Neue 22-Amino-5 alpha a-Dinorcholane und Verfahren zu deren Herstellung

摘要

1,217,913. 22 - Amino - 23,24 - bisnorcholane derivatives. SCHERING A.G. 6 Feb., 1968 [7 Feb., 1967; 9 Jan., 1968], No. 5807/68. Heading C2U. Novel steroids of the formula (in which R 1 and R 2 are each H, acyl, aliphatic or cycloaliphatic hydrocarbon, aryl, aralkyl or heterocyclic which may be substituted, or NR 1 R 2 is cyclic and may be substituted or interrupted by a further hetero atom; Z is CH 2 , CH(OH) or CO; and rings A and B are saturated or there is a #1, #2, #3, #4 or #5 double bond or more than one such double bond, the hydrogen atom at the 5-position being in the α-configuration if rings A and B are saturated) and acidaddition and quaternary ammonium salts thereof are prepared by (1) reduction of the corresponding 20-carboxylic acid (22-oic acid) amides, (2) conversion of the corresponding 22-ols to sulphonic acid esters and reaction of these, either directly or via the 22-halo compounds, with the appropriate amines; (3) reduction of the corresponding 22-azido compounds (themselves prepared from the sulphonic acid esters of (2) and lithium azide); (4) reduction of the corresponding 20-cyano compounds; (5) degradative conversion of the corresponding 22-carboxylic acids e.g. via their halides to their azides and degradation of these; (6) N-alkylation or acylation of the free 22-amino compounds; (7) removal of an oxygenated group from the 3-position with formation of at least one nuclear double bond; (8) hydrogenation of a ring A or B unsaturated compound; or (9) salt formation. #3 5# - bisnorcholene - 22 - acid is prepared by saponification of the methyl ester (itself prepared by elimination of water from 5# - bisnorcholan - 3α - ol - 22 - acid methyl ester). This and other 22 - oic acids (20 - carboxylic acids) are converted to amides via acid chlorides by standard procedures. 22 - Hydroxy - #3,5 - bisnorchloladiene is prepared by warming 3,22- dihydroxy - #4 - bisnorcholene (prepared by reduction of the 3-one with LiAlH 4 , the 3-one being prepared by reduction of the 22-al with NaBH 4 ) with acetone and p-toluenesulphonic acid. 22 - (N - Piperidyl) - #4 - bisnorcholene- 3,11# - diol is prepared by reduction of the 3,11 - dione, prepared in turn from the 22 - acid. 5# - Bisnorcholan- 3α-ol- 22 - acid piperidide - 3 - tosylate is prepared by tosylation of the 3α-ol. 20- Cyano - #3 - 5# - pregnene is prepared by heating the 3α-ol tosylate with collidine, the last-named steroid being prepared from 5# - bisnorcholan- 3α - ol - 22 - acid amide and tosyl chloride in pyridine. #3,5 - Bisnorcholadien - 22 - ol is prepared from the #4 - 3 - one and LiAlH 4 . #2 - 5α - Bisnorcholen - 22 - ol is prepared by tosylating 3# - hydroxy - 5α - bisnorcholane acid methyl ester (from the free acid and diazomethane) to give the 3# - tosylate, converting. this to #2 - 5α - bisnorcholen - acid methyl ester and reducing this. 22 - (N - Piperidino) - 5α- bisnoroholan - 3# - ol - tosylate is prepared by converting 5α - bisnorcholan - 3# - ol 22 - acid chloride 3 - acetate to the 22 - acid piperidide, reducing this to a mixture of 22 - (N - piperidino) - 5α - bisnorcholan - 3# - ol - 3 - acetate and the 3#-ol and tosylating the latter. #3-5#- Bisnorcholene - 22 - acid methylamide is prepared from the acid chloride and methylamine; other acid amides are prepared similarly. #3 - 5#- Norcholene - 22 - acid is prepared from norlithocholic acid methyl ester by tosylation, heating in collidine and saponification. #3-5α- Bisnorcholen - 22 - ol is prepared by hydrolysis of its 22-acetate, prepared in turn by heating #4- bisnorcholen - 22 - ol - 3 - one with acetic anhydride after reaction with LiAlH 4 and BF 3 etherate at 0‹ C. 23,24 - Dinor - 5α - cholan - 22- ol is prepared by hydrogenation of the corresponding #3,5-choladiene, itself prepared by LiAlH 4 reduction of 23, 24 - dinor - 4 - cholen- 3-on-22-ol. The steriods of the invention, which are antimicrobial agents, may be made up into pharmaceutical compositions with suitable carriers