Benzenesulfonamide compounds and the use thereof

• US 8,937,181 B2
• Filed: 04/13/2007
• Issued: 01/20/2015
• Est. Priority Date: 04/13/2006
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P., Shionogi & Co., Ltd.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Matsumura, Akira, Mikamiyama, Hidenori, Shao, Bin, Tsuno, Naoki, Yao, Jiangchao
• Primary Examiner(s): O DELL, DAVID K
• Application Number:
  US12/296,788
• Publication Number:
  US 20090306136A1
• Time in Patent Office: 2,839 Days
• Field of Search: 546/194, 546/207, 546/208, 546/223, 546/224, 546/226, 514/318, 514/326, 514/329
• US Class Current: 546/194
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: C07D 211/58 attached in position 4

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, Z, p and q 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, haying the Formula I:

4. The compound of any one of claims 1-3, 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.

5. The compound of any one of claims 1-3, 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.

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, or R¹ and R² are both hydrogen.

9. The compound of any one of claims 1-3, having the Formula III:

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

11. The compound of claim 10, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, and nitro;

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

12. The compound of claim 10, wherein R⁴ is selected from the group consisting of

hydrogen;

alkyl;

alkenyl;

hydroxyalkyl;

haloalkyl;

mercaptoalkyl;

aminoalkyl;

alkylaminoalkyl;

dialkylaminoalkyl;

alkoxyalkyl; and

phenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, hydroxy, nitro, haloalkyl, and alkoxy; and

R⁵ is C_3-7 cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, and alkoxycarhonyl.

13. The compound of claim 12, wherein R⁴ is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, 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.

14. The compound of claim 13, wherein R⁴ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, isopentyl, hydroxymethyl, hydroxyethyl, and unsubstituted phenyl.

15. The compound of claim 12, wherein R⁵ is C_3-7 cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl.

16. The compound of claim 10, wherein R⁴ and R⁵ together form a bridge —

CH₂—

CHG¹-CHG²-CH₂—

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

17. The compound of claim 1, wherein Z=Z² having the Formula V:

18. The compound of claim 17, 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;

and 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.

19. The compound of claim 17, wherein R⁶ is selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxy, hydroxy, hydroxy(C_1-6)alkyl, amino, amino(C_1-6)alkyl, C_1-3 alkylamino, and di(C_1-3)alkylamino.

20. The compound of claim 17, wherein r is 1.

21. The compound of claim 17, wherein r is 2.

22. The compound of claim 1, wherein Z=Z³ having the Formula VI:

23. The compound of claim 22, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy, nitro, amino, aminoalkyl, and dialkylamino;

and 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.

24. The compound of claim 22, wherein R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, C_1-6 alkoxy, halogen, halo(C_1-6)alkyl, hydroxy, hydroxy(C_1-6)alkyl, cyano, amino, amino(C_1-6)alkyl, C_1-3 alkylamino, nitro, di(C_1-3)alkylamino, and hydroxy(C_1-3)alkylamino.

25. The compound of claim 22, wherein Y is —

C(O)—

.

26. The compound of claim 22, wherein Y is —

COH—

.

27. The compound of claim 22, wherein R¹² is hydrogen or C_1-6 alkyl.

28. The compound of claim 1, wherein Z=Z⁴ having the Formula VII:

29. The compound of claim 28, 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;

and 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.

30. The compound of claim 28, wherein R⁹ and R¹⁰ are both hydrogen, and R¹¹ is hydroxy(C_1-3)alkylamino;

wherein R¹¹ is attached to the 2 position of the phenyl ring.

31. The compound of any one of claims 1-3, wherein Z³ is

33. A pharmaceutical composition, comprising the compound of claim 1, 2, 3, or 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. A method for treating ameliorating pain in a mammal, comprising administering an effective amount of a compound of any of claim 1, 2, 3, or 32, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein the method is for treating or ameliorating pain selected from the groups consisting of chronic pain, neuropathic pain, acute pain, and surgical pain.

3. A compound having the Formula I:

32. A compound selected from the group consisting of:

N-cyclopropyl-N-{1-[3-(4-hydroxy-cyclohexylamino)-propionyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

rac-N-[1-((1S,2R)-2-amino-cyclohexanecarbonyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

rac-N-[1-((1S,2R)-2-amino-cyclopentanecarbonyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-[1-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide;

N-cyclopropyl-N-{1-[2-(2-hydroxy-ethylamino)-benzoyl]-piperidin-4-yl}-3-trifluoromethyl-benzenesulfonamide;

rac-N-[1-((1S,2R)-2-amino-cyclopentanecarbonyl)-piperidin-4-yl}-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

N-[1-(2-cyclohexylamino-acetyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

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

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

N-[1-(2-1,3-dihydro-isoindol-2-yl-acetyl)-piperidin-4-yl]-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

N-{1-[2-(3,3-difluoro-piperidin-1-yl)-acetyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethylbenzenesulfonamide; and

N-{1-[2-(3,3-difluoro-pyrrolidin-1-yl)-acetyl]-piperidin-4-yl}-N-isopropyl-3-trifluoromethylbenzenesulfonamide;

or a pharmaceutically acceptable salt thereof.