Kappa opioid receptor ligands

1. A method of binding a kappa opioid receptor in a subject having a disease state selected from the group consisting of opiate addiction, cocaine addiction, nicotine addiction and ethanol addiction, comprising:

administering to said subject a composition comprising a kappa opioid receptor antagonist and a physiologically acceptable carrier, wherein the kappa opioid receptor antagonist is a compound of formula (1):

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 1-9 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, O or S; where Z is O or S, there is no R 5

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 (c)-(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 ) 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

and pharmaceutically acceptable salts thereof.

2. The method of claim 1 , wherein R 6 is a group having a formula selected from the group consisting of structures (d)-(p).

3. The method of claim 1 , wherein

Y 3 is H;

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 ; and

and pharmaceutically acceptable salts thereof.

4. The method of claim 3 , wherein R 6 is a group having a formula selected from the group consisting of structures (d)-(p).

5. The method 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;

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 ; and

and pharmaceutically acceptable salts thereof.

6. The method of claim 5 , wherein R 6 is a group having a formula selected from the group consisting of structures (d)-(p).

7. The method 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 (c) and (h)-(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 ; and

and pharmaceutically acceptable salts thereof.

8. The method of claim 7 , wherein R 6 is a group having a formula selected from the group consisting of structures (h)-(p).

9. The method 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;

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 ; and

and pharmaceutically acceptable salts thereof.

10. The method of claim 9 , wherein R 6 is a group having a formula selected from the group consisting of structures (d)-(p).

11. The method of claim 1 , further comprising administering L-dopa to the subject.

12. The method of claim 1 , wherein the compound is administered orally, intraveneously, or intramuscularly.

13. The method of claim 1 , wherein the compound is administered in a form selected from the group consisting of tablets, capsules, troches, powders, solutions, dispersions, emulsions and suspensions.