Benzenesulfonamide Compounds and the Use Thereof

• US 20090306136A1
• Filed: 04/13/2007
• Published: 12/10/2009
• Est. Priority Date: 04/13/2006
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Matsumura, Akira, Shao, Bin, Tsuno, Naoki, Mikamiyama, Hidenori, Yao, Jiangchao
• Granted Patent: US 8,937,181 B2
• Time in Patent Office: Days
• US Class Current: 514/318
• 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:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein;

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

R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;

Z is selected from the group consisting of Z¹, Z², Z³, and Z⁴ wherein;

Z¹ is

Z² is

Z³ is

Z⁴ is

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, dialkylamino, 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 alkoxycarbonyl;

or

R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, and halogen;

or

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;

R⁶, R⁷, and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, and dialkylamino;

R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, nitro, and hydroxy(C_1-3)alkylamino;

Y is —

C(O)—

, —

COH—

or —

CH—

;

where

when Y is —

C(O)—

, the bond between N and Y is a single bond and R¹² is present; and

when Y is —

COH—

or —

CH—

, the bond between N and Y is a double bond and R¹² is absent;

R¹² is selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl;

m is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

q is 0, 1, 2, or 3; and

p is 1 or 2

provided that

1) when Z is Z², then none of R⁶, R⁷, or R⁸ is attached to the 1-position of the cycloalkyl ring;

2) when Z is Z³, Z³ is other than;

3) when Z is Z⁴, the compound is not N-cyclopropyl-N-{1-[(3-trifluoromethyl-4-methoxy)benzoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide or N-cyclopropyl-N-[1-(4-dimethylaminobenzoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide.

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, wherein q is 1 and p is 2.

6. The compound of any one of claims 1-3, having the Formula II:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

7. The compound of any one of claims 1-6, 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 7, 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.

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

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

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

11. The compound of any one of claims 1-3, 6, or 10, wherein Z=Z¹ having the Formula IV:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

12. The compound of claim 11, 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, cyclopropylethyl, methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl, methylsulfonamidomethyl, methylsulfonamidoethyl, aminocarbonylmethyl, and aminocarbonylethyl.

13. The compound of claim 11, 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 form 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 alkoxycarbonyl

14. The compound of claim 13, wherein R⁴ is 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.

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

16. The compound of claim 13, 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.

17. The compound of claim 11, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, and halogen.

18. The compound of claim 17, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring substituted with one or two substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, and halogen.

19. The compound of claim 11, 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.

20. The compound of any one of claims 1-3, 6, or 10, wherein Z=Z² having the Formula V:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

21. The compound of claim 20, 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.

22. The compound of claim 20, wherein R⁶, R⁷, and R⁸ are each independently selected from the group consisting of hydrogen, halogen, 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.

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

24. The compound of claim 20, wherein r is 2.

25. The compound of any one of claims 1-3, 6 or 10, wherein Z=Z³ having the Formula VI:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

26. The compound of claim 25, 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.

27. The compound of claim 25, 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.

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

C(O)—

.

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

COH—

.

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

CH—

.

31. The compound of claim 25, wherein R¹² is hydrogen or C_1-6 alkyl.

32. The compounds of any one of claims 1-3, 6, or 10, wherein Z=Z⁴ having the Formula VII:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

33. The compound of claim 32, 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.

34. The compound of claim 32, 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, di(C_1-3)alkylamino, nitro and hydroxy(C_1-3)alkylamino.

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

37. A pharmaceutical composition, comprising the compound of any of claims 1-36 and a pharmaceutically acceptable carrier.

38. 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 any of claims 1-36.

39. The method of claim 38, wherein a disorder responsive to the blockade of N-type calcium channels is treated, prevented or ameliorated.

40. 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 any of claims 1-36.

41. The method of claim 40, wherein the method is for treating, preventing or ameliorating pain selected from chronic pain, neuropathic pain, acute pain, and surgical pain.

42. A method of modulating calcium channels in a mammal, comprising administering to the mammal at least one compound of any one of claims 1-36.

43. The method of claim 42, wherein the N-type calcium channel is modulated.

44. A compound having the Formula I as claimed in claims 1-3, wherein the compound is ³H, ¹¹C, or ¹⁴C radiolabeled.

45. A method of screening a candidate compound for the ability to bind to a receptor using a radiolabeled compound of claim 44, 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.

46. A compound according to any one of the preceding claims 1 to 36 for the use as a medicament.

47. Use of a compound according to any one of the preceding claims 1 to 36 for the manufacture of a medicament for the treating, preventing or ameliorating of a disorder responsive to the blockade of calcium channels.

48. Use of a compound according to claim 47, wherein the disorder is a disorder responsive to the blockade of N-type calcium channels.

49. Use of a compound according to any one of claims 1 to 36 in the manufacture of a medicament for the 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.

50. Use of a compound according to any one of claims 1 to 36 in the manufacture of a medicament for the treating, preventing or ameliorating pain selected from chronic pain, neuropathic pain, acute pain, and surgical pain.

2. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein;

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

R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;

Z is selected from the group consisting of Z¹, Z², Z³, and Z⁴ wherein;

Z¹ is

Z² is

Z³ is

Z⁴ is

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, dialkylamino, 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 alkoxycarbonyl;

or

R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl;

R⁶, R⁷, and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, and dialkylamino;

R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxy(C_1-3)alkylamino;

Y is —

C(O)—

, —

COH—

or —

CH—

;

where

when Y is —

C(O)—

, the bond between N and Y is a single bond and R¹² is present; and

when Y is —

COH—

or —

CH—

, the bond between N and Y is a double bond and R¹² is absent;

R¹² is selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl;

m is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

q is 0, 1, 2, or 3; and

p is 1 or 2

provided that when Z is Z³, Z³ is other than;

3. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein;

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

R³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylalkyl, 3-tetrahydrofuranylalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;

Z is selected from the group consisting of Z¹, Z², and Z³, wherein;

Z¹ is

Z² is

Z³ is

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, dialkylamino, 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 alkoxycarbonyl;

or

R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring substituted with one or more substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl;

R⁶, R⁷, and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, and dialkylamino;

R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino;

Y is —

C(O)—

or —

COH—

;

where

when Y is —

C(O)—

, the bond between N and Y is a single bond and R¹² is present; and

when Y is —

COH—

, the bond between N and Y is a double bond and R¹² is absent;

R¹² is selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl;

m is 0, or 1, 2, or 3;

r is 0, 1, 2, or 3;

q is 0, 1, 2, or 3; and

p is 1 or 2;

provided that when Z is Z², then none of R⁶, R⁷, or R⁸ is attached to the 1-position of the cycloalkyl ring.

36. A compound selected from the group consisting of:

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

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-(pyridine-2-carbonyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide;

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

N-cyclopropyl-N-[1-(pyridine-4-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-cyclopropyl-N-[1-(2-nitro-benzoyl)-piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide;

N-[1-(2-amino-benzoyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide;

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

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

N-[1-(2-cyclopentylamino-acetyl)-piperidin-4-yl]-N-cyclopropyl-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, prodrug or solvate thereof.