Neurosteroid analogues:: synthesis of 6-aza-allopregnanolone

An efficient synthesis of 6-azapregnane derivatives and their biological activity is described. The nitrogen was introduced into the B ring using Beckmann rearrangement of the (E)-oxime of 6-oxo-B-nor-5alpha-pregnane derivatives. The required 3alpha-hydroxyl was produced either by solvolysis of the corresponding 3beta-mesyloxy group or by the Meerwein-Ponndorf-Verley reduction of the 3-oxo group; this reduction could be carried out selectively with an unprotected 3,20-dioxo derivative. The binding of the 6-aza-steroids to the gamma-aminobutyric acid receptor (GABA(A)) was measured using [S-35]-tert-butyl-bicyclo[2.2.2]phosphorothion ate (TBPS) and [H-3]flunitrazepam. The only analogue to be slightly active was that lacking any oxygen function in position 3. (C) 2005 Elsevier Ltd. All rights reserved.