(+)-morphinans as antagonists of Toll-like receptor 9 and therapeutic uses thereof
View Patent ↗The present invention provides (+)-morphinans comprising Toll-like receptor 9 (TLR9) antagonist activity, as well as methods for using the (+)-morphinans to treat pain. Also provided are pharmaceutical combination compositions comprising a (+)-morphinan and an opioid agonist/monoamine reuptake inhibitor, as well as methods for using the combination compositions to treat pain.
1. A method for treating stroke in a subject in need thereof, the method comprising administering to the subject a compound of Formula (IIb) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, alkyl, allyl, or cycloalkylmethyl;
R a is hydrogen, alkyl, or phenyl;
R b is hydrogen, alkyl, alkylalcohol, alkylcarboxyl, alkylcarboxylalkylester, acyl, acylalkyl, acylaryl, acyloxy, acyloxyalkyl, or acyloxyaryl; and
Y is hydrogen or hydroxy.
2. The method of claim 1 , wherein the compound of Formula (IIb) is a Toll-like receptor 9 (TLR9) antagonist.
3. The method of claim 1 , wherein wherein R is methyl, allyl, or cyclopropylmethyl.
4. The method of claim 1 , wherein R a is hydrogen or methyl.
5. The method of claim 1 , wherein R b is alkyl, alkylalcohol, or alkylcarboxylalkylester.
6. The method of claim 1 , wherein wherein R is cyclopropylmethyl, R a is hydrogen, R b is methyl, and Y is hydroxy.
7. The method of claim 1 , wherein R is methyl, R a is methyl, R b is methylacetylmethylester; and Y is hydrogen.
8. The method of claim 1 , wherein R is allyl, R a is methyl, R b is ethylalcohol; and Y is hydrogen.
9. The method of claim 1 , wherein the compound of Formula (IIb) is provided as a pharmaceutical composition.
10. The method of claim 9 , wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
11. The method of claim 1 , wherein the method further comprises administering at least one other therapeutic agent.
12. The method of claim 1 , wherein the subject is human.