KR20120037408A - Novel phenylimidazole derivative as pde10a enzyme inhibitor - Google Patents

Abstract

(I).The present invention provides compound 5,8-dimethyl-2- [2- (1-methyl-4-phenyl-1 H-imidazol-2-yl) -ethyl]-[1,2,4] triazolo [1,5 -a] pyrazine and pharmaceutically acceptable acid addition salts thereof:

(I).

Description

Novel phenylimidazole derivatives as PDE10A enzyme inhibitors {NOVEL PHENYLIMIDAZOLE DERIVATIVE AS PDE10A ENZYME INHIBITOR}

The present invention provides compounds that are PDE10A enzyme inhibitors and are useful for treating neurodegenerative and mental disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating disorders using the compounds of the invention.

Throughout this application, various publications are all referenced. As such, the disclosures in these publications are incorporated by reference in this application in order to fully describe the technical level to which the present invention applies.

Cyclic nucleotide cyclic-adenosine monophosphate (cAMP) and cyclic-guanosine monophosphate (cGMP) function as intracellular second messengers that regulate the arrangement of countless processes in neurons. Intracellular cAMP and cGMP are generated by adenyl and guanyl cyclases and degraded by cyclic nucleotide phosphodiesterases (PDEs). Intracellular levels of cAMP and cGMP are controlled by intracellular signals and stimulation / inhibition of adenyl and guanyl cyclases in response to GPCR activation is a well characterized way of controlling cyclic nucleotide concentrations (Antoni, FA Front. Neuroendocrinol. 2000, 21, 103-132). Eventually cAMP and cGMP levels control the activity of cAMP- and cGMP-dependent kinases as well as other proteins with cyclic nucleotide response elements, through which subsequent phosphorylation of proteins and other processes can be attributed to synaptic transmission, neuronal differentiation and survival. Regulates major nerve function

There are 21 phosphodiesterase genes that can be divided into 11 gene groups. PDE is a class of intracellular enzymes that regulate levels of cAMP and cGMP through hydrolysis of cyclic nucleotides to each nucleotide monophosphate. Some PDEs degrade cAMP, some cGMP, and some. Most PDEs have broad expression and are involved in many tissues, while some are more tissue-specific.

Phosphodiesterase 10A (PDE10A) is a bispecific phosphodiesterase capable of converting cAMP to AMP and cGMP to GMP (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K et al. Eur. J. Biochem. 1999, 266, 1118-1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A is primarily expressed in neurons in striatum, brain nucleus (n. Accumbens) and olfactory nodules (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger , TF et al. Brain Research, 2003, 985, 113-126).

Mouse PDE10A is the first identified member of the PDE10 group of phosphodiesterases (Fujishige, K. et al. J. Biol. Chem. 1999, 274, 18438-18445 and Loughney, K. et al. Gene 1999, 234, 109-117), N-terminal split mutations of both rat and human genes are identified (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Fujishige, K. et. al. Eur. J. Biochem. 1999, 266, 1118-1127). There is a high degree of homology between species. PDE10A is uniquely confined to mammals with respect to other PDE families. MRNA for PDE10 is highly expressed in testis and brain (Fujishige, K. et al. Eur J Biochem. 1999, 266, 1118-1127; Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96 , 7071-7076 and Loughney, K. et al. Gene 1999, 234,109-117). These studies indicate that PDE10 expression in the brain is highest in the striatum (doe and crust), the nucleus and olfactory nodules in the brain. More recently, PDE10A mRNA (Seeger, TF et al. Abst. Soc. Neurosci. 2000, 26, 345.10) and PDE10A protein (Menniti, FS et al. William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal , Dec. 5-7, 2001) have been analyzed for expression patterns in rodent brains.

PDE10A is expressed at high levels by the caudate nucleus, the medium spine neurons of the lateral septal nucleus (MSN), and the neurons of the corresponding olfactory nodules. These constitute the center of the basal ganglia. MSN plays a major role in integrating converging cortical / thalamic stimuli and sending this integrated information back into the cortex in the cortex-basal-nucleus-gestral circuit. MSN shall expressing neurons of two functional classes: D ₁ D ₁ and D ₂ class expressing D ₂ class of dopamine receptors expressing dopamine receptors. The D ₁ class of neurons is part of the 'direct' striatum output pathway, which broadens the functions that enable behavioral responses. The D ₂ class of neurons is part of the 'indirect' striatum output pathway, which functions to inhibit behavioral responses that compete with what is possible by the 'direct' pathway. This competitive path acts like a brake and an Excel in the car. In the simplest aspect, lack of exercise in Parkinson's disease results from over-activity of the 'indirect' pathway, while over-exercise of disorders such as Huntington's disease indicates over-activity of the direct pathway. PDE10A regulation of cAMP and / or cGMP signals in the dendritic compartment of these neurons may be involved in infiltrating cortical / thalamic stimuli into MSN. In addition, PDE10A may be involved in the regulation of GABA release in melanoma and gall bladder (Seeger, TF et al. Brain Research, 2003, 985, 113-126).

Dopamine D ₂ receptor antagonism is well followed in the treatment of schizophrenia. Since the 1950s, dopamine D ₂ receptor antagonism has been central to the treatment of psychosis, and all effective antipsychotic drugs antagonize the D ₂ receptor. The effect of D ₂ is primarily mediated through neurons in the striatum, the nucleus of the brain, and the olfactory nodules, since these regions receive the most dense dopamine processes and have the strongest expression of the D ₂ receptor (Konradi, C). and Heckers, S. Society of Biological Psychiatry, 2001, 50, 729-742). Dopamine D ₂ receptor agonism causes a decrease in cAMP levels in cells expressed through adenylate cyclase control, which is a component of the D ₂ signal (Stoof, JC; Kebabian JW Nature 1981, 294, 366-368 and Neve, KA et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205). In contrast, D ₂ receptor antagonism effectively increases cAMP levels, and this effect can be mimicked by the control of cAMP degraded phosphodiesterase.

Most of the 21 phosphodiesterase genes are expressed in a variety of ways; Therefore, control is likely to have side effects. Since PDE10A in this context has a desired expression profile with high and relatively specific expression in the neurons of the striatum, the nucleus of the striatum and the olfactory nodule, PDE10A control is likely to have an effect similar to D ₂ receptor antagonism and thus have antipsychotic effects. Have

While PDE10A control is expected to partially mimic D ₂ receptor antagonism, it may be expected to have a different profile. The D ₂ receptor has a signal component in addition to cAMP (Neve, KA et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205), whereby cAMP interference through PDE10A control directly modulates dopamine signaling through the D ₂ receptor. Rather than antagonizing This may reduce the risk of extratrapyrimidal side effects that appear to be strong D ₂ antagonists. In contrast, PDE10A control may have some effects that do not appear to be D ₂ receptor antagonism. PDE10A is also expressed on D ₁ receptors expressing progenitor neurons (Seeger, TF et al. Brain Research, 2003, 985, 113-126). Since D ₁ receptor synergy induces stimulation of adenylate cyclase and consequently increases cAMP levels, PDE10A control is likely to have the effect of mimicking D ₁ receptor synergy. Finally, because PDE10A is a bispecific phosphodiesterase, PDE10A control can be expected not only to increase cAMP in cells but also to increase cGMP levels. cGMP activates a number of target proteins in cells such as cAMP, and also interacts with cAMP signaling pathways. As a result, PDE10A control is likely to partially mimic D ₂ receptor antagonism and therefore has antipsychotic effects, but profiles may differ from those observed using classical D ₂ receptor antagonists.

The PDE10A inhibitor papaverine has been shown to be active in some antipsychotic models. Papaverine increased the cataleptic effect of the D ₂ receptor antagonist haloperidol in rats, but did not cause stiffness alone (WO 03/093499). Papaverine reduced the hyperactivity in PCP-induced rats, but the reduction in amphetamine-induced hyperactivity was minimal (WO 03/093499). This model suggests that PDE10A control has the classical antipsychotic potential expected from theoretical considerations. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of related neurological and psychiatric disorders. In addition, PDE10A control reverses the subtype of PCP-induced lowering in attentional set-shifting of rats (Rodefer et al. Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A inhibition may alleviate the cognitive decline associated with schizophrenia.

The tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise the level of cAMP and / or cGMP in cells expressing PDE10 enzymes, particularly in the neurons comprising the basal ganglia, so that the PDE10A inhibitors of the present invention are neurological and mental disorders. It will be useful for treating various related neuropsychiatric conditions involving basal ganglia, such as schizophrenia, mood swings, obsessive compulsive disorder, etc., and may have the advantage of not having unwanted side effects associated with current therapies on the market.

In addition, a recent publication (WO 2005/120514, WO 2005012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873) states that PDE10A inhibitors may be useful in the treatment of obesity and non-insulin dependent diabetes mellitus. It is.

With regard to inhibitors of PDE10A, EP 1250923 discloses the use of selective PDE10 inhibitors, generally papaverine, in particular for the treatment of certain neurological and psychiatric disorders.

WO 05/113517 discloses benzodiazepine stereospecific compounds as inhibitors of phosphodiesterases, in particular types 2 and 4, and the prevention and treatment of pathologies involving central and / or peripheral disorders. WO 02/88096 discloses benzodiazepine derivatives and their use as phosphodiesterases, in particular type 4 inhibitors, in the therapeutic field. WO 04/41258 discloses benzodiazepineone derivatives and their use as phosphodiesterases, in particular type 2 inhibitors, in the therapeutic field.

Pyrrolodihydroisoquinoline and variants thereof are disclosed in WO 05/03129 and WO 05/02579 as inhibitors of PDE10. Piperidinyl-substituted quinazolines and isoquinolines provided as PDE10 inhibitors are disclosed in WO 05/82883. WO 06/11040 discloses substituted quinazoline and isoquinoline compounds which serve as inhibitors of PDE10. US 20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. In particular, US 20050182079 relates to such compounds which are selective inhibitors of PDE10. Similarly, US 20060019975 discloses piperidine derivatives of quinazoline and isoquinoline which serve as effective phosphodiesterase (PDE) inhibitors. US 20060019975 also relates to compounds which are selective inhibitors of PDE10. WO 06/028957 discloses cinnoline derivatives as inhibitors of phosphodiesterase type 10 for the treatment of psychiatric and neurological syndromes. However, this disclosure does not apply to the compounds of the invention and is not structurally related to any of the known PDE10 inhibitors (Kehler, J. et al. Expert Opin. Ther. Patents 2007, 17, 147-158). .

The compounds of the present invention are first disclosed in WO 09/152825, where priority applications are claimed. Compounds of the present invention regress PCP-induced hyperactivity by 99%, thus providing effective PDE10A enzyme inhibitors and in vivo active compounds that may provide an alternative to current marketed treatment of neurodegenerative and / or mental disorders that are not effective for all patients. Is proven. Thus, there remains a need for alternative treatment methods.

Summary of the Invention

It is an object of the present invention to provide compounds which are selective PDE10A enzyme inhibitors.

Another object of the present invention is to provide compounds having the above activity, which have good, preferably improved solubility, metabolic stability and / or bioavailability as compared to the compounds of the prior art.

Another object of the present invention is to provide effective treatments, in particular long term treatments, of human patients without causing typical side effects associated with current therapies for neurological and mental disorders.

Further objects of the present invention will become apparent as the specification is read.

Thus, the present invention relates to compounds of formula I 5,8-dimethyl-2- [2- (1-methyl-4-phenyl-1 H-imidazol-2-yl) -ethyl]-[1,2,4] tria It is related to the solo [1,5-a] pyrazine :

Formula I-Compounds of the Invention

In the context of the present application, the term “compound of the invention” refers to 5,8-dimethyl-2- [2- (1-methyl-4-phenyl-1 H-imidazol-2-yl) -ethyl]-of the formula (I). [1,2,4] triazolo [1,5-a] pyrazine and ph salts thereof.

 The present invention further provides a compound of the present invention or a pharmaceutically acceptable acid addition salt thereof for use as a medicament.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.

The invention further provides the use of a compound of the invention for the manufacture of a medicament for the treatment of neurodegenerative or psychiatric disorders.

The invention further provides a compound of the invention for use as a medicament.

The present invention further provides schizophrenia, eg, delusional type, dissolution type, tension type, indistinguishable type, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Personality disorder of delusional type; And schizophrenic type personality disorders.

In addition, the present invention provides a method of treating a patient suffering from a neurodegenerative disorder, comprising administering a compound of the present invention to a patient. In a further aspect, the present invention provides a method for treating a patient suffering from a mental disorder, comprising administering a compound of the present invention to a patient. In another embodiment, the present invention provides a method of treating a patient suffering from drug addiction, such as alcohol, amphetamine, cocaine, or opioid poisoning, comprising administering a compound of the present invention to a patient.

Detailed description of the invention

Throughout this application, the terms PDE 10, PDE 10A and PDE 10A enzymes are used interchangeably.

Compounds of the invention, when tested as described in the PDE10A Enzyme Inhibition Assay section, have an IC ₅₀ value of about 2.2 nM, which makes them compounds useful for the inhibition of PDE 10A enzyme activity.

In addition, the compounds have been tested for their ability to regress penciclidine (PCP) induced hyperactivity. Degeneration of PCP effects is measured as described in the section "Penciclidine (PCP) Induced Hyperactivity". Experiments have shown that the compounds of the present invention are active compounds in vivo that degrade PCP induced hyperactivity by 99%.

Pharmaceutically acceptable salts

The invention also includes salts of the compounds of the invention, typically pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid and the like. Representative examples of suitable organic acids are formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid, maleic acid, malic acid, malonic acid, mannose Delic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methane sulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid , EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, and 8-haloteophylline such as 8-bromotephylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts are described in Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, the pharmaceutically acceptable salts of which are incorporated herein by reference.

In addition, the compounds of the present invention may exist in unsolvated form as well as in solvated forms using pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

Pharmaceutical composition

The present invention further provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or diluent. The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention may be administered in one or several administrations, alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient. Pharmaceutical compositions according to the invention are pharmaceutically acceptable according to conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 ^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995 As well as any other known auxiliaries and excipients.

Pharmaceutical compositions specifically include oral, rectal, nasal, lung, topical (including buccal and lingual), transdermal, intraoral, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. And may be formulated for administration by any suitable route. The route will be considered variable depending on the general condition and age of the patient to be treated, the nature of the condition to be treated and the active ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. If desired, the composition may be prepared with a coating, such as an enteric coating, or may be formulated to provide controlled release of the active ingredient, such as sustained or sustained release, according to methods well known in the art. Liquid formulations for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders to be restored in sterile injectable solutions or dispersions prior to use. Other suitable dosage forms include but are not limited to suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.

Typical oral dosages of the compounds of the invention range from about 0.001 to about 100 mg / kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg / kg body weight per day. Typical oral dosages of the compounds of the invention also range from about 0.05 to about 10 mg / kg body weight per day. Oral dosages are usually administered in one or more dosages per day, typically from one to three dosages. The exact dosage will vary depending on the frequency and manner of administration of the patient being treated, gender, age, weight and general conditions, the nature and severity of the condition being treated and any concomitant disease to be treated and other factors apparent to those skilled in the art.

The composition may also be present in unit dosage form by methods known to those skilled in the art. For illustrative purposes, typical unit dosage forms for oral administration may contain about 0.01 to about 1000 mg, about 0.05 to about 500 mg, or about 0.5 mg to about 200 mg of a compound of the present invention.

For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, the typical dosage is about half of the dosage used for oral administration.

The invention also provides a process for the preparation of a pharmaceutical composition comprising a mixture of a compound of the invention and one or more pharmaceutically acceptable carriers or diluents.

The compounds of the present invention are generally used as free substances or pharmaceutically acceptable salts thereof.

For parenteral administration, solutions of the compounds of the invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil can be used. Such aqueous solutions should be properly buffered if necessary and the liquid diluent should first be isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of the present invention can be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrups, peanut oils, olive oils, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may comprise any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax. Pharmaceutical compositions formed by combining the compounds of the invention and pharmaceutically acceptable carriers are readily administered in a variety of formulations suitable for the disclosed routes of administration. The composition may suitably be presented in unit dosage form by methods known in the art of pharmacy.

It may be provided as a separate unit, such as a capsule or tablet, each containing a composition of the invention suitable for oral administration, a predetermined amount of the active ingredient and optionally a suitable excipient, respectively. In addition, orally available compositions may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.

When a solid carrier is used for oral administration, the preparation may be tableted in hard gelatin capsules in powder or pellet form, or in troche or lozenge form. The amount of solid carrier varies widely but will range from about 25 mg to about 1 g per dosage unit. If liquid carriers are used, they may be prepared in sterile injectable liquid form, such as syrups, emulsions, soft gelatin capsules, or aqueous or non-aqueous liquid suspensions or solutions.

The pharmaceutical compositions of the present invention can be prepared by conventional methods in the art. For example, tablets can be prepared by mixing the active ingredient with common adjuvants and / or diluents and then compressing the mixture in a conventional tableting machine that produces tablets. Examples of adjuvants or diluents include corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvant or additive conventionally used for purposes such as coloring, flavoring, preservation, etc. may be used that is compatible with the active ingredient.

Disorder Treatment

As mentioned above, the compounds of the present invention are PDE10A enzyme inhibitors useful for treating related neurological and mental disorders.

The present invention therefore provides a compound of formula (I), a compound of the present invention and a pharmaceutical composition containing the compound for use in the treatment of neurodegenerative disorders, mental disorders or drug addiction in a patient; Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And age-related cognitive decline; Mental disorders include schizophrenia, for example delusional type, disorganized type, tension type, indistinguishable type, or residual type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And a schizophrenic type of personality disorder; Drug addiction is alcohol, amphetamine, cocaine, or opioid addiction.

The compounds of the present invention may be used in combination with one or more other drugs in which the compounds of the present invention are useful in treating a disease or condition in which the drug combination is safer or more effective than the drug alone. In addition, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may therefore be administered simultaneously or sequentially with the compounds of the invention in the amounts and routes conventionally used. Accordingly, the pharmaceutical compositions of the present invention include compositions containing one or more other active ingredients in addition to the compounds of the present invention. The combination may be administered as part of a unit dosage form product, or as a kit or treatment protocol, wherein one or more additional drugs are administered in separate formulations as part of the treatment plan.

The present invention provides a method of treating a patient suffering from a neurodegenerative disorder selected from cognitive impairment or movement disorder comprising administering a compound of the invention to a patient.

The invention also provides a method of treating a patient with a mental disorder comprising administering a compound of the invention to a patient. Examples of psychiatric disorders that can be treated in accordance with the present invention include schizophrenia, eg, delusional type, disorganized type, tension type, indistinguishable type, or residual type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And schizophrenic type personality disorders; Anxiety disorders are panic disorders; Agoraphobia; Specific phobias; Social phobia; Paranoid disorder; Post-traumatic stress disorder; Acute stress disorder; And generalized anxiety disorder.

The compounds of the present invention may be administered in combination with one or more neuroleptics (which may be typical or unusual antipsychotics) to provide improved treatment of mental disorders such as schizophrenia. The combinations, uses and methods of treatment of the present invention may also provide advantages in treating patients who do not respond sufficiently or are resistant to other known treatments.

Accordingly, the present invention provides a method of treating a patient suffering from a mental disorder, such as schizophrenia, comprising administering a compound of the present invention to a patient in combination therapy or monotherapy with one or more neuroleptics.

The term “nerve relaxant” as used herein refers to a drug that has an effect on the recognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor irritation in patients with psychosis. Neuroleptics, also known as antipyretics and antipsychotic drugs, include but are not limited to: phenothiazines, and further include aliphatic compounds, piperidine, and piperazine, thioxanthene (eg, seesaw) Rudinol), butyrophenone (e.g. haloperidol), dibenzoxazepine (e.g. roxapin), dihydroindolone (e.g. molindon), diphenylbutylpiperidine (e.g. pimozide) Typical antipsychotic drugs, and atypical antipsychotic drugs including benzisoxazole (eg, risperidone), sertindol, olanzapine, quetiapine, osanthant and ziprasidone.

Particularly preferred neuroleptics for use in the present invention are sertindol, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

The invention also provides a method of treating a patient with a cognitive disorder comprising administering a compound of the invention to a patient. Examples of cognitive disorders that can be treated according to the present invention include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia ; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And aging-related cognitive decline.

The invention also provides a method of treating a movement disorder in a patient comprising administering a compound of the invention to a patient. Examples of motor disorders that can be treated in accordance with the present invention include, but are not limited to, dyskinesia and Huntington's disease associated with dopamine agonist therapy. The present invention further provides a method of treating a movement disorder selected from Parkinson's disease and restless leg syndrome, comprising administering a compound of the invention to a patient.

The present invention also provides a method of treating a mood disorder comprising administering a compound of the invention to a patient. Examples of mood disorders and mood illustrations that can be treated in accordance with the present invention include mild, moderate or moderate types of depressive episodes, manic or mixed mood episodes, hypomania symptoms; Depressive episodes with typical characteristics; Depressive episodes with depressive characteristics; Depressive episodes with strain characteristics; Mood illustrations of postpartum onset; Disorders after a stroke; Major depressive disorder; Dysthymic disorders; Minor depressive disorder; Premenstrual discomfort disorders; Depressive disorder after psychosis of schizophrenia; Overlapping depressive disorder for psychiatric disorders such as delusional disorder or schizophrenia; Manic depression, such as, but not limited to, type I manic depression, type II manic depression, and cyclic mood disorders. Mood disorders are understood to be mentally disabled.

The invention also provides a method of treating drug addiction, eg, alcohol, amphetamine, cocaine, or opioid addiction in a patient, comprising administering to the patient an amount of a compound of the invention effective to treat drug addiction.

The term “drug addiction” as used herein refers to an abnormal craving for a drug and is generally characterized by motivational disorders such as an illustration of strong drug cravings and the urge to ingest the desired drug.

Drug addiction is widely regarded as a pathological condition. Addiction disorders involve the development of drug-searching behavior, vulnerability to recurrence, and the progression of acute drug use to reduced and slow ability to respond to natural reward stimuli. For example, the Mental Disorders Diagnosis and Statistics Manual, 4th Edition (DSM-IV) categorizes three stages of addiction: obsession / expectation, binge eating / addiction, and withdrawal / negative emotions. These steps are, respectively, a constant craving and obsession for drug acquisition everywhere; Use of drugs more than necessary to experience addiction effects; And reduced motivational experience with tolerance, withdrawal phenomena, and everyday life.

The present invention provides a method of treating a disorder in a patient comprising administering to the patient an amount of a compound of the invention effective to treat the disorder comprising the patient's attention and / or cognitive deficits as symptoms.

Other disorders that can be treated in accordance with the present invention are paranoid / compulsive disorders, Tourette's syndrome and other tic disorders.

As used herein, unless otherwise indicated, a "neurodegenerative disorder or condition" refers to a disorder or condition caused by dysfunction and / or death of neurons in the central nervous system. Treatment of such disorders and conditions impairs in a manner related to the prevention of dysfunction and death of neurons at risk in the disorder or condition and / or to compensation for loss of function caused by dysfunction or death of at-risk neurons. Or by the administration of agents that enhance the function of healthy neurons. As used herein, the term "economics" refers to a substance or agent having some or all of the above properties.

Examples of neurodegenerative disorders and conditions that can be treated according to the invention include Parkinson's disease; Huntington's disease; Dementia such as Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and prefrontal dementia; Neurodegeneration associated with brain trauma; Stroke related neurodegeneration, cerebral infarction related neurodegeneration; Hypoglycemia-induced neurodegeneration; Neurodegeneration associated with epileptic seizures; Neurodegeneration associated with neurotoxin poisoning; And multiple brain nervous system atrophy.

In one embodiment of the invention, the neurodegenerative disorder or condition involves neurodegeneration of the striatum's striatal medium spiny neurons.

In a further embodiment of the invention, the neurodegenerative disorder or condition is Huntington's disease.

In another embodiment, the present invention relates to administering a compound of the present invention to a patient in need thereof to reduce body fat or weight, or to treat non-insulin demanding diabetes (NIDDM), metabolic syndrome, or glucose intolerance. It provides a method of treating the patient comprising. In some embodiments, the patient is overweight or obese and the compounds of the present invention are administered orally. In another preferred embodiment, the method further comprises a second therapeutic agent, preferably an antiobesity agent, such as limonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, or peptide YY3-36 in a patient. , Or analogues thereof.

The term “metabolic syndrome” as used herein refers to a group of conditions that have put people at high risk of coronary artery disease. Such conditions include type 2 diabetes, obesity, high blood pressure, and poor HDL ("good") cholesterol, poor fat conditions with elevated LDL ("bad") cholesterol, and elevated triglycerides. All of these conditions are associated with hypertension insulin levels. A fundamental defect in metabolic syndrome is insulin resistance in adipose tissue and muscle.

All references, including publications, patent applications, and patents cited herein, are incorporated in their entirety, individually and in detail, to be incorporated by reference in their entirety (maximum range permitted by law), all and such To the extent incorporated herein by reference.

Headings and subheadings are used herein for convenience only and should not be understood to limit the invention in any way.

The use of any and all example or exemplary language herein (including "for example", "example" and "such as") is intended to explain the invention only well, and unless otherwise indicated, the invention It does not raise any limitations on its scope.

The citation and integration of patent documents herein is for convenience only and does not reflect any aspect of the validity, patentability and / or exerciseability of such patent documents.

The invention includes both modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

Experiment Division

Preparation of Compounds of the Invention

Compounds of the invention can be prepared as described in Scheme 1 below.

In particular, the compounds of the present invention may be prepared by reduction of alkenes of formula V by hydrogenation using a transition metal catalyst such as palladium metal with a hydrogen source such as hydrogen gas, ammonium bicarbonate, or cyclohexadiene. . The alkene of formula (V) is a phosphonium salt of formula (III) and an aldehyde of formula (IV) in a suitable solvent such as tetrahydrofuran in the presence of a suitable base such as 1,8-diazabicyclo [5.4.0] undes-7-ene. It can be prepared by the Wittich reaction of the liver. The phosphonium salts of formula III are readily available by reaction of the compound of formula II with triphenylphosphine by methods known to chemists in the art. Aldehydes of formula IV are readily available and are known in the art, for example, as described in Journal of Medicinal Chemistry (2009), 52 (21), 6535-6538, or WO-2004024705 and US-4826833. have.

Electrophiles II (Scheme 2) are described, for example, in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 1996, (19), 2345-2350 and Journal of Heterocyclic Chemistry (1981), 18 ( 3), 555-8] can be prepared from dimethylchloropyrazine of formula VI known in the art. Compound VI can be converted to aminopyrazine of Formula VII as described in the literature, for example in Science of Synthesis (2004), 16 751-844 and Synthesis 1994, (9), 931-4. Amination of 6-membered heterocycles such as pyrazine of Formula VIII using, for example, an electrophilic aminoating agent such as O-mesitylenesulfonylhydroxylamine is described, for example, in Organic Process Research & Development 2009, 13, 263-267, are well known in the art. The reaction of the compound of formula VIII with methyl chloroacetate yields electrophile II .

Schematic 2

The invention disclosed herein is further illustrated by the following non-limiting examples.

General method

The analytical LC-MS data was obtained using the following method.

Method A:

PE Sciex API 150EX instrument equipped with atmospheric photoionization and Shimadzu LC-8A / SLC-10A LC system was used. Column: 4.6 × 30 mm Waters Symmetry C18 column (particle size 3.5 μm); Column temperature: 60 ° C .; Solvent system: A = water / trifluoroacetic acid (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid (5: 95: 0.035); Method: Linear gradient elution Within 2.4 minutes A: B = 90:10 to 0: 100 and flow rate 3.3 ml / min.

 Preparative LC-MS-purification was performed on a PE Sciex API 150EX instrument using atmospheric chemical ionization. Column: 50 × 20 mm YMC ODS-A (particle size 5 μm); Method: Linear gradient elution Within 7 minutes A: B = 80: 20 to 0: 100 and flow rate 22.7 ml / min. Fraction collection was performed with split flow MS detection.

¹ H NMR spectra were recorded at 500.13 MHz for the Bruker Avance AV500 instrument or 250.13 MHz for the Bruker Avance DPX250 instrument. TMS was used as an internal reference standard. Chemical shift values are expressed in ppm. The following abbreviations were used for a number of NMR signals: s = singlet, d = doublet, t = triplet, q = quadruplet, qui = quintet, h = hexard, dd = double doubling, dt = Double triplet, dq = double triplet, tt = triplet triplet, m = multiplet, br s = wideband singlet and Br = wideband signal.

The abbreviations are described in [ACS Style Guide: "The ACS Styleguide-A manual for authors and editors" Janet S. Dodd, Ed. 1997, ISBN: 0841234620].

Intermediate manufacturing

2- Chloromethyl -5,7-dimethyl- [1,2,4] Triazolo [1,5-a] pyrimidine

400 4,6- ㎖ in CH ₂ Cl ₂ in dimethyl-pyrimidin-2-ylamine (25 g, 200 mmol) of hydroxylamine-2,4,6-CH ₂ Cl ₂ to a solution of 300 ㎖ trimethyl- A solution of benzenesulfonate (105 g, 488 mmol) was added dropwise at 0 ° C. and the mixture was stirred at 0 ° C. for 1 hour and filtered manually. The collected solid was washed with CH ₂ Cl ₂ (100 mL) to yield 1-amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-trimethyl-benzenesulfonate. (40 g, yield: 62%).

1-amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-trimethyl-benzenesulfonate (40 g, 0.1 mol) in 500 mL of EtOH and NaOH (10 g, 0.2 mol) was stirred at 50-60 ° C. for 1 hour. After addition of chloroacetic acid methyl ester (16.6 g, 0.15 mol), the resulting mixture was stirred under reflux for 4 hours. After concentration under reduced pressure, the residue was diluted with water (1000 mL) and extracted with CH ₂ Cl ₂ (300 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc = 2/1) to give 2 g of 2-chloromethyl-5,7-dimethyl- [1,2,4] triazolo [1,5- a] pyrimidine was calculated in 9% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ8.55 (s, 1H), 6.25 (s, 2H), 4.05 (s, 3H), 3.95 (s, 3H); LC-MS (MH ⁺ ): m / z = 196.9, t _R (min, method A) = 0.52

The following intermediates were prepared analogously:

2-chloromethyl-5,8-dimethyl- [1,2,4] -triazolo [1,5-a] pyrazine from 2-amino-3,6-dimethylpyrazine. 60% yield, ¹ H NMR (500 MHz, CDCl ₃ ): δ7.91 (s, 1H), 4.87 (s, 2H), 2.91 (s, 3H), 2.74 (s, 3H), LC-MS: m / z = 196.9 (MH ⁺ ), t _R = 0.64 min, method A

Trans-5,8-dimethyl-2-[(E) -2- (1- methyl -4- Phenyl -1H- Imidazole -2-yl) -vinyl]-[1,2,4] triazolo [1,5-a] pyrazine

2-chloromethyl-5,8-dimethyl- [1,2,4] -triazolo [1,5-a] pyrazine (1.351 g, 6.87 mmol) and triphenylphosphine (1.80 g, in 150 mL acetonitrile, 6.87 mmol) was heated at reflux for 12 h. The solvent is removed in vacuo, the residue slurried in ether, filtered and dried (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-ylmethyl) -Triphenyl-phosphonium; Chloride was calculated as an off-white solid (2.412 g, 74.9%). LC-MS: m / z = 423.2 ([M-Cl] < + >), tR = 0.86 min, Method A.

A solution of 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde (220 mg, 1.18 mmol) in dry THF was dissolved in (5,8-dimethyl- [1,2,4] triazolo [1,5 -a] pyrazin-2-ylmethyl) -triphenyl-phosphonium; Chloride (500 mg, 1.18 mmol) was added under argon and 1,8-diazabicyclo [5.4.0] undes-7-ene (176 μl, 1.18 mmol) was added. The reaction mixture was stirred at rt for 2 h and then evaporated on silica gel (2 g). Silicagel chromatography (tilt eluting; A: B 50: 50 → 100: 0, where A is ethyl acetate and B is heptane) yielded the title compound (334 mg, 79%) as an off-white solid. LC-MS: m / z = 331.4 (MH ⁺ ), t _R = 0.65 min, Method A.

Preparation of Compounds of the Invention

Example  One

5,8-dimethyl-2- [2- (1- methyl -4- Phenyl -1H- Imidazole -2-yl) -ethyl]-[1,2,4] Triazole in[ 1,5-a] pyrazine

Continuous-flow Hydrogenation Reactor (ThalesNano) 를 통과시켰다. 휘발성물질을 증발시켜 표제 화합물을 산출하였다 (178 mg, 51 %). LC-MS: m/z = 333.2 (MH⁺), t _R = 0.57 분, 방법 A.Trans-5,8-dimethyl-2-[(E) -2- (1-methyl-4-phenyl-1H-imidazol-2-yl) -vinyl] -imidazo [1, in methanol (50 mL) 2-a] pyrazine (330 mg, 1.0 mmol) solution was purified by H-Cube at a flow rate of 1 ml / min through a small cartridge of 10% Pd / C (THS01111) with an internal temperature of 25 ° C. and hydrogen pressure of 1 bar.

Passed through the Continuous-flow Hydrogenation Reactor (ThalesNano). The volatiles were evaporated to yield the title compound (178 mg, 51%). LC-MS: m / z = 333.2 (MH ⁺ ), t _R = 0.57 min, Method A.

Pharmacological test

PDE10A Enzyme

Active PDE10A enzymes were prepared in a number of ways for use in PDE assays (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. et al. Eur J Biochem. 1999, 266, 1118). -1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A can be expressed as a full length protein or a short axis protein as long as it expresses a catalytic domain. PDE10A can be produced in different cell types, for example insect cells or E. coil. An example of a method of obtaining catalytically active PDE10A is as follows: The catalytic domain of human PDE10A (amino acids 440-779 from the sequence of accession number NP 006652) is amplified from whole human brain whole RNA by standard RT-PCR and pET28a It is cloned into the BamH1 and Xho1 sites of the vector Novova. Expression in E. coli is performed according to standard protocols. Briefly, the expression plasmid was transformed into BL21 (DE3) Escherichia coli, and 50 ml of culture inoculated with cells proliferating with an OD600 of 0.4-0.6 prior to protein expression were induced with 0.5 mM IPTG. Following induction, cells were incubated overnight at room temperature before cells were collected by centrifugation. Cells expressing PDE10A were resuspended in 12 ml (50 mM TRIS-HCl-pH8.0, 1 mM MgCl ₂ and protease inhibitor). After lysing the cells, all cells were lysed and TritonX100 was added according to the Novagen protocol. PDE10A was partially purified in Q Sepharose and the most active fractions collected.

PDE10A  Inhibition Assay

PDE10A assays can be performed, for example, as follows: an amount of relevant PDE enzyme, buffer (50 mM HEPES7.6; 10 mM MgCl ₂ , sufficient to be converted to 20-25% cyclic nucleotide substrate). 0.02% Tween20), 0.1 mg / ml BSA, 225 pCi of ³ H-labeled cyclic nucleotide substrate, tritium-labeled cAMP with a final concentration of 5 nM, and 60 uL samples containing various amounts of inhibitors. Essays were performed. The reaction was started by adding a cyclic nucleotide substrate, and the reaction was allowed to proceed at room temperature for 1 hour and then terminated by mixing with 15 uL 8 mg / ml yttrium silicate SPA beads (Amersham). The beads were allowed to settle in the dark for 1 hour and the plates were counted with a Wallac 1450 Microbeta counter. The measured signal can be converted to activity for an uninhibited control (100%) and IC ₅₀ values can be calculated using Xlfit extending to EXCEL.

In the context of the present invention, 60 uL assay buffer (50 mM HEPES pH 7.6; 10 mM MgCl ₂ ; 0.02% Tween20) containing PDE10A and various amounts of inhibitors sufficient to convert 20-25% of 10 nM ³ H-cAMP The assay was performed in The reaction was then terminated by adding 15 uL 8 mg / mL yttrium silicate SPA beads (Amersham) after 1 hour incubation. The beads were allowed to settle in the dark for 1 hour and the plates were counted with a Wallac 1450 Microbeta counter. IC ₅₀ values were calculated by nonlinear regression using XLfit (IDBS).

Experimental results showed that the compounds of the invention tested inhibited the PDE10A enzyme with an IC ₅₀ value of about 2.2 nM.

Penciclidine  ( PCP Induced hyperactivity

Male mice (NMRI, Charles River) weighing 20-25 g were used. Eight mice were used for each group to receive test compound (5 mg / kg) + PCP (2.3 mg / kg), as well as a parallel control to receive vehicle + PCP or vehicle infusion of test compound only. The injection amount was 10 ml / kg. Experiments were conducted under normal bright conditions in an unobstructed room. Test substances were injected orally 60 minutes before PCP infusion administered subcutaneously.

Immediately after PCP injection, mice were placed in specially designated test cages (20 cm x 32 cm), respectively. Activity was measured with a photovoltaic cell and a 5 × 8 infrared light source at 4 cm intervals. The light beam passed through the cage 1.8 cm above the bottom of the cage. Since the recording of the number of movements requires the obstruction of adjacent light beams, the number caused by the change in the posture of the mouse is avoided.

Mobility was recorded at 5 minute intervals for 1 hour. The drug effect on the total number during the 1 hour behavioral test period was calculated in the following manner:

Average motility induced by vehicle treatment without PCP was used as a baseline. Therefore, 100% of the PCP effect was calculated as the total number of motions-baseline. Responses in groups receiving test compounds were determined by total number of movements-baseline and expressed in% of similar results recorded in parallel PCP controls. The percentage response converted to a percentage degeneration of PCP induced hyperactivity.

Experimental results showed that the compounds of the present invention are active compounds in vivo that 99% deteriorate PCP induced hyperactivity.

Claims (9)

Compound 5,8-dimethyl-2- [2- (1-methyl-4-phenyl-1H-imidazol-2-yl) -ethyl]-[1,2,4] triazolo [1,5-a] Pyrazine and its pharmaceutically acceptable acid addition salts:

. The compound of claim 1 for use as a medicament. The neurodegenerative or recited in claim 1, alone or in combination with one or more neuroleptics selected from the group consisting of sertindol, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanthane. Compounds for use in treating mental disorders:
Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And age-related cognitive decline, wherein the mental disorder is schizophrenia, eg, delusional type, deconstruction type, tension type, indistinguishable form, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Personality disorder of delusional type; And a schizophrenic type of personality disorder. Use of the compound of claim 1 for the manufacture of a medicament for the treatment of neurodegenerative or mental disorders:
Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And aging-related cognitive decline, and the mental disorder is schizophrenia, eg, delusional type, deconstruction type, tension type, indistinguishable form, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And a schizophrenic type of personality disorder. A method comprising administering an effective amount of a compound according to claim 1, alone or in combination with one or more neuroleptics selected from sertindol, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, and osanthant. Treatment of patients with neurodegenerative or mental disorders
Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And aging-related cognitive decline, and the mental disorder is schizophrenia, eg, delusional type, deconstruction type, tension type, indistinguishable form, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And a schizophrenic type of personality disorder. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier, diluent and excipient. A compound according to claim 1 for the preparation of a medicament for the treatment of neurodegenerative or psychiatric disorders, and selected from the group consisting of sertindol, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanthane Uses of Additional Compounds:
Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And aging-related cognitive decline, and the mental disorder is schizophrenia, eg, delusional type, deconstruction type, tension type, indistinguishable form, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And a schizophrenic type of personality disorder. The compound according to claim 1 or 2, as a combination formulation for simultaneous, separate or continuous use in the treatment of neurodegenerative or psychiatric disorders, and sertindol, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, zipras Additional compounds selected from the group consisting of Sidon and Osanetane:
Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And aging-related cognitive decline, and the mental disorder is schizophrenia, eg, delusional type, deconstruction type, tension type, indistinguishable form, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And a schizophrenic type of personality disorder. The compound of claim 1 for the treatment of neurodegenerative or psychiatric disorders:
Such neurodegenerative disorders include Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, intracranial tumor or brain trauma-related dementia, Huntington's or Parkinson's-related dementia, or AIDS-related dementia; Delirium; Amnesia disorders; Post-traumatic stress disorder; Mental retardation; Learning disabilities, such as reading disorders, arithmetic disorders, or writing disorders; Attention-deficiency / hyperactivity disorder; And aging-related cognitive decline, and the mental disorder is schizophrenia, eg, delusional type, deconstruction type, tension type, indistinguishable form, or remnant type; Schizophrenic disorders; Schizoaffective disorders such as delusional type or depressive type; Delusional disorder; Mood swings, such as type I depression, type II mood swings, and cyclic mood disorders; Substance-induced psychotic disorders such as psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or penciclidine; Delusional personality disorder; And a schizophrenic type of personality disorder.