IP Library › Granted Patent US 8,536,177

Granted Patent B2

US 8,536,177 · App. 13/205,323 · Granted Sep 17, 2013

Therapeutic agents useful for treating pain

Inventors: Qun Sun (Princeton, NJ); Laykea Tafesse (Robbinsville, NJ); Sam Victory (Oak Ridge, NC)

Assignee: Purdue Pharma L.P.

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Quick Facts

Patent No.: US 8,536,177
App. No.: 13/205,323
Granted: Sep 17, 2013
Kind: B2

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Abstract

A compound of formula: wherein Ar 1 , A, R 3 , x, and m are as disclosed herein and Ar 2 is a benzothiazolyl, benzooxazolyl, or benzoimidazolyl group or a pharmaceutically acceptable salt thereof (a “Benzoazolylpiperazine Compound”), compositions comprising a Benzoazolylpiperazine Compound, and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of a Benzoazolylpiperazine Compound are disclosed.

Claims (161)

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is:

A is:

R 1 is —H, -halo, —(C 1 -C 6 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

(a) -halo, —CN, —OH, —O(C 1 -C 6 )alkyl, —NO 2 , or —NH 2 ; or

(b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups; or

(c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

each R 3 is independently:

(a) -halo, —CN, —OH, —O(C 1 -C 6 )alkyl, —NO 2 , or —NH 2 ; or

(c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

R 4 is —H;

each R 5 is independently —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ;

each R 6 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 3 -C 5 )heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 2 , or —S(O) 2 R 7 ;

each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 3 -C 5 )heterocycle, —C(halo) 3 , —CH 2 (halo), or —CH(halo) 2 ;

R 8 and R 9 are each independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7, —S(O)R 7 , or —S(O) 2 R 7 ;

each -halo is —F, —Cl, —Br, or —I;

p is an integer ranging from 1 to 2;

m is 0 or 1; and

x is 0 or 1.

2. The compound of claim 1 , wherein x is 0.

3. The compound of claim 1 , wherein x is 1

4. The compound of claim 1 , wherein p is 1.

5. The compound of claim 4 , wherein R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

6. The compound of claim 5 , wherein R 2 is —(C 1 -C 10 )alkyl substituted with two R 5 groups.

7. The compound of claim 1 , wherein R 3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A) x - group.

8. The compound of claim 7 , wherein the carbon to which R 3 is attached is in the (R) configuration.

9. The compound of claim 8 , wherein R 3 is —CH 3 .

10. The compound of claim 1 , wherein:

R 1 is —CH 3 , —CF 3 , —Cl, —Br, or —I;

m is 0;

p is 1;

x is 1;

R 8 is —H; and

R 9 is —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, or —F.

11. The compound of claim 10 , wherein R 1 is —CH 3 or —Cl and R 9 is —Cl, —Br, or —F.

12. The compound of claim 1 , wherein:

R 1 is —CH 3 , —CF 3 , —Cl, —Br, or —I;

m is 1;

R 3 is —(C 1 -C 10 )alkyl;

p is 1;

x is 1;

R 8 is —H; and

R 9 is —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, or —F.

13. The compound of claim 12 , wherein R 3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A) x - group.

14. The compound of claim 13 , wherein the carbon to which R 3 is attached is in the (R) configuration.

15. The compound of claim 14 , wherein R 3 is —CH 3 .

16. The compound of claim 15 , wherein R 1 is —CH 3 or —Cl and R 9 is —Cl, —Br, or —F.

17. The compound of claim 1 , wherein the compound is selected from:

and pharmaceutically acceptable salts thereof.

18. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is:

A is:

R 1 is —H, -halo, —(C 1 -C 6 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

(a) -halo, —CN, —OH, —O(C 1 -C 6 )alkyl, —NO 2 , or —NH 2 ; or

(c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

each R 3 is independently:

(a) -halo, —CN, —OH, —O(C 1 -C 6 )alkyl, —NO 2 , or —NH 2 ; or

(b) —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups; or

(c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

R 4 is —H;

each R 7 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 3 -C 5 )heterocycle, —C(halo) 3 , —CH 2 (halo), or —CH(halo) 2 ;

R 10 is —H or —(C 1 -C 4 )alkyl;

each -halo is —F, —Cl, —Br, or —I;

p is an integer ranging from 1 to 2;

m is 0 or 1; and

x is 0 or 1.

19. The compound of claim 18 , wherein x is 0.

20. The compound of claim 18 , wherein x is 1.

21. The compound of claim 18 , wherein p is 1.

22. The compound of claim 21 , wherein R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

23. The compound of claim 22 , wherein R 2 is —(C 1 -C 10 )alkyl substituted with two R 5 groups.

24. The compound of claim 18 , wherein R 3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A) x - group.

25. The compound of claim 24 , wherein the carbon to which R 3 is attached is in the (R) configuration.

26. The compound of claim 25 , wherein R 3 is —CH 3 .

27. The compound of claim 18 , wherein R 10 is —H.

28. The compound of claim 18 , wherein R 10 is —CH 3 .

29. The compound of claim 18 , wherein:

R 1 is —CH 3 , —CF 3 , —Cl, —Br, or —I;

m is 0;

p is 1;

x is 1;

R 8 is —H; and

R 9 is —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, or —F.

30. The compound of claim 29 , wherein R 1 is —CH 3 or —Cl and R 9 is —Cl, —Br, or —F.

31. The compound of claim 18 , wherein:

R 1 is —CH 3 , —CF 3 , —Cl, —Br, or —I;

m is 1;

R 3 is —(C 1 -C 10 )alkyl;

p is 1;

x is 1;

R 8 is —H; and

R 9 is —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, or —F.

32. The compound of claim 31 , wherein R 3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A) x - group.

33. The compound of claim 32 , wherein the carbon to which R 3 is attached is in the (R) configuration.

34. The compound of claim 33 , wherein R 3 is —CH 3 .

35. The compound of claim 34 , wherein R 1 is —CH 3 or —Cl and R 9 is —Cl, —Br, or —F.

36. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is:

A is:

R 1 is —H, -halo, —(C 1 -C 6 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

(a) -halo, —CN, —OH, —O(C 1 -C 6 )alkyl, —NO 2 , or —NH 2 ; or

(b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups; or

each R 3 is independently:

(a) -halo, —CN, —OH, —(C 1 -C 6 )alkyl, —NO 2 , or —NH 2 ; or

(c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

R 4 is —H;

each -halo is —F, —Cl, —Br, or —I;

p is an integer ranging from 1 to 2;

m is 0 or 1; and

x is 0 or 1.

37. The compound of claim 36 , wherein x is 0.

38. The compound of claim 36 , wherein x is 1.

39. The compound of claim 36 , wherein p is 1.

40. The compound of claim 39 , wherein R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

41. The compound of claim 40 , wherein R 2 is —(C 1 -C 10 )alkyl substituted with two R 5 groups.

42. The compound of claim 36 , wherein R 3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A) x - group.

43. The compound of claim 42 , wherein the carbon to which R 3 is attached is in the (R) configuration.

44. The compound of claim 43 , wherein R 3 is —CH 3 .

45. The compound of claim 36 , wherein:

R 1 is —CH 3 , —CF 3 , —Cl, —Br, or —I;

m is 0;

p is 1;

x is 1;

R 8 is —H; and

R 9 is —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, or —F.

46. The compound of claim 45 , wherein R 1 is —CH 3 or —Cl and R 9 is —Cl, —Br, or —F.

47. The compound of claim 36 , wherein:

R 1 is —CH 3 , —CF 3 , —Cl, —Br, or —I;

m is 1;

R 3 is —(C 1 -C 10 )alkyl;

p is 1;

x is 1;

R 8 is —H; and

R 9 is —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, or —F.

48. The compound of claim 47 , wherein R 3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A) x - group.

49. The compound of claim 48 , wherein the carbon to which R 3 is attached is in the (R) configuration.

50. The compound of claim 49 , wherein R 3 is —H 3 .

51. The compound of claim 50 , wherein R 1 is —CH 3 or —Cl and R 9 is —Cl, —Br, or —F.

52. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

53. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 18 and a pharmaceutically acceptable carrier or excipient.

54. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 36 and a pharmaceutically acceptable carrier or excipient.

55. A method for preparing a composition comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

56. A method for preparing a composition comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of claim 18 and a pharmaceutically acceptable carrier or excipient.

57. A method for preparing a composition comprising the step of admixing a compound or a pharmaceutically acceptable, salt of the compound of claim 36 and a pharmaceutically acceptable carrier or excipient.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 3, 2011

From: SUN, QUN; TAFESSE, LAYKEA F; VICTORY, SAM

To: EURO-CELTIQUE S.A.

Reel/Frame 027170/0325 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 3, 2011

From: EURO-CELTIQUE S.A.

To: PURDUE PHARMA L.P.

Reel/Frame 027170/0408 →

Continuity (6)

Continuation 12499480 · Jul 8, 2009

Division 10739190 · Dec 19, 2003

Provisional Application 60435917 · Dec 24, 2002

Provisional Application 60459626 · Apr 3, 2003

Provisional Application 60473856 · May 29, 2003

Related Publication 20120004217A1 · Jan 5, 2012