Large substituent, non-phenolic opioids

1. A compound of 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, hydroxy, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;

R 5 is lower alkyl;

R 6 is lower alkyl;

R 7 is chosen from hydrogen and hydroxy; or together R 4 , R 5 , R 6 and R 7 may form from 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. A compound according to claim 1 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 hydroxy or carbonyl;

R 5 is lower alkyl;

R 6 is lower alkyl; and

R 7 is hydrogen or hydroxy.

3. A compound 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. A compound according to claim 2 of formula

wherein R 6 is methyl or ethyl.

5. A compound according to claim 1 wherein together R 5 and R 6 form one ring and R 7 is hydrogen, said compound having the structure:

wherein

R 3a is chosen from hydrogen, C 1 -C 7 hydrocarbon, heterocyclyl, and hydroxyalkyl; and

R 7 is H or OH.

6. A compound according to claim 5 wherein

R 2 and R 2a are hydrogen;

R 3a is chosen from hydrogen, cyclopropyl, cyclobutyl, vinyl and tetrahydrofuranyl; and

R 4 is hydrogen, hydroxy or amino.

7. A compound according to claim 1 wherein together R 5 , R 6 and R 7 form two rings, having the structure:

wherein

R 3a is chosen from hydrogen, C 1 -C 7 hydrocarbon, heterocyclyl, and hydroxyalkyl

R 4 is hydrogen, hydroxy, amino or lower alkoxy;

R 19 is hydrogen or lower alkyl;

R 20 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); or together, R19 and R20 form a spiro-fused carbocycle of 5 to 10 carbons;

R 21 is hydrogen;

R 22 is chosen from hydroxy, lower alkoxy and —NR 13 R 14 ; or

together, R 21 and R 22 form a carbonyl or a vinyl substituent; or

together, R 4 and R 21 form a sixth ring.

8. A compound according to claim 7 , wherein together, R 4 and R 21 form a sixth ring, of formula:

9. A compound according to claim 7 , wherein R 4 and R 21 form a sixth ring, of formula

wherein

R 19 is hydrogen;

R 20 is hydroxy(lower alkyl); and

R 22 is lower alkoxy.

10. A compound according to claim 1 wherein

is phenyl, R 10 is hydrogen and R 11 is chosen from pyridinyl, phenyl, halophenyl, methylphenyl, methoxyphenyl and phenoxy.

11. A compound according to claim 1 wherein

is chosen from phenyl, naphthyl, fluorenyl, carbazole, dibenzofuran and dibenzothiophene and one of R 10 and R 11 is hydrogen and the other is hydrogen, methoxy, halogen or methyl.

12. A compound according to claim 1 wherein

is pyridinyl, R 10 is hydrogen and R 11 is chosen from phenyl, halophenyl, methylphenyl, methoxyphenyl and phenoxy.

13. A compound according to claim 1 wherein n is 2.