HU182529B - Process for preparing 4-aza-17-substituted-5-alpha-androstan-3-one derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of novel compounds of formula (I) wherein A is an ethylene group or an ethenylene group, B is a group of formula Ia, where a hydrogen atom at the 17a position and a mono 17/3 position are present. - or di (1-4C) alkylaminocarbonyl or alkyl in the 1-4C-alkylcarbonyl or alkoxycarbonyl-5. The compounds of formula I are valuable antiandrogens. R1 R1 is hydrogen or methyl, or C4, N4, IR, X1, where R1 is methyl, X® is hydroxyl anion, and R4 is -NR6R7 where R6 is hydrogen and R7 are methyl, and Z is 1, wherein the dotted line is substituted with 17a-hydrogen; or 30 15 20 (1) 182529 -1-

Description

The present invention relates to novel 4-aza-17-substituted-5a-androstan-3-one derivatives. THE

4-Aza-17-substituted-5α-androstan-3-one derivatives are useful as testosterone-5α-reductase inhibitors.

It is known that hyperandrogen pacing (stimulation) caused by an excess accumulation of testosterone and similar androgenic hormones in the metabolic system causes certain undesirable physiological symptoms, such as inflammation of the gland (acne vulgaris), malignant glandular fibrosis, seborrheic cause. Previous research into the preparation of chemotherapeutic agents to counteract the undesirable effects of hyperandrogenic stimulation has developed steroidal anti-androgens which themselves have undesirable hormonal activity. Estrogens, for example, not only neutralize the effect of androgens, but also have a feminizing effect. Non-steroidal anti-androgens, such as 4'-nitro-3'-trifluoromethylisobutylanilide, have also been developed (see Neri et al., Endo., Vol. 91, No. 2 (1972)). These products, although lacking hormonal activity, are peripheral; share natural receptor androgens with natural androgens, thereby feminizing male or female fetuses.

It is also known that in some target organs 5a-dihydrotestosterone, which is produced locally by testosterone 5? -Reductase, is the major carrier of androgenic activity. On this basis, it has been hypothesized and proved that testosterone-5α-reductase inhibitors can prevent or reduce the symptoms of hyperandrogenic stimulation. Nayfeh et al., Steroids, 14, 269 (1969), have demonstrated that 4-androstene-3-one-17 (3-carboxylic acid methyl ester is an in vitro testo-esterone-5α-reductase inhibitor. Voigt and Hsia, Endocrinology, 92; 1216 (1973), Canadian Patent No. 970,692, also demonstrated that the above ester and the corresponding free acid, i.e., 4-androstene-3-one-17/3-carboxylic acid, are active in testosterone-5α-reductase in vitro. In addition, both testosterone and 5α-dihydrotestosterone have been shown to increase the rate of female hamsters with topical administration, which is an androgen-dependent sebaceous structure. but did not inhibit the reaction induced by 5α-dihydrotestosterone. Based on the above results, it was concluded that the above compounds are antiandrogen due to their ability to inhibit testosterone-5α-reductase wedge.

Accordingly, the novel compounds of the present invention are potent antiandrogens due to their potent inhibition of testosterone-5α-reductase.

Until now, it has not been known that 4-aza-17-substituted-5α-androstan-3-one derivatives are useful in the treatment of hyperandrogenous conditions, although Selye in Belgian Patent 775 919 discloses such compounds, derivatives containing one or more carbonitrile substituents , such as catatoxic agents, which are useful, for example, in the treatment of prostatic hyperplasia.

Many 4-aza steroid compounds are known (see, for example, U.S. Patent Nos. 2,227,876, 3,239,417, 3,263,301 and 3,285,918, French Patent No. 1465,544, Doorenbos and Solomons, J.). Phar. Sci., 62, 4, pp. 638-640 (1973) and Doorenbos and Brown, J. Phar. Sci., 60, 8, pp. 1234-1235 (1971)]. However, the use of the 4-aza compounds of the invention and their use in the treatment of hyperandrogenic conditions has not been described so far.

The novel compounds of the invention are represented by the general formula (I) in which

A is ethylene or ethenylene,

B represents

C // \ /

Ο N is a group of the formula wherein R is ¹

R ¹ is hydrogen or methyl, or

I c

/% /

A group of the formula R ⁴ jq® χ ©, wherein R ¹ '

R ¹ 'is methyl,

X® is a hydroxyl anion, and

R ⁴ is —NR ⁶ R ⁷ wherein R ⁶ is hydrogen and R ^{7 is} methyl, and

Z represents

A group of formula wherein the dashed line replaces 17a-hydrogen; ^v or a 17-position hydrogen atom and a 170-position mono- or di (C 1 -C 4) alkylaminocarbonyl or an alkylcarbonyl or alkoxycarbonyl group containing from 1 to 4 carbon atoms in the alkyl moiety.

Unless otherwise noted, the substituents may be in the a- or (5-configuration).

Preferred novel compounds of the invention are the following:

17 / 3- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5űí-androstane-3-one,

170- (N, N-diethylcarbamoyl) -4-aza-5-yl. ^v -androstane-3-οη,

4-aza-20-spirox-5a-an-3-one;

4-methyl-4-aza-20-spirox-5a-an-3-one;

17 (5- (N-ethylcarbamoyl) -4-methyl-4-aza-5a-androst-3-one;

4-ethyl-4-aza-5a-20-spiroxanan-3-one and

17 (5-methoxycarbonyl () -4-methyl-4-aza-5.alpha.-androstan-3-one.

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According to the invention, B is replaced by

C

H \ /

N I

Compounds of formula (I) wherein R ¹ group may be prepared by reacting a compound (IV) of formula, is treated with Z is as defined above, at a low temperature with an oxidizing agent: wherein, in (V) 5-oxo-3 formula 5-sec-androstane-3-acid, wherein Z is as defined above, is reacted with an amine of formula R ¹ NH ₂ , wherein R ¹ is as defined above, and the resulting compound of formula VI the 4-aza-5-androsten-3-one derivative substituted with R *, wherein Z and R ¹ are as defined above, is catalytically hydrogenated.

In the final hydrogenation step, 5a-hydrogen is introduced into the molecule. The reactions described above are illustrated in FIGS. Examples 1 to 4 are detailed and illustrated in Scheme A.

In place of B

C /% /

R ⁴ N®

I

R ¹ '

A process for preparing a compound of formula (I) containing a group of formula X® is carried out by reacting a compound of formula (VII), wherein Z and R ¹ are as defined above, with a compound of formula (VII) alkylation of the lactam carbonyl group of the above-mentioned lactam with trialkyloxonium tetrafluoroborate and the resulting alkyl iminium ether, that is, a compound of formula I wherein B is as defined above and R ⁴ is -OR ⁵ R ^s represents a C 1-4 alkyl group - is treated, and mineral acids, and then alkali - a HNR ⁶ R ⁷ with an amine of the formula: - wherein ^R6 and ^R7 are as defined above.

The reaction of Step 1 is described in the first part of Example 10 and the reaction of Step 2 in Example 17.

Compounds of formula (I) wherein A is -CH = CH- can be prepared by subjecting the compounds of formula (I) to one of the methods described above;

(1) treating the 1,2-saturated compound with lithium diisopropylamide to produce the corresponding enolate, (2) treating the enolate obtained in step (1) with diphenyl disulfide to produce the corresponding α-phenylthio compound, (3) ) oxidizing the product of step (2) to produce the corresponding sulfoxy compound and (4) heating the product of step (3),

The above reaction is described in Example 9.

17β- (N, N-Diethyl] carbamoyl) -4-methyl-4-aza-5α-androstan-3-one, which is a highly representative of the compounds of the invention, is preferably prepared by: (a) Pregnenolone (VIII), a readily available starting material, is reacted with King reaction, pyridine and iodine to give pyridinium iodide (IX); (b) converting the pyridinium iodide derivative (IX) with sodium methoxide in methanol into the methyl ester of androstene-3-ol-17-carboxylic acid (X), which is preferably used to carry out the Oppenhauer reaction; (c) reacting the methyl androstene-3-ol-17-carboxylic acid methyl ester (X) in the presence of a suitable solvent, such as toluene, with aluminum isopropoxide and cyclohexanone to produce the methyl 4-androstene-3-one-17 carboxylic acid ester (XI). ; (d) hydrolyzing the 4-androstene-3-one-17-carboxylic acid methyl ester of formula (XI) in an acidic medium with a 4: 1 methanol-water mixture to the acid of formula (XII); (e) treating the acid of formula (XII) with a 1: 1 oxalyl chloride-pyridine complex in toluene or other suitable solvent such as xylene to produce the 17-acid chloride of formula (XIII); (f) treating the acid chloride of formula (ΧΠΙ) with excess diethylamine in situ to produce 17β- (N, N-diethylcarbamoyl) -4-androsten-3-one of formula (XIV); (g) using 4-androsten-3-one of formula (XIV) as a solvent system with tert-butanol and water with sodium periodate and potassium permanganate to form the corresponding 5-oxo-3,5-sec-androstane-3-acid of formula XV oxidized; (h) reacting the seco-androstanoic acid of formula (XV) with methylamine in ethylene glycol medium for 1 hour while raising the temperature of the reaction mixture to 140-180 ° C and maintaining for 0.5 to 5 minutes at the same temperature (XVI). 4-aza; (i) hydrogenating the resulting 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androsten-3-one of formula XVI using platinum oxide as catalyst at room temperature to 60 ° C, the resulting 170-N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one (XVII) is separated and purified. The above reactions are illustrated in Scheme B.

The novel compounds of formula I according to the invention may also be prepared by applying the methyl group to the nitrogen of the ring A in the final step. In this case, the reaction is carried out as follows:

converting 5-oxo-3,5-sec-androstane-3-acid (XVIII) with ammonia to the corresponding 4-aza-5-androsten-3-one (XIX);

4-aza-5-androsten-3-one of formula (XIX) by catalytic hydrogenation at

18252?

converting it to the corresponding 4-aza-5-androstan-3-one compound of formula XX;

treating the compound of formula XX with methyl iodide in the presence of sodium hydride to produce 4-methyl-4-aza-5-androstan-3-one of formula XXI.

For example, 170 (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one, which is a prominent representative of the compounds of the present invention, can be prepared as a starting material. , N-diethylcarbamoyl) -5-oxo-3,5-sec-androstanoic acid.

The above reaction is described in more detail in Example 11 and is illustrated in Scheme C.

The novel compounds of formula (I) of the present invention may also be prepared by a process, not claimed, which comprises forming the nitrogen-containing ring A in the final ring closure step. In this case, the reaction is carried out as follows:

reacting 5-oxo-3,5-sec-androstane-3-acid of formula XXII with methylamine

Converting 5-methylamino-3,5-sec-5-androstene-3-acid:

converting the product of Step 1 to the corresponding 5a-hydrogen derivative (ΧΧΠΙ) by catalytic hydrogenation;

the compound of formula (ΧΧΙΠ) is heated in situ to produce the 4-methyl-4-aza-5α-androstan-3-one compound of formula (XXIV).

For example, 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one, an outstanding representative of the compounds of the present invention, can be prepared in the same manner as starting material 170- (N0N). -diethylcarbamoyl) -5-oxo-3,5-sec-androstane-3-acid.

The above reaction is described in more detail in Example 12 and is illustrated in Scheme D.

The 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-50-androstan-3-one can also be prepared by a process not included in our patent application by introducing the 170-diethylamide side chain in the final step. . In this case, the reaction is carried out as follows:

oxidizing the 170-carboxy-4-androsten-3-one of formula (XXV) with an oxidizing agent such as sodium peododate to the 170-carboxy-5-oxo-3,5-seco-androstane-3-acid of formula (XXVI);

reacting compound (XXVI) with methylamine to form 170-carboxy-4-methyl-4-aza-5-androsten-3-one (XXVII);

converting compound (XXVII) to 170-carboxy-4-methyl-4-aza-5a-androstan-3-one (XXVIII) by catalytic hydrogenation;

forming a sodium salt of compound (XXVIII) which is reacted with oxalyl chloride to produce 4-methyl-4-aza-5a-androstane-3-one-170-carbonyl chloride (XXIX); and reacting compound (XXIX) with diethylamine to produce 170- (N, N -diethylcarbamoyl) -4-methyl-4-aza-5a-1 androstan-3-one (XXX).

The above reaction is described in detail in Example 13 and is illustrated in Scheme E.

The 170- (N, N -diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one may also be prepared by a process not included in the scope of the invention by diethylating the corresponding 170-carbamoyl compound in the final step. or the corresponding 170- (N-ethylcarbamoyl) compound is alkylated. The above two procedures consist of the following steps:

converting 170-carboxy-4-methyl-4-aza-5α-androstan-3-one with oxalyl chloride to 4-methyl-4-aza-3-oxo-5α-androstane-170-carbonyl chloride;

reacting the product of the preceding step with ammonia; the resulting 170-carbamoyl-4-methyl-4-aza-5α-androstan-3-one is reacted in the presence of an equimolar amount of sodium hydride or sodium methylate with an ethylating agent such as ethyl bromide or diethyl sulfate to provide the desired product; The product of Step 1 is reacted with monoethylamine and the resulting 170- (N-ethylcarbamoyl) compound is reacted with a monoalkylating agent, such as sodium hydride, to give the desired product.

The above reactions are described in detail in Examples 15 and 16 and are illustrated in Scheme F.

Compounds of the present invention wherein A is -CH = CH- and the nitrogen at the 4-position has a substituent other than hydrogen may be prepared as described in Example 9. The compounds of the present invention having a hydrogen atom at the 4-position can be prepared as described in Example 10.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

Example 1

Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

A. Preparation of 3-oxo-NNi-diethyl-4-androstene-170-carboxamide The sodium salt of 3-oxo-4-androstene-170-carboxylic acid was suspended in a mixture of 360 ml of anhydrous benzene and 0.13 ml of pyridine. Cool to C. To the suspension was added 21 ml of oxalyl chloride and the mixture was stirred for 15-20 minutes at 15 ° C. The suspension is evaporated to dryness and slurried in 125 ml of anhydrous tetrahydrofuran. The suspension is added to a solution of 25 ml of diethylamine in 125 ml of tetrahydrofuran, the reaction mixture is stirred for 1 hour at room temperature and then poured into 4 liters of ice water. The precipitated semi-crystalline precipitate was extracted with ethyl acetate, and the extract was washed with water and brine, dried and evaporated. 25.7 g of product are obtained, which is recrystallized from ethyl ether. The first 10.0 g portion had a melting point of 127-129 ° C and the second 3.1 g portion had a melting point of 114-119 ° C.

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Β) Preparation of 17/3 - (Ν, N-diethylcarbamoyl) -5-oxo-3,5-secoandrostane-3-acid

Dissolve 15 g of the product obtained in Step A in a mixture of 150 ml of dichloromethane and 75 ml of methanol, cool the solution to -78 ° C and then ozone is bubbled through the solution until the blue color of the solution disappears. The reaction mixture was warmed to room temperature, purged with a stream of nitrogen and evaporated to dryness at 35 ° C. The residue was dissolved in benzene and extracted three times with 2.5N sodium hydroxide solution. The alkaline extracts were combined, acidified with concentrated hydrochloric acid, extracted with benzene, washed, dried and evaporated. 11.5 g of white crystals are obtained. After recrystallization from ethyl acetate, m.p. 205-208 ° C.

C) Preparation of 17β- (N, N-diethylcarbamoyl) -4-aza-4-methyl-5-androsten-3-one

26.3 g of the product of Step B are dissolved in 190 ml of ethanol. The solution was cooled in an ice bath, saturated with methylamine and heated at 180 ° C for 8 hours. The reaction mixture was then cooled to room temperature and concentrated. 22.3 g of a yellow solid are obtained. After chromatography and recrystallization from ethyl ether, m.p. 120-122 ° C.

D) Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

36.5 g of the product of Step C are dissolved in 1 liter of glacial acetic acid. The solution was hydrogenated in the presence of 3.5 g of platinum oxide catalyst for 8 hours at room temperature and 2.722 atm. Upon completion of hydrogenation, the reaction mixture is filtered and evaporated to dryness. The residue was dissolved in chloroform, washed with sodium bicarbonate solution and brine, dried and evaporated to dryness. The product was recrystallized from ethyl ether to give 30.65 g of white crystals. Mp 168-170 ° C.

2-8. examples

In the same manner as in Example 1, but

In step A, using another appropriate 3-οχο-Δ compound, or equimolar amounts of other suitable amines instead of diethylamine, the compounds of formula XLI of Table 1 are prepared.

Table 1

example Number R ¹ Z melting point (° C) 2 H -CON (CH ₂ CH ₃ ) ₂ 263-265 3 H υ 283-285 4 -ch ₃ 138-140 5 H -COCH ₃ 272-275 6 -ch ₃ -coch ₃ 218-220 7 -ch ₃ -conhch ₂ ch ₃ 249-251 8 H --COOCH 300-302

Example 9

Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androst-1-en-3-one

To a solution of 0.20 g of anhydrous diisopropylamine in 5.0 ml of anhydrous tetrahydrofuran was added 0.9 ml of 2.2 M butyllithium under nitrogen at -78 ° C, the reaction mixture was allowed to stand for 20 minutes at -78 ° C, and 388 mg of i70- A solution of (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one in THF (3 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at -78 ° C and a solution of 440 mg diphenyl disulfide in 1 ml tetrahydrofuran was added slowly. The reaction mixture was stirred at -78 ° C for 10 minutes and then allowed to warm to room temperature. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution, water, dilute hydrochloric acid solution and saturated sodium chloride solution. The solution was dried over calcium sulfate and concentrated. 30 g of the crude sil-5182529 solid product obtained are eluted on silica gel with increasing amounts of ethyl acetate in hexane. The 2-phenylthio derivative is obtained in the form of two isomers. The resulting material is suspended in 5 ml of 20% aqueous methanol and treated with a solution of 225 mg of sodium metaperiodate in 2 ml of water. After stirring for 1 h, the reaction mixture is diluted with water and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated. A solution of the resulting crude sulfoxide in toluene (5 mL) was heated to reflux for 30 minutes. The solvent was removed and the residue was chromatographed on 20 g of silica gel using increasing volumes of ethyl acetate as the eluent. The final product crystallizes by trituration with ether. Mp 202.5-204.5 ° C.

Example 10

17β = ((, N-Diethylcarbamoyl) -4-aza-5α-androst 1-en-3-one

A solution of 291 mg of 170- (N, N-diethylcarbamoyl) -4-aza-5a-androstan-3-one in 3 ml of methylene chloride was added at 0 ° C to a solution of 117 mg of trimethyloxonium fluoroborate in methylene chloride. After stirring for 6 hours at 0 ° C, 125 mg of 1,5-diazabicyclo [5.4.0] undec-5-ene was added. Stirring was continued for a further 2 hours and the reaction mixture was diluted with anhydrous ether. The organic solution was separated from the residue and concentrated under reduced pressure, the crude lactim ether is converted to the corresponding Δ ¹ Compund. 276-278 ° C.

Example 11

Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

A) Preparation of 170- (N, N-diethylcarbamoyl) -4-aza-5-androsten-3-one g 17β- (N, N-diethylcarbamoyl) -5-oxo-3,5- A solution of seco-androstane-3-acid in 600 ml of anhydrous ethanol, saturated with ammonia at 0 ° C, was heated in a bomb tube at 180 ° C for 8 hours. After cooling, the brown solution was allowed to evaporate and concentrated to dryness. The resulting yellowish foam was triturated with cyclohexane to give 170- (N, N-diethylcarbamoyl) -4-aza-5-androsten-3-one.

B) Preparation of 17β-3- (NN-diethylcarbamoyl) -4-aza-5a-androstan-3-one A solution of the product of Step A in 140 ml of glacial acetic acid in the presence of 2.5 g of platinum oxide and 0.1 ml of perchloric acid at room temperature 2,722 atm hydrogenation under pressure. After uptake of the calculated amount of hydrogen (about 6 hours), the residue is filtered off and the filtrate is evaporated to dryness. The residue was dissolved in 100 ml of methylene chloride, washed twice with 50 ml of saturated sodium chloride solution and then with 50 ml of 5% sodium bicarbonate solution. After drying over magnesium sulfate, the solution is concentrated to dryness, the residual oil is dissolved in ethanol, filtered through charcoal and water is added slowly until crystallization begins. After cooling to 5 ° C, the crystalline product is filtered off. , washed with water and dried.

C) A solution of 17β- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one in step B in 700 ml of toluene was treated with 5.4 g of 50% sodium slurry of the emulsion in 20 ml of toluene followed by slow addition of 16 g of methyl iodide. After stirring for 3 hours at room temperature, 5 ml of ethanol / 25 ml of toluene and 1 liter of water were added to quench the excess sodium hydride. The product was extracted with toluene (3 x 500 mL), the combined extracts were washed with water (3 x), dried over anhydrous magnesium sulfate and concentrated to dryness. Pure 17β- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one is obtained by crystallization from ethanol and water. The product had the same melt as in Example 1.

Example 12

Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one g of 170- (N, N-diethylcarbamoyl) -5-oxo-3,5-sec. A slurry of androstane-3-acid in 120 ml of ethanol is saturated with methylamine gas and filled into an autoclave containing 2 g of pre-reduced platinum oxide in 25 ml of ethanol. The reaction mixture was hydrogenated at 2.722 atm for 6 hours at 40 ° C. The autoclave is then vented, resealed and then heated at 180 ° C for 8 hours to effect ring closure. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. The residue was crystallized from ether. After filtration and drying, essentially pure 17β- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one is obtained. Your identity is the same all. Example.

Example 13

Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one A) 17) Preparation of 3-carboxy-5-oxo-3,5-seco-androstan-3-acid

To a solution of 31.6 g (0.1 mol) of 17β-carboxy-4-androsten-3-one in 1100 ml of tert-butanol is added 27.6 g of potassium carbonate in 150 ml of water. 185 ml of a solution of 148 g of sodium metapeiodate in 925 ml of water are added at a time, and the residue is added at 37 ml / min. THE

Together with the first portion of the pe 6182529 peodate solution, a 1.6% aqueous solution of potassium permanganate (18.5 mL) is added and then added to maintain the color of the pink reaction mixture. During the addition period, the temperature of the reaction mixture was maintained at 35 ° C. After stirring for a further 3 hours, the reaction mixture is filtered and added with enough sodium bisulfide to remove the pink color. The reaction mixture was then concentrated to half volume, acidified and extracted with ethyl acetate. The solution is concentrated to give 17/5-carboxy-5-oxo-3,5-sec-androstanoic acid, which can be used in the next step without further purification.

B) Preparation of 17β-Carboxy-4-methyl-4-aza-5-androsten-3-one A suspension of the product of Step A in ethanol (150 mL) was saturated with methylamine gas and autoclaved for 8 hours. Heat at <RTI ID = 0.0> C </RTI>. The reaction mixture was then cooled and concentrated to dryness. The residue is slurried in water and filtered. 17.3-Carboxy-4-methyl-4-aza-5-androsten-3-one is obtained.

C) Preparation of 170-carboxy-4-methyl-4-aza-5a-androstan-3-one

A solution of 10.0 g of the product of Step B in 40 ml of glacial acetic acid and 0.05 ml of perchloric acid in the presence of 1.0 g of platinum oxide catalyst at room temperature is 40 p.s.i. (2.722 atm). After uptake of hydrogen, the catalyst was filtered off and the filtrate was concentrated to near dryness. The residue was dissolved in dilute aqueous sodium bicarbonate solution, treated with 1.0 g of activated carbon, filtered and the filtrate was acidified. The product was filtered and dried.

D) Preparation of 17β-N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one

5.0 g of the product of Step C are treated with an equivalent amount of 1 N sodium hydroxide solution. The reaction mixture was stirred overnight, lyophilized and dried in vacuo over phosphorus pentoxide. The resulting 17-carboxylic acid sodium salt was suspended in 100 ml of anhydrous toluene. The suspension was cooled to 15 ° C and 3 ml of oxalyl chloride was added dropwise at this temperature. The reaction mixture was stirred for an additional 50 minutes and then concentrated to dryness. THF (30 mL) was added and the reaction mixture was added to a solution of diethylamine (6 mL) in THF (30 mL) under cooling and stirring. The reaction mixture was stirred for one hour and then poured into 1 liter of water. The product was extracted with chloroform, washed thoroughly with dilute sodium bicarbonate solution, then with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The chloroform extract was distilled in vacuo and the residue crystallized from ether. In this way, substantially pure 17 (3- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one) is obtained.

Example 14 Preparation of 17β-3- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one

A) Preparation of N- (30-Hydroxy-pregn-5-en-2-one-21-yl) prridinium iodide Add 1 kg (3.16 mol) of pregnenolone per liter of pyridine and mix at 90-95 ° C with moderate stirring. Heat to C until pregnenolone is dissolved. Carefully add 8.66.1 g (3.41 mol) of iodine over a period of 15 to 20 minutes and raise the reaction temperature to 120 ° C. The reaction mixture was stirred at 100 ° C or higher for 1 hour, then allowed to cool gradually over 1 hour and finally cooled to room temperature in a water bath. The product was collected on a medium porosity silica gel funnel (rubber and gel-like material). Filtration is facilitated by the addition of pyridine, and the filtered product is washed six times with 300 ml of pyridine, then six times with 300 ml of ether and air-dried. 1635.8 g (99%) of product are obtained, m.p. 228-230 ° C.

B) Preparation of 5-androstene-3/3-ol-17/3-carboxylic acid methyl ester

The flask was charged with 2.7 kg (5.177 mol) of N- (3β-hydroxypregn-5-en-20-one-21-yl) pyridinium iodide, 13.5 liters of methanol and 900 g of sodium methoxide. The reaction mixture was heated at reflux for 1 hour, then allowed to cool to 53 ° C, then cooled to 5 ° C by addition of 24 L of ice and 2 L of water. The reaction mixture was then neutralized to pH 6-7 with 2100 mL of 1: 1 hydrochloric acid / water. After standing for 45 minutes, the precipitate was collected in a Lapp funnel and washed thoroughly with cold water until the dye was washed off. The product was briefly dried on a funnel and transferred to two glass trays and dried overnight in a 50 ° C oven. 1440 g (83.6%) of product are obtained.

C) Preparation of 4-androsten-3-one-17 (3-carboxylic acid methyl ester)

To the flask was added 160.0 g of 5-androstene-30-ol-170-carboxylic acid methyl ester, 2.4 L of filter-dried toluene and 680 mL of cyclohexanone. The reaction mixture is heated to reflux and the small amount of water present is removed by azeotropic distillation over 15 minutes (azeotropic distillation is continued until the distillate is clear). A suspension of 88 g of aluminum isopropoxide in 320 ml of anhydrous toluene is then added to the reaction mixture, and the reaction mixture is refluxed while approximately 800 ml of toluene is removed over a period of about 1 hour. The reaction mixture was cooled to 25 ° C and 40 g of diatomaceous earth and 80 ml of water were added. The mixture was stirred for 10 minutes, then was born on diatomaceous earth and washed three times with 300 ml of toluene. The filtrate was concentrated to near dryness and then cooled in an ice bath. The precipitated crystalline product was collected, washed with cold hexane and dried in vacuo. 133 g (83.6%) of product are obtained, m.p. 130-132 ° C.

D) Preparation of 4-androstene-3-one-170-carboxylic acid

To a solution of 4-androstene-3-one-170-carboxylic acid methyl ester (2.422 kg) in methanol (24.6 ml) was added a solution of potassium hydroxide (1.23 kg) in water (4.9 ml). The reaction mixture was refluxed under nitrogen for 6 hours and then allowed to cool to room temperature overnight. The reaction mixture was acidified with 3200 ml of 6N hydrochloric acid, whereby most of the product precipitated as fine crystals. The reaction mixture was then stirred for 4 hours at 30 ° C, filtered and washed with water until the wash water was neutral. The product was dried in an oven at 50 ° C overnight. 2.313 g (98%) of product are obtained with a melting point of 245-248 ° C.

E) Preparation of 170- (N, N-diethylcarbamoyl) -4-androsten-3-one

The flask was charged with 700 g of 4-androstene-3-one-170-carboxylic acid and 11.6 liters of azeotropically dried toluene. To the reaction mixture was added pyridine (226 mL), dried over a filter, and then a solution of oxalyl chloride (250 mL) in dry toluene (250 mL) was carefully added over 20 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour, cooled to 10'C, and basified with filter-dried diethylamine in an equal volume of anhydrous toluene (about 2.4 liters required). The reaction mixture was allowed to stand for 30 minutes and then cooled with ice water (16 L). The layers were separated and the aqueous phase was extracted three times with 4 L of ethyl acetate. The combined organic layers were washed with 8 L aqueous hydrochloric acid, adjusting the pH to 3, and then with 8 L water and 8 L saturated sodium chloride. The mixture was dried over sodium sulfate and concentrated on a rotary evaporator to 3-4 liters. Hexane (4 L) was added and cooled to 0-5 ° C over 1 hour. The product was collected, washed three times with a small amount of cold hexane and dried overnight in a 40-50 ° C oven. 616.5 g (75%) of product are obtained. 119-121 ° C.

F) Preparation of 170- (N, N-diethylcarbamoyl) -5-oxo-3,5-seco-androstanoic acid In a liter of t-butanol, 600 g of 170- (N, N-diethylcarbamoyl) -4-androstene are dissolved. -3-one and then a solution of 258 g of sodium carbonate in 1200 ml of water is added. Then, 1.5 kg of sodium periodate in 18 liters of water and 1340 ml of 2% potassium permanganate solution are added over 1.5 hours. During the addition, the temperature of the reaction mixture was maintained at 25-40 ° C. The reaction mixture was allowed to stand for 2 hours, then filtered and washed with water. The tert-butanol is distilled off, the aqueous solution is cooled to 10 ° C and then acidified to pH 3 with 110 ml of 50% sulfuric acid. The aqueous solution was then extracted with ethyl acetate (3 x 6 L). The single ethyl acetate phases are washed with 4 L of 5% sodium hydrogen sulfate solution and twice with 4 L of saturated sodium chloride solution. The combined extracts were dried over sodium sulfate, concentrated to 1.5 liters, heated to reflux and allowed to stand at 5-10 ° C for 2 hours. After filtration, the filter cake was washed with ethyl acetate. 488 g (77%) of product are obtained, m.p. 205-208 ° C.

G) Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5-androsten-3-one

In a dry ice bath, a graduated cylinder was condensed with 200 ml of methylamine, which was added to 1250 ml of ethylene glycol with stirring at room temperature, and a 16% increase in volume was observed. The methylamine-ethylene glycol solution is added to 250 g of 170- (N, N-diethylcarbamoyl) -5-oxo-3,5-sec-androstanoic acid in a 3 liter flask. A solution is obtained within a few seconds. The reaction mixture is heated to 110 ° C under 40 spins and heating is continued at 2 rpm until the reaction temperature is 180 ° C (about 70 minutes). The reaction mixture was then poured into water (10 L) and the resulting cloudy solution was extracted with CH 2 Cl 2 (5 L). The combined organic extracts were washed with water (4 L), acidified with concentrated hydrochloric acid (4 L), 5% sodium bicarbonate (4 L) and water (3 L). The combined organic phases are dried over sodium sulfate, treated with 50 g of silica and evaporated to dryness. The residue was dissolved in a solution of 750 mg of cyclohexanone in 750 ml of n-hexane and stirred overnight at room temperature. The product is filtered off, washed with n-hexane and dried in vacuo. 226 g (91%) of product are obtained, m.p. 115-118 ° C.

Η) Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

150 g of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5-androsten-3-one and 750 ml of glacial acetic acid were weighed into a flask and the reaction mixture was stirred for 3.0 hours under nitrogen at 3.05 heated at 60 ° C. The product is filtered off, the filter cake is washed with dichloromethane and the filtrate is evaporated to dryness. The residue is dissolved in 750 ml of dichloroethane, washed twice with 500 ml of 1N sulfuric acid, once with 500 ml of water and once with 500 ml of saturated sodium bicarbonate solution. The solution was dried over magnesium sulfate, treated with charcoal (15 g) and filtered through a pad of silica (75 g). The filter cake was washed with 1 L dichloromethane and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (450 mL) and allowed to stand at room temperature for 1 hour and in an ice bath for 1 hour. The product was filtered off, washed with ethyl acetate (50 mL) and n-hexane (100 mL) and dried. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate (100 mL), allowed to stand at room temperature for 2 hours, filtered and washed with ethyl acetate (15 mL) and n-hexane (100 mL). 115 g (76.6%) of product are obtained, m.p. 172-174 ° C.

-8182529

Example 15

Preparation of 17 / 3- (N, N-diethyl] carbamoyl) -4-methyl-4-aza-5a-androstan-3-one

A) Preparation of 17β-carbamoyl-4-methyl-4-aza-5α-androstan-3-one

Ammonia was added to a solution of 4-methyl-4-aza-5a-androstane-3-one-17β-carboxylic acid in tetrahydrofuran solution and the reaction mixture was stirred for 2 hours at room temperature. After addition of water and extraction with ethyl acetate, the intermediate amide is obtained.

B) Preparation of 17 / 3- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5-androstan-3-one

The product of Step A is ethylated with ethyl bromide in an equimolar amount of sodium hydride in toluene. One mole of the product of Step A is reacted with two moles of ethyl bromide to give the title product. Its identification data is the same as that of Example 12.

Example 16

Preparation of 170- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

A) Preparation of 170- (N-ethylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

To a toluene solution of 4-methyl-4-aza-5α-androstane-3-one-17β-carboxylic acid is added a solution of monoethylamine in tetrahydrofuran and the reaction mixture is stirred for 2 hours at room temperature. Addition of water and extraction with ethyl acetate gives the product 17/3 (N-ethylcarbamoyl).

Β) Preparation of 17β- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one

The product of Step A is reacted with ethyl bromide in the presence of sodium hydride as in Example 15B, except that a molar equivalent of ethyl bromide is used. Your identity is the same all. Example.

Example 17

Preparation of N-Methyl- [170- (N ', N'-diethylcarbamoyl) -4-aza-4-methyl-5a-androst-3-en-3-yl] -amine hydrochloride

To a mixture of 160 mg of trimethyloxonium fluoroborate in 3 ml of methylene chloride at 0 ° C was 375 mg of 17β- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one in 3 ml of methylene The reaction mixture was stirred at 0-5 ° C for 6 hours, then allowed to stand overnight at room temperature, followed by the addition of diazabicyclo [5.4.0] undec-5-ene (160 mg) and The organic phase was diluted with 10 anh. The solid residue was removed by centrifugation and the organic phase was evaporated to dryness to give lactiminomethyl ether, a mixture of the product and 1.0 g of methylamine in 5 ml of toluene in a sealed tube for 100 hours. After cooling, the tube is opened and the solution is evaporated to dryness under a stream of nitrogen, the residue is dissolved in 8 ml of ethyl acetate and slowly anhydrous hydrogen chloride solution is added at 0 [deg.] C. The precipitated product is centrifuged twice with washed and dried in vacuo to give N-methyl- [17β- (N ', N'-diethylcarbamoyl) -4-aza-4-methyl-5a-androstan-3-en-3-yl] amine. -hydrochloride is obtained. The corresponding free base has a melting point of 183-186 ° C.

The results of experiments performed in vitro to inhibit 5α-reductase are described below. Each test compound is incubated with an aliquot of 0.21 mL of a test mixture containing said enzyme. Percent inhibition expresses the extent to which the test compound inhibits the conversion of radioactive testosterone to dihydrotestosterone.

For the compounds of Examples 1, 2, 3, 4, 7 and 8, progesterone is used as an internal standard or comparator. Inhibition values obtained with progesterone are as follows:

150 mg / test tube: 70%, 90%, 87%, 100%, 76%, 54%, 63%, 68.6%. 68.5%, 59%, 64%, 69%. 78%, 74% 50 mg / test tube: 38%, 57%, 38% Example 1 Compound: 150 mg / test tube: 99.4%, 87%, 100% 50 mg / test tube: 75% Example 2: 150 mg / test tube: 95%, 95% 50 mg / test tube: 81% Example 3: 150 mg / test tube: 68% 50 mg / test tube: 62% 25 mg / test tube: 48% Example 4: 150 mg / test tube: 81%, 84% 50 mg / test tube: 73% 25 mg / test tube: 63% Example 7: 150 mg / test tube: 83% Example 8: 150 mg / test tube: 95% 50 mg / test tube: 98%, 72.5% 25 mg / test tube: 54%

Example 17 uses the compound of Example 1 as an internal standard. The inhibition values obtained with it are as follows:

-919 mg / test tube: 25 mg / test tube:

16.75 mg / tube 5.5 mg / tube

1.9 mg / test tube: 1.0 mg / test tube: 0.2 mg / test tube:

88%, 87%, 89%, 88%

80%, 77%, 78%, 83%, 85%, 77%, 81%, 74%, 80%, 58%, 74%, 91%, 84%

66%, 64%

53%, 34%, 63%, 54%, 47%, 39%, 50%, 40%, 49%, 36%, 45%, 60%

23%

28%, 12%, 14%

24% characterized in that B is I / N I

R ¹

Claims (2)

Patent claims: A process for the preparation of a novel compound of formula I wherein: A is ethylene or ethenylene, B represents I c // \ / Ο N is a group of the formula wherein R is ¹ R ¹ is hydrogen or methyl, or! C / w / R ⁴ N® X® wherein R ¹ 'is prepared by the preparation of compounds of formula I wherein A is as defined in the specification but not ethenylene and Z and R ^{1 are} also in the scope of any one of the formula (VI). a compound of formula - wherein Z and ^R1 are as defined above - is catalytically hidrogéne15 placed, if desired, the resulting R is reacted with a compound of formula (I) wherein ^R1 is hydrogen a suitable methylating agent R ¹ of formula (I) containing a methyl group of the formula and ^{20 at} the B site C / R ⁴ i / N® I R ¹ ' X® R ¹ 'is methyl, X® is a hydroxyl anion and R ⁴ is -NR ⁶ R ⁷ wherein R ^{6 is} hydrogen and R ^{7 is} methyl; Z is a group of the formula wherein the dashed line replaces the 17a-hydrogen atom, or a 17a-hydrogen atom and a 17 / J-mono- or di (C 1-4) alkylaminocarbonyl or 1- For the preparation of compounds of formula I having 4 carbon atoms of alkylcarbonyl or alkoxycarbonyl groups, wherein A is as defined above, R * ', R ⁴ and X® are as defined above and Z is a hydrogen at 17a and a 17/3 position The di (C 1 -C 4) alkylaminocarbonyl group is a compound of formula (I) as defined above wherein A and Z are as defined above and R ^{1 is} methyl with trialkyl oxonium tetrafluoroborate and then Intermediate 35 alkyl alkyl iminether is reacted with a compound of the formula HNR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are as defined herein, and then treated with a mineral acid followed by an alkali, and If desired, to obtain the compounds of formula (I) wherein A is ethenylene, the 1,2-saturated compound obtained above is treated with lithium diisopropylamide followed by in situ diphenylsulfide 45 heat. 2. A process for the preparation of a compound of formula (XXX) as defined in claim 1, wherein the compound is selected from the group consisting of 17β- (N, N-diethylcarbamoyl) of formula (XVI). -4-Aza-4-methyl-5-androsten-3-one is catalytically hydrogenated. 13 sheets with formulas