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Claims for Patent: 6,953,787

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Claims for Patent: 6,953,787

Title: 5HT2C receptor modulators
Abstract:The present invention relates to novel compounds of Formula (I): ##STR1## which act as 5HT.sub.2C receptor modulators. These compounds are useful in pharmaceutical compositions whose use includes the treatment of obesity.
Inventor(s): Smith; Brian (San Diego, CA), Smith; Jeffrey (San Diego, CA)
Assignee: Arena Pharmaceuticals, Inc. (San Diego, CA)
Application Number:10/410,991
Patent Claims: 1. A compound of Formula (I): ##STR60##

wherein: R.sub.1 is H or C.sub.1-8 alkyl; R.sub.2 is C.sub.1-8 alkyl, --CH.sub.2 --O--C.sub.1-8 alkyl, --C(.dbd.O)--O--C.sub.1-8 alkyl, --C(.dbd.O)--NH--C.sub.1-8 alkyl, OH, or CH.sub.2 OH; R.sub.2a is H; or R.sub.2 and R.sub.2a together form --CH.sub.2 --CH.sub.2 --; R.sub.3 is halogen, perhaloalkyl, CN, SR.sub.5, NHR.sub.5, N(R.sub.5).sub.2, aryl, or heteroaryl, wherein said aryl can be optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, perhalo alkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C.sub.1-8 alkyl; R.sub.4 is H, halogen, perhaloalkyl, CN, SR.sub.5, NHR.sub.5, N(R.sub.5).sub.2, aryl, or heteroaryl, wherein said aryl can be optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, perhalo alkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C.sub.1-8 alkyl; each R.sub.5 is independently C.sub.1-8 alkyl, C.sub.1-8 alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl, or allyl; and R.sub.6 is H or C.sub.1-8 alkyl; wherein heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furanyl, pyranyl, thienyl, benzimidazolyl, quinolinyl, isoquinolinyl, oxazolyl, thiazolyl or thiadiazolyl; or a pharmaceutically acceptable salt, solvate or hydrate thereof provided that: (B) if R.sub.6 is other than H, then neither R.sub.3 nor R.sub.4 can be H; (C) if R.sub.1 and R.sub.2 are methyl, and R.sub.4 is H, then R.sub.3 cannot be NHR.sub.5 or N(R.sub.5).sub.2 ; and (D) if R.sub.1 and R.sub.2 are methyl, and R.sub.4 is H, then R.sub.3 cannot be imidazole, substituted imidazole, or an imidazole derivative.

2. A compound of Formula (I): ##STR61##

wherein: R.sub.1 is H or C.sub.1-8 alkyl; R.sub.2 is C.sub.1-8 alkyl, --CH.sub.2 --O--C.sub.1-8 alkyl, --C(.dbd.O)--O--C.sub.1-8 alkyl, --C(.dbd.O)--NH--C.sub.1-8 alkyl, OH, or CH.sub.2 OH; R.sub.2a is H; or R.sub.2 and R.sub.2a together form --CH.sub.2 --CH.sub.2 --; R.sub.3 is H, halogen, perhaloalkyl, CN, SR.sub.5, NHR.sub.5, N(R.sub.5).sub.2, aryl, or heteroaryl, wherein said aryl can be optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, perhalo alkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C.sub.1-8 alkyl; R.sub.4 is halogen, perhaloalkyl, CN, SR.sub.5, NHR.sub.5, N(R.sub.5).sub.2, aryl, or heteroaryl, wherein said aryl can be optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, perhalo alkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C.sub.1-8 alkyl; each R.sub.5 is independently C.sub.1-8 alkyl, C.sub.1-8 alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl, or allyl; and R.sub.6 is H or C.sub.1-8 alkyl; wherein heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furanyl, pyranyl, thienyl, benzimidazolyl, quinolinyl, isoquinolinyl, oxazolyl, thiazolyl or thiadiazolyl; or a pharmaceutically acceptable salt, solvate or hydrate thereof provided that: (A) if R.sub.2 methyl and R.sub.1 and R.sub.3 are both H, then R.sub.4 is not thiazole, substituted thiazole or a thiazole derivative; and (B) if R.sub.6 is other than H, then neither R.sub.3 nor R.sub.4 can be H.

3. The compound according to claim 1 wherein R.sub.1 is H.

4. The compound according to claim 1 wherein R.sub.1 is methyl.

5. The compound according to claim 1 wherein R.sub.2 is methyl, ethyl, n-propyl or isopropyl.

6. The compound according to claim 1 wherein R.sub.2 is methyl or ethyl.

7. The compound according to claim 1 wherein R.sub.2 and R.sub.2a together form --CH.sub.2 --CH.sub.2 --.

8. The compound according to claim 1 wherein R.sub.3 is chlorine.

9. The compound according to claim 1 wherein R.sub.3 is bromine.

10. The compound according to claim 1 wherein R.sub.3 is perhaloalkyl.

11. The compound according to claim 10 wherein R.sub.3 is CF.sub.3.

12. The compound according to claim 1 wherein R.sub.3 is selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyl.

13. The compound according to claim 1 wherein R.sub.4 is selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyl optionally substituted with one or two substituents selected from halogen or methyl.

14. The compound according to claim 1 wherein R.sub.4 is phenyl optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, and alkoxy.

15. The compound according to claim 1 wherein: R.sub.2 is methyl, ethyl, isopropyl, or CH.sub.2 OH; or R.sub.2 and R.sub.2a taken together form --CH.sub.2 --CH.sub.2 --; R.sub.3 is halogen, or a 5-membered heteroaryl ring having up to two heteroatoms selected from O, N and S, and up to two substituents selected from halogen and C.sub.1-8 alkyl; R.sub.4 is H, a 5-membered heteroaryl ring having up to two heteroatoms selected from O, N and S and up to two substituents selected from halogen and C.sub.1-8 alkyl, or phenyl optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, and alkoxy; and R.sub.6 is H or methyl; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

16. The compound according to claim 1 wherein: R.sub.1 is H; R.sub.2 is methyl; R.sub.3 is chlorine, bromine, or thienyl; R.sub.4 is pyrrazoly-3-yl or phenyl wherein said pyrazolyl-3-yl optionally has up to two substituents selected from halogen and C.sub.1-8 alkyl, and said phenyl optionally has a single halogen substitutent; and R.sub.6 is H; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2 and a pharmaceutically acceptable carrier or excipient.

18. A method of decreasing food intake of a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound as in any one of claims 1 and 2.

19. A method of inducing satiety in a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound as in any one of claims 1and 2.

20. A method of controlling weight gain of a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound as in any one of claims 1 and 2.

21. A method of treatment of obesity comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound as in any one of claims 1 and 2.

22. The method of claim 21 further comprising the step of identifying a subject, said subject being in need of treatment for obesity, wherein said identifying step is performed prior to administering to said subject said pharmaceutically effective amount of said compound.

23. The compound of claim 1 wherein: R.sub.1 is H or Me; R.sub.2 is Me, Et, or OH; R.sub.2a is H; R.sub.3 is F, Cl, Br, I, CF.sub.3, or 2-chlorophenyl; R.sub.4 is H; and R.sub.6 is H.

24. The compound of claim 1 wherein: R.sub.1 is H; R.sub.2 is C.sub.1-8 alkyl; R.sub.2a is H; R.sub.3 halogen; R.sub.4 is H; and R.sub.6 is H.

25. A method of preparing a composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

26. The compound according to claim 2 wherein R.sub.3 is H and R.sub.4 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, thiazolyl or thiadiazolyl having up to two substituents selected from halogen and C.sub.1-8 alkyl, or R.sub.4 is phenyl optionally substituted with up to two substituents selected from C.sub.1-8 alkyl, halogen, and alkoxy.

27. The compound according to claim 2, wherein R.sub.3 is H and R.sub.4 is a disubstituted pyrazolyl or monohalo-substituted phenyl.

28. The compound according to claim 27 wherein said substitutents of said disubstituted pyrazolyl are bromine and methyl.

29. A compound according to claim 1 that is 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

30. A compound according to claim 29 that is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

31. A compound according to claim 29 that is (S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

32. A compound according to claim 1 that is 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

33. A compound according to claim 32 that is (R)-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

34. A compound according to claim 32 that is (S)-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

35. A compound according to claim 1 that is 8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

36. A compound according to claim 35 that is (R)-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

37. A compound according to claim 35 that is (S)-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

38. A compound according to claim 1 that is 8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

39. A compound according to claim 38 that is (R)-8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

40. A compound according to claim 38 that is (S)-8trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

41. A compound according to claim 1 that is 8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

42. A compound according to claim 41 that is (R)-8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

43. A compound according to claim 41 that is (S)-8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

44. A compound according to claim 1 that is 8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

45. A compound according to claim 44 that is (R)-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

46. A compound according to claim 44 that is (S)-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

47. A compound according to claim 1 that is 8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

48. A compound according to claim 47 that is (R)-8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

49. A compound according to claim 47 that is (S)-8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

50. A compound according to claim 1 that is 8-iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

51. A compound according to claim 50 that is (R)-8-iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

52. A compound according to claim 50 that is (S)-8-iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

53. A compound according to claim 1 that is 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

54. A compound according to claim 53 that is (R)-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

55. A compound according to claim 53 that is (S)-8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

56. A compound according to claim 1 that is 7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

57. A compound according to claim 56 that is (R)-7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

58. A compound according to claim 56 that is (S)-7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

59. A compound according to claim 1 that is 8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

60. A compound according to claim 59 that is (R)-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

61. A compound according to claim 59 that is (S)-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

62. A compound according to claim 1 that is 8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

63. A compound according to claim 62 that is (R)-8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

64. A compound according to claim 62 that is (S)-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

65. A composition comprising a mixture of R and S enantiomers of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

66. A composition comprising a mixture of R and S enantiomers of 8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

67. A composition comprising a mixture of R and S enantiomers of 8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

68. A composition comprising a mixture of R and S enantiomers of 8-trifluoromethyl -1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

69. A composition comprising a mixture of R and S enantiomers of 8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

70. A composition comprising a mixture of R and S enantiomers of 8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

71. A composition comprising a mixture of R and S enantiomers of 8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

72. A composition comprising a mixture of R and S enantiomers of 8-iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

73. A composition comprising a mixture of R and S enantiomers of 7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

74. A composition comprising a mixture of R and S enantiomers of 7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

75. A composition comprising a mixture of R and S enantiomers of 8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

76. A composition comprising a mixture of R and S enantiomers of 8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

77. A method of treatment of depression or anxiety comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound according to any one of claims 1 and 2.
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