AZACYCLIC COMPOUNDS

• US 20090186921A1
• Filed: 01/16/2009
• Published: 07/23/2009
• Est. Priority Date: 03/06/2000
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Hansen, E. L., Croston, Glenn, Uldam, Allan Kjaersgaard, Andersson, Carl-Magnus A.
• Application Number:
  US12/355,737
• Publication Number:
  US 20090186921A1
• Time in Patent Office: Days
• US Class Current: 514/331
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

Compounds and methods are provided for the treatment of disease conditions in which modification of serotonergic receptor activity has a beneficial effect. In the method, an effective amount of a compound is administered to a patient in need of such treatment.

Claims

1-17. -17. (canceled)

18. A compound of formula (I)

wherein

Z is

in which

R is hydrogen, C_1-6alkyl, C_3-6cycloalkyl, or C_3-6cycloalkyl(C_1-6 alkyl);

n is 1;

X₁ is NH or N(lower alkyl) group and X₂ is methylene;

Y₁ is methylene and Y₂ is methylene or a bond;

Ar₁ is an unsubstituted or substituted phenyl group;

Ar₂ is an unsubstituted or substituted phenyl group, provided that Ar₁ and Ar₂ are not simultaneously unsubstituted phenyl;

wherein when Ar₁ and Ar₂ are substituted, Ar₁ and Ar₂ can be independently substituted with one or more substituents selected from the group consisting of halo, hydroxy, amino, cyano, nitro, C_1-6 alkylamido, acyl, C_1-6 alkoxy, C_1-6 alkyl, hydroxy-C_1-6 alkyl, amino-C_1-6 alkyl, C_1-6 alkylamino, C_1-6 alkylsulfenyl, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, sulfamoyl and CF₃; and

W is oxygen or sulfur;

or

a pharmaceutically acceptable salt or prodrug thereof.

19. A compound according to claim 18, wherein W is oxygen.

20. A compound according to claim 18, wherein X₁ is NH and X₂ is methylene.

21. A compound according to claim 18, wherein Ar₁ is a mono-substituted phenyl group.

22. A compound according to claim 18, wherein Ar₂ is a mono-substituted phenyl group.

23. A compound according to claim 18, wherein Ar₁ and Ar₂ can be independently substituted with one or more substituents selected from the group consisting of halo, hydroxy, amino, C_1-6 alkoxy, C_1-6 alkyl and CF₃

24. A compound according to claim 18, wherein the compound is selected from the group consisting of:

N-((4-methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N′

-phenylmethylcarbamide;

N-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′

-phenylmethylcarbamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′

-benzyl-carbamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-methoxybenzyl)-carbamide; and

N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N′

-(4-methoxybenzyl)-carbamide.

25. A compound according to claim 18, wherein the compound is N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-N′

-phenylmethylcarbamide.

26. A pharmaceutical composition comprising an effective amount of one or more compounds of claim 18.

27. A method of inhibiting an activity of a serotonin receptor comprising contacting the serotonin receptor or a system containing the serotonin receptor with an amount of one or more of the compounds of claim 18 that is effective in inhibiting the activity of the serotonin receptor.

28. The method of claim 27, wherein the serotonin receptor is the 5-HT2A subclass.

29. The method of claim 27, wherein the serotonin receptor is in one or more selected from the group consisting of the central nervous system, the peripheral nervous system, the blood cells and the blood platelets.

30. The method of claim 27, wherein the serotonin receptor is mutated or modified.

31. A method of inhibiting an activation of a serotonin receptor comprising contacting the serotonin receptor or a system containing the serotonin receptor with an amount of a compound of one or more of the compounds of claim 18 that is effective in inhibiting the activation of the serotonin receptor.

32. The method of claim 31, wherein the activation is by an agonistic agent.

33. The method of claim 31, wherein the activation is constitutive.

34. The method of claim 31, wherein the serotonin receptor is the 5-HT2A subclass.

35. The method of claim 31, wherein the serotonin receptor is in one or more selected from the group consisting of the central nervous system, the peripheral nervous system, the blood cells and the blood platelets.

36. The method of claim 31, wherein the serotonin receptor is mutated or modified.

37. A method of treating a disease condition associated with a serotonin receptor comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more of the compounds of claim 18, wherein the disease condition is selected from the group consisting of schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.

38. The method of claim 37, wherein the serotonin receptor is the 5-HT2A subclass.

39. A method of treating or alleviating a symptom of schizophrenia or psychosis in a human, comprising administering a pharmaceutical composition comprising an amount of a 5-HT2A inverse agonist that effectively attenuates or abolishes 5-HT2A receptor activity in the human, wherein the 5-HT2A inverse agonist has little or substantially no activity on dopamine receptors.

40. The method of claim 39, wherein 0.001 mg/kg to 10 mg/kg of body weight per day of 5-HT2A inverse agonist is orally administered to the human.

41. The method of claim 39, wherein the 5-HT2A inverse agonist has little or no activity at 5-HT1A, 5-HT1B, histaminergic, adrenergic or muscarinergic receptors.

42. A method for selectively inhibiting 5-HT2A activity in a human, comprising administering a compound that selectively inhibits activity of 5-HT2A receptors to a human in need of such treatment.

43. The method of claim 42, wherein the compound has little or no activity at 5-HT1A, 5-HT1B, dopaminergic, histaminergic, adrenergic or muscarinergic receptors.

44. A method of attenuating or abolishing an undesired side effect associated with administration of a “

typical”

anti-psychotic agent, comprising administering an anti-psychotic agent to a schizophrenic or psychotic human in an amount sufficient to treat or alleviate a symptom of schizophrenia or psychosis in the human, wherein the anti-psychotic agent is a selective 5-HT2A inverse agonist with little or no activity at 5-HT1A, 5-HT1B, dopaminergic, histaminergic, adrenergic or muscarinergic receptors.

45. The method of claim 44, wherein the undesired side effect comprises akathisias, tremor or tardive dyskinesia.

46. A method for the treatment of a disease or disorder selected from the group consisting of psychosis, schizophrenia, depression, anxiety, sleep disorders, appetite disorders, affective disorders, major depression, bipolar disorder, Tourette'"'"'s Syndrome or migraine comprising administering to a human in need of said treatment an amount of a compound effective to treat the disease or disorder, wherein the compound is a selective 5-HT2A inverse agonist or antagonist with little or no activity at 5-HT1A, 5-HT1B, dopaminergic, histaminergic, adrenergic or muscarinergic receptors.

47. A pharmaceutical composition for treating or alleviating a symptom of schizophrenia or psychosis in a human, comprising a pharmaceutically acceptable diluent or excipient and a serotonin receptor subtype 2A (“

5-HT2A”

) inverse agonist that selectively attenuates or abolishes 5-HT2A activity in the human, wherein the 5-HT2A inverse agonist has little or substantially no activity on dopamine receptors.