Substituted 1,2,3,4-tetrahydroisoquinolines as kappa opioid antagonists
Potent opioid receptor antagonists of formula (I) and their use as pharmacotherapies for treating depression, anxiety, schizophrenia, eating disorders, and addiction to cocaine, methamphetamine, nicotine, alcohol, and opiates are disclosed. More specifically, the disclosure provides potent and selective kappa opioid receptor antagonist compounds, pharmaceutical compositions of those compounds and uses of those compounds to ameliorate or treat addictions, eating disorders, etc.
1. A compound of formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is H, C 1-6 alkyl, NHR 9 , N(C 1-8 alkyl)R 9 , N(C 2-8 alkenyl)R 9 , N(C 3-8 cycloalkyl)R 9 , OR 8 , C 3-8 cycloalkyl, C 5-8 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, phenyl, or heteroaryl, wherein the heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected alkyl substituents;
R 2 is H, C 1-4 alkyl, CH 2 (CH 2 ) n OH, C 3-6 cycloalkyl, or aryl;
R 3 is H or C 1-4 alkyl;
R 4 is O or S;
R 5 is H or C 1-4 alkyl;
R 6 is H or C 1-4 alkyl;
R 7 is halogen, CN, NO 2 , N 3 , CF 3 , CH 2 (CH 2 ) n Y, C(O)NR 8 R 9 , C(O)OR 8 , C(S)NR 8 R 9 , NH 2 , NHC(O)R 8 , NHC(O)OR 8 , OR 8 , or S(O) 2 CF 3 ;
Y is H, CF 3 , C(O)OR 8 , or NR 8 R 9 ;
each R 8 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;
each R 9 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl; or
R 8 and R 9 , together with the nitrogen atom to which they are attached, form a C 3 -C 8 heterocycloalkyl;
R 10 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl;
R 11 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.
2. The compound of claim 1 , or a stereoisomer thereof, wherein the stereoisomer of the compound is of formula II:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , or a stereoisomer thereof, wherein the stereoisomer of the compound is of formula III:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-8 cycloalkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is NHR 9 , N(C 1-8 alkyl)R 9 , N(C 2-8 alkenyl)R 9 , N(C 3-8 cycloalkyl)R 9 , OH, heterocycloalkyl, heterocycloalkenyl, or heteroaryl.
6. The compound of claim 5 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is heterocycloalkyl, heterocycloalkenyl, or heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, or heteroaryl contains at least one nitrogen heteroatom.
7. The compound of claim 6 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is heterocycloalkyl, wherein the heterocycloalkyl contains at least one nitrogen heteroatom.
8. The compound of claim 7 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is a 6-membered heterocycloalkyl, wherein the 6-membered heterocycloalkyl contains at least one nitrogen heteroatom.
9. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is C 2-6 alkyl, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, or phenyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is H, C 3-4 alkyl, CH 2 OH, C 3-4 cycloalkyl, or phenyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is H or CH 3 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is O.
13. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 5 is H; or
R 6 is H.
14. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 5 is H; and
R 6 is H.
15. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 3 is H;
R 5 is H; and
R 6 is H.
16. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is halogen, C(O)NH 2 , or OH.
17. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 10 is H; or
R 11 is H.
18. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 10 is H; and
R 11 is H.
19. The compound of claim 1 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
21. A method for treating anxiety, depression, an eating disorder, or schizophrenia in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is H, C 1-6 alkyl, NHR 9 , N(C 1-8 alkyl)R 9 , N(C 2-8 alkenyl)R 9 , N(C 3-8 cycloalkyl)R 9 , OR 8 , C 3-8 cycloalkyl, C 5-8 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, phenyl, or heteroaryl, wherein the heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected alkyl substituents;
R 2 is H, C 1-4 alkyl, CH 2 (CH 2 ) n OH, C 3-6 cycloalkyl, or aryl;
R 3 is H or C 1-4 alkyl;
R 4 is O or S;
R 5 is H or C 1-4 alkyl;
R 6 is H or C 1-4 alkyl;
R 7 is halogen, CN, NO 2 , N 3 , CF 3 , CH 2 (CH 2 ) n Y, C(O)NR 8 R 9 , C(O)OR 8 , C(S)NR 8 R 9 , NH 2 , NHC(O)R 8 , NHC(O)OR 8 , OR 8 , or S(O) 2 CF 3 ;
Y is H, CF 3 , C(O)OR 8 , or NR 8 R 9 ;
each R 8 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;
each R 9 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl; or
R 8 and R 9 , together with the nitrogen atom to which they are attached, form a C 3 -C 8 heterocycloalkyl;
R 10 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl;
R 11 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.
22. A method for treating substance abuse addiction in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is H, C 1-6 alkyl, NHR 9 , N(C 1-8 alkyl)R 9 , N(C 2-8 alkenyl)R 9 , N(C 3-8 cycloalkyl)R 9 , OR 8 , C 3-8 cycloalkyl, C 5-8 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, phenyl, or heteroaryl, wherein the heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected alkyl substituents;
R 2 is H, C 1-4 alkyl, CH 2 (CH 2 ) n OH, C 3-6 cycloalkyl, or aryl;
R 3 is H or C 1-4 alkyl;
R 4 is O or S;
R 5 is H or C 1-4 alkyl;
R 6 is H or C 1-4 alkyl;
R 7 is halogen, CN, NO 2 , N 3 , CF 3 , CH 2 (CH 2 ) n Y, C(O)NR 8 R 9 , C(O)OR 8 , C(S)NR 8 R 9 , NH 2 , NHC(O)R 8 , NHC(O)OR 8 , OR 8 , or S(O) 2 CF 3 ;
Y is H, CF 3 , C(O)OR 8 , or NR 8 R 9 ;
each R 8 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;
each R 9 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl; or
R 8 and R 9 , together with the nitrogen atom to which they are attached, form a C 3 -C 8 heterocycloalkyl;
R 10 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl;
R 11 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.
23. The method of claim 22 , wherein the substance abuse addiction is selected from the group consisting of alcohol addiction, cocaine addiction, methamphetamine addiction, nicotine addiction, and opioid addiction.
24. A compound of formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is H, C 1-6 alkyl, NHR 9 , N(C 1-8 alkyl)R 9 , N(C 2-8 alkenyl)R 9 , N(C 3-8 cycloalkyl)R 9 , OR 8 , C 3-8 cycloalkyl, C 5-8 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, phenyl, or heteroaryl, wherein the heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected alkyl substituents;
R 2 is H, C 1-4 alkyl, CH 2 (CH 2 ) n OH, C 3-6 cycloalkyl, or aryl;
R 3 is H or C 1-4 alkyl;
R 4 is O or S;
R 5 is H or C 1-4 alkyl;
R 6 is H or C 1-4 alkyl;
R 7 is halogen, CN, NO 2 , N 3 , CF 3 , CH 2 (CH 2 ) n Y, C(O)NR 8 R 9 , C(O)OR 8 , C(S)NR 8 R 9 , NH 2 , NHC(O)R 8 , NHC(O)OR 8 , OR 8 , or S(O) 2 CF 3 ;
Y is H, CF 3 , C(O)OR 8 , or NR 8 R 9 ;
each R 8 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;
each R 9 is independently H, C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;
R 10 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl;
R 11 is H, C 1-8 alkyl, C 3-8 alkynyl, OC 1-8 alkyl, or C 3-8 cycloalkyl; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.
25. A compound, or a stereoisomer thereof, wherein the stereoisomer of the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.