Substituted piperidine compounds and methods of their use
View Patent ↗Novel 3,4-disubstituted-4-aryl-piperidine compounds are disclosed. Pharmaceutical compositions containing the 3,4-disubstituted-4-aryl-piperidine compounds and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as antagonists of opioid receptors.
1. A compound of formula I:
wherein:
R 1 is H or C 1 -C 6 alkyl;
R 2a is C 1 -C 6 alkyl or C 2 -C 6 alkenyl;
R 2b is H, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
R 3 is H, unsubstituted C 1 -C 6 alkyl, or unsubstituted benzyl;
R 5 is —(CHR 8 )—W;
R 4 and R 8 when taken together with the atoms through which they are connected, form a pyrrolidine or tetrahydroisoquinoline ring, wherein said pyrrolidine or tetrahydroisoquinoline ring is optionally substituted by one or more substituents selected from —OH, unsubstituted C 1 -C 6 alkyl, or unsubstituted C 1 -C 6 alkoxy;
W is —C(═O)OR 9 ;
R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, C 3 -C 8 cycloalkylC 1 -C 3 alkyl, C 5 -C 8 cycloalkenylC 1 -C 3 alkyl, or C 6 -C 10 arylC 1 -C 4 alkyl;
m is the integer 0, 1, 2, 3, or 4; and
q is the integer 0, 1, or 2;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
2. A compound according to claim 1 , wherein R 1 is H.
3. A compound according to claim 1 , wherein R 2a and R 2b are trans to each other.
4. A compound according to claim 1 , of formula II:
5. A compound according to claim 1 , wherein R 2a and R 2b are each methyl.
6. A compound according to claim 1 , of formula III:
7. A compound according to claim 1 , wherein R 3 is:
8. A compound according to claim 1 , of formula V:
9. A compound according to claim 8 , of formula VII:
10. A compound according to claim 9 , wherein R 3 is:
11. A compound according to claim 10 , wherein R 2a and R 2b are each methyl.
12. A compound according to claim 11 , of formula VIIa:
13. A compound according to claim 11 , of formula VIIb:
14. A compound according to claim 1 , wherein W is —CO 2 H.
15. A compound according to claim 1 , wherein m is the integer 1.
16. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
an effective amount of a compound according to claim 1 .
17. A compound according to claim 1 , which is selected from the group consisting of:
1-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4 -dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2(R)-carboxylic acid;
2-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4 -dimethylpiperidin-1-yl]-propionyl }-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid;
1-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4 -dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2-(S)-carboxylic acid;
1-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4 -dimethylpiperidin-1-yl]-propionyl }-4(R)-hydroxypyrrolidine-2(R)-carboxylic acid;
2-{3-[4(R)-(3-Hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl }-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid;
4(R)-Hydroxy-1-{3[4(R)-(3-hydroxyphenyl)-3(R),4 -dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2(R)-carboxylic acid; and
1-{3-[4-(3-Hydroxyphenyl)-3 ,4-dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2(R)-carboxylic acid;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
18. A compound according to claim 17 which is 4(R)-Hydroxy-1-{3-[4(R)-(3-hydroxy-phenyl)-3 (R),4-dimethylpiperidin-1-yl]-propionyl}pyrrolidine-2(R)-carboxylic acid.