INTERMEDIATES IN THE SYNTHESIS OF DIAMINO-ANDROSTANE DERIVATIVES

Abstract: The present invention relates to Compounds of formula (VI) or of formula (V) wherein Y″ is hydrogen, hydroxy or an OAc group, wherein Ac is an alkylcarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, and X is a bromine atom or an OAc group.

Description: The present invention relates to intermediates in the synthesis of diamino-androstane derivatives. There are certain 2,16-diamino-androstane derivatives known in the art, which show curare-like muscle relaxant activity. Of these, the compounds disclosed in United States Patent Specification No. 3,553,212 have a shortened duration of activity, while compounds with a more extended duration of action are disclosed in British Patent Specification No. 1,398,050. Since the administration of these compounds is far from being free from any risk, an extensive research is going on to find new derivatives with an extremely short or intermediate duration of activity or having an onset time as close to administration as possible. Our research activity in this field has resulted in the discovery of a range of biologically active 6,16-diamino-androstane derivatives and their diquaternary or monoquaternary salts; see the compounds of formula (I). and physiologically acceptable diquaternary and monoquaternary salts thereof. This structure is further exemplified by the following formulae: In the formula (I) and formula (Ia) to (Id), Y is hydrogen or an -OAc group, Ac is an alkylcarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, A is methylene or a group of the formula N-R¹, in which R¹ is alkyl having from 1 to 4 carbon atoms, B is methylene, or a group N-R¹ or N-R², in which R¹ is as defined above and R² is a -CH₂-CH₂-COOR¹ group, and n is 1 or 2, m is 1, 2 or 3. In the formula (Ia), (Ib), (Ic) and (Id), B¹ is a group N-R¹ or N-R², in which R¹ and R² are as defined above, R³ is alkyl or alkenyl having from 1 to 4 carbon atoms, and Z is an anion, eg. a halogen or sulfonyloxy. The activity data are set forth in the following Table in comparison with pancuronium bromide, the best compound disclosed in the United States Patent Specification No. 3,553,212, which exerts its activity according to a non-depolarizing mechanism [Negwer (1971) 4821]. No. of the Example disclosing the test compound onset time (sec.) 46 41 47 21 48 20 53 30 57 22 58 27 61 17 pancuronium bromide 55 To determine the time when they begin to exert their activity, the compounds according to the invention were administered in equiactive doses resulting in extremital paralysis in 90 to 100 % of the test animals. The tests were carried out on male albino mice, following the method of Pradhan and De [Br. J. Pharmacol. Chemoter. 8:399-405 (1953)], testing each compound in 4 to 6 different doses on 10 animals each time. The compounds were administered intravenously and the period between the injection and myoparalysis was defined as the onset time. The results show that the effect of the new compounds (at the same extent of muscle relaxation) developed within a substantially shorter time after administration than that of pancuronium bromide. It is known that the non-depolarizing muscle relaxants with a more clear activity profile are preferred in therapy to compounds acting through a depolarising mechanism. The reason why depolarizing muscle relaxants are widely employed in surgery as initiators of surgical muscle relaxation (intubation) and at short interventions is that their action develops rapidly after the administration of doses resulting in the desired degree of muscle relaxation. For the hitherto known non-depolarizing muscle relaxants the same quick action can be achieved only by relative overdosage, which extends the duration of activity and exposes the patient to an unnecessary drug load. The compounds have a satisfactorily early start of action even in minimum therapeutic doses and have a non-depolarizing action mechanism, i.e. they inhibit the transmittance of the nervous stimulus on the striated muscle without initial depolarization and muscle twitching. Their effect can be antagonized with acetyl cholinesterase inhibitors, e.g. neostigmine. They have no influence on blood circulation and have no hormonal effect. The new compounds may de synthestized starting from compounds of formula (VIII) or (VII) wherein Y' is hydrogen or hydroxyl. Certain examples of compounds of formulae (VIII) and (VII) are known in the art [D.H.R. Barton: J. Chem. Soc. 1962 , 470-476 and Tetrahedron Letters 24 , 1605-1608 (1983); M. Numazava: Steroids, 32 , 519-527 (1978)] while others are new. Preparation of the new compounds is illustrated by Example 2 herein below. From compounds of formula (VIII) the compounds according to the invention having formula (VI) wherein Y" is hydrogen, hydroxyl or an -OAc group, in which Ac is as defined above and X is bromine may be prepared via two different reaction routes: The compounds of formula (VI), in which both Y" and X represents an -OAc group may be prepared by reacting a compound of formula (VIII) with the anhydride of an alkanecarboxylic acid having from 1 to 4 carbon atoms in the alkyl moiety or with an alkenyl acetate containing from 2 to 5 carbon atoms in the alkenyl moiety, in the presence of an acid, such as sulfuric acid, p -toluenesulfonic acid, etc. The compounds of formula (IV), in which Y" represents hydrogen or hydroxyl and X is bromine may be prepared by converting a compound of formula (VIII) into a compound of the formula (VII) by reaction with hydrazine hydrate in presence of a tertiary amine (Y' is as defined above) and transforming the latter compound with N-bromo-succinimide into a compound of formula (VI) (Y" is hydrogen or hydroxyl, X is bromine) at a temperature between 0 °C and 10 °C, in the presence of pyridine. The compounds of formula (VI) may then be converted into the diepoxyandrostanes of formula (V) which are also valuable intermediates and are a further subject matter of the present invention. wherein Y" and X are as defined above, by reaction with a peracid (preferably perbenzoic acid, m -chloro-perbenzoic acid, or peracetic acid ) in an inert organic solvent, such as benzene, chlorinated hydrocarbons, or ether. The diepoxyandrostanes of formula (V) may then be reacted with an amine of formula (IX) wherein A, n and m are as defined above. Depending on the reaction conditions either the new 16-amino-androstanes of formula (IV) or the new 6,16-diamino-androstanes of formula (IVa) are obtained. In formulae (IV) and (IVa) the substituents are as defined above. If a compound of formula (V) is reacted with an amine of formula (IX) in the presence of an inert organic solvent, e.g. acetonitrile at room temperature or under boiling for a short time (about 2 hours), a 16-monoamino-product of formula (IV) is obtained. If the reaction is performed under heating over a longer period (about 100 hours) in the presence of water, a 6,16-diamino-product of the formula (IVa) is obtained. The compounds of formula (IV) may be converted into the corresponding new compounds of formula (II) through the compounds of formula (III) while from the compounds of formula (IVa) compounds of formula (II), which are the starting compounds of the process as described in the foregoing, may be directly obtained. In formula (II) B' is methylene, a group NR¹ or NH, in which R¹ is as defined above, Y', A, n and m are as defined above. The compounds of the formula (IV) may be reduced to compounds of formula (III) with a boron complex, preferably sodium, calcium or trimethoxy borohydride, in an alcoholic medium, and the desired new compounds of formula (II) may be obtained by reacting the compound of formula (III) obtained with an amine of formula (X) The amine of formula (X) is preferably reacted with the compound of the formula (III) in the presence of water, at elevated temperature (about 100 °C). In formulae (III) and (X) the substituents have the same meanings as given hereinabove. By reducing the compounds, of formula (IVa) with a complex metal hydride compound of formula (II), in which B' = A and the other substituents are as defined above, may be obtained. The borohydrides mentioned above may be employed as complex metal hydrides in alcohol but lithium aluminium hydride is equally suitable in an ether-type solvent. The compounds of formula (II), in which B' is an N-R¹ group, if desired, may be converted into the diquaternary salts of formula (IIa) Similarly, from the compounds of formula (II), in which B' is methylene the monoquaternary salts of formula (IIb) may be prepared. Quaternization may be carried out by methods known per se , e.g. by using a reactant of the formula (XI) R³-Z (XI) In formulae (IIa), (IIb) and (XI) the substituents are as defined above. The compounds of formula (I) may be prepared by acylating compounds of formula (II). Alternatively the compounds of formula (II), in which B' represents an NH group may first be converted into compounds of formula (IIc) wherein A, Y', R², n and m are as defined above, and then the compounds of formula (IIc) may be acylated yielding the compounds of formula (I). The compounds of formula (I) may be converted into their diquaternary salts of formula (Ia) or monoquaternary salts of the formulae (Ic) or (Id) by known techniques. The monoquaternary salts of formula (Ib) may be prepared from the diquaternary salts of formula (Ia) in an original manner, by adjusting the pH of the reaction mixture to 8.5 to 9. The formation of the desired monoquaternary salts takes place at lower pH as well, but at a slower rate. The invention will now be illustrated in greater detail with the aid of the following non-limiting Examples. Example 1 3β-Hydroxy-17-bromo-androsta-5,16-diene 315 g (1.048 moles) of 3β-hydroxy-androst-5-ene-17-hydrazone are dissolved in 3150 ml of dry pyridine, the solution is cooled to 0 °C, whereupon a solution of 280.3 g. (1.574 moles) of N-bromo-succinimide in 4000 ml of dry pyridine is added in 30 minutes. (The temperature must not exceed 10 °C during the addition.) Thereafter the reaction mixture is stirred for one hour, whereupon it is added to 30 lit. of ice water. After stirring for an additional hour, the precipitate is allowed to concentrate, filtered and washed pyridine-free with a 5 % aqueous hydrochloric acid solution and subsequently neutral with water. The wet precipitate is dissolved in 800 ml of benzene, water is separated from the insoluble solid (azine by-product). The benzene solution is dried over magnesium sulfate and purified on a chromatographic column containing 1500 g of silica gel. The desired product is eluted with benzene. Benzene is eliminated under reduced pressure, and the residue is dried until a constant weight is obtained. Yield: 206.8 g (56 %) of the title compound Melting point: 162 ° to 164 °C ¹H-NMR spectrum (CDCl₃): δ 0,86 s (3H), 1.07 s (3H), 2.06 s (1H) 3.45 br (1H), 5.32 m (1H), 5.8 m (1H) Example 2 17-Bromo-androsta-5,16-diene 100 g (0.35 mole) of androst-5-ene-17-hydrazone are dissolved in 860 ml of dry pyridine, the solution is cooled to 0 °C whereupon a solution of 75 g (0.41 mole) of N-bromo-succinimide in 1350 ml of dry pyridine is added in 30 minutes. (During the addition the temperature must not exceed 10 °C.) Thereafter, the reaction mixture is stirred at 0 °C for two hours and is then added to 25 lit. of ice water. The precipitated substance is filtered off, washed with water, dissolved in 4000 ml of dichloromethane and washed with a 5 % aqueous hydrochloric acid solution and subsequently with water. The organic layer is then dried over magnesium sulfate and the solvent is evaporated under reduced pressure. 91 g of a crude product are obtained, which is purified on a chromatographic column filled with 1200 g of silica gel. The elution is performed with benzene. Yield: 47 g (40 %) of the title compound. Melting point: 109 ° to 113 °C ¹H-NMR spectrum (CDCl₃): δ 0.87 s (3H), 1.05 s (3H), 5.25 s (1H), 5.8 s (1H). The new androst-5-ene-17-Hydrazone used as starting material is prepared as follows: 100 g (0.37 mole) of androst-5-ene-17-one are suspended in 1000 ml of ethanol. 170 ml (1.22 moles) of triethyl amine are added to the solution, followed by the dropwise addition of 500 ml (10.3 moles) of hydrazine hydrate. Thereafter, the reaction mixture is refluxed for two hours, cooled to room temperature and poured into 20 lit. of ice water. The precipitated white substance is filtered off, washed with water several times and dried. Yield: 103 g (97 %) of androst-5-ene-17-hydrazone Melting point: 140 ° to 142 °C ¹H-NMR spectrum (CDCl₃): δ 0.9 s (3H), 1.05 s (3H), 4.75 s (2H), 5.25 m (1H). Example 3 3β-Hydroxy-5α,6α,16α,17α-diepoxy-17β-bromo-androstane 190 g (0.495 mole) of 3β-hydroxy-17β-bromo-androsta-5,16-diene are dissolved in 1900 ml of chloroform, whereupon 285 g (1.65 moles) of metha-chloro-perbenzoic acid are added within one hour, taking care that the temperature should remain between 10 ° to 20 °C. Thereafter, the reaction mixture is stirred at room temperature for further 10 hours, diluted to twice its original volume with chloroform, washed acid-free with an aqueous sodium hydroxide solution cooled to 0 °C and dried over magnesium sulfate. The chloroform is distilled off and the residue is recrystallized from acetonitrile. Yield: 126.4 g (61 %) of the title compound Melting point: 150 ° to 153 °C ¹H-NMR spectrum (CDCl₃): δ 0.83 s (3H), 1.07 s (3H), 2.41 s (1H), 2.89 d (1H), 3.62 s (1H), 3.87 br (1H). Example 4 5α,6α,16α,17α-Diepoxy-17β-bromo-androstane The title compound is prepared starting from 17β-bromo-androsta-5,16-diene, following the procedure described in Example 3 with a yield of 46.5 %. Melting point: 184 ° to 187 °C ¹H-NMR spectrum (CDCl₃): δ 0.82 s (3H), 1.06 s (3H), 2.85 d (J = = 3.5 Hz, 1H). 3.61 s (1H). Example 5 3β-Hydroxy-5α,6α-epoxy-16β-(4'-methyl-1-piperazino)-androstane-17-one 26 g (0.067 mole) of 3β-hydroxy-5α,6α,16α,17α-diepoxy-17β-bromo-androstane are suspended in 260 ml of acetonitrile, whereupon 19 ml (0.17 mole) of freshly distilled N-methyl-piperazine are added under vigorous stirring. The heterogenous system becomes homogenous within several minutes, whereupon th precipitation of the desired product starts rapidly. The precipitous solution is vigorously stirrred for a further 20 hours at room temperature, the precipitated crude product is filtered off, washed to almost neutral with water, and dried under reduced pressure until a constant weight is obtained. The product is then boiled in two 100 ml-portions of acetonitrile. Yield: 19.4 g (79.8 %) of the title compound Melting point: 233 ° to 235 °C ¹H-NMR spectrum (CDCl₃): δ 0.81 s (3H), 1.10 s (3H), 2.26 s (3H), 2.9 d (1H), 3.4 s (1H), 3.8 br, m (1H). Example 6 3β-Hydroxy-5α,6α-epoxy-16β-(1'-piperidino)-androstane-17-one The title compound is prepared from 3β-hydroxy-5α,6α,16α,17α-diepoxy-17β-bromo-androstane, essentially following the procedure described in Example 5, with a yield of 83 %. Melting point: 152 ° to 155 °C ¹H-NMR spectrum (CDCl₃): δ 0.79 s (3H), 1.07 s (3H), 2.9 d (1H), 3.26 br (1H), 3.8 br (1H). Example 7 5α,6α-Epoxy-16β-(4'-methyl-1'-piperazino)-androstane-17-one The title compound is prepared starting from 5α,6α,16α,17α-diepoxy-17β-bromo-androstane, essentially following the procedure described in Example 5, with a yield of 75 %. Melting point: 127 ° to 132 °C. IR spectrum (KBr): 830, 1050, 1740, 2700, 2765, 2800 cm⁻¹ Example 8 5α,6α-Epoxy-(1'-piperidino)-androstane-17-one The title compound is prepared starting from 5α,6α,16α,17α-diepoxy-17β-bromo-androstane, essentially following the procedure described in Example 5, with a yield of 53 %. Melting point: 135 ° to 138 °C IR spectrum (KBr): 860, 1040, 1735, 2800,2830 cm⁻¹. Example 9 3β,5α-Dihydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane-17-one 60 g of 3β,17β-diacetoxy-5α,6α,16α,17α-diepoxy-androstane are dissolved in a mixture of 250 ml of freshly distilled N-methyl-piperazine and 37 ml of water, and the solution is refluxed for 110 hours, under nitrogen atmosphere. When the reaction is complete, which is monitored by thin layer chromatography, the excess of N-methyl-piperazine is distilled off under reduced pressure. The residue is dissolved in 1000 ml of dichloromethane and washed with three 200 ml portions of water. The solution is dried over magnesium sulfate, filtered off and the dichloromethane is removed. The residue is triturated with a 1:1 mixture of acetone and ether, filtered and dried. Yield: 49.6 g (66.8 %) of the title compound Melting point: 239 ° to 242 °C ¹H-NMR spectrum (CDCl₃ + CD₃OD): δ 0.86 s (3H), 1.10 s (3H), 2,27 s (6H), 4.0 br (1H). Example 10 3β,5α-Dihydroxy-6β,16β-bis(1'-piperidino)-androstane-17-one The title compound is prepared starting from 3β,17β-diacetoxy-5α,6α,16α,17α-diepoxy-androstane, essentially following the procedure described in Example 9, with a yield of 58 %. Melting point: 202 ° to 205 °C. Example 11 5α,6α-Epoxy-17β-hydroxy-16β-(4'-methyl-1'-piperazino)-androstane 18 g (0.046 mole) of 5α,6α-epoxy-17-oxo-16β-(4'-methyl-1'-piperazino)-androstane are dissolved in 450 ml of methanol. The solution is cooled to 0 °C and 3.6 g (0.095 mole) of sodium borohydride are added portionwise, under stirring and cooling. When the addition is complete, the reaction mixture is allowed to warm up to room temperature and stirred for further 24 hours, Thereafter the solvent is eliminated under reduced pressure, the residue is triturated with water and dried. Yield: 16.65 g (92 %) of the title compound Melting point: 161 ° to 165 °C ¹H-NMR spectrum (CDCl₃): δ 0.64 s (3H), 1.06 s (3H), 2.28 s (3H), 2.86 d (J=4 Hz, 1H), 3.39 d (J=9Hz, 1H), 3.75 br (1H). Example 12 5α,6α-Epoxy-17β-hydroxy-16β-(1'-piperidino)-androstane The title compound is prepared starting from 5α,6α-epoxy-17-oxo-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 11, with a yield of 89 %. Melting point: 140 ° to 144 °C IR spectrum (KBr): 2810, 2700, 1075, 1050, 880 cm⁻¹. Example 13 3β,17β-Dihydroxy-5α,6α-epoxy-16β-(1'-piperidino)-androstane The title compound is prepared starting from 3β-hydroxy-5α,6α-epoxy-17-oxo-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 11, with a yield of 82 %. Melting point: 245 ° to 246 °C ¹H-NMR spectrum (CDCl₃): δ 0.63 s (3H), 1.07 s (3H), 2.9 d (1H), 3.38 d (1H), 3.83 m (1H). Example 14 3β,17β-Dihydroxy-5α,6α-epoxy-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 3β-hydroxy-5α,6α-epoxy-17-oxo-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 11, with a yield of 96 %. Melting point: 174 ° to 176 °C ¹H-NMR spectrum (CDCl₃): δ 0.61 s (3H), 1.06 s (3H), 2.26 s (3H), 2.9 d (1H), 3.2 br (2H), 3.4 d (1H), 3.9 m (1H). Example 15 3β,5α,17β-Trihydroxy-6β-(1'-piperazino)-16β-(4'-methyl-1'-piperazino)-androstane 25 g (0.069 mole) of 3β,17β-dihydroxy-5α,6α-epoxy-16β-(4'-methyl-1'-piperazino)-androstane are dissolved in 250 ml of propyl alcohol, 80 g of piperazine and 24 ml of water are added, and the reaction mixture is refluxed under nitrogen atmosphere for 110 hours. When the reaction is complete, propyl alcohol, water and the excess of piperazine are eliminated under reduced pressure. The residue is triturated with water to eliminate piperazine traces, the precipitate is filtered, dissolved in chloroform, water is separated and the chloroform solution is dried. The solvent is distilled off under reduced pressure and the crude product is purified by mixing it with acetonitrile. Yield: 22.3 g (66 %) of the title compound Melting point: 210 ° to 215 °C ¹H-NMR spectrum (CDCl₃): δ 0.68 s (3H), 1.1 s (3H), 2.25 s (3H), 3.4 d (1H), 3.92 br (1H). Example 16 3β,5α,17β-Trihydroxy-6β-(1'-piperazino)-16β-(1'-piperidino)-androstane The title compound is prepared starting from 3β,17β-dihydroxy-5α,6α-epoxy-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 15, with a yield of 86 %. Melting point: 180 ° to 185 °C. Example 17 5α,17β-Dihydroxy-6β-(1'-piperazino)-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 5α,6α-epoxy-17β-hydroxy-16β-(4'-methyl-1'-piperazinyl)-androstane, essentially following the procedure described in Example 15, with a yield of 70 %. Melting point: 131 ° to 140 °C (decomp.) ¹H-NMR spectrum (CDCl₃/DMSO/d₆): δ 0.67 s (3H), 1.08 s (3H), 2.26 s (3H), 3.39 d (1H). Example 18 5α,17β-Dihydroxy-6β,16β-(4'-methyl-1'piperazino)-androstane 9.8 g (0.025 moles) of 5α,6α-epoxy-17β-hydroxy-16β-(4'-methyl-1'-piperazino)-androstane are refluxed in a mixture of 175 ml (1.57 moles) of N-methyl-piperazine and 25 ml of water, under nitrogen atmosphere for 100 hours. The reaction mixture is evaporated under reduced pressure, the residue is triturated with water and dried. The product is purified by mixing it with acetonitrile. Yield: 7.7 g (62 %) of the title compound Melting point: 218 ° to 222 °C ¹H-NMR spectrum (CDCl₃/DMSO/d₆): δ 0.69 s (3H), 1.06 s (3H), 2.2 s and 2.23 s (2 x 3H), 3.41 d (J=9Hz, 1H). Example 19 5α,17β-Dihydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 5α,6α-epoxy-17β-hydroxy-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 18, with a yield of 60 %. Melting point: 112 ° to 116 °C ¹H-NMR spectrum (CDCl₃-CD₃OD): δ 0.7 s (3H), 1.07 s (3H), 2.26 s (3H), 3.43 d (1H). Example 20 5α,17β-Dihydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane The title compound is prepared starting from 5α,6α-epoxy-17β-hydroxy-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 18, with a yield of 65 %. Melting point: 124 ° to 127 °C ¹H-NMR spectrum (MeOD): δ 0.71 s (3H), 1.11 s (3H), 2.25 s (3H), 3.4 d (1H). Example 21 3β,5α,17β-Trihydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane The title compound is prepared starting from 3β,17β-dihydroxy-5α,6α-epoxy-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 18, with a yield of 45 %. Melting point: 150 ° to 154 °C ¹H-NMR spectrum (CDCl₃): δ 0.66 s (3H), 1.08 s (3H), 2.21 s (3H), 3.27 d (J=8Hz , 1H), 3.85 br (1H). Example 22 3β,5α,17β-Trihydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 3β,17β-dihydroxy-5α,6α-epoxy-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 18, with a yield of 49 %. Melting point: 154 ° to 157 °C ¹H-NMR spectrum (CDCl₃): δ 0.66 s (3H), 1.08 s (3H), 2.23 s (3H), 3.35 d (J=9Hz, 1H), 3.8 br (1H). Example 23 3β,5α,17β-Trihydroxy-6β,16β-bis(1'-piperidino)-androstane 8.4 g (0.018 mole) of 3β,5α-dihydroxy-6β,16β-bis(1'-piperidino)-androstane-17-one are dissolved in a mixture of 70 ml of tetrahydrofurane and 42 ml of methyl alcohol. The solution is cooled to 10 °C and 6.7 g (0.18 mole) of sodium borohydride are added so that the temperature should remain between 10 °C and 20 °C. The reaction mixture is stirred for a further 4 hours, whereupon the solvent is eliminated under reduced pressure. The residue is dissolved in chloroform, washed with a 2 % aqueous sodium hydroxide solution and subsequently with water, dried and the solvent is distilled off under reduced pressure. The crude product is purified by trituration with acetonitrile. Yield: 4.4 g (52 %) of the title compound Melting point: 146 ° to 150 °C ¹H-NMR spectrum (CDCl₃): δ 0.68 s (3H), 1.1 s (3H), 3.42 d (1H), 3.98 br (1H), 3.0-3.7 br (1H). Example 24 3β,5α,17β-Trihydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 3β,5α-dihydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane-17-one, essentially following the procedure described in Example 23, with a yield of 72 %. Melting point: 235 ° to 237 °C Alternatively, the title compound is prepared starting from 3β,17β-dihydroxy-5α,6α-epoxy-16β-(4'-methyl-1'-piperazino)-androstane, following the procedure described in Example 18. Yield: 68 % Melting point: 235 ° to 237 °C. Example 25 3β,5α,17β-Trihydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane 13 g (0.027 mole) of 3β,5α,17β-trihydroxy-6β-(1'-piperazino)-16β-(4'-methyl-1'-piperazino)-androstane are dissolved in 78 ml of chloroform, whereupon 15.6 ml (0.17 mole) of acrylic acid methyl ester are added to the solution. The reaction mixture is allowed to stand at room temperature for 24 hours, chloroform and the excess of acrylic acid methyl ester are distilled off, the residue is dissolved in ether and decoloured on silica gel. The absorbent is filtered off, ether is eliminated by distillation and the residue is crystallized from acetonitrile. Yield: 11 g (72 %) of the title compound Melting point: 148 ° to 150 °C ¹H-NMR spectrum (CDCl₃): δ 0.65 s (3H), 1.06 s (3H), 2.23 s (3H), 3.2 br (1H), 3.33 d (1H). Example 26 3β,5α,17β-Trihydroxy-6β-[4'.(methoxycarbonylethyl)-1'-piperazino]-16β-(1'-piperidino)-androstane The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-(1'-piperazino)-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 25, with a yield of 80 %. Melting point: 100 °C ¹H-NMR spectrum (CDCl₃): δ 0.77 s (3H), 1.08 s (3H), 3.4 d (1H), 3.68 s (3H), 4.95 br (1H). Example 27 5α,17β-Dihydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 5α,17β-dihydroxy-6β-(1'-piperazino)-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 25, with a yield of 62 %. Melting point: 115 ° to 119 °C ¹H-NMR spectrum (CDCl₃): δ 0.66 s (3H), 1.05 s (3H), 2.26 s (3H), 3.39 d (1H), 3.68 s (3H). Example 28 3β,17β-Diacetoxy-5α-hydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane 10 g (0.019 mole) of 3β,5α,17β-trihydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane are dissolved in 100 ml of dichloromethane, and 8.6 ml (0.091 mole) of acetic anhydride and 4 ml (0.028 mole) of triethyl amine are added to the solution. The reaction mixture is allowed to stand at room temperature for 24 hours. The progress of the reaction is monitored by thin layer chromatography. When the reaction is complete, the excess of acetic anhydride is decomposed with 3 ml of water, the solution is diluted to twice of its volume with dichloromethane and washed acid-free with a 10 % aqueous sodium hydroxide solution cooled to 0 °C and subsequently neutral with water. The dichloromethane solution is dried over magnesium sulfate, the solvent is distilled off and the residue is crystallized from ether. Yield: 6.9 g (59 %) of the title compound Melting point: 140 °C ¹H-NMR spectrum (CDCl₃): δ 0.82 s (3H), 1.11 s (3H), 2.03 s (3H), 2.09 s (3H), 2.26 s (6H), 2.95 s (1H), 3-3.4 m (1H), 4.81 d (1H), 5.15 s, br (1H). Example 29 3β,17β-Diacetoxy-5α-hydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane, following the procedure described in Example 28, with a yield of 49 %. Melting point: 180 ° to 182 °C ¹H-NMR spectrum (CDCl₃): δ 0.80 s (3H), 1.09 s (3H), 2.03 s (3H), 2.08 s (3H), 2.28 s (3H), 2.8-3.3 m (1H), 4.69 d (J= =9Hz, 1H), 5 br (1H). Example 30 3β,17β-Diacetoxy-5α-hydroxy-6β,16β-bis(1'-piperidino)-androstane The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β,16β-bis(1'-piperidino)-androstane, essentially following the procedure described in Example 28, with a yield of 68 %. Melting point: 125 ° to 129 °C Example 31 3β,17β-Diacetoxy-5α-hydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 28, with a yield of 72 %. Melting point: 145 ° to 147 °C ¹H-NMR spectrum (CDCl₃): δ 0.80 s (3H), 1.08 s (3H), 2.0 s (3H), 2.08 s (3H), 2.21 s (3H), 2.8-3.3 m (1H), 4.66 d (J=9.5 Hz, 1H), 5 br (1H). Example 32 5α-Hydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-17β-acetoxy-androstane The title compound is prepared starting from 5α,17β-dihydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 28, with a yield of 71 %. Melting point: 178 ° to 181 °C ¹H-NMR spectrum (CDCl₃): δ 0.82 s (3H), 1.03 s (3H), 2.08 s (3H), 2.25 s (6H), 4.74 d (J=9Hz, 1H). Example 33 5α-Hydroxy-6β-(1'-piperidino)-17β-acetoxy-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 5α,17β-dihydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)- androstane, essentially following the procedure described in Example 28, with a yield of 80 %. ¹H-NMR spectrum (CDCl₃): δ 0.83 s (3H), 1.09 s (3H), 2.10 s (3H), 2.27 s (3H), 4.8 d (J=9Hz, 1H). Example 34 17β-Acetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting rom 5α,17β-dihydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 28, with a yield of 98 %. Melting point: 87 °C ¹H-NMR spectrum (CDCl₃): δ 0.80 s (3H), 1.06 s (3H), 2.08 s (3H), 2.23 s (3H), 3.68 s (3H), 4.75 d (J=10Hz, 1H). Example 35 3β,17β-Diacetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(1'-piperidino)-androstane The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 28, with a yield of 63 %. ¹H-NMR spectrum (CDCl₃): δ 0.79 s (3H), 1.09 s (3H), 2.03 s (3H), 2.08 s (3H), 3.68 s (3H), 4.76 d (1H), 5.1 br (1H). Example 36 3β,17β-Diacetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 28, with a yield of 59 %. Example 37 5α,17β-Dihydroxy-6β,16β-bis(4',4'-dimethyl-1'-piperazino)-androstane dibromide 1.2 g (2.24 mmoles) of 5α,17β-dihydroxy-6β,16β-bis-(4'-methyl-1'-piperazino)-androstane are dissolved in 80 ml of a 1:1 mixture of acetone and ethanol, and 20.6 ml (0.03 mole) of a 1.46 molar acetonic methyl bromide solution are added to the first solution. The flask is sealed and is allowed to stand in darkness. After two days the reaction mixture is partially evaporated under reduced pressure, the precipitated crystals are filtered off and purified by means of acetone. Yield: 1 g (60 %) of the title compound Melting point: 230 ° to 232 °C ¹H-NMR spectrum (D₂O): δ 0.86 s (3H), 1.07 s (3H), 3.36 s (12 H). Example 38 5α,17β-Dihydroxy-6β-(1'-piperidino)-16β-(4',4'-dimethyl-1'-piperazino)-androstane bromide The title compound is prepared starting from 5α,17β-dihydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane, in an acetone solution, following the procedure described in Example 37. Yield: 70 % Melting point: 248 ° to 252 °C ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.78 s (3H), 1.09 s (3H), 3.21 s (6H). Example 39 5α,17β-Dihydroxy-6β-(4',4'-dimethyl-1'-piperazino)-16β-(1'-methyl-1'-piperidino)-androstane dibromide The title compound is prepared starting from 5α,17β-dihydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane, in a 1:1 mixture of ethanol and chloroform, essentially following the procedure described in Example 37. Yield: 72 % Melting point: 240 ° to 251 °C ¹H-NMR spectrum (MeOD): δ 0.9 s (3H), 1.11 s (3H), 3.2 and 3.7 s (2 x 3H). Example 40 3β,5α,17β-Trihydroxy-6β-(4',4'-dimethyl-1'-piperazino)-16β-(1'-methyl-1'-piperidino)-androstane dibromide The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane, in an acetone solution, essentially following the procedure described in Example 37. Yield: 96 % Melting point: 273 ° to 275 °C ¹H-NMR spectrum (D₂O): δ 0.83 s (3H), 1.08 s (3H), 3.1 s (9H), 4.0 br (2H). Example 41 3β,5α,17β-Trihydroxy-6β-(1'-piperidino)-16β-(1'-methyl 1'-piperidino)-androstane bromide The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β,16β-bis(1'-piperidino)-androstane, in an acetone solution, essentially following the procedure described in Example 37. Yield: 83 % Melting point: 238 ° to 242 °C ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.85 s (3H), 1.11 s (3H), 3.2 s (3H). Example 42 3β,5α,17β-Trihydroxy-6β-(1'-piperidino)-16β-(4',4'-dimethyl-1'-piperazino)-androstane bromide The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane, in an acetone solution, essentially following the procedure described in Example 37. Yield: 92 % Melting point: 214 ° to 220 °C ¹H-NMR spectrum (CDCl₃/CD₃OD 8-2): δ 0.75 s (3H), 1.08 s (3H), 3.2 s (6H), 3.9 br (2H). Example 43 3β,5α,17β-Trihydroxy-6β,16β,-bis(4',4'-dimethyl-1'-piperazino)-androstane diiodide The title compound is prepared starting from 3β,5α,17β-trihydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane, in a 3:1 mixture of acetone and methanol, essentially following the procedure described in Example 37. Yield: 85 % Melting point: 256 ° to 258 °C Example 44 3β,17β-Diacetoxy-5α-hydroxy-6β,16β-bis(4',4'-dimethyl-1'-piperazino)-androstane dibromide 5 g (0.008 mole) of 3β,17β-diacetoxy-5α-hydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-androstane are dissolved in a mixture of 100 ml of dry acetone and 5 ml of dichloromethane, and a solution of 3.22 g (0.033 mole) of methyl bromide in 18 ml of acetone is added to the first solution. The reaction mixture is allowed to stand at room temperature for 24 hours. The precipitation of the crystalline title compound starts within about 15 minutes. When the reaction is complete, the crystals are filtered off, washed thoroughly with acetone and dried until steady weight. Yield: 6.3 g (99 %) of the title compound Melting point: 240 ° to 245 °C ¹H-NMR spectrum (CDCl₃): δ 0.83 s (3H), 1.07 s (3H), 2.03 s (3H), 2.12 s (3H), 3.42 br (12H), 4.79 d (1H). Example 45 3β,17β-Diacetoxy-5α-hydroxy-6β-(4',4'-dimethyl-1'-piperazino)-16β-(1'-methyl-1'-piperidino)-androstane dibromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 44, with a yield of 75 %. Melting point: 268 ° to 270 °C (decomp.) ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.90 s (3H), 1.08 s (3H), 2,01 s (3H), 2.16 s (3H), 3.23 br (9H), 4.3 br (1H), 5.15 br (1H), 5.25 d (1H). Example 46 5α-Hydroxy-6β,16β-bis(4',4'-dimethyl-1'-piperazino)-17β-acetoxy-androstane dibromide The title compound is prepared starting from 5α-hydroxy-6β,16β-bis(4'-methyl-1'-piperazino)-17β-acetoxy-androstane, essentially following the procedure described in Example 44, with a yield of 79 %. Melting point: 190 °C (decomp.) ¹H-NMR spectrum (D₂O): δ 0.77 s (3H), 1.06 s (3H), 2.11 s (3H), 3.16 s (12H), 4.8 d (1H). Example 47 5α-Hydroxy-6β-(1'-piperidino)-17β-acetoxy-16β-(4',4'-dimethyl-1'-piperazino)-androstane bromide The title compound is prepared starting from 5α-hydroxy-6β-(1'-piperidino)-17β-acetoxy-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 44, with a yield of 80 %. Melting point: 198 ° to 203 °C ¹H-NMR spectrum (CDCl₃): δ 0.81 s (3H), 1.09 s (3H), 2.14 s (3H), 3.51 s (6H), 4.78 d (J=9Hz, 1H). Example 48 3β,17β-Diacetoxy-5α-hydroxy-6β-(1'-piperidino)-16β-(4',4'-dimethyl-1'-piperazino)-androstane bromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-(1'-piperidino)-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 44, with a yield of 51.5 %. Melting point: 208 ° to 215 °C (decomp.) ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.81 s (3H), 1.09 s (3H), 2.01 s (3H), 2.08 s (3H), 3.26 s (6H), 4.69 d (J=9Hz, 1H), 5.0 br (J=20Hz, 1H). Example 49 3β,17β-Diacetoxy-5α-hydroxy-6β-[4'-allyl-4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-allyl-4'-methyl-1'-piperazino)-androstane dibromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 44, with a yield of 82 %. ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.81 s (3H), 1.06 s (3H), 2.01 s (3H), 2.08 s (3H), 3.15 s (3H). Example 50 3β,17β-Diacetoxy-5α-hydroxy-6β-[4'-methyl-4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4',4'-dimethyl-1'-piperazino)-androstane dibromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 44, with a yield of 88 %. Melting point: 230 °C (decomp.) ¹H-NMR spectrum (CDCl₃): δ 0.80 s (3H), 1.15 s (3H), 2.04 s (3H), 2.11 s (3H), 3.07 s (3H), 3.18 s (6H), 3.73 s (3H). Example 51 3β,17β-Diacetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-4'-methyl-1'-piperazino]-16β-(1'-methyl-1'-piperidino)-androstane dibromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-[4'-methoxycarbonylethyl)-1'-piperazino]-16β-(1'-piperidino)-androstane, essentially following the procedure described in Example 46, with a yield of 93 %. Melting point: 235 ° to 240 °C (decomp.) ¹H-NMR spectrum (CDCl₃): δ 0.90 s (3H), 1.07 s (3H), 2.03 s (3H), 2.2 s (3H), 3.4 s (6H), 3.8 s (3H), 5.4 d (1H). Example 52 17β-Acetoxy-5α-hydroxy-6β-[4'-methyl-4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4',4'-dimethyl-1' piperazino)-androstane dibromide The title compound is prepared starting from 17β-acetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-1'-piperazino)-androstane, essentially following the procedure described in Example 44, with a yield of 85 %. Melting point: 230 ° to 240 °C (decomp.) ¹H-NMR spectrum (D₂O): δ 0.76 s (3H), 1.06 s (3H), 2.12 s (3H), 3.03 s (3H), 3.16 s (6H), 3.72 s (3H). Example 53 3β,17β-Diacetoxy-5α-hydroxy-6β-(1'-piperidino)-16β-(1'-methyl-1'-piperidino)-androstane bromide 0.5 g (0.89 mmole) of 3β,17β-diacetoxy-5α-hydroxy-6β,16β-bis(1'-piperidino)-androstane are dissolved in a mixture of 5 ml of acetone and 2 ml of dichloromethane, and a solution of 0.3 ml (5.5 mmole ) of methyl bromide in 3 ml of acetone is added to the first solution. The flask is sealed and allowed to stand at room temperature for 18 hours. The reaction mixture is diluted with ether and the precipitated substance is filtered off. Yield: 0.55 g (95 %) of the title compound Melting point: 213 ° to 216 °C ¹H-NMR spectrum (CDCl₃): δ 0.8 s (3H), 1.07 s (3H), 2.0 s (3H), 2.12 s (3H), 2.16 s (3H), 2.73 br (1H), 3.33 s (3H), 5.4 d (1H). Example 54 3β,17β-Diacetoxy-5α-hydroxy-6β-(4'-methyl-4'-propyl-1'-piperazino)-16β-(1'-piperidino)-androstane bromide 1.0 g (0.0017 mole) of 3β-17β-diacetoxy-5α-hydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-piperidino)-androstane are dissolved in 10 ml of acetone and 2 ml (0.022 mole) of propyl bromide are added to the solution. The reaction mixture is refluxed for 4 hours, cooled to room temperature and the product is precipitated with ether. Yield: 207 ° to 210 °C ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.8 s (3H), 1.06 s (3H), 2.03 s (3H), 2.1 s (3H), 3.2 s (3H), 4.8 d (1H), 5.0 (1H). Example 55 3β,17β-Diacetoxy-5α-hydroxy-6β-(4'-methyl-4'-propyl-1'-piperazino)-16β-(1'-methyl-1'-piperidino)-androstane dibromide 0.6 g (0.86 mmole) of 3β,17β-diacetoxy-5α-hydroxy-6β (4'-methyl-4'-propyl-1'-piperazino)-16β-(1'-piperidino)-androstane bromide are dissolved in 5 ml of acetone and 10 ml (5.2 mmoles) of acetonic methyl bromide are added to the solution. The flask is sealed and allowed to stand at room temperature of 24 hours. The reaction mixture is diluted with ether and the precipitated product is filtered off. The crude product is dissolved in ethyl alcohol, decoloured with charcoal, precipitated with ether and filtered. Yield: 0.6 g (88 %) of the title compound Melting point: 245 ° to 250 °C (decomp.) ¹H-NMR spectrum (D₂O): δ 0.9 s (3H), 1.03 s (3H), 2.03 s (3H), 2.2 s (3H), 3,16 s (3H), 3.3 s (3H), 5.1 br (1H), 5.25 d (1H). Example 56 3β,17β-Diacetoxy-5α-hydroxy-6β-(4'-methyl-1'-piperazino)-16β-(4',4'-dimethyl-1'-piperazino)-androstane bromide 4 g (0.0048 mole) of 3β,17β-diacetoxy-5α-hydroxy-6β-[4'-(methoxycarbonylethyl)-4'-methyl-1'-piperazino]-16β-(4',4'-dimethyl-1'-piperazino)-androstane dibromide are dissolved in 20 ml of ethanol, the solution is cooled to 0 °C and the pH of the solution is adjusted to 8.5 to 8.9 with a 1 N aqueous sodium hydroxide solution of 0 °C, under control with potentiometric titration. Ethanol is then distilled off under reduced pressure, at an ambient temperature of 30 °C. The residue is treated with dichloro methane, and the insoluble sodium bromide by-product is filtered off by means of charcoal. This treatment is repeated two more times. Dichloromethane is distilled off and the residue is crystallized from acetone. Yield: 2.5 g (77 %) of the title compound Melting point: 230 ° to 235 °C (decomp.) ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.81 s (3H), 1.1 s (3H), 2.04 s (3H), 2.12 s (3H), 2.42 s (3H), 3.38 s (6H), 4.78 d (J=10Hz, 1H), 5.1 br (1H). Example 57 3β,17β-Diacetoxy-5α-hydroxy-6β-(4'-allyl-1'-piperazino)-16β-(4'-methyl-4'-allyl-1-piperazino)-androstane bromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-[4'-allyl-4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4'-methyl-4'-allyl-1'-piperazino)-androstane dibromide, essentially following the procedure described in Example 56, with a yield of 95,5 %. Melting point: 180 ° to 185 °C ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.8 s (3H), 1.1 s (3H), 2.03 s (3H), 2.11 s (3H), 3.23 s (3H), 4.25 m (4H). Example 58 3β,17β-Diacetoxy-5α-hydroxy-6β-(4'-methyl-1'-piperazino)-16β-(1'-methyl-1'-piperidino)-androstane bromide The title compound is prepared starting from 3β,17β-diacetoxy-5α-hydroxy-6β-[4'-methyl-4'-(methoxycarbonylethyl)- 1'-piperazino]-16β-(1'-methyl-1'-piperidino)-androstane dibromide, essentially following the procedure described in Example 56, with a yield of 74 %. Melting point: 220 ° to 230 °C ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.83 s (3H), 1.1 s (3H), 2.0 s (3H), 2.18 s (3H), 2.3 s (3H), 3,32 s (3H), 4.6 br (1H), 5.05 br (1H), 5.26 d (1H). Example 59 5α-Hydroxy-17β-acetoxy-6β-(4'-methyl-1'-piperazino)-16β-(4',4'-dimethyl-1'-piperazino)-androstane bromide The title compound is prepared starting from 5α-hydroxy-17β-acetoxy-6β-[4'-methyl-4'-(methoxycarbonylethyl)-1'-piperazino]-16β-(4',4'-dimethyl-1'-piperazino)-androstane dibromide, essentially following the procedure described in Example 56, with a yield of 85 %. Melting point: 215 ° to 225 °C (decomp.) ¹H-NMR spectrum (CDCl₃/CD₃OD): δ 0.8 s (3H), 1.07 s (3H), 2.1 s (3H), 2.27 s (3H), 3.3 s (6H), 4.77 d (1H).

Claims: Compounds of formula (VI) or of formula (V) wherein Y" is hydrogen, hydroxy or an OAc group, wherein Ac is an alkylcarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, and X is a bromine atom.

Inventors: HORVATH, JUDIT, KARPATI, EGON, LOVASNEE-MARSAI, MARIA, RIESZ, MIKLOS, SZPORNY, LASZLO, TUBA, ZOLTAN
Applicants: RICHTER GEDEON VEGYESZETI GYAR R.T.
Application year: 1986
Main classification: C07J13
IPC codes: A61P21, A61K31, C07J13, C07J43, C07J41, C07J71