. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

X is SO or SO ² ,

R1 is H or alkyl,

R2 is alkyl or halogen.

In specific embodiments, R1 is Me. In other specific embodiments R1 is F. In certain embodiments R2 is t-Bu. In specific embodiments, R1 is methyl. In more specific embodiments, the compounds are selected from:

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

where

R1 is alkyl,

R2 is aryl or heteroaryl,

R3 is alkyl, aryl, cycloalkyl or alkylaryl.

In specific embodiments, R1 is methyl. In certain embodiments R2 is furanyl or thiophenyl. In other specific embodiments, R2 is phenyl or substituted benzyl. In preferred embodiments, R3 is isobutyl. In more specific embodiments, the compounds are selected from:

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

where

R1 is nitrile or alkylcarboxylate,

R2 is alkyl, aryl or heteroaryl.

In specific embodiments, R1 is nitrile or methylcarboxylate. In certain embodiments, R 2 is a five-membered heteroaryl. In more specific embodiments, R2 is furanyl or thienyl. In other embodiments, R2 is a six-member aryl. In more specific embodiments, R2 is substituted phenyl.

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

where

R1 is alkyl, alkenyl or alkylcarboxylic acid,

R2 is halogen.

In certain embodiments R1 is butyl. In other embodiments R1 is terminal alkenyl. In more specific embodiments R1 is allyl or vinyl. In other embodiments, R 1 is C ^1-4 alkyl. In specific embodiments R1 is methylcarboxylic acid. In certain embodiments R2 is Cl or Br. In more specific embodiments, the compounds are selected from:

In other related embodiments, the PDE7 inhibitors useful in the methods of the invention have the formula:

where

R1 is CO or alkylalcohol, R2 is alkyl, R3 is alkoxy, and the stereo sites C4 and C9 are independently (R) or (S).

In certain embodiments R1 is carbonyl or 2-methylpropan-1-ol. In specific embodiments R2 is methyl. In certain embodiments, R3 is methoxy. In more specific embodiments, the compounds are selected from:

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

where

R1 is hydrogen, hydroxyl, carbonyl or alkylalcohol,

R2 and R3 are independently selected from hydrogen, alkyl, alkylcarboxylate or carboxylic acid,

R4 is hydrogen or alkyl,

R5 is hydrogen, alkyl, hydroxyl or acetate,

R6 is hydrogen or alkoxy, and the stereo sites C4 and C9 are independently (R) or (S).

In certain embodiments R1 is 2-methylpropan-1-ol. In specific embodiments R2 is methyl. In certain embodiments, R 2 is methylcarboxylate. In specific embodiments R2 and R3 are both methyl. In other embodiments, R2 is methyl and R3 is methylcarboxylate. In specific embodiments R4 is iso-propyl. In specific embodiments, R5 is methyl. In certain embodiments, R6 is methoxy. In more specific embodiments, the compounds are selected from:

With respect to the above compounds, the terms "alkyl", "alkenyl" and the prefix "alk-" include both straight chain and branched chain groups and cyclic groups, ie cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. The cyclic groups may be monodilic or polycyclic and preferably have from 3 to 10 carbon atoms in the ring. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, adamantyl, norbornane and norbornene. This is also true for groups that include the prefix "alkyl-", such as alkylcarboxylic acid, alkyl alcohol, alkylcarboxylate, alkylaryl, and the like. Examples of alkylcarboxylic acid groups are methylcarboxylic acid, ethylcarboxylic acid, and the like. Examples of suitable alkylalcohols are methylalcohol, ethylalcohol, isopropyl alcohol, 2-methylpropan-1-ol, and the like. Examples of suitable alkylcarboxylates are methylcarboxylate, ethylcarboxylate, and the like. Examples of suitable alkylaryl groups are benzyl, phenylpropyl, and the like.

The term "aryl" as used herein includes rings or carbodilic aromatic ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes rings or aromatic ring systems containing at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, thiazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzoimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl. , isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.

The aryl and heteroaryl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy. , formyl, aryl, aryloxy, arylioxy, arylalkyloxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl , arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkysulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, arylcarbonylaminoalkyl, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarilalquilaminocarbonilamino and, in the case of heterocyclyl, oxo. If other groups are described as "substituted" or "optionally substituted", then those groups may also be substituted by one or more of the substituents listed above.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2008/142550. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

m is 0, 1 or 2,

n is 0, 1, 2 or 3,

X is O, S or N-CN,

R1 is halogen or CN,

A is a simple link, CH ² , O or S,

B is a single bond, CH ² or OCH ^2, each R2 is independently halogen, (C ^1-6) (optionally substituted by 1 to 3 fluorine atoms), OH, (C ^1-6) or CN,

R3 is selected from the following groups (i) to (x):

R is H or (C ^1-6) (optionally substituted by 1 to 3 fluorine atoms), R 'is alkyl (C ^1-6) (optionally substituted by 1 to 3 fluorine atoms), or a pharmaceutically acceptable salt , solvate, polymorph or profarmaco thereof.

With respect to the above compounds, the term "alkyl" denotes a monovalent, straight or branched, saturated hydrocarbon chain containing from 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, fer-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl and 2,2-dimethylbutyl. Preferred alkyl groups are in particular methyl and ethyl, especially methyl.

Where indicated, the alkyl groups may be substituted by 1 to 3 fluorine atoms. The substitution can be in any position in the alkyl chain. Preferably, said fluorinated alkyl groups have from 1 to 4 carbon atoms, more preferably from 1 to 2 carbon atoms. Especially preferred are mono, di and trifluoromethyl groups (especially trifluoromethyl) and mono, di and trifluoroethyl groups (especially 2,2,2-trifluoroethyl).

The term "alkoxy" means "alkyl-O-", wherein "alkyl" is as defined above, in its broadest aspect or a preferred aspect. Preferred alkoxy groups are groups, particularly methoxy and ethoxy. The term "alkylthio" means "alkyl-S-", wherein "alkyl" is as defined above, in its broadest aspect or a preferred aspect. Preferred alkylthio groups are (C ^1-4 ) alkylthio groups, particularly methylthio and ethylthio. The term "halogen" indicates fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro and chloro.

Preferably, m is 0 or 1, more preferably 1.

Preferably, n is 0 or 1, more preferably 0.

Preferably, X is O or N-CN, more preferably O.

Preferably, R1 is F or Cl, more preferably Cl.

Preferably, A is a single bond or O, more preferably O.

When group B is OCH ² , the oxygen atom is linked with the benzene ring and the methylene group with the group R 3.

Preferably, B is a single bond.

Preferably, R2 is F or Cl, more preferably F.

Preferably, R3 is a group (i), (ii), (iii), (iv), (v) or (vi), more preferably a group (i) or (ii) and especially a group (ii).

In one embodiment, the group -B-R3 is present in the 2-position of the phenyl ring (the position of group A being position 1). In other embodiments, the group -B-R3 is present in the position 3. In further embodiments, the group -B-R3 is present in the position 4.

PDE7 inhibitors useful in the methods of the invention include those in which each variable in the above formula is selected from the appropriate and / or preferred groups for each variable. Even more preferred PDE7 inhibitors useful in the methods of the invention include those in which each variable in the above formula is selected from most preferred or most preferred groups for each variable.

In a related embodiment, the following PDE7 inhibitors are useful in the methods of the invention:

5 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl)] - 2-fluorobenzoic acid,

3- (8'-chloro-2-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-ylbenzoic acid,

5 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -4'-yl)] - 2-fluorobenzoic acid,

8-chloro-5 [4-fluoro-3- (2H-tetrazol-5-yl) phenyl] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2 '(3'H) -one,

acid [3- (8'-chloro-2-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) phenoxy] acetic,

2 - {(8'-chloro-2'-oxo-2,3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxy} -3-fluorobenzoic acid, 2 - {(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclopentane-1,4'-quinazolin] -5'-oxy] -3-fluorobenzoic acid, acid 3-chloro-2 - {(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxy} benzoic acid , 3-chloro-2 - {(8'-fluoro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxy] }benzoic,

8'-chloro-5 '- [2-fluoro-6- (2H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-chloro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -one,

8'-chloro-5 '- [2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -one,

8'-Chloro-5 '- [2-fluoro-6- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenoxy] -1'H-spiro [cyclohexane-1] , 4'-quinazolin] -2 '(3'H) -one,

8'-chloro-5 '- [2-fluoro-6- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) phenoxy] -1'H-spiro [cyclohexane] -1,4'-quinazolin] -2 '(3'H) -one,

2 - [(8'-doro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoNn] -5'-N) oxy] -3-fluoro- N- (methylsulfonyl) benzamide,

N- {2 - [(8'-doro-2'-oxo-2'3'-dihydro-1'H-spiro [ddohexane-1,4'-quinazoNn] -5'-N) oxy] -3- fluorofeml} -1,1,1-trifluoromethanesulfonamide,

acid {2 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxy] -3- fluorophenyl} acetic, acid {2 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxy ] phenoxy) acetic,

acid {4 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin-5'-yl) oxy] phenoxy} acetic,

methyl 2 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxy] -3-fluorobenzoate ,

and pharmaceutically acceptable salts, solvates or prodrugs thereof.

In another related embodiment, the following PDE7 inhibitors are useful in the methods of the invention:

8'-Chloro-5 '- [2-fluoro-6- (2H-tetrazol-5-yl) phenoxy] -1'H-spirocyclohexane-1,4'-quinazolin] -2' (3'H) -one ,

8'-chloro-5 '- [4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-chloro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -one,

8'-chloro-5 '- [2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -one,

and pharmaceutically acceptable salts, solvates or prodrugs thereof.

The following compounds are preferred:

8'-chloro-5 '- [2-fluoro-6- (2H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazolin] -2' (3'H) -ona,

8'-chloro-5 '- [2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazolin] -2' (3'H) -one,

and pharmaceutically acceptable salts, solvates or prodrugs thereof.

The preparation of these compounds is described in WO 2008/142550.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 7498334, US 2005/0059686 and WO 2003/055882. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

X is phenyl or Het, each of which is unsubstituted or monosubstituted or polysubstituted by R1 and / or R2, R1 and R2 are each, independently of one another, A, OH, OA, SA, SOA, SO2A, SO2NH2 , SO2NHA, s 02AA ', CN, NO ² , NH2,

NHA, NAA ', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or Hal, R 'and R2 together are alternatively -OCH2O- or -OCH2CH2O-, R3 is A, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA ', CN, NO2, NH2, NHA, NHB, NAA', NHCOA, NHCOOA, NHCOB, NHCOOB, COOH, COOA, COOB, CONH2, CONHA, CONHB, CONAA 'or Hal, R4 is a linear or branched alkyl or alkenyl having up to 10 carbon atoms, which may be substituted by 1 to 5 atoms of F and / or Cl and / or in which one or more CH2 groups may be replaced by O, S, SO , SO2, NH, NA, NHCO, NACO, Nh Co O or NACOO, or cycloalkyl or cycloalkenyl having from 3 to 7 carbon atoms, in which one or two CH2 groups may be replaced by O, S, SO, SO2, SO2NH, SO2NA, NH, NHA, NHCONH, NACONH, NACONA, NHCO, NACO, NHCOO or NACOO, R5 is OH, OA, SA, SOA , SO2A, SO2NH2, SO2NHA, SO2AA ', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA 'or Hal, R6 is H, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA ', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA 'or Hal, A and A' are each, independently of each other, linear or branched alkyl or alkenyl having up to 10 carbon atoms, which may be substituted by 1 to 5 atoms of F and / or Cl and / or in which one or more CH2 groups may be replaced by O, S, SO , So 2, NH, NR7, NHCO, NR7CO, NHCOO or NR7COO. A and A 'together are alternatively alkylene having from 3 to 7 carbon atoms, in which one or two CH2 groups may be replaced by CHR7, CHR7R8, O, S, SO, SO2, NH, NR7, NHCO, NR7CO , NHCOO or NR7COO. B is phenyl or Het, each of which is unsubstituted or monosubstituted or polysubstituted by R 1 and / or R 2, Het is a 5- or 6-membered aromatic heterocyclic ring having 1-3 N, O and / or S atoms that they are unsubstituted or mono-substituted, disubstituted or trisubstituted by A ", Hal or CF3, R7 and R8 are each, independently of one another, linear or branched alkyl or alkenyl having up to 5 carbon atoms, which may be substituted by 1 at 5 atoms of F and / or Cl and / or in which one or more CH2 groups may be replaced by O, S, SO, SO2 or NH, A "is alkyl having from 1 to 6 carbon atoms, and Hal is F, Cl, Br or I, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention include compounds of the above formula wherein R5 is OH and may also be in the form of their tautomers of the formula:

With respect to the above compounds, PDE7 inhibitors useful in methods include optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds. The term solvates of the compounds is understood as adductions of inert solvent molecules on the compounds that are formed due to their mutual attraction force. Solvates are, for example, monohydrates, dihydrates or alcoholates.

With respect to the above compounds, it is understood that the expression "pharmaceutically usable derivatives" means, for example, the salts of the above compounds and the so-called prodrug compounds. It is understood that the expression derived from prodrugs means, for example, the above compounds that have been modified, for example, with alkyl or acyl groups, sugars or oligopeptides and that are rapidly cleaved in the body and thus release the active compounds. These also include biodegradable polymer derivatives of the above compounds, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).

With respect to the above compounds, the meanings of all the radicals that appear more than once are in each case independent of each other.

A and A 'are preferably alkyl, further preferably alkyl which is substituted by from 1 to 5 fluorine and / or chlorine atoms, furthermore preferably alkenyl.

In the above formulas, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms , and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl or fer-butyl, but also npentyl, neopentyl, isopentyl or n-hexyl. Particular preference is given to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl.

A "is preferably alkyl having 1,2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or fer-butyl, but also n -pentyl, neopentyl, isopentyl or n-hexyl Particular preference is given to methyl, ethyl, propyl, isopropyl or butyl.

Cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropyl or cyclobutyl, further preferably cyclopentyl or cyclohexyl, also also cycloheptyl; Particular preference is given to the cyclopentyl.

The alkenyl is preferably vinyl, allyl, 2- or 3-butenyl, isobutenyl or sec-butenyl; Preference is further given to 4-pentenyl, isopentenyl or 5-hexenyl.

The alkylene is preferably unbranched and is preferably methylene or ethylene, furthermore preferably propylene or butylene.

Hal is preferably F, Cl or Br, in addition also I.

The radicals R1 and R2 can be identical or different and are preferably in the 2 or 4 position of the phenyl ring. They are, for example, independently of one another, A or Hal, or together they are methylenedioxy.

However, they are preferably each methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, but also fluoro-, difluoro- or trifluoro-methoxy, or 1-fluoro-, 2-fluoro-, 1,2- difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy, furthermore fluorine or chlorine.

R1 is particularly preferably fluorine, chlorine, methyl, ethyl or propyl.

R 2 is particularly preferably fluorine, chlorine, methyl, ethyl or propyl.

X is preferably a phenyl radical which is monosubstituted by R 1 or is unsubstituted Het.

X is particularly preferably 2-chlorophenyl, 2-fluorophenyl, 4-methyl-phenyl, 3-chlorophenyl or 4-chlorophenyl. Het is preferably, for example, 2- or 3-unsubstituted furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 2-, 3 - or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazole-1-, -4- or -5-yl, 1,2,4-triazole-1 -, -3- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- o -5-yl, 1,3,4-thiadiazole -2- or -5-yl, 1,2,4-thiadiazol-3- o -5-yl, or 1,2,3-thia-diazol-4- or -5-yl.

R3 is preferably, for example, COOA "or COOH.

R 4 is preferably, for example, unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by 1-5 atoms of F or Cl, preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl or fer-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Particular preference is given to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl.

R5 is preferably Cl or OH.

R6 is preferably H.

With respect to the above compounds, at least one of said radicals has one of the preferred meanings indicated above.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds, wherein X is a phenyl radical that is monosubstituted by R1 or is unsubstituted Het; R1 is A or Hal; R3 is COOA "or COOH; R4 is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by 1-5 atoms of F or Cl; R5 is Cl or OH ; and R6 is H;

In other related embodiments, the PDE7 inhibitors useful in the methods of the invention include the following compounds, wherein X is a phenyl radical that is monosubstituted by R1 or is unsubstituted Het, R1 is A or Hal, R3 is COOA. or COOH, R4 is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by 1-5 atoms of F or Cl, R5 is Cl or OH, R6 is H , Het is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl, A and A "are each, independently of one another, unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by 1-5 F or Cl atoms, Hal is F, Cl or Br, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

The preparation of the above compounds and also the starting materials for their preparation have been described in the literature (for example in the usual works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart), to be precise, under reaction conditions that are known and suitable for such reactions. It is also possible to make use of variants which are known per se, but are not mentioned here in greater detail.

In another related embodiment, PDE7 inhibitors useful in the methods of the invention include:

5-isopropyl-4-oxo-7-p-tolyl-4,7-dihydro-3H-pyrrolo [2,3-d] -pyrimidine-6-carboxylic acid ethyl ester, 5-methyl-4-oxo-7- (3-chlorophenyl) -7,7-dihydro-3H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid ethyl ester, 5-methyl-4-oxo-7- (2- chlorophenyl) -4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid ethyl ester, 5-methyl-4-oxo-7- (2-fluorophenyl) -4,7-dihydro-3H -pyrrolo [2,3-d] pyrimidine-6-carboxylic acid ethyl ester, 5-propyl-4-oxo-7- (2-chlorophenyl) -4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidine Ethyl-6-carboxylate, ethyl 5-methyl-4-oxo-7- (4-chlorophenyl) -4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidine-6-carboxylate, 5-methyl 4-Oxo-7-p-tolyl-4,7-dihydro-3H-pyrrolo [2,3-d] -pyrimidine-6-carboxylic acid ethyl ester, 5-methyl-4-oxo-7- (2-chlorophenyl) ) -4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methyl, 5-methyl-4-oxo-7-phenyl-4,7-dihydro-3H-pyrrolo [2, 3-d] -pyrimidine-6-carboxylic acid methyl, 5-methyl-4-oxo-7- (2-thienyl) -4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid methyl , and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

The preparation of the above compounds is described in US 7498334 and WO 2003/055882.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6884800 and WO 01/36425. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R1 and R2, independently of one another, each indicate A1, OA1, SA1 or Hal, A1 denotes H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, A denotes alkyl having 1-10 carbon atoms, Hal indicates F, Cl, Br or I, and x indicates O, S, SO or SO2, and their physiologically acceptable salts and / or solvates.

With respect to the above compounds, A denotes alkyl having 1-10 carbon atoms and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and preferably indicates methyl, ethyl or propyl , also preferably isopropyl, butyl, isobutyl, sec-butyl or fer-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. In these radicals, 1-7 atoms of H can also be replaced by F and / or Cl. A therefore also indicates, for example, trifluoromethyl or pentafluoroethyl. The cycloalkyl has 3-9 carbon atoms and preferably denotes, for example, cyclopentyl or cyclohexyl. The alkenyl has 2-10 carbon atoms, is linear or branched and preferably indicates vinyl, propenyl or butenyl. The alkylenecycloalkyl has 4-10 carbon atoms and indicates, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl. R1 and R2 preferably indicate, in each case independently of one another, H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, cyclopentyl or cyclohexyl.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds, wherein

X is S;

X is S, R1 is H;

X is S, R1 is F or Cl;

X is S, R2 is H;

X is S, R2 is F or Cl;

X is S, R1 is H, R2 is F or Cl;

X is S, R1 is F or Cl, R2 is H;

X is S; A1 is H or A, A is alkyl having 1, 2, 3 or 4 carbon atoms;

X is S, R1 and R2, independently of each other, indicate either A1 or Hal, A1 is H or A, A is alkyl having 1, 2, 3 or 4 carbon atoms, Hal is F or Cl;

and their physiologically acceptable salts and solvates.

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds:

10-Chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2,1-kl] phenothiazine, 4-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2,1kl] phenothiazine, 10-methoxy-3-imidazol-1-yl-2,3-dihydro-1H- pyrido [3,2,1-kl] phenothiazine, 10-propoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2,1-kl] phenothiazine, 10-methylthio-3- imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2,1-kl] phenothiazine, 10-fluoro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido [3, 2,1-kl] phenothiazine, 4,10-dichloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2,1-kl] phenothiazine, 10-trifluoromethyl-3-imidazole- 1-yl-2,3-dihydro-1H-pyrido [3,2,1-kl] phenothiazine, 4-cyclopentoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2, 1-kl] phenothiazine, 10-chloro-3-imidazol-1-yl-2,3-dihydro-1H-7-oxa-11b-azabenzo [de] -anthracene and 7,7-dioxide of 10-chloro-3 -imidazol-1-yl-2,3-dihydro-1H-pyrido [3,2,1-kl] phenothiazine.

The preparation of these compounds is described in U.S. Patent No. 6,884,800 and WO 01/36425.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,531,498 and WO 01/32175. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents of the above compounds are defined as follows:

R1, R2, R3, R4 are each, independently of each other, Hal, OA1, SA1, A, H, COOA1, CN or CONA1A2, R5 is COOA1, CN or CONA1A2,

A1, A2 are each, independently of one another, H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, A is alkyl having from 1 to 10 C atoms,

Hal is F, Cl, Br or I,

and their physiologically acceptable salts and / or solvates.

With respect to the above compounds, A is alkyl having 1-10 C atoms and having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms and is preferably methyl, ethyl or propyl , also preferably isopropyl, butyl, isobutyl, secbutyl or fer-butyl, but is also n-pentyl, neopentyl, isopentyl or hexyl. It is also possible that the 1-7 atoms of H in the radicals are replaced by F and / or Cl. A is therefore also, for example, trifluoromethyl or pentafluoroethyl.

The cycloalkyl has 3-9 C atoms and is preferably, for example, cyclopentyl or cyclohexyl. The alkenyl has 2 10 C atoms, is linear or branched and is preferably vinyl, propenyl or butenyl.

The alkylenecycloalkyl has 4-10 C atoms and is, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention include the compounds wherein R1 is H;

R1 and R2 are H;

R1 is H and R2 is F or Cl;

R1, R2 are each, independently of one another, H or Hal;

R1, R2 are each, independently of one another, H or Hal, A1, A2 are each, independently of one another, H or A;

A1, A2 are each, independently of one another, H or A;

R1, R2 are each, independently of each other, H or Hal, A1, A2 are each, independently of one another, H or A, A is alkyl having 1, 2, 3 or 4 C atoms, Hal is F or Cl.

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention include the compounds:

5- [2- (2-Fluoro-4-hydroxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (2,4-Difluorophenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (3-Methylthiophenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (2,4-Dimethoxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- (2-Amino-2-phenylvinyl) -4-methylaminocarbonyl-3-phenylisoxazole,

5- (2-Phenylaminovinyl) -4-methoxycarbonyl-3-phenylisoxazole,

5- [2- (4-Carboxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (4-Carboxyphenylamino) vinyl] -4-methoxycarbonyl-3-phenylisoxazole,

5- [2- (5-Chloro-2-hydroxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (3,4-Dimethylphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (4-Chlorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- (2-Phenylaminovinyl) -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (4-Methoxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (4-Carboxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (2-Fluoro-4-hydroxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (4-Fluorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (3,5-Dichlorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- [2- (3-Chlorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,

5- (2-Phenylaminovinyl) -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (4-Chlorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- (2-Phenylaminovinyl) -4-methoxycarbonyl-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (4-Chlorophenylamino) vinyl] -4-methoxycarbonyl-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (4-Carboxyphenylamino) vinyl] -4-methoxycarbonyl-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (2,4-Difluorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (2,4-Dichlorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (4-Carboxyphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (3,5-Dichlorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (4-Methoxyphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (2,4-Dimethoxyphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (2-Phenylphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- [2- (4-Methylphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,

5- (2-Phenylaminovinyl) -4-cyano-3- (2-chloro-6-fluorophenyl) isoxazole,

5- [2- (4-Carboxyphenylamino) vinyl] -4-cyano-3- (2-chloro-6-fluorophenyl) isoxazole,

5- [2- (4-Chlorophenylamino) vinyl] -4-cyano-3- (2-chloro-6-fluorophenyl) isoxazole,

5- [2- (3-Methoxyphenylamino) vinyl] -4-cyano-3- (2-chloro-6-fluorophenyl) isoxazole,

5- [2- (4-Chlorophenylamino) vinyl] -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isoxazole,

5- (2-Phenylaminovinyl) -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isoxazole,

5- [2- (2,4-Dichlorophenylamino) vinyl] -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isoxazole,

5- (2-Phenylaminovinyl) -4-cyano-3-phenylisoxazole,

5- [2- (3-Trifluoromethoxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (4-Methoxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (4-Methoxyphenylamino) vinyl] -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isoxazole,

5- [2- (3-Methylthiophenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (2,4-Difluorophenylamino) vinyl] -4-cyano-3-phenylisoxazole,

5- [2- (2-Fluoro-4-hydroxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole.

The preparation of these compounds is described in U.S. Patent No. 6531498 and WO 01/32175.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 7491742 and WO 2001/29049. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents of the above compounds are defined as follows:

R1 is H, A, benzyl, indan-5-yl, 1,2,3,4-tetrahydronaphthalen-5-yl, dibenzothien-2-yl or phenyl which is unsubstituted or mono, di or trisubstituted by Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or COOA, R2 is H or A, X is O or S, Hal is F, Cl, Br or I, A is alkyl with 1 to 6 C atoms, and the salts and / or physiologically acceptable solvates thereof.

With respect to the above compounds, A is alkyl with 1-6 C atoms and has 1, 2, 3, 4, 5 or 6 C atoms and is preferably methyl, ethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl or fer-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. A is also cycloalkyl such as, for example, cyclohexyl. Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy. Hal is preferably F or Cl. A-CO-NH is preferably acetamido.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the following compounds:

1-Phenyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Benzyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Cyclohexyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Cyclopentyl- [1] benzopyrano [3,4-d] imidazole-4- (lH) -one, 1-Butyl- [l] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Isopropyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Propyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Ethyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1-Methyl- [1] benzopyran [3,4-d] imidazole-4- (1H) -one, [1] Benzopyrano [3,4-d] imidazole-4- (1H) -one, 2-Methyl- [1] benzopyran [3,4-d] imidazole-4- (1H) -one, 1-phenyl- [1] benzothiopyrano [3,4-d] imidazole-4- (1H) -one, 1-Benzyl- [1] benzothiopyrano [3,4-d] imidazole4- (1H) -one, 1-Cyclohexyl- [1] benzothiopyrano [3,4-d] imidazole-4- (1H) -one, 1-Cyclopentyl- [1 ] benzothiopyrano [3,4-d] imidazole-4- (1H) -one, 1-Butyl- [1] benzothiopyrano [3,4-d] imidazole-4- (1H) -one, 1-Isopropyl- [1 ] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-Propyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-Ethyl- [1 ] benzothiopyrano [3,4-d] imidazole4- (1H) -one, 1-Me til- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, [1] Benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 2-Methyl- [1] ] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2-chlorophenyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- ( 4-Methylphenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) -phenyl) -one, 1- (4-fluorophenyl) - [1] benzopyrano [3,4-d] imidazole 4- (1H) -one, 1- (2,4-Dimethyl-phenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (3-chlorophenyl- [1] benzo] -pirano [3,4-d] imidazol-4- (1H) -one, 1- (2,4-Dichlorophenyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1 - (2,5-Dichlorophenyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (4-Acetamido-phenyl) - [1] benzopyran [3,4-d] imidazole-4- (1H) -one, 1- (2-Fluorophenyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (3-Fluorophenyl- [1] benzopyran [ 3,4-d] imidazole-4- (1H) -one, 1- (2-Benzyloxy-phenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- ( 2,6-Dimethyl-phenyl) - [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (Indan-5-yl) - [1] benzopyran [3,4-d] ] imidazole-4- (1H) -one, 1- (2-methoxy-phenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1 H) -one, 1- (2,3-Dimethyl-phenyl) - [1] benzopyrano [3,4-d] imidazole- (1H) -4-one, 1- (2,3-Dichlorophenyl- [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (3-chloro-4-methyl-phenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) phenyl) -one, 1- (2,5-dimethyl-phenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (4-chlorophenyl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (1,2,3,4-tetrahydronaphthalen-5-yl) - [1] -benzopyrano [3,4-d] imidazole4- (1-H) -one, 1- (Dibenzothien-2-yl) - [1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (3-methoxy-phenyl) - [ 1] benzo-pyrano [3,4-d] imidazole-4- (1H) -one, 1- (4-Carboxy-2-methyl-phenyl) - [1] benzopyrano [3,4-d] imidazole-4 - (1H) -one, and their physiologically acceptable salts and / or solvates thereof.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,737,436 and WO 01/32618. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R1 and R2, independently of one another, each indicate H, A, OA, SA or Hal,

R3 indicates H or A,

R4 indicates A or NH2,

R5 indicates H, NH2, NHA or NA2,

A denotes alkyl having from 1 to 10 carbon atoms, alkenyl, cycloalkyl or alkylenecycloalkyl,

Hal indicates F, Cl, Br or I,

and their physiologically acceptable salts and / or solvates.

With respect to the above compounds, A denotes alkyl having 1-10 carbon atoms and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and preferably indicates methyl, ethyl or propyl , also preferably isopropyl, butyl, isobutyl, sec-butyl or fer-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. In these radicals, 1-7 atoms of H can also be replaced by F and / or Cl. A therefore also indicates, for example, trifluoromethyl or pentafluoroethyl.

A also denotes cycloalkyl having 3-8 carbon atoms and preferably indicates, for example, cyclopentyl or cyclohexyl.

A also denotes alkenyl. The alkenyl has 2-10 carbon atoms, is linear or branched and indicates, for example, vinyl, propenyl or butenyl. A further denotes alkylenecycloalkyl. The alkylenecycloalkyl has 4-10 carbon atoms and preferably denotes, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl. R1 and R2 preferably indicate each, independently of one another, H, methyl, ethyl, propyl, butyl, isopropyl, fer-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, S-methyl, S-ethyl, F or Cl .

R3 preferably denotes H, methyl or ethyl.

R 4 preferably denotes methyl, ethyl, propyl, butyl or NH 2.

R5 preferably denotes H, amino, methylamino, ethylamino, dimethylamino or diethylamino.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention include compounds of the above formula wherein R1 and R2 are not both H and wherein one of R1 and R2 is H, the other can not be CH3, OCH3 or Cl.

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention include compounds wherein

R1, R2, R3 and R5 are H and R4 is methyl;

R1 is 4-Cl, R2 is H, R3 is ethyl, R4 is amino and R5 is H;

R1 and R2 are H, R3 is ethyl, R4 is methyl and R5 is amino;

R1 and R2 are H, R3 is ethyl, R4 is amino and R5 is H;

R1 and R2 are H, R3 is ethyl, R4 is H and R5 is amino;

R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is amino and R5 is H;

R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is methyl and R5 is amino;

R1 is 4-OCF3, R2 is H, R3 is ethyl, R4 is amino and R5 is H;

R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is amino and R5 is H;

R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is methyl and R5 is amino;

R1 is 4-OCF3, R2 is H, R3 is ethyl and R4 is amino and r5 is H.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,613,778 and WO 01/34601. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

R1 indicates CONR4R5,

R2 indicates H or A,

R4 and R5, independently of each other, indicate each H or A1,

R3 indicates Hal,

Hal indicates F, Cl, Br or I,

A denotes alkyl having 1-4 carbon atoms,

A1 denotes alkyl having 1-10 carbon atoms,

X denotes alkylene having 1-4 carbon atoms, in which an ethylene group can also be replaced by a double or triple bond,

and their physiologically acceptable salts and / or solvates.

With respect to the above compounds, A denotes alkyl having 1-4 carbon atoms and having 1,2, 3 or 4 carbon atoms and preferably denotes methyl, ethyl or propyl, further preferably isopropyl, butyl, isobutyl, secbutyl or ferric. -butyl. 1-7 atoms of H in the radicals can also be replaced by F and / or Cl. A therefore also indicates, for example, trifluoromethyl or pentafluoroethyl.

A1 denotes alkyl having 1-10 carbon atoms and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and preferably denotes methyl, ethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl or fer- tbutyl, but also n-pentyl, neopentyl, isopentyl or hexyl. 1-7 atoms of H in the radicals can also be replaced by F and / or Cl. A1 therefore also indicates, for example, trifluoromethyl or pentafluoroethyl.

X denotes alkylene having 1-4 carbon atoms, preferably methylene, ethylene, propylene or butylene, in which an ethylene group can also be replaced by a double or triple bond. X therefore also indicates, for example, -CH2-CH = CH-H2- or -CE-C-.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds:

2- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) -N, N-dimethylacetamide

2- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) acetamide,

2- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) propionamide,

2- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) butyramide,

2- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) -N-hexylacetamide,

2- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) -N-octylacetamide,

4- (3-Butyl-7-chloro-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) but-2-enoic acid dimethylamide.

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds, wherein

R3 is Cl;

R3 is Cl and X is alkylene having 1-4 carbon atoms;

R3 is Cl, X is alkylene having 1, 2, 3 or 4 carbon atoms, and A1 is alkyl having 1, 2, 3 or 4 carbon atoms.

The preparation of these compounds is described in U.S. Patent No. 6,613,778 and WO 01/34601.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in WO 2008/113881 and ES P 200700762. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

A is a 5-, 6- or 7-membered carbocycle or fused heterocycle and may be saturated or unsaturated; the discontinuous lines represent, independently, a single or double bond; X and Y are independently selected from the group consisting of alkyl, hydrogen, = O, = S, -N (alkyl), -N (aryl), aryl, O-alkyl, O-aryl, S-alkyl and aryl-S ; and R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, cycloalkyl, (Z) n-aryl, heteroaryl, -OR3; -C (O) OR 3, - (Z) n-C (O) OR 3 and -S (O), or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.

Exception: when A is unsubstituted benzene, X = O, Y = S, when A is unsubstituted benzene, X = O, Y = O, when A is unsubstituted benzene, X = O, Y = S-Me, when A is unsubstituted thiophene, X = O, Y = S, and when A is benzothiophene without replace, X = O, Y = S.

In related embodiments, the above compounds constitute a useful pharmaceutical composition that includes a therapeutically effective amount of the above compounds, or mixtures thereof, a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof together with a carrier, adjuvant or pharmaceutically acceptable vehicle, for IV administration to a patient.

In other related embodiments, the PDE7 inhibitors useful in the methods of the present invention include the following compound: 4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, and derivatives thereof selected from the following group:

6-Bromo-2,3,4-tetrahydroquinazoline, 6-Bromo- (2,6-difluorophenyl) -4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 6 Bromo- (2,3, 4-trifluorophenyl) -4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 6-Bromo- (2-bromophenyl) -4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline , 3- (2,6-Difluorophenyl) -8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 3- (2,3,4-T-trifluorophenyl) -8-methyl- 4-Oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline and 3- (2-Bromophenyl) -8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline.

In a further related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the following compound: 2-methylthio-4-oxo-3,4-dihydroquinazoline and derivatives thereof selected from the following group:

6-Bromo- (2,6-difluorophenyl) -2-methylthio-4-oxo-3,4-dihydroquinazoline, 6-Bromo- (2,3,4-trifluorophenyl) -2-methylthio-4-oxo-3, 4-dihydroquinazoline, 6-Bromo- (2-bromophenyl) -2-methylthio-4-oxo-3,4-dihydroquinazoline, 3-phenyl-8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline, 3- (2,6-Difluorophenyl) -8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline, 3- (2,3,4-trifluorophenyl) -8-methyl-2-methylthio-4- oxo-3,4-dihydroquinazoline and 3- (2-Bromophenyl) -8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline.

In another related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the following compound: 2,4-dithioxo-1,2,3,4-tetrahydroquinazoline, and derivatives thereof selected from the following group:

3-Phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline, 3- (2,6-Difluorophenyl) -2,4-dithioxo-1,2,3,4-tetrahydroquinazoline and 3- (2 , 3,4-Trifluorophenyl) -2,4-dithioxo-1,2,3,4-tetrahydroquinazoline.

In another related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the following compound: (2-methylthio-4-thioxo-3,4-dihydroquinazoline) and derivatives thereof selected from the following group:

3-Phenyl-2-methylthio-4-thioxo-3,4-dihydroquinazoline, 3- (2,6-Difluorophenyl) -2-methylthio-4-thioxo-3,4-dihydroquinazoline, 3- (2,3,4 -Trifluorophenyl) -2-methylthio-4-thioxo-3,4-dihydroquinazoline and 3- (2-Bromophenyl) -2-methylthio-4-thioxo-3,4-dihydroquinazoline.

The preparation of the above compounds is described in WO 2008/113881.

In a related embodiment, PDE7 inhibitors useful in the methods of the invention are described in ES P 200700762. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 7,214,676 and U.S.

2007/0049558. In one embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds:

Spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 6'-methoxy-spiro [cyclohexane-1-4' - (3 ', 4'- dihydro) quinazolin] -2 '(1'H) -one, Spiro [cycloheptane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 7 'Metoxiespiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 6'-Phenylspiro [ddoheptane-1-4 '- (3', 4 '-dihydro) quinazolin] -2'(1'H) -one, 8'-methoxystypiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one , 8'-Chlorospiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 7'-Chlorospiro [ddohexane-1-4' - (3 ' , 4'-dihydro) quinazolin] -2 '(1'H) -one, 5'-dorospiro [cyclohexane-1-4' - (3,4-dihydro) quinazolin] -2 '(1'H) -one , 8'-methylspiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 6'-dorospiro [ddohexane-1-4' - (3 ' , 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-bromoespiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-fluorospiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 6'-methylspiro [ddohexane-1-4' - ( 3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 5 ', 8'-didorospiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 6'7'-didorospiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1H) -one, 5', 6'-didorospiro [ ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 6'-phenylspiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-iodoespiro [ddohexane-1-4' - ( 3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Bromoespiro [ddobutane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1' H) -one, 8'-Bromoespiro [cycloheptane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Bromo-4-methylspiro [cyclohexane- 1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Bromoespiro [biddo [3,2,1] odano-2-4' - (3 ' , 4'-dihydro) quinazolin] -2 '(1'H) -one, 6', 8'-dichlorospiro [cidohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1H ) -one, 8'-chloro-6'-iodoespiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-doro-6' -methoxyspiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro-6'-phenylspiro [cidoheptane-1-4' - ( 3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-chloro-6'-phenylspiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] - 2 '(1'H) -one, 8'-doro-6'-methylspiro [ddohexane-1-4' - (3,4-dihydro) quinazolin] -2 '(1'H) -one, 8'- chloro-6 '- (3-pyridyl) spiro [cidohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-doro-6 '- (4-pmdil) spiro [ddohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 6'- (4-carboxyphenyl) -8'-chlorospiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 6' - (3-carboxyphenyl) -8 '-dorospiro (ddohexane-1-4' - (3 ', 4'-dihydro) -quinazolin] -2'(1'H) -one, 8'-doro-6 '- (1H-indol-5il) spiro [ddohexane-1-4 '- (3', 4'-dihydro) qumazolin] -2 '(1'H) -one, 8'-chloro-6' - (2-pyridyl) spiro [cidohexane-1-4] '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro-6' - (3-dimethylamino-prop-1-ynyl) spiro [cyclohexane-1-4] '- (3', 4'-dihydro) -quinazolin] -2 '(1'H) -one, 8'-chloro-6' - (3-methylaminoprop-1-ynyl) spiro [cyclohexane-1-4 ' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-doro-6 '- [4- (4-methyl-piperazine-1-carbonyl) phenyl] spiro [cyclohexane] -1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro-6' - [4- (3-N-dimethylaminopropylcarboxamide) phenyl] -spiro - [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro-6' - [4- (2-N-dimethylaminoethylcarboxamide) phenyl ] -spiro- [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) - ona, 8'-doro-6 '- [3- (3-N-dimethylamino-propylcarboxamide) phenyl] -spiro- [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2' ( 1'H) -one, 8'-chloro-6 '- [3- (4-methyl-piperazine-1-carbonyl) -phenyl] spiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro-6' - [3- (2-N-dimethylamino-ethylcarboxamide) phenyl] spiro- [cyclohexane-1-4 '- (3', 4 '-dihydro) quinazolin] -2'(1'H) -one, 8'-Chlorospiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -thione , 8'-Chloro-2'-danoiminoespiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazoline, 8'-Chloro-6 '- [4- (4-pyriiriidin-2-N-piperazm -1-carboml) feml] spiro [-ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-doro-6' - [4- (4- (2-morpholm-4-N-ethyl) -piperazm-1-carboml) -feml] spiro [-ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1 'H) -one, 8'-doro-6' - [4- (4- (2-morpholm-4-N-2-oxo-etN) -piperazine-1-carbonyl) -feml] spiro [-dodohexane- 1-4 '- (3', 4'-dihydro) qumazolin] -2 '(1'H) -one, 8'-doro-6' - [4- (4- (2-hydroxy-ethoxy) -ethyl) ) -piperazm-1-carboml) -phenyl] spiro [-cyclohexane-1-4 '- (3', 4'-dihydro) quina zolin] -2 '(1'H) -one, Spiro [ddohexane-1-9' - (8 ', 9'-dihydro) -pyrazolo [4', 3'-f] quinazolin] -7 '(6' H) -one, 8'-Chloro-5'-methoxyspiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 5', 8'- difluorospiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5'-methylspiro [ddohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-6 '- (morpholin-4-yl) methylspiro [cyclohexane-1-4' - (3 ', 4' dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5'-hydroxyespiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2' (1 ' H) -one, 8'-Chloro-5'-hydroxy-6'-iodo-spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one , 8'-Chloro-6'-iodo-5'-methoxy-spiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'- Chloro-6'-dane-5'-methoxy-spiro [ddohexane-1-4 '- (3', 4'-dihydro) qumazolm] -2 '(1'H) -one, 8'-Chloro-5' - [2- (4-morpholino) ethoxy] spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5'- [2-dimethylaminoethoxy] spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - (2-amin oethoxy) -spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - [2- (methylairino) ethoxy] -spiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - [2- (2-aminoethoxy) ethoxy] spiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - [3-dimethylaminopropoxy] spiro [ddohexane-1-] 4 '- (3', 4'-dihydro) qumazolm] -2 '(1'H) -one, 8'-Chloro-5'-ethoxycarbonylmethoxy spiro [cyclohexane-1-4' - (3 ', 4'-dihydro ) quinazolin] -2 '(1'H) -one, 5'-carboxymethoxy-8'-chloro-spiro [cidohexane1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 5'-carboxypropoxy-8'-chlorospiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-doro-5'- (3-sulfopropoxy) -spiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - [2- (tetrahydro -piran-2-yloxy) -ethoxy] -spiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5'- (2-hydroxy-ethoxy) -spiro [ddohexane-1-4 '- (3', 4'-dihydro) qumazolm] -2 '(1'H) -one, 8'-Chloro-5' - (5- ethoxycarbonyl-furan-2-ylmethoxy) -spiro [cyclohexane-1-4 '- (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-5 '- (5-carboxy-furan-2-ylmethoxy) -spiro [cyclohexane-1-4' - ( 3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-5'-cyanomethoxy-spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] - 2 '(1'H) -one, 8'-Chloro-5' - (1H-tetrazol-5-ylmethoxy) -spiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - (5-hydroxy- [1,2,4] oxadiazol-3-ylmethoxy) -spiro [cyclohexane-1-4 '- (3', 4 '-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-6'-iodo-5 '- [2-dimethylaminoethoxy] spiro [cyclohexane-1-4' - (3 ', 4' dihydro) quinazolin] -2 '(1'H) -one, 6' - (4-carboxyphenyl) -8'-chloro-5'-methoxyspiro [cyclohexane-1-4 '- (3', 4'-dihydro ) quinazolin] -2 '(1'H) -one, 6' - (3-carboxyphenyl) -8'-chloro-5'-methoxyspiro [cyclohexane-1-4 '- (3', 4'-dihydro) quinazolin ] -2 '(1'H) -one, 8'-chloro-6' - [2- (4-methyl-piperazine-1-carbonyl) phenyl] spiro [cyclohexane-1-4 '- (3', 4 '-dihydro) quinazolin] -2'(1'H) -one, 8'-chloro-6 '- [2-methyl-4- (4-methyl-piperazine-1-carbonyl) phenyl] spiro [cyclohexane-1 -4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-clo ro-6 '- [4- (piperazin-1-carbonyl) -phenyl] spiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8 '-doro-6' - [4-carbamoyl-phenyl] -spiro [ddohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro -6 '- [4 - ((1-methyl-piperidin-4-yl) -piperazine-1-carbonyl) phenyl] spiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-chloro-5'-methoxy-6- [4- (4-methyl-piperazine-1-carbonyl) phenyl] spiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Trifluoromethylpiro [cyclohexane-1-4 '(3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-6'-cyanomethylpiro [cyclohexane-1-4'- (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-5 '- (3-dimethylamino-2-hydroxypropoxy) -spiro [cidohexane-1-4' - ( 3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-5 '- (3-methylamino-2-hydroxy-propoxy) -spiro [cyclohexane-1-4'- (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-5 '- [2- (ethoxycarbonylmethyl-amino) -ethoxy] -spiro [cyclohexane-1-4' - (3 ', 4'-dihydro) quinazolin] -2'(1'H) -one, 8'-Chloro-5 '- [2- (carboxymethyl-amino) -ethoxy] -spiro [cyclohexane-1] hydrochloride -4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - (2-methanesulfonylamino-2-oxo-ethoxy) -spiro [cyclohexane- 1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one, 8'-Chloro-5' - (2 - [(5-methyl-isoxazol-3-ylmethyl) -amino] ethoxy) -spiro [cidohexane-1-4 '- (3', 4'-dihydro) quinazolin] -2 '(1'H) -one.

The preparation of these compounds is described in U.S. Patent No. 7,087,614, US documents 2007/0049558 and WO 2002/074754.

In another embodiment, the PDE7 inhibitors and dual PDE4 / 7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 7,087,614, US 2003/0162802 and WO 2002/102313. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

PDE7 inhibitors useful in the methods of the invention include enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts, prodrugs and solvates of the compounds of the above formula.

The substituents for the above compounds are defined as follows:

R1 is H or alkyl;

R2 is (a) heteroaryl or heterocycle, any of which may be optionally substituted with one to three groups T1, T2, T3; (b) aryl substituted with one to three groups T1, T2, T3 provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl ring or heterocycle wherein the combined ring system can be optionally substituted with one to three groups T1, T2, T3;

Z is (a) -OR4, -C (O) R4, -C (O) OR4, -SR4, -NR3R4, -C (O) NR3R4, -NR3SO2R4c, halogen, nitro, haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocycle or cycloalkyl, any of which may be optionally substituted with one to three groups T1a, T2a T3a;

J is (a) hydrogen, halo, -OR4a, or (b) alkyl, alkenyl or alkynyl, any of which may be optionally substituted with one to three T 1b, T2b or T3b groups;

L is (a) hydrogen, -OR4b, -C (O) R4b, -C (O) OR4b, -SR4b, -NR5R6, -C (O) NR5R6, -NR5SO2R4d, halogen, haloalkyl, nitro, or (b) alkyl, aryl, heteroaryl, heterocycle or cycloalkyl, any of which may be optionally substituted with one to three T1c, T2c or T3c groups;

R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyl or (heterocycle) alkyl any of which may be optionally substituted with one to three groups T 1a, T2a or T3a;

or R3 and R4 together with the nitrogen atom to which they are attached can be combined to form a 4- to 8-membered heterocycle ring optionally substituted with one to three T1a, T2a or T3a groups;

R 4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocyl, (heterocycle) alkyl, cycloalkyl or (cycloalkyl) alkyl any of which may be optionally substituted with one to three T 1b groups, T2b or T3b;

R4b is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocyl, (heterocycle) alkyl, cycloalkyl or (cycloalkyl) alkyl any of which may be optionally substituted with one to three T1 c groups, T2c or T3c;

R4c and R4d are independently alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyl or (heterocycle) alkyl any of which may be optionally substituted with one to three groups T1a, T2a or T3a;

R5 and R6 are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclyl or (heterocycle) alkyl any of which may be optionally substituted independently when allow valence with one to three groups T 1c, T2c or T3c;

or R5 and R6 together with the nitrogen atom to which they are attached can be combined to form a 4- to 8-membered heterocycle ring optionally substituted with one to three T1c, T2c or T3c groups;

T 1-1c T2-2c and T3-3c are each independently (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl , cycloalkenyl, (cycloalkenyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl or (heteroaryl) alkyl; (ii) a group (i) that is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) that is independently replaced by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1c, T2-2c and T3-3c (2) -OH or -OT6, (3) -SH or -ST6, (4) -C (O) tH, - C (O) tT6 or -OC (O) T6, where t is 1 or 2; (5) -SO3H, -S (O) T6 or S (O) tN (T9) T6, (6) halo, (7) cyano, (8) nitro, (9) -T4-NT7T8, (10) - T4-N (T9) -T5-NT7T8, (11) -T4-N (T10) -T5-T6, (12) -t 4-N (T10) -t 5-H, (13) oxo, T4 and T5 are each independently (1) a single bond, (2) -T11-S (O) t-T12-, (3) -T11-C (O) -T12-, (4) -T11-C (S) ) -T12-, (5) -T11-O-T12-, (6) -T11-S-T12-, (7) -T11-OC (O) -T12-, (8) -T11-C (O ) -O-T12-, (9) -T11-C (= NT9a) -T12- or (10) -T11-C (O) -C (O) -T12,

T7, T8, T9, T9a and T10 (1) are each independently hydrogen or a group provided in the definition of T6, or (2) T7 and T8 can be alkylene or alkenylene together, completing a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T 1-1c, T2-2c and T3-3c, or (3) T7 or T8, together with T9, it can be alkylene or alkenylene by completing a saturated or unsaturated ring of 3 to 8 members together with the nitrogen atoms to which they are attached, said ring being unsubstituted or substituted with one or more groups listed in the description of T1 -1c, T2-2c and T3-3c, or (4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached can be combined to form a group -N = CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6;

and T11 and T12 are each independently (1) a single bond, (2) alkylene, (3) alkenylene or (4) alkynylene.

In a related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the above compounds, wherein:

Z is (a) halogen, alkoxy, haloalkyl, -NR3R4, -C (O) OR4, -C (O) NR3R4; (b) aryl or heteroaryl any of which may be optionally substituted with one or more T 1a, T2a, T3a (especially cyano, optionally substituted alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH , -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6); (c) optionally substituted alkyl (especially substituted with one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5-H or -T4-N (T10) -T5-T6 );

J is (a) H, or (b) alkyl or alkenyl any of which may be optionally substituted (especially with one or more -OH, -OT6, -COtH or -COtT6);

L is (a) H; (b) halogen, alkoxy, haloalkyl, -NR5R6, -C (O) OR4b, -C (O) NR5R6; (c) aryl or heteroaryl any of which may be optionally substituted with one or more T1c, T2c, T3c (especially cyano, optionally substituted alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6); or (d) optionally substituted alkyl (especially substituted with one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5-H, or; -T4-N (T10) - T5-T6);

R1 is H or alkyl;

R2 is (a) heteroaryl (more preferably thiazolyl or oxazolyl) optionally substituted with one to three groups T1, T2, T3, preferably including H, alkyl, haloalkyl, halo, heteroaryl, cyano, C (O) tT6, OT6, - T4NT7T8; (b) aryl substituted with one to three groups T1, T2, T3 (preferably including heteroaryl (preferably, imidazolyl, oxazolyl or thiazolyl any of which may also be optionally substituted), cyano, C (O) tT6, S (O ) tN (T9) T6, haloalkyl and haloalkyl); or (c) aryl fused to a heterocycle ring (eg, 2,3-dihydro-1 H-indole linked via the aryl ring, quinolyl linked via the aryl ring (especially quinol-6-yl), quinazolinyl attached by the aryl ring (especially quinazolin-7-yl), cinolinyl linked by the aryl ring (especially cinolin-6-yl), isoquinolinyl linked by the aryl ring (especially isoquinol-6-yl) and phthalazinyl linked by the aryl ring (especially phthalazin-6-yl) wherein the combined ring system may be optionally substituted with one to three groups T1, T2, T3 (especially halo, OH, OT6, alkyl, -COtH, -COtT6 or -C (O) NT7T8);

R3 is H or optionally substituted alkyl (especially substituted with one or more -OH or -OT6);

R4 is (a) hydrogen; (b) (aryl) alkyl wherein the aryl group is optionally substituted independently with one or more groups T 1 a, T 2 a, T 3 a (especially optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT 6 , -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl); (c) (heteroaryl) alkyl wherein the heteroaryl group is optionally substituted independently with one or more groups T1a, T2a, T3a (especially optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl); (d) (heterocycle) alkyl wherein the heterocycle group is optionally substituted independently with one or more groups T1a, T2a, T3a (especially optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, - OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl); (e) alkyl optionally substituted independently with one or more T1a, T2a, T3a groups (especially -OH, -OT6, -COtH, -COtT6, -T4NTT8 or -T4-N (T10) -T5-T6); (f) heterocycle optionally substituted independently with one or more T groups 1a, T2a, T3a (especially optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocycle, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT2T8);

or R3 and R4 together with the nitrogen atom to which they are bound combine to form a 4- to 8-membered heterocycle ring (especially pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro [4.5 ] decan-8-yl) optionally substituted with one to three groups T1a, T2a, T3a (especially optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocycle, cyano, -OH, -OT6, - COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8); R5 is hydrogen or alkyl;

R6 is (a) hydrogen; (b) (aryl) alkyl wherein the aryl group is optionally substituted independently with one or more groups T1c, T2c, T3c (especially optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4-N (T10) -T5-T6, heterocycle or heteroaryl); (c) (heteroaryl) alkyl wherein the heteroaryl group is optionally substituted independently with one or more groups T1c, T2c, T3c (especially optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4-N (T10) -T5-T6, heterocycle or heteroaryl); (d) (heterocycle) alkyl wherein the heterocycle group is optionally substituted independently with one or more groups T1c, T2c, T3c (especially optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, - OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4-N (T10) -T5-T6, heterocycle or heteroaryl); (e) alkyl optionally substituted independently with one or more groups T 1c, T2c, T3c (especially -OH, -OT6, -COtH, -COtT6, -T4NT7T8 or -T4-N (T10) -T5-T6); (f) heterocycle optionally substituted independently with one or more groups T1c, T2c, T3c (especially optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocycle, cyano, -OH, -OT6, - COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8); or R5 and R6 together with the nitrogen atom to which they are attached combine to form a 4- to 8-membered heterocycle ring (especially pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro [4.5 ] decan-8-yl) optionally substituted with one to three groups T1c, T2c, T3c (especially optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocycle, cyano, -OH, -OT6, - COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8).

In another related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the above compounds, wherein:

Z is (a) halogen, alkoxy, haloalkyl, -NR3R4, -C (O) OR4, -C (O) NR3R4; (b) aryl or heteroaryl any of which can be optionally substituted with one or more T1a, T2a, T3a selected from cyano, optionally substituted alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6, where T4 is a bond or -C (O) -; T5 is -C (O) - or -C (O) O-; T6 is alkyl or haloalkyl; T7 and T8 are independently H; alkyl optionally substituted with cycloalkyl, heteroaryl, hydroxy or -NT7T8 cycloalkyl; or aryl optionally substituted with halogen; or T7 and T8 together with the nitrogen atom to which they are attached combine to form a heterocycle ring optionally substituted with (hydroxy) alkyl, COtH or COtT6, T10 is hydrogen; (c) alkyl optionally substituted with one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5-H or -T4-N (T10) -T5-T6 where T4 is -CO)-; T5 is -alkylene-O-; T6 is alkyl; T7 and T8 are independently H, alkyl, cycloalkyl, aryl, (aryl) alkyl (optionally substituted as described in the definition of R4) or heterocycle (optionally substituted as described in the definition of R3 and R4 which combine to form a heterocycle ring); and T10 is H; J is (a) H, or (b) alkyl or alkenyl any of which may be optionally substituted with one or more -OH, -OT6, -COtH or -COtT6, where T6 is alkyl;

L is (a) H; (b) halogen, alkoxy, haloalkyl, -NR5R6, -C (O) OR4b, -C (O) NR5R6; (c) aryl or heteroaryl any of which can be optionally substituted with one or more T1c, T2c, T3c selected from cyano, optionally substituted alkyl (especially substituted with COtH or COtT6), (hydroxy) alkyl, -OH, -OT6, - ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6, where T4 is a bond or -C (O) -; T5 is -C (O) - or -C (O) O-; T6 is alkyl or haloalkyl; T7 and T8 are independently H; alkyl optionally substituted by cycloalkyl, heteroaryl, hydroxy or -NT7T8; cycloalkyl; or aryl optionally substituted with halogen; or T7 and T8 together with the nitrogen atom to which they are attached combine to form a heterocycle ring optionally substituted with (hydroxy) alkyl, COtH or COtT6; T10 is hydrogen; (d) alkyl optionally substituted with one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5-H or -T4-N (T10) -T5-T6 where T4 is -CO)-; T5 is -alkylene-O-; T6 is alkyl; T7 and T8 are independently H, alkyl, cycloalkyl, aryl, (aryl) alkyl (optionally substituted as described in the definition of R4) or heterocycle (optionally substituted as described in the definition of R3 and R4 which combine to form a heterocycle ring); and T10 is H;

R1 is H or alkyl;

R2 is (a) heteroaryl (more preferably thiazolyl or oxazolyl) optionally substituted with one to three groups T1, T2, T3, preferably including H, alkyl, haloalkyl, halo, heteroaryl, cyano, C (O) tT6, OT6, - T4NT7T8; (b) aryl substituted with one to three groups T1, T2, T3 (preferably including heteroaryl (preferably, imidazolyl, oxazolyl or thiazolyl any of which may also be optionally substituted), cyano, C (O) tT6, S (O ) tN (T9) T6, haloalkyl and haloalkyl); or (c) aryl fused to a heterocycle ring (e.g., 2,3-dihydro-1 H-indole linked by the aryl ring) wherein the combined ring system can be optionally substituted with one to three groups T1, T2, T3 (especially halo, -OH, -OT6, alkyl, - COtH, -COtT6 or -C (O) NT7T8);

R3 is H or optionally substituted alkyl (especially substituted with one or more -OH or -OT6);

R4 is (a) hydrogen; (b) (aryl) alkyl wherein the aryl group is optionally substituted independently with one or more groups T1a, T2a, T3a selected from optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4N (T10) -T5-T6, heterocycle or heteroaryl) where T4 is a bond, -SO2- or -C (O) -; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl) alkyl wherein the heteroaryl group is optionally substituted independently with one or more groups T1a, T2a, T3a selected from optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, - OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl) where T4 is a bond , -SO2- or -C (O) -; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (d) (heterocycle) alkyl wherein the heterocycle group is optionally substituted independently with one or more groups T1a, T2a, T3a selected from optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl) where T4 is a bond, -SO2- or -C (O) - ; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (e) alkyl optionally substituted independently with one or more groups T1a, T2a T3a selected from -Oh, -OT6, -COtH, -COtT6, -T4NT7T8 or -T4-N (T10) -T5-T6) where T4 is a link; T5 is -C (O) -; T6 is alkyl; T7 and T8 are independently H or alkyl; and T10 is hydrogen; heterocycle optionally substituted independently with one or more groups T1a, T2a, T3a selected from optionally substituted alkyl (especially substituted with -T4NT7T8), optionally substituted aryl (especially substituted with halogen or haloalkyl), cyano, -OH, -OT6, - COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8) where T4 is a bond or -C (O) -; T5 is -C (O) -, -SO2- or -alkylene-C (O) O-; t 6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl; or T7 and T8 together with the nitrogen atom to which they are attached combine to form an optionally substituted heterocycle ring; or R3 and R4 together with the nitrogen atom to which they are bound combine to form a heterocycle ring selected from pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro [4.5] decan-8- ilo), any of which is optionally substituted independently with one to three T 1a, T2a, T3a groups selected from optionally substituted alkyl (especially substituted with -T4NT7T8), optionally substituted aryl (especially substituted with halogen or haloalkyl), cyano , -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8) where T4 is a bond or -C (OR)-; T5 is -C (O) -, -SO2- or -alkylene-C (O) O-; T6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl; or T7 and T8 together with the nitrogen atom to which they are attached combine to form an optionally substituted heterocycle ring; R5 is hydrogen or alkyl;

R6 is (a) hydrogen; (b) (aryl) alkyl wherein the aryl group is optionally substituted independently with one or more groups T1c, T2c, T3c selected from optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -TNT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl) where T4 is a bond, - SO2- or -C (O) -; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl) alkyl wherein the heteroaryl group is optionally substituted independently with one or more groups T1c, T2c, T3c selected from optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, - OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl) where T4 is a bond , -SO2- or -C (O) -; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (d) (heterocycle) alkyl wherein the heterocycle group is optionally substituted independently with one or more T ic, T2c, T3c groups selected from optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6 , -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -T4NT7T8, -T4-N (T10) -T5-T6, heterocycle or heteroaryl) where T4 is a bond, -SO2- or -C (O) -; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (e) alkyl optionally substituted independently with one or more T ic, T2c, T3c groups selected from -Oh, -OT6, -OCtH, -COtT6, -T4NT7T8 or -T4-N (T10) -T5-T6) where T4 is a link; T5 is -C (O) -; T6 is alkyl; T7 and T8 are independently H or alkyl; and T10 is hydrogen; heterocycle optionally substituted independently with one or more T ic, T2c, T3c groups selected from optionally substituted alkyl (especially substituted with -T4NT7T8), optionally substituted aryl (especially substituted with halogen or haloalkyl), cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8, where T4 is a bond or -C (O) -; T5 is -C (O) -, -SO2- or -alkylene-C (O) O-; T6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl; or T7 and T8 together with the nitrogen atom to which they are attached combine to form an optionally substituted heterocycle ring;

or R5 and R6 together with the nitrogen atom to which they are bound combine to form a heterocycle ring selected from pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro [4.5] decan-8- ilo), any of which is optionally substituted independently with one to three T ai, T2a, T3a groups selected from optionally substituted alkyl (especially substituted with -T4NT7T8), optionally substituted aryl (especially substituted with halogen or haloalkyl), cyano , -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8 where T4 is a bond or -C ( OR)-; 5 is -C (O) -, -SO2- or -alkylene-C (O) O-; t 6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl; or T7 and T8 together with the nitrogen atom to which they are attached combine to form an optionally substituted heterocycle ring.

In a further related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the following compounds:

Acid ethyl ester 2 - [[4 - [[4- (Aminosulfonyl) phenyl] methyl] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5- thiazolecarboxylic; acid ethyl ester trifluoroacetate salt 2 - [[4 - [[(3,4-dimethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico; 2 - [[4 - [[[4- (Aminosulfonyl) phenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; ethyl 4-methyl-2 - [[4 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; Ethyl acid ester 2 - [[4 - [[(4-Methoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid; Ethyl acid ester 2 - [[4 - [[(3-Methoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid; 2 - [[4 - [[(2-methoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-Methyl-2 - [[4- (1-piperazinyl) -6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester ; Ethyl acid ester 2 - [[4 - [[(2-Ethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid; Ethyl acid ester 2 - [[4 - [[(2,5-Dimethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl; Ethyl acid ester 2 - [[4 - [[(3,5-Dimethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl; Ethyl acid ester 2 - [[4 - [[(2,6-Dimethylphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl; Ethyl acid ester 2 - [[4 - [[[4- (Methoxycarbonyl) phenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl; Ethyl acid ester 2 - [[4 - [[(3-Bromophenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl) amino] -4-methyl-5-thiazolecarboxylic acid; 2 - [[4 - [(1,3-Benzodioxol-5-ylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; Ethyl ester of 4-Methyl-2 - [[4- [methyl (3-pyridinylmethyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ester; -Methyl-2 - [[4- (1-piperazinyl) -6 - [[[4- (1,2,3-thiadiazol-4-yl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -5 -thiazolecarboxylic acid ethyl ester 2 - [[4 - [[3- (Cyclopentyloxy) -4-methoxyphenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4- methyl-5-thiazolecarboxylic acid ethyl ester 4-Methyl-2 - [[4 - [(phenylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester of 4-Methyl-2 - [[4- (4-methyl-1-piperazinyl) -6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxyl acid Ethyl acid ester 2 - [[4- (4-Hydroxy-1-piperidinyl) -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl -5-thiazolecarboxylic acid ethyl ester 4-Methyl-2 - [[4 - [[2- (1-methylethoxy) ethyl] amino] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino ] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [3- (Aminocarbonyl) -1-piperidinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl; Ethyl acid ester 2 - [[4 - [[(2- (1H-imidazol-4-yl) ethyl] amino] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 4-Methyl-2 - [[4 - [[4- (methylsulfonyl) phenyl] methyl] amino] -6 - [[3- (4-morpholinyl)] ) propyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [(2-Methoxy-1-methylethyl) amino-6 - [[[4- (methylsulfonyl]] Phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 4-Methyl-2 - [[4 - [[[4- (methylsulfonyl) phenyl] methyl] amino ] -6 - [[(Tetrahydro-2-furanyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4- (2-Hydroxyethyl) - 1-piperazinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [ 2- (Aminocarbonyl) -1-pyrrolidinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 4 -Methyl-2 - [[4- [methyl (3-pyridinylmethyl) amino] -6 - [[[4- (me tilsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxamyl; Ethyl acid ester 2 - [[4- [4- (Hydroxymethyl) -1-piperidinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid; ethyl ester of acid 2 - [[4 - [[2- (diethylamino) ethyl] methylamino] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid; Ethyl acid ester 4-Methyl-2 - [[4 - [[4- (methylsulfonyl) phenyl] methyl] amino] -6 - [[3- (2-oxo-1-pyrrolidinyl) propyl] amino] -2 -pyrimidinyl] amino] -5-thiazolecarboxylic; Acid ethyl ester 2 - [[4- [3- (Hydroxymethyl) -1-piperidinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid; Ethyl acid ester 4-Methyl-2 - [[4- (4-methyl-1-piperazinyl) -6 - [[(4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -5- thiazolecarboxyl, ethylic acid ester 2 - [[4 - [[2 - [(Acetylamino) ethyl] amino] -6 - [[[(4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino ] -4-Methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4-Ethyl-1-piperazinyl) -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2 -pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4-Acetyl-1-piperazinyl) -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [[2- (Dimethylamino) ethyl] amino] - [[[4- (methylsulfonyl) phenyl]] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [3- (Aminocarbonyl) -1-piperazinyl] -6 - [[[4 - (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (3-Hydroxy-1-pyrrolidinyl) -6- [[[4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amin or] -4-methyl-5-thiazolecarboxylic acid; Ethyl acid ester 2 - [[4 - [(4-Hydroxybutyl) amino-6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid; Ethyl acid ester 2 - [[4 - [(2,3-Dihydroxypropyl) amino] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5 -thiazolecarboxyl; Ethyl acid ester 2 - [[4 - [(4-Amino-1-piperidinyl) -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5 -thiazolecarboxyl; Ethyl acid ester 2 - [[4- [4-Hydroxy-3- (hydroxymethyl) -1-piperidinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] - 4-methyl-5-thiazolecarboxylic; Ethyl acid ester 2 - [[4- (4-Dimethylamino-1-piperidinyl) -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5- thiazole carboxylic acid; 2 - [[4 - [[4- (Aminosulfonyl) phenyl] methyl] amino] -6- (methylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester; Ethyl ester of 2- [4,6-Bis- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; Ethyl acid ester 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5- carboxyl; ethyl ester of 2- [4- (3-Hydroxymethyl-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxy acid ethyl ester lico Ethyl ester of 4-Methyl-2- [4- (4-methyl-piperazin-1-yl) -6-morpholin-4-pyrimidin-2-ylamino] -thiazole-5-carboxylic acid ester; Ethyl ester of 2- [4- (4-Amino-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; acid ester of acid2- [4,6-Bis- (4-hydroxy-piperidin-1-yl) -pinmidm-2-ylamino] -4-methyl-thiazole-5-carboxylic acid; Ethyl acid ester 2- [4- (4-oxo-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidm-2-ylammo] -4-methyl-thiazole-5- carboxyl; Ethyl acid ester 2- [4- (4-methyl-4-hydroxy-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylammo] -4-methyl- thiazole-5-carboxyl; acid ethyl ester 2 - [- (4-hydroxy-piperidin-1-yl) -6- (4-dimethylmethyl-piperazin-1-yl) -pyrimidin-2-ylammo] -4-methyl-thiazole-5-carbox ^ lico; Ethyl ester of 2- [4- (4-hydroxymethylpiperidin-1-yl) -6- (4-dimethylmethyl-piperazm-1-yl) -pyrimidm-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester lico acid ethyl ester 2- [4- (3-hydroxymethyl-piperidm-1-yl) -6- (4-dimethylmethyl-piperazin-1-yl) -pinmidin-2-ylammo] -4-methyl-thiazole-5- carboxylic; acid ethyl ester 2- [4- (4-hydroxymethyl-piperidin-1-yl) -6- (4-hydroxy-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5- carboxyl; 4-Methyl-2- [4- (4-hydroxy-piperazin-1-yl) -6-morpholin-4-yl-pyrimid-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; acid 2 - [[(4 - [[[4- (Methylsulfoml) fem] methyl] amino] -6-chloro-2-pyrimidim] aminoj-4-methyl-5-thiazolecarboxylic acid ester 2 - [[4 - [[[4- (Aminosulfoml) feml] methyljamino] -6-chloro-2-pyrimidiml] aminoj-4-methyl-5-thiazolecarboxylic ester, ethyl ester, ethyl ester of acid 2 - [[4- (4- (Dimethylamino) -1-piperidiml) -6 - [[(3,4,5-trimethoxifemyl) methyl] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; [[4- [1-piperizirnl] -6-methyl-6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl ester Ethyl acid 2 - [[4- (4-Amino-1-piperidiml) -6 - [[[4- (methylsulfoml) fem] methyl] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid , ethyl ester; acid 2 - [[4- (4-hydroxy-1-piperidinyl] -6-methyl-6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-methyl-6-amino] -4-methyl- 5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4- (Hydroxymethyl) -1-piperidinyl) -6-methyl6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2- pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic ester, ethyl ester; ethyl ester of 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (3-oxo-piperazin-1-yl) acid) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid: 2 - [[4- (3- (Aminocarbonyl) -1-piperizinyl] -6-methyl-6 - [[(3, 4,5-trimethoxyphenyl) methyl] amino] -2-methyl-6-amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [1-morpholinyl] -6-methyl-6- [[(3,4,5-trimethoxifem) methyl] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ester 2 - [[4- [3-Oxo-1- piperiziml] -6 - [[(1,1-dioxy-3-oxo-1,2-benzisothiazol-2- (3H) -yl) methyl] amino] -2-pyrimidiml] amino] -4-methyl-5- thiazolecarboxylic acid ethyl ester; 2 - [[4- (3-Oxo-1-piperiziml] -6 - [[(4- (ethylsulfomlamino) phenyl) methyl] ammo] -2-pyrimidiml] amino] -4-methyl- 5-thiazolcarb oxyphilic, ethyl ester; acid 2 - [[4- (3-Oxo-1-piperizinyl] -6 - [[(4- (hydroxysulfoml) phenyl) methyl] ammo] -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic ester Ethyl, Ethyl acid ester 2- [4- (4-Hydroxy-pperidin-1-yl) -6- (4-methyl-3-oxo-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl- thiazole-5-carboxylic acid ethyl ester 2- [4- (4 (Dimethylamino) -piperizin-1-yl) -6- (4 - ((1-pyrrolidinyl) carbonylmethyl) piperazin-1-yl) - pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid: 2 - [[4- (3- (Aminocarbonyl) -1-piperazinyl] -6 - [[(3,4,5-trimethoxyphenyl) methyl] ] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4-Amino-1-piperidinyl) -6 - [[(3,4, 5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4- (Hydroxymethyl) -1-piperidinyl] -6- [4- [tetrazol-5-yl] -4-hydroxypiperidin-1-yl] 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester; 2 - [[4- (4-methyl)] acid 1-piperazinyl) -6- [N-methyl-N - [(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5- thiazolecarboxyl, ethyl ester; 2 - [[4-Hydroxy-1-piperidiml] -6 - [[(4- (hydroxysulfoml) fem) methyl] ammo] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic ester, ethyl ester ; 2 - [[4 - [[(4-Cyanophenyl) methyl] ammo] -6- (1-piperazyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester; trifluoroacetate (1: 1); acid 2 - [[4 - [[4- (Aminosulfoml) phenyl] methyl] amino] -6- (4-morpholyl) -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; acid 2 - [[4- [4-Hydroxy-1-piperidinyl] -6 - [(1-oxa-3,8-diazaspiro [4,5] decan-2,4, dion-8-yl] -2- pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [4- (2-Dimethylamino) ethyl) -piperazin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid; 2 - [[4- (4-Hydroxy-1-piperidinyl) -6- [methyl (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2 - [[4- [4-Hydroxy-3-hydroxymethylpiperidiml-1-yl] -6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl- acid 5-thiazolecarboxylic acid ester; acid 2 - [[4- (3,4-Dihydro-6,7-dihydroxy-2 (1H) -isoquinolinyl) -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl -5-thiazolecarboxyl, ethyl ester, trifluoroacetate 1: 1); acid 2 - [[4- [4 - [(Methoxyacetyl) ammo] -1-piperidyl] -6 - [[4- (methylsulfoml) phenyl] methyl] ammo] -2-pyrimidinyl] amino] -4-methyl-5 -thiazolecarboxyl, ethyl ester; 2 - [[4 - [[(3,4-Dimetoxifemyl) methyl] amino] -6- [4- (dimethylamino) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-thiazolecarboxylic acid, ethyl ester; acid 2 - [[4- [4- (Hydroxyethyl) piperidin-1-yl] -6- [4- (dimethylamino) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid , ethyl ester; acid 2 - [[4- (4- (Dimethylamino) -1-piperidinyl] -6- [methyl (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester ; acid 2 - [[4- [4- (Hydroxy) piperidin-1-yl] -6- [4- (methoxycarbonyl) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico, ethylene ester, acid 2 - [[4- [4- (Hydroxy) piperidin-1-yl] -6- [4- (methyl) -4- (hydroxy) -1-piperidinyl] -2-pyrimidinyl] amino ] -4-Methyl-5-thiazolecarboxylic ester, ethyl ester; Ethyl ester of 2- [4- (3-oxopiperazin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-acid ilamino] -4-methyl-thiazole-5-carboxyl; acid 2 - [[4 - [[(4-Cyanofeml) methyl] amino] -6- [4-dimethylammo] -1-piperidiml] -2-pyrimidiml ] ammo] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-Methyl-2 - [[4 - [[(3-nitrophenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -5-thiazolecarboxyl, ethyl ester, trifluoroacetate (1: one); 2- [[4- (4-Hydroxy-1-piperidiml) -6 - [[(3,4,5-trimethoxifemyl) methyl] amino] -2-pyrimidyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; Ethyl acid ester 2- [4- (Dimethylamino) -piperazin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-2-ylamino] -4-methylthiazole-5-carbox ^ lico; Ethyl acid ester 2- [4- (Dimethylamino) -piperidin-1-yl) -6- (3- (aminocarbonyl) -1-piperazinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carbox ^ lico; Ethyl ester of 2- [4- (2-Hydroxyethyl) -piperazin-1-yl) -6- (4-methyl-1-piperazin) -pyrimidin-2-ylammo] -4-methyl-thiazole-5-carboxylic acid ester ; acid 2 - [[4- [4- (Aminocarbonyl) -1-piperidinyl] -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico, ester etflico; 2 - [[4- (4- (Hydroxymethyl) -1-piperidinyl] -6- [N-methyl-N- (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Organic, ethyl ester; acid 2 - [[4- (4-Methylpiperazin-1-yl) -6 - [[(3,4-dimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid ester 2 - [[4- [piperazin-1-yl) -6 - [[(4-carboxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5 -thiazolecarboxyl alcohol, ethyl ester; 2 - [[4- [3-Hydroxymethipiperidin-1-yl] -6 - [[N - [(3,4,5-trimethoxyphenyl) methyl]] - N- (methyl) amino] -2-pyrimidinyl] amino acid ] -4-Methyl-5-thiazolecarboxylic acid ester; ethyl 2- (4- (4-Hydroxy-piperidin-1-yl) -6- (4-carboxypiperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2 - [[4- [Piperazin-1-yl] -6 - [[(3,4-dimethoxyphex) methyl] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; acid 2 - [[4- (4-Formyl-1-piperaziml) -6 - [[[4- (methylsulfoml) fem] methyl] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic ester Ethyl ester Ethyl acid 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (4- (hydroxy) -4- (4-dorophenyl) piperidin-1-yl) -pyrimidin-2-ylamino] -4- methylthiazole-5-carboxyl; Ethyl acid ester 4-Methyl-2 - [[4- [4-dimethylamino-1-piperidyl] -6 - [[(tetrahydro-2-furaml) methyl] ammo] -2-pmmidiml] ammo] -5-thiazolecarboxylic acid ; acid 2 - [[4- [Piperazm-1-yl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] ammo] -2-pyrimidyl] amino] -4-methyl-5-thiazolecarboxyl, Ethyl ester 2 - [[4- [4-Morpholinyl] -6- [4- [tetrazol-5-yl] -4-l ^ idroxypiperidm-1-yl] -2-pyrimidiml] amino] -4-methyl -5-thiazolecarboxyl, ethyl ester, 2 - [[4- [4-hydroxy-1-piperidiml] -6 - [[(1,1-dioxy-3-oxo-1,2-benzisothiazole-2- (3 H) -yl) methyl] amino] -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic ester, ethyl ester, ethyl ester of 2- [4- (4-hydroxypiperidin-1-yl) - 6- (4- (1-Methyl-1-hydroxyethyl) piperidm-1-yl) -pyrimidm-2-ylamino] -4-methyl-thiazole-5-carboxylic acid; 2 - [[4- [3- (Aminocarbonyl) -1-piperidiml] -6 - [[N-methyl-N- (3-pyridimethylmethyl) amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ester, acid 2 - [[ 4- [4-Hydroxymethyl-1-piperidiml] -6 - [[(4- (ethylsulfomlammo) feml) methyl] amino] -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid ethyl ester; [[4- (4-Hydroxy-1-piperidiml] -6- [4- [tetrazol-5-yl] -4-hydroxypiperidin-1-yl] 2-pyrimidiml] amino] -4-methyl-5-thiazolecarbox lico, ethyl ester; acid 2 - [[4- [4-tertiarybutyloxycarbonylammo-1-piperidiml] -6 - [[N - [(3,4,5-trimethoxifemyl) methyl]] - N- (methyl) ammo] -2-pyrimidiml] amino ] -4-Methyl-5-thiazolecarboxylic acid, ethyl ester; 2 - [[4 - [[(4-Cyanophenyl) methyl] amino] -6- (4-methyl-1-piperaziml] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxyl ester, ethyl ester , trifluoroacetate (1: 1); acid 2 - [[4- [4 - [[(2-Ethoxy-2-oxoethyl) amino] carboml] -1-piperazyl] -6- [methyl (3-pyridimlmethyl) amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester, trifluoroacetate (1: 1), ethyl ester of 2- [4- (4-Hydroxypiperidin-1-yl) -6- ( 3-hydroxypiperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester 2- [4- (4-Hydroxy-pperidin-1-yl) -6- ( 4-hydroxy-4-phenyl-1-piperidinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester 4-Methyl-2 - [[4- [4-morpholinyl] - 6 - [[(Tetrahydro-2-furanyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid 2 - [[4 - [(Tetrahydro-2-furaml) methyl] amino] -6 - [[N - [(3,4,5-trimethoxifemyl) methyl]] - N- (methyl) amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester; [[4- [4-Morpholinyl] -6 - [[(4- (hydroxysulfonyl) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4 methyl-5-thiazolecarboxylic acid ester; Ethyl ester of 2- [Bis-4,6- (4-Cyano-1-piperidinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; acid 2 - [[4- [4- (Cyclopentylaminocarbonyl) -1-piperazinyl] -6- [N-methyl-N- (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico, ester etflico; Ethyl ester of 2- [4- (2-Methoxyethyl) -piperazin-1-yl) -6- (4-methyl-1-piperazinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester ^ lico; 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (3-carboxypiperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2 - [[4- (4-Methylpiperazin-1-yl) -6- [3- (acetylammo) -1-pyrrolidyl] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ester; acid 2 - [[4- [3- (Aminocarbonyl) -1- piperaziml] -6 - [[N-methyl-N- (3-pyridimethylmethyl) amino] -2-pyrimidiml] amino] -4-methyl-5- thiazole carboxylic acid ester; acid 2 - [[4- [2-Methyl-3-oxo-piperiziml] -6- (4-metiM-piperaziml] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ester, acid 2- [[4- [3- (Aminocarboml) -1-piperaziml] -6- (4-methyl-1-piperaziml] -2-pyrimidyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [ [4- [3- (Aminocarbonyl) -1-piperidinyl] -6- (4-dimethylamino-1-piperidinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl ester, ethyl ester; [[4- [1-piperazinyl] -6 - [[N-methyl-N- (2-furylmethyl)] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester; 2 - [[4 - [[(4-Methoxycarbonylphenyl) methyl] amino]] - 6- [4-dimethyl-1-piperidinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester , trifluoroacetate (1: 1); acid 2 - [[4- [3-Oxo-1-piperazinyl] -6 - [[(4- (methylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4 methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (3-Oxo-1-piperazinyl] -6 - [[(4- (propylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2 - [[4- (3- (Aminocarbonyl) -l-piperidinyl] -6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico, ethyl ester; Ethyl ester of 2- [Bis-4,6- (4-Hydroxy-4-methyl-1-piperidinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; Ethyl acid ester 4-Methyl-2 - [[4- [4-dimethylamino-1-piperidinyl] -6 - [[(2-oxo-1-pyrrolidinyl) propyl] amino] -2-pyrimidinyl] amino] -5 -thiazolecarboxyl; 2 - [[4- (3-Oxo-1-piperazinyl] -6 - [[(4- (isopropylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid , Ethyl ester; Ethyl ester of 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (3-hydroxymethyl-1-piperidiml) -pyrimidin-2-ylammo] -4-methyl-thiazole-5- carboxylic acid ethyl ester 4-Methyl-2 - [[4- [4-hydroxy-1-piperidiml] -6 - [[(2- (4-morpholiml) ethyl] amino] -2-pyrimidiml] ammo] - 5-thiazolecarboxylic acid: 2 - [[4 - [[[4- (Ethaminosulfonyl) phenyl] methyl] amino] -6-methoxy-2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, methyl ester, trifluoroacetate (1: 1); acid 2 - [[4- [4-Morpholinyl] -6 - [(1-oxa3,8-diazaspiro [4.5] decan-2,4, dion-8-yl] -2 -pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4-Hydroxy-1-piperidinyl] -6 - [[(4- (ethylsulfomlammo) feml) methyl] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [tert-Butyloxycarboml-1-piperazyl] -6 - [[(3,4,5-trimethoxifem) methyl] amino] ] -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic ester, eti lico 2 - [[4- [3- (Aminocarbonyl) -1-piperidinyl] -6 - [[(3,4-dimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethylene ester; 2 - [[4- [4-ethoxycarbonyl-1-piperazinyl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester ; acid 2 - [[4- (3-Oxo-1-piperizinyl] -6 - [[(4- (cyclopropylsulfomlamino) fem) methyl] ammo] -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid, Ethyl ester: 2 - [[4- [4-Hydroxymethyl-1-piperidyl] -6 - [[(4- (methylsulfomlamino) feml) methyl] amino] -2-pyrimidiml] amino] -4-methyl-5- thiazolecarboxylic acid ethyl ester; Ethyl ester of 2- [4- (4-Dimethylamino-1-piperaziml) -6- (4-tertbutyloxycarbonylammo-1-piperidiml) -pyrimidin-2-ylamino] -4-methyl-thiazole-5 -carboxylic acid ethyl ester 2- [4- (4-Hydroxy-pperidin-1-yl) -6- (4-methoxymethyl-1-piperidinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5 -carboxylic acid ethyl ester 2- [4- (4-Hydroxy-pperidin-1-yl) -6- (4-hydroxyethyl-1-piperidiml) -pyrimidm-2-ylamino] -4-methyl-thiazole-5 -carboxylic acid ethyl ester 2- [4- (4-Hydroxypiperidin-1-yl) -6- (4- (hydroxy) -4- (3-trifluoromethylphenyl) piperidin-1-yl) -pyrimidin-2-ylamino ] -4-meti lthiazole-5-carboxyl; 2 - [[4- [4-morpholinyl] -6- [4- [1-methyl-1-hydroxyethyl] -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethylene ester; acid 2 - [[4- (3-Oxo-1-piperizinyl] -6 - [[3-pyridyl] oxy] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester; - [[4- [4-Methyl-1-piperazinyl] -6 - [(1,4-dioxaespiro [4.5] decan-8-yl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic Ethyl ester: 2 - [[4- [4-Morpholinyl] -6 - [[(4- (methylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid , ethyl ester; acid 2 - [[4- [3-Oxo-1-piperazinyl] -6 - [(1-oxa-3,8-diazoespiro [4.5] decan-2,4, dion-8-yl] - 2-pyrimidinyl] amino] -4-methyl-5-thiazole-carboxylic acid, ethyl ester, 2 - [[4- [4-hydroxy-1-piperidinyl] -6 - [[(4- (carboxy) phenyl) methyl] ] amino] -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester, ethyl ester of 2- [4- (4-Hydroxypiperidin-1-yl) -6- (4- (hydroxy) - 4- (4-Bromophenyl) piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid;2 - [[4- [4-Morpholinyl] -6 - [[(4-ethylsulfomlamino) -femyl) methyl] amino] -2-pmmidiml] ammo] -4-methyl] -5-thiazolecarboxylic acid ester; 2 - [[4- [3- (Aminocarbonyl) -1-piperazyl] -6 - [[(3,4-dimethoxyphex) methyl] amino] -2-pinmidiml] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; acid 2 - [[4- (4-Formyl-1-piperazinyl] -6 - [[(3- (5- (1H) tetrazolyl) phenyl) methyl] amino] -2-pyrimidyl] amino] -4-methyl- 5-thiazolecarboxylic acid ethyl ester; acid 2 - [[4- [4- (Hydroxymethyl] -1-Piperidiml] -6 - [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pinmidiml] amino] -4-Methyl-5-thiazolecarboxylic acid ethyl ester; 2 - [[4- [4-Methyl-1-piperazinyl] -6 - [[(2,5-dimethyl) fe-1-methyl] amino] -2-pyridinimide; ] ammo] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [3- (2-oxo-1-pyrrolidinyl) propyl] amino] -6- [N-methyl-N- (3 -pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [(1-Morpholiml)] - 6 - [[N-methyl-N] - (5-Tetrazolylmethyl] amino] -2-pinmidiml] amino] -4-methyl-5-thiazolecarboxylic acid ester 2 - [[4- [4-methyl-1-piperazinyl] -6- [4- [ Methylsulfonylamino] -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2 - [[4- [4-hydroxy-1-piperidiml] -6 - [[(2, 5-dimethyl) phenyl) methyl] amino] -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid ester, 4-Met acid il-2 - [[4- (4-morpholiml) -6 - [[(3,4,5-trimethoxifemyl) methyl] ammo-2-pyrimidiml] amino] -5-thiazolecarboxylic acid ester; ethyl 2- (4- (4-Hydroxy-piperidin-1-yl) -6- (3-hydroxy-1-piperidimyl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-Methyl-2 - [[4- (4-methyl-1-piperazinyl) -6- [methyl (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid, ethyl ester; acid 2 - [[4- (3-Oxo-1-piperazinyl] -6 - [[(2- (5- (1H) tetrazolyl) phenyl) methyl] amino] -2-pyrimidyl] amino] -4-methyl- 4-thiazolecarboxyl, ethyl ester; 2 - [[4 - [(2-Furanylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, Ethyl ester, trifluoroacetate (1: 1): acid 2 - [[4 - [[(3,4-Dimetoxifemyl) methyl] amino] -6- (4-morpholiml) -2-pyrimidiml] ammo] -4-methyl- 5-thiazolecarboxylic acid ethyl ester 4-Methyl-2 - [[4- [methyl (3-pyridinylmethyl) amino] -6 - [[(tetrahydro-2-furanyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxyl, ethyl ester, 2 - [[4 - [(4-hydroxy-1-piperidinyl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] -2-pyrimidinyl] amino]] 4-methyl-5-thiazolecarboxylic acid ester ethyl ester 2- [4- (4-Hydroxy-piperidin-1-yl) -6 - [(4- (hydroxy) -4- (femmethyl) piperidm- 1-yl)] - pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester 2- [4- (4-Dimethylamino-1-piperazinyl) -6 - [[2- (1 -morpholinyl) ethyl] amino] pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxyl; acid 2 - [[4- (4-h idroxy-1-piperidinyl) -6 - [[(3-pyridinylmethyl)] oxy] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester; acid 2 - [[4- [3- (Aminocarbonyl) -1-piperidinyl] -6 - [[(2,6-dimethylphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico, ethylene ester; 2 - [[4- [4-hydroxy-1-piperidinyl] -6 - [[(4- (methylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid , ethyl ester; 2 - [[4- [4-hydroxy-1-piperidinyl] -6 - [[(4- (propylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid , ethyl ester; 2 - [[4- [3- (Aminocarbonyl) -1-piperidinyl] -6- (4-methyl-1-piperazinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester ; acid 2 - [[4- (3,4-Dihydro-6,7-dimethoxy-2 (1H) -isoquinolinyl) -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4- methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4-formyl-1-piperazinyl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [[4 - [[(4-Carboxifeml) methyl] amino] -6- [4- (hydroxymethyl) -1-piperidiml] -2 -pyrimidiml] amrno] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [[(4-Carboxyphenyl) methyl] amino] -6- (4-methyl-1-piperazinyl) -2- pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester, monohydrochloride, 4-Methyl-2 - [[4- (4-methyl-1-piperazinyl) -6 - [[(tetrahydro-2-acid furanyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ester 2 - [[4 - [[(4-Carboxyphenyl) methyl] amino] -6- [3- (hydroxymethyl) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, ester etfl ico; acid 2 - [[4 - [[[4 - [[(2-Methoxyethyl) amino] carbonyl] phenyl] methyl] amino] -6- (4-methyl-1-piperazinyl] -2-pyrimidinyl] amino] -4 -methyl-5-thiazolecarboxyl, ethyl ester, trifluoroacetate (1: 1); ethyl ester of 2- [4,6-Bis- (1-morpholinyl) -pyrimidin-2-ylamino] -4-methyl-thiazole -5-carboxylic acid ethyl ester 2 - [[4- [3- (Aminocarbonyl) -1-piperazinyl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidiml] ] amino] -4-methyl-5-thiazolecarboxylic acid 4-Methyl-2 - [[4- [methyl (3-pyridinylmethyl] amino] -6- [4-morpholinyl] -2-pyrimidinylmethyl] amino] -5- thiazolecarboxyl, ethyl ester; acid 2 - [[4- [3- (Aminocarbonyl) -1-piperazinyl] -6 - [[[4- (methoxycarboml) femyl] methyl] amino] -2-pyrimidiml] amino] - 4-Methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4-Chloro-6 - [(1-oxa-3,8-diazaspiro [4.5] decan-2,4, dion-8-yl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4- (Hydroxymethyl) -1-piperidinyl] -6 - [[(3,4,5 -trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ester; do 2 - [[4- [3- (Hydroxymethyl) -1-Piperidinyl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5- thiazolecarboxyl, ethyl ester; acid 2 - [[4- [3- (Hydroxymethyl) -1-pyrrolidinyl] -6 - [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5- thiazolecarboxyl, ethyl ester, 4-Methyl-2 - [[4- [methyl (phenylmethyl) amino] -6- (4-methyl-1-piperazinyl] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid , ethyl ester; acid 2 - [[4- (Dimethylamino) -6 - [[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl ester Ethyl; acid 2 - [[4- [4-Hydroxy-1-piperidinyl] -6 - [[(3- (5- (1H) tetrazolyl) phenyl) methyl] amino] -2-pyrimidyl] amino] -4- methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4-hydroxymethyl-1-piperidinyl] -6 - [[(4- (propylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino ] -4-Methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4-hydroxymethyl-1-piperidinyl] -6 - [[(4- (cyclopropylsulfonylamino) phenyl) methyl] amino] -2 -pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [3- (Hydroxymethyl) -1-piperidinyl] -6 - [[(3,4,5-trimethoxyphenyl)] ) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico, ethylene ester; acid 2 - [[4- [4-tetrahydropyranyl] oxy-6 - [[N - [(3,4,5-trimethoxyphenyl) methyl]] - N- (methyl) amino] -2-pyrimidinyl] amino] -4 methyl-5-thiazolecarboxylic acid ester; 2 - [[4- [4-Methyl-1-piperazinyl] -6 - [(4-methoxyphenyl) oxy] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; Ethyl acid ester 4-Methyl-2- [4- (4-methyl-piperazin-1-yl) -6 - [[[4- (aminosulfonyl) phenyl] methyl] amino] pyrimidin-2-ylamino] -thiazole- 5-carboxylic; Ethyl ester of 2- [4-Isopropyl-6- (4-sulfamoyl-benzylamino) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; 4-Methyl-2- [4- (4-sulfamoyl-benzylamino) -6-methyl-pyrimidin-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 4-Methyl-2- [4- (4-sulfamoyl-benzylamino) -6-hydroxymethyl-pyrimidin-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; Ethyl acid ester 4-Methyl-2- [4- (4-methyl-piperazin-1-yl) -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylamino] - thiazole-5-carboxyl; Ethyl acid ester 2- [4- (4-Hydroxy-piperidin-1-yl) -6- [4- (1 H -tetrazol-5-yl) -benzylammo] -pyrimidin-2-ylammo] -4-methyl- thiazole-5-carboxylic; 4-Methyl-2- [4 - [(tetrahydro-furan-2-ylmethyl) -amino] -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylamino acid ethyl ester ] -thiazole-5-carboxylic acid; acid ethyl ester 4-Methyl-2- [4-morpholin-4-yl-6- [4- (1 H-tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylamino] -thiazole-5-carbox ^ lico; Ethyl acid ester 2- [4- (3-Carbamoyl-piperidin-1-yl) -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylamino]) - 4-methyl -thiazole-5-carboxyl; acid ester of acid2- [4- (4-Hydroxymethylpiperidin-1-yl) -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid; Ethyl ester of 2- [4- (2-Hydroxymethyl-1-pyrrolidyl) -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylammo] -4-methyl-thiazole- 5-carboxyl; Ethyl acid ester 2- [4- (3-N, N-Diethylcarbamoyl-1-piperidiml) -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidm-2-ylamm] -4- methyl-thiazole-5-carboxyl; Ethyl acid ester 2- [4- (3-HydroxM-pyrrolidiml) -6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2-ylamino] -4-methyl-thiazole-5- carboxyl; Ethyl acid ester 4-Methyl-2 - [[[2- [4-morpholin-4-yl] ethyl] amino-6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidin-2- ilamino] -thiazole-5-carboxylic acid; acid ethyl ester 4-Methyl-2 - [[[[4-hydroxy] butyl] ammo-6- [4- (1 H -tetrazol-5-yl) -benzylamino] -pyrimidm-2-ylamino] -thiazole-5- carboxyl; Acid ethyl ester 2- [4- (4-FormiM-piperaziml) -6- [4- (1 H -tetrazol-5-yl) -benzylammo] -pyrimidm-2-ylamino] -4-methyl-thiazole-5- carboxyl; ethyl ester of 2 - [[4 - [[(4-Clorofeml) methyl] amino] -6- (5-oxazolyl) -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ester; Ethyl acid ester 2 - [[4 - [[(4-Aminosulfomlfemyl) methyl] amino] -6- (5-oxazolyl) -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid; Ethyl acid ester 2 - [[4-Morpholino-6- (5-oxazolyl) -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid; 2 - [[4 - [[(3,4-dimethoxyphex) methyl] amino] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; Ethyl acid ester 2 - [[4- (1,4-Dioxa-8-aza-spiro [4.5] dec-8-yl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4 -methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [4-Hydroxy-4-phenyl-piperidinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [[(4-methylsulfonylphenyl) methyl] amino] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox Ethyl acid ester 2 - [[4- [4-Hydroxy-piperidinyl] -6- (5-oxazolyl) -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [[4- [4-Ethoxycarbonyl-piperidinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4-piperidinyl-6] - (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4-Methylpiperazinyl-6- (5-oxazolyl) -2-pyrimidinyl] amino] 4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [N- (2-Furylcarbonyl) piperazinyl-6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [N-Acetyl- [1,4-diazepyl] -6- (5-oxazolyl) -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid; Acid ethyl ester 2 - [[4- [N-Methyl-N- (N-methyl-4-piperidinyl) -amino] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5 -thiazolecarboxyl; Ethyl acid ester 2 - [[4- [N-Methyl- [1,4] -diazepyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid; 2 - [[4-N, N-Dimethoxyethylamino-6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; Ethyl acid ester 2 - [[4 - [(1 ', 4] -Bipiperidinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (3,4,5-trimethoxifem) -pyrimidm-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester 2- [(4- (4-Hydroxy-piperidin-1-yl) -6- [4- (1 H -tetrazol-5-yl) -phenyl] -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid Ethyl 2- (4- (4-Hydroxy-piperidin-1-yl) -6-pyridin-3-yl-pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-Methanesulfonyl-benzylamino) -6-pyridin-3-yl-pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid, ethyl acid ester 2- [4- (4 -Hydroxy-piperidin-1-yl) -6-pyrimidin-4-yl-pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester 2- [4- (4-cyano-phenyl) ) -6- (4-hydroxypiperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester 2- [4- (4-Acetyl-phenyl) -6- (4 - (hydroxypiperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic ester; Ethyl acid 2- [4- (4-Hydroxymethyl-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid; 2- [4- (4-Hydroxy-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; Ethyl ester of 2- [4- (4-Methanesulfonylbenzylamino) -6- (3,4,5-trimethoxy-phenyl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ester; Ethyl acid ester 2- [4- (4-methanesulfimethyl) -6- (4-hydroxypyridin-1-yl) -pyrimidm-2-ylamino] -4-methylthiazole-5-carboxylic acid; ethyl 2- (4- (4- (Amino) phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-Carboxymethyl-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; ethyl 2- (4- (4-trifluoromethylcarbonylamino) phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; Ethyl acid ester 2- [4- (4- (Ethoxycarbonylmethyl) phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid; Ethyl ester of 2- [4- (1,2,3,6-Tetrahydropyridin-4-yl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole- 5-carboxylic; Ethyl acid ester 2- [4- (3- (cyano) phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid; Ethyl acid ester 2- [4- (4- (Methoxycarbonyl) phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid; Ethyl ester of 2- [4- (2- (Methoxy) -5-pyrimidyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxy acid ^ lico Ethyl acid ester 2- [4- (4-fercButyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] - 4-methylthiazole-5-carboxylic acid; Ethyl acid ester 2- [4- (1,4-Dioxaespiro [4,5] dec-en-7-8-yl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino ] -4-methylthiazole-5-carboxylic acid; ethyl 2- (4- (4-MetiM-piperazin-yl) -6- (3,4,5-trimethoxy-fem) -pyrimidm-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; Ethyl ester of 2- [4- (4-Morpholyl) -6- (3,4,5-trimethoxy-phenyl) -pyrimidm-2-ylamino] -4-methylthiazole-5-carboxylic acid ester; 2- [4- (4-Morpholyl) -6- (3-pyridinyl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (Piperadin-4-yl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2 - [[4- [4-Hydroxy-piperidinyl] -6- (3,5-dimethyl-4-isoxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazole-carboxylic acid ethyl ester ; ethyl acid ester 2- [4- (4-fer-butoxycarbomlamino-fem) -6- (4-hydroxy-piperidm-1-yl) -pyrimidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid; ethylic acid ester 2- [4- (4-Cyano-feml) -6- (4-methanesulfoml-benzylamino) -pyrimidm-2-ylammo] -4-methyl-5-thiazolecarboxylic acid; ethyl 2- (4- (4-methanesulfonylphenyl) -6- (4-hydroxypyridin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; Ethyl ester of 2- [4- (4-methanesulfanylphenyl) -6- (4-hydroxypyridin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ester; Ethyl ester of 2- [4- (4-Carboxy-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; Ethyl ester of 2- [4- (4-Carboxy-phenyl) -6- (3-oxo-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ester; Ethyl ester of 2- [4- (4-Carboxy-phenyl) -6- (4-methyl-piperazin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ester; Ethyl ester of 2- [4- (4-Carboxy-phenyl) -6-morpholin-4-yl-pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ester; Ethyl acid ester 2- [4- (4-Carboxy-phenyl) -6- (4-methyl- [1,4] diazepan-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carbox ^ lico; Ethyl acid ester 2- [4- (4- (Carboxyphenyl) -6- (3-R-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic ester Ethyl acid 2- [4- (4-Carboxy-phenyl) -6- (3-hydroxymethyl-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid; 2- [4- (4-Acetyl- [1,4] diazepan-1-yl) -6- (4-carboxy-phenyl) -pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid; Ethyl ester of 2- [4- (4-Carboxy-phenyl) -6- [N-methyl-N- (1-N-methyl-piperidin-4-yl) -amino] -pyrimidin-2-ylamino] - 4-Methylthiazole-5-carboxylic acid ethyl ester 2- [4- (4-Carboxy-phenyl) -6-piperazin-1-yl-pyrimidin-2-ylamino] -4-methylthiazole-5-carboxylic acid ^ lico 2- [4- (4-Carboxy-fem) -6- (4-sulfamoyl-benzylamino) -pyrimidm-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2 - [[4 - [[5-Allyl [4- (ammosulfomyl) femyl] methyl] amino] -6-chloro-2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2 - [[4 - [[[4- (Aminosulfonyl) phenyl] methyl] amino] -5-methyl-6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid , ethyl ester, trifluoroacetate (1: 3); acid 2 - [[4 - [[[4- (Ammosulfonyl) femyl] methyl] amino] -5-methyl-6- (4-morpholiml) -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid , ethyl ester; 2 - [[4 - [[5-Allyl [4- (aminosulfomyl) femyl] methyl] amino] -6- (4-methylpiperazyl) -2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid, ethylene ester; acid 2 - [[4 - [[5- [2- [2-Methylprop-3-en]] - 4- [4- (aminosulfonyl) phenyl] methyl] amino] -6- (4-methylpiperazinyl) -2- pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester; acid 2 - [[4 - [[[(3,4,5- (Trimethoxy) femyl] methyl] ammo] -5-methyl-6- (1-piperaziml) -2-pyrimidiml] amino] -4-methyl- 5-thiazolecarboxyl, ethyl ester, trifluoroacetate; acid 2 - [[4 - [[5- [2,3-propanediol] [4- (aminosulfoml) femyl] methyl] amino] -6- (4-methylpiperazyl) - 2-pyrimidiml] ammo] -4-methyl-5-thiazolecarboxylic acid ester 2 - [[4 - [[[3,4,5- (trimethoxy) phenyl] methyl] amino] -5-methyl- 6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, ethyl ester, trifluoroacetate; 2 - [[4 - [[5- [2- [2 Methylprop-3-en]] - 4- [4- (aminosulfomyl) femyl] methyl] amino] -6-chloro-2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [ [4 - [[[4- (Aminosulfoml) phenyl] methyl] amino] -5-methyl-6- (4-fer-butyloxycarboml-1-piperaziml) -2-pyrimidyl] ammo] -4-methyl-5-thiazolecarboxylic acid , ethyl ester, 2 - [[4- [N - [[3,4,5- (trimethoxy) phenyl] methyl] -N-methylamino] -5-methyl-6- (4-methyl-1-piperazinyl) acid -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester, ethyl ester of 2- [4,6-Bis- (4-hydroxypiperidin-1 -yl) -5-methylpyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid; Ethyl ester of 2- [4,6-Bis- (3-oxo-piperazin-1-yl) -5- [ethoxycarbomethyl] pyrimidm-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ester; 2- [4,6-Bis- (4-hydroxy-piperidin-1-yl) -5-methoxypyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2 - [[4- [N - [[3,4,5- (Trimethoxy) phenyl] methyl] -N-methylamino] -5-methoxy-6- (4-methyl-1-piperazinyl) -2-pyrimidinyl acid ] amino] -4-methyl-5-thiazolecarboxylic acid ester; 2 - [[4 - [[3-pyridyl] methyloxy] -5- (2-propenyl-6- (4-morpholinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, ethyl ester Ethyl 2 - [(4-Ethoxycarbomethylmethyl-6-morpholin-4-yl-pyrimidin-2-yl) -amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [(4-Ethoxycarbonylmethyl) ethyl ester -6- [3-oxo-1-piperaziml] -pyrimidm-2-yl) amino] -4-methyl-5-thiazolecarboxylic acid 2 - [(4-carboxymethyl-6-morpholin-4-yl-pyrimidin-2) -yl) -amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [4-Morpholin-4-yl-6 - [(3,4,5-trimethoxy-femcarcarmoyl) -methyl] - pyrimidm-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [2-oxo-2- (3-oxo-piperazin-1-yl) -ethyl] -6- ( 4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4-sulfamoyl-benzylamino) -6 - [(4-sulfamoyl- benzylcarbamoyl) -methyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [4- [2- (1,4-Dioxa-8-aza-spiro [4, 5] dec-8-yl] -2-oxo-ethyl] -6- (4-sulfamoylbenzylamino) -2-pyrimid inyl] amino] -4-methyl-5-thiazolecarboxylic; Ethyl acid ester 2 - [[4 - [(4-Chloro-phenyl) -methylcarbamoyl] -methyl] -6- (4-sulfamoyl-benzylamino) 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ; Ethyl acid ester 2 - [[4- [2- (4-Hydroxy-piperidm-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidiml] amino] -4 -methyl-5-thiazolecarboxylic acid; acid ethyl ester 2 - [[4- [2- (4-Ethoxycarbonyl-piperidin-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4 methyl-5-thiazolecarboxyl; acid ethyl ester 2 - [[4- (2-oxo-2-piperidin-1-yl-ethyl] -6- (4-sulfamoyl-benzylamino) 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarbox ^ lico; acid ethyl ester 2 - [[4- [2- [4- (Furan-2-carbonyl) -piperazin-1-yl] -2-oxoethyl] -6- (4-sulfamoyl-benzylamino) 2-pyrimidinyl ] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4 - [(Cyclohexylmethyl-carbamoyl) -methyl] -6- (4-sulfamoyl-benzylamino) 2-pyrimidinyl] amino] - 4-Methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [2- (4-Acetyl- [1,4] diazepan-1-yl) -2-oxo-ethyl] -6- ( 4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [Methyl- (1-methyl-piperidin-4-yl) -carbamoyl] - methyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [2- (4-methyl- [1 , 4] diazepan-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 [[4 - [[Bis- (2-methoxyethyl) -carbamoyl] -methyl] -6- (4-sulfamoyl-benzylamino) -2-pirim idinyl] amino] -4-methyl-5-thiazolecarboxylic; Ethyl acid ester 2 - [[4- (2- [1,4 '] Bipiperidinyl-1'-yl-2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] - 4-Methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- [2- (4-Hydroxy-4-phenylpiperidin-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl -benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4-Ethoxycarbonyl-6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] - 4-Methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4-Carboxyl-6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid; acid 2 - [[4 - [(Carboxymethyl-carbamoyl) -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (4-methylsulfanyl-benzyl) -pyrimidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2- [4- (4 Hydroxy-piperidin-1-yl) -6- (4-methanesulfinyl-benzyl) -pyrimidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2 - [[4- (4- Hydroxy-piperidin-1-yl) -6- (4- methanesulfonylbenzyl) -2-pyrimidiml] amino] -4-methyl-5-thiazolecarboxylic acid; acid 2 - [[4- (4-methyl-1-piperazinyl) -6- [N-methyl-N - [(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4- trifluoromethyl-5-thiazolecarboxylic acid ester; acid 2 - [[4- [4-Methylpiperazin-1-yl] -6- [N-methyl-N - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4 -methyl-5-cyanothiazole; acid 2 - [[4- [4-Methylpiperazin-1-yl] -6-methyl-6 - [[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid, 2-methoxyethyl ester; acid 2 - [[4- [4-Hydroxy-piperidin-1-yl] -6- [N-methyl [[N - [(3,4,5-trimethoxyphenyl) methyl] [- N-methyl] amino] - 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxyl, butyl ester; 2 - [[4- [1-morpholinyl] -6 - [[2- [1-morpholinyl] ethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, butyl ester; 2 - [[4- [4-methyl-1-piperazinyl] -6 - [[N - [(3,4,5-trimethoxyphenyl) methyl]] - N- (methyl) amino] -2-pyrimidinyl] amino acid ] -4-isopropyl-5-thiazolecarboxylic acid, ethyl ester; 2 - [[4- [4-methyl-1-piperazinyl] -6 - [[N - [(3,4,5-trimethoxyphenyl) methyl]] - N- (methyl) amino] -2-pyrimidinyl] amino acid ] -4-methyl-5-thiazolecarboxylic acid, methyl amide; Ethyl acid ester 2- [4- [4- (2-Diisopropylamino-ethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5- thiazolecarboxylic; ethyl ester of 2- [4- [4- (3-Dimethylamino-propylcarbamoyl) -phenyl] -6- (4-hydroxypiperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ester; Ethyl Ethyl Acid 2- [4- [4- (Cyclohexylmethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid; acid ethyl ester 2- [4- [4- (pyridin-4-ylmethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] 4-methyl-5-thiazolecarbox ^ lico; ethyl 2- (4- [4- (Isobutylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; Ethyl acid ester 2- [4- [4- (N-Cyclohexyl-N-methylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl- 5-thiazolecarboxylic acid; acid ester of acid2- [4- [4- (N-Cyclopropylmethyl-N-propylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pindmidin-2-ylamino] -4-methyl-5-thiazolecarboxylic acid; Ethyl acid ester 2- [4- [4- (4-Ethoxycarbonylpiperidin-1-carbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-Mamino] -4-metM- 5-thiazolecarboxy-Mco; acid ethyl ester 2- [4- [4- (3-Hydroxymethyl-piperidin-1-carbonyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4- methyl-5-thiazolecarboxylic; acid ethyl ester 2- [4- [4- (N-2-Hydroxyethyl-N-ethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4- methyl-5-thiazolecarboxylic; acid ethyl ester 2- [4- [4- (Tiomorpholin-1-carbonyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5- thiazole carboxylic acid; acid ethyl ester 2- [4- [4- (Morpholin-1-carbonyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5- thiazolecarboxylic; and ethyl acid ester 2- [4- [4- (4-Chloro-penylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidin-2-ylamino] -4-methyl-5 -thiazolecarboxylic; or a stereoisomer, a pharmaceutically acceptable salt or a hydrate thereof.

In another related embodiment, the PDE7 inhibitors useful in the methods of the present invention include the following compounds:

Ċ

or a stereoisomer, a pharmaceutically acceptable salt or a hydrate thereof.

The preparation of these compounds is described in U.S. Patent No. 7,087,614, U.S.

20030162802 and WO 2002/102313.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in US 2007/0129388 and WO 2007/063391. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

The substituents for the above compounds are defined as follows:

m is 0, 1 or 2; X is O, S or N-CN; R is F, Cl or CN; R 1 is a C ^3-6 cycloalkylene group optionally substituted with C ^1-4 alkyl; and B is a single bond or a C ^1-2 alkylene group; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

With respect to the above compounds, the term "alkylene" indicates a divalent saturated hydrocarbon chain having 1 or 2 carbon atoms. Examples of alkylene groups include methylene, ethylene and methylmethylene, of which methylene is preferred.

The term "cycloalkylene" denotes a saturated divalent carbodic ring having from 3 to 6 carbon atoms. Examples of cycloalkylene groups include cyclopropylene (e.g., 1,1-cyclopropylene and cis- and trans-1,2-cyclopropylene), cyclobutylene (e.g., 1,1-cyclobutylene, cis and trans- 1,2-cyclobutylene, and cis and trans- 1,3-cyclobutylene), cyclopentylene (for example, 1,1-cyclopentylene, cis and trans-1,2-cyclopentylene, and cis and trans-1,3-cyclopentylene) and cyclohexylene (for example, 1,1-cyclohexylene, cis- and trans-1,2-cyclohexylene, cis and trans-1,3-cyclohexylene) and cis and trans- 1,4-cyclohexylene). Preferred examples include cyclobutylene and cyclohexylene, more preferably cyclobutylene, even more preferably 1,3-cyclobutylene and most preferably trans-1,3-cyclobutylene.

The term "alkyl" denotes a monovalent, linear or branched, saturated hydrocarbon chain containing from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Preferred examples include methyl and ethyl, especially methyl.

The cycloalkylene group is optionally substituted with a C ^1-4 alkyl group. Preferably, the alkyl substituent, if present, is a methyl or ethyl group, more preferably a methyl group. The alkyl substituent, if present, may be present at any position on the ring, but is preferably present at the 1-position (ie, the same position as the carboxylic acid group).

Preferably, m is 1 or 2, more preferably 1.

Preferably, X is O or N-CN, more preferably O.

Preferably, R is F or C1, more preferably C1.

Preferably, A is a cyclobutylene or cyclohexylene group optionally substituted with a methyl group. More preferably, A is a cyclobutylene group. Even more preferably, A is a 1,3-cyclobutylene group, especially a trans-1,3-cyclobutylene group.

Preferably, B is a single bond or a methylene group. More preferably, B is a single bond.

In another embodiment, a PDE7 inhibitor useful in the methods of the invention is selected from the following compounds:

cis-3 - [(8'-Chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazo-lin] -5'-yl) oxy] acid] cyclobutanecarboxyl; trans-3 - [(8'-Chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazo-lin] -5'-yl) oxy] cyclobutanecarboxyl; 3 - [(8'-fluoro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxymethyl] cyclobutanecarboxylic acid; trans-3 - [(8'-cyano-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinaz-olin] -5'-yl) oxy] acid] cyclobutanecarboxyl; 1 - [(8'-Fluoro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazolin] -5'-yl) oxymethyl] cyclobutanecarboxyl acid ; frans-3 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cycloheptane-1,4'-quina-zolin] -5'-yl) oxy] acid] Cyclobutanecarboxylic; and trans-3 - [(8'-chloro-2'-oxo-2 ', 3'-dihydro-1'H-spiro [cyclopentyl-1,4'-quinazolin] -5'-yl) oxy] cyclobutanecarboxy acid ^ lico; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

The preparation of the above compounds is described in US 2007/0129388 and WO 2007/063391.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention include the compound ASB16165 (1-Cyclohexyl-W- [6- (4-hydroxy-1-piperidinyl) -3-pyridinyl] -3-methyl- monohydrate. 1H-Thieno [2,3-c] pyrazole-5-carboxamide) described in Kadoshima-Yamaoka, K. et al., "ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suppresses IL-12-induced IFN-g T lymphocytes, "Immunology Letters 122: 193-197, 2009. In one embodiment, a PDE7 inhibitor useful in the methods of the invention has the formula:

Methods for preparing the above compound are described in WO 2006/004040.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention include compound YM-393059 ((±) -W- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4- methoxy-3-methylphenyl) -5- (4-methylpiperazin-1-yl) -4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide) described in Yamamoto, S. et al., " The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. " European Journal of Pharmacology 541: 106-114, 2006, expressly incorporated herein by reference in its entirety. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in Martinez et al., "Benzyl derivatives of 2,1,3-benzo- and benzothieno 3,2-aathiadiazine. 2,2-dioxides: first phosphodiesterase 7 inhibitors, "J. Med. Chem. 43: 683-689, 2000, which is expressly incorporated herein by reference in its entirety. In one embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds:

2,2 - [(4-Methoxyphenyl) carbonylmethyl] benzothieno- [3,2-a] -1,2,6-thiadiazine-493H) -one 2,2-dioxide; and 1 - [(3,4-dichlorophenyl) -methyl] -2,1,3-benzothiadiazin-4 (3H) -one 2,2-dioxide.

The preparation of the above compounds is described in J. Med. Chem. 43; 683-689, 2000.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in Castro, A. et al., "CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors as In an embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds:

In another embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

The substituents for the above compounds are defined as follows:

X = O or S,

R = H, Ph, 4-OMePh, 2,6-diFPh, 2,3,4-triFPh, 2-BrPh, Bn, Naphthyl or Me.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds: 5.2.4. 3- (2,3,4-T-rifluorophenyl) -2-thioxo- (1H) -quinazolin-4-one;

5.3.2. 3-Phenyl-2-thioxo- (1H) -thieno [3,2-d] pyrimidin-4-one;

5.3.3. 3- (2,6-Difluorophenyl) -2-thioxo- (1H) -thieno [3,2-d] pyrimidin-4-one; Y

5.4.2. 3- (2,6-Difluorophenyl-2-thioxo- (1 H) -benzo [4,5] -thieno [3,2-d] -pyrimidin-4-one.

The preparation of the above compounds is described in J. Med. Chem. 43; 1349-1359, 2008.

In another embodiment, PDE7 inhibitors useful in the methods of the invention include BMS-586353, as described in Yang, G. et al., "Phosphodiesterase 7A-deficient mice have functional T cells," J. Immunol 171: 6414 -6420, 2003.

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in Pitts, WJ et al., "Identification of purine inhibitors of phosphodiesterase 7 (PDE7)," Bioorg. Med. Chem. Lett. 14: 2955-2958, 2004, and Kempson, J. et al., "Fused pyrimidine based inhibitors of phosphodiesterase 7 (PDE7): synthesis and initial structure-activity relationships," Bioorg. Med. Chem. Lett. 15: 1829 1833, 2005. In one embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

(fifty)

The substituents for the above compounds are defined as follows:

R1 is

or

R2 is

or

wherein the ethyl group can be attached to the 7 or 9 position.

In a related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formulas:

Y

In another related embodiment, the PDE7 inhibitors useful in the methods of the invention have the formula:

where X = CH2, CH2CH2 or OCH2;

Ar is

or

and NRR 'is

or

In another embodiment, the PDE7 inhibitors useful in the methods of the invention are selected from the compounds disclosed generally or specifically in Kang, NS et al., "Docking and 3-D QSAR studies of dual PDE4-PDE7 inhibitors," Molecular Simulation 33: 1109-1117, 2007. In one embodiment, the PDE7 inhibitors useful in the methods of the invention include the following compounds:

Y

Methods for preparing the above compounds are described in Molecular Simulation 33: 1109-1117, 2007.

Polypeptide or peptide inhibitors

In some embodiments, the PDE7 inhibitory agent comprises polypeptide or peptide PDE7 inhibitors isolated, including isolated natural peptidic inhibitors and peptide synthetic inhibitors that inhibit p DE7 activity. As used herein, the term "isolated PDE7 polypeptide or peptide inhibitors" refers to polypeptides or peptides that inhibit PDE7-dependent cleavage of cAMP by binding to PDE7, competition with PDE7 for binding to a substrate and / or direct interaction with PDE7 to inhibit the PDE7-dependent cleavage of cAMP, which are substantially pure and are essentially free of other substances with which they can be found in nature to a practical extent and appropriate for their intended use.

Peptide inhibitors have been used successfully in vivo to interfere with protein-protein interactions and catalytic sites. For example, peptide inhibitors of adhesion molecules structurally related to LFA-1 have recently been licensed for their use in clot coagulopathies (Ohman, EM, et al., European Heart J. 16: 50-55, 1995). Short linear peptides (<30 amino acids) that prevent or interfere with integrin-dependent adhesion have been described (Murayama, O., et al., J. Biochem.120: 445-51, 1996). Longer peptides, with lengths ranging from 25 to 200 amino acid residues, have also been used successfully to block integrin-dependent adhesion (Zhang, L., et al., J. Biol. Chem. 271 (47): 29953-57, 1996). In general, longer peptide inhibitors have higher affinities and / or slower dissociation rates than short peptides and, therefore, may be more potent inhibitors. It has also been shown that cyclic peptide inhibitors are effective inhibitors of integrins in vivo for the treatment of inflammatory disease in humans (Jackson, DY, et al., J. Med. Chem. 40: 3359-68, 1997). . A method to produce cyclic peptides involves the synthesis of peptides in that the terminal amino acids of the peptide are cystems, thus allowing the peptide to exist in a disulfide form via a disulfide bond between the terminal amino acids, which has been shown to improve the affinity and half-life in vivo for the treatment of hematopoietic neoplasms ( for example, United States Patent No. 6,649,592 to Larson).

Peptide inhibitors of synthetic PDE7

The PDE7 inhibitory peptides useful in the methods of the invention are illustrated by amino acid sequences that mimic the target regions important for the enzymatic activity of PDE7, such as the catalytic domain of pDE7. PDE7A and PDE7B have a 70% identity in the catalytic domain. (Hetman, JM, et al., PNAS 97 (1): 472-476, 2000.) The catalytic domain of PDE7A1 is from the amino acid residue 185 to 456 of SEQ ID NO: 2. The catalytic domain of PDE7A2 is amino acid residue 211 to 424 of SEQ ID NO: 4. The catalytic domain of PDEB is from amino acid residue 172 to 420 of SEQ ID NO: 6. The inhibitory peptides useful in the practice of the methods of the invention have a size ranging from about 5 amino acids to about 250 amino acids. Molecular modeling and rational molecular design can also be used to generate and screen peptides that mimic the molecular structure of the catalytic regions of PDE7 and inhibit the enzymatic activity of PDE7. Molecular structures used for modeling include the CDR regions of anti-PDE7 monoclonal antibodies. Methods for identifying peptides that bind to a particular target are well known in the art. For example, molecular imprinting may be used for the de novo construction of macromolecular structures such as peptides that bind to a particular molecule. See, for example, Shea, KJ, "Molecular Imprinting of Synthetic Network Polymers: The De Novo Synthesis of Macromolecular Binding and Catalytic Sties," TRIP 2 (5), 1994.

As an illustrative example, one method for preparing mimetics of PDE7 binding peptides is as follows. Functional monomers are polymerized from a binding region of an anti-PDE7 antibody that shows inhibition of PDE7 (the template). The mold is then removed, followed by the polymerization of a second class of monomers in the gap left by the mold, to provide a new molecule that shows one or more desired properties that are similar to the mold. In addition to preparing the peptides in this manner, other PDE7 binding molecules which are PDE7 inhibiting agents, such as polysaccharides, nucleosides, drugs, nucleoprotemas, lipoproteins, carbohydrates, glycoproteins, steroids, ftpidos and other biologically materials can also be prepared. assets. This method is useful for designing a wide variety of biological mimics that are more stable than their natural counterparts because they are usually prepared by free radical polymerization of functional monomers, resulting in a compound with a non-biodegradable backbone.

Peptide inhibitors of PDE7 can be prepared using techniques well known in the art, such as the solid phase synthetic technique initially described by Merrifield in J. Amer. Chem. Soc. 85: 2149-2154, 1963. Automatic systems can be obtained, for example, using the Applied Biosystems 431A peptide synthesizer (Foster City, Calif.) In accordance with the instructions provided by the manufacturer. Other techniques can be found, for example, in Bodanszky, M., et al., Peptide Synthesis, second edition, John Wiley & Sons, 1976, as well as in other reference works known to those skilled in the art. The peptides can also be prepared using conventional genetic engineering techniques known to those skilled in the art.

A candidate PDE7 inhibitor peptide can be assayed for the ability to act as a PDE7 inhibitor in one of several assays, including, for example, a PDE7 phosphodiesterase assay.

Inhibitors of PDE7 expression

In some embodiments of the methods of the invention, the PDE7 inhibitory agent is an inhibitor of PDE7 expression capable of inhibiting cleavage of PDE7-dependent AMPc (PDE7A, PDE7B or both). In the practice of this embodiment of the invention, the representative PDE7 expression inhibitors include PDE7 antisense nucleic acid molecules (such as antisense mRNA, antisense DNA or antisense oligonucleotides), PDE7 ribozymes and PDE7 RNAi molecules.

The antisense DNA and RNA molecules act to directly block the translation of PDE7 mRNA by hybridizing with PDE7 mRNA and preventing the translation of PDE7 protein. An antisense nucleic acid molecule can be constructed in several different ways, as long as it is capable of interfering with the expression of PDE7. For example, an antisense nucleic acid molecule can be constructed by inverting the coding region (or a portion thereof) of PDE7A1 cDNA (SEQ ID NO: 1), PDE7A2 cDNA (SEQ ID NO: 3) or PDE7B cDNA ( SEQ ID NO: 5) in relation to its normal orientation for transcription to allow the transcription of its complement. Methods for designing and administering antisense oligonucleotides are well known in the art and are described, for example, in Mautino et al., Hum Gene Ther 13: 1027-37, 2002; and Pachori et al., Hypertension 39: 969 75, 2002.

The antisense nucleic acid molecule is usually substantially identical to at least a portion of the target gene or genes. It is not necessary, however, that the nucleic acid be perfectly identical to inhibit the expression. In general, a larger homology can be used to compensate for the use of a shorter antisense nucleic acid molecule. The minimum percentage identity is usually greater than approximately 65%, but a percentage of greater identity can exert a more effective repression of the expression of the endogenous sequence. A substantially higher percent identity of more than about 80% is usually preferred, although more than about 95% absolute identity is usually preferred.

It is not necessary that the antisense nucleic acid molecule have the same pattern of introns or exons as the target gene, and the non-coding segments of the target gene can be equally effective in achieving antisense suppression of the target gene expression as coding segments. A DNA sequence of at least about 8 nucleotides can be used as the antisense nucleic acid molecule, although a longer sequence is preferable. In the present invention, a representative example of a PDE7 inhibitory agent util is an antisense PDE7 nucleic acid molecule that is at least ninety percent identical to the complement of a part of the PDE7A1 cDNA that consists of the exposed nucleic acid sequence in SEQ ID NO: 1. Another representative example of a PDE7 inhibitory agent util is an antisense PDE7 nucleic acid molecule that is at least ninety percent identical to the complement of a part of the PDE7A2 cDNA consisting of the sequence of nucleic acid disclosed in SEQ ID NO: 3. Another representative example of a PDE7 inhibitory agent util is an antisense PDE7 nucleic acid molecule that is at least ninety percent identical to the complement of a part of the PDE7B cDNA consisting of the nucleic acid sequence set forth in SEQ ID NO: 5.

The targeting of the antisense oligonucleotides to bind to PDE7 mRNA is another mechanism that can be used to reduce the level of synthesis of the PDE7 protein. For example, the polygalacturonase synthesis and the muscarmic type 2 acetylcholine receptor is inhibited by antisense oligonucleotides directed to their respective mRNA sequences (U.S. Patent No. 5,739,119 to Cheng and U.S. Pat. No. 5,759,829 to Shewmaker). Also, examples of antisense inhibition have been demonstrated with the nuclear cyclin protein, the multidrug resistance gene (MDG1), ICAM-1, E-selectin, STK-1, striatal GABAa receptors and human EGF (see, for example, patent No. 5,801,154 to Baracchini, United States Patent No. 5,789,573 to Baker, United States Patent No. 5,718,709 to Considine, and United States Patent No. 5,610,288 to Reubenstein).

A system has been described which allows a typical expert to determine which oligonucleotides are useful in the invention, which involves exploring the appropriate sites in the target mRNA using cleavage with RNase H as an accessibility indicator for the sequences within the transcripts. Scherr, M., et al., Nucleic Acids Res. 26: 5079-5085, 1998; Lloyd, et al., Nucleic Acids Res. 29: 3665-3673, 2001. A mixture of antisense oligonucleotides that are complementary to certain regions of the PDE7 transcript is added to cell extracts that express PDE7 and hybridizes to create a site vulnerable to RNasaH. This method can be combined with the computer-assisted sequence selection that can predict optimal sequence selection for antisense compositions based on their relative ability to form dimer, hairpin, or other secondary structures that reduce or prevent specific binding to target mRNA in a host cell. These considerations of secondary structure analysis and target site selection can be made using the OLIGO primer analysis software (Rychlik, I., 1997) and BlASTN 2.0.5 algorithm software (Altschul, SF, et al., Nucl Acids Res. 25: 3389-3402, 1997). Antisense compounds directed against the target sequences preferably comprise from about 8 to about 50 nucleotides in length. Antisense oligonucleotides comprising from about 9 to about 35 nucleotides are particularly preferred. The inventors contemplate that all oligonucleotide compositions in the range of 9 to 35 nucleotides (ie, those of about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 bases in length) are highly preferred for the practice of methods of the invention based on antisense oligonucleotides. Very preferred target regions of the PDE7 mRNA are those which are at or near the start coding of the AUG translation, and the sequences which are substantially complementary to the 5 'regions of the mRNA, for example, between regions 0 and 10 of the nucleotide sequence of the PDE7 gene (SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5).

The term "oligonucleotide" as used herein refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimics thereof. This term also encompasses oligonucleotides composed of nucleotides of natural origin, sugars and covalent internucleosphidic bonds (backbone) as well as oligonucleotides having modifications of non-natural origin. These modifications allow introducing certain desirable properties that are not offered by oligonucleotides of natural origin, such as reduced toxic properties, greater stability against degradation by nucleases and improved cell reuptake. In illustrative embodiments, the antisense compounds of the invention differ from natural DNA by modifying the phosphodiester backbone to prolong the life of the antisense oligonucleotide in which the phosphate substituents have been replaced by phosphorothioates. Analogously, one or both ends of the oligonucleotide can be substituted by one or more acridine derivatives that are interspersed between adjacent base pairs within a nucleic acid chain.

Another alternative to antisense is the use of "RNA interference" (RNAi). Double-stranded RNAs (dsRNA) can cause genic silencing in mammals in vivo. The natural function of RNAi and cosuppression appears to be the protection of the genome against invasion by mobile genetic elements such as retrotransposons and viruses that produce RNA or dsRNA abnormalities in the host cell when activated (see, for example, Jensen, J., et al., Nat. Genet, 21: 209-12, 1999). The double-stranded RNA molecule can be prepared by synthesizing two RNA strands capable of forming a double-stranded RNA molecule, each having a length of about 19 to 25 (eg, 19-23 nucleotides). For example, a dsRNA molecule useful in the methods of the invention may comprise the RNA corresponding to a part of at least one of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 and its complement. Preferably, at least one RNA strand has a 3 'overhang of 1-5 nucleotides. The synthesized RNA strands are combined under conditions that form a double-stranded molecule. The RNA sequence may comprise at least a portion of 8 nucleotides of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5 with a total length of 25 nucleotides or less. The design of siRNA sequences for a given target is among the usual abilities of a person skilled in the art. Commercial services are available that design siRNA sequences and guarantee at least 70% attenuation of the expression (Qiagen, Valencia, CA). PDE7 RNAs and siRNAs are available from Sigma-Aldrich Company (product # SHDNA_-NM_002603; SASI_Hs01_00183420 to SASI_Hs01_00010490).

The dsRNA can be administered as a pharmaceutical composition and carried out by known methods, wherein a nucleic acid is introduced into a desired target cell. The methods commonly used for gene transfer include calcium phosphate, DEAE-dextran, electroporation, microinjection and vmcos methods. Such methods are taught in Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., 1993. Nucleic acid molecules can be modified to cross the blood-brain barrier. For example, it has been demonstrated that a phosphorothiolate antisense oligonucleotide directed towards the Abeta mid region of the amyloid precursor protein (APP) provided by icv administration can reverse learning and memory deficits in an Alzheimer's mouse model. Banks WA et al., Journal of Pharm. and Exp. Therapeutics, 297 (3): 1113-1121, 2001.

Ribozymes:

In some embodiments, a PDE7 inhibitory agent is a ribozyme that specifically cleaves mRNA from a target PDE7, such as PDE7A, PDE7B or both. Ribozymes that target PDE7 can be used as PDE7 inhibitors to reduce the amount and / or biological activity of PDE7. Ribozymes are catalytic RNA molecules that can cleave nucleic acid molecules having a sequence that is fully or partially homologous to the ribozyme sequence. It is possible to design transgenes of ribozymes encoding RNA ribozymes that specifically pair with a target RNA and cleave the phosphodiester backbone in a specific location, thus functionally inactivating the target RNA. When carrying out this cleavage, the ribozyme itself is not altered and, therefore, can be reused and other molecules cleaved. The inclusion of ribozyme sequences in antisense RNA transmits RNA cleavage activity, thereby increasing the activity of the antisense constructs.

Useful ribozymes in the practice of the invention usually comprise a hybridization region of at least about nine nucleotides, which is complementary to the nucleotide sequence of at least part of the target PDE7 mRNA, and a catalytic region that is adapted to cleave the Target PDE7 mRNA (see, in general, European Patent No. 0321 201; WO 88/04300; Haseloff, J., et al., Nature 334: 585-591, 1988; Fedor, MJ, et al. , Proc. Natl. Acad. Sci. USA 87: 1668-1672, 1990; Cech, TR, et al., Ann. Rev. Biochem. 55: 599-629, 1986).

The ribozymes can be directed directly to cells in the form of RNA oligonucleotides that incorporate ribozyme sequences, or introduced into the cell as an expression vector encoding the desired ribozyme RNA. Ribozymes can be used and applied in a manner very similar to that described for antisense polynucleotides.

The antisense DNA and RNA, ribozymes and RNAi molecules useful in the methods of the invention can be prepared by any method known in the art for the synthesis of DNA and RNA molecules. These include techniques for chemically synthesizing oligodeoxyribonucleotides and oligoribonucleotides well known in the art, such as, for example, solid phase chemical synthesis of phosphoramidite. Alternatively, the RNA molecules can be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Said DNA sequences can be incorporated into a wide variety of vectors incorporating suitable RNA polymerase promoters, such as the promoters of the T7 or SP6 polymerase. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be stably introduced into cell lines.

Various well-known modifications of DNA molecules can be introduced as a means of increasing stability and half-life. Useful modifications include, but are not limited to, the addition of ribonucleotide or deoxyribonucleotide flanking sequences at the 5 'and / or 3' ends of the molecule or the use of phosphorothioate or 2 'O-methyl in place of phosphodiesterase bonds within the Oligodeoxyribonucleotide main chain.

IV. EXPLORATION METHODS FOR PDE7 INHIBITORS USEFUL TO TREAT ADDICTION

In another aspect, methods are provided for identifying an agent that inhibits PDE7 activity useful for treating an addiction in a mammalian subject in need thereof. The methods of this aspect of the invention comprise: (a) determining IC ⁵⁰ to inhibit PDE7 activity for each of a plurality of agents; (b) select agents of the plurality of agents having an IC ⁵⁰ for inhibition of PDE7 activity of less than about 1 pM; (c) determining IC ⁵⁰ to inhibit PDE4 activity of agents having an IC ⁵⁰ to inhibit PDE7 activity of less than about 1 pM; (d) identifying agents useful for treating an addiction by selecting compounds having an IC ⁵⁰ to inhibit PDE4 activity more than 10 times the IC ⁵⁰ to inhibit PDE7; and (e) evaluating the activity of the compounds identified in a model system of addiction, wherein an agent having an IC ⁵⁰ for inhibition of p DE7 of less than 1 pM, and an IC ⁵⁰ for inhibiting the activity of PDE4 greater than 10 times the IC ⁵⁰ for inhibiting PDE7, and determined to be effective for treating an addiction in an animal model is indicative of a PDE7 inhibitory agent useful for treating an addiction in a mammalian subject.

Representative agents that can be used in the practice of methods of this aspect of the invention include molecules that bind PDE7 and inhibit the enzymatic activity of PDE7 (such as small inhibitory molecules or blocking peptides that bind with PDE7 and reduce the enzymatic activity) and molecules that reduce the expression of PDE7 at the transcriptional and / or translational level (such as PDE7 antisense nucleic acid molecules, PDE7 specific RNAi molecules and PDE7 ribozymes), thus preventing PDE7 from cleaving cAMP .

V. GENERAL DESCRIPTION OF THE COMPOSITION AND DEFINITIONS.

In one aspect, the invention provides a method for treating an addiction comprising administering to a patient in need thereof an amount of a PDE7 inhibitory agent effective to inhibit the enzymatic activity of PDE7, wherein said inhibition of the enzymatic activity of PDE7 is The main therapeutic mode of action of the PDE7 inhibitor in the treatment of addiction. Addictions include addictions to addictive agents or addictive behaviors. Addictive agents include, without limitation, psychostimulants, alcohol, opioids and nicotine. A preferred psychostimulant for the treatment of addiction using PDE7 inhibitors is cocama or methamphetamine. A preferred addictive behavior for treatment using PDE7 inhibitors is compulsive overeating.

For each of the PDE7 inhibitory chemical compounds useful in the method of the present invention, all possible stereoisomers and geometric isomers are included. The compounds include not only racemic compounds, but also optically active isomers. When a PDE7 inhibitor is desired as a single enantiomer, it can be obtained by resolution of the final product or by stereoseffective synthesis from isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Ma, Z., et al., Tetrahedron: Asymmetry 8 (6): 883-888, 1997. The resolution of the final product, an intermediate or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the compounds are possible, it is intended that the present invention include all tautomeric forms of the compounds.

PDE7 inhibiting agents containing acidic moieties can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include alkali metal cations (eg, sodium or potassium) and alkaline earth metals (eg, calcium or magnesium). The pharmaceutically acceptable salts of the PDE7 inhibitory agents, which contain a basic center, are addition salts of acids formed with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartarate, gluconate, methaneflugonate, benzenesulfonate and p-toluenesulfonate salts. In view of the foregoing, it is intended that any reference to useful compounds in the method of the invention appearing herein include PDE7 inhibitory agents, as well as pharmaceutically acceptable salts and solvates thereof.

The compounds of the present invention can be administered therapeutically as the pure chemical product, but it is preferable to administer the PDE7 inhibitory agents as a pharmaceutical composition or formulation. Accordingly, the present invention further provides pharmaceutical compositions or formulations comprising a PDE7 inhibitory agent, or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and / or prophylactic ingredients. Suitable vehicles are compatible with the other ingredients of the formulation and not detrimental to the recipient thereof. The compounds of the present invention can also be transported in a delivery system to provide sustained release or enhanced uptake or activity of the compound, such as a liposomal or hydrogel system for injection, a system of microparticles, nanoparticles or micelles for oral or parenteral delivery. or system of capsules in stages for oral supply.

Blood-brain barrier:

In some embodiments, the PDE7 inhibitory agent is administered to cross or avoid the blood-brain barrier. Preferably, the inhibitory agent, compound or composition administered in the treatment method can cross the blood-brain barrier in sufficient quantities and at a sufficient rate to allow treatment of the movement disorder. Methods for allowing agents to cross the blood-brain barrier are known in the art and include minimizing the size of the agent, providing hydrophobic factors that facilitate passage, and conjugation with a carrier molecule having substantial permeability through the blood-brain barrier.

In some embodiments, an effective amount of a PDE7 inhibitor is an amount that achieves a concentration in brain tissue at or above IC ⁵⁰ for the activity of a given PDE7 inhibitor. In some embodiments, the PDE7 inhibitory agent is administered in a manner already at a dosage that provides a maximum concentration of about 1, 1.5, 2, 2.5, 5, 10, 20 or more times the IC ⁵⁰ concentration to inhibit the largest of PDE7A or PDE7B.

Examples

Example 1

Inhibition of PDE7 relieves cocaine addiction

to. Reduction of cocaine self-administration

The ability of PDE7 inhibition to reduce cocaine use by reducing cocaine addiction relapse and reducing the self-administration of chronic cocaine was demonstrated in a rat model of cocaine addiction. Cocaine hydrochloride (obtained from the National Institute of Drug Abuse, Bethesda, MD) was dissolved in sterile physiological saline at a concentration of 0.25 mg / 0.1 ml. A drug or vehicle solution was infused at a volume of 0.1 ml for 4 seconds. PDE7 inhibitors were tested according to Formulas 1A (WHO182056) and 1B (OMS181869) hereinabove and a PDE7 inhibitor according to Formula 6 hereinbefore (OMS182401) to determine the effects on cocaine self-administration . OMS182056 and OMS181869 were provided intraperitoneally (i.p.) 12 hours and 1 hour before the start of cocaine self-administration. WHO 182401 was provided intraperitoneally.

Male Wistar rats weighing between 180 and 200 g were used at the time of arrival at the laboratory. The rats were housed in groups of three in an animal house with humidity control (45-55%) and temperature (22 ° C) in a 12 h light / dark cycle: 12 h inverse (lit, 5:00 p.m. ; off, 05:00) with access at will to food and water. Experiments were performed during the dark phase of the light / dark cycle. One week after arrival, the rats underwent surgery and a silastic catheter was implanted in the right jugular vein. The experimental stations consisted of operant conditioning chambers (Med Associate Inc.) enclosed in ventilated, sound-absorbing environmental cubicles. Cocaine was delivered through a plastic tube connected to the catheter before the beginning of the session. A fusion pump was activated by responses in the active lever, while responses were recorded in the inactive lever but did not result in any programmed consequence. Activation of the pump resulted in a supply of 0.1 ml of liquid. A computer compatible with IBM controlled the supply of liquids and the recording of behavioral data.

For studies evaluating OMS182056 and OMS181869 PDE7 inhibitors, rats were trained to self-administer cocaine at 2-h daily sessions in a fixed-ratio reinforcement program 5, in which each response resulted in the supply of 0 , 25 mg / 0.1 ml of liquid cocaine solution. Cocaine self-administration training continued until a stable baseline response was reached (less than 10% variation for 3 consecutive days calculated for each individual rat). At this point, it started in the pharmacological trial.

The rats were treated with PDE7 inhibitors (0.0, 0.3, 1.0 and 3.0 mg / kg) provided i.p. 12 hours and 1 hour before the start of the self-administration session. The number of responses to the active and inactive levers was recorded. An interval of 3 days was left between the pharmacological tests. During these intervals, cocaine self-administration continued to reestablish basal lever responses.

The results are shown in FIGURES 1 and 2. Treatment with OMS182056 or OMS181869 did not significantly reduce the self-administration of cocaine, although there was a tendency toward reduction at higher dosages.

For the studies evaluating WHO182401, the rats were trained to self-administer cocaine in daily training sessions of 2 hours (short access) or 6 hours (long access) in which each actuation of the active lever triggered the delivery of 0.25 mg of cocaine while the inactive lever actuated did not provide cocaine; After 1 week, the ratio was increased so that 5 triggers were needed lever to receive an equal amount of cocama. Cocama self-administration training continued until a stable baseline response was reached (less than 10% variation for 3 consecutive days calculated for each individual rat). At this point, it started in the pharmacological trial. The vehicle or drug was injected 15 minutes before the test session. The number of responses in the active and inactive levers was recorded.

The results are shown in FIGURE 3. The treatment with OMS 182401 significantly reduced the self-administration of cocama in the long access model but not in the short access model.

PDE7 inhibitors increase the cellular levels of cAMP by reducing the degradation of cAMP by phosphodiesterase-7 activity. The cellular levels of cAMP are also increased by the activation of Gs-selective protein-coupled receptors, for example, the dopamine D1 receptor (DRD1). To test the effect of increased cAMP levels by activating DRD1 in the self-administration of cocama, the DRD1 agonist SKF82958 was administered i.p. trained rats to self-administer cocama. (±) -hydrochloride SKF-82958 [(±) -6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide of 6-Chloro-N-allyl-SKF-38393] or "SKF82958", is available from Sigma Aldrich. SKF82958 was administered at 1.0 mg / kg. The results are shown in FIGURE 4. Treatment with SKF82958 significantly reduced the self-administration of cocama in the short access model. The long access model was not evaluated in this case. In the first hour after treatment, a significant reduction of self-administration was observed at both doses. Two hours after treatment, the tendency of reduction of self-administration was not significant (data not shown). However, the animals also showed significant anomalo behavior and were extremely aggressive, suggesting that their ability to operate the lever was compromised by the administration of SK82958 with cocama. The behavior shown was similar to that shown after cocama overdose (data not shown).

The PDE7 inhibitor OMS182056 and the dopamine agonist D1 SKF82958 were administered without cocama during a period of extinction to determine whether these agents have addictive properties. The results are shown in FIGS. 5 and 6. None of the agents caused leverage to be increased by rats when administered by themselves. OMS182056 sf showed a slight, but statistically insignificant, trend towards lever-action reduction. Therefore, none of the agents showed addictive properties.

Although both PDE7 inhibitors and dopamine D1 agonists can increase cellular levels of cAMP, these two classes of agents produce very different effects when administered with cocama.

WHO182401 was also tested to determine its effect on the self-administration of cocama for a longer period of time. Jugular catheters were surgically implanted and allowed to recover for a week. Then the animals underwent daily training sessions of six hours (long access) in which each active lever activated the supply of 0.25 mg of cocama. After a week, the ratio was increased so that five lever-operated ones were needed to receive the same amount of cocama. The animal training continued for approximately six weeks. After achieving a stable rate of active lever actuation for six consecutive days, i.p. vehicle or drug (4.5 mg / kg) twice daily. Reinforced responses were evaluated during periods of two hours.

The results are shown in FIGURE 7. Chronic treatment with WHO 182401 reduced self-administration of cocama in the long-access rat model. The effect of WHO 182401 remained stable for at least six days of treatment. The self-administration of cocama returned to the basal level when treatment with OMS 182401 was stopped. OMS 182401 did not alter the actuation of the inactive lever (data not shown). This experiment confirms the efficacy of PDE7 inhibitors observed in acute models of treatment of cocaine addiction and indicates that OMS 182401 may be suitable for chronic administration.

b. Reduction of the cocama search after the extinction

WHO182056 was tested to determine its effect on cocama search behavior immediately after extinction. The rats were trained to self-administer cocama, as above, and were then exposed to extinction conditions. On the first day, the cocama was replaced with saline solution, OMS182056 (1.0 and 3.0 mg / kg) was administered to the rats i.p. and the lever operated ones were counted. The results are shown in FIGURE 8. WHO182056 at 3 mg / kg significantly reduced the amount of cocama search behavior at the beginning of the extinction process, indicating that OMS 182056 facilitates the extinction of cocama.

c. Reduction in the search for cocama after the relapse

WHO182056 and WHO182401 were also tested to determine their effects on cocama search behavior after a stress-induced addiction relapse. The rats were trained to self-administer cocama, as above, and were then exposed to extinction conditions. For the restoration phase, the day after the last extinction session, yohimbine (1.25 mg / kg) was injected into the rats and after thirty minutes were placed in the operating chamber and the lever operated ones were monitored for thirty minutes. It is known that the administration of the adrenergic receptor antagonist a-2 yohimbine, which increases cell activation and the release of norepinephrine in the brain, acts as a pharmacological stressor and facilitates the relapse in the search for alcohol. (Le et al., Psychopharmacology 179: 366-73 (2005)). The results are shown in UrGs 9 and 10. At doses of 1.0 and 3.0 mg / kg (FIGURE 9), WHO182056 showed significant effects in the prevention of relapse in stress-induced cocaine addiction. Similarly, at doses of 0.3, 1.0, and 3.0 mg / kg (FIGURE 10), WHO182401 showed significant effects in the prevention of relapse in stress-induced cocaine addiction.

WHO182056 was tested to determine its effect on cocama search behavior after a relapse in signal-induced addiction. The rats were trained to self-administer cocama, with the addition of a visual or olfactory signal, and were then exposed to extinction conditions without cocama. For the restoration phase, the day after the last extinction session, the rats were re-exposed to signals previously learned. Lever actuators were monitored and the results are shown in FIGURE 11. Although the results were not statistically significant, the administration of increasing amounts of WHO182056 (1.0 or 3.0 mg / kg) resulted in a trend towards reduction related to the dose of signal-induced relapse in animals. WHO182401 was also tested to determine its effect on cocama search behavior after a relapse in signal-induced addiction. The results are shown in FIGURE 12. Three concentrations of WHO 182401 were tested: 0.3 mg / kg, 1.0 mg / kg and 3.0 mg / kg, and the results were statistically significant at all three concentrations. The administration of increasing amounts of WHO 182401 resulted in a statistically significant reduction of signal-induced relapse in the animals, in a dose-related manner.

Next, PDE7 inhibitors and DRD1 agonists were tested for their effect on relapse induced by cocaine stimulation. The rats were trained to self-administer cocama, as above, and were then exposed to extinction conditions. Cocaine was replaced with saline solution. After having significantly reduced the lever actuation, resettlement procedures were initiated. The rats were treated with vehicle or agent and ten minutes later they were administered cocama. The lever operated was counted for one hour after the administration of cocama. The results for the OMS182056 PDE7 inhibitor are shown in FIGURE 13. The administration of OMS182056 did not have a significant effect on the response to cocama-induced stimulation. The results for the DRD1 agonist SKF82958 are shown in FIGURE 14. The treatment with SKF82958 significantly reduced the lever actuation induced by cocama stimulation. However, as previously the animals treated with SKF82958 showed significantly anomalous behavior. Once again, the administration of PDE7 inhibitors and D1 agonist had very different results in animals addicted to cocama.

Example 2

Inhibition of PDE7 relieves nicotine addiction

to. Reduction of nicotine self-administration

The ability of PDE7 inhibition to reduce the use of nicotine was demonstrated in a rat model of nicotine addiction. Male Wistar rats weighing between 180 and 200 g were used at the time of arrival at the laboratory. The rats were housed in groups of three in an animal house with humidity and temperature control (22 ° C) in a 12-hour light / dark cycle: 12 hours inverse (switched on, 17:00, off, 05:00 ) with access at will to food and water.

Jugular catheters were surgically implanted and allowed to recover for a week. The animals underwent daily training sessions of two hours (short access) or six hours (long access) in which every three activated active levers triggered the supply of 0.03 mg of nicotine. After achieving a stable rate of active lever actuation, animal or drug IP (OMS182401 or OMS182399, another PDE7 inhibitor according to Formula 6 above) was injected 15 minutes before the test session. The measured reading was the number of responses reinforced during two hours. The half-life of OMS182401 in the rats is between 1.7 - 4.9 hours. The results are shown in FIGURES 15 (WHO182401, short access), 16 (OMS182401, long access) and 17 (OMS182399, short access). Inhibition of PDE7 by WHO 182401 reduced nicotine self-administration in a dose-dependent manner in both short and long access rat models. Inhibition of PDE7 by OMS182399 reduced self-administration of nicotine at 3.0 mg / kg and 9.0 mg / kg in the short access rat model. The compounds did not alter the actuation of the inactive lever in any case.

b. Effect of PDE7 inhibition on self-administration of food

The effect of PDE7 inhibitors OMS182399 and OMS1823401 on food self-administration was evaluated to assess whether the effect of PDE7 inhibition is specific for drugs of abuse. Eight male Wistar rats were tested for each compound. Each drug is tested at concentrations of 0.0, 3.0 and 9.0 mg / kg formulated in acid 0.03 M tartaric acid. The solutions were administered intraperitoneally (ip).

The self-management stations consisted of operant conditioning chambers (Med Associate Inc.) enclosed in ventilated, sound-absorbing, lightweight environmental cubicles. The front door and the rear wall of the camera were made of transparent plastic and the other walls were opaque metal. Each camera was equipped with two retrace levers located on the front panel of the camera. A minimum downward pressure (approximately 25 g) on a lever was sufficient to result in a programmed response. A recessed food receptacle in which microgranules of food (45 mg each; BioServInc., Frenchtown, NJ) could be dosed from a microgranule dispenser was located between the two levers. A computer compatible with IBM controlled the supply of liquids and the recording of behavioral data.

For data evaluation, analysis of variance (ANOVA) was used followed by post-hoc tests (Newman-Keuls) when appropriate. The data was analyzed to determine the effect of the treatment. The statistical significance was fixed at p <0.05.

FIGURES 18A and 18B show the results obtained for OMS182399 and OMS182401, respectively. None of the compounds showed a statistically significant effect on self-administration of food compared to the vehicle, demonstrating that the effect of PDE7 inhibition is specific for drugs of abuse. The study provides evidence that the previously observed inhibition of operant related to nicotine and cocama that responds to these PDE7 inhibitors is selective and does not depend on a general inhibition of locomotor activity or motivation.

c. Reduction of nicotine self-administration in a progressive relationship study

Male Wistar rats were first trained to self-administer nicotine as described above in this Example 2 in an element release reinforcement program 1 (FR1). After the establishment of a stable initial measure of nicotine response, the animals were tested under conditions of progressive relationships, in which the response requirement (ie, the number of leverage responses necessary to receive a dose of 0.03 mg of nicotine) increased progressively.

Each response with nicotine reinforcement resulted in a 20-second illumination of the internal lumen. The sessions stopped when they had spent more than 60 minutes since the last reinforced response. The data collected were the breaking point (the number of lever actuated in the last session), the total number of lever actuated (active lever) throughout the study and the total number of rewards. Fifteen animals were tested using a Latin square design, that is, each animal received each dose. The effect of the PDE7 inhibitor OMS182401 at different doses was compared with the vehicle alone.

The results for the total number of rewards, breaking point and total active lever are shown in FIGS. 19A-19C, respectively. These data illustrate that the PDE7 inhibitor reduces in a dose-dependent manner the motivation of the addict animal to acquire nicotine, ie, motivation for nicotine.

Example 3

Reduction of self-administration of nicotine extinction

The ability of PDE7 inhibition to accelerate nicotine extinction was demonstrated in a rat model of nicotine addiction. The rats were trained to a stable level of self-administration of nicotine. The active lever was not associated with any reinforced reward. Before the first extinction session, the vehicle animals WHO182401 were injected. Total responses were counted in the active lever during the first hour of the first extinction session. The results are shown in FIGURE 20. WHO182401 facilitated the nicotine extinction in a statistically significant manner.

Another study evaluated the effect of WHO 182401 on the unreinforced response on the first day of extinction in rats that had been trained for microgranules of food to confirm the specificity of the effect of WHO 182401 on drugs of abuse. Sixteen male Wistar rats were trained to self-administer microgranules of food for eight days and then divided into two groups and injected with OMS182401 (9.0 mg / kg in 0.03 M tartaric acid) or vehicle 15 minutes before the first session. of extinction. The results showed that OMS 182401 did not reduce the non-reinforced response in rats trained with microgranules of food (data not shown), which provides additional support for the specificity of the effect of OMS182401 on drugs of abuse.

Example 4

Reduction of nicotine use after recovery

The ability of PDE7 inhibition to reduce nicotine use after signal-induced reestablishment was demonstrated in a rat model of nicotine addiction. The rats were trained to a stable rate of nicotine self-administration and to differentiate between nicotine availability and saline. During the nicotine sessions, a tone was constantly present (7 kHz, 70 dB) and the light signal (on the active lever) was on after the responses. During the sessions of saline solution, the test chamber was always illuminated by the internal light and the background noise was on after each response. The phase of differentiation was followed by a period of extinction that continued until the lever actuated was less than 20% of the stable rate. To test the compound, vehicle or WHO182401 was injected and the animals were exposed to nicotine stimulation conditions. Responses were counted in the active lever during the first hour of the nicotine stimulation condition. The results are shown in FIGURE 21. The inhibition of PDE7 by OMS182401 statistically reduced signal-induced nicotine relapse in the target animals. The response in the inactive lever was not affected by the administration of WHO 182401.

The ability of PDE7 inhibition to reduce the use of nicotine after signal-induced reestablishment was demonstrated in a rat model using yohimbine, an α2-adrenergic antagonist, as a stressor. Yohimbine acts as a pharmacological stressor and facilitates relapse in the search for nicotine. WHO182401 was tested to determine its effect on nicotine search behavior. The rats were trained to a stable rate of nicotine self-administration. The active lever was not associated with any reinforced reward (extinction) and the "active" lever actuation rate was reduced for several sessions. When the lever actuation rate was reduced to less than 20% of the stable rate, animals were injected with 1.25 mg / kg of intraperitoneal yohimbine (i.p.) with vehicle or test compound. Total responses were counted in the active lever during the first hour after the administration of yohimbine. The results are shown in FIGURE 22. Inhibition of PDE7 by or Ms 182401 statistically significantly reduced stress-induced relapse in search of nicotine by target animals. The inactive lever response was not affected by administration of yohimbine or OMS182401.

Example 5

Inhibition of PDE7 reduces compulsive overeating in response to stress

To mimic the compulsive overactive disorder in laboratory animals, a compulsive overactive model was developed where compulsive overacting is induced by yo-yo dieting and stressful exposure to very tasty foods (HPF). In this model, female rats are exposed to repeated cycles of restriction and a stressful procedure characterized by exposure of animals to HpF without the possibility of accessing it. This procedure induces a selective increase in the consumption of highly palatable foods that are consumed in excess for a very short period of time. As described below, using this model, endowed with significant apparent and predictive validity, the effect of PDE7 inhibitors on compulsive overeating (one of the most significant forms of food addiction) was investigated.

Restoration of compulsive overactive behavior in experimental animals has been obtained through a combination of repeated food restriction and stress. [Cifani et al, Psychopharmacology 204: 113 125 (2009)]. For the present invention, tension-induced compulsive overeating is tested as in Cifani. The effects of two different PDE7 inhibitors, WHO182401 and OMS182056, were evaluated and compared with vehicle and with topiramate, an antiepileptic drug that has been shown in clinical trials to inhibit compulsive overactive episodes.

The rats were housed in individual cages and provided with feed and water ad libitum for two weeks prior to the experiment. During the experiment, the rats were provided with one of two food sources: microgranules of conventional rat foods (feed) or highly palatable food (HPF) consisting of a 52% mix of Nutella TM chocolate cream, 33% microgranules of rats and 15% water (5.33 kcal / g, 56%, 31% and 7% carbohydrate, fat and protein, respectively).

The rats were divided into four groups. The individual groups were subjected to the following cycles of 8 days, three consecutive times. A PDE7 inhibitor or vetulum on day 25 was administered to the rats.

(1) Control group - without restriction, without tension (NR NS). The rats had feed at will for four days. On days 5 and 6, they received feed at will and HPF for two hours. On days 7 and 8, the rats had feed at will. On day 25 the animals were not exposed to tension.

(2) Restricted, without tension (R NS). The rats had feed restricted to 66% of normal consumption for four days. On days 5 and 6, they received feed at will and HPF for two hours. On days 7 and 8, the rats had 66% of normal feed intake. On day 25 the animals were not exposed to tension.

(3) Without restriction, with tension (NR S). The rats had feed at will for four days. On days 5 and 6, received feed at will and HPF for two hours. On days 7 and 8, the rats had feed at will. On day 25 the animals were exposed to stress.

(4) Restricted and with tension (R + S). The rats had feed restricted to 66% of normal consumption for four days. On days 5 and 6, they received feed at will and HPF for two hours. On days 7 and 8, the rats had 66% of normal feed intake. On day 25 the animals were exposed to stress.

Tension was induced by placing HPF in an unobtainable container within sight and smell of the animal for fifteen minutes before allowing the animal to eat the HPF.

On day 25, after subjecting suitable animals to tension, animals were administered the PDE7 inhibitor WHO182401 (1.0 or 3.0 mg / kg ip), the PDE7 inhibitor OMS182056 (1.0 or 3.0 mg / kg ip), topirimate (60 mg / kg ip) or a control vetnculo. After one hour, the animals were given HPF and I fed at will. The HPF consumption was measured after two hours.

The results are shown in FIGURES 23A-23D for OMS182401, in FIGURES 24A-24D for OMS 182056 and in FIGURES 25A-25D for topirimate.

In all groups, animals ate increasing amounts of HPF during the two-hour period. In the groups NR + NS, NR + S and R + NS the administration of WHO 182401 did not significantly affect the amount of HPF consumed by the animals. In the R + S group, both the initial rate of HPF consumption and the total amount eaten in two hours were greater than in the other three groups. Therefore, the R + S condition models the compulsive overactiveness of human beings. In addition, in the R + S group, the animals that were administered WHO182401 3.0 mg / kg consumed less HPF than other animals. At the end of the two-hour period, the difference in the intake of HPF between the control animals and the animals to which WHO 182401 3.0 mg / kg was provided was significant. Therefore, administration of the PDE7 inhibitor WHO 182401 reduced the stress induced compulsive overeating in a rat model of the condition.

A statistically significant effect of OMS 182056 was observed in only one (R + S) of the four groups of rats: group R + S [F (2,22) = 10.79, p <0.001], group NR + NS [ F (2.24) = 0.31, p> 0.05]; R + NS group [F (2.24) = 0.84, p> 0.05]; group NR + S [F (2.24) = 1.41, p> 0.05]. The post-hoc comparisons showed significant statistical differences in the consumption of HPF in response to both doses of WHO182056 in the R + S group. The effect of the higher dose (3 mg / kg i.p.) was observed at all observation times, while the dose of 1 mg / kg i.p. it was effective only at 15 and 120 min (* p <0.05).

Topiramate (60 mg / kg ip) also reduced the intake of HPF only in the R + S group: [F (1,15) = 9.03, p <0.01] but not in the others: NR + group NS [F (1,16) = 0.84, p> 0.05]; R + NS group [F (1,16) = 1.59, p> 0.05]; group NR + S [F (1,16) = 0.49, p> 0.05]. Post-hoc comparisons showed that the effect was evident at all observation times (* p <0.05).

Statistical analysis showed that exposure to stress in animals with a history of food restriction induces a remarkable compulsive overactive behavior. These animals (R + S group) consume a significantly greater amount of HPF compared to control rats (NR + NS) that did not undergo food restriction and stress experiences. The efficacy of WHO182401 and WHO182056 in the reduction of HPF in the R + S group but not in the other groups (in which the animals do not demonstrate compulsive overactive behavior) further demonstrates the validity of the model. These drugs appear to reduce compulsive overactive behavior without affecting general food intake. Interestingly, at the highest dose, WHO182056 seemed to reduce compulsive use more strongly than the reference drug topiramate.

Example 6

Inhibition of PDE7 reduces stress-induced relapse in the search for food

To evaluate the ability of PDE7 inhibitors to prevent relapse in excessive food intake in food addict, the PDE7 inhibitor WHO 182399 was evaluated in a yohimbine-induced relapse model in the search for food. Sixteen male Long Evans rats were habituated first and fed on a 60% normal food intake daily during a two-month training phase. During the training phase, the rats were trained to a stable rate of self-administration of highly palatable foods. The rats were trained to activate an active lever in a test chamber for the delivery of microgranules of 45 mg of highly palatable food (HPF) containing high levels of fat (35% w / w) and moderate levels of carbohydrates (45%). p / p), available from Bioserve, Frenchtown NJ. The rats were trained for three hours, in alternate days, in a program of reinforcement of fixed ratio 1, reinforcing each lever actuated with a microgranule of HPF and a resting time of 20 seconds between actuated. The depression of an inactive lever did not lead to food reinforcement.

This phase of self-administration was followed after a phase of extinction, during which the depression of the active lever did not lead to any HPF or other reward. The extinction phase continued daily for fourteen sessions. During the last four sessions, the rats became accustomed to injections.

After the phase of extinction, the trial phase was started, in which yohimbine was injected into the rats, which acts as a pharmacological stressor and facilitates the relapse in the excessive search for food. It was injected into rats i.p. WHO182399 (0.3, 1.0 or 3.0 mg / kg) or saline, followed 10 minutes after injections of yohimbine or distilled water. A test session started 30 minutes after the injection of yohimbine or distilled water, in which the rats were placed in a test chamber with an active lever that supplied HPF and an inactive lever. The reset behavior (depression of the active lever) was measured at time points of 14, 30, 45, 60 and 180 minutes. When the total active lever responses during the first hour were compared in rats treated with yohimbine, it was shown that WHO182399 has reduced stress-induced relapse in search of foods in a statistically significant and dose-dependent manner, as shown in FIGURE 26. The inactive lever response was not affected by yohimbine or OMS182399 (data not shown). In contrast to the effect of OMS182399 in rats treated with yohimbine, in a further experiment, the injection of OMS182399 did not reduce the levering in rats treated with vehicle (data not shown).

Example 7

Effect on basal and nicotine-induced release of dopamine in the nucleus accumbens

To elucidate the mechanism of action of PDE7 inhibitors on addictive behaviors, their influence on dopamine (DA) levels in the nucleus accumbens (NAc) was examined. It is known that drugs of abuse increase DA levels in the cortex of NAc, an effect directly implicated in its addictive properties (Laviolette, SR, Van der Kooy, D., 2004. The neurobiology of nicotine addiction: bridging the gap from molecules to behavior, Nat. Rev. Neurosci 5, 55-65). A study was conducted to evaluate the effect of OMS182399 on the release of basal and nicotine-induced DA in the NAc of Wistar rats by an in vivo microdialysis study . Male Wistar rats (Harlan, Italy) weighing 275-300 g in groups of six per cage were housed with conventional foods (Morini, Italy) and water ad libitum, for at least five days in the central animal garden at constant temperature (23 ° C). C), humidity (60%) and a light / dark cycle of 12 hours (light from 8 am to 8 pm).

Concentric dialysis probes were prepared with a dialysis part of 1.5 mm with dialysis fiber of AN69 (acrylonitrile sodium metalloxy sulfonate copolymer) (310 pm of220 pm from Hospal, Dasco, Italy), according to De Luca's method et al. (2007). The rats were anesthetized with chloral hydrate (400 mg / kg ip) and placed in a stereotactic apparatus. An incision was made on the scalp and the skull was leveled between lamba and bregma. Two small holes were drilled to expose the dura and two probes were inserted vertically at the level of the cortex and the nucleus of the NAc according to the atlas of Paxinos and Watson (1998) (coordinates of the cortex: A: 2,2, L: 1 , 0 from the bregma, V: -7.8 from the dura mater, core coordinates: A, 1.4, L, 1.6 from the bregma, V -7.6 from the dura mater). The probes were fixed to the skull with glasionomeric cement (CX-Plus, Shofu Inc., Japan). Experiments were performed on rats with free movement 24 hours after the implantation of the probe. A Ringer's solution (147 mM NaCl, 4 mM KCl, 2.2 mM CaCb) was pumped through the dialysis probe at a constant rate of 1 pl / min. Samples were taken from each of the cortex and nucleus of the NAc every 10 or 20 minutes (depending on the experiments) and analyzed.

Dialyzed samples (10 or 20 μl) were injected into an HPLC equipped with a reversed phase column (C8 3.5 um, Waters, Mildford, MA, United States) and a coulometry detector (ESA, Coulochem II, Bedford, MA) to quantify DA. The first electrode was adjusted to 125 mV and the second electrode to -175 mV. The following solution was used as the mobile phase: NaH2PO450 mM, Na ² -EDTA 0.1 mM, sodium sulfate n-octyl 0.5 mM, methanol 15% (v / v), pH 5.5. The mobile phase was pumped with a Jasco pump with a flow rate of 0.6 ml / min. The sensitivity of the assay for DA was 5 fmol per sample. At the end of the experiment, the animals were sacrificed by transcardhal perfusion with 100 ml of saline solution (0.9% NaCl) and 100 ml of formaldehyde (10%). The probes were removed and the brains were cut in a vibratome in frontal cuts in series to locate the position of the microdialysis probes. Analysis of variance (ANOVA) was applied for repeated measurements to the raw data obtained from the serial DA trials after each treatment. The results of treatments showing significant general changes were tested Tukey post hoc, considering p <0.05 statistically significant. The means of three consecutive samples that differed by no more than 10% were considered basal values.

To determine the effect of OMS182399 on the release of basal and nicotine-induced DA in the cortex and nucleus of NAc, double microdialysis probes were implanted in the rats and, 24 hours later, they were administered vehicle or WHO182399 (9 mg / kg, ip). DA dialysate of cortex and nucleus of NAc was monitored for at least three hours. If no effect is observed in extracellular DA levels or, if there is any effect, at least two hours after returning to basal levels of AD, the same animals are injected or WHO182399 10 minutes before an injection. of nicotine (0.4 mg / kg per subcutaneous route (sc)). Dialysate DA was monitored for at least three hours after nicotine treatment.

FIGURE 27 shows the resulting effect of OMS 182399 (9 mg / kg ip) on extracellular DA levels of the cortex / nucleus of NAc. The results are indicated as mean ± SEM of change in the extracellular levels of DA expressed as the percentage of basal values. WHO182399 had no effect on the baseline levels of AD of any of the NAc regions.

FIGURE 28 shows the effect of nicotine (0.4 mg / kg sc) on extracellular DA levels of the NAc cortex in rats pretreated with OMS 182399 (9 mg / kg ip, 10 minutes before nicotine) . The results are indicated as mean ± SEM of change in the extracellular levels of DA expressed as the percentage of basal values. The administration of nicotine increases the release of DA in the cortex of NAc and this effect is substantially reduced by OMS182399.

Example 8

Effect of PDE7 inhibition on the spontaneous activity of dopaminergic neurons in the ventral tegmental area and against nicotine

The following electrophysiological studies show that selective PDE7 inhibitors are effective in a nicotine addiction model and act by potentiating dopamine signaling by DRD1. It is believed that the effects of reinforcement of nicotine are the result of its activation of dopaminergic neurons in the ventral tegmental area (VTA) (Pidoplichko VI et al., Nature 390: 401-404 (1997); Liu L, et al. , Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing a4 and a6 subunits Mol Pharmacol, 81 (4): 541-8 (2012)). The inventors attempted to evaluate the antiadictive potential of PDE7 inhibitors by studying their ability to modify the dopamine activity of basal VTA and changes in it induced by abuse drug by making recordings by current clamp of whole cells of horizontal slices of rat VTA ex alive. To this end, nicotine was used as an example of a drug of abuse. On the other hand, taking into account that the isoform of PDE7 is widely expressed in all the main areas of the brain and is frequently coexpressed in the same neurons with DRD1 [Reyes-Irisarri, E., et al., "Neuronal expression of cAMP-specific phosphodiesterase 7B mRNA in the mouse brain, "Neuroscience 132: 1173-85 (2005); Miro, X., et al., "Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs," Synapse 40: 201-214 (2001)], and that in the open-field activity assay the activity DRD1 agonist is enhanced by the inhibition of PDE7 (Example 10 below), the effects of these agents were also compared in an electrophysiological study.

Dopaminergic neurons were identified by the presence of a high hyperpolarizing current. Johnson, SW, et al., "Opioids excite dopamine neurons by hyperpolarization of local interneurons," J Neurosci 12: 483-488 (1992). The application of the PDE7 inhibitor OMS182401 significantly reduced the rate of spontaneous activation of dopaminergic VTA neurons (FIGURE 29A) at 0.3 and 1.0 pM. Notably, a similar effect was observed by the application of DR D1 SKF82958 agonist at concentrations of 3.0 and 10.0 uM as also shown in FIGURE 29A.

On the other hand, when ineffective concentrations (ie, concentration too low) were applied together of both SKF82958 and WHO 182399, the combination also produced a substantial reduction in activity (FIGURE 29B), indicating that inhibition of PDE7 potency the activation action of DRD1 and that the PDE7 inhibitor and the DRD1 agonist acted synergistically in this regard.

Because the stimulation of DRD1 increases the amplitude of inhibitory postsynaptic potentials (PPSI) mediated by GABAB and inhibitory postsynaptic currents (CPSI) mediated by GABAA [Bonci, A., et al., "Increased probability of GABA release during morphine, "J Neurosci 17: 796-803 (1997)], the inventors raised the hypothesis that this observation (ie, reduction of spontaneous activity of DA neurons of the VTA after inhibition of PDE7 or activation of DRD1) could be attributed to to an increase in the probability of GABA release from presynaptic terminals. The hypothesis was confirmed in part by analysis of miniature inhibitory postsynaptic potentials (PPSIm) (FIGURE 30), which demonstrated an increase in the frequency but not the amplitude of PPSIm after inhibition of PDE7. In addition, when the PDE7 inhibitor was applied in the presence of the GABA-A receptor antagonist picrotoxin (100 microM, data not shown), inhibition was still present, suggesting the involvement of GABA-B receptors in the inhibitory effects of PDE7. . In fact, in the presence of the GABA-B antagonist CGP35348 (100 uM), the inhibitory effect of OMS182401 on the spontaneous activation of VTA DA neurons was no longer observed (data not shown).

In a further study, it was observed that OMS 182401 inverted the activation of VTA dopaminergic neurons by nicotine (FIGURE 31). Additionally, although OMS182401 30 nM or SKF82958 1 uM alone were ineffective, the combination of 30 nM OMS182401 with 1 uM SKF82958 reversed the nicotine-induced activation (p <0.05). This demonstrates that inhibition of PDE7 enhances the signaling of DRD1 and that the combination of PDE7 inhibitor and DRD1 agonist acted more than additively in this regard.

To demonstrate in vivo that VTA is the site of action of the effects of PDE7 inhibition, WHO 182401 was delivered directly to the rat VTA and its effects on nicotine self-administration were evaluated. Jugular catheters were surgically implanted and allowed to recover for a week. Then they underwent intracranial surgery for bilateral implantation of cannae in the VTA. After the recovery, they underwent daily training sessions of two hours (short access), in which each activated lever actuated the supply of 0.03 mg of nicotine. After achieving a stable rate of actuated active lever, vehicle or drug injected into the VTA immediately before the test session. Reinforced responses were recorded in a Latin square design experiment (dedr, each animal receives each dose). The location of the jugular catheters was confirmed histologically at the moment of conclusion of the experiments. As shown in FIGURE 32, direct administration of the PDE7 inhibitor in the rat VTA reduced the self-administration of nicotine, confirming that the VTA is the site of action of the effects of PDE7 inhibition in animals.

Example 9

Effect of PDE7 inhibition on the neuronal dopamine activity of the ventral tegmental area and against cocarna, morphine and alcohol

An additional electrophysiological study was completed to evaluate the effect of the OMS182399 PDE7 inhibitor on the neuronal activity of VTA DA in the context of cocaine, morphine or alcohol. The preparation of VTA cuts was as described above in Example 8.

The drug-induced changes in the activation rate were calculated by averaging the effects after drug administration (five minutes) and normalizing with respect to the initial measurement prior to the drug. All numerical data are given as mean ± etm Data were compared and analyzed using two-way ANOVA for repeated measurements (treatment-time), or Student's t- test for repeated measures, when appropriate. Statistical analysis was carried out through the GraphPad Prism program. The level of significance was established at P <0.05.

The acute effect of WHO182399 on dopamine neurons of the VTA was investigated in a horizontal brain-cutting preparation of the rat that accounts for the mesencephalon. Records were made by current clamp of whole cells of VTA dopamine neurons. The acute application in the WHO182399 bath (0.05, 0.5 and 2.5 pM, 5 min) significantly reduced the spontaneous activity of VTA dopamine neurons in a dose-dependent manner, as shown in FIGURE 33. A one-way ANOVA for repeated measurements revealed that the means were significantly different: F3.42 = 5.67, P = 0.002 (n = 15). The data are expressed as the mean ± ETM. ** P <0.005.

As shown also in FIGURE 33, the acute application of the PDE7 inhibitor OMS182399 (five minutes before the application of morphine) was able to block the morphine induced excitation of VTA DA cells (morphine 1 pM, 3 min: 224 , 4 ± 19.5% basal activation rate, n = 7) in a dose-dependent manner, with statistical significance (t test for unrelated samples) at the dose of 50 nM (P <0.0001, n = 7); 0.5 pM (p = 0.0001, n = 8); 2.5 pM (p = 0.0002, n = 7); that by itself does not affect the basal spontaneous activity of DA neurons. The dashed line in FIGURE 33 represents the basal spontaneous basal activity of DA cells of the VTA. The data are expressed as the mean ± SEM, *** P <0.0001. Notably, the statistical analysis (t-test of related samples) did not reveal any difference in DA cell activation activity of the VTA between the effects of WHO182399 in the presence or absence of morphine, ie, the addition of morphine could not exceed the effect of WHO182399 (P> 0.05 at all concentrations tested).

As shown in FIGURE 34, the acute application of the OMS182399 PDE7 inhibitor (five minutes before application in ethanol bath) blocks the ethanol-induced excitation of VTA DA cells (100 mM ethanol, 5 min: 158.3 ± 26.7% basal activation rate, n = 6) in a dose-dependent manner, with statistical significance (f test for unrelated samples) at the dose of 500 nM (P = 0.007, n = 8) ; 0.05 pM (p> 0.05, n = 7); 2.5 pM (p = 0.02, n = 7); which in itself reduced spontaneous basal activity of DA neurons. The dashed line in FIGURE 34 represents the basal spontaneous basal activity of DA cells of the VTA. The data are expressed as the mean ± SEM, ** P <0.001, * P <0.05. Notably, the statistical analysis (t-test of related samples) revealed a difference in DA cell activation activity of the VTA between the effects of WHO182399 in the presence and absence of ethanol at a dose of WHO182399 of 500 nM (P = 0, 01, n = 8), while no statistical difference was revealed for the other two doses tested (P = 0.6 at both concentrations tested).

As shown in FIGURE 35, the acute application of the PDE7 inhibitor OMS182399 (five minutes before cocaine application) was able to block cokerin-induced inhibition of VTA DA cells (cocaine 1 pM, 5 min: 36, 4 ± 9.1% basal activation rate, n = 7) at the doses of 50 nM (P = 0.036, n = 7) and 0.5 pM (P = 0.049, n = 7). The discontinuous line in FIGURE 35 represents the normalized basal spontaneous activity of DA cells of the VTA. The data are expressed as the mean ± SEM, * P <0.05. Notably, at the highest dose tested (2.5 pM), which alone produces an effect qualitatively similar to cocarna (ie, reduction of the activation rate of dopamine neurons), OMS182399 failed to prevent the inhibition induced by cocarna of the spontaneous activity of dopamine neurons (t test of unrelated samples versus cocarna P = 0.5, t test of unrelated samples against OMS182399 P = 0.8). Notably, in the presence of the lowest dose tested (ie, 50 nM) the effects of cocarna on neuronal dopamine activity are opposite to control (i.e., excitation rather than inhibition).

Claims (9)

A composition comprising (a) an inhibitor of a phosphodiesterase 7 (PDE7) which is a selective inhibitor of PDE7 for which the lower of IC ⁵⁰ for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than one-tenth of the IC ⁵⁰ that the agent has to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11; and (b) a dopaminergic agent for use in the treatment of an addiction that is an addiction to an addictive substance or that is the practice of a compulsive behavior associated with a primary impulse control disorder or an obsessive-compulsive disorder. 2. A pharmaceutical composition comprising (a) an inhibitor of a phosphodiesterase 7 (PDE7) that is a selective inhibitor of PDE7 for which the lower of IC ⁵⁰ for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than one tenth of the IC ⁵⁰ that has the agent to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11; and (b) a dopaminergic agent for use in the treatment of an addiction that is an addiction to an addictive substance or that is the practice of a compulsive behavior associated with a primary impulse control disorder or an obsessive-compulsive disorder. 3. A kit for use in the treatment of an addiction that is an addiction to an addictive substance or that is the practice of a compulsive behavior associated with a primary impulse control disorder or an obsessive-compulsive disorder, comprising: a first recipient which comprises an inhibitor of a phosphodiesterase 7 (PDE7) which is a selective inhibitor of PDE7 for which the lower of the IC ⁵⁰ for inhibiting the activity of PDE7A and the IC ⁵⁰ for inhibiting the activity of PDE7B is less than one-tenth of the IC ⁵⁰ having the agent to inhibit the activity of any other PDE enzyme from the families of enzymes PDE1-6 and PDE8-11; and a second container comprising a dopaminergic agent. 4. The PDE7 inhibitor and dopaminergic agent, composition or kit for use according to any of claims 1-3, for the treatment of a subject addicted to an addictive agent selected from the group consisting of: alcohol, nicotine, marijuana, a Marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate and a psychostimulant. 5. The PDE7 inhibitor and dopaminergic agent, composition or kit for use according to any of claims 1-3, for the treatment of a compulsive behavior associated with a primary impulse control disorder or an obsessive-compulsive disorder selected from the group which consist of: compulsive overeating, addiction to food, ludopathy, pathological use of electronic devices, pathological use of electronic video games, pathological use of electronic communication devices, pathological use of mobile phones, addiction to pornography, sex addiction, spending compulsive, anorexia, bulimia, intermittent explosive disorder, kleptomania, piromarna, tricotilomama, excessive compulsive exercise and excessive compulsive work. 6. The PDE7 inhibitor and dopaminergic agent, composition or kit for use according to claim 5, wherein the subject has or is at risk of developing a food addiction. 7. The PDE7 inhibitor and dopaminergic agent, composition or kit for use according to any of claims 1-6, wherein the dopaminergic agent is selected from dopamine precursors, dopamine cofactors, inhibitors of dopamine metabolising enzymes, dopamine receptor, precursor compounds that are metabolically converted into a dopamine receptor agonist, dopamine reuptake inhibitors, and facilitators of dopamine release. 8. The PDE7 inhibitor and dopaminergic agent, composition or kit for use according to claim 7, wherein the dopaminergic agent is selected from levodopa, carbidopa, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, rotigotine and quinagolide and fenoldopam. 9. The PDE7 inhibitor and dopaminergic agent, composition or kit for use according to any of claims 1-6, wherein the dopaminergic agent is a dopamine agonist.