HU209796B - New process for the production of 17 beta-substituted -4-aza-androstane derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a 17β-substituted-4-aza-androstane derivative of the general formula (I), wherein R is hydrogen or a C 1 -C 3 alkyl group, R 1 is C 1 -C 8, open or branched. or a carboxyl group esterified with a C 1-5 open or branched saturated alcohol, and the bond lines are single or double-bonded. : 8 pages (including 1 page figure)

Description

According to the present invention, a 17-halo-4-aza-androstene derivative of formula II wherein R and the --- bond lines are as defined above and X is a chlorine, bromine or iodine atom is dimethyl-. in a formamide or dimethylsulfoxide medium, in the presence of a palladium (II) salt and a phosphine, or in the presence of a palladium (II) complex and a tertiary amine base, with a primary or secondary alkylamine having 1 to 8 carbon atoms; with an open or branched saturated carbon atom of carbon atom at a temperature of 35-80 ° C in a carbon monoxide atmosphere, then, if desired, a compound of formula (I) obtained and containing a single bond at the point of bonding (I). ) in the presence of a catalyst and / or a resulting carboxylic acid esterified at R ¹ a compound of formula I containing a soporte, is saponified in a manner known per se to prepare compounds of formula I wherein R ¹ is a free carboxyl group, and / or a resulting compound of formula I wherein R and a are bonded as is a pharmaceutically acceptable base is reacted in known manner form a salt as defined in formula and R ¹ is a free carboxyl group.

The present invention relates to a novel process for the preparation of 17β-substituted-4-aza-androstane derivatives of formula (I) wherein R is hydrogen or a (C 1 -C 3) alkyl group,

R ^{1 is} a aminocarbonyl group mono- or disubstituted with C 1 -C 8, open or branched alkyl, or a C 1 -C 5 open or branched saturated alcohol ester or free carboxyl group, and the a = bonding lines are single or a double bond - and, in the case of R ^{1, a} free carboxyl group, for the preparation of their salts with pharmaceutically acceptable bases.

The compounds of formula I inhibit the action of the 5α-reductase enzyme and thereby inhibit the conversion of testosterone to dihydrotestosterone, and are therefore useful in the treatment of dihydrotestosterone-dependent diseases such as prostate hyperplasia, acne vulgaris, seborrhea, female hirsutism.

Several processes are known in the literature for the preparation of known compounds of formula (I).

PCT Patent Publication No. WO 91/12261 relates to urethane derivatives other than the compounds of the present invention. 14-17. Examples 4-methyl-4-aza-5α-androstane-3,17-dione give 4-methyl-4-aza-5α-androstane-3-one-17β-carboxylic acid with a side chain structure. Steps of side chain construction: cyanohydrin addition, water elimination, hydrolysis to A ^{16 '17} -carboxylic acid saturation of A ¹⁶ ' ^{, 7-} double bond. Total yield is only 3.9%.

EP 200 959 relates to carboxylic acid derivatives substituted at the 12-position and / or having a longer alkyl chain at the 17-position and optionally substituted at the 4-position by a -OR ² atom. The target compounds are thus different from the compounds of the present invention.

U.S. Pat. No. 4,377,584 discloses the side chain degradation of 17-carboxylic acid derivatives starting from the hard-to-reach pregnenolone. In Example 32, a carboxylic acid derivative is prepared from 4-methyl-4-aza-5α-androstane-3,17-dione by a WittigHomer reaction, i.e. a side chain structure, but this is a 21-acid (20-carboxylic acid). 17-carboxylic acid derivatives.

Pregnenolone is also a starting material for the process of U.S. Patent No. 4,220,775. This yields 17-carboxylic acid derivatives by side-chain degradation.

The conversion of 4-aza-5α-androstane-3-oxo-17-carboxylic acid methyl ester from pregnenol is described in EP 155,096. The reaction sequence comprises the following steps: the formation of a double bond into the A ring, the corresponding 17-carboxamide derivative, of which the 20-oxo derivative, and the alkylation of the 4-position> NH. Thus, in the process described, 17-carboxamides are prepared from the corresponding 17-carboxylic acid methyl ester.

AJ. Med. Chem., 27 (72), 1690 (1984) also discloses various 4-aza-17-substituted compounds, including 4-aza-17-carboxamides, and esters. According to the art, they are prepared from pregnenolone by side chain degradation. By side chain structure, only 20-carboxylic acids (21-acids) are prepared from 17-oxo compounds.

AJ. Chem., 29 (77), 2298 (1986), D-homo-17α-carboxylic acid compounds are prepared from the corresponding oxo derivative by side chain structure. The reaction pathway used is 17a-oxo, 17a-methylene, 17a-hydroxymethylene and then 17a-carboxylic acid by oxidation.

As can be seen, the known processes are not suitable for industrial production, in part because of the low yields available and the reactions requiring special reaction conditions. Methods based on pregnenolone are further disadvantaged2

The raw material, pregnenolone, obtained by hydrogenation of the 16-position double bond of pregnaidene-ol-on-acetate obtained by the degradation of naturally occurring diosgenin or solosodine, is becoming less accessible due to the wild Dioscorea species in Mexico. , the root of which extracts diosgenin from the root by extraction, and on the other hand, the cultivation of Solanum aviculare and the isolation of solasodine from it is not economical.

Because of their therapeutic effect, the target compounds are claimed in pharmaceutical production, but the need arises to be more and more difficult to be met by the known production process, as discussed above.

It is an object of the present invention to provide a production process for which the required starting material is readily available and thus provided. From this point of view, the novel 17-halo-4-aza-androstene derivatives of formula II have been found to be useful.

Surprisingly, it has now been found that a process for the preparation of the target compounds of formula (I) can be achieved by any one of the above-mentioned processes by reacting a 17-halo-4-aza-androstene derivative of formula (II) --- bond lines have the meaning given above and X represents a chlorine, bromine or iodine atom - in a dimethylformamide or dimethylsulfoxide medium, a palladium (II) salt and a phosphine or a palladium (II) complex and a tertiary amine base in the presence of a C 1 -C 8 alkyl group containing a primary or secondary alkylamine or a C 1 -C 5 open or branched saturated alcohol at a temperature of 35-80 ° C in a carbon monoxide atmosphere and optionally a a compound of formula (I) containing a double bond at the point of bonding by a single bond at the location of the --- bonding lines to produce Compound nos hydrogenated catalyst and / or received, and esterified carboxyl having R ¹ of formula (I) compound of the formula R 'preparation of compounds of formula containing a free carboxyl group (I) as saponified in a known manner in place, and / or converting the resulting compound of formula (I), wherein R ¹ is free carboxyl, into a salt by reaction with a pharmaceutically acceptable base in a manner known per se.

According to the invention, it is preferred that the compound of the formula II is present in dimethylformamide, in the presence of palladium (II) acetate, triphenylphosphine, and triethylamine, with a primary or secondary amine in an atmosphere of carbon monoxide of 1.5-2. for 60 hours at 60 ° C. After completion of the reaction, the amines and dimethylformamide are distilled off under reduced pressure, the residue is dissolved in chloroform, and the solution is washed neutral with water, aqueous hydrochloric acid, aqueous sodium bicarbonate solution and again with water. After drying, the solvent is distilled off, and the residue is purified by chromatography or recrystallization or the two methods are combined.

The resulting compound of formula (I), wherein R ¹ is a mono- or di-substituted aminocarbonyl group, has a double bond which is 16 or 5 and 16, respectively, depending on the starting compound (II). position, optionally in formic acid in the presence of palladium on carbon or in glacial acetic acid in the presence of a platinum oxide catalyst and hydrogen gas.

^R1 is a compound of formula (I) containing an alkoxycarbonyl group of the formula (II) compound, preferably dimethyl sulfoxide, palladium (II) acetate, 1,4-bis (diphenylphosphino) butane, triethyl- amine mixture with a C 1 -C 5 alkanol under carbon monoxide atmosphere for 10-15 hours at 60 ° C. After the reaction was complete, the volatile components were distilled off under reduced pressure, the residue dissolved in chloroform and the water-soluble components removed by washing with water. After the solution is dried, the solvent is distilled off and the residue is purified by chromatography or recrystallization or the two methods are combined.

The resulting unsaturated compound of formula (I) is optionally hydrogenated, as described above, in palladium-on-carbon or in glacial acetic acid in the presence of a platinum oxide catalyst and hydrogen gas and / or hydrolyzed optionally in an alkaline medium to a Πβ-carboxylic acid derivative.

1,4-bis (diphenylphosphino) butane, 1,2-bis (diphenylphosphino) ethane, triphenylphosphine or 1,3-bis (diphenylphosphino) propane is preferably used as the phosphine in the process of the invention. However, a complex of the above phosphines and palladium (II) salts may also be used. For example, in the presence of palladium (II) bis (triphenylphosphino) dichloride, the reaction is carried out with primary or secondary amines at 35-60 ° C and with C 1-5 alcohols at 4080 ° C.

The process of the present invention makes it possible to start from the readily available 3-keto-A ⁴ derivatives obtained by degradation of sitosterol. According to the invention, the construction of the aminocarbonyl or carboxyl group at position 17 can be safely carried out, and the enlargement of the process to industrial production is not a problem.

The starting materials used in the process of the invention, such as the "4-aza-17-hydrazone" derivatives and the compounds of formula II, are novel. Unsaturated 4-aza-17-aminocarbonyl of formula (I) and 4-aza-17-alkoxycarbonyl are also novel compounds. Saturated 4-aza-17-aminocarbonyl derivatives and saturated 4-aza-17- (methoxycarbonyl) derivatives are known in the art, European Patent No. 0 004 949, J. Med. Chem., 27, 1690. -1701. (1984)]

The novel 17-halo-4-aza-androstene derivatives of formula (II) used as starting materials in the process of the present invention can be prepared as follows.

From the known 17? -Hydroxyandrost-4-en-3-one in the literature [J. Pharm. Sci., 63, 19-23. (1974); J.

HU 209 796 A

Chem. 27, 1690-1701. (1984); J. Org. Chem., 46, 1442-1446. (1981)], the known 4-aza-5a-androstane-3,17-dione, 4-methyl-4-aza-androstane-3,17-dione and 4-aza-androstane 5-ene-3,17-dione (hereinafter referred to as 4-aza-17-keto derivatives).

The known "4-aza-17-keto derivatives" are reacted with hydrazine hydrate in the presence of triethylamine in ethanol, and

No. 1 In the same manner as in Example 1, the resulting "hydrazone derivatives" are recovered and the crude product is used directly without purification to prepare the 17-halo-4-aza-androstene derivatives of formula II as follows.

For the preparation of the 17-iodo-4-aza-androstene derivatives, the "hydrazone derivatives" are dissolved in chloroform or benzene or in a mixture of chloroform-benzene or tetrahydrofuran and reacted with elemental iodine at room temperature in the presence of a tertiary amine base. After completion of the reaction, the compounds of formula (II) are prepared as described in Scheme 4. is obtained as described in Example 1b.

For the preparation of 17-halo-4-aza-androstene derivatives containing a chlorine or bromine atom in position 17, the "hydrazone derivatives" are dissolved in pyridine optionally substituted with C 1-4 alkyl and then -10 to + 10 ° C. with N-chloro or N-bromosuccinimide. The resulting compound of formula (II) is prepared as described in U.S. Pat. EXAMPLE 1 was obtained as described in Example 1b.

Further details of the process are illustrated by the following non-limiting examples.

Example 1

To a suspension of 17-hydrazono-4-aza-5α-androstan-3-one g (0.0346 mol) in 4 ml of ethanol (100 ml) in 14 ml (0.1 mol) triethylamine and 50 ml (1.0 mol) of hydrazine hydrate were added and refluxed for 3 hours. (The reaction is monitored by TLC.) After the reaction is complete, the reaction mixture is cooled, the solution is concentrated to one tenth, and the product is precipitated with about 10 times water. After compaction, the precipitate is filtered off, washed with water until neutral and dried. Yield: 9.44 g (90%) of the title compound. Mp .: 254-258 'C.

Δ 1 H NMR 300 MHz _(CDCl} in); 0.86 (s, 3H, 18CH ₃ ), 0.93 (s, 3H, 19-CH ₃ ), 2.41 (m, 2H, H-2),

3.07 (dd, 1H, H-5), 4.77 (br, 2H, NH ₂ ), 5.74 (br,

1H, NH). ²

Example 2

17 -hydrazono-4-aza-androst-5-en-3-one

Starting from 4-aza-androst-5-ene-3,17-dione, proceed as in Example 1. The title compound was obtained in 35% yield. Mp .: 379-383 'C.

IR (KBr, [nu] cm- ¹ ): 1633 (C = C), 1661 (C = N), 1693 (C = O), 3200 (NH), 3350 (NH ₂ ).

Example 3

17-Hydrazono-4-methyl-4-aza-5α-androstan-3-one Starting from 4-methyl-4-aza-5α-androstane-3,17-dione, proceed as in Example 1. The title compound was obtained in 75% yield. Op: 211-218 'C. 1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.86 (s, 3H, 18CH ₃ ), 0.91 (s, 3H, 19-CH ₃ ), 2.93 (s, 3H, N _CH3), 3.05 <dd (J = 3.6; J = 12.6), 1H, H-5>, 4.78 (vbr, 2H, _NH2).

Example 4

17-iodo-4-aza-5a-androst-16-en-3-one

17-Hydrazono-4-aza-5α-androstan-3-one (9.1 g, 0.03 mol) was dissolved in chloroform / benzene (1: 1) and triethylamine (90 ml) was added. A solution of 11.4 g (0.045 mol) of iodine in 110 ml of benzene is added dropwise and the reaction mixture is stirred at room temperature for a further 1-1.5 hours. After completion of the reaction, the solution was diluted with chloroform (500 mL) and treated with 10% aqueous hydrochloric acid, water, 5% aqueous sodium thiosulfate, water, 5%, washed with aqueous sodium bicarbonate solution, and finally with water, and dried over sodium sulfate. The solvents were evaporated in vacuo and the residue was purified by silica gel column chromatography. (Eluents: chloroform, 95: 5 chloroform: acetone). The product is crystallized from ethanol. 5.9 g (50%) of the title compound are obtained. Mp .: 278282 'C.

1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.73 (s, 3H, 18CH ₃ ), 0.91 (s, 3H, 19-CH ₃ ), 3.1 (dd, 1H, H 5), 6.18 (m, 1H, H-16), 6.9 (br, 1H, NH).

Example 5

17-Iodo-4-aza-androsta-5,16-dien-3-one Starting from 17-hydrazono-4-aza-androsta-5-en-3-one proceed as in Example 4. The title compound was obtained in 57% yield. Op: 227-230 ° C. ¹H NMR 300 MHz (in _CDCl3) δ: 0.78 (3H, s, 18CH _3), 1.13 (s, 3H, _19-CH3), 4.9 <dd (J = 2, 4; J = 5.1, 1H, H-6, 6.15 <dd (J = 3.2; J = 1.7), 1H, H-16, 8.27 (br, 1H, NH).

Example 6

17-iodo-4-methyl-4-aza-5a-androst-16-en-3-one

Starting with 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one, the procedure of Example 4 was followed except that the reaction was carried out in benzene. The title compound was obtained in 52% yield. Mp .: 176-181 'C.

1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.74 (s, 3H, 18CH ₃ ), 0.92 (s, 3H, 19-CH ₃ ), 2.94 (s, 3H, N CH ₃ ), 3.07 <dd (J = 3.7; J = 12.6), 1H, H-5>, 6.13 <dd (J = 3.2; J = 1.7), 1H H-16>.

Example 7

17-Chloro-4-methyl-4-aza-5α-androst-16-en-3-one 4 g (0.0126 mol) of 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one 40 g. ml of anhydrous pyridine

After dunking and then cooling to 0 ° C, a solution of N-chlorosuccinimide (3.2 g, 0.024 mol) in pyridine (40 ml) was added dropwise with vigorous stirring. After vigorous nitrogen evolution ceased, the reaction mixture was stirred for 15 minutes and then added dropwise to 800 ml of water. After the precipitate has solidified, the crude product is filtered off, washed with water to neutral and dried under vacuum at room temperature with phosphorus pentoxide. The crude product was chromatographed on a silica gel column using chloroform as eluent. The eluate was evaporated and the residue was crystallized from petroleum ether. 2.15 g (53%) of the title compound are obtained. Mp .: 139-140 'C.

1 H-NMR 60 MHz (in CDCl ₃ ) δ: 0.88 (s, 3H, 18CH ₃ ), 0.93 (s, 3H, 19-CH ₃ ), 2.89 (s, 3H, N CH ₃ ), 3.0 (dd, 1H, H-5), 5.53 (m, 1H, H-16).

Example 8

17-Bromo-4-methyl-4-aza-5a-andmszt-16-en-3-one

Starting from 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one, proceed as in Example 7. N-Bromosuccinimide is used as the reactant. The title compound was obtained in 55% yield. M.p. 159-161 ° C. 1 H-NMR 60 MHz (in CDCl ₃ ) δ: 0.82 (s, 3H, 18CH ₃ ), 0.91 (s, 3H, 19-CH ₃ ), 2.86 (s, 3H, N CH ₃ ), 3.0 (dd, 1H, H-5), 5.68 (m, 1H, H-16).

Example 9

3-Oxo-4-aza-5u-androst-16-ene-17 (3- (N-tert-butylcarboxamide)

3.99 g (0.01 mole) of 17-iodo-4-aza-5a-androst-16-ene-3-one are dissolved in 150 ml of dimethylformamide, followed by 0.224 g (0.001 mole) of palladium (II) acetate, 0.524 g. Triphenylphosphine (0.002 mol), triethylamine (10 ml), tert-butylamine (15 ml, 0.14 mol) were added and the mixture was heated at 60 ° C for 1.5-2 hours under carbon monoxide. After completion of the reaction, the amines and dimethylformamide are distilled off in vacuo and the residue is dissolved in 150 ml of chloroform, followed by chloroform solution with water, 5% aqueous hydrochloric acid, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride to neutral and finally dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography. Elution was carried out with ethyl acetate. 3.16 g (85%) of the title compound are obtained. Mp .: 292-297 'C.

1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.93 (s, 3H, 19CH ₃ ), 1.0 (s, 3H, 18-CH ₃ ), 1.4 (s, 3H, C ( CH ₃ ) ₃ ), 2.15 (m, 2H, H-15a + H-15b), 2.4 (m, 2H, H-2), 3.08 <dd (J = 4.5; J = 7.0), 1H, H-5>, 5.48 (brs, 1H, NH), 5.6 (brs, 1H, NH), 6.18 <dd (J = 1.7, J = 1, 4), 1H, H-16.

Example 10

3-Oxo-4-aza-5α-androst-16-ene-17β - [N- (2,2-dimethylpropyl) carboxamide] 17-iodo-4-aza-5α-androst-16-ene Starting with -3-one, proceed as in Example 9 using 2,2-dimethylpropylamine (neopentylamine) as reactant. The title compound was obtained in 82% yield. 1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.92 (s, 9H,

C (CH ₃ ) ₃ ), 0.95 (s, 3H, 19-CH ₃ ), 1.02 (s, 3H, 18CH ₃ ), 2.4 (m, 2H, H-2), 3.1 (m, 3H, NCH ₂ , H-5),

5.66 (brs, 1H, NH), 5.85 (brs, 1H, NH), 6.3 (brs,

1H, H-16).

II. example

4-Methyl-3-oxo-4-aza-5a-androst-16-ene-17-carboxylic acid methyl ester

0.41 g (0.001 mol) of 17-iodo-4-methyl-4-aza-5α-androst-16-en-3-one, 0.0224 g (0.1 mmol) of palladium (II) acetate, A mixture of 0213 g (0.05 mmol) of 1,4-bis (diphenylphosphino) butane, 0.3 ml of triethylamine, 2 ml of methanol and 15 ml of dimethylsulfoxide was stirred under carbon monoxide atmosphere for 60 hours at 60 ° C. . After completion of the reaction, the reaction mixture is concentrated in vacuo, the residue is dissolved in 15 ml of chloroform, and the chloroform solution is washed four times with water, dried over anhydrous sodium sulfate and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography. The eluent was ethyl acetate / petroleum ether 1:10. Yield: 0.014 g (40%). Mp .: 182-186 'C.

1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.93 (s, 6H, 18CH ₃ + 19-CH ₃ ), 2.45 (m, 2H, H-2), 2.94 (s, 3H,

NCH ₃ ), 3.07 (dd, 1H, H-5), 3.72 (s, 3H, OCH ₃ ),

6.76 (brs, 1H, H-16).

Example 12

3-Oxo-4-aza-5a-androst-16-ene-17-carboxylic acid methyl ester

Starting from 17-iodo-4-aza-5α-androst-16-en-3-one. follow the example. The title compound was obtained in 42% yield. Mp .: 270 'C.

¹H NMR 300 MHz (in _CDCl3) δ: 0.92 (3H, s, 19CH _3), 0.94 (s, 3H, _18-CH3), 2.4 (m, 2H, H 2), 3.07 (dd, 1H, H-5), 3.72 (s, 3H, OCH ₃ ), 6.15 (brs, 1H,

NH), 6.75 (brs, 1H, H-16).

Example 13

3-Oxo-4-aza-androsta-5,16-diene-17? - (N-tert-butylcarboxamide)

Starting from 17-iodo-4-aza-androsta-5,16-dien-3-one, proceed as in Example 9 using tert-butylamine as reactant. The title compound was obtained in 78% yield. Mp .: 266-269 'C.

1 H NMR 300 MHz (in CDCl ₃ ) δ: 1.04 (s, 3H, 18CH ₃ ), 1.14 (s, 3H, 19-CH ₃ ), 1.38 (s, 9H, C (CH ₃ ) ₃ ),

2.5 (m, 2H, H-2), 4.88 <dd (J = 2.1, J = 2.7), 1H,

H-6,5, 5.5 (brs, 1H, NH), 6.2 <dd (J = 1.8, J = 0.9),

1H, H-16, 8.08 (brs, 1H, NH).

Example 14

4-Methyl-3-oxo-4-aza-5α-androst-16-ene-17 (3- (N, N-diethylcarboxamide)

a.) Starting from 17-iodo-4-methyl-4-aza-5α-androst-16-en-3-one and proceeding as in Example 9,

EN 209 796 Using Dance as diethylamine. This gave the title compound in 84% yield. Mp .: 205-210 'C.

1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.93 (s, 3H, 19CH ₃ ), 1.09 (s, 3H, 18-CH ₃ ), 1.13 (t, 6H,

N (CH ₂ CH ₃ ) ₂ ), 2.94 (s, 3H, NCH ₃ ), 3.06 (dd, 1H,

H-5), 5.26 (m, ΙΗ, Η-16).

b) Starting from 17-bromo-4-methyl-4-aza-5α-androst-16-en-3-one and proceeding as in Example 9 using diethylamine as reactant. The title compound was obtained in 85% yield. M.p .: 205-210'C.

Example 75

4-Methyl-3-oxo-4-aza-5α-androstane-17β - (N, N-diethylcarboxamide) g (2.6 mmol) 4-Methyl-3-oxo-4-aza-5α-androst16 -en-173- (N, N-dictylcarboxamide) was dissolved in 40 ml of formic acid and a suspension of 1 g of palladium on charcoal in 6 ml of water was added under a nitrogen atmosphere. The heterogeneous solution was stirred at room temperature for 4-5 hours. The progress of the reduction is monitored by thin layer chromatography. After the reaction was complete, the catalyst was filtered off and washed with chloroform / methanol (1: 1). The combined solutions are evaporated to dryness, the residue is triturated with water, the precipitate is filtered off and washed with water. 0.88 g (87%) of the title compound are obtained. Mp 180-181 'C (recrystallized from ethyl acetate).

Example 76

3-Oxo-4-aza-5a-androstane-17 $ - (N-tert-butyl-carboxamide)

3-Οχο 4-3Ζ3-5α-3ηΰΓθ5ζΐ-16 έη-17β- (Ν-ΙεΓθ-0υΰ1

carboxamide) and proceed as in Example 15. The title compound was obtained in 90% yield. Mp .: 283-286 'C.

Example 7

3-Oxo-4-aza-5a-andmsztán $ 17-carboxylic acid methyl ester

Starting from 3-oxo-4-aza-5α-androst-16-ene-17-carboxylic acid methyl ester, proceed as in Example 15. The title compound was obtained in 85% yield. Mp: 301-304 ° C (recrystallized from ethyl acetate).

Example 18

3-Oxo-4-aza-5a-androstane-17 $ - (N-tert-butyl-carboxamide)

Starting from 3-oxo-4-aza-5α-androst-5,16-ene-17β- (ΐ-ΐεκ-karb util carboxamide) and proceeding as in Example 15. This gave the title compound in 70% yield. Mp .: 283-286 'C.

Example 79

- Oxo-4-aza-5a-androstane-17? -Carboxylic acid

Methyl 3-oxo-4-aza-5α-androstane-4-carboxylic acid methyl ester (1.67 g, 0.005 mol) was dissolved in tert-butyl alcohol (60 ml) and a solution of potassium hydroxide (1.6 g) in water (32 ml) was added. The reaction mixture was heated at reflux for 8 hours under nitrogen. The progress of the reaction is monitored by thin layer chromatography. After completion of the reaction, the solvent was removed under reduced pressure, the residue was dissolved in water, the insoluble matter was removed by filtration and the aqueous phase was acidified to pH 1 with concentrated hydrochloric acid. The precipitated material is filtered off and washed with water until neutral. Yield: 1.44 g (90%) of the title compound. Mp .: 380-384 'C.

Claims (10)

PATENT CLAIMS 1. A process for the preparation of 17β-substituted 4-aza-androstane derivatives of formula I - where R is hydrogen or a C 1-3 alkyl group, R ^{1 is} a mono- or disubstituted aminocarbonyl group having ¹ to 8 carbon atoms, open or branched, or a carboxyl group esterified with a free or branched saturated alcohol with 1 to 5 carbon atoms, and the == bond lines are single or a double bond, or a R ¹ free carboxyl group for the preparation of their salts with pharmaceutically acceptable bases, wherein a 17-halo-4-aza-androstene derivative of formula II wherein R and the bond lines are the above and X represents a chlorine, bromine or iodine atom - in the presence of a palladium (II) salt and phosphine or a palladium (II) complex and a tertiary amine base in dimethylformamide or dimethylsulfoxide; with a primary or secondary alkylamine containing a C 1 -C 5 alkyl group, or an open or branched C 1 -C 5 alkyl group reaction with saturated alcohol in a carbon monoxide atmosphere at 35-80 ° C and then, if desired, i) is received, and a compound of formula (I), the = bond line represents a double bond wherein R and R ¹ are as defined above - a compound of formula (I), the = bond line represents a single bond thereof, - wherein R and R ¹ are as defined above hydrogenated catalysis, and / or ii) is obtained, and the compound containing an esterified carboxy group (I), R ¹ is wherein R and -kötésvonal are as defined in formula (I) - R represents a free carboxyl group at ^one location (I ), where R and a bond are as defined in formula (I), and / or (iii) a resulting compound of formula (I), wherein R and the bond lines are as defined in formula (I). and R ^{1 is a} free carboxyl group and converting it into salts with pharmaceutically acceptable bases in a manner known per se. HU 209 796 A 2. A process according to claim 1 wherein the tertiary amine base is triethylamine. The process according to claim 1 or 2, wherein the palladium (II) salt is palladium (II) acetate or palladium (II) chloride. 4. A process according to any one of claims 1 to 3, wherein the phosphine is triphenylphosphine, 1,4bis (diphenylphosphino) butane, 1,2-bis (diphenylphosphino) ethane, or 1,3-bis (diphenylphosphino) - propane. The process according to claim 1 or 2, wherein the palladium (II) complex is palladium (II) bis (triphenylphosphino) dichloride or diacetate. 6. Process according to any one of claims 1 to 3, characterized in that the amidation or alkoxycarbonylation reaction is carried out at 50-60 ° C. 7. A process according to any one of claims 1 to 3, characterized in that the saturation of the double bonds is carried out in the presence of palladium or platinum catalyst. 8. The process of claim 7, wherein the hydrogenation reaction is carried out in glacial acetic acid or formic acid. 9. A process according to any one of claims 1 to 4 wherein R ¹ is Ν, Ν-diethylaminocarbonyl, N-tert-butylaminocarbonyl or N- (2,2-dimethylpropyl) amino10 carbonyl. characterized in that the alkylamine is diethylamine, tert-butylamine and 2,2-dimethylpropylamine. 10. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein R * is methoxycarbonyl, wherein the alcohol is methanol.