Large substituent, non-phenolic opioids and methods of use thereof
8-Substituted-2,6-methano-3-benzazocines of general structure are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.
1. A method of treating a patient suffering from a disease or condition wherein said disease or condition is chosen from the group consisting of pain, pruritis, irritable bowel syndrome, respiratory depression, and drug addiction comprising administering to said patient a compound having the formula:
wherein
is an aryl or heteroaryl residue of one to three rings;
A is (CH 2 ) n , wherein one or more CH 2 may be replaced by —O—, cycloalkyl or CR 1a R 1b ;
R 1a and R 1b are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio;
R 2 and R 2a are both hydrogen or taken together R 2 and R 2a are ═O;
R 3 is chosen from hydrogen, C 1 -C 8 hydrocarbon, heterocyclyl, heterocyclylalkyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxyl, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxyl or carbonyl;
R 5 is lower alkyl;
R 6 is lower alkyl;
R 7 is chosen from hydrogen and hydroxyl; or
together R 4 , R 5 , R 6 and R 7 may form one to three rings, said rings having optional additional substitution;
R 10 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio;
R 11 is H or
is an aryl or heteroaryl residue of one to three rings;
A′ is (CH 2 ) m wherein one or more CH 2 may be replaced by —O—, cycloalkyl, —CR 1a R 1b , —C(═O)— or —NH—;
R 12 is chosen from hydrogen and lower alkyl;
R 15 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio;
m is zero or an integer from 1 to 6; and
n is an integer from 1 to 6;
with the proviso that A is other than CH 2 .
2. The method according to claim 1 wherein said compound is of formula:
wherein
R 3a is chosen from hydrogen, C 1 -C 7 hydrocarbon, heterocyclyl, and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxyl or carbonyl;
R 5 is lower alkyl;
R 6 is lower alkyl; and
R 7 is hydrogen or hydroxy.
3. The method according to claim 2 wherein:
R 3a is chosen from hydrogen, cyclopropyl, cyclobutyl, phenyl, vinyl, dimethylvinyl, hydroxycyclopropyl, furanyl, and tetrahydrofuranyl;
R 4 is chosen from hydrogen and 3-oxo-5-cyclopentyl-1-pentanyl;
R 5 is methyl; and
R 6 is methyl or ethyl.
4. The method according to claim 1 wherein said drug addiction is selected from heroin, cocaine, nicotine and alcohol addiction.
5. The method of claim 1 wherein said disease or condition is pruritis.
6. A compound selected from Table A:
TABLE A
No.
Structure
15
18
19
44
45
46
47
48
49
50
51
52
30
29
53
37
38
40
41
25
26
33
35
34
54
55
56
57
58
11
12
60
61
62
63
64
65
66
27
67
68
69
13
14
20
21
71
73
75
79
81