Novel Aryl- and Heteroarylpiperazines

• US 20090264435A1
• Filed: 02/09/2009
• Published: 10/22/2009
• Est. Priority Date: 02/05/2002
• Status: Abandoned Application

• Current Assignee: High Point Pharmaceuticals, LLC
• Original Assignee: High Point Pharmaceuticals, LLC
• Inventors: Hohlweg, Rolf, Pettersson, Ingrid, Peschke, Bernd, Dorwald, Florencio Zaragoza, Stephensen, Henrik
• Application Number:
  US12/367,952
• Publication Number:
  US 20090264435A1
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 241/26 with nitrogen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 295/03 with the ring nitrogen atoms directly attached to acyclic carbon atoms
• CPC Class Codes: C07D 295/033 with the ring nitrogen atoms directly attached to carbocyclic rings
• CPC Class Codes: C07D 295/073 with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/088 to an acyclic saturated chain
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/112 with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Novel aryl- and heteroarylpiperazines, use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds, and a method of treatment employing these compounds and compositions. The compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor.

Claims

1. A compound of the general formula (II):

2. A compound according to claim 1, wherein R¹ is branched C_4-6-alkyl, C_3-5-cycloalkyl or C_3-6-cycloalkyl-C_1-3-alkyl with the proviso that R¹ is not isobutyl.

3. A compound according to claim 2, wherein R¹ is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl.

4. A compound according to claim 3, wherein R¹ is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

5. A compound according to claim 1, wherein R¹ is branched C_4-6-alkyl or C_3-5-cycloalkyl with the proviso that R¹ is not isobutyl.

6. A compound according to claim 5, wherein R¹ is 1-ethylpropyl, cyclopropyl or cyclopentyl.

7. A compound according to any one of the claims 1 to 6, wherein Z is —

C(H)═

, —

N═

, or —

C(F)═

.

8. A compound according to claim 7 wherein Z is —

C(H)═

or —

N═

.

9. A compound according to claim 8 wherein Z is —

C(H)═

.

10. A compound according to claim 8 wherein Z is —

N═

.

11. A compound according to any one of the claims 1 to 10 wherein X is —

C(H)═

, —

N═

, or —

C(F)═

.

12. A compound according to claim 11 wherein Z is —

C(H)═

or —

N═

.

13. A compound according to claim 12 wherein Z is —

C(H)═

.

14. A compound according to claim 12 wherein Z is —

N═

.

15. A compound according to any one of the claims 1 to 14 wherein W is —

N═

.

16. A compound according to any one of the claims 1 to 14 wherein W is —

C(R¹⁰)═

.

17. A compound according to any one of the claims 1 to 16 wherein Y is —

N═

.

18. A compound according to any one of the claims 1 to 16 wherein Y is —

C(R¹¹)═

.

19. A compound according to any one of the claims 1 to 18 wherein R² is hydrogen.

20. A compound according to any one of the claims 1 to 18 wherein R² is C_1-4-alkyl.

21. A compound according to claim 20 wherein R² is methyl or ethyl.

22. A compound according to claim 1 of the general formula (III)

23. A compound according to any one of the claims 1 to 22 wherein R³ is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-10-alkyl, C_1-6-alkoxy, aryl, aryl-C_1-6-alkyl, amino, C_3-8-cycloalkyl, C_3-8-cycloalkyloxy, cyano or nitro.

24. A compound according to claim 23 wherein R³ is hydrogen, halogen, hydroxy, trifluoromethyl, C_1-10-alkyl, C_1-6-alkoxy, cyano or nitro.

25. A compound according to claim 24 wherein R³ is hydrogen, halogen, hydroxy, trifluoromethyl, C_1-6-alkyl, or cyano.

26. A compound according to claim 25 wherein R³ is hydrogen, halogen, or C_1-6-alkyl.

27. A compound according to claim 25 wherein R³ is hydrogen or methyl.

28. A compound according to any one of the claims 1 to 27 wherein R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —

SCF₃, amino, or cyano,

C_1-10-alkyl, C_3-8-cycloalkyl, C_1-6-alkoxy, C_3-8-cycloalkyloxy, C_2-10-alkanoyl, C_4-9-cycloalkanoyl, C_3-8-heterocyclyl or C_4-9-heterocycloalkanoyl, which may optionally be substituted with one or more substituents selected from R¹⁶

aryl, aryl-C_1-6-alkyl, aryl-C_1-6-alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from R¹⁷,

aroyl, heteroaroyl, aryloxy, heteroaryloxy, which may optionally be substituted with one or more substituents selected from R¹³,

or two of R⁵, R⁶, R⁷, R⁸, R⁹ in adjacent positions together form a C_1-6-alkylene bridge or an —

O—

C_1-6-alkyl-O—

bridge.

29. A compound according to claim 28 wherein R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —

SCF₃, or cyano,

C_1-10-alkyl, C_1-6-alkoxy, C_3-8-cycloalkyloxy, which may optionally be substituted with one or more substituents selected from R¹⁶

Aryl or aryl-C_1-6-alkyl, which may optionally be substituted with one or more substituents selected from R¹⁷,

Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R¹³,

or two of R⁵, R⁶, R⁷, R⁸, R⁹ in adjacent positions together form a C_1-6-alkylene bridge or an —

O—

C_1-6-alkyl-O—

bridge.

30. A compound according to claim 28 wherein R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ independently represent

hydrogen, halogen, or cyano,

C_1-10-alkyl or C_1-6-alkoxy which may optionally be substituted with one or more substituents selected from R¹⁶

Aryl optionally substituted with one or more substituents selected from R¹⁷,

Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R¹³,

or two of R⁵, R⁶, R⁷, R⁸, R⁹ in adjacent positions together form a C_1-6-alkylene bridge or an —

O—

C_1-6-alkyl-O—

bridge.

31. A compound according to claim 30 wherein C_1-10-alkyl represents methyl, ethyl, propyl, or isopropyl.

32. A compound according to claim 30 wherein C_1-6-alkoxy represents methoxy, ethoxy or propoxy.

33. A compound according to claim 32 wherein C_1-6-alkoxy represents methoxy.

34. A compound according to claim 30 wherein aryl represents phenyl.

35. A compound according to claim 30 wherein aroyl represents —

C(═

O)-phenyl.

36. A compound according to claim 30 wherein aryloxy represents —

O-phenyl.

37. A compound according to claim 1, wherein R¹ is ethyl or isopropyl.

38. A compound according to claim 37 wherein R¹ is isopropyl.

39. A compound according to claim 37 wherein R¹ is ethyl

40. A compound according to claim 39 wherein R¹ and R² together form a C_3-4-alkylene bridge.

41. A compound according to any one of the claims 37 to 40 wherein R¹⁰, R¹¹, R¹² and R¹³ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or —

C(═

O)NR¹⁴R¹⁵

C_1-10-alkyl, C_3-8-cycloalkyl, C_1-6-alkoxy, C_2-10-alkanoyl, C_4-9-cycloalkanoyl, C_3-8-heterocyclyl or C_4-9-heterocycloalkanoyl, C_4-9-heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R¹⁶

aryl, aryl-C_1-6-alkyl, aryl-C_1-6-alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from R¹⁷,

aroyl optionally substituted with one or more substituents selected from R¹⁸,

or two of R¹⁰, R¹¹, R¹² and R¹³ in adjacent positions together form a C_1-6-alkylene bridge.

42. A compound according to claim 41 wherein R¹⁰, R¹¹, R¹² and R¹³ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or —

C(═

O)NR¹⁴R¹⁵

C_1-10-alkyl, C_3-8-cycloalkyl, C_1-6-alkoxy, C_2-10-alkanoyl, C_4-9-cycloalkanoyl, C_3-8-heterocyclyl or C_4-9-heterocycloalkanoyl, C_4-9-heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R¹⁶

aryl, aryl-C_1-6-alkyl, aryl-C_1-6-alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from R¹⁷,

aroyl optionally substituted with one or more substituents selected from R¹⁸,

or two of R¹⁰, R¹¹, R¹² and R¹³ in adjacent positions together form a C_1-6-alkylene bridge.

43. A compound according to claim 42 wherein R¹⁰, R¹¹, R¹² and R¹³ independently represent

hydrogen, halogen, trifluoromethyl, or —

C(═

O)NR¹⁴R¹⁵

C_1-10-alkyl, C_1-6-alkoxy, C_2-10-alkanoyl, C_4-9-cycloalkanoyl, C_4-9-heterocycloalkanoyl or C_4-9-heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R¹⁶

aryl, aryl-C_1-6-alkyl, or aryl-C_1-6-alkoxy, which may optionally be substituted with one or more substituents selected from R¹⁷

aroyl optionally substituted with one or more substituents selected from R¹⁸, or two of R¹⁰, R¹¹, R¹² and R¹³ in adjacent positions together form a C_1-6-alkylene bridge.

44. A compound according to claim 43 wherein R¹⁰, R¹¹, R¹² and R¹³ independently represent

hydrogen, halogen, trifluoromethyl, or —

C(═

O)NR¹⁴R¹⁵

C_1-10-alkyl or C_4-9-heterocycloalkanoyl, which may optionally be substituted with one or more substituents selected from R¹⁶

aryl optionally substituted with one or more substituents selected from R¹⁷,

aroyl optionally substituted with one or more substituents selected from R¹⁸

or two of R¹⁰, R¹¹, R¹² and R¹³ in adjacent positions together form a C_1-6-alkylene bridge.

45. A compound according to claim 44 wherein C_1-10-alkyl represents methyl, ethyl, or propyl.

46. A compound according to claim 44 wherein C_4-9-heterocycloalkanoyl represents piperidin-alkanoyl or pyrrolidin-alkanoyl.

47. A compound according to claim 44 wherein aryl represents phenyl

48. A compound according to any one of the claims 1 to 47 wherein R¹⁴ and R¹⁵ are independently methyl, ethyl or benzyl.

49. A compound according to any one of the claims 1 to 48 wherein R¹⁶ is halogen, trifluoromethyl, trifluoromethoxy and C_1-6-alkoxy.

50. A compound according to any one of the claims 1 to 49 wherein R¹⁷ is halogen, hydroxy, trifluoromethyl, C_1-6-alkoxy, C_1-6-alkyl, C_1-6-alkylsulfonyl, or cyano.

51. A compound according to claim 50 wherein R¹⁷ is halogen, trifluoromethyl, C_1-6-alkoxy or C_1-6-alkylsulfonyl.

52. A compound according to any one of the claims 1 to 51 wherein R¹³ is C_1-10-alkyl, halogen, trifluoromethyl, C_1-6-alkoxy, cyano, amino and hydroxy.

53. A compound according to claim 52 wherein R¹³ is halogen, C_1-6-alkoxy and hydroxy.

54. Use of a compound according to any one of the preceding claims 1 to 53 as a pharmaceutical composition.

55. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 53 together with one or more pharmaceutically acceptable carriers or excipients.

56. A pharmaceutical composition according to claim 55 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 53.

73. A method for the treatment of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 57 or a pharmaceutical composition according to claim 55 or 56.

74. The method according to claim 73 wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.

57. Use of a compound of the general formula (II′

);

58. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect.

59. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.

60. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the reduction of weight.

61. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.

62. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the suppression of appetite or for satiety induction.

63. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity.

64. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.

65. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of IGT.

66. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.

67. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.

68. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

69. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect.

70. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition having histamine H3 agonistic activity.

71. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.

72. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of Alzheimer'"'"'s disease, narcolepsy or attention deficit disorders.