5HT2c receptor modulators

• US 8,207,158 B2
• Filed: 05/27/2011
• Issued: 06/26/2012
• Est. Priority Date: 04/12/2002
• Status: Expired due to Term

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Smith, Brian, Smith, Jeffrey
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/118,126
• Publication Number:
  US 20120135982A1
• Time in Patent Office: 396 Days
• Field of Search: 514/212.02, 514/215, 514/217.01
• US Class Current: 514/212.02
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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 223/16 : Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems

Abstract

The present invention relates to novel compounds of Formula (I):

which act as 5HT_2C receptor modulators. These compounds are useful in pharmaceutical compositions whose use includes the treatment of obesity.

Claims

1. A method of decreasing food intake of a subject comprising

identifying a subject in need of decreasing food intake;

and

administering to said subject a pharmaceutically effective amount of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

2. The method of claim 1, wherein identifying a subject in need of decreasing food intake comprises determining the body mass index (BMI) of said subject.

3. The method of claim 2, wherein said subject has a BMI greater than 30 kg/m².

4. The method of claim 2, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

5. The method of claim 1, wherein identifying a subject in need of decreasing food intake comprises determining the body fat content of the subject.

6. The method of claim 5, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

7. The method of claim 1, wherein identifying a subject in need of decreasing food intake comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

8. The method of claim 1, further comprising advising said subject to increase physical activity.

9. The method of claim 1, further comprising advising said subject to reduce dietary fat content.

10. The method of claim 1, further comprising advising said subject to consume fewer calories.

11. A method of decreasing food intake of a subject comprising

identifying a subject in need of decreasing food intake;

and

administering to said subject a pharmaceutically effective amount of a hydrate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

12. The method of claim 11, wherein identifying a subject in need of decreasing food intake comprises determining the body mass index (BMI) of said subject.

13. The method of claim 12, wherein said subject has a BMI greater than 30 kg/m².

14. The method of claim 12, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

15. The method of claim 11, wherein identifying a subject in need of decreasing food intake comprises determining the body fat content of the subject.

16. The method of claim 15, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

17. The method of claim 11, wherein identifying a subject in need of decreasing food intake comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

18. The method of claim 11, further comprising advising said subject to increase physical activity.

19. The method of claim 11, further comprising advising said subject to reduce dietary fat content.

20. The method of claim 11, further comprising advising said subject to consume fewer calories.

21. A method of decreasing food intake of a subject comprising

identifying a subject in need of decreasing food intake;

and

administering to said subject a pharmaceutically effective amount of a solvate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

22. The method of claim 21, wherein identifying a subject in need of decreasing food intake comprises determining the body mass index (BMI) of said subject.

23. The method of claim 22, wherein said subject has a BMI greater than 30 kg/m².

24. The method of claim 22, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

25. The method of claim 21, wherein identifying a subject in need of decreasing food intake comprises determining the body fat content of the subject.

26. The method of claim 25, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

27. The method of claim 21, wherein identifying a subject in need of decreasing food intake comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

28. The method of claim 21, further comprising advising said subject to increase physical activity.

29. The method of claim 21, further comprising advising said subject to reduce dietary fat content.

30. The method of claim 21, further comprising advising said subject to consume fewer calories.

31. A method of method of controlling weight gain of a subject comprising

identifying a subject in need of weight gain control;

and

administering to said subject a pharmaceutically effective amount of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

32. The method of claim 31, wherein identifying a subject in need of weight gain control comprises determining the body mass index (BMI) of said subject.

33. The method of claim 32, wherein said subject has a BMI greater than 30 kg/m².

34. The method of claim 33, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

35. The method of claim 31, wherein identifying a subject in need of weight gain control comprises determining the body fat content of the subject.

36. The method of claim 35, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

37. The method of claim 31, wherein identifying a subject in need of weight gain control comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

38. The method of claim 31, further comprising advising said subject to increase physical activity.

39. The method of claim 31, further comprising advising said subject to reduce dietary fat content.

40. The method of claim 31, further comprising advising said subject to consume fewer calories.

41. A method of controlling weight gain of a subject comprising

identifying a subject in need of weight gain control;

and

administering to said subject a pharmaceutically effective amount of a hydrate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

42. The method of claim 41, wherein identifying a subject in need of weight gain control comprises determining the body mass index (BMI) of said subject.

43. The method of claim 42, wherein said subject has a BMI greater than 30 kg/m².

44. The method of claim 42, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

45. The method of claim 41, wherein identifying a subject in need of weight gain control comprises determining the body fat content of the subject.

46. The method of claim 45, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

47. The method of claim 41, wherein identifying a subject in need of weight gain control comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

48. The method of claim 41, further comprising advising said subject to increase physical activity.

49. The method of claim 41, further comprising advising said subject to reduce dietary fat content.

50. The method of claim 41, further comprising advising said subject to consume fewer calories.

51. A method of controlling weight gain of a subject comprising

identifying a subject in need of weight gain control;

and

administering to said subject a pharmaceutically effective amount of a solvate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

52. The method of claim 51, wherein identifying a subject in need of weight gain control comprises determining the body mass index (BMI) of said subject.

53. The method of claim 52, wherein said subject has a BMI greater than 30 kg/m².

54. The method of claim 52, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

55. The method of claim 51, wherein identifying a subject in need of weight gain control comprises determining the body fat content of the subject.

56. The method of claim 55, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

57. The method of claim 51, wherein identifying a subject in need of weight gain control comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

58. The method of claim 51, further comprising advising said subject to increase physical activity.

59. The method of claim 51, further comprising advising said subject to reduce dietary fat content.

60. The method of claim 51, further comprising advising said subject to consume fewer calories.

61. A method of method of inducing satiety of a subject comprising

identifying a subject in need of inducing satiety;

and

administering to said subject a pharmaceutically effective amount of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

62. The method of claim 61, wherein identifying a subject in need of inducing satiety comprises determining the body mass index (BMI) of said subject.

63. The method of claim 62, wherein said subject has a BMI greater than 30 kg/m².

64. The method of claim 62, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

65. The method of claim 61, wherein identifying a subject in need of inducing satiety comprises determining the body fat content of the subject.

66. The method of claim 65, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

67. The method of claim 61, wherein identifying a subject in need of inducing satiety comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

68. The method of claim 61, further comprising advising said subject to increase physical activity.

69. The method of claim 61, further comprising advising said subject to reduce dietary fat content.

70. The method of claim 61, further comprising advising said subject to consume fewer calories.

71. A method of inducing satiety of a subject comprising

identifying a subject in need of inducing satiety;

and

administering to said subject a pharmaceutically effective amount of a hydrate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

72. The method of claim 71, wherein identifying a subject in need of inducing satiety comprises determining the body mass index (BMI) of said subject.

73. The method of claim 72, wherein said subject has a BMI greater than 30 kg/m².

74. The method of claim 72, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

75. The method of claim 71, wherein identifying a subject in need of inducing satiety comprises determining the body fat content of the subject.

76. The method of claim 75, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

77. The method of claim 71, wherein identifying a subject in need of inducing satiety comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

78. The method of claim 71, further comprising advising said subject to increase physical activity.

79. The method of claim 71, further comprising advising said subject to reduce dietary fat content.

80. The method of claim 71, further comprising advising said subject to consume fewer calories.

81. A method of inducing satiety of a subject comprising

identifying a subject in need of inducing satiety;

and

administering to said subject a pharmaceutically effective amount of a solvate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

82. The method of claim 81, wherein identifying a subject in need of inducing satiety comprises determining the body mass index (BMI) of said subject.

83. The method of claim 82, wherein said subject has a BMI greater than 30 kg/m².

84. The method of claim 82, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

85. The method of claim 81, wherein identifying a subject in need of inducing satiety comprises determining the body fat content of the subject.

86. The method of claim 85, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

87. The method of claim 81, wherein identifying a subject in need of inducing satiety comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

88. The method of claim 81, further comprising advising said subject to increase physical activity.

89. The method of claim 81, further comprising advising said subject to reduce dietary fat content.

90. The method of claim 81, further comprising advising said subject to consume fewer calories.

91. A method for treatment of obesity of a subject comprising

identifying a subject in need of obesity treatment;

and

administering to said subject a pharmaceutically effective amount of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

92. The method of claim 91, wherein identifying a subject in need of obesity treatment comprises determining the body mass index (BMI) of said subject.

93. The method of claim 92, wherein said subject has a BMI greater than 30 kg/m².

94. The method of claim 92, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

95. The method of claim 91, wherein identifying a subject in need of obesity treatment comprises determining the body fat content of the subject.

96. The method of claim 95, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

97. The method of claim 91, wherein identifying a subject in need of obesity treatment comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

98. The method of claim 91, further comprising advising said subject to increase physical activity.

99. The method of claim 91, further comprising advising said subject to reduce dietary fat content.

100. The method of claim 91, further comprising advising said subject to consume fewer calories.

101. A method for treatment of obesity of a subject comprising

identifying a subject in need of obesity treatment;

and

administering to said subject a pharmaceutically effective amount of a hydrate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

102. The method of claim 101, wherein identifying a subject in need of obesity treatment comprises determining the body mass index (BMI) of said subject.

103. The method of claim 102, wherein said subject has a BMI greater than 30 kg/m².

104. The method of claim 102, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

105. The method of claim 101, wherein identifying a subject in need of obesity treatment comprises determining the body fat content of the subject.

106. The method of claim 105, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

107. The method of claim 101, wherein identifying a subject in need of obesity treatment comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

108. The method of claim 101, further comprising advising said subject to increase physical activity.

109. The method of claim 101, further comprising advising said subject to reduce dietary fat content.

110. The method of claim 101, further comprising advising said subject to consume fewer calories.

111. A method for treatment of obesity of a subject comprising

identifying a subject in need of obesity treatment;

and

administering to said subject a pharmaceutically effective amount of a solvate of a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

112. The method of claim 111, wherein identifying a subject in need of obesity treatment comprises determining the body mass index (BMI) of said subject.

113. The method of claim 112, wherein said subject has a BMI greater than 30 kg/m².

114. The method of claim 112, wherein said subject has a BMI ranging from 25.0 to 29.9 kg/m².

115. The method of claim 111, wherein identifying a subject in need of obesity treatment comprises determining the body fat content of the subject.

116. The method of claim 115, wherein the subject has greater than 25% body fat content if male and greater than 30% body fat content if female.

117. The method of claim 111, wherein identifying a subject in need of obesity treatment comprises determining whether the subject suffers from coronary insufficiency, atheromatous disease, cardiac insufficiency, and/or diabetes.

118. The method of claim 111, further comprising advising said subject to increase physical activity.

119. The method of claim 111, further comprising advising said subject to reduce dietary fat content.

120. The method of claim 111, further comprising advising said subject to consume fewer calories.