Lomevactone Explained

Lomevactone (INN; developmental code name DR-250) is a drug described as a psychostimulant and antidepressant which was synthesized and assayed in the 1980s, but was never marketed.^{[1] [2]}

Stereoisomers

There are eight possible stereoisomers of lomevactone. It is the (3R,4R,6R)-form that has the psychotherapeutic properties.^{[3] [4]}

Synthesis

The conjugate 1,4-alkylation reaction between 4-chlorobenzylideneacetone (1) and phenylacetonitrile (2) gives 3-(4-chlorophenyl)-5-oxo-2-phenylhexanenitrile (3). The selective reduction of the keto group to the alcohol with sodium borohydride gives 3-(4-chlorophenyl)-5-hydroxy-2-phenylhexanenitrile (4). Hydrolysis of the nitrile to an acid gives 3-(4-chlorophenyl)-5-hydroxy-2-phenylhexanoic acid. This is followed by lactone formation completing the synthesis of lomevactone (5).

Notes and References

1. Book: David J. Triggle . Dictionary of pharmacological agents . Chapman & Hall . London . 1997 . 0-412-46630-9 .
2. Poncelet M, Chermat R, Soubrie P, Simon P . The progressive ratio schedule as a model for studying the psychomotor stimulant activity of drugs in the rat . Psychopharmacology . 80 . 2 . 184–9 . 1983 . 6136063 . 10.1007/BF00427967. 2372145 .
3. Axiotis, S.; Druex, J.; Perrin, M.; Royer, J. (1982). "Conformations in the tetrahydropyran-2-one ring". Tetrahedron. 38 (4): 499–504. doi:10.1016/0040-4020(82)80093-8.
4. ((Axiotis, S.)), ((Sollier, J.-C.)), ((Dreux, J.)), ((Chermat, R.)), ((Poncelet, M.)), ((Simon, P.)) . European Journal of Medicinal Chemistry . Tétrahydropyrones-2 III. Recherche d'une activité psychostimulante spécifique . 22 . 4 . 293–303 . July 1987 . 10.1016/0223-5234(87)90266-2.