Deuterated morphine derivatives

摘要

The invention relates to new morphine derivatives deuterated at the 7,8-position of the morphine ring, furthermore to a process for the preparation thereof, and to pharmaceutical compositions comprising them. The new deuterated morphine derivatives show high and selective μ-opioid receptor binding activity leading to the benefit of higher analgesic activity at lower dosages inducing thereby reduced adverse effects compared to the hydrogenated derivatives. The compounds of the invention are useful for example in the treatment of pain or can be used as antitussive agents with a reduced risk of the possibility of drug abuse.

主权项

1. A compound of general formula (I) wherein R1 is —OH, —OR4, —O-2,4-dinitrophenyl, —OC(═O)C1-6 alkyl, —OC(═O)phenyl, —OC(═O)pyridyl; R2 is hydrogen, —OH, —OR4, —Cl, —N3, bis(2-chloroethyl)amino-, —OC(═O)—C1-16 alkyl, —OC(═O)phenyl, —OC(═O)pyridyl, —(N-methyl-N—C(═O)—CH═CH-fur-3-yl), and the dotted line is absent or R2 is —O, —CH2, —N—NH2, —NOH, —N—O—C1-6alkyl wherein the alkyl is optionally substituted with a caboxyl group, and the dotted line represents a chemical bond, R3 is hydrogen, —O, —C1-6 alkyl optionally substituted by phenyl, (C3-7 cycloalkyl)-(C1-6 alkyl)-, —(C1-6alkyl)-O—(C1-6alkyl), —C2-7 alkenyl; R4 is —C1-6 alkyl optionally substituted by a phenyl or by a 6 membered saturated heterocycle attached by a nitrogen and containing at least one more heteroatom selected from O, S and N; R5 is absent or is —C1-6 alkyl and the ring nitrogen bears a positive charge, with the proviso that R5 is not absent when R2 is ═O; R6 is hydrogen, —C1-6 alkyl; X is hydrogen, —OH, —OR4, —O-cinnamoyl, —NH(C1-6 alkyl); D is deuterium and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof.