CS195304B2 - Process for preparing derivatives of 6-amino-5 beta 19-cycloandrostane - Google Patents

Description

Proprietor of the patent RICHTER GEDEON VEGYÉSZE-TY GYÁR R.T., BUDAPEST (MLR) (54) Process for the preparation of 8-amino-S, 19-cycloandrostane derivatives

The invention relates to a process for the preparation of novel 6-amino-5 / 3,19-cycloandrostane derivatives of the general formula I,

X is = CH (OR), = CO or = C = N — OR 1, and

Y represents a group of the formula = CO, = CH (OR 1), = C = NOR 1, = C (OR 1) —CsCH or

19S3Q4 in which R represents a hydrogen atom, a C1-4 alkyl group or a 2-5 carbon acyl group, and R1 a hydrogen atom or a 2-5 carbon acyl group;

R 2 represents a hydrogen atom or a straight or branched carbon chain aliphatic group having 1 to 5 carbon atoms which is optionally substituted by a hydroxyl group, a 1-4 carbon atom alkoxy or a 1-4 carbon acyloxy group, a 3-8 alicyclic group C 7 -C 10 allyl or aralkyl, optionally substituted on the aromatic ring with C 1 -C 4 alkoxy;

R 3 has the same meaning as R 2, but when R 2 is secondary or tertiary. an alkyl group or an alicyclic group, R5 can only represent a hydrogen atom, and if R5 is an aralkyl group, Rj can only represent a hydrogen atom or a primary alkyl group having 1 to 4 carbon atoms, and further " '.

R 2 and R 3, together with the nitrogen to which they are attached, can be a pyrrolidine, piperdine, morphine, or a morphine group. piperazine, N-alkylpiperazine or N-oxyalkylpiperazine groups having from 1 to 4 carbon atoms in alkyl or N-benzylpiperazine, and their acid addition salts.

When R is C1 -C6 alkyl, this may preferably be methyl. When R represents a C 2 -C 5 acyl group, this may preferably be an acetyl or propionyl group. .

When R 1 represents a C 2 -C 5 acyl group, it may preferably be an acetyl or a pionyl group.

When R a represents a straight-chain alkyl group having 1 to 5 carbon atoms, it may preferably be a methyl, ethyl, n-propyl or n-butyl group. Indicates if R ₂ branched alkyl group may be a group is preferably isopropyl, isobutyl or tertiary butyl. It represents when R ₂ an aliphatic group substituted by a hydroxyl group, this group may be conveniently hydrGxyethylová 2-or 3-hydroxypropyl. When R2 represents an aliphatic group bearing an alkoxy group, the group may preferably be a 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl group. If R 2 represents an aliphatic group bearing an acyloxy substituent, it may preferably be a 2-acetoxyethyl, 3-acetoxypropyl, 2-trimethoxybenzoyl ethyl or 3-trimethoxybenzoylpropyl group. When R2 represents an alicyclic group, it may preferably be a cyclopropyl or cyclohexyl group. When R represents _{2-unsubstituted} aralkyl group, this group may be preferably a benzyl group. When R2 represents an aralkyl group substituted with an alkoxy group, the group may be a p-methoxybenzyl group.

When R 2 and R 5 together with the nitrogen atom to which they are attached represent an N-alkylpiperazine group, this group may preferably be an N-methylpiperazine group. When R 2 and R 5 together with the nitrogen atom represent an N-oxyalkylpiperazine group, this may preferably be an N- (2-hydroxyethyl) piperazine or N- (3-hydroxypropyl) piperazine group. When R @ 2 and R @ 3 together with the nitrogen atom represent an N- (alkoxyalkyl) piperazine group, the group may preferably be N- (2-methoxyethyl) piperazine, N- (3-methoxypropyl) piperazine or N- (3-ethoxypropyl) piperazine group. . Represent where R ₂ and R together with the nitrogen of N- (acyloxyalkyljpiperazinovou group, this group may be preferably N- (2-acetoxyethyljpiperazinová or N- (3-trimethoxybenzoylpropylj piperazlnová group constitutes 11 R ₂ and R together with the nitrogen Naralkylpiperazinovou group, the group may preferably be an N-benzylpiperazine group.

Numerous steroids, naturally occurring or prepared by a semi-synthetic or synthetic route, are known to have excellent therapeutic value. Thus, for example, from the group of semisynthetic steroids containing a nitrogen atom in the molecule, it has found widespread application in the past few years to perform anesthesia in surgical procedures of pancuronium bromide, which outperforms d-tubocurarine and has more advantageous properties.

It is an object of the present invention to provide novel steroid derivatives containing a nitrogen atom in their molecule which possess outstanding pharmacological properties.

The invention is based on the finding that when steroid II is mentioned,

in which it denotes

Y ‘carbonyl or ethylenketal group,

R 4 is C 1-4 alkyl or acyl. a group having 2-5 carbon atoms, and a

R @ 5 is C1-4 alkyl, phenyl or tolyl, reacted with a secondary or primary amine of formula III,

R a in which R 2 and R 5 are as defined above, gives compounds of formula I wherein R ₂ and R 3 are as defined above, X represents a group of the formula = CH (OR) in which R is as defined above, and Y 'represents an ethylene ketal group.

Tadanier and Cole ·. (Tetrahedron Letters 1964, 1345) described the reaction of 3/2-methoxy-19-mesyloxy- ^{5 5} -androsten-17-one, a compound belonging to the group of compounds of formula II, with a buffer containing potassium acetate in aqueous acetone. Hydrolysis of the reaction product gave 3β-methoxy-6α-hydroxy-5,19-cycloandrostane-17-dione. At about the same time, Halpern and coworkers (Steroids 4, 1 [1964]] reported that heating 3/3-acetoxy-19-tosyloxy- ^{5 5} -androsten-17-one in pyridine to boil yielded 3/3-acetoxy-5. According to British Patent Specification 1049 317, compounds of formula II can be converted into derivatives in aqueous acetone, in the presence of a potassium acetate buffer. hydroxy-5 (3,19-cycloandrostane). Tadanier reports (J. Org. Chem. 31, 3204 ^: [1966] by heating to boiling the above-mentioned 3,3-methoxy-19-mesyloxy- ^{5 5} -androsten-17-one in glacial acetic acid in the presence of acetic anhydride and hydrolyzing the resulting product to give the corresponding 3 (3-methoxyl-6β- (hydroxymethyl) ester-5 (10) en-17-one).

The above data suggests that although the reactions of the compounds of formula I with potassium acetate buffer in acetone, pyridine and then glacial acetic acid are well investigated, the literature on the reaction of the compounds cannot be found to date. of formula (II) with secondary or primary amines.

The novel 6-amino-5 (3,19-cycloandrostane derivatives of the formula I in which X, Y, f and R 1 are as defined above) and their acid addition salts; a steroid of formula II in which Y 1, R 1 and R 5 are as defined above reacts with a secondary or primary amine of formula III wherein R 2 and R 5 are as defined above, and the compound of formula I obtained; wherein R 2 and R 2 are as defined above, X is a group of formula = CH (OR), in which R is as defined above, and Y is a carbonyl or ethylene ketal group, optionally converted by hydrolysis and / or by oxidation and / or oxime formation and / or; by ethinylation and / or acylation and / or reduction to another compound of formula I, and the compound of formula I thus obtained is optionally converted by reaction with a pharmaceutically acceptable acid to the corresponding addition salt.

The pharmacological investigation of the novel steroids of formula (I) has been carried out with their therapeutically acceptable water-soluble salts, usually with their hydrochloride. The group of novel compounds of formula I exhibits in rats. antagonistic effect; Effective doses of the substances are 2 to 10 mg / kg by subcutaneous administration. The diuretic activity of the compounds of formula I is almost the same as that of spirolactone, i.e., β-lactone of (3- (7α-acetylthio-17 (3-hydroxy-3-oxoandrost-4-en-17α-yl) propionic acid) which is The compounds of formula I have a favorable acute toxicity in castrated male mice (at 1.5 mg for 2 weeks) and in infantile, male rats. (9 mg / 2 weeks) no androgenic, anaboic, antiandrogenic, antigonadotropic or thymolytic effect of the compounds was observed, and no uterotropic and antiestrogenic effects were observed in the infantile female mice.

The process according to the invention is preferably carried out by dissolving 1 mole of a compound of formula II in 2 to 20 moles of an amine of formula III or an equal amount of compounds IIa _: III dissolved or suspended in dimethylformamide or dimethylacetamide or aliphatic alcohol. The reaction mixture is heated at atmospheric pressure or in a sealed tube to a temperature in the range of 70 to 180 ° C for a period of from 1 to 10 hours. Excess reagent (III) is removed by distillation at. under reduced pressure, and / or by dissolving the reaction mixture in an organic solvent that is not mixed with water, followed by washing the solution with water. The organic portion is dried, the solvent is distilled off, the residue is dissolved in anhydrous ethanol or ether and the basic product is precipitated in the form of a salt by addition of an ethanolic or ethereal solution of a suitable acid, for example hydrochloric acid, maleic acid; perchlorates. and the like. . The desired compound of formula I wherein Rx and R5 are as defined above, X is a group of formula = CH (OR), wherein R is as defined above, and Y is a carbonyl or ethyl ethyl ketal group, is obtained from the resulting mixture crystallization and / or, upon liberation of the base, from the salt by column chromatography. The product thus obtained can be converted to another compound of the formula I by known methods, by hydrolysis, oxidation, oxime formation / ethinylation, acylation, reduction or a combination of these methods.

The steroids of formula II used in the process of the invention as starting materials are compounds already described in the literature. The physical constants of 3 (S-acetoxy-19-tosyloxy- ^{5 5} -androsten-17-one) were described in 1963. (Chem. And Ind. 1963, 1.16) and its preparation was published. in 1966 by Halperne et al., (Org. Chem .; 31, 693; [1966]) The preparation of 3- (3-methoxy-19-hydroxy-A ⁵ -androsten-17-ones) has been described by Tadanir et al. 1963 (J. Org. Chem. 28, 1744 [1963]] Compounds of formula II - with the exception of 17-ethylene ketal derivatives, are described as starting materials in British Patent Specification 1,049,317. The 17-ethylenedioxy compounds can be prepared from the latter. by known methods.

The preparation of the novel 6-amino-5 (3,19-cycloandrostane derivatives) is illustrated by the following non-limiting examples.

He did

3- (3-Acetoxy-6H-dimethylamino-17-oxo-5,3,19-cycloandrostane hydrogen chloride)

A mixture of 5 00 g (0.01 mol) of 3- (3-acetoxy-17-oxo-19-tosyloxy-A ⁵ -androstene) and 20 ml of anhydrous Ν, dim-dimethylacetamide containing 22% by weight of dimethylamine is heated at room temperature for 7 hours. The tube is poured into 400 ml of ice-water, stirred for 15 minutes, the precipitate formed is filtered off, washed with water and dissolved in 150 ml of benzene.The benzene solution is washed with water, dried and the solvent is dried. The residue is dissolved in 20 ml of anhydrous ethanol, the solution is neutralized with ethanolic perchloric acid solution and the mixture is allowed to stand at 0 DEG C. to -5 DEG C. for two hours. The precipitated crystalline substance is filtered off, washed with anhydrous ethanol and dried. under vacuum at 60 ° C to give 1.70 g of product, mp 200-203 ° C, mp 208-209 ° C after recrystallization from methanol.

Example 2

3/3-Acetoxy-6H-diethylamino-17-oxo-5 (3,19-cycloandrostane) hydrogen chloride

A mixture of 10 g (0.02 mol) of 3- (3-acetoxy-17-oxo-19-tosyloxy- ^{5 5} -androstene) and 25 ml (0.24 mol) of freshly distilled diethylamine was heated in a sealed tube at 130 ° C for 5 hours. After cooling, the volatiles were removed by distillation under reduced pressure, the residue was triturated with 50 ml of benzene, the precipitate formed was filtered and washed with benzene, and the combined filtrates were washed with water, dried and the solvent was distilled off under reduced pressure. 20 ml of anhydrous ethanol, the solution is neutralized with ethanolic perchloric acid solution and allowed to stand for several hours.The precipitated crystalline material is filtered off, washed with anhydrous ethanol and dried under vacuum at 60 [deg.] C. to give 3.20 g (32%). m.p. 1.181-185 ° C, after recrystallization from methanol, the melting point is increased to 184-185 ° C.

Example 3

3/3-Acetoxy-6H-piperidino-17-oxo-5H, 19-cycloandrostane hydrogen chloride

Method (a):

g (0.04 mol) of 3- (3-acetoxy-17-oxo-19-tosyloxy- ^{5 5} -androstene) was dissolved hot in 20 ml (0.20 mol) of freshly distilled piperidine and heated to reflux for 5 hours 150 DEG C. After cooling, the excess piperidine was distilled off under reduced pressure and the residue was triturated with 50 ml of benzene, the precipitated piperidine salt was filtered off, washed with 2 x 10 ml of benzene, and the traces of piperidine were removed by shaking. water, the benzene was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the viscous oily residue obtained was dissolved in 20 ml of anhydrous ethanol, and the solution was neutralized with ethanolic perchloric solution. After drying under vacuum at 60 ° C the product weighs

10.5 g (51%), mp 206-210 ° C; recrystallization from methanol, mp 214-216 ° C. Mp 202-205 ° C (from ethanol).

Method (b):

To a solution of 20 g (0.04 mol) of 3 N-acetoxy-17-oxo-19-tosyloxy-Á ⁵ -androstene in 200 mL of anhydrous dimethylformamide was added. 12 ml (0.12 mol) of freshly distilled piperidine. The reaction mixture was heated at 100 ° C for 10 hours, then the solvent was distilled off under reduced pressure and the residue was further worked up as described above for method a). A product identical to that prepared according to method a) is obtained; yield 41%.

Method (c):

To a solution of 20 g (0.04 mol) of 3/3-acetoxy-17-oxo-19-tosyloxy- ^{5 5} -androstene in 80 ml of anhydrous isopropanol is added 12 ml (0.12 mol) of freshly distilled piperidine and the mixture is heated 3 hours at reflux. After cooling, the solvent was distilled off under reduced pressure and the residue was further worked up as described under method a). A product identical to that prepared according to method a) is obtained; 40% yield.

Example 4.

3/3-Acetoxy-6H- (N-methylpiperazino) -17-oxo-5, 3,19-cycloandrostane hydrochloride

The procedure described in Example 3 was followed but using 20 g (0.04 mol) of 3/3-acetoxy-17-oxo-19-tosyloxy-A ⁵ -aididene and 20 ml of N-methylpiperazine as starting materials. and the product is isolated as the hydrochloride. Yield: 9.00 g (48%); tt 213-215 ⁶ C.

Example 5

3/3-Acetoxy-6'-morpholino-17-oxo-5 ', 19-cycloandre hydrogen chloride

The procedure described in Example 3 was followed, but starting from 20 g (0.047 mol) of 3 H -acetoxy-17-oxo-19-mesyloxy- ^{5 5} -androstene and 20 mL (0.23 mol). freshly distilled morpholine. Yield: 11.80 g (49%); mp 202-204 ° C; after recrystallization from methanol-water, mp 207-208 ° C. Melting point of hydrogen chloride: 214-217 ° C (from ethanol).

Example 6 '

33-Acetoxy-6,6-tert-butylamino-17-oxo-5,13,19-cycloandrostane hydrochloride.

A mixture of 10 g (0.0.2 mol) of 3 H -acetoxy-17-oxo-19-tosyloxy-Á ⁵ -androstene and 22 ml (0.21 mol) of freshly distilled tertiary butylamine was heated in a sealed tube at 150 ° C for 5 hours. The reaction mixture was worked up as described in Example 2, except that the residue obtained by evaporating the benzene solution to dryness was dissolved in anhydrous ether, and the base hydrochloride was prepared by adding saturated solutions of dry hydrogen chloride in anhydrous ether. Yield: 3.9 g (45%) of product, mp, 207-208 ° C; after recrystallization from anhydrous ethanol, mp 208-210 ° C. Example 7

3.beta.-acetoxy-17-oxo-19-tosylQxy-.alpha.- ^5- aancirostene hydrochloride is dissolved in 20 ml (0.02 mol) of (.02 mol). .0.18 mol) freshly distilled. of hot cyclohexylamine and the reaction mixture was heated to reflux in a 160 ° C oil bath for 5 hours. After cooling the excess cyclohexylamine was distilled off under reduced pressure, the residue was stirred with 50 ml of benzene and the precipitate formed was filtered off and washed with 2 x 10 ml of benzene. Traces of cyclohexylamine are removed from the combined benzene fractions by shaking, into water, the benzene solution is dried and the solvent is evaporated under reduced pressure. The thick, viscous oily residue was dissolved in 30 ml of ether and neutralized with saturated qtheric anhydrous hydrogen chloride solution. The mixture was allowed to stand for two hours. The precipitate formed was filtered off, washed with ether. and dried in. vacuum at 60 ° C; 8.50 g of crude product are obtained.

The crude product was dissolved in 200 ml of water, the aqueous solution was shaken with 3 x 30 ml of benzene, the aqueous portion basified with 10% sodium hydroxide solution and the base was shaken with 3 x 50 ml of benzene. The benzene extracts were combined, the solution was washed, dried and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous ethanol and neutralized with a saturated ethanolic solution of anhydrous hydrogen chloride. The neutral solution was evaporated, the residue is triturated with acetone and the crystals were filtered, washed with acetone and dried in vacuo at 60 DEG C. ⁹ to obtain 5.30 g of product, mp 219 -221 · ^Q C; after recrystallization from a mixture of acetone and hexane, the substance has tl 223-225 ° C.

Example 8

3β-Acetoxy-6β-benzylamino-17-ethylenedioxy-5,13,19-cycloacetamide hydrochloride

1.0 g (1.84 mmol) of 3β-acetoxy-17-ethylenedioxy-19-tosyloxy- ^{5 5} -androstene was dissolved in a mixture of 3.00 mL of N, N-dimethylliacetamide and 1.00 mL (9.10) with heating. mmol) of freshly distilled benzylamine and the reaction mixture is heated at room temperature for 3.5 hours. Mp 110 ° C. After cooling down. the homogeneous solution is poured slowly, with stirring / into 15 ml of ice water, stirred for 15 minutes, the precipitate formed is filtered off, dissolved in 60 ml of benzene and the solution is washed with water. After drying, the solvent is distilled off under reduced pressure, the residue is dissolved in 15 ml of anhydrous ethanol, neutralized with a saturated ethanolic solution of anhydrous hydrogen chloride and the solution is evaporated to dryness under reduced pressure at a temperature not exceeding 50 ° C. The viscous oily residue obtained is converted to a crystalline form after 1 hour. trituration with a small amount of acetone. The crystalline product is filtered off, washed with acetone and dried under vacuum at 0 ° C. There was obtained 0.45 g (44%) of the substance, m.p. 234-236 ° C; after recrystallization from methanol, the melting point rose to 239-241 ° C. '. J;:.

Example 9 L. .. ·. ··

3'-Acethoxy-6S-cyclohexylamino-17-ethylenedioxy-5d, 19-cycloandrostane hydrochloride.

1.00 g (1.84 mmol) of 3,3-acetoxy-17-ethylenedioxy-19-tosyloxy- ^{5 5} -androstene are dissolved in a hot mixture of 3.00 ml of N, N-dimethylacetamide and 1.00 ml of (8, 74 mmol) of freshly distilled cyclohexylamine and the reaction mixture were heated at 110 ° C for 2.5 hours. The procedure was followed in the same manner as described in Example 8. Yield: 0.50 g (50%) of product, mp 218-220 ° C. After recrystallization from acetone-hexane, m.p 224-227 C. ^Q

Example 10

3/3-Acetoxy-17-ethylenedioxy-6H-cyclopropylamino-5 / 3,19-cycloandrostane hydrochloride g (18.4 mmol) of 3/3-acetoxy-17-ethylenedioxy-19-tasyloxy- ^{5 5} -androstene dissolve in heating in a mixture of 6.4 ml (92.0 mmol) of freshly distilled cyclopropylamine and 50 ml of Ν, Ν-dimethylacetamide and the solution was heated to 95 ° C for 5 hours. After cooling, the reaction mixture is poured slowly, with stirring, into 1 liter of ice water, the precipitated precipitate is quickly filtered off, washed with water and dissolved on the filter in 150 ml of benzene. The benzene solution was washed with water, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue is dissolved in 30 ml of ether, neutralized with a saturated ethereal solution of dry hydrogen chloride, the precipitate formed is filtered off, washed with ether and then with petroleum ether and dried by infrared radiation. The crude product thus obtained (4.80 g) is suspended in benzene, the solid is filtered off, washed with benzene / petroleum ether 1: 1 and dried under vacuum at 60 ° C. 3.80 g (44%) of the product having a mp of 212-214 ° C are obtained. After recrystallization from isopropanol, mp 218-220 ° C.

Example 11

3/3-Acetoxy-17-oxo-6? -Allylamino-5 / 3,19-cycloandrostane hydrochloride

5.44 g (0.01 mol) of 3S-acetoxy-17-ethylenedioxy-19-tosyloxy-A ⁵ -androstene and 3 ml (0.04 mol) of freshly distilled allylamine are dissolved in 20 ml of anhydrous za, with heating, Of Ν-dimethylacetamide and the solution was heated

2.5 hours at 110 ° C. The reaction mixture is cooled to room temperature, added dropwise to 200 ml of ice-water with vigorous stirring, the precipitate formed is rapidly filtered off and dissolved in benzene on the filter. The benzene solution was washed with water, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous ethanol, the pH of the solution was adjusted to 4 with saturated ethanolic dry hydrogen chloride solution and the solution was left at room temperature overnight. The solvent was distilled off under reduced pressure at 60 ° C and the viscous oily residue was triturated with ether to solidify. The crude product was filtered off, washed with ether and dried under an infrared lamp. 2.00 g (47.5%) of m.p. 208-211 ° C are obtained. After recrystallization from Isopropanol, the compound has 1.1. 215-216 ° C.

Example 12

3'-Methoxy-17-oxo-6'-piperidino-5 ', 5'9-cycloandrane hydrochloride g (0.013 mol) of 3'-methoxy-17-oxo-19-mesyloxy- ^{5 5} -androstene is dissolved with heating in 15 ml of anhydrous N, N-dimethylacetamide and 5.2 ml (0.052 ml) of freshly distilled piperidine. The reaction mixture is heated at 110 ° C for 4 hours, then cooled and the solution is poured slowly into 500 ml of ice-water with stirring. The mixture is stirred for 10 minutes, then the precipitate formed is filtered off and dissolved in 100 ml of benzene on the filter. The benzene solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The residue is dissolved in 20 ml of anhydrous ethanol, neutralized with a saturated ethanolic solution of dry hydrogen chloride, the neutral solution is evaporated to dryness under reduced pressure and the residue is triturated with benzene. The solidified product is filtered off, washed with a small amount of benzene, then with a 1: 1 mixture of acetone and petroleum ether and dried in a vacuum desiccator at 60 ° C. 2.70 g (51%) of m.p. 217-220 ° C are obtained. After recrystallization from isopropanol, 1.1. 222-224 ° C.

Example 13

3/3-Acetoxy-6β-piperidino-5 (3,19-cycloandrostane-17-oxime hydrochloride g (0.004 mol) 3/3-acetoxy-6β-piperidino-17-oxo-5 / 3,19- hydrogen chloride The cycloandrostane was added with vigorous stirring to a mixture of 5 ml of a 20% aqueous sodium hydroxide solution and 30 ml of benzene, and stirred for 15 minutes at room temperature After transfer to a separatory funnel, the benzene layer was separated and the aqueous was shaken twice. The benzene fractions were combined, washed with water, dried, and the solvent was distilled off under reduced pressure to give 1.40 g of a viscous oily residue which was dissolved in 30 ml of anhydrous ethanol. (0.007 mol) of hydroxylamine hydrochloride and 0.92 g (0.01 mol) of anhydrous sodium acetate were added and the reaction mixture was heated under reflux for 4 hours, the precipitated salt was filtered off, the filtrate was evaporated to dryness under reduced pressure and the residue was dissolved. in 60 ml of water The mixture was made alkaline with a 10% aqueous solution of sodium hydroxide and shaken with 3 x 20 ml of chloroform. The chloroform extracts were combined, washed with water, dried and the solvent was evaporated to dryness under reduced pressure. The syrupy residue obtained is dissolved in 10 ml of anhydrous ethanol, neutralized with saturated ethanolic dry hydrogen chloride solution, the neutral solution is concentrated to one third of the original volume and left to crystallize in a refrigerator overnight. The precipitated crystalline material is filtered off, washed with ethanol and dried under vacuum at 60 ° C. 2) 1.45 g (78 percent) of the product with a melting point of 224-226 ° C are obtained. After recrystallization from anhydrous ethanol, m.p. 228-230 ° C.

Example 14

3/2-hydroxy-6'-dimethylamino-17-oxo

-5 / 3,19-cycloandrostane

To a solution of 10 g (0.021 mol) of 3/3-acetoxy-6? -Dimethylamino-17-oxo-5 / 3,19-cycloandrostane hydrogen chloride in 340 ml of hot methanol is added a solution of 10 g (0.073 mol) of anhydrous potassium carbonate in 30 ml. ml of water and the mixture was heated under reflux for 1.5 hours. _T The mixture was cooled, precipitated salts were filtered off and the filtrate was concentrated under reduced pressure to a volume of 30 ml. The concentrated solution was shaken with ethyl acetate, the ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off until crystallization began. The concentrated mixture was allowed to stand for several hours, the precipitated product was filtered off, washed with ethyl acetate and dried under vacuum at 60 ° C. It is obtained

5.70 g (82%) of product, mp, 118-122 ° C. After recrystallization from a mixture of acetone and water, the base has 1.1. Mp 123-125 ° C.

Example 15

30-hydroxy-6H-diethylamino-17-oxo-5 / 3,19-cycloandrostane

The procedure was as described in Example 14 but using 10 g (0.020 mol) of 3/3-acetoxy-6H-diethylamino-17-oxo-5 / 2,19-cycloandrostane hydrogen perchlorate as the starting material. 5.90 g (82%) of the product with mp 124-125 ° C are obtained. After recrystallization from ethyl acetate, mp 128-130 ^° C. ··. '

Example 16

3/3-hydroxy-6H-piperidino-17-oxo-5 / 3,19-cycloandrostane

To a solution of 20 g (0.038 mol) of 3/3-acetoxy-6H-piperidino-17-oxo-5 / 3,19-cycloandrostane hydrogen perchlorate in 2000 ml of hot methanol was added a solution of 16 g of anhydrous potassium carbonate in 30 ml of water. was heated at reflux for 1.5 hours. The reaction mixture was filtered, the filter was washed with methanol, and the combined filtrates were concentrated under reduced pressure until crystalline material began to precipitate. The solution is allowed to stand for several hours, then the crystalline material is filtered off, washed with water and dried under vacuum at 60 ° C. 13.0 g (91 o / o) of product are obtained, m.p. 175-178 ° C. After recrystallization from acetone, m.p. 178-181 ° C.

Example 17

3/3-Hydroxy-6 - [(N-methylplperazino) -17-oxo-5 / 3,19-cycloandrostane]

To a solution of 10 g (0.021 mol) of 3β-acetoxy-6β- (N-methylpiperazino) -17-oxo-5 / 3,19-cycloandrostane hydrochloride in 1000 mL of methanol at room temperature was added a solution of 10 g of anhydrous potassium carbonate in 20 ml of water and the mixture was heated under reflux for one hour. 80 ml of water are added to the solution, the mixture is concentrated under reduced pressure to a volume of 100 ml and the concentrated solution is shaken with 3 x 30 ml of chloroform. The chloroform extracts are combined, washed with water, dried and the solvent distilled off under reduced pressure. A thick oily residue is obtained which crystallizes on scratching. The crystals are filtered off and washed with a small amount of cold acetone; 7.5 g (89%) of m.p. 182-185 ° C. M.p. 208-210 ° C.

Example 18

3β-Hydroxy-6H-morpholino-Γ7-ΟΧΟ-5 / 3,19-cycloandrostane hydrochloride

The procedure is as described in Example 8, except that 20 g (0.038 mol) of 3/3-acetoxy-6? -Morpholino-17-oxo-5 (3,19-cycloandrostane) hydrogen perchlorate is used as starting material and that: A solution of the crude material in ethanol was converted to the hydrochloride by treatment with ethanolic hydrogen chloride solution and recrystallized from ethanol to give 12.6 g (87%) of the product, mp 198-200 ° C.

Example 19

3- (3-Hydroxy-6H-tert-butylamino-17-oxo-5 / 3,19-cyclo-indrostane)

The procedure was as described in Example 16, but starting with 20 g (0.046 mol) of 3/3-acetoxy-6-tert-butylamino-17-oxo-5,19-cycloandrostane hydrochloride. The yield was 14.0 g (85%) of the product, mp, 197-200 ° C. After recrystallization from methanol-water, m.p. 204-207 ° C. '

Example 20

3/3-Hydroxy-6b-cyclohexylamino-17-ethylenedioxy-5R, 19-cycloandrostane

1.00 g (1.84 mmol) of 3- (3-acetoxy-17-ethylenedioxy-19-tosyloxy- ^{5 5} -androstene) was dissolved in hot in 3.00 ml (26.2 mmol) of freshly distilled cyclohexylamine and the reaction mixture was stirred for 30 min. heated at 150 DEG C. After cooling, excess cyclohexylamine is distilled off under reduced pressure, the residue is dissolved in benzene / water 1: 1 and traces of cyclohexylamine are removed by shaking in water. The oily residue was dissolved in ether and neutralized with saturated ethereal dry hydrogen chloride solution, and the precipitate was filtered off, washed with acetone and dried to give 0.58 g of crude product.

To a solution of this crude product in 50 ml of methanol was added a solution of 0.4 g of anhydrous potassium carbonate in 2 ml of water, and the mixture was heated under reflux for one hour. After cooling, 10 ml of water are added to the reaction mixture, and the solution is concentrated under reduced pressure to one quarter of the original volume. The concentrated solution is shaken with 3 x 10 ml of ethyl acetate, the combined organic extracts are washed with water, dried and the solvent is distilled off under reduced pressure. 0.38 g of product, m.p. Mp 168-172 ° C.

Example 21

3 / 3,17 / 3-dihydroxy-6β-piperidino-5 / 3,19-cycloandrostane

To a solution of 3 g (0.008 mol) of 3/3-hydroxy-6 H -piperidino-17-oxo-5 / 3,19-cycloandrostane in 150 ml of methanol is added, with cooling and vigorous stirring, at 10-15 ° C, during 20 min. minutes in small portions

1.5 g (0.04 mol) of solid sodium borohydride. The reaction mixture was stirred for an additional hour and then water was added until a precipitate formed. The precipitate was filtered off, washed with water and dried under vacuum at 60 ° C over phosphorus pentoxide. The amorphous substance obtained was dissolved in hot acetone and water was added until the turbidity started. The mixture is allowed to stand for several hours, the precipitated crystalline material is filtered off and dried under vacuum at 60 ° C. Yield: 2.0 g (66%). M.p. 172-174 ° C. Recrystallization from acetone / water gave the title compound, m.p. 176-178 ° C. Melting point of the hydrochloride recrystallized from ethanol 209-211 ° C.

Example 22

3/3-hydroxy-6H-piperidino-5 / 3,19-cycloandrostane-17-oxime

A mixture of 20 g (0.054 mol) of 3/3-hydroxy-6H-piperidino-17-OX-5 / 3,19-cycloandrostane, 8 g (0.11 mol) of hydroxylamine hydrochloride and 9 g (0.11 mol) of anhydrous acetate The mixture was refluxed in 460 ml of anhydrous ethanol for 2.5 hours. The reaction mixture is cooled, the precipitated salts are separated. The filtrate is evaporated to dryness. The residue is dissolved in 200 ml of water, made alkaline with 20% sodium hydroxide solution and immediately shaken with 3 x 50 ml of chloroform. The chloroform extracts were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A thick syrupy residue is obtained, which crystallizes after trituration with acetone. 19.2 g (92%) of the product are obtained, m.p. 202-204 ° C. After recrystallization from ethanol-water, m.p. 206-208 ° C.

Example 23

3/3-Hydroxy-6'-piperidino-17a-ethynyl-17/3-hydroxy-5 / 3,19-cycloandrostane

Weigh 11 g (0.10 mol) of potassium tertiary butylate into a four-necked, 500 ml round-bottomed flask equipped with a stirrer, thermometer and gas inlet and outlet tubes, bringing the dry nitrogen stream into the apparatus. The weighed substance is suspended with stirring in 200 ml of anhydrous tetrahydrofuran, the nitrogen purging is complete and the reaction mixture is added. A gentle stream of dry, refined acetylene is introduced for 40 minutes, with stirring. A solution of 10 g (0.027 mole) of 3/3-hydroxy-6 H -piperidino-17-oxo-5/3 is added dropwise to the reaction mixture over a period of 40 minutes, while the acetylene gas is continuously introduced and cooled to 1.8 to 22 ° C. Of 19-cycloandrostane in 100 ml of anhydrous tetrahydrofuran. After the dropwise addition of the solution, the acetylene was continued for an additional 2 hours at 18-22 ° C, then the apparatus was purged with nitrogen and the orange-colored jelly-like reaction mixture was poured into 100 ml of saturated ammonium chloride-ice solution with stirring. After standing for half an hour, the organic phases are separated in a separatory funnel and the aqueous layer is shaken with 3 x 20 ml of benzene. The combined organics were washed with saturated aqueous sodium chloride solution and dried over anhydrous. sodium sulfate and the solvents were distilled off under reduced pressure. The residue is transferred to a filter, washed with a small amount of cold benzene and dried at 60 ° C under reduced pressure. Yield: 8.70 g (81%). Mp 205-207 ° C. After recrystallization from acetone, m.p. 208-211 ° C.

Example 24

3,17-dioxo-6'-dimethylamino-5 / 3,19-cycloandrostane

In a 500-ml round-bottomed flask fitted with a distillation head, 5 g (0.015 mol) of 3/3-hydroxy-6-dimethylamino-17-oxo-5 / 3,19-cycloandrostane, 150 ml of anhydrous toluene and 29 ml ( 30 ml of distillate are distilled off at atmospheric pressure and then a solution of 1.5 g (0.007 mol) of aluminum isopropylate in 15 ml of anhydrous toluene is added dropwise to the reaction mixture over a period of one hour while the solvent is distilled off. About 60 ml of distillate were distilled off while the solution was added dropwise, and a further 30 ml was distilled off, and the reaction mixture was then shaken with 2 x 10 ml of saturated aqueous potassium sodium tartrate solution and subjected to steam distillation. The organic extracts were combined, washed with water, dried and concentrated to a small volume under reduced pressure, after cooling a crystalline material precipitated, which was filtered off and dried under vacuum at 60 ° C. 3.90 g (78%) of m.p. 146-150 [deg.] C. After recrystallization from ethanol, m.p. 149-152 [deg.] C.

Example 25 ‘;

3, 7-Dioxo-6? -Diethylamino-, 5R, 19-cyclandrostane hydrochloride

A 750 ml round flask equipped with a distillation cap was charged with 10 g (0.028 mol) of 3 (S-hydroxy-6H-diethylamino-17-oxo-5 (3,19-cycloandrostane), 270 ml of anhydrous toluene and 58 ml (0). In order to remove traces of water from the reaction mixture, 30 ml of distillate are distilled off at atmospheric pressure, and then a solution of 5.8 g (0.028 mol) of aluminum isopropylate is added dropwise over a period of 1.5 hours. 40 ml of anhydrous toluene and distilled off 100 ml of distillate for a while, after distilling for a further 50 ml of distillate, the residue in the flask is cooled to room temperature, shaken with 2 x 20 ml of saturated aqueous sodium potassium tartrate solution and subjected to steam distillation. The organic extracts were combined, washed with water, dried, and the solvent was distilled off under reduced pressure to obtain a viscous oily yellow residue. With 20 ml of anhydrous ethanol, the solution is neutralized with saturated ethanolic dry hydrogen chloride solution, concentrated to one third of its original volume and left to stand in a refrigerator overnight. The precipitated crystalline material is filtered off, washed with ethanol and dried under vacuum at 60 ° C. Yield: 8.0 g (80%) m.p. 205 DEG-207 DEG C. Recrystallization from acetone / hexane gave m.p. 212 DEG -214 DEG.

Example 26

3,17-Dioxo-6? -Piperidin-5 / S, 19-cycloanedane ^: Method a): Oxidizing Oppensation • Add 20.00 grams (0/05) to a 1000 ml round flask equipped with a distillation cap. mol) of 3? -hydroxy-6? -piperidino-17-oxo-5S, 19-cycloandrostane, 580 ml of anhydrous toluene and 106 ml of distilled cyclohexanone and 60 ml of distillate are distilled off under atmospheric pressure. A solution of 11.00 g (0.054 mol) of aluminum isopropylate in 80 ml of anhydrous toluene is added dropwise to the reaction mixture over a period of one hour while distilling off. 150 ml distillate. After distilling an additional 150 ml of distillate, the residue in the flask was cooled to room temperature, shaken. 2 x 20 ml of saturated aqueous sodium potassium tartrate solution and distilled with water vapor. The residue in the flask after water vapor is dissolved in 100 ml of chloroform, the solution is repeatedly shaken with water, the chloroform is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The thick, viscous residue obtained was dissolved in ethyl acetate while warming and the ether solution was allowed to stand overnight. 14.40 g (72%) of crystalline product, mp 127-129 ° C, precipitated. After recrystallization from ether, it has a mp. mp 130-132 ° C.

The base hydrochloride, recrystallized from acetone / hexane, mp 253-255 ° C.

Method b): oxidation by Jones reagent

To a solution of 2.0 g. (0.005 mol) of 3/3-hydroxy-6H-piperidin-7-ΟΧΟ-5H, 19-cycloandrostane in 40 ml of anhydrous acetone is stirred at 10 DEG C. for 30 minutes with vigorous stirring. 15 [deg.] C, dropwise with 3.8 ml of 8 N-chromic acid solution. The reaction mixture was stirred for a further 2 hours at 10-15 ° C. The excess chromic acid was then quenched with 3 ml of isopropanol and 40 ml of water were added. The reaction mixture is stirred for 10 minutes, then 4 g of tartaric acid are added and the solution is basified with 10% sodium hydroxide and shaken with 3 x 50 ml of benzene. The benzene extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ether and hot and crystallized. The precipitated crystalline substance is filtered, washed with cold, ether and dried in vacuo at 60 C to give ^6, a product identical to that prepared by Oppenauer oxidation method a).

Example 27

3.17- Dioxo-6 - [(N-methylpiperazino) -5 / 3,19-cycloandrostane]

By βppenauer oxidation, in the manner described in Example 26a, starting from 20.0 g (0.052 mol) of 3-methyl-6-oxo-5-oxo-5 (3,19- of cycloandrostane yields 14.40 g (72 o / o) of the free base, mp. 202-205 ° C.

Example 28

3.17-Dioxo-6? -Morpholino-5?, 19-cycloandro-. tent

By openauer oxidation as described in Example 26a, starting from 20.0. g (0.054 mol) of 3? -hydroxy-6? -morpholino-5 (?, 97 -cycloandrostane) yields 13.60 g (68%)., 3,17-dioxo-6? -morpholino-5? The cyclohexylamine having a melting point of 138 DEG-140 DEG C. (from ethanol). The base hydrochloride recrystallized from acetone-hexane had a melting point of 225 DEG-228 DEG C. EXAMPLE 2 9.

3,5-Dioxo-6-tert-butylamino-5 (3,19-cyclohexyl)

Using the procedure described in Example 24, but using 5 g (0.014 mol) of 3/3-hydroxy-6f198004

-terc.hutylamlnc> 17-OXP-5 /? 49 ^and čykloandro. · '; Tent as starting material, 4.2 g (84%) of the free base, mp 201-203 ° C. After recrystallization from methanol / water, mp 203-204 ° C. The base hydrochloride, recrystallized from ethanol, had mp 226-228 ° C.

Example 1 a d 3 0

3-Oxo-6β-piperidine-5 '(3,19-cycloandrostane-17-oxime);

To a 250 mL round bottom flask was added 2.0 g (0.005 mol) of 3/3-hydroxy-6'-piperidino-5 / S, 19'-cycloandrostane-17-oxime, 60 mL of anhydrous toluene. and 11 ml of distilled cyclohexanone. In order to remove traces of water from the reaction mixture, 10 ml of distillate are distilled off and then, while continuously distilling off, a solution of 1.06 g (0.005 mol) of aluminum isopropylate in 10 ml of anhydrous toluene is added dropwise over 30 minutes, distilling off 15 ml of distillate. distillation was continued and an additional 10 mL of solvent was distilled off from the reaction system. The remaining gelatinous reaction mixture was transferred to the consistency. Shake the separating funnel, shake 2x with 10 T of a saturated aqueous solution of sodium potassium tartrate and then distil with water vapor. The residue in the flask was shaken with chloroform, the chloroform portion was washed with water, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was mixed with acetone and scratched to give 1.50 g (75%) of the crystalline product: mp 197-200 ° C. After recrystallization from anhydrous ethanol, m.p. 20-203 ° C. Base hydrochloride, recrystallized. The mixture has a melting point of 263-264 ° C. .

Example .31 ť / · '

3-Oxo-6β-piperidino-17α-ethnyl-17 / S-hydroxy-5 / 3,19-cycloandrostane

In a 500 ml round-bottomed flask equipped with a distillation head, 10 g (0.025 mol) of 3- (3-hydroxy-6? -Piperidino-17? -Ethines 1-17 / 3-hydroxy-5/3) was added. , 19-cycloandrostane, 54 ml (0.52 mol): of distilled cyclohexanone and 300 ml of anhydrous toluene, 40 ml of distillate are distilled off at atmospheric pressure and the solution is added dropwise to the reaction mixture while the solvent is distilled off. 5.1 g (0.025 mol) of aluminum isopropylate in 40 ml of anhydrous toluene distilling about 100 ml of distillate After distilling another 50 ml of distillate, the residue in the distillation flask is cooled to room temperature, shaken with 2 x 20 ml of saturated aqueous sodium potassium tartrate solution. The residue in the flask is shaken with 2 x 30 ml of chloroform, the combined chloroform extracts are washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The thick, viscous oily residue obtained is triturated with a small amount of acetone to give a crystalline substance which is filtered off, washed with acetone and petroleum ether (b. 30-40 ° C) and dried under vacuum at 60 ° C. Yield: 6.40 g (63%). M.p. 173-175 ° C. After recrystallization from acetone / water, m.p. 178-179 ° C.

Example 32

S-Oxo-N-piperidino-1 H -ethynyl-1 H -acetoxy-5,3,19-cycloandrostane g (0.01.3 mol) 3-o.xo-6 H -piperidin-17 H -ethynyl-17 H -hydroxy -5 / 3,19-cycloandrostane and 5 g (0.027 mol) of p-toluenesulfonic acid monohydrate. was dissolved in ⁵⁰ ml of acetic anhydride and the solution was heated 1.5 hours at .60 ° C. The reaction mixture is poured into 300 ml of ice water, allowed to stand for half an hour, then made alkaline with 20%. rozto-. sodium hydroxide and shake with benzene. The benzene extracts were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The amorphous residue obtained was triturated with petroleum ether (bp 30-40 ° C) to give a crystalline substance which was filtered off, washed with petroleum ether. dried in vacuo at 60 ° C. 3.80 g (86%) of the product with a melting point of 142 DEG-145 DEG C. are obtained.

Example 33

6b-Piperidino-5 / 3,19-cycloandrostane-3,17-dioxime · · ... ·. ··· ···

A mixture of 5 g (0.014 mol) of 3,17-dioxo-6? -Piperidino-5?, 19-cycloandrostane, -.3.8 g - (0-, 054 mol) of hydrochloride-hydroxylaroins, 7.8 g (0.095) mol) of anhydrous sodium acetate and 130 ml of anhydrous ethanol are heated for 2.5 hours. reflux condenser on a water bath. The reaction mixture is cooled to room temperature, the precipitated salts are filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of water, made alkaline with a 10% sodium carbonate solution and shaken with benzene. The benzene extracts were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. under reduced pressure. The residue is triturated with acetone, the crystalline product is filtered off, washed with acetone and dried under vacuum at 60 ° C. 4.40 g (81%) of m.p. 222-223 ° C are obtained.

Example 34

3-Oxamino-6H-piperidino-17.alpha.-ethynyl-17.beta.-acetoxy-5.beta., 3,19-cycloandrostane

135304 g (0.007 mol) of 3-oxo-6H-piperidino-17'-ethyl-17 '(3-acetoxy-5), 3,19-cycloandrostane. and 1.1 g (0.016 mol) of hydroxylamine hydrochloride were dissolved in 30 ml of anhydrous pyridine and heated in a boiling water bath for one hour. Reaction mixture. Cool to room temperature, pour into 200 mL. ice water and basified with 10% sodium carbonate solution. The precipitate formed is filtered off, washed with water and dried in vacuo over phosphorus pentoxide. 2.40 g (77%) of the product having a melting point of 210 DEG-213 DEG C. are obtained. After recrystallization from a mixture of ethanol and water, bt 217-219 ⁹ Celsius.

Example 35

3/3-Acetoxy-6'-amino-17-ethylenedioxy-5 / 3,19-cycloandrostane hydrochloride

Dissolve 1.00 g (1.94 mmol) of 3/3-acetoxy-6? - (beige lamino) -17-ethylenedioxy-5 / 3,19-cycloandrostane hydrochloride in 20 ml of water, basify with 10% hydroxide solution sodium chloride and shake with 3 x 15 ml benzene. The benzene fractions were combined, washed with water, dried and the solvent was distilled off under reduced pressure. The residue is dissolved in 25 ml of ethanol and the solution is hydrogenated at room temperature, at atmospheric pressure and in the presence of 5% palladium-on-carbon catalyst until the consumption of hydrogen is complete. The catalyst is filtered off, the filtrate is neutralized with a saturated ethanolic solution of dry hydrogen chloride and the neutral solution is evaporated to dryness under reduced pressure. The amorphous residue obtained after recrystallization from isopropanol gave 0.55 g (65%) of the product, m.p. 189-192 ° C.

Example 1 a d 3 6

3β-Acethoxy-6β - [(2‘-hydroxyethyl) amino] -17-ethylenedioxy-5 / 3,19-cycloandrostane hydrochloride · ···

1.00 g. (1.84 mmol) of _3β -acetoxy-17-ethylenedioxy-19-tosyloxy- ^{5 5} -androste were dissolved in a mixture of 5 ml of N, N-dimethylacetamide and 0.5 ml of (8, 40 mmol) of freshly distilled α-hydroxyethylamine and the reaction mixture is heated at 110 ° C for 5 hours. The solution is cooled, poured slowly into 50 ml of a 25% aqueous sodium chloride solution with stirring, and the mixture is stirred for minutes. The precipitate formed is filtered off, dissolved in 30 ml of benzene, the benzene solution is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of anhydrous ethanol, the solution is neutralized with a saturated ethanolic solution of dry hydrogen chloride and the neutral solution is evaporated to dryness under reduced pressure. The residue is triturated with acetone, the resulting crystalline material is filtered off, washed with acetone and dried at 60 ° C under reduced pressure. 0.35 g (40%) of the product with mp 199-202 ° C is obtained. After recrystallization from acetone, mp 203-206 ° C.

EXAMPLE 3-7.

3/3-Acetoxy-6- (2-hydroxyethyl) piperazino-17-oxo-5 / 3,19-cycloandrostane hydrochloride g (0.011 mol) of 3- (3-acetoxy-17-oxo-19-tosyloxy- ^{5 5} -androstene) Dissolve in 15 mL of anhydrous Ν, Ν-dimethylacetamide and 5 mL (0.04 mol) of freshly distilled N- (2-hydroxyethyl) piperazine with heating and heat the reaction mixture to 110 ° C for 4 hours. After cooling, the solution is poured slowly into 250 ml of ice-water with stirring and the precipitate formed is filtered off and dissolved in 100 ml of benzene, washed with water, dried and then evaporated under vacuum. The resulting crystals were filtered, washed with anhydrous ethanol and dried under vacuum at 60 ° C to give 2.1 g (42.5%) of product, m.p. 196-198 °. C, after recrystallization, from isopropanplu is · bt 203. to 205 ° C.

Example-3 8 '· · 3d-Acetoxy-6H-N-benzylpiperazino-17-oxo-5 / 3,19-cycloandrostane hydrochloride ·

The procedure of Example 37 was followed, except that the reaction was carried out with 5 g. (0.01 mol) of 3, 3-acetoxy-17-oxo-19-tosyloxy- ^{5 5} -androstene and 5.2 g. ml (0.03 mol) of N-benzylpiperazine. Yield 2.4 g (44.5%), mp 222-224 ° C. mp 226-229 ° C after recrystallization from isopropanol.

SUBJECT

Claims (1)

VYNALEZU A process for the preparation of the novel 6-amino-5 / 3,19-cycloandrostane derivatives of the general formula (I), a (C1-C4) -cyl group, and R 2 and R 5 together with the nitrogen to which they are attached may be a pyrrolidinone, piperidine, morpholino group ^; piperazine, N-alkylpiperazine having 1 to 4 carbon atoms in the alkyl, N-oxyalkyl group having 1 to 4 carbon atoms in alkyl or the N-benzylpiperazine group, and their acid addition salts, characterized in that the steroid of the formula II is present. in which X represents a group of the formula = CH (OR), = GO or = C = N-OR 1 a Y represents a group of the formula = CO, = CH (OR 1), = C = N — OR 1, = C (OR 1) - CSCH, or O-CH, o-ch ₂ in which R is hydrogen, C 1 -C 4 alkyl or C 2 -C 5 acyl, and R 1 is hydrogen or C 2 -C 5 acyl, R2 represents a hydrogen atom or a straight or branched C 1 -C 5 aliphatic carbon chain optionally substituted by hydroxyl, C 1 -C 4 alkoxy or C 1 -C 4 acyloxy, C 3 -C 8 alicyclic a C 7 -C 10 allyl or aralkyl group optionally substituted on the aromatic ring with a C 1 -C 4 alkoxy group, R 3 has the same meaning as R 2, but when R 2 represents a secondary or tertiary alkyl group or an alicyclic group, R 3 denotes only a hydrogen atom, and when R 2 represents an aralkyl group, R 3 denotes only a hydrogen atom or a primary alve Y * a carbonyl or ethylene ketal group, R 1 is C 1 -C 4 alkyl or C 2 -C 5 acyl, and R 5 is a C 1 -C 4 alkyl, phenyl or tolyl group reacted with a secondary or primary amine of formula III, HN (III) in which R 2 and R 3 are as defined above, and the compound of formula I in which R 2 and R 3 are as defined above, X represents a group of the formula = CH (OR), in which R is as defined above, and Y 'represents a carbonyl or ethylene ketal group, optionally converted by hydrolysis and / or oxidation and / or oxime formation and / or ethinylation and / or acylation and / or reduction to another compound of formula I and the compound of formula I thus obtained is optionally converted by reaction with a pharmaceutically acceptable acid to the corresponding acid addition salt of the acid.