Patent GB-765871-A (GB)
Title: Manufacture of highly concentrated preparations of steroid anti-hormones suitable for injection
IPC: A61K31/569
Filed: 1953-08-11
Abstract: The preparation of the following steroid antihormone compounds is described in relation to the manufacture of solutions or melts suitable for injection: D 5-17a -ethinylandrostene-3b  : 17-diol - 3 - monobutyrate, monovalerate and monocaproate by reacting the diol dissolved in pyridine with the acid anhydride, introducing into water, extracting the crude ester with ether, washing, evaporating the ether, and recrystallizing from hexane.  D 5 - 17a  - ethinylandrostenediol - (3b  : 17)-enanthrate - (3) by reacting the diol in pyridine (a) for 1 1/2 hours at 125 DEG  C., or (b) for 70 hours at room temperature, with enanthic acid anhydride.  Pyridine is removed by steam distillation, and the ester taken up in ether which is removed by evaporation.  The product of (a) is recrystallized from an ether-pentane mixture; that of (b) is purified by crystallization and chromatography.  17 - esters of 3b - methyl - androstane - 3a : 17a  diol with n-butyric acid, n-valerianic acid, caproic acid and caprylic acid by a method similar to that first described above.  The following further compounds are mentioned: 3a - methyl - 17a  - ethinyl - D 4 - androstenediol-3a  : 17a  - dimethylandrostanediol - (3 : 17), 3b : 17a  - dimethylandrostanediol - (3 : 17), 3b-methylandrostanediol - (3 : 17b ), 3a - methylandrostanediol - (3b : 17b ), 3 - methyl - D 4-androstanediol - (3 : 17), 3#x - ethinylandrostandiol - (3 : 17b ), 3a - methylandrostanediol-(3b : 17a ), 3a - methylandrostanol - (3b) - one-17 and 3b - methylandrostanol - (3a) - one - 17. Specifications 738,576 and 743,445 are referred to.ALSO:The invention comprises a highly concentrated, stable homogeneous injectible preparation of a steroid antihormone compound of the type of 17-strinyl androstendiol as described in Specifications 738,576 [Group IV(b)] or 743,445, [Group IV(b)], containing more than 50 mg. of antihormone substance per cc. and melting at 37 DEG C. or below and being a mixture having a melting point below that of at least one of its constituents and comprising either two or more of the said steroid antihormones or esters thereof, or a steroid antihormone or ester thereof and an inert substance.  It also comprises an injectible preparation, being an oleaginous solution of an ester of a steroid antihormone as specified above with an aliphatic carboxylic acid containing 4-10 carbon atoms, which solution contains more than 50 mg. hormone per cc.  Examples disclose (1) a preparation obtained by melting together the mono caproate-(3), monoenanthrate-(3) and monobutyrate (3) or monovalerate-(3) of 17  - ethyinyl - D 5 - androstendiol - (3b : 17), (2) and (3) melts of 17 -ethenyl - d 5 - androstendiol - (3 : 17) - monobutyrate or monoenanthrate, and phenyl salicylate, (4) and (5) melts of 3a - methyl - 17  - ethinyl - androstendiol, -(3 : 17) and ethyl urethane or phenyl salicylate, (6) a melt of 3 - b - methyl - 17  - ethinyl - androstandiol - (3 : 17) and phenyl salicylate. Other antihormone compounds mentioned are 3a - methyl - 17  - ethinyl - d 4 - androstrindiol - (3 : 17), 3a : 17  - dimethyl -androstandiol - (3 : 17), 3b : 17  - dimethyl - androstandiol - (3 : 17b ) 3b - methyl - androstandiol - (3 : 17b ), 3a - methyl - androstandiol -(3b : 17b ), 3 - methyl - d 4 - androstandiol -(3 :17), 3#z - ethinyl - androstandiol - (3 : 17b ), 3a - methyl - androstandiol - (3b : 17 ), 3a -methyl-androstanol (3b)- one - 17, and 3b - methyl - androstan - ol - 3a - one 17.  Other melting point depressants are N - methyl acetamide and methyl urethane.  Substances regulating absorption are cetyl alcohol, palmitol, and myricyl alcohol.  The preparation of various antihormone substances is described.  (see Group IV).