Benzenesulfonamide compounds and the use thereof

• US 8,765,736 B2
• Filed: 09/26/2008
• Issued: 07/01/2014
• Est. Priority Date: 09/28/2007
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Shao, Bin, Yao, Jiangchao
• Primary Examiner(s): CHONG, YONG SOO
• Application Number:
  US12/599,608
• Publication Number:
  US 20100311792A1
• Time in Patent Office: 2,104 Days
• Field of Search: 514/183, 514/213.01, 514/279, 514/410
• US Class Current: 514/213.01
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 211/58 attached in position 4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to azetidinyl, pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds of Formula (I): and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R¹, R², R³, Z and q are defined as set forth in the specification. The invention is also directed to the use compounds of Formula I to treat 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, 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, methyl sulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.

3. The compound of claim 2, wherein R³ is iso-propyl.

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

5. The compound of claim 1, wherein q is 1 and p is 2.

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.

7. The compound of claim 6, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, fluoromethyl, cyano, nitro, methoxy and difluoromethoxy.

8. The compound of claim 7, wherein R¹ is hydrogen and R² is trifluoromethyl.

9. The compound of claim 4, having the Formula III:

10. The compound of claim 1, wherein Z=Z¹, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

11. The compound of claim 10, wherein R⁴ is phenyl which is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxyalkylamino.

12. The compound of claim 10, wherein R⁴ is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, and pyrazolyl, all of which can be optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxyalkylamino.

13. The compound of claim 10, wherein said compound is N-(2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}ethyl)-4-fluorobenzamide or N-(2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidin-1-yl}ethyl)-3,5-bis(trifluoromethyl)phenylbenzamide or a pharmaceutically acceptable salt, prodrug or solvate thereof.

14. The compound of claim 1, wherein Z=Z², or a pharmaceutically acceptable salt, prodrug or solvate thereof.

15. The compound of claim 14, wherein R⁷ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

16. The compound of claim 14, wherein R⁵ is C_1-4 alkyl and R⁶ is hydrogen or C_1-4 alkyl.

17. The compound of claim 14, wherein R⁷ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, R⁵ is C_1-4 alkyl, and R⁶ is hydrogen or C_1-4 alkyl.

18. The compound of claim 14, wherein R⁷ is optionally substituted C_6-10 aryl, optionally substituted C_6-10 aryl(C_1-4)alkyl, optionally substituted heteroaryl having 5-10 ring atoms, or optionally substituted heteroaryl(C_1-4)alkyl having 5-10 ring atoms.

19. The compound of claim 18, wherein R⁷ is selected from the group consisting of phenyl, naphthyl, indenyl, isoindenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, and pyrazolyl, any of which can be optionally substituted.

20. The compound of claim 19, wherein R⁷ is unsubstituted phenyl or phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxyalkylamino.

21. The compound of claim 14, wherein said compound is 2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-propionic acid ethyl ester, 2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-2-methyl-propionic acid ethyl ester, {4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetic acid 4-chloro-phenyl ester, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

22. The compound of claim 1, wherein Z=Z³, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

23. The compound of claim 22, wherein R¹⁰ is selected from the group consisting of oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, and thiazolyl, any of which is optionally substituted with one or two substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino.

24. The compound of claim 22, wherein R¹⁰ is selected from the group consisting of

25. The compound of claim 1, wherein Z=Z⁴, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

26. The compound of claim 25, wherein R¹¹, R¹² and R¹³ are each independently hydrogen, alkyl or phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

and R¹⁴ is alkyl, monocycloalkyl, bicycloalkyl, or unsubstituted tricycloalkyl, optionally substituted heterocyclo, optionally substituted aryl;

provided that when R¹⁴ is alkyl or optionally substituted aryl, then R¹¹ or R¹² is other than hydrogen.

27. The compound of claim 26, wherein R¹¹, R¹² and R¹³ are each hydrogen and R¹⁴ is monocycloalkyl, bicycloalkyl, or unsubstituted tricycloalkyl or optionally substituted heterocyclo.

28. The compound of claim 25, wherein R¹¹ is hydrogen, R¹² and R¹³ together form a bridge —

CH₂—

CH₂—

or —

CH₂—

CH₂—

CH₂—

, and R¹⁴ is hydrogen, monocycloalkyl, bicycloalkyl, unsubstituted tricycloalkyl, optionally substituted heterocyclo, or optionally substituted aryl.

29. The compound of claim 28, wherein R¹⁴ is optionally substituted phenyl.

30. The compound of claim 25, wherein R¹¹ and R¹² are both hydrogen and R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring.

31. The compound of claim 25, wherein said compound is N-isopropyl-N-[1-(3-oxo-3-piperidin-1-yl-propyl)-piperidin-4-yl]-3-trifluoromethyl-benzene-sulfonamide, N-[1-(2-azepan-1-yl-2-oxo-ethyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethyl-benzenesulfonamide, N-isopropyl-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide, N-(2-chloro-4-fluoro-phenyl)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-isobutyramide, 2-{4-[cyclopropyl-(3-trifluoromethyl-benzene-sulfonyl)-amino]-piperidin-1-yl}-N-(4-fluoro-phenyl)-isobutyramide, 3-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-piperidin-1-yl}-N-tert-butyl-butyramide, N-isopropyl-N-[1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide, 2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]piperidin-1-yl}-N-phenyl-propionamide, N-cycloheptyl-2-{4-[isopropyl-(3-trifluoromethyl-benzene-sulfonyl)-amino]-piperidin-1-yl}-acetamide, N-bicyclo [2.2.1]hept-2-yl-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide, 2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-N-(tetrahydrofuran-3-yl)-acetamide, or N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2-{4-[isopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidin-1-yl}-acetamide, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

32. The compound of claim 1, wherein Z=Z⁵, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

33. The compound of claim 32, wherein Z⁵ is aryl substituted with at least one of alkoxycarbonyl, haloalkyl, carboxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl, wherein said aryl can be further optionally substituted.

34. The compound of claim 33, wherein Z⁵ is C_6-10 aryl substituted with at least one of alkoxycarbonyl or haloalkyl, wherein said C_6-10 aryl can be farther optionally substituted.

35. The compound of claim 34, wherein Z⁵ is phenyl substituted with at least one of C_1-4 alkoxycarbonyl or trifluoromethyl.

36. The compound of claim 35, wherein said phenyl is further substituted with a substituent selected from the group consisting of halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.

37. The compound of claim 32, wherein Z⁵ is heteroaryl substituted with at least one of alkoxycarbonyl, haloalkyl, carboxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl, wherein said heteroaryl can be further optionally substituted.

38. The compound of claim 37, wherein Z⁵ is heteroaryl having 5-10 ring atoms substituted with at least one of alkoxycarbonyl or haloalkyl, wherein said heteroaryl can be further optionally substituted.

39. The compound of claim 38, wherein Z⁵ is pyridyl substituted with at least one of C_1-4 alkoxycarbonyl or trifluoromethyl.

40. The compound of claim 32, wherein said compound is 2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoic acid methyl ester, 4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]-3,4,5,6-tetrahydro-2H-[1,2′

]-bipyridinyl-3′

-carboxylic acid ethyl ester, 3-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}-5-fluorobenzoic acid ethyl ester, 4-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidin-1-yl}benzoic acid ethyl ester, N-[1-(3,5-bis-(trifluoromethyl)phenyl)piperidin-1-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide, or a pharmaceutically acceptable salt, prodrug or solvate thereof.

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

42. 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.