Opioid antagonists
View Patent ↗Certain quinolizidine and octahydropyridopyrazine compounds, pharmaceutical compositions, and methods of their use, inter alia, as opioid receptor antagonists are disclosed.
1. A compound of formula I:
wherein:
R 1 is —C(═O)NR 6 R 7 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;
X is NR 5 ;
R 5 is —C(═O)R 8b ;
R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
R 7 is H, alkyl, aralkyl, or aryl;
R 8b is H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aralkyl, or aryl;
m is 1; and
n is 1,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 6 is H or alkyl.
3. The compound of claim 2 , wherein R 7 is H or alkyl.
4. The compound of claim 1 , having the structure of formula IIa:
wherein
R 6 and R 7 are each independently alkyl;
R 2 and R 3 are each independently alkyl; and
R 8b is heteroaryl, heteroarylalkyl, aralkyl, or aryl.
5. The compound according to claim 4 , having the structure of formula IIb:
6. The compound of claim 4 , wherein R 6 and R 7 are each independently methyl.
7. The compound of claim 4 , wherein R 8b is aralkyl or aryl.
8. The compound of claim 7 , wherein R 8b is aryl and R 6 and R 7 are each independently methyl.
9. The compound of claim 8 , wherein R 8b is aryl substituted with halo.
10. The compound of claim 9 , wherein R 8b is aryl substituted with fluoro.
11. A method for binding delta opioid receptors, comprising the step of: contacting one or more delta opioid receptors with a compound of formula (I) or a salt thereof in an amount effective to bind to the opioid receptor,
wherein:
R 1 is —C(═O)NR 6 R 7 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;
X is NR 5 ;
R 5 is —C(═O)R 8b ;
R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
R 7 is H, alkyl, aralkyl, or aryl;
R 8b is H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aralkyl, or aryl;
m is 1; and
n is 1.
12. The method of claim 11 , wherein the compound has the structure of formula IIa:
wherein
R 6 and R 7 are each independently alkyl;
R 2 and R 3 are each independently alkyl; and
R 8b is heteroaryl, heteroarylalkyl, aralkyl, or aryl.
13. The method of claim 12 , wherein the compound has the structure of formula IIb:
14. The method of claim 12 , wherein R 6 and R 7 are each independently methyl.
15. The method of claim 12 , wherein R 8b is aralkyl or aryl.
16. The method of claim 15 , wherein R 8b is aryl and R 6 and R 7 are each independently methyl.
17. The method of claim 16 , wherein R 8b is aryl substituted with halo.
18. The method of claim 17 , wherein R 8b is aryl substituted with fluoro.