IMIDAZO[1,2-A]PYRIDINE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

• US 20110263592A1
• Filed: 08/14/2008
• Published: 10/27/2011
• Est. Priority Date: 08/15/2007
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Feichtinger, Konrad, Xiong, Yifeng, Ren, Albert S., Ullman, Brett
• Granted Patent: US 9,567,327 B2
• Time in Patent Office: Days
• US Class Current: 514/233.2
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Imidazo[1,2-α]pyridine derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT_2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of insomnia, dyssomnia, parasomnia and related sleep disorders, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to methods for the treatment of 5-HT_2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

Claims

1. A compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof:

2. The compound according to claim 1, wherein R¹ and R² are each independently selected from the group consisting of H, C₃-C₆ acyloxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ allylsulfonyl, aryl, aryl-C₁-C₄-alkylenyl, carbo-C₁-C₆ alkoxy, carboxy, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, heterocyclyl and hydroxyl.

3. The compound according to claim 1, wherein R¹ and R² are each independently selected from the group consisting of H, methyl, t-butyl, phenyl, cyano, trifluoromethyl, chloro and bromo.

4. The compound according to claim 1, wherein R¹ is H;

and R² is cyano, chloro or bromo.

5. The compound according to claim 1, wherein R¹ and R² are both H.

6. The compound according to any one of claims 1 to 5, wherein R³, R⁴ and R⁵ are each independently selected from the group consisting of H, methyl, methoxy and bromo.

7. The compound according to any one of claims 1 to 5, wherein R³, R⁴ and R⁵ are each H.

8. The compound according to any one of claims 1 to 8, wherein R⁶ and R⁷ are each independently selected from the group consisting of H and methyl.

9. The compound according to any one of claims 1 to 8, wherein R⁶ and R⁷ are both H.

10. The compound according to any one of claims 1 to 11, wherein:

R⁸ and R⁹ are each independently selected from the group consisting of H, C₁-C₃ alkyl, aryl, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, C₁-C₃ haloalkyl, halogen and hydroxyl;

or

R⁸ and R⁹ taken together form oxo;

or

R⁸ and R⁹ together with the atom to which they are both bonded form a C₃-C₇ cycloalkyl ring.

11. The compound according to any one of claims 1 to 11, wherein R⁸ and R⁹ are both H.

12. The compound according to any one of claims 1 to 11, wherein R⁸ and R⁹ together form oxo.

13. The compound according to any one of claims 1 to 12, wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are each independently selected from the group consisting of H, C₁-C₆ acyloxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₁-C₆ alkylcarboxamide, C₁-C₆ alkylsulfonamide, C₁-C₆ alkylsulfonyl, amino, carboxamide, carboxy, cyano, C₃-C₆ cycloalkyl, C₂-C₆ dialkylcarboxamide, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro, phenyl, sulfonamide and sulfonic acid;

wherein said phenyl group is optionally substituted with 1, 2 or 3 halogens.

14. The compound according to any one of claims 1 to 12, wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are each independently selected from the group consisting of H, methyl, methoxy, dimethylamino, —

NHSO₂CH₃, methylsulfonyl, carboxamide, carboxy, cyano, cyclohexyl, fluoro, chloro, trifluoromethoxy, difluoromethoxy, trifluoromethyl, morpholin-4-yl, pyrrolidin-1-yl, thien-2-yl, hydroxyl, nitro, phenyl and sulfonic acid.

15. The compound according to any one of claims 1 to 12, wherein:

R¹⁰ and R¹² are both F; and

R¹¹, R¹³ and R¹⁴ are each H.

16. The compound according to claim 1, selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates or hydrates thereof:

17. The compound according to claim 1, selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates or hydrates thereof:

18. The compound according to claim 1, selected from compounds of Formula (Ie) and pharmaceutically acceptable salts, solvates or hydrates thereof:

19. The compound according to claim 1, selected from compounds of Formula (Ie) and pharmaceutically acceptable salts, solvates or hydrates thereof:

20. The compound according to claim 1 selected from the following compounds and pharmaceutically acceptable salts, solvates or hydrates thereof:

(3-bromoimidazo[1,2-α

]pyridin-8-yl)(4-(2,4-difluorophenethyl)piperazin-1-yl)methanone;

8-(4-(2,4-difluorophenethyl)piperazine-1-carbonyl)imidazo[1,2-α

]pyridine-3-carbonitrile;

(4-(2,4-difluorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

1-(4-fluorophenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(2-(trifluoromethyl)imidazo[1,2-α

]pyridin-8-yl)methanone;

(2-tert-butylimidazo[1,2-α

]pyridin-8-yl)(4-(4-fluorophenethyl)piperazin-1-yl)methanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(2-methylimidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(2-phenyl imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(2-fluoro-2-(4-fluorophenyl)ethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(3-chloroimidazo[1,2-α

]pyridin-8-yl)(4-(2,4-difluorophenethyl)piperazin-1-yl)methanone;

imidazo[1,2-α

]pyridin-8-yl(4-(4-methoxyphenethyl)piperazin-1-yl)methanone;

(4-(3,4-dimethoxyphenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(3-fluorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(4-chlorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(3-chlorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(2-chlorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(2-fluorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

(4-(2,4-dichlorophenethyl)piperazin-1-yl)(imidazo[1,2-α

]pyridin-8-yl)methanone;

1-(2,4-difluorophenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(pyrrolidin-1-yl)phenyl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(trifluoromethoxy)phenyl)ethanone;

N-(2-hydroxy-5-(2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)acetyl)phenyl)methanesulfonamide;

1-(2-chloro-5-(trifluoromethyl)phenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(biphenyl-4-yl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(methyl sulfonyl)phenyl)ethanone;

(4-(2,4-difluorophenethyl)piperazin-1-yl)(5,7-dimethylimidazo[1,2-α

]pyridin-8-yl)methanone;

1-(4-cyclohexylphenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(4-(difluoromethoxy)phenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-phenylpropan-1-one;

1-(4-chloro-2-fluoro-5-methylphenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(5-chloro-2-methoxy-4-methylphenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(3,5-bis(trifluoromethyl)phenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(thiophen-2-yl)phenyl)ethanone;

(4-(2,4-difluorophenethyl)piperazin-1-yl)(7-methoxyimidazo[1,2-α

]pyridin-8-yl)methanone;

2-hydroxy-5-(2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)acetyl)benzamide;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(2-(trifluoromethyl)phenyl)ethanone;

4-(2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)acetyl)benzonitrile;

1-(4-hydroxyphenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(4-(dimethylamino)phenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(5-chloro-2-methoxy-4-methyl-3-nitrophenyl)-2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-α

]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-morpholinophenyl)ethanone; and

(6-bromoimidazo[1,2-α

]pyridin-8-yl)(4-(2,4-difluorophenethyl)piperazin-1-yl)methanone.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

22. A method for treating a 5-HT_2A mediated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

23. The method according to claim 22, wherein said 5-HT_2A mediated disorder is a sleep disorder.

24. The method according to claim 23, wherein said sleep disorder is a dyssomnia.

25. The method according to claim 23, wherein said sleep disorder is insomnia.

26. The method according to claim 23, wherein said sleep disorder is a parasomnia.

27. A method for increasing slow wave sleep in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

28. A method for improving sleep consolidation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

29. A method for improving sleep maintenance in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

30. A method for treating a condition associated with platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

31. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a 5-HT_2A mediated disorder.

32. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a sleep disorder.

33. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a dyssomnia.

34. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of insomnia.

35. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a parasomnia.

36. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for increasing slow wave sleep.

37. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for improving sleep consolidation.

38. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for improving sleep maintenance.

39. Use of a compound according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a condition associated with platelet aggregation.

40. A compound according to any one of claims 1 to 20 for use in a method of treatment of the human or animal body by therapy.

41. A compound according to any one of claims 1 to 20 for use in a method for the treatment of a 5-HT_2A mediated disorder.

42. A compound according to any one of claims 1 to 20 for use in a method for the treatment of a sleep disorder.

43. A compound according to any one of claims 1 to 20 for use in a method for the treatment of a dyssomnia.

44. A compound according to any one of claims 1 to 20 for use in a method for the treatment of insomnia.

45. A compound according to any one of claims 1 to 20 for use in a method for the treatment of a parasomnia.

46. A compound according to any one of claims 1 to 20 for use in a method for increasing slow wave sleep.

47. A compound according to any one of claims 1 to 20 for use in a method for improving sleep consolidation.

48. A compound according to any one of claims 1 to 20 for use in a method for improving sleep maintenance.

49. A compound according to any one of claims 1 to 20 for use in a method for the treatment of a condition associated with platelet aggregation.

50. A process for preparing a composition comprising admixing a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier.