IP Library › Granted Patent US 7,772,254

Granted Patent B2

US 7,772,254 · App. 11/387,073 · Granted Aug 10, 2010

Therapeutic agents useful for treating pain

Assignee: Purdue Pharma L.P.

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Quick Facts

Patent No.: US 7,772,254
App. No.: 11/387,073
Granted: Aug 10, 2010
Kind: B2

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Abstract

The present invention discloses a compound of formula: where Ar 1 , Ar 2 , X, Z 1 , Z 2 , R 3 , and m are as disclosed herein or a pharmaceutically acceptable salt thereof (a “Pyridylene Compound”); compositions comprising an effective amount of a Pyridylene Compound; and methods for treating or preventing pain or other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Pyridylene Compound.

Claims (198)

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is

Ar 2 is

X is O or S;

R 1 is -halo, —CH 3 , —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)heteroaryl, 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 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 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, —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 s )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R g 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, —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —S(O)R 7 , or —S(O) 2 R 7 ;

each halo is independently —F, —Cl, —Br, or —I;

m is an integer ranging from 0 to 3;

n is an integer ranging from 1 to 3; and

r is an integer ranging from 0 to 5.

2. The compound of claim 1 , wherein

X is O; and

R 1 is —CH 3 , -halo or —C(halo) 3 .

3. The compound of claim 2 , wherein:

m is 0;

r is 1; and

R 8 is —(C 1 -C 6 )alkyl, -halo, —OCF 3 or —CF 3 .

4. The compound of claim 3 , wherein the —(C 1 -C 6 )alkyl is a tert-butyl group, optionally substituted at the para-position of Ar 2 .

5. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is

Ar 2 is

X is O or S;

R 1 is -halo, —CH 3 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

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

(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, —NO 2 , or —NH 2 ;

(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 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 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 ;

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 an integer ranging from 0 to 3;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

q is an integer ranging from 0 to 6; and

s is an integer ranging from 0 to 4.

6. The compound of claim 5 , wherein:

Ar 2 is

X is O;

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

m is 0;

(R 8 ) a is —H; and

(R 8 ) b is —H, —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, —I, or —F.

7. The compound of claim 6 , wherein R 1 is —CH 3 , —CF 3 or —Cl and (R 8 ) b is —Cl, —F, —CF 3 or tert-butyl.

8. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is

Ar 2 is

X is O or S;

R 1 is -halo, —CH 3 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

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

(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, —NO 2 , or —NH 2 ;

(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;

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 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 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 an integer ranging from 0 to 3;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

9. The compound of claim 8 , wherein:

Ar 2 is

X is O; and

R 1 is —CH 3 , -halo or —C(halo) 3 .

10. The compound of claim 9 , wherein:

m is 0;

r is 1; and

R 8 is —(C 1 -C 6 )alkyl, -halo, —OCF 3 or —CF 3 .

11. The compound of claim 10 , wherein the —(C 1 -C 6 )alkyl is a tert-butyl group, optionally substituted at the para-position of Ar 2 .

12. The compound of claim 8 , wherein:

Ar 2 is

X is O;

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

m is 0;

(R 8 ) a is —H; and

(R 8 ) b is —H, —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, —I, or —F.

13. The compound of claim 12 , wherein R 1 is —CH 3 , —CF 3 or —Cl and (R 8 ) b is —Cl, —F, —CF 3 or tert-butyl.

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

15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 8 and a pharmaceutically acceptable carrier or excipient.

16. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is

Ar 2 is

X is O or S;

R 1 is -halo, —CH 3 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

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

(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, —NO 2 , or —NH 2 ;

(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;

each R 5 is independently —CN, —OH, —(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, 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 halo is independently —F, —Cl, —Br, or —I;

m is an integer ranging from 0 to 3;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

17. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 8 .

18. An in vitro method for inhibiting VR1 function in a cell comprising:

contacting a cell expressing VR1 in vitro with a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

19. The method of claim 18 , wherein said calcium ion mobilization is reduced by 50% or more.

20. An in vitro method for inhibiting VR1 function in a cell comprising:

contacting a cell expressing VR1 in vitro with a compound of claim 8 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

21. The method of claim 20 , wherein said calcium ion mobilization is reduced by 50% or more.

22. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 5 and a pharmaceutically acceptable carrier or excipient.

23. An in vitro method for inhibiting VR1 function in a cell comprising:

contacting a cell expressing VR1 in vitro with a compound of claim 5 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

24. The method of claim 23 , wherein said calcium ion mobilization is reduced by 50% or more.

25. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is

Ar 2 is

X is O or S;

R 1 is -halo, —CH 3 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 3 is independently:

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

(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 5 is independently —CN, —(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 halo is independently —Cl, —Br, or —I;

m is an integer ranging from 0 to 3;

n is 0; and

r is an integer ranging from 0 to 5.

26. The compound of claim 25 , wherein 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, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —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 .

27. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 25 and a pharmaceutically acceptable carrier or excipient.

28. An in vitro method for inhibiting VR1 function in a cell comprising:

contacting a cell expressing VR1 in vitro with a compound of claim 25 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

29. The method of claim 28 , wherein said calcium ion mobilization is reduced by 50% or more.

30. 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.

31. The compound of claim 30 , wherein R 2 is —(C 1 -C 10 )alkyl which is substituted with two R 5 groups.

32. The compound of claim 8 , 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.

33. The compound of claim 32 , wherein R 2 is —(C 1 -C 10 )alkyl which is substituted with two R 5 groups.

34. The method of claim 16 , 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.

35. The method of claim 34 , wherein R 2 is —(C 1 -C 10 )alkyl which is substituted with two R 5 groups.

36. The compound of claim 5 , 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.

37. The compound of claim 36 , wherein R 2 is —(C 1 -C 10 )alkyl which is substituted with two R 5 groups.

38. The method of claim 16 , wherein:

Ar 2 is

X is O; and

R 1 is —CH 3 , -halo or —C(halo) 3 .

39. The method of claim 38 , wherein:

m is 0;

r is 1; and

R 8 is —(C 1 -C 6 )alkyl, -halo, —OCF 3 or —CF 3 .

40. The method of claim 16 , wherein:

Ar 2 is

X is O;

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

m is 0;

(R 8 ) a is —H; and

(R 8 ) b is —H, —CH 3 , —CF 3 , —OCH 2 CH 3 , tert-butyl, —Cl, —Br, —I, or —F.

41. The method of claim 40 , wherein R 1 is —CH 3 , —CF 3 or —Cl and (R 8 ) b is —Cl, —F, —CF 3 or tert-butyl.

42. The compound of claim 5 , wherein X is O; and R 1 is —CH 3 , -halo or —C(halo) 3 .

43. The compound of claim 25 , wherein X is O; and R 1 is —CH 3 , -halo or —C(halo) 3 .

44. The compound of claim 43 , wherein:

m is 0;

r is 1; and

R 8 is —(C 1 -C 6 )alkyl, -halo, —OCF 3 or —CF 3 .

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 3, 2008

From: EURO-CELTIQUE S.A.

To: PURDUE PHARMA L.P.

Reel/Frame 020311/0270 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 15, 2006

From: SUN, QUN

To: EURO-CELTIQUE S.A.

Reel/Frame 017978/0094 →

Continuity (3)

Continuation PCTUS20043082500 · Sep 21, 2004

Provisional Application 6050473000 · Sep 22, 2003

Related Publication 20060241117A1 · Oct 26, 2006