Patent GB-1082640-A (GB)
Title: Improvements in or relating to b-norsteroids
Inventor: FARE LOUIS RICHARD
IPC: C07J61/00
Filed: 1966-03-10
Abstract: The invention comprises (a) compounds of formula <FORM:1082640/C2/1> wherein X is hydrogen, chlorine or bromine and R is 1-cyclopentenyl, 1-cyclohexenyl or 2-tetrahydropyranyl, and their preparation by 17-etherification; (b) compounds of formula <FORM:1082640/C2/2> wherein R1 is hydrogen or methyl, and the D 1,4-analogue where R1 is methyl, and their preparation by (i) treatment of B-nor progesterone with enzymes of Penicillium citrinium, followed by reflux in a base to form B-nor-testolic acid, and cyclizing this with a strong acid, followed if desired by chemical or microbiological 1,2 dehydrogenation; or (ii) decarboxylation of 10-carboxy-19-nortestololactone; (c) compounds of formula <FORM:1082640/C2/3> wherein R2 is hydrogen, methyl or ethyl, R3 is hydrogen, acyl, or, when R2 is hydrogen, 1-cyclopentenyl, 1-cyclohexenyl or 2-tetrahydropyranyl, R4 is hydrogen or, when R2 is methyl or ethyl, chlorine, bromine or hydroxy, R5 is hydrogen or C1- 4 alkyl, and R6 is hydrogen or hydroxy, and the D 9(11) and D 14 analogues thereof when R4, R5 and R6 are hydrogen, with the proviso that one of R4, R5 and R6 must be other than hydrogen, except in a D 9(11) or D 14 analogue, and the preparation (i) of the 2-alkyl compounds by treatment of a 2-unsubstituted compound with ethyl oxalate in the presence of a strong base to give the enol of the 2-ethoxalyl compound, reacting this with an alkyl halide to form a 2-alkyl-2-ethoxalyl compound, and allowing this to stand in an alcoholic alkoxide solution; (ii) of the 11b -hydroxy compounds by microbiological hydroxylation to form an 11a -hydroxy compound, oxidation to an 11-keto compound, reduction to the 3b ,11b -diol and oxidation to the 3-one; (iii) of the 6-substituted compounds by microbiological hydroxylation to a 6-ol, followed if desired by treatment with a tosyl halide; (iv) of the D 9(11) and D 14 compounds by microbiological hydroxylation to an 11a - or 15a -hydroxy compound, conversion of this to its tosylate, and treatment of this with a base; or (v) of the 17-ethers and esters by etherification or acylation; and (d) 17a  - methyl - D 1 - B - nor - testosterone, and its preparation by 1,2 dehydrogenation with a micro-organism of the genus Septomyxa. 10 - Carboxy - B - nor - 19 - testololactone is prepared by treatment of 3b ,19-diacetoxy-androst-5-en-17-one with m-chloroperbenzoic acid to give its 5b ,6b -epoxide, treatment of this with chromic acid to give 3b ,19 - diacetoxy - 5a -hydroxy - androstane - 6,17 - dione, treatment of this with m-chloroperbenzoic acid to give 3b ,19 - diacetoxy - 5,17 - dioxo - 5,6 - secoandrostan-6-oic acid, reaction of this with benzyl chloride in pyridine to give 3b ,19 - diacetoxy-5b -hydroxy - 17 - oxo - B - nor-androstane-6b -carboxylic acid 5,6-lactone, reaction of this with peracetic acid to give 3b ,19-diacetoxy-5b ,13-dihydroxy - B - nor - 13,17 - seco - androstane-6b ,17 - dicarboxylic acid 5,6; 13,17-dilactone, heating this to form the D 5-13,17-monolactone, refluxing this in sodium hydroxide to give 3b , 13a ,19 - trihydroxy - B - nor - 13,17 - secoandrost - 5 - en - 17 - oic acid, treatment with perchloric acid to give the 19-hydroxy-13,17-lactone, Oppenauer oxidation to 19 - hydroxy-B - nor - testololactone and treatment of this with chromic acid.  The compounds of the invention have antiandrogenic and central nervous system depressant activity and may be used in pharmaceutical compositions in combination with a carrier, for example in forms suitable for oral or parenteral administration.