Deuterated Alpha5 subunit-selective negative allosteric modulators of gamma-aminobutyric acid type A receptors as fast acting treatment for depression and mood disorders
The present invention relates to novel alpha5 subunit-selective negative allosteric modulators of GABA A receptors that have been deuterated to improve their medicinal properties by prolonging their half-lives, rendering them useful as fast-acting pharmaceutical treatments for depression related disorders.
1. A deuterated GABA A5 -NAM compound according to Formula I:
wherein R 1 , R 2 , and R 3 each independently are H or D, with the proviso that at least one of R 1 , R 2 and R 3 is D, and
wherein R 4 and Rs each independently are H or D.
2. The GABAA5-NAM compound:
(1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone (RG-1662); which is deuterated.
3. The deuterated GABA A5 -NAM compound of claim 1 according to Formula II
4. A deuterated Basmisanil compound of claim 1 which is synthesized by:
(a) treating (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol with a base or under basic conditions in the presence of a deuterium donor or followed by a deuterium donor;
(b) adding the product of step (a) to 6-chloronicotinonitrile or methyl 6-chloronicotinate;
(c) hydrolyzing the product of step (b) to the carboxylic acid; and
(d) amide coupling the product of step (c) with thiomorpholine 1,1-dioxide or a salt there.
5. The compound of claim 3 wherein the deuterium donor is D 2 O or CD 3 OD.
6. A deuterated GABA A5 -NAM compound of claim 1 which has a longer biological half-life when administered to a mammal than a non-deuterated compound of the same structure.