Substituted piperidine compounds and methods of their use
View Patent ↗Certain 4-aryl-piperidine compounds, including N-substituted 9β-substituted-5-(3-substituted-phenyl)morphans and N-substituted octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines, pharmaceutical compositions, and methods of their use, inter alia, as opioid antagonists are disclosed.
1. A compound of formula II:
wherein:
R 1 is —OR 7 , —NR 7 R 8 , —COOR 7 , —CONR 7 R 8 , or —CH 2 OH;
each R 7 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
each R 8 is independently H, alkyl, aralkyl, or aryl;
R 3 is alkyl;
R 6 is H or —(CHR 9 ) m W;
each R 9 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl;
W is H, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, —CH 2 OH, —CH 2 OR 7 , or —C(═O)R 10 ;
R 10 is —OR 7 or —NR 7 R 11 ;
R 11 is H, alkyl, aralkyl, aryl or —(CHR 9 ) n C(═O )R 12 ;
R 12 is —OR 7 or —NR 7 R 8 ;
m is an integer from 1 to 4; and
n is an integer from 1 to 4;
provided that when R 1 is —OH, then W is heterocycloalkyl, alkylheterocycloalkyl, —CH 2 OH, or —C(═O)R 10 ; and when R 1 is —OH and W is heterocycloalkyl or alkylheterocycloalkyl in which the heterocyclic ring moiety of the heterocycloalkyl or alkylheterocycloalkyl contains only one heteroatom, wherein the heteroatom is nitrogen, then the heterocyclic ring moiety is connected to —(CHR 9 ) m — through a heterocyclic ring carbon atom;
or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate or N-oxide form thereof.
2. A compound according to claim 1 ,
wherein R 1 is —OR 7 , —NR 7 R 8 , or —CONR 7 R 8 .
3. A compound according to claim 2 ,
wherein R 1 is —OH, —NHR 8 , or —CONHR 8 .
4. A compound according to claim 1 ,
wherein R 6 is —(CHR 9 ) m W.
5. A compound according to claim 4 ,
wherein:
R 6 is:
R 9a is H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl.
6. A compound according to claim 5 ,
wherein:
R 6 is:
7. A compound according to claim 5 ,
wherein:
R 6 is:
8. A compound according to claim 5 ,
wherein W is aryl, —CH 2 OH, —CH 2 OR 7 , or —C(═O)R 10 .
9. A compound according to claim 8 ,
wherein W is aryl, —CH 2 OH, or —(═O)OH.
10. A compound according to claim 8 ,
wherein W is —C(═O)NR 7 R 11 .
11. A compound according to claim 10 ,
wherein W is —C(═O)NHR 11 .
12. A compound according to claim 11 ,
wherein R 11 is —(CHR 9 ) n C(═O)R 12 .
13. A compound according to claim 12 ,
wherein R 11 is —(CHR 9 ) n C(═O)OH.
14. A compound according to claim 1 ,
wherein m is 1 or 2.
15. A compound according to claim 1 ,
wherein n is 1 or 2.
16. A compound according to claim 15 ,
wherein n is 1.
17. A compound according to claim 1 , of formula IIIa or IIIb:
18. A compound according to claim 17 , of formula IIIa.
19. A compound according to claim 17 ,
wherein R 3 is methyl.
20. A compound according to claim 17 ,
wherein R 1 is —OR 7 , —NR 7 R 8 , or —CONR 7 R 8 .
21. A compound according to claim 17 ,
wherein:
R 6 is:
R 9a is H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl.
22. A compound according to claim 21 ,
wherein:
R 6 is:
23. A compound according to claim 22 ,
wherein W is aryl, —CH 2 OH, or —C(═O)R 10 .
24. A compound according to claim 21 ,
wherein R 6 is:
25. A compound according to claim 24 ,
wherein W is aryl, —CH 2 OH, or —C(═O)R 10 .
26. A compound according to claim 21 ,
wherein:
W is —C(═O)R 10 ;
R 10 is —OR 7 ;
R 1 is —NR 7 R 8 ;
R 7 , R 8 , and R 9 are each H;
R 3 methyl;
R 9a is benzyl; and
m is 2.
27. A compound according to claim 21 ,
wherein:
W is phenyl;
R 1 is —C(═O)NR 7 R 8 ;
R 3 is methyl;
R 7 , R 8 , R 9 , and R 9 a are each H; and
m is 2.
28. A compound according to claim 22 ,
wherein:
W is —CH 2 OH;
R 1 is —NR 7 R 8 ;
R 3 is methyl;
R 7 and R 9 are each H;
R 8 is —CH 2 CH 3 ;
R 9a is benzyl; and
m is 2.
29. A compound according to claim 24 ,
wherein:
W is —CH 2 OH;
R 1 is —NR 7 R 8 ;
R 3 methyl;
R 7 and R 9 are each H;
R 8 is —CH 2 CH 3 ;
R 9a is benzyl; and
m is 2.
30. A compound according to claim 24 ,
wherein:
R 1 is —OR 7 ;
W is —C(═O)R 10 ;
R 10 is —OR 7 ;
R 3 methyl;
each R 7 and R 9 is H;
R 9a is benzyl; and
m is 2.
31. A compound according to claim 24 ,
wherein:
R 1 and R 12 are each —OR 7 ;
W is —C(═O)R 10 ;
R 10 is —NR 7 R 11 ;
R 3 methyl;
each R 7 and R 9 is H;
R 9a is benzyl;
R 11 is —(CHR 9 ) n C(═O)R 12 ;
m is 2; and
n is 1.
32. A compound according to claim 1 ,
wherein the compound is:
2-benzyl-3-[5-(3-hydroxy-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propionic acid;
{2-benzyl-3-[5-(3-hydroxy-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propionylamino}acetic acid;
2-benzyl-3-[5-(3-ethylamino-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propan-1-ol;
2-benzyl-3-[5-(3-ethylamino-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propan-1-ol;
3-[5-(3-amino-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-2-benzyl-propionic acid;
3-[9-methyl-2-phenylethyl-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
or stereoisomers thereof.
33. A compound according to claim 32 ,
wherein the compound is:
2(S)-benzyl-3-[5-(3-hydroxy-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propionic acid;
{2(S)-benzyl-3-[5-(3-hydroxy-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propionylamino}acetic acid;
2(S)-benzyl-3-[5-(3-ethylamino-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propan-1-ol;
2(R)-benzyl-3-[5-(3-ethylamino-phenyl)-9-methyl-2-aza-bicyclo[3.3.1]non-2-yl]-propan-1-ol;
or partial stereoisomers thereof.
34. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
an effective amount of a compound according to claim 1 .