IP Library › Granted Patent US 9,447,026
Granted Patent B2
US 9,447,026 · App. 14/439,636 · Granted Sep 20, 2016

Bicyclic analgesic compounds

Inventor: Kevin Duane Bunker (San Diego, CA)
Assignee: Kalyra Pharmaceuticals, Inc.
C07C233/52A61K31/13A61K31/14A61K31/16A61K31/215A61K31/216A61K31/22A61K31/235A61K45/06C07C211/62C07C217/52C07C233/06C07C233/23C07C233/41C07C235/74C07C2102/38
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Quick Facts
Patent No.
US 9,447,026
App. No.
14/439,636
Granted
Sep 20, 2016
Kind
B2
Abstract

Analgesic compounds for treatment of pain or fever that include a bicyclopentane moiety linked to an amine, combinations of the compounds with opioid analgesic drugs, and methods for treating pain or fever by administering a compound described herein.

Claims (96)

1. A method for reducing pain or fever comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

wherein

R 1 is H, —CH 3 , or a substituted or unsubstituted (C 2 to C 5 ) alkyl;

R 2 is H or —C(═Y)R 4 ;

R 3 is H, F, D, hydroxy, NH 2 , a (C 1 to C 10 ) alkoxy, a substituted or unsubstituted (C 1 to C 30 ) alkyl, a substituted or unsubstituted (C 2 to C 30 ) alkenyl, a substituted or unsubstituted (C 2 to C 30 ) alkynyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkenyl, a substituted or unsubstituted (C 8 to C 30 ) cycloalkynyl, a substituted or unsubstituted —N-linked amido, —(C═O)L or —O(C═O)R 5 , wherein—(C═O)L is a hydrolyzable prodrug ester leaving group,

R 4 is a substituted or unsubstituted (C 1 to C m ) alkyl;

R 5 is a substituted or unsubstituted (C 1 to C 6 ) alkyl, a substituted or unsubstituted aryl(C 1-6 alkyl) or

and

Y is S or O.

2. The method of claim 1 , further comprising administering an opioid analgesic.

3. The method of claim 2 , wherein the opioid analgesic is selected from the group consisting of morphine, codeine, hydrocodone, oxycodone, fentanyl, pethidine, methadone, pentazocine, sufentanil, levorphanol, dihydrocodeine, nalbuphine, butorphanol, tramadol, meptazinol, buprenorphine, dipipanone, alfentanil, remifentanil, oxymorphone, tapentadol, propoxyphene and hydromorphone.

4. The method of claim 1 , wherein the administration is intravenous.

5. The method of claim 1 , wherein the administration is topical.

6. The method of claim 1 , wherein the pain is post-operative pain.

7. The method of claim 1 , wherein R 2 is —C(═Y)R 4 .

8. The method of claim 7 , wherein Y is O.

9. The method of claim 7 , wherein Y is S.

10. The method of claim 1 , wherein R 4 is a substituted or unsubstituted (C 1 to C 10 ) alkyl.

11. The method of claim 1 , wherein R 2 is H.

12. The method of claim 1 , wherein R 1 is H.

13. The method of claim 1 , wherein R 1 is —CH 3 .

14. The method of claim 1 , wherein R 1 is a substituted or unsubstituted (C 2 to C 5 ) alkyl.

15. The method of claim 1 , wherein R 3 is H.

16. The method of claim 1 , wherein R 3 is F.

17. The method of claim 1 , wherein R 3 is D.

18. The method of claim 1 , wherein R 3 is hydroxy.

19. The method of claim 1 , wherein R 3 is NH 2 .

20. The method of claim 1 , wherein R 3 is a (C 1 to C 10 ) alkoxy.

21. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 1 to C 30 ) alkyl.

22. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 2 to C 30 ) alkenyl.

23. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 2 to C 30 ) alkynyl.

24. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 3 to C 30 ) cycloalkyl.

25. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 3 to C 30 ) cycloalkenyl.

26. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 8 to C 30 ) cycloalkynyl.

27. The method of claim 1 , wherein R 3 is a substituted or unsubstituted (C 6 to C 30 ) aryl.

28. The method of claim 1 , wherein R 3 is a substituted or unsubstituted heteroaryl.

29. The method of claim 1 , wherein R 3 is a substituted or unsubstituted heterocyclyl.

30. The method of claim 1 , wherein R 3 is a substituted or unsubstituted aryl(C 1-6 alkyl).

31. The method of claim 1 , wherein R 3 is a substituted or unsubstituted heteroaryl(C 1-6 alkyl).

32. The method of claim 1 , wherein R 3 is a substituted or unsubstituted —N-linked amido.

33. The method of claim 1 , wherein R 3 is —(C═O)L.

34. The method of claim 33 , wherein —(C═O)L is —(C═O)OR 6 , wherein R 6 is a substituted or unsubstituted (C 1 to C 30 ) alkyl, a substituted or unsubstituted (C 2 to C 30 ) alkenyl, a substituted or unsubstituted (C 2 to C 30 ) alkynyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkenyl, a substituted or unsubstituted (C 8 to C 30 ) cycloalkynyl, a substituted or unsubstituted (C 6 to C 30 ) aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl(C 1-6 alkyl), a substituted or unsubstituted heteroaryl(C 1-6 alkyl).

35. The method of claim 34 , wherein R 3 is —(C═O)L, and L is —O—C 1-6 alkyl.

36. The method of claim 1 , wherein R 3 is —O(C═O)R 5 .

37. The method of claim 36 , wherein R 5 is a substituted or unsubstituted (C 1 to C 6 ) alkyl.

38. The method of claim 36 , wherein R 5 is a substituted or unsubstituted aryl(C 1-6 alkyl).

39. The method of claim 36 , wherein R 5 is

40. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

41. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

R 1 is H, —CH 3 , —CF 3 , or a substituted or unsubstituted (C 2 to C 5 ) alkyl;

R 2 is —C(═Y)R 4 ; and

R 3 is H, F, D, hydroxy, NH 2 , a (C 1 to C 10 ) alkoxy, a substituted or unsubstituted (C 1 to C 30 ) alkyl, a substituted or unsubstituted (C 2 to C 30 ) alkenyl, a substituted or unsubstituted (C 2 to C 30 ) alkynyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkenyl, a substituted or unsubstituted (C 8 to C 30 ) cycloalkynyl, a substituted or unsubstituted —N-linked amido, —(C═O)L or —O(C═O)R 5 , wherein —(C═O)L is a hydrolyzable prodrug ester leaving group; or

R 1 is H, —CH 3 , —CF 3 , or a substituted or unsubstituted (C 2 to C 5 ) alkyl;

R 2 is H;

R 3 is H, D, a (C 1 to C 10 ) alkoxy, a substituted (C 1 to C 30 ) alkyl, an unsubstituted (C 2 to C 30 ) alkyl, a substituted or unsubstituted (C 2 to C 30 ) alkenyl, a substituted or unsubstituted (C 2 to C 30 ) alkynyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkyl, a substituted or unsubstituted (C 3 to C 30 ) cycloalkenyl, a substituted or unsubstituted (C 8 to C 30 ) cycloalkynyl, a substituted or unsubstituted —N-linked amido or —O(C═O)R 5 ;

R 4 is a substituted or unsubstituted (C 1 to C 10 ) alkyl;

R 5 is a substituted or unsubstituted (C 1 to C 6 ) alkyl, a substituted or unsubstituted aryl(C 1-6 alkyl) or

and

Y is S or O; and

with the proviso that when R 3 hydrogen, then R 1 and R 2 cannot both be hydrogen.

42. The compound of claim 41 , wherein R 2 is —C(═Y)R 4 .

43. The compound of claim 42 , wherein Y is O.

44. The compound of claim 42 , wherein Y is S.

45. The compound of claim 41 , wherein R 4 is a substituted or unsubstituted (C 1 to C 10 ) alkyl.

46. The compound of claim 41 , wherein R 2 is H.

47. The compound of claim 41 , wherein R 1 is H.

48. The compound of claim 41 , wherein R 1 is —CH 3 .

49. The compound of claim 41 , wherein R 1 is —CF 3 .

50. The compound of claim 41 , wherein R 1 is a substituted or unsubstituted (C 2 to C 5 ) alkyl.

51. The compound of claim 41 , wherein R 3 is H.

52. The compound of claim 41 , wherein R 3 is D.

53. The compound of claim 41 , wherein R 3 is a (C 1 to C 10 ) alkoxy.

54. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted (C 2 to C 30 ) alkyl.

55. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted (C 2 to C 30 ) alkenyl.

56. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted (C 2 to C 30 ) alkynyl.

57. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted (C 3 to C 30 ) cycloalkyl.

58. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted (C 3 to C 30 ) cycloalkenyl.

59. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted (C 8 to C 30 ) cycloalkynyl.

60. The compound of claim 41 , wherein R 3 is a substituted (C 6 to C 30 ) aryl.

61. The compound of claim 41 , wherein R 3 is an unsubstituted (C 7 to C 30 ) aryl.

62. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted heteroaryl.

63. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted heterocyclyl.

64. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted aryl(C 1-6 alkyl).

65. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted heteroaryl(C 1-6 alkyl).

66. The compound of claim 41 , wherein R 3 is a substituted or unsubstituted —N-linked amido.

67. The compound of claim 41 , wherein R 3 is —O(C═O)R 5 .

68. The compound of claim 67 , wherein R 5 is a substituted or unsubstituted (C 1 to C 6 ) alkyl.

69. The compound of claim 67 , wherein R 5 is a substituted or unsubstituted aryl(C 1-6 alkyl).

70. The compound of claim 67 , wherein R 5 is

71. The compound of claim 41 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

72. A pharmaceutical composition comprising an effective amount of a compound of claim 41 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

73. The method of claim 10 wherein R 4 is CF 3 .

74. The method of claim 14 , wherein R 1 is CF 3 .

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 27, 2025
From: RECURIUM IP HOLDINGS, LLC
To: KTHERA, LLC
Reel/Frame 070653/0373 →
CHANGE OF NAME Recorded Jan 3, 2020
From: ZENO ROYALTIES & MILESTONES, LLC
To: RECURIUM IP HOLDINGS, LLC
Reel/Frame 051478/0353 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 30, 2015
From: BUNKER, KEVIN DUANE
To: KALYRA PHARMACEUTICALS, INC.
Reel/Frame 035541/0148 →
Continuity (2)
Provisional Application 61781580 · Mar 14, 2013
Related Publication 20160016892A1 · Jan 21, 2016