MXPA98009265A - Piridil- and pyrimidil-piperazines in the treatment of disorders from the abuse of sustain - Google Patents

Abstract

The present invention relates to: The use of a compound of formula (I) and of the pharmaceutically acceptable acid addition salts of the same compound is disclosed, wherein R 1 is halogen or hydrogen and R 2 is halogen, X is CH 2, O or S R3 and R4 are the same or different and are selected from hydrogen or lower alkyl, n is 2 or 3, A is selected from the pyrimidyl- or pyridyl- (a), (b) or (c) groups wherein R5, R6 and R7 are as defined in the description, for the manufacture of a medicament for the relief or prevention of the withdrawal syndrome that results from the addiction to a drug or substance from which it can be abused or for the treatment of the same.

Description

PIRIDIL- AND PYRIMIDIL-PIPERAZINES IN THE TREATMENT OF DISORDERS FROM SUBSTANCE ABUSE FIELD OF THE INVENTION The present invention relates to a new use of certain pyridyl- and pyrimidylpiperazines substituted at the 1-position of the piperazine ring with an allylalkyl group, an aryloxyalkyl or an arylthioalkyl, in the treatment of substance abuse disorders . More particularly, this invention relates to the improvement of abstinence syndromes and the modification of drug-seeking behavior.

BACKGROUND OF THE INVENTION It is extremely difficult to escape from dependence on drugs. This is independent of whether the dependence is on alcohol, amphetamines, barbiturates, benzodiazepines, cocaine, nicotine, opioids and phencyclidine or the like. That is why there is a need for an agent to diminish or overcome such addiction and if it is possible to reduce or eliminate the symptoms related to the abstinence of such drugs or substances of abuse. Different classes of neuronal receptors and brain neurotransmitters have been implicated in the underlying complex mechanisms, such as, for example, P1712 / 98MX compulsive alcohol consumption. The experimental findings have favored the opioid, dopaminergic, serotonergic and benzodiazepine receptor subtypes. Based on a large number of genetic and pharmacological studies, neurons that contain serotonin (5-HT) in the limbic-mesencephalic and limbic-forebrain pathways are apparently involved, in part, in the underlying underlying mechanisms, for example, the consumption of alcohol. It has been found that Buspirone (The Merck Index llth.Ed. , No. 1493), a partial 5-HT1A agonist, is effective for the treatment of anxiety. It was reported that Buspirone significantly reduces alcohol consumption in pets. In a clinical trial comparing buspirone with placebo in alcohol-dependent individuals, there was a lower proportion of dropout in the group treated with buspirone, which also reported less desire signs. It is reported that amperozide (The Merck Index llth.Ed., No. 612), a 5-HT2 antagonist, significantly attenuates alcohol intake in rats without affecting either food intake or body weight level (Myers et al., Pharmacol. Biochem. Behav. 43: 661-667, 1992). It is also reported that the bisphenylalkyl-2-pyridinyl-piperazine derivative FG5893 has a P1712 / 98MX action analogous to amperozide (Singh et al., Alcohol 10: 243-248, 1993).

SUMMARY OF THE INVENTION With surprise it has now been found that the compounds of general formula (I) and that the pharmaceutically acceptable acid addition salts thereof, wherein R 1 is halogen or hydrogen and R 2 is halogen; X is CH2, O or S; R3 and R4 are the same or different and are selected from hydrogen or a lower alkyl; n is 2 or 3 A is selected from the following pyrimidyl- or pyridyl- groups: where P1712 / 98MX R5 is selected from hydrogen, lower alkyl or halogen; R6 and R7 are the same or different and are selected from hydrogen or lower alkyl, halogen, lower alkoxy, hydroxy, cyano, nitro, trifluoromethyl, COOR8, CONR9R10 or COB; wherein R8 is hydrogen or lower alkyl; R9 and RIO are the same or different and are selected from hydrogen, lower alkyl and cycloalkyl; B is selected from wherein m is 1,2,3 or 4; Rll is selected from hydrogen or lower alkyl, and when the term "lower alkyl" is used in the preceding definitions it means that it includes straight or branched hydrocarbon groups having from 1 to 5 carbon atoms; cycloalkyl means that it includes groups of P1712 / 98MX cyclic hydrocarbons having from 3 to 8 carbon atoms; "lower alkoxy" means that it includes linear or branched alkoxy groups having from 1 to 5 carbon atoms; halogen means that it includes F, Cl and Br, are unexpectedly effective and specific in the treatment of individuals addicted to drugs or substances of abuse who suffer from the symptoms related to the abstinence of such drugs or substances. This finding explores a new method to treat dependence on drugs such as alcohol, hallucinogens, minor tranquilizers, nicotine, opiates and stimulants. The above-mentioned term "pharmaceutically acceptable acid addition salt" is intended to comprise the salts obtained by treating the basic form of the active ingredients of formula (I) with appropriate acids such as, for example, inorganic acids, for example, hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid and phosphoric acid or organic acids, for example, acetic acid, propanic acid, glycolic acid, lactic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid and pamico acid. Conversely, salt can be converted to the free basic form by alkali treatment.

P1712 / 98MX The compounds of the formula (I) as well as their use in other areas of medicine are known from the prior art (see U.S. Patent No. 5,034,390, which is incorporated herein by reference ).

DETAILED DESCRIPTION OF THE INVENTION Twenty years of research has consistently shown that drugs or substances that man abuses are usually self-administered by laboratory animals. Ethanol, amphetamines, barbiturates, benzodiazepines, cocaine, nicotine, opioids and phencyclidine and the like are just a few examples of substances that man abuses and that are self-administered in animal models. The value of animal models to investigate the pharmacological and behavioral mechanisms underlying drug dependence has been demonstrated repeatedly. In fact, animal models are our only resource for the investigation of compounds that alleviate or modify the behavior of drug seeking. In relation to this there is considerable experimental evidence that supports the existence of a relationship in the very mechanism of the brain stem addictive process, which underlies the predilection to abuse drugs above.

P1712 / 98MX mentioned. Drug addiction includes two important characteristics, the chronic compulsive or uncontrollable use of drugs and a withdrawal syndrome when the use of drugs is suspended. Studies have shown that a person dependent on alcohol often abuses concomitantly other substances, for example, cocaine. The subjective effects of these two substances in a dependent individual often seem to be more similar than different. Drugs of abuse have various effects on various neurotransmitters and systems, which ultimately interact to produce the feeling of being eagerly sought by many individuals. This eventually leads to producing a dependency, which has associated social and medical consequences. Biological theories of drug reinforcement have emerged that center around the assumption that drugs of abuse, which include, for example, ethanol, cocaine and nicotine, directly or indirectly activate "reward substrates" central, that they serve as intermediaries of motivated and reinforcing behavior. A substantial part of the evidence implicates the mesocorticolimbic dopamine system in mediating the acute effects of these drugs of abuse. Thus, P1712 / 98r.X d There is considerable evidence to suggest a common biological basis in the reinforcement of ethanol and other substances of abuse, including cocaine and nicotine. The present invention relates to a method for treating substance abuse disorders which comprises administering to patients suffering from said disorders a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt of the same. Specifically, the invention relates to the alleviation or prevention of the withdrawal syndrome that results from the addiction to a drug or substance of abuse and / or by the suppression of dependence on drugs or substances of abuse. The repeated administration to a subject of certain substances such as alcohol, hallucinogens, minor tranquillizers, nicotine, opiates and stimulants can lead to the physical and / or psychological dependence of that drug or substance. When the drug or substance of abuse is removed from a dependent subject, it develops certain symptoms, including sleep and mood disorders and an intense desire for the drug or substance of abuse. These symptoms can be described together as a withdrawal syndrome in relation to the present invention.

P1712 / 98MX Although treatments for substance abuse disorders are available, they remain largely ineffective or non-specific and, therefore, it is necessary to improve them. The anorectic effect and other effects of, for example, 5-HT reuptake blockers and buspirone blockers, constitute the greatest impediment to considering them for clinical treatment. It has been found that the compounds of formula (I) are different, both chemically and pharmacologically, from those drugs suggested hitherto for the treatment of drug dependence. The compounds of formula (I) represent a new and original class of psychotropic agents because they have a high affinity for 5-HT1A and 5-HT2 receptors and of low to moderate inhibitory properties of 5-HT reabsorption. A preferred compound is (1- [4- (p-fluorophenyl) -butyl] -4- (β-methy1-2-pyridinyl) -piperazine fumarate, hereinafter called Compound A. The following examples are intended to illustrate the invention without limiting the scope thereof.

Examples The affinity for Compound A and other drugs acting on serotonergic receptors was determined according to standard procedures. The results are P1712 / 98MX presented below in Table 1.

TABLE 1 AFFINITY OF DRUGS TO SEROTONÉRGIC RECEIVER SUBTITLES a) Radioligand: H-8-OH-DPAT Fabric: Hippocampus b) Radioligand: H-Ketanserin Tissue: Cerebral cortex c) Chemical Name: 1- [4- (p-flurophenyl) -butyl] -4- (3 -ethoxy-2-pyridinyl) piperazine d) Chemical Name: 2- [4- [4,4-bis (4-fluorophenyl) butyl] -l-piperazine-3-pyridinecarboxylic acid ethyl ester dihydrochloride To demonstrate that the chemical differences between the substances according to WO 93/20821 and the substances according to the present invention cause different pharmacological effects, the absorption of [3H] -5-HT was evaluated. The results are presented below in Table 2.

P1712 / 98MX TABLE 2 ABSORPTION OF [3H] -5-HT BY SINAPTOSOMES OF RAT CEREBRAL CORTEX IC50 is the concentration of drug that inhibits absorption by 50%.

Effects of drugs on the ingestion of alcohol. To further illustrate the useful pharmacological properties of the compounds of formula (I), the effect of Compound A systematically administered to rats (P) having preference for alcohol was determined. Due to its pattern of alcohol consumption, animal P seems to represent a valid genetically based model that approximates the condition of human alcoholism (Me Bride et al., Alcohol 7: 199-205, 1990; Lankford et al., Pharmacol Biochem. Behav 8: 293-299, 1991). After the most preferred alcohol concentrations had been stabilized for four days, Compound A was administered at doses of 2.5 and 10 mg / kg two P1712 / 98MX times a day for four consecutive days. While saline control injections had no effect on alcohol consumption, during both administration, both doses of Compound A significantly reduced alcohol intake in both absolute terms g / kg and in proportion of alcohol to total fluid intake . The highest dose of Compound A reduces the intake of alcohol by more than 40%. During the five days following the administration of Compound A, the alcohol intake in the rats rebounded, however, it remained significantly lower than that of the pretreatment level. In addition, each dose increased the intake of food and water above pretreatment levels during the injection period. After the injections of Compound A, the food and water returned to the pre-medication levels. The compounds of formula (I) and their acid addition salts are therefore indicated for use in the alleviation of withdrawal syndromes and in the modification of drug-seeking behavior. The effective amounts of the compounds of formula (I) and their acid addition salts are preferably administered to patients in need of treatment according to the usual routes of administration and formulated in the usual pharmaceutical compositions comprising a P1712 / 98MX effective amount of the active ingredient and a suitable pharmaceutically acceptable vehicle. Such compositions may have a variety of forms, for example, solutions, suspensions, emulsions, tablets, capsules and powders prepared for oral administration, patches for transdermal administration or sterile solutions for parenteral administration. An adequate daily dose to be used in the treatment of disorders by substances of abuse is considered to vary between 0.1 mg / kg and 2 mg / kg of body weight, depending on the specific conditions to be treated, the age and the weight of the specific patient, and the patient's specific response to the medication. The exact individual dose, as well as the daily dose, will be determined according to standard medical principles under the direction of a physician. Various additives are considered to enhance the stability or ease of administration of the medicament. The pharmaceutical composition may also contain additional therapeutically useful substances other than the compound of formula (I).

P1712 / 98MX

Claims (3)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. The use of a compound of formula (I) and the pharmaceutically acceptable acid addition salts thereof, wherein R 1 is either halogen or hydrogen and R 2 is halogen X is CH 2, O or S; R3 and R4 are the same or different and are selected from hydrogen or lower alkyl; n is 2 or 3 A is selected from the following pyrimidyl- or pyridyl- groups: where P1712 / 98KX R5 is selected from hydrogen, lower alkyl or halogen; R6 and R7 are the same or different and are selected from hydrogen or lower alkyl, halogen, lower alkoxy, hydroxy, cyano, nitro, trifluoromethyl, COOR8, CONR9R10 or COB; wherein R8 is hydrogen or lower alkyl; R9 and RIO are the same or different and are selected from hydrogen, lower alkyl and cycloalkyl; B is selected from where 'm is 1,2,3 or 4; Rll is selected from hydrogen or lower alkyl, and when the term "lower alkyl" is used in the definitions mentioned above it means that it includes straight or branched hydrocarbon groups having from 1 to 5 carbon atoms; "cycloalkyl" means that it includes cyclic hydrocarbon groups having from 3 to 8 carbon atoms. P1712 / 98MX carbon; "lower alkoxy" means that it includes linear or branched alkoxy groups having from 1 to 5 carbon atoms; halogen means that it includes F, Cl and Br. for the manufacture of a medicament for the alleviation or prevention of the withdrawal syndrome that results from the addiction to a drug or substance of abuse and / or to suppress the dependence to drugs or substances of abuse.
2. 2. A method for the alleviation or prevention of withdrawal syndrome resulting from addiction to a drug or substance of abuse and / or to suppress dependence on drugs or substances of abuse, which comprises the administration of an amount of a compound of formula and the pharmaceutically acceptable acid addition salts thereof, wherein R 1 is either halogen or hydrogen and R 2 is halogen X is CH 2, 0 or S; P1712 / 98MX R3 and R4 are the same or different and are selected from hydrogen or lower alkyl; n is 2 or 3 A is selected from the following pyrimidyl- or pyridyl- groups: -C Ny- -R5 _ N- "Re _ - R6 R7 wherein R5 is selected from hydrogen, lower alkyl or halogen; R6 and R7 are the same or different and are selected from hydrogen or lower alkyl, halogen, lower alkoxy, hydroxy, cyano, nitro, trifluoromethyl, COOR8, CONR9R10 or COB; wherein R8 is hydrogen or lower alkyl; R9 and RIO are the same or different and are selected from hydrogen, lower alkyl and cycloalkyl; B is selected from , P1712 / 98MX where m is 1,2,3 or 4; Rll is selected from hydrogen or lower alkyl, and when the term "lower alkyl" is used in the definitions mentioned above it means that it includes straight or branched hydrocarbon groups having from 1 to 5 carbon atoms; "cycloalkyl" means that it includes cyclic hydrocarbon groups having from 3 to 8 carbon atoms; "lower alkoxy" means that it includes linear or branched alkoxy groups having from 1 to 5 carbon atoms; halogen means that it includes F, Cl and Br. The use according to claim 1, wherein R 1 is hydrogen and R 2 is halogen, especially F; R3 and R4 are the same or different and are selected from hydrogen or lower alkyl; n is 2; A is A method according to claim 2, in P1712 / 98MX where R1 is hydrogen and R2 is halogen, especially F; R3 and R4 are the same or different and are selected from hydrogen or lower alkyl; n is 2 A is

   5. The use according to claim 1, wherein R 1 is hydrogen and R 2 is F; X is CH2; R3 and R4 are hydrogen; n is 2; A is

   6. A method according to claim 2, wherein R 1 is hydrogen and R 2 is F; X is CH2; R3 and R4 are hydrogen; n is 2; A is P1712 / 98MX