Kappa opioid receptor ligands
Kappa opioid receptor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors relative to nor-BNI, 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.
1. A kappa opioid receptor antagonist compound represented by the formula (I):
wherein Q is H or COC 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 3 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 CH2(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; when 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 (a)-(w) and (cc)-(bbb):
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 substitiients 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 kappa opioid receptor antagonist compound of claim 1 , wherein R 1 , R 4 , R 5 , Y 1 , Y 2 , Z, n, X 1 , X 2 , and R 7 -R 17 are as in claim 1 ;
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
R 6 is a group having a formula selected from the group consisting of structures (a)-(w) and (cc).
3. The kappa opioid receptor antagonist compound of claim 1 , wherein Y 1 , Y 2 , R 4 , R 5 , Z, n, X 1 , X 2 and R 8 R 15 are as in claim 1 ;
R 1 is C 1-8 alkyl, or one of the following structures:
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 6 is a formula selected from the structures (a)-(r); 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 compound of claim 1 , wherein Y 1 , Z, n, X 1 , X 2 and R 8 -R 15 are as in claim 1 ;
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, CH 2 CO 2 C 1-8 alkyl;
R 6 is a group having a formula selected from the group consisting of structures (a)-(c) and (h)-(o); 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 compound of claim 1 , wherein Y 1 , Z, n, X 1 , X 2 and R 8 -R 14 are as in claim 1 ;
R 1 is methyl,
Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NHR 10 R 11 , NHCOR 12 , NHCO2R 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 2-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S);
R 5 is H;
R 6 is a group having a formula selected from the group consisting of structures (a) and (b); 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 , wherein said compound is a compound selected from formulae 14-21 as follows:
7. A pharmaceutical composition comprising:
an effective amount of a kappa opioid receptor antagonist and a physiologically acceptable carrier, wherein the kappa opioid receptor antagonist is a compound of formula (I):
wherein Q is H or COC 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, C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH2(CH 2 ) n Y 2 ;
Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R11, NHCOR 12 , NHCO2R 12 , CONR 3 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 Y2;
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; when 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 (a)-(w) and (cc)-(bbb):
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, ═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
or a pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition of claim 7 , wherein said kappa opioid receptor antagonist is a compound of formula (I), wherein R 1 , R 4 , R 5 , Y 1 , Y 2 , Z, n, X 1 , X 2 , and R 7 -R 17 are as in claim 7 ;
Y 3 is H;
R 2 and R 3 are each, independently, H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or CH 2 aryl substituted by one or more substituents Y 1 ; and
R 6 is a group having a formula selected from the group consisting of structures (a)-(w) and (cc).
9. The pharmaceutical composition of claim 7 , wherein said kappa opioid receptor antagonist is a compound of formula (1), wherein Y 1 , Y 2 , R 4 , R 5 , Z, n, X 1 , X 2 and R 8 -R 15 are as in claim 7 ;
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 6 is a formula selected from the structures (a)-(r) shown above; 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 .
10. The pharmaceutical composition of claim 7 , wherein said kappa opioid receptor antagonist is a compound of formula (I), wherein Y 1 , Z, n, X 1 , X 2 and R 8 -R 15 are as noted-above in claim 7 ;
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, CH 2 CO 2 C 1-8 alkyl;
R 6 is a group having a formula selected from the group consisting of structures (a)-(c) and (h)-(o); 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 .
11. The pharmaceutical composition of claim 7 , wherein said kappa oploid receptor antagonist is a compound of formula (1), wherein Y 1 , Z, n, X 1 , X 2 and R 8 -R 14 are as in claim 7 ;
R 1 is methyl,
Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R12, CONR 13 R 14 , CH2OH, 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 6 is a group having a formula selected from the group consisting of structures (a) and (b); and
R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y, or CH 2 (CH 2 ) n Y 2 .
12. The pharmaceutical composition of claim 7 , wherein said kappa opioid receptor antagonist is a compound selected from formulae 14-21 as follows:
13. The pharmaceutical composition of claim 7 , wherein said composition is an injectable composition.
14. The pharmaceutical composition of claim 7 , wherein said composition is an orally administrable composition.
15. The pharmaceutical composition of claim 14 , wherein said orally administrable composition is in a form selected from the group consisting of tablets, capsules, troches, powders, solutions, dispersions, emulsions and suspensions.
16. The kappa opioid receptor antagonist according to claim 1 , having the chemical formula: