Methods for treating diseases with 4-hydroxybenzomorphans
4-Hydroxybenzomorphans containing carboxamide or thiocarboxamide at the 3-position are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.
1. A method for treating a disease or condition mediated by an opioid receptor which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula:
wherein
A is chosen from —C(═O)NH 2 and —C(═S)NH 2 ;
R 2 and R 2a are both hydrogen or taken together R 2 and R 2a are ═O;
R 3 is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ;
or
together, R 11 and R 12 form a carbonyl or a vinyl substituent;
R 13 and R 14 are chosen independently from hydrogen and C 1 to C 7 hydrocarbon; and
the dotted line represents an optional double bond.
2. A method according to claim 1 wherein
R 2 and R 2a are hydrogen;
R 3 is chosen from hydrogen, cyclopropyl, and cyclobutyl, vinyl and tetrahydrofuranyl;
R 4 is chosen from hydrogen and hydroxyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen and hydroxy;
or
together, R 11 and R 12 form a carbonyl.
3. A method according to claim 1 wherein the compound is of formula:
wherein
R 2 and R 2a are both hydrogen or taken together R 2 and R 2a are ═O;
R 3 is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ;
or
together, R 11 and R 12 form a carbonyl or a vinyl substituent;
R 13 and R 14 are chosen independently from hydrogen and C 1 to C 7 hydrocarbon; and
the dotted line represents an optional double bond.
4. A method according to claim 3 wherein:
R 2 and R 2a are hydrogen;
R 3 is chosen from hydrogen, cyclopropyl, and cyclobutyl, vinyl and tetrahydrofuranyl;
R 4 is chosen from hydrogen and hydroxyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen and hydroxy;
or
together, R 11 and R 12 form a carbonyl.
5. A method according to claim 4 wherein the compound is selected from the group of
6. A method according to claim 5 wherein said compound is of formula
7. A method according to claim 1 wherein the compound is of formula:
wherein
R 2 and R 2a are both hydrogen or taken together R 2 and R 2a are ═O;
R 3 is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ;
or
together, R 11 and R 12 form a carbonyl or a vinyl substituent;
R 13 and R 14 are chosen independently from hydrogen and C 1 to C 7 hydrocarbon; and
the dotted line represents an optional double bond.
8. A method according to claim 7 wherein:
R 2 and R 2a are hydrogen;
R 3 is chosen from hydrogen, cyclopropyl, and cyclobutyl, vinyl and tetrahydrofuranyl;
R 4 is chosen from hydrogen and hydroxyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen and hydroxy;
or
together, R 11 and R 12 form a carbonyl.
9. A method of treating a disease or condition chosen from the group consisting of pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, hyperalgesia and drug addiction by administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula:
wherein
A is chosen from —C(═O)NH 2 and —C(═S)NH 2 ;
R 2 and R 2a are both hydrogen or taken together R 2 and R 2a are ═O;
R 3 is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
R 11 is hydrogen;
R 12 is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ;
or
together, R 11 and R 12 form a carbonyl or a vinyl substituent;
R 13 and R 14 are chosen independently from hydrogen and C 1 to C 7 hydrocarbon; and
the dotted line represents an optional double bond.
10. A method according to claim 9 wherein said disease or condition is obesity.
11. A method according to claim 9 wherein said disease or condition is drug addiction.
12. A method according to claim 9 wherein said disease or condition is respiratory depression.
13. A method according to claim 9 wherein said disease or condition is a gastrointestinal motility disorder.
14. A method according to claim 6 wherein said disease or condition is obesity.
15. A method according to claim 6 wherein said disease or condition is drug addiction.
16. A method according to claim 6 wherein said disease or condition is respiratory depression.
17. A method according to claim 6 wherein said disease or condition is a gastrointestinal motility disorder.