IP Library › Granted Patent US 7,776,861
Granted Patent B2
US 7,776,861 · App. 11/338,502 · Granted Aug 17, 2010

Therapeutic agents useful for treating pain

Assignee: Purdue Pharma L.P.
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Quick Facts
Patent No.
US 7,776,861
App. No.
11/338,502
Granted
Aug 17, 2010
Kind
B2
Abstract

A compound of formula: where Ar 1 , Ar 2 , X, R 3 , and m are as disclosed herein or a pharmaceutically acceptable salt thereof (a “Cycloheteroalkenyl Compound”); compositions comprising an effective amount of a Cycloheteroalkenyl 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 Cycloheteroalkenyl Compound are disclosed herein.

Claims (85)

1. A compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein

Ar 2 is

X is O, S, N—CN, N—OH, or N—OR 10 ;

R 1 is -halo, —CH 3 , —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, —OH, —NH 2 , —CN, or —NO 2 ;

(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)heterocycle, each of which is unsubstituted or substituted with one or more R 6 groups;

each R 3 is independently:

(a) -halo, —CN, —OH, —NO 2 , or —NH 2 ;

(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)heterocycle, each of which is unsubstituted or substituted with one or more R 6 groups;

each R 5 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 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, -(3- to 5-membered)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 , —COR 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 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, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 8 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(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 , —COR 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 ;

R 10 is —(C 1 -C 4 )alkyl;

each R 11 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(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 , —COR 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 independently —F, —Cl, —Br, or —I;

m is 0 or 1;

o is an integer ranging from 0 to 4;

n is an integer ranging from 0 to 3;

q is an integer ranging from 0 to 6;

s is an integer ranging from 0 to 4; and

r is an integer ranging from 0 to 5.

2. The compound of claim 1 , wherein X is O.

3. The compound of claim 2 , wherein m is 0 and n is 0.

4. The compound of claim 3 , wherein R 1 is —Cl or —CH 3 .

5. The compound of claim 1 , wherein Ar 2 is

wherein R 8 and s are as defined in claim 1 .

6. The compound of claim 5 , wherein s is 0.

7. The compound of claim 5 , wherein Ar 2 is

wherein (R 8 ) a and R( 8 ) b are each —H or —(C 1 -C 6 alkyl); (R 8 ) a is —H and (R 8 ) b is —(C 1 -C 6 )alkyl, -halo, —C(halo) 3 , —O(C 1 -C 6 )alkyl, or —OC(halo) 3 ; or (R 8 ) b is —H and (R 8 ) a is —(C 1 -C 6 )alkyl, -halo, —C(halo) 3 , —O(C 1 -C 6 )alkyl, or —OC(halo) 3 .

8. The compound of claim 7 , wherein (R 8 ) a is —H and (R 8 ) b is —(C 1 -C 6 )alkyl or -halo.

9. The compound of claim 8 , wherein (R 8 ) b is an iso-propyl group or a tert-butyl group.

10. The compound of claim 3 , wherein Ar 2 is

11. The compound of claim 10 , wherein r is 1 and R 8 is a —(C 1 -C 6 )alkyl.

12. The compound of claim 11 , wherein the Ar 2 is substituted in the 4-position.

13. The compound of claim 12 , wherein the —(C 1 -C 6 )alkyl group is a tert-butyl group.

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

15. The compound of claim 1 , wherein Ar 2 is

wherein r is one.

16. The compound of claim 7 , wherein X is O.

17. The compound of claim 5 , wherein Ar 2 is

18. The compound of claim 5 , wherein Ar 2 is

19. The compound of claim 5 , wherein Ar 2 is

20. The compound of claim 1 , wherein Ar 2 is

21. The compound of claim 1 , wherein Ar 2 is

22. The compound of claim 1 , wherein m is 0.

23. The compound of claim 1 , wherein R 1 is -halo.

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

25. The compound of claim 1 , wherein R 1 is —C(halo) 3 .

26. The compound of claim 1 , wherein n is 1 and R 2 is -halo, —OH, —NH 2 , —CN, or —NO 2 .

27. The compound of claim 1 , wherein

n is 1,and

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.

28. The compound of claim 1 , wherein m is 1 and R 3 is -halo, —CN, —OH, —NO 2 , or —NH 2 .

29. The compound of claim 1 , wherein m is 1 and R 3 is —CH 3 .

30. The compound of claim 1 , wherein Ar 2 is

o is 1; and

R 8 is —(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 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 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 .

31. The compound of claim 1 , wherein Ar 2 is

o is 1; and

R 8 is —(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 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 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 .

32. The compound of claim 1 , wherein Ar 2 is

r is 1; and

R 8 is —(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 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 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 .

33. The compound of claim 1 , wherein X is O, m is 0, and Ar 2 is

34. A compound of claim 1 , which is:

or a pharmaceutically salt thereof.

35. A compound of claim 1 , which is:

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 15 , wherein Ar 2 is substituted at the 4-position, n is zero, m is zero, R 1 is halo, —CH 3 , —NO 2 , —CN, —OH, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo), and R 8 is halo, —(C 1 -C 6 )alkyl, —OC(halo) 3 , —O(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, or —C(halo) 3 .

37. The compound of claim 36 , wherein R 1 is halo.

38. The compound of claim 37 , wherein R 1 is F.

39. The compound of claim 38 , wherein X is O.

40. The compound of claim 36 , wherein R 1 is halo, —CH 3 , —NO 2 , —CN, —OH, —CF 3 , —CHF 2 , or —CH 2 F.

41. The compound of claim 16 , wherein (R 8 ) a and (R 8 ) b are each —H or —CH 3 ; (R 8 ) a is —H and (R 8 ) b is —(C 1 -C 6 )alkyl, -halo, —CF 3 , —OCH 3 , —OCH 2 CH 3 , or —OCF 3 ; or (R 8 ) b is —H and (R 8 ) a is —Cl, —Br, —F, —CH 3 , -iso-propyl, -tert-butyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , or —OCF 3 .

42. The compound of claim 16 , wherein n and m are each 0, R 1 is halo, —CH 3 , —NO 2 , —CN, —OH, —CF 3 , or —CHF 2 .

43. A compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is halo, —CH 3 , —NO 2 , —CN, —OH, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); X is O; m and n are each zero, Ar 2 is

wherein r is 1, and R 8 is —CH 2 CF 3 attached to the 4-position of the Ar 2 ring.

44. The compound of claim 43 , wherein R 1 is halo, —CH 3 , —NO 2 , —CN, —OH, —CF 3 , or CHF 2 .

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 22, 2008
From: EURO-CELTIQUE S.A.
To: PURDUE PHARMA L.P.
Reel/Frame 020396/0989 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 26, 2006
From: SUN, QUN; WEN, XIN
To: EURO-CELTIQUE S.A.
Reel/Frame 017684/0820 →
Continuity (3)
Provisional Application PCTUS200402391400 · Jul 23, 2004
Provisional Application 6048951600 · Jul 24, 2003
Related Publication 20060128717A1 · Jun 15, 2006