IP Library › Granted Patent US 7,700,597

Granted Patent B2

US 7,700,597 · App. 11/292,264 · Granted Apr 20, 2010

Substituted piperazines as CB1 antagonists

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Quick Facts

Patent No.: US 7,700,597
App. No.: 11/292,264
Granted: Apr 20, 2010
Kind: B2

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Abstract

Compounds of Formula (I): or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB 1 receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.

Claims (104)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein:

Ar 1 and Ar 2 are each independently aryl, wherein each said aryl is substituted with one or more independently selected groups Y 1 ;

wherein each said Y 1 attached to Ar 1 and Ar 2 is independently selected from the group consisting of —(C 2 -C 20 ) alkyl, cycloalkyl, halo, haloalkyl, benzyl, aryl, —O-aryl, —S-aryl, —S(O) 2 -alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -aryl -alkylene-CN, —CN, —C(O)-alkyl, —C(O)-aryl, —C(O)-haloalkyl, —O-haloalkyl, —O-alkylene-C(O)OH, —S-alkyl, —S-haloalkyl, -alkylene-OH, -alkylene-C(O)—O-alkyl, —O-alkylene-aryl, and —N(R 5 ) 2 ,

wherein said aryl, the aryl portion of said O-aryl, the aryl portion of said —S-aryl, the aryl portion of said S(O) 2 -aryl, the aryl portion of said benzyl, the aryl portion of said C(O)-aryl, and the aryl portion of said —O-alkylene-aryl of Y 1 are unsubstituted or substituted with one or more groups Z:

X is selected from the group consisting of —C(R 2 )═C(R 2 )-aryl and —(C(R 2 ) 2 ) s -aryl wherein s is 0, 1, or 2,

wherein the aryl portion of said —C(R 2 )═C(R 2 )-aryl and the aryl portion of said —(C(R 2 ) 2 ) s -aryl of X are unsubstituted or substituted with one or more groups Y 1 :

wherein each said Y 1 , when attached to said aryl portion of said —C(R 2 )═C(R 2 )-aryl or said aryl portion of said —(C(R 2 ) 2 ) s -aryl of X, is independently selected from the group consisting of alkyl, cycloalkyl, halo, haloalkyl, benzyl, aryl, —O-aryl, —S-aryl, —S(O) 2 -alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -aryl, -alkylene-CN, —CN, —N(R 2 )C(O)-alkyl, —N(R 2 )C(O)—N(R 2 ) 2 , —OH, —O-alkyl, —O-haloalkyl, —O-alkylene-C(O)OH, —S-alkyl, —S-haloalkyl, -alkylene-OH, -alkylene-C(O)—O-alkyl, —O-alkylene-aryl, and —N(R 5 ) 2 ,

wherein said aryl, the aryl portion of said O-aryl, the aryl portion of said —S-aryl, the aryl portion of said —S(O) 2 -aryl, the aryl portion of said benzyl, the aryl portion of said C(O)-aryl, and the aryl portion of said —O-alkylene-aryl of Y 1 are unsubstituted or substituted with one or more groups Z;

each R 1 is independently selected from the group consisting of alkyl, haloalkyl, -alkylene-N(R 5 ) 2 , -alkylene-OR 2 , alkylene-N 3 , -alkylene-CN, and alkylene-O—S(O) 2 -alkyl: or

two R 1 groups attached to the same ring carbon atom form a carbonyl group;

p is 0, 1, 2, 3, or 4:

each R 2 is independently H, alkyl, or aryl,

wherein said aryl of R 2 is unsubstituted or substituted with one or more groups Y 1 ;

wherein each Y 1 , when attached to said aryl of R 2 , is independently selected from the group consisting of alkyl, cycloalkyl, halo, haloalkyl, benzyl, aryl, —O-aryl, —S-aryl, —S(O) 2 -alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -aryl, -alkylene-CN, —CN, —C(O)-alkyl, —C(O)-aryl, —C(O)-haloalkyl, —C(O)O-alkyl, —N(R 2 )C(O)-alkyl, —N(R 2 )C(O)—N(R 2 ) 2 , —OH, —O-alkyl, —O-haloalkyl, —O-alkylene-C(O)OH, —S-alkyl, —S-haloalkyl, -alkylene-OH, -alkylene-C(O)—O-alkyl, —O-alkylene-aryl, and —N(R 5 ) 2 ,

wherein said aryl, the aryl portion of said —O-aryl, the aryl portion of said —S-aryl, the aryl portion of said —S(O) 2 -aryl, the aryl portion of said benzyl, the aryl portion of said —C(O)-aryl, and the aryl portion of said —O-alkylene-aryl of Y 1 are unsubstituted or substituted with one or more groups Z;

each R 5 is independently selected from the group consisting of H, alkyl, aryl, —S(O) 2 -alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -aryl, —C(O)—N(R 2 ) 2 , —C(O)-alkyl, and -alkylene-OH.

wherein said aryl and the aryl portion of said —S(O) 2 -aryl of R 5 are unsubstituted or substituted with one or more Z groups;

and

each Z is independently selected from the group consisting of alkyl, halo, haloalkyl, —OH, —O-alkyl, and —CN.

2. A compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein:

Ar 1 and Ar 2 are independently —(C 6 -C 10 )aryl,

wherein said (Co—C 10 )aryl is substituted with one or more groups Y 1 ;

wherein each Y 1 attached to Ar 1 and Ar 2 is independently selected from the group consisting of (C 2 -C 6 )alkyl. (C 3 -C 10 )cycloalkyl, halo, (C 1 -C 6 )haloalkyl, benzyl, (C 6 -C 10 )aryl, (C 2 -C 10 )heteroaryl, —O—(C 6 -C 10 )aryl, —S—(C 6 -C 10 )aryl, —S(O) 2 —(C 1 -C 6 )alkyl, —S(O) 2 —(C 3 -C 10 )cycloalkyl, —S(O) 2 —(C 6 -C 6 )alkylene-CN, —CN, —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 1 -C 6 )haloalkyl, —C(O)O—(C 1 -C 6 )alkyl, —N(R 2 )C(O)—(C 1 -C 10 )aryl, —C(O)—(C 1 -C 6 )haloalkyl, —OH, —O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )alkylene-C(O)OH, —S—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-OH, —(C 1 -C 6 )alkylene-C(O)—O—(C 1 -C 10 )alkyl —O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, and —N(R 5 ) 2 ,

wherein said (C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —O—(C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —S—(C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —S(O) 2 —(C 6 -C 10 )aryl, said benzyl, the (C 6 -C 10 )aryl portion of said —C(O)—(C 6 -C 10 )aryl, and the (C 6 -C 10 )aryl portion of said —O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, of Y 1 are unsubstituted or substituted with one or more groups Z;

X is selected from the group consisting of and —(C(R 2 ) 2 ) s —(C 6 -C 10 )aryl wherein s is 0, 1 or 2,

wherein the (C 6 -C 10 )aryl portion of said —C(R 2 )═C(R 2 )—(C 6 -C 10 )aryl and the (C 6 -C 10 )aryl portion of said —(C(R 3 ) 2 ) s (C 6 -C 10 )aryl of X are unsubstituted or substituted with one or more groups Y 1 ;

wherein each Y t , when attached to said aryl portion of said —C(R 2 )═C(R 2 )—(C 6 -C 10 )aryl or said aryl portion of said —(C(R 2 ) 2 ) s —(C 6 -C 10 )aryl of X, is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, halo, (C 1 -C 6 )haloalkyl, benzyl, (C 6 -C 10 )aryl, (C 2 -C 10 )heteroaryl, —O—(C 6 -C 10 )aryl, —S—(C 6 -C 10 )aryl, —S(O) 2 —(C 1 -C 6 )alkyl, —S(O) 2 —(C 3 -C 10 )cycloalkyl, —S(O) 2 —(C 6 -C 10 )aryl, —(C 1 -C 6 )alkylene-CN, —CN, —CN, —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl, —C(O)—(C 1 -C 6 )haloalkyl, —C(O)O—(C 1 -C 6 )alkyl, —N(R 2 )C(O)—(C 1 -C 6 )alkyl, —N(R 2 ) 2 , —OH, —O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )alkylene-C(O)OH, —S—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-OH, —(C 1 -C 6 )alkylene-C(O)—O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, and —N(R 5 ) 2 ,

wherein said (C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —O—(C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —S—(C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —S(O) 2 —(C 6 -C 10 )aryl, said benzyl, the (C 6 -C 10 )aryl portion of said —C(O)—(C 6 -C 10 )aryl, and the (C 6 -C 10 )aryl portion of said —O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl of Y 1 are unsubstituted or substituted with one or more groups Z:

each R 1 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-N(R 5 ) 2 , —(C 1 -C 6 )alkylene-OR 2 , —(C 1 -C 6 )alkylene-N3, -(C 1 -C 6 )alkylene-CN, and (C 1 -C 6 )alkylene-O—S(O) 2 —(C 1 -C 6 )alkyl; or

two R groups attached to the same ring carbon atom form a carbonyl group;

p is 0, 1, 2, 3, or 4;

each R 2 is independently H. (C 1 -C 6 )alkyl, or (C 6 -C 10 )aryl,

wherein said (C 6 -C 10 )aryl of R 2 is unsubstituted or substituted with one or more groups Y 1 ;

wherein each Y 1 , when attached to said (C 6 -C 10 )aryl of R 2 , is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, halo, (C 1 -C 10 )haloalkyl, benzyl, (C 1 -C 10 )aryl, (C 2 -C 10 )heteroaryl, —O—(C 6 -C 10 )aryl, —S—(C 6 -C 10 )aryl, —S(O) 2 —(C 1 -C 6 )alkyl, —S(O) 2 —(C 3 -C 10 )cycloalkyl, —S(O) 2 —(C 6 -C 10 )aryl, —(C 1 -C 6 )alkylene-CN, —CN, —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl, —C(O)—(C 1 -C 6 )haloalkyl, —C(O)O—(C 1 -C 6 )alkyl, —N(R 2 )C(O)—(C 1 -C 6 )alkyl, —N(R 2 )C(O)—N(R 2 ) 2 , —OH, —O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )alkylene-C(O)OH, —S—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-OH. —(C 1 -C 10 )alkylene-C(O)—O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, and —N(R 5 ) 2 ,

wherein said (C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —O—(C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —S—(C 6 -C 10 )aryl, the (C 6 -C 10 )aryl portion of said —S(O) 2 —(C 6 -C 10 )aryl, said benzyl, the (C 6 -C 10 )aryl portion of said —C(O)—(C 6 -C 10 )aryl, and the (C 6 -C 10 )aryl portion of said —(O)—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl of Y 1 are unsubstituted or substituted with one or more groups Z;

each R 5 is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, —S(O) 2 —(C 1 -C 6 alkyl, —S(O) 2 —(C 3 -C 10 )cycloalkyl, —S(O) 2 -aryl, —C(O)—N(R 2 ) 2 , —C(O)—(C 1 -C 6 )alkyl, and —(C 1 -C 10 )alkylene-OH,

wherein said (C 6 -C 10 )aryl and the (C 6 -C 10 )aryl portion of said —S(O) 2 —(C 6 -C 10 )aryl of R 5 are unsubstituted or substituted with one or more Z groups;

each Z is independently selected from the group consisting of (C 1 -C 6 )alkyl, halo, (C 1 -C 6 )haloalkyl, —OH, —O—(C 1 -C 6 )alkyl, and —CN.

3. A compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein:

Ar 2 is a phenyl substituted with two independently selected Y 1 groups.

4. A compound of claim 3 , or a pharmaceutically acceptable salt or ester thereof, wherein:

Ar 2 is a phenyl substituted with two independently selected Y 1 groups at the 2- and 4-position.

5. A The compound of claim 4 , or a pharmaceutically acceptable salt or ester thereof, wherein:

Ar 1 is a phenyl substituted with one Y 1 group at the 4-position.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein X is —(C(R 2 ) 2 ) s -aryl, and said aryl of X is unsubstituted or substituted with one or more independently selected Y 1 groups.

7. A compound according to claim 6 , wherein s is 0.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, wherein:

X is —C(R 2 )═C(R 2 )-aryl, and said aryl of X is unsubstituted or substituted with one or more independently selected Y 1 groups.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, having the following Formula (IA):

10. A compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, having the following Formula (IB):

11. A compound according to claim 1 , or a pharmaceutically acceptable salt or ester thereof, having the following Formula (IC):

12. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is a phenyl substituted with 1 Y 1 group.

14. A compound of claim 5 , or a pharmaceutically acceptable salt or ester thereof, wherein each Y 1 is independently selected from the group consisting of halo, —OH, —CN, —(C 2 -C 6 )alkyl, haloalkyl, and —O-haloalkyl.

15. A compound of claim 5 , or a pharmaceutically acceptable salt or ester thereof, wherein p is 0.

16. A compound of claim 5 , or a pharmaceutically acceptable salt or ester thereof, wherein p is 0, 1, 2, 3, or 4, and each R 1 is independently selected from the group consisting of alkyl and haloalkyl.

17. A compound of claim 5 , or a pharmaceutically acceptable salt or ester thereof, wherein p is 2 and two R groups bound to the same ring carbon atom are taken together to form a carbonyl group.

18. A compound according to claim 6 , or a pharmaceutically acceptable salt or ester thereof, wherein s is 1.

19. A compound according to claim 6 , or a pharmaceutically acceptable salt or ester thereof, wherein s is 2.

20. A compound according to claim 6 , or a pharmaceutically acceptable salt or ester thereof, wherein X is —(C(R 2 ) 2 ) s -phenyl, and said phenyl of X is unsubstituted or substituted with one or more Y 1 groups independently selected from the group consisting of halo, —OH, —CN, alkyl, haloalkyl, phenyl, —O-alkyl, —O-haloalkyl, —S-phenyl, —S-alkyl, —S-haloalkyl, and —S-phenyl.

21. A compound according to claim 8 , or a pharmaceutically acceptable salt or ester thereof, wherein X is —C(R 2 )═C(R 2 )-phenyl, and said phenyl of X is unsubstituted or substituted with one or more Y 1 groups independently selected from the group consisting of halo, —OH, —CN, alkyl, haloalkyl, phenyl, —O-alkyl, —O-haloalkyl, —S-phenyl, —S-alkyl, —S-haloalkyl, and —S-phenyl.

22. A composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt of said at least one compound, and at least one pharmaceutically acceptable carrier.

23. A composition comprising at least one compound according to claim 12 , or a pharmaceutically acceptable salt of said at least one compound, and at least one pharmaceutically acceptable carrier.

24. A compound of the following formula;