GB1384372A — Dereivatives of 17alpha-hydroxyandrost-4-ene-17beta-carboxylic acids

USPTO Abstract

1384372 Derivatives of 17α-hydroxy-androst- 4 - ene - 17# - carboxylic acid GLAXO LABORATORIES Ltd 20 Jan 1972 [20 Jan 1971] 2787/71 Heading C2U [Also in Division A5] Novel steroids of the formulµ wherein (a) X is H, Cl or F; R 1 is #-OH or, when X is Cl, R 1 may also be #-Cl; R 2 is H, =CH 2 or α- or #-CH 3 ; R 3 is H, C 1-3 alkyl or phenyl; R 4 is C 1-4 alkyl optionally substituted by either at least one halogen or by C 2-5 alkoxycarbonyl, or is (C 2-5 alkanoyloxy)-(C 2-4 alkyl) and the #<SP>1</SP>- double bond is optional; or (b) X is Cl or F; R 1 is = O ; R 3 is CH 3 or C 2 H 5 ; and R 2 , R 4 and the #<SP>1</SP>-double bond are as defined above, but excluding the n- and iso-propyl and n-butyl esters of 17α - formyloxy - 11# - hydroxy - 3 - ketoandrost - 4 - ene - 17# - carboxylic acid and also excluding the C 1-4 alkyl esters of 11#,17α- dihydroxy - 3 - keto - androst - 4 - ene - 17#- carboxylic acid, and the novel anhydrides (including mixed anhydrides) of the free 17#- carboxylic acids, and the novel 2<SP>1</SP>-hydroxyethyl 9α - fluoro - 11# - hydroxy - 16# - methyl - 3- oxo - 17α - propionyloxy - androsta - 1,4 - diene- 17#-carboxylate, are prepared from the corresponding 17α - hydroxy - 17# - carboxy - steroids by standard esterification and acylation procedures. Resulting 11#-ols may be oxidized to 11-ones and 17-acylates may be hydrolysed to 17α-ols and subsequently re-esterified. Acylation of the free 17α-OH-17#-CO 2 H compounds with carboxylic acid anhydrides results in the formation of 17α-esters of the mixed anhydrides which are then subjected to solvolysis to give the free 17#-CO 2 H compounds. Substituents in the alkyl group R 4 may be interconverted by standard procedures or formed from other substituents, e.g. a hydroxyalkyl ester may be prepared, then converted via a sulphonyloxy ester to a halo-alkyl ester or, alternatively, O- acylated. Products wherein R 4 contains an α-halogen atom may be obtained by reacting the 17#- CO 2 H compound with an aldehyde and a hydrohalic acid. #<SP>1,4</SP>-products may be partially reduced to #<SP>4</SP>-products. 17α - Hydroxy - 17# - carboxy - steroid starting materials are prepared by oxidation of pregnanes containing a 17#-COCH 2 OH side chain. This reaction may also be effected on 17α-acyloxy starting materials, giving 17α-acyloxy products. The novel 17α-acyloxy-17#-(esterified carboxy)-steroids of the above formula are antiinflammatory agents and may be incorporated in pharmaceutical compositions (see Heading A5B).