17 BETA-HYDROXY-4-ANDROSTEN-3-ONES AND PROCEDURE FOR THEIR PREPARATION.

Description

INTERNATIONAL PATENT TECHNICAL OFFICE 1NG. ALESSANDRO ZINI 'DESCRIPTION of the industrial invention entitled: "17 / 8-IJM)3SI-4-ANDROSTEN-3-ONI AND PROCEDURE FOR THEIR PREPARATION" of SCHERING AKTIENGESELLSCHAPT, of German nationality, with headquarters in Berlin and Bergkamen (Germany) Deposited on . A -Α-β 28 39 2 A / 78 eposx 1 g MA& 19?8 ^ DESCRIPTION TEXT The invention relates to new 17 / 3-hydroxy-4-an-drosten-3“Ones of the general formula I CD· '.&2 stands for hydrogen or an organic acid radical,i * R^ for methyl or ethyl, Ra for hydrogen q methyl, ί T for <? CO-R, non R^ nel significato di un radicale alchilico in-! feriore, e ? per*—c As organic acid radicals R^, all those deriving from biologically compatible acids should be taken into consideration. INTERNAL TECHNICAL OFFICE?IMG. ALESSAM L>RC OH ME PATENTS,) ZINI In particular, those that derive from the I am from alkanoyl acids with 1-18 C atoms, better 2-8 C atoms, for example mono-alkanoyl acids Basic acids, such as formic, acetic, propionic, butyric, isobutyric, 4-ethylbutyric, 4-valorionic, isovaleric, 4-ethylvaleric, trimethylacetic, 2-methylbutyric, 3-ethylbutyric, 4-pronic, triethylacetic, enanthic or capric acids, or cyclic acids, preferably cycloaliphatic acids, such as cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, 3-cyclopentylpropionic, cyclohexylcarboxylic I co, or cyclohexylacetic, or also arylic or araikyl carbocyclic acids, such as benzoic, 2-, 3- or 4-methylbenzoic acids. j Since the chemical character of the acid radical; ! I ^2 »0^ is decisive for the characteristics of the compounds according to the invention, provided that the acid radical has no toxic effect and that the corresponding acid forms an ester with the primary hydroxyl group, other aliphatic and aromatic carboxylic acids, unsubstituted and substituted, mono-, di- and polybasic, saturated and unsaturated, aliphatic, araliphatic and aromatic carboxylic acids with a number of atoms from 0 to 18, are also suitable, · ... · · ·• * · · · · · · · · · · · * · ,· ... * ····♦ · ·· · . * ··· • · ... better up to δ. Examples include undecylic, dodecane, tetradecane, hexadecane, octadecane, paimitic, stearic and β-cycloasylpropionic acids, 2,3-, 2,4-, 2,6-, 3,4- and 3,5-dimethylbenzoic acids, ethylbenzoic acid, naphthoic acid, 3-methyl-pi-naphthoic acid, β-phenylpropionic acid, diphenylbenzoic acid, and β-phenylpropionic acid. acetic acid and β-naphthylacetic acid, or the dibasic alkanoyl acids, such as oxalic, maleic, fumaric, succinic, malic, glutaric, β-methylglutaric, β-methylglutaric, β-dimethylglutaric, β-oedipic, pimelic and sebacic, or the dibasic aromatic acids, such as those which can form internal anhydrides, such as phthalic acid, the carbamic acids, such as carbamic, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic and alkylcarbanic acids, or the heterocyclic acids, such as β-furylcarboxylic, pyrrolecarboxylic, β-pyrrolidinopropioncarboxylic, N-methylpyrrolidino-2-carboxylic acids, 't'boxyl and pyrrol-2-carboxylic. 1 i ì The acid radicals according to the invention can also be substituted with one or more substituents. , ! ; For example, the following radicals are cited as substituents: hydroxy, halo, alkoxy, acyloxy, sulfonyloxy, amido, sulfate, nitro, meroapto and eia. F PATENTS ZINI no, such as for example the radicals of glycolic, lactic, citric, tartaric, maleic, glyceric, inharmonic, gluconic and salicylic acids, or the radicals of amino acids, such as glycine, aminopropionic acid, diglycolamino acid and triglycolamino acid, methylglycine, dimethylglycine, ethylglycine, p-aminosalicylic acid, p-aminobenzoic acid, ethylmercaptoacetic acid, benzylmercaptoacetic acid, chloroacetic acid, fluoroacetic acid, trichloroacetic acid, trifluoroacetic acid, thioglycolic acid, m-nitrobenzoic acid, 2,3,4-trimethoxybenzoic acid, phenoxyacetic acid and naphthyloxyacetic acid. In particular, the a- are especially suitable. THE Saturated and unsaturated dibasic carboxylic acids. The salts are derived from the corresponding hemiacylates of these dibasic acids. The alkali metals sodium and potassium, as well as ammonium, are the most commonly considered cations. However, divalent alkaline earth metals such as calcium are also suitable, since two equivalents of hemiacylate are then present for a large amount of calcium. Lower alkyl radicals are those having up to 5 carbon atoms, such as methyl, ethyl, propyl, n-butyl, i-butyl, jt-butyl and n-pentyl. The compounds obtainable according to the invention have valuable pharmacological properties. -5- offncio tγ·iγ'Ί !ίA. ENG. ALLISSARÚ -· c. "· γ':'·ττιO ZINI The compounds according to the invention are, among other things, diuretics of the type of alpha-d-sterone antagonists, i.e. they reverse the effect of deoxy-4 i 5 corticosterone on the separation of sodium and potassium. The compounds according to the invention show, in the Hollmann test model (G. Hollmann et al.f Effects on the tubules and renal elimination of spirolactones, | THE Maunyn-dchmiedebergs Arch. Bip. Path* Pharmak. 247 | (1964) 419 f P» Marx, Renal effects of d-aldosterone | and of its antagonist spirolactone, Pisa· Med. Pale· 'j ! PU Berlin 1966) extraordinarily superior in their effect to the known potassium canreonate. { The invention also relates to a process for the preparation of compounds of the general formula J. I ! | ì |3 which is characterized in that, in a manner per se known, 3-keto*-4j6-androstadiene-*spiragatones of the general formula 11 are treated (II), where fCD-, and have the meaning indicated in formula I, with lithium aluminum hydride in a protic solvent, first providing the keto group in 3 *· ··« t ··.* ,·· e ♦# · · ..... • · · ·• · * e » · t ··« « «MM « . · e · « · · * ♦ · ··*'♦ ··. • * * ,··· *** ··.*„ · · . · · · . . · * · · » « #· ♦·· · · · * » · · · •»i·· . f> m * Φ • · * * 9 . * 9 ·#*· -6- TECHNICAL OFFICE IN7rRNtfn!'!fE RREVETTfING. ALESSANDRO) ZINI with a protective group, ea) in the case where -AB- stands for the group The reaction -GH^-GH—S-GO-tì^ is made to react, in a manner known per se, with a thioalkanic acid in a protic organic solvent or in a mixture of solvents, possibly in the presence of a dissolution intermediate; ! ì lution, or j ì ib) in the case in which -AB- stands for the group. ment -OH CH- , is methylated in a manner of per i 0J »2 It is known with dimethylsulfoxonium methylide in dimethylsulfoxide as solvent, and in the case where it is an acid radical, it is esterified in a manner known per se, adding an esterification catalyst, possibly the ester obtained is partially saponified and, in the required amount, it is esterified with the required acid and possibly converted into the salt. A particular embodiment of the process according to the invention for the case in which the radical of a dibasic acid is represented consists in the fact that the hemiacylate is converted into the ammonium salt, ì*1 i The alkali metal or alkaline earth metal · :To prepare the compounds according to the invention of & · * ' »*φι· ·**· • ··· · ·: · ··· · * * ·· · • · · · » • · ·♦ » ·*··» · · ....... • * * · · .··· .*· • ι · • · » ·* » » ***·<• · » · 4 * · · ♦ · *··*• · · · general formula 1 in which the group -AB- stands for -7- 'r ';l '"V Ιΐνϋ- · / If there is a double bond, it is advisable to intermediately equip the spirolactone of general formula 11 with a protecting group in position 3. Ketalization with ethylene glycol is suitable. 4 6 For this purpose, the γ-3-ketosteroid of formula II is dissolved in a suitable solvent, such as methylene glycol, and the ethylene glycol and the triethyl ester of o-formic acid are reacted in the presence of a catalyst, such as p-toluenesulfonic acid, suitably by heating slightly to 1 g above room temperature. The γ-3-ethyl enedioxysteroid thus obtained is dissolved in an inert solvent, such as tetrahydrofuran or dioxane, and is treated, suitably under cooling, with lithium aluminum hydride, the temperature not exceeding 1 g. The Veneto region rises above the ambient value. In the acid treatment the protecting group is again detached. To prepare the compounds according to the invention of general formula 1 which contain the -S-CO-fi^ group in the 7-position with the meaning indicated above, the 17 / 3-hydroxy-| A**-steroid of general formula I is dissolved in a protic solvent or in a mixture of solvents, a thioalkanic acid of the general formula HS-CQRlf is added. n INGf· Ji· • HI ί,ϋ,'ιΐΐ where R1 has the meaning given above, and the reaction mixture is heated to temperatures from above ambient to the boiling point of the solvent. Suitable solvents or mixtures of them are: me Tanol, acetone and tetrahydrofuran. Solution intermediates such as asopropyl ethers, benzene and heptane, which may be used, do not disturb the reaction process. To prepare compounds according to the invention of the general formula X which have a methylene group in the 6,7 position, the The steroid of general formula I, conveniently dimethylsulfoxonium methylide. For this purpose, the steroid is slowly dissolved under a protective gas atmosphere such as nitrogen or argon, or in a suspension of trimethylsulfoxonium iodide with sodium hydroxide in a mineral oil dimethylsulfoxide, or in a solution of trimethylsulfoxonium iodide and sodium hydroxide in dimethylsulfoxide. The reaction, carried out at 20-40°C, is completed after 10-30 hours. The reaction product is extracted and the 6-(0,0,0)-methylene compound is separated from the 6-(0,0,7,0,0)-methylene compound formed simultaneously. The esterification of the primary hydroxyl group in the side chain in Dosage 17 occurs on *S ·· ·♦ • · *· * · *·* ..... .··· .· · *··*• · · + ♦ • · • · · · · **··* ··*♦*· · ······ · ♦ * !· · ♦ * * . .· · · · · • * . · · ·.*· · .· • .... .. * . « · * # «4 • ·*·< ··*· # · · • · · · » -9- Uifrio μο ' f· ; L 1NG. ALEÌsSAf'U^i-'-p according to methods known per se. A suitable method is, for example, the reaction with an anhydride or an acid halide in the presence of a tertiary amine, such as pyridine, collidine, triethylamine, or 4-dimethylaminopyridine, at room temperature or above. The hydroxyl group can also be extended with the anhydride of the acid using a strong acid such as p-toluenesulfonic acid or with the corresponding acid and trifluoroacetic anhydride or using a heavy metal salt of the corresponding acid, such as lead acetate, in the presence of the corresponding anhydride of the acid as the anhydride of acetic acid. Saponification is best carried out under mild conditions, such as with methanolic potassium hydroxide under cold conditions. However, it is also possible, in addition to introducing the 7-acylthiogroup, to simultaneously esterify the primary hydroxyl group. To this end, conduct the reaction under heat with the required thioacid without using another solvent. In the case where the primary hydroxyl group is esterified with a dibasic acid, the conversion of the hemi-oylate to the required alkaline salt can be achieved by reaction, for example, with a methanolic solution of sodium or potassium methylate. For the preparation of the ammonium salt, a solution of ammonia in methanol is conveniently used. The reaction products according to the invention are separated by methods known per se, such as precipitation, filtration or extraction, and are purified, for example, by chromatography and / or recrystallization. The starting material» 3-oxo-4,6,15-androstadien- )-spiro-5[]-ptyrihydrofuran-2*-one can be prepared as follows: Mix 20.0 g of 3-β-hydroxy-S,leandrostadien-17-one in 280 ml of absolute tetrahydrofuran. *S with 4»34 g of freshly extruded lithium. Then, cooling with ice, 36 “l of 1-bromo-3-dimethoxypropane are added dropwise over a period of 30 minutes. After an hour and a half of stirring at the temperature of the ice bath, the unreacted lithium is filtered off and the filtrate, still in the solution, is poured into ice water. The precipitate is filtered off, washed with water and dissolved in dimethylene chloride. i After dehumidification and evaporation, chromatograph the residue on silica gel. Yes they obtain 19.9 g of 17&-iS'-dimethopsipropylì-SylS-androstadien- ·· · · • · » · · .·.*.·.. ···· **·;· #«··• · · · · • « » · · · ·Μ·«ι «·♦*·* · ···*· * · · J · · M » ♦*··* ·*. * !* ....... •ί.ί, · · , » . ·. .·*··• · . · *··«* · ·· • ... * ***** ·.··• · · · ·. · *. · · -11- TECHNICAL OFFICE 10 ENG. ALESSANDRO N ÌIPEVtTTIZINI 3 (¾ ^17 -diol as oil* 19.9 g of the said compound is mixed in 500 ml of acetone and cooled over ice with 1.0 g of p-toluenesulfonic acid and stirred for 15 minutes while cooling. It is then poured, stirring, into ice-cold water containing sodium bicarbonate, the precipitate is filtered, washed and taken up in methylene chloride. After dehumidification and evaporation, 19.2 g of 2*^-methyl ether of 3fl-hydroxy-5,15-androstadiene-[17((3-1 1)]-spiro-] perhydrofuran is obtained as a crude oil. ! _ II Mix 19.2 g of the said product in 391 ml of absolute toluene and 39.4 ml of cyclohexanone, with 13.94 g of aluminum isopropanol in 40 ml of absolute toluene and heat for 45 minutes with slow distillation. Then dilute with methylene chloride, THE The solution is washed with diluted H2SO4 and water, dried and evaporated. The residue is chromatographed on silica gel. 17.5 g of 2-methyl ether of 3-oxo-4-(5-11)-androstadien-(5-11)-spiro-5-perhydrofuran are obtained as an oil. UV: 239 ~ 16200 Mix 17.5 g of the said product in 350 I i ml of acetone, cooling on ice, with 35 ml / Iij ! chromosulfuric acid (obtained from 267 g of CrO^ > 400 .··· I · • t····* · · t'1 t«·** ·*·* • vttVtM • · ♦ * * • ·*#·• · · * » • ·* · ·«·«· 49 ψ4 4 ·, • 7 · + ·»· • · 4 * 4.. * • ·M«V|···** .*·· • ♦ • · ·4*44 t tt * ·** *• · · • · OFFICE ΤΕ0Ν·'·Ο ι^:^Γ;ν' / :IlSiC?· V ^ιΛ. 't -12- uj ά,Λ,ί ml of water and 230 ml of concentrated sulfuric acid made up to a volume of 1 liter with water) and stirred continuously for 30 minutes, cooling in an ice bath. Then it is poured into water and ice, the residue is filtered, washed with water and dissolved in dimethylene chloride. After drying and evaporation, the residue is chromatographed on silica gel. 11.8 g of 3-OXO-4 (S-androstadien-Jl7((0-1 ' )-spiro-5 'Jperhydrofuran-2-one) are obtained. A sample recrystallized from isopropyl ether (acetone melts at 189.5-191.5°C m 6 240 - 17300 Mix 10.0 g of the said product in 100 ml of absolute dioxane with 10 ml of orthoformic acid triethyl ester and 10 ml of dioxane / H2SO4 with concentrated z4 (obtained from 13.5 ml of absolute dioxane and 0.48 ml of concentrated H2SO4). Stir continuously for 30 minutes at room temperature, mix with 2 ml of pyridine and dilute with ether. Wash the ether phase with water, dehumidify and evaporate. The residue is ground with methanol containing pyridine and the precipitated crystals are filtered off with a pump. 8.9 g of 3-ethoxy-3,5 * 15-androstatrien-j~17 j( ^ - 1 ' )-spiro-5 J -perhydrofuran-2 T-one of PF 15 3,5- are obtained. I : *-240 19800 OFFICE 'ϊ'1'0 ! ! 1NG- J -13- Dissolve 8.9 g of the said product in 2(Jl ! ml of acetone, cool in an ice bath, and ! Mix with 1.38 ml of pyridine, 6.36 g of sodium acetate, and 63.6 ml of water. Then add 5.72 g of N-bromosuccinimide and add 6.36 ml of acetic acid dropwise for 15 minutes. Continue stirring. The mixture is left to cool for 45 minutes on ice, diluted with ether and washed with water to neutrality. After dehydration and evaporation, 10.35 g of 6-β-bromo-3-oxo-4, 15-androstadien-β-17 ((β-11)-spiro-5'Ί-perhydrofuran-21-one is obtained as an oil. I UV : £ = 12700 ì 245 jt 10.35 g of the above product were stirred for 18 hours at 100°C in 103.5 ml of dimethylformamide, with 4.6 g of lithium carbonate and 6.5 g of dilithium bromide. Then the mixture was poured into ice-cold water, the precipitate was filtered, washed with water, and dissolved in methylene chloride. After dehydration and evaporation, the residue was chromatographed. After recrystallization from diisopropyl ether / acetone, 6.5 g of 3-oxo-4,6,15-androstafrien-17-(13-14) ί pyro-50-perhydrofuran-21-one were obtained. PF, 182.5-184.5°C. UV: £ 284 = 27100 The starting material, 15 o( , 16 Ck -methylen- 3-4,6-androstadien jl7( fì> -1' )-spiro-5 'J -perhydrofuran ····• · * * ♦ - * v • · • * · · « •·*·* · ♦ *··· · · · · · · J · · * · · · · ···· ·♦ • . · ...... ·!.· · · ....... • · · » *• · .• · ··,··*·· · *' • · « « · ..... ..·· . . · · · oxo 1 • · ί OFFICE You will be :.· - IMG· ALLlSsAi -14- ' . ·. ΪΠ zirii 21-one can be prepared as follows j Mix 15 g of 3^ -hydroxy-15 ,16^ -methyl· [len-5-androsten-17-one (produced, for example, seconi "I give you German patent application 2,109,555), in 150 ml of absolute tetrahydrofuran, cooling on ice with 3.6 g of lithium and then adding dropwise, during 30 minutes, 30 ml of l-orpro-3-dimethoxypropan| 1 no. After 2.5 hours of stirring at the temperature of the ice bath, the unreacted lithium separates; I and pour the filtrate into ice-cold water while stirring! ! ;The separated precipitate is filtered, washed with water and dissolved in methylene chloride. After dehumidification! After evaporation and chromatography, the residue is chromatographed on silica gel. 16.8 g of 17Λ-(3-1-ddymethoxypropyl)-15λ, 1ό<λ-methylen-5-androsten-3 is obtained. A sample recrystallized from diisopropyl ether / acetone melts at 153-159°C. 16.5 g of the above product is stirred for 18 hours at room temperature in 410 ml of 705S acetic acid. It is poured into ice-cold water while stirring, the separated precipitate is filtered, and the solution is dissolved in chloro-! Iform and wash with sodium bicarbonate solution!, and water. After dehydration and evaporation, the residue is photographed on silica gel. 11.5 g of 3 [b-hydroxy-15 d ; lóo( -methylene-S-androsten-; are obtained; ·· · * • · *·* ··· I · ··· ··.♦♦ ···· ···· * •z * · # · · ···♦ · 4 4 •••Il * II ........ • · Hit ··♦♦ ·· ···. • ·* · · · • · * · · ···*· · ,· • · · * · ··*♦* • · * · ♦ · • · · · · · · · · · · · ···. UFi;ì!X! . _ IN ϋ· -15- iy_( _ 1 τ ) -spiro-5 -perhydrofuran-2 -ol. A dog pion recrystallized from diisopropyl ether / acetQ Ί melts at 194-202°C. i Mix 10.5 g of the said product in 210 ml of absolute toluene with 21 ml of cyclohexanone 22, 1 g of aluminium isopropylate in 20 ml of toluene as solute and heat for 45 minutes with slow distillation; I ! tion, It is then diluted with methylene chloride, washed with H SO 2n and water, dried and steamed. 11.5 g of crude 15 (À >10Λ -methylen-3-oxo-4-androsten-£17( (ì -1 ' )-spiro-5 J -perhydrofuran- 2^-ol are obtained, as an oil. A purified sample me j THE I during preparative layer chromatography and recrystallization from diisopropyl ether / acetone melts at 259-268°C. * j UV : = 16500 I 241 i < 10.5 g of the said product in 100 ml of acetone are mixed, cooling on ice with -19 ml of chromosulfuric acid (produced from 267 g of CrO, ! ó 400 ml of water and 230 ml of concentrated H^SO^, all then brought to the boil with water), and are stirred continuously for one hour. Then, stirring, it is poured into ice-cold water, washed with water and taken up in methylene chloride. After dehumidification and evaporation, ► * · · ***** · • · · · · • · » · * · *• · · · · · #»» · ·• · * · · # ·; · *···..... ··. **·*: * *; · · ·. .···*·• · · · ····· .· ♦ » · · · ..... ...· ·· · · · *• · * · · * the residue is chromatographed on silica gel. It is ob- ut.'.·- -16- Contains 8.2 g of 15 o{ , 16 <* -methylene-3-oxo-4-androsten~ fl7( fi-1 ' )-spiro-5-perhydrofuran-2'-one. A sample crystallized from diisopropyl ether / acetone melted at 180-181°C. :UV : E „ . . - 166001 240 Mix 7.2 g of the above product in 72 ml of absolute dioxane and 7.2 ml of orthoformic acid triethyl ester with a solution of 7.2 ml of absolute dioxane and 0.26 ml of concentrated H2SO4 and stir for 30 minutes at room temperature. Then add 2 ml of picidine, dilute with ether, rinse with water and dehumidify. After evaporation, 8.5 g of crude 3-ethoxy-15-ol,16-d-methylene-3,5-androstadien-]Ì7(iì>-1')-spiro--5-perhydrofuran-2'-onp are obtained. * juv : & 241 = 15700 The 8.5 g of the above product are dissolved in 192 ml of acetone, cooled in the ice bath, mixed with 1.32 ml of pyridine, 6.08 g of Γ I acetate and 60.8 ml of water, then 4.51 g of Γ I f 1 l· ίί-bromosuccinimide are added and, during 10 minutes, the solution is introduced. I add 6.08 ml of acetic acid drop by drop. Stir continuously for one hour at the temperature of the ghee bath. II ! 1 ply, dilute with ether, wash with water and purify. After evaporation, 9.6 g of όβ~ are obtained. I bromo-3-oxo-4 -, androste.n.-£l7-( fi -11 )-spiro-5 'J -peri ·· · · 1#·#« ··♦ #···•Γ · * · · · Φ * MI· • * · · ·• ♦ · * ♦ « * IMM IMI · • I #• · • M MM·· » • E ♦ I ·• I · IMI • · I · • 1 · IMI • The I ····II ·IMI drofuran—2 1 "One^TSZZO, I 9.6 g of the said product in 96 ml of dimethylformamide are stirred with 3.75 g of lithium carbonate and 4.4 g of lithium bromide at 100°C for 18 hours. | ri Then it is poured, stirring in ice water, the separated precipitate is filtered, it is taken up in methylene chloride, it is washed with H2SO2 and with water and it is dehumidified. After evaporation, the residue is chromatographed. I on silica gel. 6.5 g of 15 oi , 16 ck -methylen-3-oxo-4 y6^androstadien-Jl7( (¾ -1' )-spiro-5 Q -perhydrofuran-21-one are obtained. A sample recrystallized from diisopropyl ether melts at 180.5 - 182.5°C. UV: ί .5* — 26300 ! 283 | ^ The starting material 15 β > 16|ì -methylen-3-οχο-4,6-androstadien- £ 17-( (ì -11 ) -spiro-5 J -perhydrofurap- t 21-one can be obtained as follows: ! 15 g of 3 jò-hydroxy-15 [ì , 16 β -methylen-5-androstadien- , I 17-one produced, for example according to the German patent; desco 1.95 3.500) in 150 ml of absolute tetrahydrofuran! The reaction mixture is made with 3.27 g of lithium and 29 ml of 1-bromo-3-dimethoxypropane for 2 hours at ice bath temperature and for 4 hours at room temperature. The unreacted lithium is filtered off, the filtrate is poured into ice water while stirring, the precipitate is filtered off and taken up in methylene chloride. After dehumidification and evaporation, the residue is chromatographed on silica gel. 17.4 g of 17 Οί-(3-dimethoxypropyl)-15-16-methylene-5-androsten73 (1, 17 β-diol) are obtained. 17.0 g of the said product in 340 ml of 70% acetic acid is stirred for 18 hours at room temperature. environment. Pour into ice water while stirring, filter the separated precipitate, and dissolve in methylene chloride. The methylene chloride phase is dissolved in sodium bicarbonate solution and dehumidified water, then evaporated.13.8 g of dihydroxy-15[i , 10(¾ -methylene-5-androsten- J 17( β “11 ) -spiro-5J-prehydrofuran-2j^ -ol are obtained as crude oil product. 8.8 ml of said product in 176 ml of absolute toluene and 17.6 ml of cyclohexanone are mixed with 1.76 g of aluminum isopropylate in 50 ml of as-absolute toluene and heated for 3 hours with slow distillation. It is then diluted with ether, washed with 2n, and with water, dehumidified and evaporated. The residue is chromatographed on silica gel. 4.3 g of 15 fi t 16 (i-methylene-3-oxo-4“androsten- j[17( (3-11)-spiro-51^) are obtained -perhydrofuran-2'-one. A sample recrystallized from diisopropyl ether / acetone melts at 178.j5- :: rr-FU-TTIAl « · * · · '.·*· / !. ··* .·*j* ···<• * · · » • · • · · * ***** · ·; · ··· ..... *·. • * .··· .·' ··*. : * · » ·***** * • · · * É• · *· · 179.5°C. -19- υ?:τ! ' : '! ΐΐΤΙL . 'il UV :L241 = 16500 4.2 g of the said product in 84 ml of tertiary butane are heated under reflux for 18 hours with 4.g of chloranil.The solvent is distilled under vacuum and the residue is chromatographed on silica gel. For further purification, preparative layer chromatography is used. 1.1 g of 15(3,16methylene-3-oxo-4 / 6-androstadien-^17-((3 ~1 ' )-spiro-5^-perhydrofuran-21-one) is obtained as an oil. m -, t2S4 - 25700. If 17&-hydroxy-17 ot-(3-hydoxypropyl 1)-15 j 16 -methylen-4,6-androstadien-3^one is used as starting material, it can be obtained as follows: 11.0 g of 3 |3-hydroxy-15 0( , 16-methylen-5-androsten-17-one (produced according to German patent 2,109,555) are mixed in 300 ml of absolute tetrahydrofuran, mixed with 4.8 g of lithium and 60 ml of 1-bromo-3-(tetrahydropyran-2-yloxy)-propane and heated under reflux for 2.5 hours. After cooling, the unreacted lithium is separated and precipitated in cold water. The precipitate is poured off, dissolved in methylene chloride, the organic phase is washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel. • * • · · · ·• » · « · · • · · · · · · 5 ♦ · · · « ·♦··· ··. • I*.··· ♦· ···*·: :. :. / ····• · · · ···.· · ·* • · · ··•·#·· ·#·* • · * * · ·« · * · · · • · · · < -20- ur,1 ìli '-< '.ΠΙ 3i obtain 16.8 g of 15 <& , 16 oi -methylene-170 / - j^3-( tetrahydropyran^^yloxyj-propylj -5-androsten-3 / 3 ;17- diol.A sample recrystallized from diisopropyl ether melts at 147.5-149.5°C. 15.8 g of the above product in 316 ml of toluene and 31.6 ml of cyclohexanone are heated to boiling and mixed with a solution of 3.16 g of isoprene (( ... * · * » ··*· • · ♦· ·· ·♦* 9···! .·«· * φ· » ···· *··· * • · • · · · · • ♦ · Φ · I ♦ · · · · « · ;· »♦# » · ... 450 mg of 17 β -hydroxy-17 α-(3-hydroxypropyl)-45θ< , 1 S oi-ethylene”4-androsten-3-one of PF 187.5-188.5°C. PV , £ 242 = 16200 are obtained 10.0 g of 17-hydroxy-15,16-methylen-17-3-(tetrahydropyran-2-yloxy-)-propyl-4-androsten-3-one are heated under reflux for 18 hours in 100 ml of tertiary buffalo tol with 10.0 g of chloranil. The precipitate that separates (hydroquinone and unreacted chloranil) is filtered, the filtrate is diluted with ether, washed with sodium bicarbonate and water, dehumidified and evaporated. 10 g of 17-3-hydroxy-15,16-methylen-17-3-(tetrahydropyran-2-yloxy-)-propyl-4-,6-androsten-3-one are obtained. raw. ,JV : & 285 = 18500 The 10.0 g of the crude product above, 5.0 g of oxalic acid, 00 ml of methanol and 40 ml of water are heated under reflux for 1 hour. Then pour in the solution. I -22- by immersing it in ice water, the precipitate is filtered, dissolved in methylene chloride, the organic phase is washed with water, dehumidified, and evaporated under vacuum. The residue is chromatographed on silica gel to obtain 7.5 g of 17-β-hydraxy-17. <?l-( 3-idrossi-propil)-l5 (A} lód -metileu-4, 6-androstadien-3’-one. Uncampione ricristallizzato da etere diisopropilico / a-cetone fonde a l80,5~l81,5°C· UV : £ 2g5 = 26900 I composti della formula generale I conformi all'invenzione, farmacologicamente attivi possono, se¬condo metodi galenici di per sè noti, essere impiegatiper medicamenti, soprattutto per l'applicazione orale II dosaggio del composto secondo 1' invenzioneè compreso, per gli esseri umani, fra 20 e 500 mg / gi or ino. The following examples are intended to illustrate the invention. Example 1 Mix 12.0 g of 3-oxo-4-6,1S-androstafHejiΓΐ7(β- 1')-spiro-5-]-perhydrofuran-11-one in 60 ml of methylene chloride with 36 ml of ethylene glycol, 24 ml of triethyl ester of o-formic acid, and 213 g of p-toluenesulfonic acid, and stir for 75 minutes at 50°C. The reaction solution is then mixed with 3 ml of pyridine, diluted with ether, washed with water, dried, and concentrated under vacuum. 13.5 g of crude 3,3-ethylenedioxy-4,6 » 1,5“androstaffien- |17-( β -1 ' )-spiro-5-perhydrofuran-2 '-one are obtained. The 13.5 g of the above product are dissolved in 650 ml of absolute tetrahydrofuran, cooled in an ice bath, mixed with stirring with 2.9 g of lithium malanate and subjected to continuous stirring for 30 minutes with further cooling. The excess reagent is then decomposed in water, the reaction solution is diluted with methylene chloride and is then washed with 2N H2S and then dried and evaporated under vacuum. The residue is chromatographed on silica gel. 5.1 g of 17^-hydroxy17 o(-(3-hydroxypropyl)-4,6,15-androstafluoroethylene-3-one are obtained. Example 2 ' 420 mg of 17β-hydroxy-17-ol-(3-hydroxypropyl)-4-j-15-androstaphthien-3-one in 8.4 ml of methanol and 1.68 ml of water with 0.84 ml of thioacetic acid are stirred at 50°C for 17 hours. The mixture is then diluted with methylene chloride, washed with sodium bicarbonate and water solution, dried, and evaporated into a vacuum. .···a · ···· *·· * > ♦ * ♦ * · * * * * · · • * * * • • • • • · · * • * * ♦ * * M*«· ft · • · * * Ψ • 4 · :· t « 1 1 • .·· ···*.. • ♦• ♦ · • ♦ · · è ** · • · · .· • • · · · ···· .. * « · · • · : * * · • · » · * Φ · · The residue is hardened by layer chromatography. After crystallization from diS3propyl ether / acetone, 320 mg of 7-(β-acetyl)-(β-7-hydroxy-1, 7-hydroxypropyl)-4, 1S^andro^tadien-S'one are obtained, PF 138.5-140°C. UV: £ 23g = 18200 Example 3 .......... pox 150 mg of 7θI -acetyl-17-hydroxy-17θ-(-(3-hydroxy-propyl)-4,15-androstadien-3-one) in 0.5 ml of dipyridine with 0.3 ml of acetic anhydride were left to stand at room temperature for 18 hours. The mixture was diluted with ether, washed with sodium bicarbonate and water solution, dried and evaporated under vacuum. The residue was chromatographed for purification by preparative layer chromatography. 11.0 ng of 17θI -(3-acetoxypropyl)-7θ-acetyl-17θ-hydroxy-4,15-androstadien-3-one were obtained. UV: t,>38 = 17800 Example 4 500 mg of 17(3-yl-roxy-17-ol-(3-hydroxypropyl)-4,6,15-androstat-H.en-3-one are stirred for 17 hours at 50°C in 10 ml of methanol and 2 ml of water with 1 ml of thiopropionic acid. The procedure is then carried out as described in example 2. After purification by preparative layer chromatography, 410 mg of 17(3-yl-roxy-17-ol-(3-hydroxypropyl)-7-ol-propionylthio-4,15- are obtained. : I · * * * * • · I·. · *··· · ♦* * · · · · ..... ...» V. * ·'"· · • · · * · · androstadien-3-one. UV : ε 23g = 17600Example 5 1.0 g of 17-(S-hydroxy-17-(-(3-hydroxypropyl)-4,6,15-andro-statrien-3-one in 10 ml of pyridine with 1 g of succinite anhydride is stirred for 48 hours at room temperature. The mixture is diluted with ether, washed with water, dried and evaporated under vacuum. The residue is chromatographed on silica gel. 850 mg of 17-(S-hydroxy-17-(3-hydroxysuccinyloxypropyl)-4,6,1S-androstatrien-3-one are obtained. UV: 8 2S5 = 24500 Mix 600 mg of the above product in 400 ml of absolute methanol with approximately 0.1 ml of methanolic nonionic acid solution to an equivalence point. The reaction solution is then perfectly concentrated in a vacuum and precipitated in ice-cooled absolute ether. The precipitate is filtered with a pump, washed with absolute ether, and dried. 350 mg of 17(3-hydroxy-17-(-(3-hydroxysucci-;yloxy-propyl)-4,6, 15-androstarylamide-3-one, as the ammonium salt, are obtained. JV example 6 *285 - 24600 They are stirred at room temperature for 1 hour and mòz am sot UffΙΓ ν' IVv":ll\iG. Al.'..,.:,. -26- mix 2.1 g of trimethylasulphonium iodide in 40 ml of dimethyl sulfoxide with. 390 mg of suspension in 55% sodium hydride oil. To this solution add under vacuum, 1.5 g of 17(¾-hydroxy-17-(3-hydroxypropyl)-4-6-15-androstadien-3-one and stirred for 24 hours at room temperature. After precipitation in ice-cold water, the precipitate is filtered, washed in water, dissolved in methylene chloride, dehumidified and evaporated. The residue is purified by preparative multiple layer chromatography. 350 mg of 17(¾-hydroxy-17-(3-hydroxypropyl)-6-17-methylen-4,15-androstadien-3-one are obtained,............... UV : i „ = 18000 200 Example 7 ; · ' ;òtt: Ai Ai 2.0 g of 17(1-hydroxy-17-(3-hydroxypropyl)-iS Ol 16^ -methylene-4,6-androstadien-3-one are mixed in 40 ml of methanol and 8 ml of water with 4 ml of thioacetic acid, and stirred for 18 hours at 50°C. The mixture is diluted with ether, washed with a solution of sodium bicarbonate and water, dried and evaporated under vacuum. The residue is chromatographed on silica gel. After re-crystallization from diisopropyl ether / acetone, 1.4 g of 7 <X-acetiltio-17 (i-idrossi-17o( -(3- idrossipropil)-15.& 116 oi -metilen“4-androsten-3-one di..P.F, 209-2l0,5°C, ·· ·· • · ·· · · «IMi♦ ·* * ··* * ♦ * * *.···.. ·* ·· · • · • * · · · * · · « · « • . - m - φ · · · · · ..... ... .... ..· » ·. .. . ...* .... ·**· . ,· * »... ..... , .·.··· 1 •. · ... . . .... -27- U?r! W : *238 ‘ 17700 Example 8 250 mg of 7-acetylthio-17(¾ -hydroxy-17 c<-(3-hydroxypropyl)*-15 t 16oL-methylene-4-androsten-3-one in 1 mipyridine and 0.5 ml of acetic anhydride are left to stand for 5 hours at room temperature. After precipitation in ice-cold water, the precipitate is filtered, dissolved in ether, washed with water, dried and evaporated. The residue is purified by preparative layer cryomatography. 285 ml of 17-acetylthio-17 1¾ -hydroxy-15 t 16oC -methylene-4-androsten-3-one are obtained, UV ; L238 = 17600. Example 9 of $ They are left to rest for 24 hours. At room temperature, 250 mg of 7Λ-acetylthio-17(β-hydroxy)-17oi-(3-hydroxypropyl)-15 6t, 16-methylene-4-androsten-3-one is added to 1 ml of pyridine and 0.5 ml of butyric anhydride. Dilute with ether, wash with water, dehumidify and evaporate to dryness under vacuum. The residue is purified by preparative layer chromatography. 2.05 mg of 7Λ-acetylthio-1,7β-(3-butyryloxypropyl)-17-hydroxy-15 16 o(-methylene-4-androsten-3-one is obtained as an oil. UV: £-238 = 17100 * ,· . ····*··. * • · • * · * * • · · t · * • •M* * * ·.·*·· · · ·Ϊ · ·«*» .. .··* ··* ····: : . :* . * · · · • · · · ·*·** · ** • Φ · ······ .· * · * : • ~ ~ * * » 9 9 99 9 m9 9 ·*· • · -28- UFFicìd τηINC- AL Example 10 500 mg of 17(β-hydroxy-17-(3-hydroxypropyl)-15 d( 16 (β-methylen-4-r6-androsten-3-one) are stirred for 24 hours at 50°C, in 5 ml of methanol and 1 ml of water, with 1 ml of thiopionic acid. It is diluted with ether, washed with sodium bicarbonate solution and water, humidified and evaporated under vacuum. The residue is chromatographed by preparative substrate chromatography. 310 mg of 17β-hydroxy-17-(3-hydroxypropyl)-15 df 16 (β-methylen-7 d-propionylthio-4-androsten-3-one are obtained. VY :1 236 = >7500 Example 11 600 mg of 17 μ-hydroxy-17 μ-(3-hydroxypropyl)-15 (A r 16o(-methyl)-4,6-androstadien-3-one in 6 ml of pyridine with 600 mg of succinic anhydride are heated under reflux for 30 minutes. The mixture is diluted with ether, washed with water, dried and evaporated under vacuum. The residue is chromatographed on silica gel. 580 mg of 17(¾-hydroxy-17 o(-(3-hydroxy-succinyl-Qxy-propyl)-15 f 160(-methylen-4,6-androstadien-3-on^ is obtained as an oil. UV: £ 285 23500 250 mg of 17 μ-hydroxy- 17 d -(3”hydressisuccinyloxypropyl)-15 ot , lófl -methylene-4,6-androstaT are dissolved • * * kk » ·>· » « * » » * · * * * * ·· * _ * * · * · * · t · • » « · · · « ...f · * ma ' m *···* ·,”• 9 # ,..*.··· |·β** *· Γ *• · · ·• „ · · ♦ « * · ♦ * **«.·........* · · · • · * i » « • · · · · · · ·. · 4 · * -29- Urr!'"ΙΓ* 1 μ" (· ìi'j λι Γ: .'; Π| Λι of clien-3-one are dissolved in 25 ml of absolute methanol and reacted with potassium methylate (0.1n methanolic solution) to the equivalence point. The reaction solution is concentrated under vacuum to about 5 ml and is precipitated in absolute ether. The precipitate is filtered off at 1 The ;>ompa„ washed with absolute ether and dehumidified. 210 mg of 17 β -hydroxy-17 o(- (3-hydroxysuccinylo^ *·.*.. ; # ; ! ·* V / · £ipropyl)-15 ·* , 16 cd -methylene-4,6- andros tadien*3-one pome *··\ * / .*. * • ♦· · • · • ♦ * · · ψ · · · • · · · • ♦ · · · # · • # » • · · · # naie potassium are obtained. UV i SJSexample 12 285 25100 React 250 mg of 17 β-hydroxy-17-(3-:L-hydroxysuccinyloxypropyl)-15 d »18 o(-methylen-14,6-androstadien-,1-one as described in example 7 with methanolic solution of sodium methylate and work up. 185 mg of 17 β-hydroxy-17 0(-(3-hydroxysuccinyloxypropyl)-15*methylsn-4»6-androstadien-3-one are obtained as the sodium salt UV mustard or 13 1.4 g of trimethylsulfoxonium iodide in 28 ml of dimethyl sulfoxide and 171 mg of 18(¾¾) sodium hydride oil suspension are stirred at room temperature for 2 hours. 1.0 g of 17β-hydroxy-17o(-(3 hydroxyproyl)-15 16°< -methylene- [6-androstadien-3-one] are added to the almost clear solution under vacuum and stirred for 24 hours at room temperature. The solution is then added, stirring, to ice-cold water, the precipitate is filtered, washed with water and dissolved in methylene chloride. After drying and evaporation, the residue is purified by Preparative multiple layer chromatography. 130 mg of 17 β-hydroxy-170^ -(3-hydroxypropyl)-6 ( 7 P ; 15 flóol -dimethylen-4”androsten-3-one are obtained. W : * 265 “ 17500Example 14 10.0 g of 15-(a rmethylen-3-οχα-4)-6-androstadien-^17-((3-11)-spiro-5-perhydrofuran-21-one are mixed in 50 ml of methylene chloride with 30 ml of 1-ethylene glycol, 20 ml of thiazolithic ester of 1-furnic acid and 300 mg of p-toluenesulfonic acid, and stirred for 75 minutes at 50°C. 3 ml of pytidine are added, the reaction solution is diluted with ether, washed with water, dried and evaporated to dryness in vacuo. 12 g of 3-ethylene-dioxy-15^,16-methylen-4,6-androstadien-^17( ($ -1) are obtained. ￢ﾀﾙ )spiro-5 ￢ﾀﾙJ -peridrofuran-2 1 -one. g of 3,3-ethylenedioxy-15 7 l - methylene-4 is dissolved; Furan-2'-one in 600 m of absolute tetrahydrofuran, cooled in an ice bath, is mixed with stirring with 2.75 g of continuous lithium silane. minutes at the temperature of the ice bath* 9 9 ﾷ* ﾷ ﾟﾟ ﾙﾦ * ﾷ * ﷷ ♦ » ·*·. 9 t • • ···· • • · *JB 9 99 • « · ·· • ♦ · · « .·** .·· • · • • · • · Φ · · • ♦ • · * ·· · * • .· is ϕφ i ·.·* ·· · ♦ · ·· » 9 * ♙ Excess reagent decomposes with water, Husband. Li * η νj··'i·"· ··· ' v - Μ.λJ i -31- and the reaction solution is diluted with methylene chloride. It is washed with 2n H2S04 and water, demidified and evaporated to dryness under vacuum. After chromatography on silica gel, 4.5 g of 17 & ~hydroxy~17*< -(3“hydroxypropyl)-15^ fl6(&-methyl4t6-androstadien-3-one are obtained. A sample recrystallized from diisopropyl ether / acetone melts at 200-201.5°C. W ; £ 285 = 25500Example 15 ·' ili u n- ate 500 mg of 17(2-hydroxy-17-(3-hydroxypropyl)-15-

[16] , β-methylen-4-[6-androstadien-3-one] are stirred at room temperature for 17 hours in 10 ml of methanol and 2 ml of water with 1 ml of thioacetic acid. It is then diluted with ether, washed with sodium bicarbonate solution and water, dried and evaporated under vacuum. The residue is purified by preparative layer chromatography and recrystallized from diisopropyl ether / acetone. 350 mg of 7A-acetyl 7(1-hydroxy-17-(3-hydroxypropyl)-15-

[16] , β-methylen-4-androsten-3-one] are obtained. PF 206-208°C, UV: &238 = 18800Example 16 fi- 100 mg of 7σί -acetylthio-17 |3 “hydroxy-17 σ( - ( 3-hydroxypropyl)-15 ji ( 16 -methylen-4-androsten-3-one i!a • ··*·*• » · · t ·** #···· ···**r ··* *·« • O·tl tt tMM • i · · * ♦ · · · ·• * ♦ ♦♦· ·- ··· M *• ·è·· · » • ·· · # # · ·♦· · · · ♦ • · • I · • · Φ · > • · ♦ · ·• * ♦ ♦ M ♦• *# • · » » ···· • · ·• · · · 0.5 0.2 ml of pyridine is dissolved in 0.2 ml of propionic anhydride. The reaction solution is diluted with ether, washed with sodium bicarbonate and water, dissolved in water, and evaporated under vacuum. The residue is chromatographed by preparative layer chromatography. 65 mg of 7-acetylthio-17-(4-hydroxy-17-(3-propionyloxypropyl)-15-3-t 16-(3-methylen-4-an-drosten-3-one) are obtained. Example 17 200 mg of 17-hydroxy-17-ol-(3-hydroxypropyl)-15(J, 16-methylene-4r6-androstadien-3-one in 4 ml of methanol and 0.8 ml of water with 0.4 ml of thiopropionic acid are left to stand at room temperature for 24 hours. Proceed as described in Example 11. After purification by preparative layer chromatography, 145 mg of 17(¾ -hydroxy-170Ì -(β-hydroxypropyl)- 15 β j 16 μ -methylen-7^ -propionylthio-4-androsten-3-one are obtained. UV: t227 = 18100Example 18 1.0 g of 17 β -hydroxy-17 ®^-(3-hydroxypropyl)-15 / ¾ , 16 (i -methylen~4,6-androstadien-3-one in 10 ml of dipyridine with 1.0 g of succinic anhydride is left to stand at room temperature for 48 hours. Dilute Uff Ì.'mC-f. . / vJ-.Ll· -Ϊ-;i... -33- with ether, wash with water, dehumidify, and evaporate under vacuum. The residue is chromatographed on silica gel. 720 mg of 17j^ -hydroxy-17fl( -( 3-hydroxysuccinyloxypropyl)-15$> , 16 -methylen-*4,6-androstadien-3-one are obtained as an oil. W ; ^2g5 = 24700. 500 mg of the above product are dissolved in 35 ml of absolute methanol and reacted with 0.1 n methanolic solution of potassium methylate to the equivalence point. The reaction solution is then perfectly concentrated under vacuum and precipitated in absolute ether cooled on ice. The precipitate is filtered with a pump, washed with absolute ether and dried. 420 mg of 17j& -hydroxy-17fl( -( 3-hydroxysuccinyloxypropyl)-15f& ^ IΙόβ are obtained ^methylen-4,6-and:stadien-3-one as a potassium salt, uv : £285 = 24500 Example 19 2.1 g of trimethylsulfoxonium diiodide are stirred at room temperature for 1.5 hours in 40 ml dimethyl sulfoxide with 390 mg of 55% sodium hydride oil suspension. To this solution 1.5 g of 17(fc-hydroxy-17 o(-(3-hydroxypropyl)-15^ flￃﾠ ￎﾲ-methylen-4^ 6-androstadien-3-one are added under nitrogen and stirred for 24 hours at room temperature. After precipitation,

Claims

1. The precipitate is dissolved in ice-cold water, the precipitate is filtered, washed with water, and dissolved in methylene chloride. After drying and evaporation, the residue is purified by preparative multilayer chromatography. 220 mg of 17β-hydroxy-17-(3-hydroxypropyl)-6 f7^> $15^ jlￃﾳ / ￎﾴ-dimethylen-4-androst 3-one are obtained. en* m ^266 " 17900 CLAIMS 1.Process for preparing 17 β-hydroxy-4-andro-iSten-3-ones of the general formula I (I) m R2 stands for hydrogen or an organic acid radical, R for methyl or ethyl, JR for hydrogen or methyl, “TB for with Rj in the sense of a lower alkyl radical, and ? for—c Di and characterized in that, in a manner known per se, 3-keto-4*6-androstadien-spirolactone of the general formula II -CD-, R^ and R^ have the meanings indicated in formula I, are treated with lithium aluminum hydride in an aprotic solvent, first providing the keto group in 3 with a protecting group, and a) in the case in which -AB- stands for the -GII-CH---S-CO-R group, one reacts, in a manner known per se, with a thioalkanic acid in a protic organic solvent and in a mixture of solvents, possibly in the presence of a dissolution intermediate, or .b) in the case where -AB- stands for the -CH CH- group, it is methylated in a manner known per se with dimethylsulfoxonium methylate in dimethyl sulfoxide as solvent, and in the case where -AB- stands for an acid radical, it is esterified in a manner known per se by adding an esterification catalyst, -36- possibly the ester obtained is partially saponified and, if required, it is esterified with the last required acid and possibly converted into the salt, 2...... Process according to claim 1, characterized in that, in the case where R represents the radical L, it is transformed into the salt of a dibasic acid, hemiacylate / di-ammonium, dialkali metal or alkali metal oxide. 3· 17 pi -hydroxy-4-androsten-3-ones of the general formula X ·· ·· • · «M1* · · · ♦ ··* • Mtt . ··· * .* * ·**·• · · # · • · • ι··ι • * * · 4 · mm 4• t · · ····»*!· · ·»· salt (I) R stands for hydrogen or an organic acid radical, ù R for methyl or ethyl, R^ for hydrogen or methyl, • · i ·· 4 ·• •Iti • ·• · ·t « i · ·.·♦ • # ♦ · Ϊ with Rj meaning a lower alkyl radical. and ? for -C Ί 4* 17 / i-hydroxy-17¢( -( 3-hydroxypropyl)-4^ 6115-anthrost^ / àen-3-one. -37- 5. 7à( -acetylthio-17(Ì -hydroxy-17 - ( 3-hydroxyprop- yl)-4,1S-androstadien-3-one. 6 17 -( 3-acetoxypropyl)-7 °l -acetxltio-17^ -hydroxy-4jl5-androstadien-3-one.

7. 7 ^-propyNylthio-17^ -hydroxy-17 Ql-(3-hydraxypropyl)-4>15-androstadien-3-ane.

8. 17 (ò -hydroxy-17 ^-(3-hydroxysuccinyloxypropy I)- tr r 4,6,15-androsta / ien-3-one.

9. Ammonium salt of 17-hydroxy-17oi-(3-hydroxy trisuccinyloxypropyl)-4^ 6 ?15-androsta / ien-3-one, 10. 17p> -hydroxy” 17o^ - (3-hydroxypropyl)-6 / 3 / 7(3 -fflethylen4t15-androstadien-3-one.

11. 17 p -hydroxy-17 ^ -(3-hydroxypropyl)-15 0(,16^methylen-4-androsten-3-one.

12. 17 j& -hydroxy-17 d-(3-hydroxypropyl)-150Ì ,Aόa,Η-methylen-4j6-androstadien-3-one.

13. 17oi -acetylthio-17fi -hydroxy-17 oi ~(3-hydroxy-propyl)-1S , l6o{ -methylen-4-androsten-3,orie... .

14. 17 o(-(3-acetoxypropyl)-7 Λ-acetylthio-17f3 - hydroxy-15 o( , lód* -methylen-4-androsten-3-one. ji 15· 7 <K -acetiltio-17 (λ-(3-butirrilossi-propil)- j17 fi -idrossi-15 CX , lóot -metilen-4~aridrosten-3*-one . 16 , 17^ -idrossi-17 -( 3-idrossipropil)-15oi f 16oi,metilen-7^ -propioniltio-4-*androsten-3-one.

17. 17ft -idrossi-17 οΐ-( 3-idrossisuccinilossipropil)· *···• ♦···· ··· ·*·#· • * * · .···#. · • • · ♦ · ···. ♦ . · • • M·· • • · » · · t ♦ v··· • · · Ψ'9 * · · ♦ » Φ · · · • » • ···· .·* • · • · · ·• • · • t ♦ • · · # • · • · · • .· « • ψ · · ·*·* • · * • 9 · 1 » * ♦ · · • ··*·· • · · · · 38- * ~> ο 15 Λ t 16 <λ -methylene-4^. 6-androstadien-3- one . 18 . 17 (¾ -hydroxy-17 <X -( 3-idrossisuccinilossipro-pil)-l5«( , 16 et -metilen-4,6-androstadien~3-one, salepqtassico. 19* 17 (3-idrossi-17 - ( 3-idrossisuccinilossipro- pil)-15 <λ , 16 ot-metilen-4,ó-androstadien-3-one, salesodico.

20. 17 (3-idrossi-17 oi -( 3-idrossipropil) -6 fi ,7} 15 Λ > 1st. <λ -dimetilen-4-androsten-3-qne.

21. 17 (i -idrossi-17 o<-(3-idrossipropil)-15 3 , l6ytìmetilen-4jó-androstadien-3-one. 22 . 7 oi-acetiltio-17 -idrossi-i7o< -(3-idrossipr<pil)xl5(i tl6(ì -metilen-4-androsten-3-one.

23. c^-+acetiltio-17(3 °t-(3-propionil-ossipropil)-l5 (&jl6(3 24.17(3 g\ -(3-idrossipropil) -15^3 116 fimetilen-7 -propioniltio-4-androsten-3-one.

25. ^-idrossi-17o( -(3-idrossisuccinilossipropil)-15(3 f 16(¾ -metilen-4 j6-androstadien-3-one.

26. (i-idrossi-17 c( -(3-idrossisu.ccinilossipropil)- 15 16(3 -metilen-4,6-androstadien-3-one, sale potasi sico.

27. 17(3 o(-(3-idrossipropil)-6^3 ,7^3 jlift (3 -dimetilen-4-androsten-3-one.

28. Compound-based medicine according to the riV. ··*· • · *· ·· ·· * * « * ·*·«#· . .··;· *#«*• · · * · • * . • ·#·ν• · · · · · * · · · · ···*· · · · ·5 · « · * · ·*«· · · ·#··· ··* ·*'·: = ·:• · * * * **·-· · « · • «· I ·• # * * · *»«··* · ······ * * ♦ ί ' * ♦♦ · ·· *·· ·*4 * 4 · .*:* *#ι****** * ·; · · ·ι ; * · · · * · · * *• · « * ·* * · * free ***** * #**<· * * · ·» · « · · * * Μ*< / λ>