Benzenesulfonamide compounds and their use

• US 8,247,442 B2
• Filed: 03/29/2007
• Issued: 08/21/2012
• Est. Priority Date: 03/29/2006
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Chen, Zhengming, Islam, Khondaker, Shao, Bin, Yao, Jiangchao, Kyle, Donald J.
• Primary Examiner(s): Chu, Yong
• Application Number:
  US12/225,743
• Publication Number:
  US 20090239910A1
• Time in Patent Office: 1,972 Days
• Field of Search: None
• US Class Current: 514/426
• 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.

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

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

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

10. The compound of claim 9, 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.

11. The compound of claim 9, 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.

12. The compound of claim 9, 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.

13. The compound of claim 9, 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.

14. The compound of claim 9, wherein R⁵ is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and alkoxyalkyl.

15. The compound of claim 9, wherein R⁶ is hydrogen and R⁷ is methyl;

propyl;

iso-propyl;

butyl;

tert-butyl;

sec-butyl;

iso-butyl;

hydroxymethyl;

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.

16. The compound of claim 9, 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.

17. The compound of claim 9, wherein R⁶ and R⁷ together with the carbon atom to which they are attached form cyclopentyl or cyclohexyl.

18. The compound of claim 9, 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.

19. The compound of claim 9, wherein the configuration at the carbon atom to which —

NR⁴R⁵ is attached is (S).

20. The compound of claim 9, having the Formula VI:

21. The compound of claim 20, wherein R⁴¹ and R⁵¹ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.

22. The compound of claim 20, wherein R⁴¹ and R⁵¹ both are hydrogen, or R⁴¹ is hydrogen and R⁵¹ is C_1-3 alkyl.

23. The compound of claim 20, 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.

24. The compound of claim 9, having the Formula VII:

25. The compound of claim 24, wherein R⁴² and R⁵² are each independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, and hydroxyethyl.

26. The compound of claim 24, 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.

27. The compound of claim 24, 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.

28. The compound of claim 24, wherein R²⁰ and R²¹ are both H when R⁴² and R⁵² together form the 5- or 6-membered heterocyclic ring.

29. The compound of claim 24, wherein R⁴² and R⁵² are both hydrogen or R⁴² is hydrogen and R⁵² is alkyl.

30. The compound of claim 24, wherein m is 1.

31. The compound of claim 1 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-methylamino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

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;

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.

32. The compound of claim 1 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-methylamino-5-methylhexanoyl)piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide;

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

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

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

34. A method for treating or ameliorating pain, or migraine in a mammal, comprising administering an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment or amelioration.

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

36. 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.