3,565,778 United States Patent Office Patented Feb. 23, 1971 1. 2 ing with a trialkylstannane an a,6-oxido-steroid-ketone in 3,565,778 PROCESS FOR THE MANUFACTURE OF a Suitable solvent, while being irradiated with ultraviolet g-HYDROXY-STEROID-KETONES light. The invention also comprises new 6-hydroxysteroid Oskar Jeger, Zollikerberg, Zurich, Hans Ueli Wehrli, ketones of the o- or 3-androstane series preparable by Schaffhausen, and Kurt Schaffner, Zurich, Switzerland, the new process, and pharmaceutical preparations con assignors to Ciba Corporation, New York, N.Y., a cor taining them. The new compounds display androgenic or poration of Delaware anti-androgenic activity. No Drawing. Filed July 9, 1968, Ser. No. 743,278 Claims priority, application Switzerland, July 13, 1967, DESCRIPTION OF THE PREFERRED . 10,108/67 EMBODIMENTS Int. CI. B01j I/10 O U.S. Cl. 204-158 12 Claims In the hydroxy-steroid-ketones obtainable with the new process of the invention the ketone group may be in the steroid ring system or in a side chain, and any desired ABSTRACT OF THE DISCLOSURE configuration is possible at the various carbon atoms, o,6-Oxido-steroid-ketones are converted into 3-hydroxy 15 especially also at those to which the hydroxyl group is ketones according to the partial formulae scheme attached. In this context the term steroid-ketones refers to any desired derivative of the cyclopentano-polyhydro -C-C-C-() (8) - - -c-bH-C- phenanthrenes, that is to say not only to the normal (Alk)3SnH. & 20 Steroids but, for example, also to 18- and 19-nor-steroids, O O O CH A-homo-, B-homo-, A-nor-, B-nor-, C-nor- or D-homo when they are treated with tri-n-butylstannane in an or steroids. ganic solvent while irradiating with ultraviolet light. New The steroid starting material used in the new process types of 5-hydroxy-steroid-ketones are inter alia 17-oxy may be any o,6-oxido-steroid-ketone, for example of the genated - 7 - methyl-5-hydroxy-3-oxo-androstanes and 19 25 androstane, pregnane, cholane, cholestane, spirostane, nor-androstanes, especially the 7cy-methyl-derivatives and cardanolide or furoStane series, for instance 4,5-oxido-3- corresponding A-steroids without the 7-methyl group. OXO - Steroids, 1,2-oxido-3-oxo-steroids, 4,5-oxido-6-oxo steroids, 5,6-oxido-7-oxo-steroids, 9,11-oxido-12-oxo-ste roids, 9,10-oxido-1 1-oxo-steroids or 3,4-oxido-2-oxo-ste BACKGROUND OF THE INVENTION 30 roids, which may contain in other free positions of the oxo-steroids, 4,5-oxido-6-oxo-steroids, 5,6-oxido-7-oxo-ste There are already known (3-hydroxy-steroid-ketones of roids, 9, 11 - oxido-12-oxo-steroids, 9,10-oxido-11-oxo-ste the various steroid series with the functional groups in roids or 3,4-oxido-2-oxo-steroids, which may contain in various positions of the cyclopentano-polyhydrophenan other free positions of the steroid skeleton further sub threne or in the side chains, for example, in the pregnane stituents, and in the rings and/or possibly in the side 17g side chain. Thus, inter alia in German specification chains, they may contain double bonds. No. 960,200, A-16-hydroxy-3,20-diones, containing a free The starting materials are known or can be manufac or esterified 21-hydroxyl groups have been described. tured in known manner. For example, ox,6-oxido-steroid These compounds are pharmacologically active and act ketones are preferably manufactured by expoxidation of as Suprarenal hormones. French Pat. 1,463,849 discloses 40 the corresponding unsaturated ketones by treatment with 5-hydroxy-3-oxosteroids of the androstane and pregnane hydrogen peroxied in the presence of sodium hydroxide Series which are suitable for use as starting materials for solution or by means of an organic per-acid, such as the process, claimed in that French specification, for the perphthalic or perbenzoic acid. manufacture of 5,10-secosteroids. 1-hydroxy-3-oxosteroids The treatment according to this invention with a tri of the pregnane series, especially the 10-hydroxy deriva 45 alkylstannane with irradiation is carried out in an inert tive of cortisone which has a much higher anti-inflam solvent that is stable towards the trialkylstannane and matory effect than cortisone, have been mentioned for towards the ultraviolet light used for the irradiation, if instance in Japanese Pat. 22, 142, and 10-hydroxy-deriva desired or required with addition of a sensitizer. tives of the 5ck-androstane series having a good anabolic Preferred solvents are aliphatic, cycloaliphatic or aro androgenic activity in South African Pat. 63/5,165, and 50 matic hydrocarbons, especially benzene. analogous compounds of the 5p3-androstane series, which As sensitizers there may be used those which are gen likewise have a good anabolic-androgenic activity, in erally employed in photoinduced reactions, for example Dutch patent application No. 6,501,292/.65. The known triphenylene. methods for the manufacture of such hydroxy-steroid A suitable source of light for the irradiation accord ketones vary from case to case; thus, the pregnane com 55 ing to this invention is artificial or natural ultraviolet light, pounds described in the aforementioned German patent preferably ultraviolet light as emitted by mercury high are obtained by adding an arylcarbinol on to the 16, 17 pressure burners. The irradiation is preferably performed double bond of 16,17-unsaturated pregnanes and reduc at room temperature. tive splitting of the 16-aryloxy group formed. In the case Preferred trialkylstannanes are tri-lower alkylstannanes, of the above-mentioned French patent 4,5-oxido-3-ketones 60 above all tri-n-butylstannane. are temporarily ketalized and then reduced to 5-hydroxy Some of the process products are known and, as men compounds with a complex light metal hydride. The 1 tioned above, they may be used as intermediates in the hydroxy-3-oxo-androstane compounds of the said South manufacture of pharmacologically active compounds or African patent are likewise obtained by splitting an oxido they possess as such pharmacological properties. 3-ketone, namely the epoxide group of a 1,2-oxido-3- 65 The present invention further includes new 6-hydroxy ketone, but in this case the reduction is carried out with steroid-ketones, in fact 17-oxygenated 7-methyl-5-hydroxy an alkali or alkaline earth metal in liquid ammonia or in 3-oxo-androstanes and 19-nor-androstanes, especially 7 oz an amine. methyl derivatives of this type; also 17-oxygenated A-5- SUMMARY OF THE INVENTION 70 hydroxy-3-oxo-androstenes and 19-nor-androstenes, espe The invention provides a new general method for the cially also their 7-methyl derivatives; and 17-oxygenated marufacture of B-hydroxy-steroids which consists in treat 56-hydroxy-3-oxo-19-nor-androstanes. 3,565,778 3 4. This group of new compounds are thus 17-oxygenated androstenes said above, thus the 17-oxygenated A-10,2a 5-hydroxy-3-oxo-compounds of the 5a- and 56-androstane oxido-3-oxo-androstene and -19-nor-androstene com and 19-nor-androstane series, which compounds are char pounds, for example A-10,2a-oxido-17 3-hydroxy-andro acterized by the presence of at least one of the following sten-3-one and its esters, such as the 17-acetate, and A features: the 1,2-double bond, a 7-methyl group, or the 10,2a-oxido-176-hydroxy-19-nor-androsten-3-one and its (3-configuration at C5 together with the 19-nor-structure. 17-esters, such as the 17(3-acetate. In these compounds the substituent in position 17 is, The invention includes also any variant of the process for example, either an oxo group or a free, etherified or in which an intermediate obtained at any stage is used esterified hydroxyl group together with a hydrogen atom as starting material and any remaining step/steps is/are or with an unsubstituted or substituted, saturated or un carried out, or the process is discontinued at any stage saturated lower aliphatic hydrocarbon residue. O thereof, or in which a starting material is formed under An esterified hydroxyl group is above all one derived the reaction conditions. from an organic carboxylic acid of the aliphatic, alicyclic, The invention includes also the manufacture of pharma aromatic or heterocyclic series, especially one that con ceutical preparations for use in human or veterinary tains 1 to 18 carbon atoms, for example formic, acetic, medicine, which contain the new pharmacologically active propionic acid, a butyric acid, a valeric such as n-valeric substances of the present invention described above as acid, or trimethylacetic, trifluoroacetic acid, a caproic acid active ingredients, in conjunction or admixture with a such as B-trimethylpropionic acid or diethylacetic acid, pharmaceutical excipient. The excipient used may be an Oenanthic, caprylic, pelargonic, capric acid and unde organic or inorganic substance suitable for enteral, for cyclic acid, for example, undecylenic acid, lauric, myristic, 20 example oral, parenteral or local administration. Suitable palmitic or stearic acids, for example oleic acid, cyclo excipients are substances that do not react with the new propane-, cyclopentane-, and cyclohexane-carboxylic acid, compounds, for example water, gelatin, lactose, starches, cyclopropylmethanecarboxylic, cyclobutylmethanecarbox magnesium stearate, talcum, vegetable oils, benzyl alco ylic, cyclopentylethanecarboxylic, cyclohexylethanecar hols, gums, polyalkyleneglycols, white petroleum jelly, boxylic acid, cyclopentyl- cyclohexyl- or phenyl-acetic or cholesterol or other known medicinal excipients. The -propionic acids, benzoic, phenoxyalkanoic acids such as pharmaceutical preparations may be in solid form, for ex phenoxyacetic acid, dicarboxylic acids such as succinic ample tablets, dragees or capsules, or in liquid or semi acid, phthalic, quinolic acid, furan-2-carboxylic, 5-tertiary liquid form solutions, suspensions, emulsions, ointments butyl-furan-2-carboxylic, 5-bromofuran-2-carboxylic acid, or creams.