HU210544B - 4-aza-androstene derivatives substituted with halogenatom in 17-position and process for their production - Google Patents

Abstract

The present invention relates to novel 4-azaandrostene derivatives of formula (I) wherein R is hydrogen or C1-C3 alkyl, X is chlorine, bromine or iodine, and the bonding line ΞΞΞ is single or double. is a chemical bond and is a process for their production. Compounds of formula (I) according to the present invention are prepared by reacting a compound of formula (II) with a halogenated hydrocarbon or aromatic solvent or a mixture of two solvents or ether to form compounds of formula (I) containing X. b) reacting a compound of formula (II) wherein X is chloro or bromo in the form of a solvent optionally substituted with one or more C 1 -C 4 alkyl groups as a solvent; in pyridine at -10 ° C to +10 ° C with N-chloro or N-bromosuccinimide. The compounds of formula (I) are preferably useful for the preparation of compounds that inhibit the function of the 5α-reductase enzyme. EN 210 544 A Scope of the description: 6 pages (including 1 sheet)

Description

The present invention relates to novel 4-aza-androstene derivatives of formula (I) wherein R is hydrogen or (C 1 -C 3) -alkyl;

X is a chlorine, bromine or iodine atom and the - bond is a single or double bond.

The present invention also relates to novel 4-aza-androstene derivatives of formula (I).

The compounds of formula (I) are useful in the preparation of compounds which inhibit the activity of the 5α-reductase enzyme, preferably in a dimethylformamide medium, in a carbon monoxide atmosphere, in the presence of palladium (II) acetate, triphenylphosphine and triethylamine. reacting with a primary or secondary alkylamine, and optionally hydrogenating the double bond of the resulting ^A16 -17β-carboxamido derivative. (See Examples 9 and 10).

5α-reductase inhibitors inhibit the conversion of testosterone to dihydro-testosterone and can thus be used in the treatment of dihydrotestosterone-dependent disorders such as prostate hyperlasia, acne, seborrhea, and female hirsutism.

It is known [J. Chem. Soc., 470-476. (1962)] that reacting the 17-hydrazone derivative of dehydroeppi-androsterone with elemental iodine in tetrahydrofuran in the presence of triethylamine gives 17-iodo-androsta-5,16-diene 3 {3-ol. Starting from the 20-hydrazone derivative of pregnenolone and using similar reaction conditions, 20-iodo-pregna-5,20-diene-3P-ol can be prepared.

A Tetrahedron Letters, 24 (75), 1605-1608. (1983) deals with the further development of the process by examining the role of base and water. They are also described as starting from the 17-hydrazone of dehydroeppi-androsterone but using tetramethyl guanidine as the base. They also provide examples of the conversion of non-sterane base hydrazone derivatives.

The reaction of hydrazone derivatives with N-bromo or N-chlorosuccinimide is described in Chem. Pharm. Bull. Japan 11, 1413-1417. (1963). The starting compound used is the 17-hydrazone derivative of epiandrosterone, which is reacted in pyridine with Ν-bromo or N-chlorosuccinimide. The reaction is completed in a few minutes, which is also indicated by the cessation of nitrogen evolution. The reaction mixture is extracted after pouring into water and the resulting "vinyl halide" type compounds are purified by chromatography or recrystallization.

171 166 applies to a similar solution. Hungarian patent specification. In this process, the hydrazone of androst-2-en-17-one is reacted in pyridine medium with N-halosuccinimide at -30 + 20 ° C to give the "vinyl halide" type end product.

The compounds of formula (I) are prepared according to the invention by:

a) for the preparation of compounds of formula I wherein X is iodine, wherein R and the bond are as defined above, a compound of formula II, wherein R and LL are as defined above, in a halogenated hydrocarbon or aromatic solvent; by reacting with elemental iodine in a mixture of two solvents or in an ethereal solvent in the presence of a tertiary amine base, or

b) for the preparation of a compound of formula I wherein X is a chlorine or bromine atom, wherein R and LLL are as defined above, a compound of formula II wherein R and the bond is as defined above is optionally one or and reacting with N-chloro or N-bromosuccinimide in pyridine substituted with several C 1-4 alkyl groups at a temperature of -10 to + 10 ° C.

According to process a), iodination is preferably carried out at room temperature. Upon completion of the reaction, as indicated by the cessation of nitrogen evolution, the tertiary amine base and excess elemental iodine were removed by treatment with dilute aqueous hydrochloric acid followed by sodium thiosulfate. The solvent was distilled off and the crude product was purified by chromatography and recrystallization. The iodination reaction is carried out in a halogenated or aromatic hydrocarbon solvent, preferably chloroform, benzene or a mixture of the two solvents or in an ethereal solvent, preferably tetrahydrofuran, in the presence of a tertiary amine base, preferably triethylamine or tetramethyl guanidine, at room temperature.

Compounds of formula (I) wherein X is chlorine or bromine are preferably prepared according to process (b) by dissolving a compound of formula (II) in pyridine and then, at a temperature of -10 ° C to + 10 ° C, N-Bromosuccinimide is added to the solution. Upon completion of the reaction, which is indicated by the cessation of nitrogen evolution, the crude product is precipitated with water, washed with water to remove pyridine, dried and chromatographed and subsequently recrystallized. Halogenation with Ν-chloro or N-bromosuccinimide is preferably carried out at 0 ° C.

The 17-hydrosone derivatives of formula (II) used as starting materials in the process of the invention are prepared as follows:

From the literature [J. Pharm. Sci., 63, 19-23. (1974), J. Med. Chem., 27, 1690. (1984), J. Org. Chem., 46, 1442-46. (1981)] known 4-aza-5α-androstane-3,17-dione, 4-aza-androst-5-ene-3,17-dione and 4-methyl-4-aza 5α-androstane-3,17 -dione is dissolved in alcohol and triethylamine and hydrazine hydrate are added to the solution. The reaction mixture is heated to reflux. After the reaction is complete, the excess hydrazine hydrate and triethylamine are distilled off (by evaporation to about one tenth the volume of the reaction mixture), the residue is precipitated with water, the precipitate is filtered off, washed with water and dried. The crude product can be used without purification to prepare compounds of formula (I).

The invention is illustrated by the following non-limiting examples.

HU 210 544 A

Example 1

17-Hydrazono-4-aza-5H-androstan-3-one g (0.0346 mol) 4-aza-5a-androstane-3,17-dione

To a suspension of 100 ml of ethanol was added 14 ml (0.1 mol) of triethylamine and 50 ml (1.0 mol) of hydrazine hydrate and refluxed for 3 hours. (The progress of the reaction is monitored by TLC.) After the reaction is complete, the reaction mixture is cooled, the solution is concentrated to a tenth volume 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; She. mp: 254-258 ° C.

1 H-NMR 300 MHz (in CDCl ₃ ) δ: 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, _NH2), 5.74 (br, 1H, NH).

Example 2

17-Hydrazono-4-aza-androst-5-en-3-one Starting from 4-Aza-androst-5-ene-3,17-dione, the compound of formula 1 is isolated.

follow the example. The title compound was obtained in 35% yield. O. p. 379-382 'C.

IR (KBr) v: (C = C), 1661 (C = N), 1693 (C = O),

3200 (NH) at 335 (NH ₂ ) cm -1.

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. O. p .: 211-218 'C.

1 H-NMR 300 MHz (in CDCl ₃ ) d: 0.86 (s, 3H,

18-CH ₃ ), 0.91 (s, 3H, 19-CH ₃ ), 2.93 (s, 3H, N-CH ₃ ), 3.05 [dd (J = 3.6; J = 12, 6), 1H, H-5], 4.78 (vbr, 2H, _NH2).

Example 4

17-iodo-4-aza-androst-5ct.-16-en-3-one

17-Hydrazono-4-aza-5α-androstan-3-one (9.1 g, 0.03 mol) was dissolved in 1200 mL of 1: 1 chloroform / benzene and 90 mL of triethylamine was added. A solution of iodine (11.4 g, 0.045 mol) in benzene (110 ml) was added dropwise and the reaction mixture was 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 diluted with 10% aqueous hydrochloric acid, water, 5% aqueous sodium thiosulfate, water, 5% aqueous solution. washed with sodium bicarbonate solution and finally with water, 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 was crystallized from ethanol to give 5.9 g (50%) of the title compound. O. pp .: 278-282 '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).

Using the same amount of tetramethylguanidine in place of triethylamine in the above reaction gives the title compound in 65% yield. Its physical constants are the same.

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. M.p .: 227-230 ° C. 1 H-NMR 300 MHz (in CDCl ₃ ) δ: 0.78 (s, 3H, 18CH ₃ ), 1.13 (s, 3H, 19-CH ₃ ), 4.9 [dd (J = 2, 4; J = 5.1), 1H, H-6], 6.15 [dd (J = 3.2; J = 1.7), 1H, H16], 8.27 (be, ΙΗ, ΝΗ) .

Example 6

I7'Jód-4-methyl-4-aza-5a-androst-16-en-3-one

Starting from 17-hydrazone-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. M.p .: 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-5-yl-androst-16-en-3-one 4 g (0.0126 mol) of 17-hydrazono-4-methyl-4-aza-5a-androstan-3-one 40 g. After cooling to 0 ° C, a solution of 3.2 g (0.024 mol) of N-chlorosuccinimide in 40 ml of pyridine was added dropwise with vigorous stirring. After vigorous nitrogen evolution ceased, the reaction mixture was stirred for another 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 residue was crystallized from petroleum ether. 2.15 g (53%) of the title compound are obtained. O. pp .: 139-140 'C. 1 H-NMR 300 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-androst-16-en-3-one

Starting from 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one, proceed as in Example 7. The reaction is carried out using N-bromosuccinimide. The title compound was obtained in 55% yield. O. pp .: 159-161 'C. 1 H-NMR 300 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-androst-5v.-16-en-17 $ - (N-tert-butyl carboxamate)

3.99 g (0.01 mol) of 17-iodo-4-aza-5α-androst-16en-3-one are dissolved in 150 ml of dimethylformamide,

Palladium (II) acetate (0.244 g, 0.001 mol), triphenylphosphine (0.524 g, 0.002 mol), triethylamine (10 ml), tert-butylamine (15 ml, 0.14 mol) were added and carbon was added. in a monoxide atmosphere at 60 ° C for 1.5-2 hours. After completion of the reaction, the amines and dimethylformamide are distilled off in vacuo and the residue is dissolved in 150 ml of chloroform and then the chloroform solution is treated with water, 5% aqueous hydrochloric acid, washed with sodium bicarbonate and saturated aqueous 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. The eluent was ethyl acetate. 3.16 g (85%) of the title compound are obtained. O. p .: 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-androstane-17β - (N-tert-butylcarboxamide) g 3-oxo-4-aza-5α-androst-16-ene 17β- (N-tert-butylcarboxamide) ) 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. The title compound was obtained in 90% yield. O. p .: 283-286 'C.

Claims (13)

PATENT CLAIMS A process for the preparation of 4-aza-androstene derivatives of the formula I wherein: R is hydrogen or C 1-3 alkyl, X is chlorine, bromine or iodine, and a ΞΣΞ A bond line represents a single or double chemical bond for its preparation, characterized in that: a) for the preparation of a compound of formula I wherein X is an iodine atom, wherein R and a L-.T. bond are as defined above, a compound of formula II wherein R and a bond are as defined above in a halogenated hydrocarbon or by reacting with elemental iodine in a mixture of two solvents or in an ethereal solvent in the presence of a tertiary amine base, or b) for the preparation of a compound of formula I wherein X is a chlorine or bromine atom, wherein R and a7-bond are as defined above, a compound of formula II wherein R and a-bond are as defined above is a solvent. In this case, N-chloro or N-bromosuccinimide is reacted in pyridine substituted with one or more C 1 -C 4 alkyl groups at a temperature of -10 ° C to + 10 ° C. (Priority: February 26, 1992) Process (a) according to claim 1, characterized in that the halogenated hydrocarbon solvent is chloroform, the aromatic solvent is benzene and the ethereal solvent is tetrahydrofuran. (Priority: February 26, 1992) 3. The process of claim 1 a) or claim 2 wherein the tertiary amine base is triethylamine or tetramethyl guanidine. (Priority: February 26, 1992) Process b) according to claim 1, characterized in that the solvent is pyridine. (Priority: February 26, 1992) Process according to claim 1 b) or claim 4, characterized in that the reaction is carried out at 0 'Con. (Priority: February 26, 1992) 6. A method according to claim 1 or a method according to claim 2-3. The process according to any one of claims 1 to 4, 17-iodo-4-aza-5a-androst-16-en-3-one, 17-iodo-4-aza-androst-5,16-dien-3-one and 17-iodo-4-methyl-4-one. for the preparation of aza-5α-androst-16-en-3-one, characterized in that starting material is 17-hydrazone-4-aza-5α-androstan-3-one, 17-hydrazono-4-aza-androst-5-ene-3 -one or 17-hydrazono-4-methyl-4-aza-5a-androstan-3-one. (Priority: February 26, 1992) 7. The method according to claim 1, b) or 4-5. Process for the preparation of 17-chloro-4-methyl-4-aza-5a-androst-16-en-3-one and 17-bromo-4-methyl-4-aza-5a-androst-16-en-3-one according to any one of claims 1 to 3 , characterized in that 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one is used as starting material. (Priority: February 26, 1992) 8. 4-Aza-androstene derivatives of the general formula (I) - wherein R is hydrogen or C 1-3 alkyl, X represents a chlorine, bromine or iodine atom, and the bond line represents a single or double chemical bond. The 17-iodo-4-aza-5α-androst-16-en-3-one of claim 8. (Priority: 07/07/1994) The 17-iodo-4-aza-androsta-5,16-dien-3-one of claim 8. (Priority: 07/07/1994) The 17-iodo-4-methyl-4-aza-5α-androst-16-en-3-one according to claim 8. (Priority: 07/07/1994) The 17-chloro-4-methyl-4-aza-5α-androst-16-en-3-one of claim 8. (Priority: 07/07/1994) The 17-bromo-4-methyl-4-aza-5α-androst-16-en-3-one of claim 8. (Priority: 07/07/1994)