Patent GB-1410767-A (GB)
Title: Anrostane derivatives
IPC: C07J71/00
Filed: 1971-10-19
Abstract: 1410767 Androsten-17α-ol derivatives GISTBROCADES NV 18 Oct 1972 [19 Oct 1971] 48648/71 Heading C2U The invention comprises compounds of formula wherein the 8,14-bond is saturated, in which case R 1  is H, Me or halo, or unsaturated, in which case R 1  is H or halo; and R 2  is H or the acyl radical of a pharmaceutically acceptable organic carboxylic acid Compounds I (R 1  is H or halo) are prepared by 1,2-methylenation (e.g. using dimethylsulphoxium methylide) of either (a) a compound of formula (wherein R 1 <SP>1</SP> is H or halo) in which case I is obtained directly; or (b) a 14α-hydroxy derivative of a compound III, with 8,14-dehydration of the resulting product to give a #<SP>8(14)</SP>-compound I; or (c) a compound of formula in which case the 14,17-bridge is hydrolysed concurrently to give 1α,2α-methylene-14α,17α- dihydroxyandrosta-4,6-dien-3-one which is converted to a compound I either (i) by 17-acylation and then 8,14-dehydration to give I(#<SP>8(14)</SP>; R 1 =H), or (ii) by 6α,7α-epoxidation, 17-acylation and reaction with hydrogen halide to give a 1α-halomethyl-6-halo-17α-acyloxyandrosta-4,6,8 (14)-trien-3-one which, upon refluxing in symcollidine, gives I (#<SP>8(14)</SP>; R 1 =halo). Compound I (R 1 =Me; R 2 =H) is prepared from the mesylate of its 17#-epimer by heating with an alkali metal acetate in an inert organic medium, e.g. N-methylpyrrolidone. Compounds I (R 2 =H or acyl) are interconvertible by acylation and hydrolysis. Compounds I (R 1 =halo) are prepared from compounds I (R 1 =H; R 2 =acyl) by epoxidation to give a 1α,2α-methylene-6α,7α-epoxy-17α-acyloxyandrost-4-en-3-one which upon reaction with a hydrogen halide yields either (i) a 1α-halomethyl-6-halo-17α-acyloxyandrosta-4,6-dien-3-one which upon refluxing in sym-collidine yields I; or (ii) a 1α,2α-methylene-6#-halo-7α-hydroxy-17α- acyloxyandrost-4-en-3-one which upon 7-mesylation and then refluxing in sym-collidine yields I. Compounds III (wherein R 1 <SP>1</SP>=H) are prepared from 17α-hydroxyandrosta-1,4-dien-3- one by 17-acylation followed by 6,7-dehydrogenation which may be effected either directly using a quinone or indirectly by 6#-halogenation with N.B.S. and 6,7-dehydrohalogenation by refluxing in sym-collidine. Compounds III (wherein R 1 1=halo) are prepared from III (R 1 1=R 2 =H) by 6α,7α-epoxidation followed by 17-acylation and reaction with a hydrogen halide. Compounds III are interconvertible by acylation and de-acylation at the 17-position. Compound IV (R 1 1=H) is prepared from the corresponding #<SP>4</SP>-monoene by 3-enol etherification followed by 1,2; 6,7-dehydrogenation with DDQ. 14α,17α-Phenylborylenedioxy-androst-4-en-3- one is prepared as described in Examples Ia, IXa, and IXb of Specification 1,314,191. 1α,2α - Methylene - 6 - methyl - 17# - mesyloxyandrosta-4,6-dien-3-one (XI) is prepared from androsta-1,4-diene-3,17-dione (X) by the sequence: X#17,17 - ethylenedioxyandrosta - 1,4- dien - 3 - one#6# - bromo - 17,17 - ethylenedioxyandrosta - 1,4 - dien - 3 - one#17,17 - ethylenedioxyandrosta - 1,4,6 - trien - 3 - one#1α,2α- methylene - 17,17 - ethylenedioxyandrosta - 4,6- dien - 3 - one#1α,2α - methylene - 6α,7α - epoxy- 17,17 - ethylenedioxyandrost - 4 - en - 3 - one# 1α,2α - methylene - 3 - methoxyimino - 6α,7α- epoxy - 17,17 - ethylenedioxyandrost - 4 - ene# 1α,2α - methylene - 3 - methoxyimino - 6# - methyl- 7α - hydroxyandrost - 4 - en - 17 - one#1α,2α- methylene - 3 - methoxyimino - 6# - methyl - 7α- mesyloxyandrost - 4 - en - 17 - one#1α,2α- methylene - 3 - methoximino - 6 - methylandrosta- 4,6 - dien - 17 - one#1α,2α - methylene - 6 - methyl androsta - 4,6 - diene - 3,17 - dione (+ the 17- methoxime thereof as - by-product)#1α,2α- methylene - 6 - methyl - 17# - hydroxyandrosta- 4,6-diene-3-one#XI. Oral, parenteral and topical antiandrogenic compositions comprise I and a carrier.