Octahydroisoquinoline compounds as opioid receptor modulators
Compounds which bind to opioid receptors are provided. In a preferred embodiment of the invention, the compounds are opioid receptor antagonists. The present invention also provides methods of treating conditions which are mediated by an opioid receptor.
1. A compound represented by the formula:
wherein
M is hydrogen, halogen, C 1 -C 4 alkyl, CN, OC 1-8 alkyl, OC 3-8 alkenyl, OC 3-8 alkynyl, or OC 1-8 alkylaryl;
R 1 is C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl,
(S) 1 is hydrogen, CH 2 CO 2 H, CH 2 CO 2 CH 3 , or CH 2 CO 2 C 2 H 5 ;
(S) 2 is hydrogen, CH 3 , C 2 H 3 , CH 2 C 6 H 5 , or CH 2 CH 2 C 6 H 5 ;
R 2 is ═O, hydrogen, NR 7 R 8 ,
X is NR, O, or S;
Y is OH, OR 9 , C 1-8 alkyl, F, Cl, Br, CF 3 , or CN;
R is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, or CO 2 R 9
W is hydrogen, OH, OCOR 9 , N(R 4 ) 2 , NR 3 COR 9 , NR 3 SO 2 R 9 , NR 3 CO 2 R 9 , CONH 2 , or NHCHO;
Z is NR3, O, or S;
n is 1, 2, or 3;
m is 1, 2, 3, or 4;
j is 2, 3, or 4;
k is 1 or 2;
each R 3 is, independently, C 1-3 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, CH 2 Y, or CO 2 R;
each R 4 is, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl;
R 5 and R 6 are each, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylcycloalkyl, or C 1-8 alkylaryl;
R 7 and R 8 are each, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylcycloalkyl, or C 1-8 alkylaryl,
R 9 is C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl,
or a pharmaceutically acceptable salt thereof and
inclusive of stereoisomers and
wherein the compound may be isotopically labeled.
2. The compound of claim 1 , which is represented by the formula:
3. The compound of claim 1 , which is represented by the formula:
wherein R is CH 3 , C 6 H 5 (CH 2 ) 2 or C 6 H 5 (CH 2 ) 3 .
4. The compound of claim 1 , which is represented by the formula:
5. The compound of claim 1 , which is represented by the formula:
wherein R is
6. The compound of claim 1 , wherein the substituents are cis.
7. The compound of claim 1 , wherein
M is hydrogen, C 1 -C 4 alkyl, or OC 1-8 alkyl;
R 1 is C 1-8 alkyl or C 1-8 alkylaryl;
R 2 is ═O, hydrogen, or NR 7 R 8 ;
W is hydrogen or OH; and
R 3 is C 1-3 alkyl.
8. The compound of claim 1 , wherein W is NH 2 .
9. The compound of claim 1 , wherein W is NHC 1-8 alkyl.
10. The compound of claim 1 , wherein W is N(R 4 ) 2 , and each R 4 therein is, independently, a C 1-8 alkyl group.
11. The compound of claim 1 , which is in the form of a pharmaceutically acceptable salt.
12. The compound of claim 1 , wherein the compound is in the form of a salt of an acid.
13. The compound of claim 1 , which is isotopically labeled.
14. The compound of claim 9 , wherein the acid is hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluoyl tartaric acid, acetic acid, sulfuric acid, hydroiodic acid, or mandelic acid.
15. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.