(+)-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 compound of Formula (IIa) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, alkyl, alkenyl, or methylcycloalkyl;
R 1 is hydrogen, aryl, or heteroaryl;
R 3 is hydroxy, alkoxy, or aryloxy;
A 1 is hydroxy, keto, aryloxy, amino, alkylamine, hydroxyalkylamine, carboxylalkylamine, alkylcarboxylalkylamine, or arylamine; provided, however, that when A 1 is keto, R 1 is other than hydrogen; when A 1 is hydroxy, R is other than alkyl or allyl; when A 1 is hydroxy, Y is other than hydroxy; or when A 1 is an amine, Y is other than hydroxy;
Y is hydrogen or hydroxy; and
the dashed line represents an optional double bond.
2. The compound of claim 1 , wherein the compound has the structure of Formula (IIb) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, methyl, allyl, methylcyclopropyl, or methylcyclobutyl;
R a is hydrogen, methyl, ethyl, or phenyl;
R b is hydrogen, alkyl, alkylalcohol, or alkylcarboxylalkylester; and
Y is hydrogen.
3. The compound of claim 2 , wherein R is methyl, R a is methyl, and R b is methylacetylmethylester.
4. The compound of claim 2 , wherein R is allyl, R a is methyl, and R b is propyl.
5. The compound of claim 2 , wherein R is allyl, R a is methyl, and R b is ethylalcohol.
6. The compound of claim 1 , wherein the compound has the structure of Formula (IIc) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, methyl, allyl, methylcyclopropyl, or methylcyclobutyl;
R 1 is hydrogen, aryl, or heteroaryl;
R a is hydrogen, methyl, ethyl, or phenyl;
R c is hydroxy or keto; provided, however, that when R c is keto, R 1 is other than hydrogen; when R c is hydroxy, R is other than methyl or allyl; or when R c is hydroxy, Y is other than hydroxy;
Y is hydrogen or hydroxy; and
the dashed line represents an optional double bond.
7. The compound of claim 6 , wherein R is methylcyclopropyl, R 1 is hydrogen, R a is methyl, R c is hydroxy; Y is hydrogen, and the optional double bond is not present.
8. The compound of claim 6 , wherein R is allyl, R 1 is furanyl, R a is methyl, R c is keto; Y is hydrogen, and the optional double bond is not present.
9. A pharmaceutical composition comprising a compound of Formula (IV) or a pharmaceutically acceptable salt thereof and a compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, the compound of Formula (IV) having the following structure:
wherein:
R 21 is hydrogen or methyl;
R 22 is dimethylamino-ethyl-methylpropyl or dimethylamino cyclohexanol; and
Z is oxygen;
and the compound of Formula (IIa) having the following structure:
wherein:
R is hydrogen, alkyl, alkenyl, allyl, methylcycloalkyl, methylaryl, acyl, acylalkyl, acylcycloalkyl, acylaryl, acyloxy, acyloxyalkyl, acyloxyaryl, alkoxy, or alkoxyalkyl;
R 1 is hydrogen, halo, hydroxy, alkoxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, alkyl, alkenyl, aryl, heteroaryl, or amine;
R 3 is hydroxy, alkoxy, aryloxy, acyl, acyloxy, or protected hydroxy;
A 1 is hydrogen, hydroxy, keto, acyl, acyloxy, amino, amide, alkylamine, hydroxyalkylamine, carboxylalkylamine, alkylcarboxylalkylamine, arylamine, alkyl, alkenyl, aryl, substituted alkyl, substituted alkenyl, or substituted aryl; provided, however, that when A 1 is keto, R 1 is other than hydrogen; when A 1 is hydroxy, Y is other than hydroxy or R is other than alkyl or allyl;
Y is hydrogen, hydroxy, alkoxy, or protected hydroxy; and
the dashed line represents an optional double bond.
10. The pharmaceutical composition of claim 9 , wherein the compound of Formula (IIa) has the structure of Formula (IIb) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, alkyl, allyl, methylcyclopropyl, or methylcyclobutyl;
R a is hydrogen, alkyl, phenyl, or benzyl;
R b is hydrogen, alkyl, alkylalcohol, alkylcarboxyl, alkylcarboxylalkylester, acyl, acylalkyl, acylaryl, acyloxy, acyloxyalkyl, or acyloxyaryl; and
Y is hydrogen or hydroxy.
11. The pharmaceutical composition of claim 10 , wherein R is methylcyclopropyl, R a is hydrogen, R b is methyl, and Y is hydroxy.
12. The pharmaceutical composition of claim 10 , wherein R is methyl, R a is methyl, R b is methylacetylmethylester; and Y is hydrogen.
13. The pharmaceutical composition of claim 10 , wherein R is allyl, R a is methyl, R b is propyl; and Y is hydrogen.
14. The pharmaceutical composition of claim 10 , wherein R is allyl, R a is methyl, R b is ethylalcohol; and Y is hydrogen.
15. The pharmaceutical composition of claim 9 , wherein the compound of Formula (IIa) has the structure of Formula (IIc) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, alkyl, allyl, methylcyclopropyl, or methylcyclobutyl;
R 1 is hydrogen, halo, hydroxy, alkoxy, amine, aryl, or heteroaryl;
R a is hydrogen, alkyl, phenyl, or benzyl;
R c is hydroxy, keto, or acyl; provided, however, that when R c is keto, R 1 is other than hydrogen; when R c is hydroxy, Y is other than hydroxy or R is other than alkyl or allyl;
Y is hydrogen or hydroxy; and
the dashed line represents an optional double bond.
16. The pharmaceutical composition of claim 15 , wherein R is methylcyclopropyl, R 1 is hydrogen, R a is methyl, R c is hydroxy; Y is hydrogen, and the optional double bond is not present.
17. The pharmaceutical composition of claim 15 , wherein R is allyl, R 1 is furanyl, R a is methyl, R c is keto, Y is hydrogen, and the optional double bond is not present.