Benzenesulfonamide Compounds and Their Use

• US 20090239910A1
• Filed: 03/29/2007
• Published: 09/24/2009
• Est. Priority Date: 03/29/2006
• Status: Active Grant

• Current Assignee: Bin Shao, Donald J. Kyle, Jiangchao Yao, Khondaker Islam, Xiaoming Zhou, Zhengning Chen
• Original Assignee: Purdue Pharma L.P.
• Inventors: Chen, Zhengning, Zhou, Xiaoming, Shao, Bin, Kyle, Donald J., Yao, Jiangchao, Islam, Khondaker
• Granted Patent: US 8,247,442 B2
• Time in Patent Office: Days
• US Class Current: 514/329
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to azetidinyl, pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds of Formula I and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R¹-R³ and Z are defined as set forth in the specification. The invention is also directed to the use compounds of Formula I to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

Claims

1. A compound having the Formula I:

2. The compound of claim 1, having the Formula I:

3. The compound of claim 1, wherein R³ is selected from the group consisting of methyl, ethyl, iso-pentyl, iso-butyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl, methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl, methylsulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.

4. The compound of claim 1, wherein q is 2.

5. The compound of claim 1, having the Formula II:

6. The compound of claim 1, wherein

R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, alkylamino, and dialkylamino.

8. The compound of claim 6, wherein R¹ is hydrogen and R² is trifluoromethyl, or R¹ and R² are both hydrogen.

9. The compound of claim 1, having the Formula III:

11. The compound of claim 1, wherein Z=Z¹ having the Formula IV:

13. The compound of claim 11, having the Formula V:

15. The compound of claim 13, wherein R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, unsubstituted phenyl, and phenyl substituted with one or two substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, haloalkyl, and alkoxy.

17. The compound of claim 13, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring wherein one or more carbon atoms of the heterocyclic ring are optionally replaced with NR¹⁷, O, or S, wherein R¹⁷ is hydrogen or C_1-3 alkyl.

18. The compound of claim 13, wherein R⁵ is R¹⁶—

C(O)—

, wherein R¹⁶ is alkyl, cycloalkyl, or phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino.

19. The compound of claim 13, wherein R⁵ is R¹⁶—

SO₂—

, wherein R¹⁶ is alkyl, phenyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and alkylcarbonylamino, or 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogen atom with alkylcarbonyl or haloalkylcarbonyl.

20. The compound of claim 13, wherein R⁵ is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl.

21. The compound of claim 13, wherein R⁶ is hydrogen and R⁷ is methyl;

propyl;

iso-propyl;

butyl;

tert-butyl;

sec-butyl;

iso-butyl;

hydroxym ethyl;

1-hydroxyethyl;

unsubstituted phenyl;

phenyl substituted with one or two substituents independently selected from the group consisting of methyl ethyl, propyl, iso-propyl, butyl, tert-butyl, halogen, cyano, amino, methylamino, dimethylamino, hydroxy, nitro, and trifluoromethyl;

unsubstituted benzyl;

benzyl substituted with one or two substituents independently selected from the group consisting of methyl ethyl, propyl, iso-propyl, butyl, tert-butyl, halogen, cyano, amino, methylamino, dimethylamino, hydroxy, nitro, and trifluoromethyl;

1-benzyloxyethyl;

cyclopentyl;

cyclohexyl;

cyclopentylmethyl;

or cyclohexylmethyl.

22. The compound of claim 13, wherein R⁶ is hydrogen, R⁷ is alkyl, and R⁴ and R⁵ are independently hydrogen, alkyl, or hydroxyalkyl, or R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring wherein one or more carbon atoms of the heterocyclic ring are optionally replaced with NR¹⁷, O, or S, wherein R¹⁷ is hydrogen or C_1-3 alkyl.

23. The compound of claim 13, wherein R⁶ and R⁷ together with the carbon atom to which they are attached form cyclopentyl or cyclohexyl.

24. The compound of claim 13, wherein R⁷ is hydrogen;

R⁴ is hydrogen, alkyl, or hydroxyalkyl; and

R⁵ and R⁶ together form a bridge —

CH₂—

CH₂—

CH₂—

or —

CH₂—

CHG¹-CHG²-CH₂—

, wherein G¹ and G² are both hydrogen or together with the carbon atoms to which they are attached form a fused phenyl group.

25. The compound of claim 13, wherein the configuration at the carbon atom to which —

NR⁴R⁵ is attached is (S).

26. The compound of claim 13, having the Formula VI:

28. The compound of claim 26, wherein R⁴¹ and R⁵¹ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.

29. The compound of claim 26, wherein R⁴¹ and R⁵¹ both are hydrogen, or R⁴¹ is hydrogen and R⁵¹ is C_1-3 alkyl.

30. The compound of claim 26, wherein R¹⁸ and R¹⁹ are each independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_3-6 cycloalkyl, halogen, cyano, amino, C_1-3 alkylamino, di(C_1-3)alkylamino, hydroxy, nitro, halo(C_1-6)alkyl, and C_1-6 alkoxy.

32. The compound of claim 13, having the Formula VII:

34. The compound of claim 32, wherein R⁴² and R⁵² are each independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, and hydroxyethyl.

35. The compound of claim 32, wherein R⁴² and R⁵² together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of oxazolidinyl, isoxazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, hexahydropyrimidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl, and tetrahydropyridyl.

36. The compound of claim 32, wherein R⁴² and R⁵² are independently hydrogen, methyl or hydroxyethyl;

or R⁴² and R⁵² together with the nitrogen atom to which they are attached form 1-pyrrolidinyl, 4-thiomorpholinyl, or 4-methylpiperazinyl.

37. The compound of claim 32, wherein R²⁰ and R²¹ are both H when R⁴² and R⁵² together form the 5- or 6-membered heterocyclic ring.

38. The compound of claim 32, wherein R⁴² and R⁵² are both hydrogen or R⁴² is hydrogen and R⁵² is alkyl.

39. The compound of claim 32, wherein m is 1.

41. The compound of claim 1, wherein Z=Z², having the Formula X:

43. The compound of claim 41, wherein R⁸ and R⁹ are both hydrogen, A is CH₂ or absent, and B is CH.

44. The compound of claim 41, wherein R⁸ and R⁹ together form ═

O, A is CH₂ or absent and B is CH, or A-B is CH═

C.

45. The compound of claim 41, wherein R⁸ and R⁹ are both hydrogen, and A is O.

46. The compound of claim 41, wherein R⁸ and R⁹ are both hydrogen, A is —

C(O)—

, and B is N.

47. The compound of claim 41, wherein R⁸ and R⁹ together form ═

O, A is CH₂ or absent and B is N.

48. The compound of claim 41, wherein n is 0, 1 or 2.

49. The compound of claim 41, wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, C_1-6 alkoxy, halo, halo(C_1-6)alkyl, hydroxy, hydroxy(C_1-6)alkyl, cyano, amino, amino(C_1-6)alkyl, C_1-3 alkylamino, and di(C_1-3)alkylamino.

50. The compound of claim 49, wherein R¹⁰ and R¹² are both hydrogen.

51. The compound of claim 41, wherein R¹¹ and R¹³ are at the para-position of their respective phenyl rings.

53. The compound of claim 1, wherein Z=Z³, having the Formula XI:

55. The compound of claim 53, wherein R¹⁴ is selected from the group consisting of:

phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or

phenyl substituted with phenyl, benzyl, phenoxy or benzyloxy, wherein each phenyl ring is optionally substituted with one or two substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, and cyano;

naphthyl;

quinolinyl; and

pyridyl.

56. The compound of claim 53, wherein R¹⁴ is unsubstituted naphthyl, quinolinyl or pyridyl.

57. The compound of claim 53, wherein R⁸ and R⁹ are both hydrogen when R¹⁴ is one of

naphthyl;

quinolinyl;

pyridyl;

phenyl substituted with phenyl optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

phenyl substituted with benzyl optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

phenyl substituted with phenoxy optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano;

or

phenyl substituted with benzyloxy optionally substituted with halogen, haloalkyl, alkyl, alkoxy, hydroxy, amino, or cyano.

58. The compound of claim 53, wherein D is —

C(O)— and

R¹⁴ is —

NR^14aR^14b, wherein R^14a and R^14b are each independently selected from the group consisting of hydrogen;

alkyl;

aryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

benzyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

heteroaryl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; and

heteroarylalkyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino.

59. The compound of claim 53, wherein R⁸ and R⁹ together form ═

O.

60. The compound of claim 53, wherein R⁸ and R⁹ are both hydrogen or together form ═

O, and D is absent or —

CH═

CH—

.

61. The compound of claim 53, wherein R⁸ and R⁹ together form ═

O and D is —

C(O)—

.

62. The compound of claim 53, wherein p is 0 or 1.

64. The compound of claim 1, wherein Z=Z⁴ having the Formula XII:

66. The compound of claim 64, wherein R¹⁵ is phenyl or naphthyl either of which is substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, amino, alkylamino and dialkylamino.

67. The compound of claim 64, wherein R¹⁵ is naphthyl substituted with amino, alkylamino or dialkylamino.

69. The compound of claim 1, wherein Z=Z⁵, having the Formula XIII:

73. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and a pharmaceutically acceptable carrier.

80. A compound having the Formula I as claimed in claim 1, wherein the compound is ³H, ¹¹C, or ¹⁴C radiolabeled, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

81. A method of screening a candidate compound for the ability to bind to a receptor using a radiolabeled compound of claim 80, comprising a) introducing a fixed concentration of the radiolabeled compound to the receptor to form a mixture;

b) titrating the mixture with a candidate compound; and

c) determining the binding of the candidate compound to said receptor.

84. A method of preparing a pharmaceutical composition, comprising admixing a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug or solvate thereof, with a pharmaceutically acceptable carrier.

7. (canceled)

10. (canceled)

12. (canceled)

14. (canceled)

16. (canceled)

27. (canceled)

31. (canceled)

33. (canceled)

40. (canceled)

42. (canceled)

52. (canceled)

54. (canceled)

63. (canceled)

65. (canceled)

68. (canceled)

70. (canceled)

71. A compound selected from the group consisting of:

N-[1-(2-amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methyl-pentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methyl-pentanoyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-(1-{3-[bis-(4-fluorophenyl)amino]propyl}-piperidin-3-yl)-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-[1-(3-isobutylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-[1-(3-isopropylaminopropionyl)-piperidin-3-yl]-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-{1-[3-(2-methoxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-{1-[3-(2-hydroxyethylamino)-propionyl]-piperidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-[1-(2-isobutylaminoacetyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

2-{3-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]-piperidin-1-yl}-N-isobutyl-acetamide;

2-{3-[cyclopropyl-(3-trifluoromethylbenzene-sulfonyl)amino]piperidin-1-yl}-N-(4-fluorophenyl)-acetamide;

N-(4-fluorophenyl)-2-[3-trifluoromethylbenzenesulfonamino)-pyrrolidin-1-yl]acetamide;

N-cyclopropyl-N-{1-[2-(4-methoxybenzylamino)acetyl]-piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;

N-cyclopropyl-N-(1-{2-[(pyridin-3-ylmethyl)amino]acetyl}-piperidin-3-yl)-3-trifluoromethylbenzenesulfonamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

72. A compound selected from the group consisting of:

(2S)N-[1-(2-amino-4-methylpentanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;

(2S)N-cyclopropyl-N-[1-(4-methyl-2-methylaminopentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

(2S)N-cyclopropyl-N-[1-(2-ethylamino-4-methylpentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

(2S)N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-N-cyclopropyl-3-trifluoromethylbenzenesulfonamide;

(2S)N-cyclopropyl-N-[1-(2-methylcarbonylpropylamino-4-methyl-pentanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

(2S)N-cyclopropyl-N-{1-[2-(3-methylbutyl)amino-4-methyl-pentanoyl]piperidin-3-yl}-3-trifluoromethylbenzenesulfonamide;

(2S)N-cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

(2S)N-cyclopropyl-N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

(2R) N-cyclopropyl-N-[1-(3-amino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

74. A method of treating, preventing or ameliorating a disorder responsive to the blockade of calcium channels in a mammal suffering from said disorder, comprising administering to a mammal in need of such treatment, prevention or amelioration an effective amount of a compound of Formula I:

75. The method of claim 74, wherein a disorder responsive to the blockade of N-type calcium channels is treated, prevented or ameliorated.

76. A method for method for treating, preventing or ameliorating stroke, neuronal damage resulting from head trauma, epilepsy, pain, migraine, a mood disorder, schizophrenia, a neurodegenerative disorder, depression, anxiety, a psychosis, hypertension or cardiac arrhythmia in a mammal, comprising administering an effective amount of a compound of Formula I:

77. The method of claim 76, wherein the method is for treating, preventing or ameliorating pain selected from chronic pain, neuropathic pain, acute pain, and surgical pain.

78. A method of modulating calcium channels in a mammal, comprising administering to the mammal at least one compound of Formula I:

79. The method of claim 78, wherein the N-type calcium channel is modulated.

82-83. -83. (canceled)

85-89. -89. (canceled)