Opioid receptor agonist compounds and their use in treatment of pain
Structurally novel opioid receptor agonists are provided, and the use of these agonists in treatment of chronic and/or acute pain.
1. A method of treating pain in a subject in need thereof, comprising:
administering to said subject a composition comprising an opioid receptor agonist and a physiologically acceptable carrier, wherein the opioid receptor agonist is a compound of formula (I):
wherein R 1 is C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl or one of the following groups:
or —(CH 2 ) n (Het), wherein (Het) is a member selected from
R is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, —CO 2 R 8 ;
R 2 is H, halogen, C 1-4 alkyl, CN or OCH 3 ;
Y is OH, OR 9 , C 1-8 alkyl, F, Cl, Br, CF 3 or CN;
W is a member selected from the group consisting of: H, OH, —CO 2 R 8 ; amino, —NR 3 SO 2 R 7 , —NR 3 CO 2 R 7 , —CONH 2 ; and —NHCHO
n is 1, 2, 3 or 4;
R 3 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, —CH 2 Y or —CO 2 R;
R 4 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl;
R 5 and R 6 are each, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl;
R 7 and R 8 are each independently, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl.
2. The method of claim 1 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, W, n, R 2 and R 8 are as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, or a group of the following formulae:
R 3 is hydrogen, or C 1-8 alkyl;
R 4 is hydrogen, or C 1-8 alkyl;
R 5 and R 6 are each independently, hydrogen, C 1-8 alkyl, or C 1-8 alkylaryl; and
R 7 is C 1-8 alkyl, or C 1-8 alkylaryl.
3. The method of claim 1 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, n, R 2 and R 8 are the same as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, or a group selected from the following formulae:
W is OH or CO 2 R 8 ;
R 3 is hydrogen, or C 1-4 alkyl;
R 4 is hydrogen or C 1-4 alkyl;
R 5 and R 6 are each independently, hydrogen, or C 1-4 alkyl; and
R 7 is C 1-4 alkyl.
4. The method of claim 1 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, n, R 2 , and R 9 are as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, C 1-4 alkylaryl or a member selected from the following formulae:
W is OH or CO 2 R 8 ;
R 3 is hydrogen, or methyl;
R 4 is hydrogen or methyl;
R 5 and R 6 are each independently, hydrogen, or C 1-4 alkyl; and
R 7 is C 1-4 alkyl.
5. The method of claim 1 , wherein said opioid receptor agonist is a compound of formula 23:
6. An opioid receptor agonist compound represented by the formula (I):
wherein R 1 is C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl or one of the following groups:
or —(CH 2 ) n (Het), wherein (Het) is a member selected from
R is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, —CO 2 R 8 ;
R 2 is H, halogen, C 1-4 alkyl, CN or OCH 3 ;
Y is OH, OR 9 , C 1-8 alkyl, F, Cl, Br, CF 3 or CN;
W is a member selected from the group consisting of: H, OH, —CO 2 R 8 ; amino, —NR 3 SO 2 R 7 , —NR 3 CO 2 R 7 , —CONH 2 ; and —NHCHO
n is 1, 2, 3 or 4;
R 3 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, —CH 2 Y or —CO 2 R;
R 4 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl;
R 5 and R 6 are each, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl, with the proviso that R 5 and R 6 cannot both be hydrogen;
R 7 and R 8 are each independently, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl.
7. The opioid receptor agonist of claim 6 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, W, n, R 2 and R 8 are as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, or a group of the following formulae:
R 3 is hydrogen, or C 1-8 alkyl;
R 4 is hydrogen, or C 1-8 alkyl;
R 5 and R 6 are each independently, hydrogen, C 1-8 alkyl, or C 1-8 alkylaryl, with the proviso that
R 5 and R 6 cannot both be hydrogen; and
R 7 is C 1-8 alkyl, or C 1-8 alkylaryl.
8. The opioid receptor agonist of claim 6 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, n, R 2 and R 8 are the same as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, or a group selected from the following formulae:
W is OH or CO 2 R 8 ;
R 3 is hydrogen, or C 1-4 alkyl;
R 4 is hydrogen or C 1-4 alkyl;
R 5 and R 6 are each independently, hydrogen, or C 1-4 alkyl, with the proviso that R 5 and R 6 cannot both be hydrogen; and
R 7 is C 1-4 alkyl.
9. The opioid receptor agonist of claim 6 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, n, R 2 , and R 9 are as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, C 1-4 alkylaryl or a member selected from the following formulae:
W is OH or CO 2 R 8 ;
R 3 is hydrogen, or methyl;
R 4 is hydrogen or methyl;
R 5 and R 6 are each independently, hydrogen, or C 1-4 alkyl, with the proviso that R 5 and R 6 cannot both be hydrogen; and
R 7 is C 1-4 alkyl.
10. A pharmaceutical composition comprising:
an effective amount of an opioid receptor agonist and a physiologically acceptable carrier, wherein the opioid receptor agonist is a compound of formula (I):
wherein R 1 is C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl or one of the following groups:
or —(CH 2 ) n (Het), wherein (Het) is a member selected from
R is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, —CO 2 R 8 ;
R 2 is H, halogen, C 1-4 alkyl, CN or OCH 3 ;
Y is OH, OR 9 , C 1-8 alkyl, F, Cl, Br, CF 3 or CN;
W is a member selected from the group consisting of: H, OH, —CO 2 R 8 ; amino, —NR 3 SO 2 R 7 , —NR 3 CO 2 R 7 , —CONH 2 ; and —NHCHO
n is 1, 2, 3 or 4;
R 3 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkylaryl, —CH 2 Y or —CO 2 R;
R 4 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl;
R 5 and R 6 are each, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl;
R 7 and R 8 are each independently, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, or C 1-8 alkylaryl.
11. The pharmaceutical composition of claim 10 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, W, n, R 2 and R 8 are as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, or a group of the following formulae:
R 3 is hydrogen, or C 1-8 alkyl;
R 4 is hydrogen, or C 1-8 alkyl;
R 5 and R 6 are each independently, hydrogen, C 1-8 alkyl, or C 1-8 alkylaryl; and
R 7 is C 1-8 alkyl, or C 1-8 alkylaryl.
12. The pharmaceutical composition of claim 10 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, n, R 2 and R 8 are the same as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, or a group selected from the following formulae:
W is OH or CO 2 R 8 ;
R 3 is hydrogen, or C 1-4 alkyl;
R 4 is hydrogen or C 1-4 alkyl;
R 5 and R 6 are each independently, hydrogen, or C 1-4 alkyl; and
R 7 is C 1-4 alkyl.
13. The pharmaceutical composition of claim 10 , wherein said opioid receptor agonist is a compound of formula I:
wherein Y, n, R 2 , and R 9 are as noted above;
R 1 is C 2-8 alkyl, C 3-8 alkenyl, C 1-4 alkylaryl or a member selected from the following formulae:
W is OH or CO 2 R 8 ;
R 3 is hydrogen, or methyl;
R 4 is hydrogen or methyl;
R 5 and R 6 are each independently, hydrogen, or C 1-4 alkyl; and
R 7 is C 1-4 alkyl.
14. The pharmaceutical composition of claim 10 , wherein said opioid receptor agonist is a compound of formula 23:
15. The pharmaceutical composition of claim 10 , wherein said composition is an injectable composition.
16. The pharmaceutical composition of claim 10 , wherein said composition is an orally administrable composition.
17. The pharmaceutical composition of claim 16 , wherein said orally administrable composition is in a form selected from the group consisting of tablets, capsules, troches, powders, solutions, dispersions, emulsions and suspensions.
18. The pharmaceutical composition of claim 10 , wherein R 5 and R 6 cannot both be hydrogen.