IP Library › Granted Patent US 8,173,678
Granted Patent B2
US 8,173,678 · App. 12/911,244 · Granted May 8, 2012

Kappa opioid receptor ligands

Assignee: Research Triangle Institute
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Quick Facts
Patent No.
US 8,173,678
App. No.
12/911,244
Granted
May 8, 2012
Kind
B2
Abstract

Kappa opioid receptor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions.

Claims (124)

1. A kappa opioid receptor antagonist represented by formula (I):

wherein

G is H, OH, OCOC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;

R 1 is C 1-8 alkyl or one of the following structures:

Y 1 is H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ;

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ;

R 2 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;

R 3 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;

wherein R 2 and R 3 may be bonded together to form a C 2-8 alkyl group;

R 4 is hydrogen, C 1-8 alkyl, CO 2 C 1-8 alkylaryl substituted by one or more groups Y 1 , CH 2 -aryl substituted by one or more groups Y 1 or CO 2 C 1-8 alkyl;

Z is N;

R 5 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, CH 2 CO 2 C 1-8 alkyl, CO 2 C 1-8 alkyl or CH 2 -aryl substituted by one or more groups Y 1 ;

n is 0, 1, 2 or 3;

R 6 is a group selected from the group consisting of structures (a)-(p):

Q is O, S, SO, or SO 2 ;

X 1 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;

X 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl,

or X 1 and X 2 together form ═O, ═S, or ═NH;

R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 16 R 17 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 16 R 17 ,

R 8 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 9 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 10 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 11 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 , alkyl;

R 12 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 13 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 14 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 15 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 16 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl; and

R 17 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

2. The kappa opioid receptor antagonist of claim 1 , wherein

Y 3 is H; and

R 2 and R 3 are each, independently, H, C 1-8 alkyl, C 3-8 alkynyl, C 3-8 alkynyl, or CH 2 -aryl substituted by one or more substituents Y 1 .

3. The kappa opioid receptor antagonist of claim 1 , wherein

R 1 is C 1-8 alkyl, or one of the following structures:

Y 3 is H;

R 2 and R 3 are each, independently, H or C 1-8 alkyl, wherein R 2 and R 3 cannot both be H at the same time; and

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .

4. The kappa opioid receptor antagonist of claim 1 , wherein

R 1 is C 1-8 alkyl;

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H;

R 2 and R 3 are each, independently, H or methyl, wherein R 2 and R 3 cannot both be H at the same time;

R 4 is H, C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 and the stereocenter adjacent to R 4 is in an (S) configuration;

R 5 is H, C 1-8 alkyl, or CH 2 CO 2 C 1-8 alkyl;

R 6 is a group having a formula selected from the group consisting of structures (d)-(p); and

R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .

5. The kappa opioid receptor antagonist of claim 1 , wherein

R 1 is methyl,

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCO 2 R 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H;

R 2 and R 3 are each H or methyl, such that when R 2 is H, R 3 is methyl and vice versa;

R 4 is C 1-8 alkyl, or CO 2 C 1-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S);

R 5 is H; and

R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , or CH 2 (CH 2 ) n Y 2 .

6. The kappa opioid receptor antagonist of claim 1 , which is in the form of a pharmaceutically acceptable salt.

7. The kappa opioid receptor antagonist of claim 1 , wherein R 6 is structure (a), (b) or (c).

8. The kappa opioid receptor antagonist of claim 1 , wherein R 6 is one of (d)-(p).

9. The kappa opioid receptor antagonist of claim 1 , wherein Q is O.

10. The kappa opioid receptor antagonist of claim 1 , wherein Q is S.

11. The kappa opioid receptor antagonist of claim 1 , wherein Q is SO.

12. The kappa opioid receptor antagonist of claim 1 , wherein Q is SO 2 .

13. The kappa opioid receptor antagonist of claim 1 , which is represented by the formula:

14. A pharmaceutical composition comprising an effective amount of a kappa opioid receptor antagonist of claim 1 and a physiologically acceptable carrier.

15. A kappa opioid receptor antagonist represented by formula (I):

wherein

G is H, OH, OCOC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;

R 1 is C 1-8 alkyl or one of the following structures:

Y 1 , is H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ;

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 , alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ;

R 2 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;

R 3 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;

wherein R 2 and R 3 may be bonded together to form a C 2-8 alkyl group;

R 4 is hydrogen, C 1-8 alkyl, CO 2 C 1-8 alkylaryl substituted by one or more groups Y 1 , CH 2 -aryl substituted by one or more groups Y 1 or CO 2 C 1-8 alkyl;

Z is N,;

R 5 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, CH 2 CO 2 C 1-8 alkyl, CO 2 C 1-8 alkyl or CH 2 -aryl substituted by one or more groups Y 1 ;

n is 0, 1, 2 or 3;

R 6 is a group selected from the group consisting of structures (d)-(p):

Q is CH 2 ;

X 1 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;

X 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;

or X 1 and X 2 together form ═O, ═S, or ═NH;

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 16 R 17 ,

R 8 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 9 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 10 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ),Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 11 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 12 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 13 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 14 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 15 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 16 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl; and

R 17 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

16. The kappa opioid receptor antagonist of claim 15 , wherein

Y 3 is H; and

R 2 and R 3 are each, independently, H, C 1-8 alkyl, C 3-8 alkynyl, C 3-8 alkynyl, or CH 2 -aryl substituted by one or more substituents Y 1 .

17. The kappa opioid receptor antagonist of claim 15 , wherein

R 1 is C 1-8 alkyl, or one of the following structures:

Y 3 is H;

R 2 and R 3 are each, independently, H or C 1-8 alkyl, wherein R 2 and R 3 cannot both be H at the same time; and

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .

18. The kappa opioid receptor antagonist of claim 15 , wherein

R 1 is C 1-8 alkyl;

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H;

R 2 and R 3 are each, independently, H or methyl, wherein R 2 and R 3 cannot both be H at the same time;

R 4 is H, C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 and the stereocenter adjacent to R 4 is in an (S) configuration;

R 5 is H, C 1-8 alkyl, or CH 2 CO 2 C 1-8 alkyl;

R 6 is a group having a formula selected from the group consisting of structures (d)-(p); and

R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .

19. The kappa opioid receptor antagonist of claim 15 , wherein

R 1 is methyl,

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCO 2 R 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H;

R 2 and R 3 are each H or methyl, such that when R 2 is H, R 3 is methyl and vice versa;

R 4 is C 1-8 alkyl, or CO 2 C 1-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S);

R 5 is H; and

R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , or CH 2 (CH 2 ) n Y 2 .

20. The kappa opioid receptor antagonist of claim 15 , wherein R 6 is structure (d), (e), (f) or (g).

21. The kappa opioid receptor antagonist of claim 15 , wherein R 6 is one of (h)-(p).

22. A pharmaceutical composition comprising an effective amount of a kappa opioid receptor antagonist of claim 15 and a physiologically acceptable carrier.

Assignments (1)
CONFIRMATORY LICENSE Recorded Sep 11, 2013
From: RESEARCH TRIANGLE INSTITUTE
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 031202/0825 →
Continuity (2)
Division 11059390 · Feb 17, 2005
Related Publication 20110065743A1 · Mar 17, 2011