(+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives
View Patent ↗The present invention provides (+)-morphinanium compounds comprising substituted 6-hydroxy or 6-amine groups. The invention also provides methods for inhibiting microglial activation by administering the compounds of the invention.
1. A (+)-morphinan compound of Formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
A is chosen from {—}OR 8 and {—}NR 8 R 9 ;
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 3 , R 4 , R 8 , and R 9 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 5 and R 6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , and {—}OR 7 ;
R 7 is chosen from hydrocarbyl and substituted hydrocarbyl;
Y is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; and
the dashed line between the carbon atoms at positions 7 and 8 represents a single bond or a double bond; provided, however:
when A is {—}OH, {—}O(CO)CH 3 , {—}NH(CH 2 ) 2 OH, {—}NH(CO)CH 3 , or {—}NH 2 , then R 1 is other than methyl; when A is {—}OH, {—}NH(CH 2 ) 2 OH, or {—}NH(CO)CH 3 , then R 1 is other than {—}(CH 2 (CH)CH 2 ; when A is {—}OH, {—}NH(CH 2 ) 2 OH, {—}NH(CO)CH 3 , {—}NH 2 , or {—}NHCH 3 then R 1 is other than {—}CH 2 (cyclopropane); when A is {—}OH, then R 1 is other than {—}CH 2 (cyclobutane); when A is —OC(═O)R, then R is H or heterocyclo; and, when A is —NR′R″ and one of R′ or R″ is substituted alkyl, then the other of R′ or R″ is H.
2. The compound of claim 1 , wherein R 1 is chosen from alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl, and A is chosen from hydroxy, alkoxy, acyloxy, amine, alkyl substituted amine, amido, carbamyl, carbonate, and urea.
3. The compound of claim 1 , wherein the compound has (+) optical activity, and wherein: the carbons at positions 5, 13, 14, and 9 have S, R, R, and S configurations, respectively, and the carbon at position 6 has an R or S configuration; or the substituted ring at position 5 is in the beta position and the Y at position 14 is in the alpha position.
4. The compound of claim 1 , wherein the compound is of Formula (IIa) or a pharmaceutically acceptable salt thereof:
wherein:
A is chosen from {—}OR 8 , and {—}NR 8 R 9 ;
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 8 and R 9 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
Y is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; provided that when A is —NR′R″ and one of R′ or R″ is substituted alkyl, then the other of R′ or R″ is H.
5. The compound of claim 4 , wherein R 1 is chosen from alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl; and A is chosen from hydroxy, alkoxy, acyloxy, amine, alkyl substituted amine, amido, carbamyl, carbonate, and urea.
6. The compound of claim 4 , wherein the compound has (+) optical activity, and wherein: the carbons at positions 5, 13, 14, and 9 have S, R, R, and S configurations, respectively, and the carbon at position 6 has an R or S configuration; or the substituted ring at position 5 is in the beta position, and the Y at position 14 is in the alpha position.
7. The compound of claim 4 , wherein the compound is chosen from (+)-nalbuphine and (+)-nalfurafine.
8. The compound of claim 1 , wherein the compound is of Formula (IIb) or a pharmaceutically acceptable salt thereof:
wherein:
A is chosen from {—}OR 8 and {—}NR 8 R 9 ;
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 8 and R 9 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
Y is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; provided that when A is —OC(═O)R, then R is H or heterocyclo.
9. The compound of claim 8 , wherein R 1 is chosen from alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, or aryl.
10. The compound of claim 8 , wherein the compound has (+) optical activity, and wherein: the carbons at positions 5, 13, 14, and 9 have S, R, R, and S configurations, respectively, and the carbon at position 6 has an R or S configuration; or the substituted ring at position 5 is in the beta position, and the Y at position 14 is in the alpha position.