Benzenesulfonyl compounds and the use thereof

• US 8,399,486 B2
• Filed: 04/08/2008
• Issued: 03/19/2013
• Est. Priority Date: 04/09/2007
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Kyle, Donald J., Yao, Jiangchao
• Primary Examiner(s): JARRELL, NOBLE E
• Application Number:
  US12/595,066
• Publication Number:
  US 20100063030A1
• Time in Patent Office: 1,806 Days
• Field of Search: None
• US Class Current: 514/317
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 207/48 Sulfur atoms
• CPC Class Codes: C07D 211/96 Sulfur atom

Abstract

The invention relates to pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds of Formula I: and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R¹, R², Z and m 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 or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, halo(C₁-C₆)alkyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, C₁-C₆ alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, cycloalkyl, and heterocyclo(C₁-C₆)alkyl, all of which can be optionally substituted;

R² is selected from the group consisting of C₁-C₆ alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and di(C₁-C₆)alkylamino;

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

Z¹ is

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

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

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

6. The compound of claim 1, wherein Z is Z¹.

7. The compound of claim 6, wherein Z¹ is Z¹¹ having the structure:

8. The compound of claim 6, wherein Z¹ is Z¹² having the structure:

9. The compound of claim 6, wherein Z¹ is Z¹³ having the structure:

10. The compound of claim 6, wherein Z¹ is selected from the group consisting of Z¹⁴, Z¹⁵ and Z¹⁶, wherein:

Z¹⁴ is

11. The compound of claim 10, wherein R⁶ is hydrogen and n is 0 or 1.

12. The compound of claim 11, wherein R⁵ is optionally substituted C_6-10 aryl or optionally substituted heteroaryl having 5-10 ring atoms.

13. The compound of claim 12, wherein R⁵ is selected from the group consisting of phenyl, naphthyl, indenyl, isoindenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, benzothiazolyl, thiazolyl, imidazolyl, benzoimidazolyl, benzoxazolyl, indolyl, indazolyl, and benzotriazolyl, all of which can be optionally substituted.

14. The compound of claim 6, wherein Z¹ is selected from the group consisting of Z¹⁷ and Z¹⁸, wherein:

Z¹⁷ is

15. The compound of claim 1, wherein Z is Z².

16. The compound of claim 15, wherein Z² is Z²¹ having the structure:

17. The compound of claim 16, wherein R⁷ is optionally substituted C_6-10 aryl or optionally substituted heteroaryl having 5-10 ring atoms.

18. The compound of claim 17, wherein R⁷ is selected from the group consisting of phenyl, naphthyl, indenyl, isoindenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzoimidazolyl, benzoxazolyl, indolyl, indazolyl, and benzotriazolyl all of which can be optionally substituted.

19. The compound of claim 18, wherein R⁷ is unsubstituted phenyl or phenyl substituted with one, two, or three substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, dialkylamino, and hydroxyalkylamino.

20. The compound of claim 1, wherein Z is Z³.

21. The compound of claim 20, wherein R⁹ and R¹⁰ are each independently selected from the group consisting of

hydrogen;

hydroxyalkyl;

alkoxyalkyl;

cycloalkyl, and

phenyl optionally substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy.

22. The compound of claim 20, wherein R⁹ is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or phenyl optionally substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;

and R¹⁰ is R¹⁷—

C(O)—

, where R¹⁷ is selected from the group consisting of optionally substituted benzyl and optionally substituted benzyloxy.

23. The compound of claim 20, wherein R⁹ and R¹⁰ 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 NR¹⁸, O, or S, wherein R¹⁸ is hydrogen or C_1-3 alkyl.

24. The compound of claim 20, wherein R¹¹ and R¹² are each independently selected from the group consisting of

hydrogen;

alkyl;

alkenyl;

hydroxyalkyl;

aminoalkyl;

cycloalkyl;

heterocyclo;

heterocycloalkyl;

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

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

benzyloxyalkyl;

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

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

25. The compound of claim 20, wherein R¹¹ and R¹² together with the carbon atom to which they are attached form a saturated or unsaturated C_3-7 cycloalkyl ring optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, phenyl, and ═

O, wherein one or more carbon atoms of the C_3-7 cycloalkyl ring are optionally replaced with NR¹⁹, O, S, or SO₂, wherein R¹⁹ is hydrogen or C_1-3 alkyl, to form a heterocyclic ring;

or wherein two adjacent carbon atoms of the C_3-7 cycloalkyl ring can form a bridge —

O—

to form a bicyclic ring;

or wherein two adjacent carbon atoms of the C_3-7 cycloalkyl ring together form a fused phenyl group optionally substituted with alkyl, haloalkyl, amino, cyano, or hydroxy.

26. The compound of claim 20, wherein R¹¹ and R¹² together form ═

O.

27. The compound of claim 20, wherein R¹² is hydrogen, alkyl, or alkenyl;

R⁹ is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or phenyl optionally substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy; and

R¹⁰ and R¹¹ 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.

28. The compound of claim 20, wherein R⁹ is hydrogen and R¹⁰ is hydrogen, hydroxyalkyl, or cycloalkyl.

29. The compound of claim 20, wherein R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring;

R¹¹ is hydrogen, and R¹² is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or benzyl optionally substituted with one or two substituents each independently selected from the group consisting of alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, alkoxy and cyano.

30. The compound of claim 20, wherein R⁹ is selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —

CH₂—

U—

V, wherein U is CH₂, CHF, CF₂ or CHOH and V is hydrogen, alkyl, or alkenyl; and

R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl.

31. The compound of claim 20, wherein R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring to give Z³¹ having the structure:

32. The compound of claim 30, wherein R¹¹ and R¹² together form ═

O.

33. The compound of claim 30, wherein R¹¹ and R¹² are each independently selected from the group consisting of hydrogen, alkyl, and alkenyl or together with the carbon atom to which they are attached form a saturated or unsaturated C_3-7 cycloalkyl ring optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, phenyl, and —

O, wherein one or more carbon atoms of the C_3-7 cycloalkyl ring are optionally replaced with NR¹⁹, O, S, or SO₂, wherein R¹⁹ is hydrogen or C_1-3 alkyl, to form a heterocyclic ring.

35. The compound of claim 20 having the Formula V:

36. The compound of claim 20, wherein Z is Z³;

R¹¹ and R¹² together form ═

O;

R⁹ is selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —

CH₂—

U—

V, wherein U is CH₂, CHF, CF₂ or CHOH and V is hydrogen, alkyl, or alkenyl; and

R¹⁰ and R¹ together form a bridge -D-E-G-, wherein D is CH₂, C(O), CHCH₃, C(CH₃)₂ or absent;

E is CH₂, C(O), C(S), CHF, CF₂, or CHOH; and

G is CH₂, C(O), CHCH₃, C(CH₃)₂ or absent.

37. The compound of claim 1, wherein R¹ is selected from the group consisting of hydrogen, C_1-6 alkyl, halo(C_1-6)alkyl, C_1-4 alkoxy(C_1-6)alkyl, halo(C_1-4)alkoxy(C_1-6)alkyl, hydroxy(C_1-6)alkyl, amino(C_1-6)alkyl, C_1-4 alkylamino(C_1-6)alkyl, di(C_1-4)alkylamino(C_1-6)alkyl, and C_3-7 cycloalkyl.

38. The compound of claim 1, wherein R² is selected from the group consisting of

a) cycloalkyl;

b) aryl optionally substituted with one, two or three substituents each independently selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, hydroxyalkylamino, —

C(O)OR²⁰, and —

C(O)NR²⁰R²¹, wherein R²⁰ and R²¹ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, optionally substituted heterocyclo, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —

CH₂—

U—

V, wherein U is CH₂, CHF, CF₂ or CHOH and V is hydrogen, alkyl, alkenyl or aryl;

c) heteroaryl optionally substituted with one, two or three substituents each independently selected from the group consisting of alkyl, alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, hydroxyalkylamino, alkoxycarbonyl, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, halogen, haloalkyl, phenyl, phenoxy, heteroaryl, and heterocyclo; and

d) di(C_1-6)alkylamino.

39. The compound of claim 38, wherein R² is phenyl or pyridyl optionally substituted with one or two substituents each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino and hydroxyalkylamino.

40. The compound of claim 38, wherein R² is phenyl substituted with alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, hydroxyalkylamino, —

C(O)OR²⁰, and —

C(O)NR²⁰R²¹, wherein R²⁰ and R²¹ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, optionally substituted heterocyclo, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —

CH₂—

U—

V, wherein U is CH₂, CHF, CF₂ or CHOH and V is hydrogen, alkyl, alkenyl or aryl.

41. The compound as claimed in claim 1, wherein said compound is:

N-(4-fluorophenyl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)piperidin-4-ylamino]acetamide;

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

N-(4-fluorophenyl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)-pyrrolidin-3-ylamino]acetamide;

N-(3,5-bis-(trifluoromethyl)phenyl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)piperidin-4-ylamino]acetamide;

N-(2,4-difluorophenyl)-N′

-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]malonamide;

or

a pharmaceutically acceptable salt thereof.

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

43. A method for ameliorating pain or hypertension in a mammal, comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a mammal in need of such amelioration.

44. The method of claim 43, wherein the method is for ameliorating pain.

45. The method of claim 44, wherein method is for palliative treatment of pain.

46. The method of claim 44, wherein said pain is selected from the group consisting of chronic pain, neuropathic pain, acute pain, and surgical pain.

47. A method of modulating calcium channels in a mammal, comprising administering to the mammal at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the N-type calcium channel is modulated.

49. A compound as claimed in claim 1, wherein the compound is ³H, ¹¹C, or ¹⁴C radiolabeled, or a pharmaceutically acceptable salt thereof.

50. A method of screening a candidate compound for the ability to bind to a receptor using a radiolabeled compound of claim 49, 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.

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

34. The compound of 33, wherein Z³ is Z³² having the structure: