(+)-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 process for preparing a (+)-morphinan compound of Formula (IV), the process comprising:
(a) contacting a compound of Formula (III) with a secondary amine of formula NHR 8 R 9 and an acid catalyst to form an intermediate enamine compound; and
(b) contacting the intermediate enamine compound with an alkali metal cyanoborohydride to form the compound of Formula (IV) according to the following reaction scheme:
wherein:
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 3 and R 4 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;
R 8 and R 9 are independently chosen from acyl, acyloxy, alkyl, cycloalkyl, alkoxy, hydroxy alkyl, alkenyl, aryl, aryloxy, substituted alkyl, substituted cycloalkyl, substituted alkenyl, substituted aryl, and together R 8 and R 9 form a ring or ring system chosen from carbocyclic, substituted carbocylic, heterocyclic, substituted heterocylic, and a combination thereof;
provided that when one of R 8 or R 9 is benzyl, then the other of R 8 or R 9 is other than C 1 -C 6 alkyl or C 6 -C 12 aryl;
Y is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy.
2. The process of claim 1 , wherein R 1 is chosen from alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, and aryl.
3. The process of claim 1 , wherein R 3 , R 4 , R 5 , and R 6 are hydrogen.
4. The process of claim 1 , wherein the mole to mole ratio of the compound of Formula (III) to the secondary amine of formula NHR 8 R 9 is from about 1:1 to about 1:3.
5. The process of claim 1 , wherein the acid catalyst is a sulfonic acid chosen from p-toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, and trifluromethanesulfonic acid.
6. The process of claim 1 , wherein the mole to mole ratio of the compound of Formula (III) to the acid catalyst is from about 1:0.005 to about 1:0.2.
7. The process of claim 1 , wherein step (a) is conducted in the presence of a solvent or solvent system comprising benzene, n-butanol, butyl acetate, carbon tetrachloride, chloroform cyclohexane, 1,2-dichloroethane, dichloromethane, ethyl acetate, di-ethyl ether, heptane, hexane, methyl-1-butyl ether, methyl ethyl ketone, pentane, di-isopropyl ether, toluene, trichloromethane, xylene, or a combination thereof.
8. The process of claim 1 , wherein the mole to mole ratio of the compound of Formula (III) to the alkali metal cyanoborohydride is from about 1:0.5 to about 1:3.
9. The process of claim 1 , wherein step (a) is conducted at a temperature of about 30° C. to about 130° C., and step (b) is conducted at a temperature of about 10° C. to about 100° C.
10. The process of claim 1 , wherein the carbons at positions 5, 13, 14, and 9 of the compounds of Formula (III) or (IV) have S, R, R, and S configurations, respectively.
11. The process of claim 1 , wherein the carbon at position 6 of the compound of Formula (IV) has a beta configuration.
12. The process of claim 1 , wherein the compound of Formula (IV) is converted to a pharmaceutically acceptable salt.
13. The process of claim 1 , wherein R 1 is chosen from methyl, cyclopropylmethyl, cyclobutylmethyl, allyl, propargyl, and benzyl; R 3 , R 4 , R 5 , and R 6 are hydrogen.
14. The process of claim 13 , wherein the mole to mole ratio of the compound of Formula (III) to the secondary amine of formula NHR 8 R 9 is from about 1:1.5 to about 1:2.
15. The process of claim 13 , wherein the acid catalyst is p-toluenesulfonic acid and the mole to mole ratio of the compound of Formula (III) to the acid catalyst is from about 1:0.01 to about 1:0.15.
16. The process of claim 13 , wherein step (a) is conducted in the presence of a solvent or solvent system comprising toluene, and step (a) is conducted at a temperature of about 110° C. to about 115° C.
17. The process of claim 13 , wherein the alkali metal cyanoborohydride is sodium cyanoborohydride; the mole to mole ratio of the compound of Formula (III) to sodium cyanoborohydride is from about 1:1 to about 1:2, and step (b) is conducted at temperature of about 20° C. to about 80° C.
18. The process of claim 13 , wherein the carbons at positions 5, 13, 14, and 9 of the compounds of Formula (III) or (IV) have S, R, R, and S configurations, respectively.
19. The process of claim 13 , wherein the carbon at position 6 of the compound of Formula (IV) has a beta configuration.
20. The process of claim 13 , wherein the compound of Formula (IV) is converted to a pharmaceutically acceptable salt.