Patent GB-1015214-A (GB)
Title: Cholesterol derivatives and preparation thereof
IPC: C07J41/00
Filed: 1964-02-28
Abstract: The invention comprises steroids of the formula <FORM:1015214/C2/1> and their 5-dehydro derivatives, and acid-addition salts thereof, in which R is chlorine, hydroxyl, C1- 4 alkoxy, or C1- 18 acyloxy; R1 is -CH.(CH3)-(CH2)n1-NR2R3 having 6 to 10 carbon atoms, -CH.(CH3)-(CH2)n2 -OR4 having 6 or 7 carbon atoms. -N.(CH3)-(CH2)2-R5, -N.(CH3)-(CH2)2-O-CH(CH3)2, -O-(CH2)n3-CH(CH3)2, -O-(CH2)n3-NR3R6 having 4 to 7 carbons atoms or -O-(CH2)2-O-CH(CH3)2; R2\t being methyl, ethyl, isopropyl, isobutyl, isopentyl, 1 - methylpropyl, 1 - ethylpropyl, 2 - methylbutyl or 2-ethylbutyl; R3 hydrogen, methyl or ethyl; R4 isopropyl, isobutyl, isopentyl or dimethylaminoethyl; R5 isopropyl, isobutyl, 1-methylpropyl or 1-ethylpropyl; R6 methyl, ethyl or isopropyl; n1 zero, 2 or 3; n2 zero, 1 or 2; and n3 2 or 3; and their preparation by hydrogenation of the corresponding steroids containing a CO or CS group in R1 next to a nitrogen or oxygen atom, or containing a -CH= N- or > C= N-group in R1; or, for compounds containing an isoalkylamino group in R1, by reaction of the corresponding steroids containing an aryl-CH= N-group instead of the desired group with the appropriate isoalkyl halide and hydrolysis of the product, or by alkylation of the corresponding primary steroid amine or by alkylation of the appropriate isoalkylamine with the appropriate steroid, or by hydrolysis or alcoholysis of the corresponding steroid containing an N-isoalkyl-N-acylamino group in R1; or, for compounds containing an ether group in R1, by etherification of the appropriate steroid - 17 -, -20-, -22- or -23-alcohol containing a chlorine atom or a functionally modified hydroxyl group in the 3-position; or, for compounds containing a tertiary amino group in R1, by alkylation of corresponding steroid secondary amines.  In the products of these processes, a functionally modified hydroxyl group in the 3-position may be converted to a free hydroxyl group, and any of these groups may be acylated, replaced by a chlorine atom or alkylated; and D 5-double bonds may be hydrogenated.  A carbonyl group in the 17-side chain of a starting material may be present as an imido-chloride group.  Alkylations referred to above may be reductive alkylation of carbonyl compounds.  Examples are given  20 - Aza - 21,24 - bisnor - cholesterol - propionate is prepared by reacting 5-androsten-3b -ol-17-one 3-propionate with isoamylamine to give 17 - (31 - methyl) - butylimino - 5 - androsten-3b -ol propionate and then reducing this. 3b -Chloro - 20 - aza - 21,24 - bisnor - 5 - cholestene is prepared similarly via 3b -chloro-17-(31-methyl)-butylimino-5-androstene.  17b  - N - Methyl - N - (isopropoxyacetyl) - amino - 5 - androsten - 3b  - ol - 3 - isopropoxy-acetate is prepared from 17b -N-methylamino-5-androsten-3b -ol and isopropoxyacetyl chloride. 20a  - N - isobutyrylamino - allopregnan - 3b  - ol - 3-isobutyrat is prepared similarly.  The above processes are described in more general terms, and also described are the following preparations of starting materials:-17b -steroid alcohols are obtained by reduction of 17-ones. 20a -steroid alcohols are prepared similarly from 20-ones.  22-Steroid-alcohols are prepared from D 22-sterols by ozone decomposition and subsequent reduction, the D 5-double bond advantageously being protected by halogen or hydrogen halide addition.  23-Steroid alcohols are prepared from 22-acids by the Arndt-Eistert procedure, followed by reduction. Reactive esters of the alcohols are prepared therefrom, Walden inversion occuring in the case of hydrohalic acid esters (for sulphur containing esters 17a  - hydroxy - or 20b  - hydroxy - steroids have to be used as starting material and are obtained by hydrolysis of the sulphonic acid esters of their epimers or, for the latter, by reduction of the corresponding 20-keto-steroids). 17b -Methylamino-steroids are obtained by reacting 17-keto-steroids with methylamine and subsequent reduction of the 17-methylimino-steroids, and are subsequently reacted with chloracetamide, alkylated and reduced to N -substituted 17b -methylamino-steroids.  24-Aza-steroids are prepared by reaction of 20-keto-compounds with cyanacetic ester and then hydrogenation of the D 20(22)-double bond, saponification, decarboxylation, reduction to 24-amino-steroids and either alkylation of these or reaction with H2O2 to give amides which are alkylated and reduced.  22-Aza-steroids are prepared by acylation of 20a -amino-pregnanes and reduction of these.  Steroids with the side chains -O-(CH2)2NHCH3, -O-(CH2)2 NH-C2H5, -CH(CH3)-O-(CH2)2NH2, -O-(CH2)2NH2, -O-(CH2)2NHCH(CH3)2 and -O-(CH2)3-NH2 are prepared from 5-andro-sten - 3b  - ol - 17 - one or 5 - pregnen - 3b  - ol -20-one or the corresponding 5,6-saturated compounds in which the 3b -hydroxy group is etherified, by reduction to 17 - or 20-ols, reaction with CO-halogen-carboxylic acid esters, giving a side chain -O-(CH2)nCO2R (n is 1 or 2 and R is a hydrocarbon), conversion to amides -O-(CH2)nCONHR1 (R1 is H, CH3, C2H5 or CH(CH3)2)) and reduction of these. Amides and thioamides are prepared from the corresponding steroid esters and aliphatic amines, or, for the thioamides, by addition of organo-metallic compounds to appropriate isothiocyanic acid esters.  Compounds containing an aryl-CH = N group in R1 are prepared from primary amines and aromatic aldehydes.  Primary amines for alkylation are prepared by reduction of the corresponding steroid oximes, nitriles or monosubstituted amides.  The cholesterol derivatives of the invention, which are stated to be useful for the treatment of hyper-cholesterolaemia, may be made up into pharmaceutical compositions with suitable carriers. Tablets, dragees, and solutions which may contain preservatives, stabilizers, wetting agents or salts to influence the osmotic pressure are referred to.