JPH0246566B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel 4-aza-17-substituted-5α-
Androstane - 3-one type of testosterone -
It relates to its use as a 5α-reductase inhibitor. Some unfavorable physiological symptoms, such as acne vulgaris, seborrhea, female baldness, male-pattern baldness, and benign prostatic hyperplasia, are caused by metabolic system changes such as testosterone or similar symptoms. It is a well-known fact among those skilled in the art that this is due to hyper-androgen stimulation caused by excessive accumulation of androgenic hormones. Several steroidal anti-androgens have been developed in an early attempt to provide chemotherapeutic agents for these undesirable consequences of hyperandrogenism, but these themselves have undesirable hormone-like activities. have. For example, estrogien not only counteracts the effects of androgien, but also has feminizing effects. Non-steroidal anti-androgiens have also been developed.
For example, there is something like 4'-nitro-3'-trifluoromethylbutylanilide. Neri
See Endo et al., Volume 91, No. 2, 1972. However, although these compounds do not have hormone-like effects, they are peripherally active and tend to compete with androgienes at the receptors, thus feminizing the fetus in the male or female womb to which they are administered. . Recently, it has become well known that the major mediator of androgien activity in several target organs is 5α-dihydrotestosterone, which is produced locally in the target organ by testosterone-5α-reductase. . It has therefore been hypothesized, and has been shown, that inhibitors of testosterone-5α-reductase would reduce or prevent the symptoms of hyperandrogen stimulation. Nayfeh et al.
Methyl 4-androstene-3- in vitro)
showed that on-17β-carboxylate is an inhibitor of testosterone-5α-reductase (Steroids, vol. 14, p. 269, 1969). Voigt and Hsia also describe the above-mentioned ester and its free acid, i.e., 4-androstene-
3-one-17β-carboxylic acid was shown to be active as an inhibitor of testosterone-5α-reductase in vitro (Endocrino-
logy, Volume 92, Page 1216, 1973, Canadian Patent No.
No. 970692). They also have testosterone or
We show that topical administration of 5α-dihydrotestosterone increases androgene-derived adipose structures in the flank organs of female hamsters. However, co-administration of 4-androsten-3-one-17β-carboxylic acid or its methyl ester inhibits the testosterone-induced response, whereas 5α
-Dihydrotestosterone-induced responses are not inhibited. These results are explained by the fact that these compounds have anti-androgien activity through their ability to inhibit testosterone-5α-reductase. The new compounds used in the pharmaceutical compositions of the present invention are therefore selective anti-androgien substances with the ability to specifically inhibit testosterone-5α-reductase. To date, 4
-Aza-17-Substitution-5α-Androstane-3-
It was not known to use on. However, Selye has a Belgian patent no.
No. 775,919 describes such compounds, and a number of other compounds with one or more carbonitrile substituents, as catatoxic agents useful in the treatment of prostatic hyperplasia. A number of 4-aza styloid compounds are known. For example, US Pat. No. 2,227,876,
No. 3239417, No. 3264301, No. 3285918, French Patent No. 1465544, Doorenbos and Solomons J.Phar.Sci., Volume 62, No. 4,
pp. 638-640, 1973, Doorenbos and Brown J. Phar.
Sci., Vol. 60, No. 8, pp. 1234-1235, 1971. However, no known compounds are suitable for the novel 4-aza compounds used in the present invention or for their use in hyperandrogenic conditions.
Not suggested. The present invention provides novel 4-aza-17β-substituted-5α-
The present invention relates to a pharmaceutical composition for inhibiting 5α-reductase and treating symptoms of hyperandrogienosis, which contains androstan-3ones as an active ingredient. That is, the present invention has the following formula: [In the formula, A is -CH ₂ -CH ₂ - or -CH=CH-, R ¹ is hydrogen or alkyl, and X is

[Formula] or

[Formula] (where X is

In the case of [Formula], the carbonyl carbon is bonded to the nitrogen atom), and R ² is α-hydrogen and R ³ is N-alkyl or N,N-dialkylcarbamoyl, lower alkanoyl, lower alkanoyloxy and is selected from the group consisting of lower alkoxycarbonyl, or R ² and R ³ together are oxaspiro-lower alkyl.
However, if X

A pharmaceutical composition for treating hyperandrogenic symptoms, comprising a compound represented by [Formula], in which R ³ is lower alkanoyloxy, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. It is a composition. Unless otherwise indicated, the configuration of various substituents is α
and β were tried. A preferred form of the new compound has the following structural formula. Here R ¹ is hydrogen or methyl, T is CONHCH ₂ CH ₃ ,

【formula】

[Formula] COCH ₃ ,

[Formula] or

[Formula]. The most preferred structure of this new compound is R ¹ is methyl and T is CONHCH ₂ CH ₃ or CON
(CH ₂ CH ₃ ) ₂ . Representative compounds of the present invention are as follows. 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one 17β-N,N-diethylcarbamoyl-4-aza-5α-androstan-3-one 17β-N, N-diethylcarbamoyl-4-amino-4-aza-5α-androstan-3-one 17β-acetoxy-4-aza-5α-androstan-3-one 4-aza-20-spiroxy-5α-an-3 -one 4-methyl-4-aza-5α-20-spiroxan-3-one 17β-N-ethylcarbamoyl-4-methyl-4
-Aza-5α-androst-3-one 4-methyl-4-aza-5α-plecnan-3,
20-dione 4-ethyl-4-aza-5α-20-spiroxan-3-one 17β-carbomethoxy-4-methyl-4-aza-
5α-Androstan-3-one The novel compound used in the present invention is produced by a method comprising the following steps. A compound having the structural formula shown in the following formula (in the following formula, A is -CH=CH- (1) By treating with an oxidizing agent at low temperature,
The corresponding 5-oxo-3,5-seco-androstane-3-oic acid compound is obtained. (2) 4-Aza-5-androstene-3- substituted with R' at the 4-position by treating the product R'NH ₂ of step (1) with an amine represented by the structural formula
of the compound. (3) By reacting the product of step (2) with hydrogen in the presence of a catalyst, B is

A compound of the formula is obtained. Thus, the final step of the process is hydrogenation to introduce 5α-hydrogen. The reactions described above are described in detail in Examples 1-8 below and are illustrated schematically in the table below. When it is desired to produce a compound in which A in the structural formula is -CH=CH-, the product produced by the method described on pages 37 to 39 is further reacted by the following steps. (1) A corresponding enolate is prepared by reacting lithium diisopropylamide with a mono- and di-saturated compound. (2) The enolate of step (1) is treated with diphenyl disulfide in situ to obtain the corresponding α-phenylthio compound. (3) Oxidize the product of step (2) to obtain the corresponding sulfoxide compound. (4) Heat the product of step (3), and in the structural formula, A is -
A compound of CH=CH- is obtained. A typical method for producing this type of compound is described in Production Example 10 below. 17β-N, which is a particularly preferred compound of the present invention,
A preferred method for producing N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one includes the following method. (a) A 20-pyridinium iodide derivative of pregnenolone (20) is obtained by subjecting the available starting material, pregnenolone (1), to a haloform King reaction with iodine and pyridine.
get. (b) This pyridinium iodide derivative ()
is methanolyzed with sodium methoxide and methanol to give the methyl ester of 17-carboxyandrostenol (). The ester type is convenient for the subsequent Otzpennauer reaction. (c) The methyl ester of 17-carboxyandrostenol () is reacted with aluminum isopropoxide and cyclohexanone in a suitable solvent such as toluene to form methyl-4-androsten-3-one-17-carboxylate (). get. (d) Methyl-4-androsten-3-one-17carboxylate () thus obtained was hydrolyzed under acidic conditions in a solvent of about 4:1 methanol:water to obtain 17-acid ( ). (e) this
17-acid (about 1:1 oxalyl chloride in a suitable solvent such as toluene or xylene)
By reacting with a complex of pyridine, the 17-acid chloride is obtained. (f) This 17-acid chloride () and an excess amount of diethylamine are reacted on the spot to 17β-
N,N-diethylcarbamoyl-4-androsten-3-one (XI) is obtained. (g) The thus produced 4-androsten-3-one (XI) is oxidized with sodium periodate and potassium permanganate in t-butanol and water as solvents to produce the corresponding 5-oxo-3,5-secco Androstan-3-
Obtain Oitsuku Assid (XII). (h) This secoandrostanic acid (XII) was heated in ethylene glycol from 140° to 180° while maintaining the temperature from 0.5 to 5 minutes.
℃ and reacted with methylamine for about 1 hour to convert to the corresponding 4-aza compound (). (i)
The obtained 17β-N,N-diethyl-carbamoyl-4-methyl-4-aza-5-androstene-
17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5a- is obtained by reacting 3-one () with hydrogen using platinum oxide as a catalyst at room temperature to 60°C or higher. androstan-3-one () is obtained as the final product,
This is separated and purified. The above reaction is detailed in Preparation Example 12 and shown in the figure below.
Represent diagrammatically. The A-homologue of the compound used in the present invention is produced by a method including the following steps. (1) A 3-dithioketal derivative of testosterone is obtained by reacting tetrasterone with ethanedithiol in the presence of boron trifluoride esterate. (2),
The product obtained in step (1) is reacted with sodium metal and liquid ammonia to remove the 3-dithioketal substituent. (3) The product of step (2) is reacted with dihydropyran in the presence of p-toluenesulfonyl chloride to obtain a 17-tetrahydropyranyloxy derivative. (4), the product of step (3) is reacted with borane, then with sodium hydride and hydrogen peroxide, and 4-
A hydroxy-5α-hydrogen compound is obtained. (5), process
The product of (4) is reacted with chromium trioxide to obtain a 4-keto compound. (6), reacting the product of step (5) with acid
The 17-tetrahydropyranyl protecting group is removed to obtain a 17-hydroxy compound. (7), the product of step (6) is reacted with acetic anhydride to obtain a 17-acetoxy compound.
(8) The product of step (7) is reacted with hydroxyamine hydrochloride to obtain a 4-oxime compound. (9), process (8)
The reaction product is reacted with thionyl chloride and further treated with potassium hydroxide to obtain the A-homo-4α-aza compound. The above reaction is detailed in Production Example 9 described later,
It is also shown schematically in the figure below. The novel compound used in the present invention in which Δ1, that is, A is -CH=CH and the nitrogen at the 4th position has a substituent other than hydrogen, can be produced according to the method shown in Production Example 10 described below. Ru. When nitrogen at the 4-position is replaced only with hydrogen, it is produced according to the method shown in Production Example 11, which will be described later. The compound of the present invention produced by the method described above is a specific inhibitor of testosterone-5α-reductase, as described above, and is therefore a potent anti-androgien agent. Therefore, the present invention provides a method for administering the above-mentioned novel compound to the hyperandrogenic symptoms of acne vulgaris, seborrhea, male pattern baldness, and female baldness by topical administration, and the above-mentioned conditions by parenteral administration. and benign prostatic hyperplasia, breast cancer, prostate cancer. Breast cancer and prostate cancer are androdiene-related conditions or diseases that are exacerbated by the presence of androgene in the metabolic system, both normal and in higher than normal amounts. Compositions containing the aforementioned compounds as active ingredients for use in the treatment of benign prostatic hyperplasia may be prepared using conventional excipients for tissue administration (e.g., oral administration in the form of tablets, capsules, solutions, or intravenous administration). It can be administered in a wide range of clinical dosages (suspensions for injection). The daily dose of this compound is 250mg
It can be varied over a wide range from 2000mg to 2000mg. The composition is 5, 10, depending on the symptoms of the patient being treated.
Preferably, it is supplied in the form of numbered tablets containing 25, 50, 100, 150, 250 and 500 milligrams of active ingredient. Effective amounts of the drug are generally provided in doses of about 1 to 50 mg per kg of body weight per day. The preferred range is 1 to 7 mg/kg body weight per day. These doses will be significantly less than harmful amounts of the compound. Capsules containing the compound that is the active substance of the present invention can be prepared by mixing the active substance of the present invention with lactose, magnesium stearate, calcium stearate, starch, talc, and other excipients, and filling this mixture into gelatin capsules. It is prepared by Tablets are prepared by mixing the active substance with excipients such as calcium phosphate, lactose, corn starch, or magnesium stearate. Solutions are prepared in suspension or dispersion with suitable flavours, such as synthetic and natural gums, such as tragacanth, acacia, and methylcellulose. Other dispersants that may be used include glycerin. For parenteral administration, sterile suspensions and solutions are preferred. If intravenous administration is desired, iso-osmotic drugs usually containing appropriate preservatives are used. For the treatment of acne vulgaris, seborrhea, baldness in women, and baldness in men, the compound which is the active substance in the present invention may contain the active substance together with a pharmaceutically acceptable excipient suitable for topical administration. administered in a form. These topical pharmaceutical compositions take the form of creams, ointments, gels, or aerosols for application to the skin. These topical pharmaceutical compositions generally contain from 0.1% to 15% of the compound of the invention, desirably about 5% active ingredient and about 95% excipients. The method for producing the novel compounds which are active substances in the present invention, as already described in general form, will be further illustrated in the following production examples. Production example 1 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstane-3-
On A 3-oxo-N,N-diethyl-4-ethienamide 20 g of sodium 3-oxo-4-ethienamide are suspended in 360 ml of dry benzene and 0.13 ml of pyridine and cooled to 14°C. This suspension
Treat with 20 ml of oxalyl chloride and stir for 15-20 minutes. This suspension was evaporated to dryness and then
Suspend in 125 ml of dry tetrahydrofuran. This suspension was then added to a solution of 125 ml of tetrahydrofuran and 25 ml of diethylamine and stirred for 1 hour at room temperature, after which the mixture was
Pour into ice water. A semi-crystalline precipitate is formed which is extracted with ethyl acetate, washed with water and then with saturated saline, dried and evaporated to give 25.7 g of product. This product is recrystallized from ethyl ether; 10.0
g has a melting point of 127-129°C, and 3.1 g of the second batch has a melting point of 114-119°C. B 17β-N,N-diethylcarbamoyl-5-
Oxo-3,5-Secoandrostane-3-Eutschacid 15 g of the product of Step A are dissolved in 150 ml of methylene chloride and 75 ml of methanol, cooled to -78°C and then bubbled with ozone until the solution retains a blue color. The reaction solution is then brought to room temperature, sparged with nitrogen, and then evaporated to dryness at 35°C.
The residue was dissolved in benzene and extracted three times with 2.5N NaOH. The basic washings are combined, extracted with benzene acidified with concentrated hydrochloric acid, washed, dried, and evaporated to yield 11.5 g of a white crystalline solid.
Recrystallizing this product from ethyl acetate yields 205
A substance with a melting point of -208°C is obtained. C 17β-N,N-diethylcarbamoyl-4-
Aza-4-methyl-5-androstene-3-
Add 26.3 g of the product from Step B to 190 ml of ethanol to make a solution. Cool this solution in an ice bath and
Saturate with methylamine and then heat at 180°C for 8 hours. The reaction mixture is then cooled to room temperature and evaporated to give 22.3 g of a yellow solid. Chromatography and reconsolidation from ethyl acetate gives the final product with a melting point of 120-122°C. D 17β-N,N-diethylcarbamoyl-4-
Methyl-4-aza-5α-androstane-3
Add 36.5 g of the product from Step C to 1 glacial acetic acid to form a solution. This solution was then treated with 3.5 g of platinum oxide catalyst and heated at 8 psi at room temperature under a pressure of 40 psi.
Hydrogenate for an hour. The reaction mixture is then filtered and evaporated to dryness. The residue was dissolved in chloroform and washed with bicarbonate solution, salt and then dried.
Evaporate to dryness. Recrystallization of this product from ethyl acetate gives 30.65 g of the final product as white crystals with a melting point of 168-170°C. Preparation Example 2-8 Instead of 3-oxo-4-ethienate in step A, equimolar amounts of others can be obtained. Alternatively, using easily prepared 3-oxo-Δ ⁴ compounds, or following the method described in Preparation Example 1 above, using equimolar amounts of other suitable amines in place of diethylamine, as listed in the table below: A compound of the formula is prepared.

[Table] Production example 9 17β-acetoxy-4α-aza-5α-A-homoandrostan-4-one A 17β-hydroxy-4-androstene-3
- Thioketal 7.5g testosterone, 37.5ml glacial acetic acid,
A solution consisting of 4.5 ml ethanedithiol and 3.0 ml trifluoroborous etherate is prepared at 0°C. The temperature of the mixture is raised to room temperature and maintained there for 1.5 hours. This mixture was then diluted with water and extracted with chloroform.
% sodium bicarbonate solution, then several times with water, and then with saturated saline. This mixture is then dried;
Evaporation gives a white solid, which is reconstituted from methanol to give 9.0 g of the final product (95% yield) with a melting point of 160-162°C. B 17β-hydroxy-4-androstene Add 1.2g of metallic sodium to 60ml of anhydrous liquid ammonia. To this solution was added 1.0 g of thioketal in 10 ml of dry tetrahydrofuran,
This solution is refluxed for 20 minutes. Stop the reaction by adding a few ml of ethanol and dry at room temperature. The solution is then diluted with water, extracted with methylene chloride, washed with water, HCl, then water, dried and evaporated to give a white solid (609 mg, 81% yield) with a melting point of 149-152°C. C 17β-Tetrahydropyranyloxy-4-androstene The product of Step B is added to 30 ml of dihydropyran containing 450 mg of p-toluenesulfonyl chloride.
6.0 g are added and the solution is stirred at room temperature for 1 hour. This solution was then diluted with ethyl acetate and diluted with 20
Washing twice with a % pyridine water mixture, then water and then brine, drying and evaporation gives a pale yellow oil. This is crystallized (8.5g) and has a melting point of
It has a temperature of 92-96℃. D 17β-Tetrahydropyranyloxy-4β-hydroxy-5α-androstane To a cooled solution (0°C) of 5 ml of 1M borane (in tetrahydrofuran) in 2.7 ml of dry tetrahydrofuran is added step C in 2.0 ml of dry tetrahydrofuran. 500 mg (1.4 mmol) of product
Add. The clear solution was stirred at room temperature for 1 hour,
It is then cooled to 0° C. and treated with 5 ml of 2.5N sodium hydroxide followed by 4 ml of 30% hydrogen peroxide. The solution is stirred at room temperature for 1 hour, diluted with water, extracted with ethyl acetate, washed with water, brine, dried and evaporated to give an oily crystalline material. Wash this product with cold methanol and
When pump dried, the final product has a melting point of 167-170°C.
You get 175 mg. E 17β-tetrahydropyranyloxy-5α-androstane-4-one 0.264 g of chromium trioxide is slowly added to 0.42 ml of dry pyridine and 6.3 ml of dry dichloromethane.
This mixture is stirred at room temperature for 15 minutes. To this mixture is added a solution of 175 mg of the product of step D in 0.7 ml of methylene chloride, and the resulting mixture is stirred at room temperature for 20 minutes. The mixture is diluted with water, extracted with ethyl acetate, and washed with 2.5N sodium hydroxide, water, and brine. The mixture is then dried and evaporated to give a clear oil. F 17β-hydroxy-5α-androstane-4
-on 2.32 g of the product of step E is added to 75 ml of ethanol to form a solution, which is then treated with 5 ml of 2.5N hydrochloric acid and heated on a steam bath for 40 minutes to reach the melting point.
2.1 g of crystalline product at 123-126°C are obtained. G 17β-acetoxy-5α-androstane-4
2.0 g of the product from step F is added to 12 ml of dry pyridine and 6 ml of acetic anhydride to form a solution, which is heated on a steam bath for 30 minutes, then poured into 175 ml of ice water and stirred to remove excess anhydride. Decomposes acetic acid. Filter the reaction mixture and wash with water under high vacuum.
Pump drying at 50°C gives 1.7 g of final product with a melting point of 160-163°C. H 17β-acetoxy-5α-androstane-4
- Oxime A solution of 2.0 g of the product of step G in 125 ml of ethanol and 30 ml of dry pyridine is treated with 420 mg of hydroxylamine hydrochloride and stirred at room temperature. The reaction mixture is purified by thin layer chromatography on silica gel (20% ethyl acetate/benzene) overnight. The product is concentrated to a small volume under high vacuum at 30-40°C and diluted with water to form a white crystalline substance.
This is filtered, washed with water, dissolved in ethyl ether, dried and reconsolidated from ethyl ether. The final product has a melting point of 222-224°C. I 17β-acetoxy-4αaza-5α-A-homoandrostane-4-one Add 500 mg of the product from Step H to 3.3 ml of distilled thionyl chloride at -78°C and dilute the resulting solution with 1-2
Stir for 5 minutes, then slowly add 50 ml at 20°C.
Add to 4N sodium hydroxide solution. A solid precipitate forms; filter it and wash well with water and then ethyl ether. This product is reconsolidated from ethyl acetate, washed with ethyl acetate and ethyl ether, and dried to give a final product with a melting point of 232-235°C.
210mg is obtained. Preparation Example 10 17β-N,N-Diethylcarbamoyl-4-methyl-4-aza-5α-androst-1-en-3-one A solution of 0.20 g of anhydrous diisopropylamine in 5.0 ml of anhydrous tetrahydrofuran was heated to -78°C. with 0.9 ml of 2.2M butyllithium under nitrogen. After 20 minutes at -78°C, a solution of 388 mg of 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one in 3 ml of tetrahydrofuran was added dropwise to the reaction mixture. do. After stirring for 30 minutes at −78° C., a solution of 440 mg of phenyl disulfide in 1 ml of tetrahydrofuran is slowly added to the reaction mixture. -78℃
After stirring for 10 minutes, the reaction mixture is brought to room temperature.
Water is then added to the mixture and the product is extracted into ethyl acetate. The organic solvent layer is washed with dilute sodium hydroxide solution, then water, then dilute hydrochloric acid solution, and finally saturated brine. The solution is dried over calcium sulfate and then concentrated to give a crude solid product.
Elution from 30 g of silica gel by increasing proportions of ethyl acetate in hexane gives the 2-phenylthio derivative as a distinct mixture of two isomers. This material suspended in 5 ml of 20% aqueous methanol is treated with a solution of 225 mg of sodium metaperiodate in 2 ml of water. After stirring for 16 hours, the reaction mixture was diluted with water and extracted with methylene chloride. The organic solvent layer is washed with water, dried and concentrated to yield the crude sulfoxide. A solution of this material in 5 ml of toluene is refluxed for 30 minutes. The solvent is removed and the residue is chromatographed on 20 g of silica gel by elution with increasing amounts of ethyl acetate in ether. The final product crystallizes when treated with ether (melting point 200°-204.5°C). Preparation Example 11 291 mg of 17β-N,N in 3 ml of methylene chloride
-Diethylcarbonyl-4-aza-5α-androstan-3-one solution is added to a solution of 117 mg of trimethyloxonium fluoroborate in methylene chloride at 0°C. This mixture was then heated at 0°C for 6
Stir for an hour and then treat with 125 mg of 1,5-diazabicyclo[5.4.0]undec-5-ene.
After continued stirring for 2 hours, the reaction mixture was diluted with anhydrous ether. The organic solvent layer is separated from the residue and concentrated under reduced pressure to leave the crude lactim ether. This material is then converted to the corresponding Δ1 compound (melting point 275°-
277.5℃). Production example 12 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstane-3-
On A (3β-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide Add 1 kg (3.16 mol) of pregnenolone to the pyridine in Step 2, and heat the mixture to 90-95°C with gentle stirring. All pregnenolone dissolves when heated to . This mixture has a total of
866.1 g (3.41 moles) of iodine is carefully added over 15-20 minutes. The temperature of the reaction mixture is
An increase in temperature to 120°C is observed. Stir this mixture at a temperature of 100°C or higher for 1 hour,
It is then slowly cooled for 1 hour and then placed in a cold water bath to bring the temperature down to room temperature.
The product was collected on a medium porosity silica gel funnel and found to be rubbery and gel-like. The filtration was aided by adding pyridine and the filtration product was washed six times with 300 ml of pyridine.
It is then washed six times with 300 ml of ether and then air dried. The product has a melting point of 228-230℃.
Obtained with a yield of 99% (1635.8 g). B Methyl 5-androstene-3β-ol-
17β carboxylate 2.7Kg (5.177 moles) of iodide (3β-
Hydroxypregne-5-ene-20-one-21
-il) pyridium, 13.5 methanol and
Add 900g of sodium methylate. The mixture is refluxed for 1 hour, then cooled to about 53°C and then quenched by adding 24 parts of ice and 2 parts of water to bring the temperature of the reaction mixture to 5°C. The mixture is then neutralized by adding 2100 ml of a 1:1 solution of hydrochloric acid and water to a pH of 6-7. The mixture is aged for 45 minutes, then collected on a ratproat and then washed thoroughly with cold water until most of the color is washed out. The product is briefly dried on a funnel, then transferred onto two glass trays and dried in an air oven at 50° C. overnight. Product yield is 83.6% (1440 g). C Methyl 4-androsten-3-one-17β
-Carboxylate 160.0 g of methyl 5-androstene-3β-ol-17β-carboxylate in a flask, toluene dried with 24 molecular sieves,
Add 680ml of cyclohexanone. The mixture is heated to reflux and the water present is azeotropically removed for 15 minutes (ie until the distillate is clear). Then 88 g of aluminum isopropoxide in 320 ml of dry toluene is added as a slurry all at once. The reaction mixture is brought to reflux, during which time approximately 800 ml of toluene is removed over a period of 1 hour. The mixture is then cooled to 25° C. and 40 g of diatomaceous earth are added followed by 80 ml of water. Add this mixture to 10
Stir for a minute, filter through diatomaceous earth and then wash three times with 300 ml of toluene. Concentrate the liquid to near dryness and then cool in an ice bath. The crystallized product is aged at 0-5°C, collected, washed with cold hexane and then dried under reduced pressure. The yield of the product is 83.6% (133g) and the melting point is 130-132
It is ℃. D 4-Androsten-3-one-17β-carboxylic acid 2.462 Kg of methyl 4 in 24.6 methanol
- Add 1.23 kg of potassium hydroxide dissolved in 4.9 parts of water to androsten-3-one-17β-carboxylate. The reaction mixture is refluxed under nitrogen for 6 hours, then cooled overnight at room temperature. This mixture is acidified with 3200 ml of 6N hydrochloric acid. Most of the product precipitates as thin crystals. Then, all the product is precipitated by running down 14 portions of water over a period of 30 minutes. Stir this mixture for 4 hours, 30
Aging with stirring at °C. The mixture is filtered through a funnel with a lid and washed with water until the washings become neutral. This product is heated in an oven at 50°C.
Let dry overnight. The product with a melting point of 245-248℃ is 98
% yield (2.313 g). E 17β-N,N-diethylcarbamoyl-4-
Androstene-3-one 700g of 4-androstene in a flask
Charge 3-one-17β-carboxylic acid and 11.6 azeotropically dried benzene. To this mixture are added 22.6 ml of pyridine dried through molecular sieves, followed by the careful addition of 250 ml of oxalyl chloride in 250 ml of dry toluene over a period of 20 minutes. The reaction mixture is aged for 1 hour at room temperature and then cooled to 10°C. Then enough molecular sieve-dried diethylamine mixed with an equal amount of dry toluene is added until the PH is permanently alkaline. Approximately 2.4 volumes of solution are required. The reaction mixture was aged for 30 min, then 16 min.
Add ice water to stop the reaction. The mixture is separated into two layers, and the aqueous layer is extracted three times with ethyl acetate from step 4. Combine the organic solvent layers and wash with water in step 8 and hydrochloric acid to make the solution acidic (PH3), then wash only with water in step 8, and finally with saturated saline solution in step 8. The solution is dried over sodium sulfate and then concentrated to a small volume (3 to 4) on a large rotary evaporator. Next, add hexane (4) to this liquid and cool it at 0-5°C for 1 hour. The product is collected and washed three times with small amounts of cold hexane, then dried in an air oven at 40-50°C overnight. melting point
The product with a temperature of 119-121 °C is obtained in 75% yield (616.5 g. F 17β-N,N-diethylcarbamoyl-5-
Add 600 g of 17β-N,N-diethylcarbamoyl-4-androsten-3-one and 18 of tertiary butanol to a flask to form a solution. Then add 258 g of sodium carbonate solution dissolved in 1200 ml of water. Next, 2.4 Kg of sodium periodate dissolved in 18 g of water are added over 1.5 hours, while simultaneously adding 1340 ml of 2% potassium permanganate to maintain the color of the reaction mixture. The temperature is maintained between 25° and 40°C during the addition. The mixture is aged for 2 hours, filtered and the cake washed with water. Concentrate until only aqueous solution remains to remove tertiary butanol, then cool to 10℃ and acidify (PH3) with 110ml of 50% sulfuric acid.
Make it. This aqueous solution was extracted three times with 6 ethyl acetate. Combine the ethyl acetate washing liquid and add 5% of 4.
Wash with sodium bisulfate solution and then twice with 4 portions of saturated saline. The combined extracts are dried over sodium sulfate, concentrated to 1.5, then boiled and then aged at 5-10°C for 2 hours. Filter this liquid and wash the filter cake with ethyl acetate. A yield of 77% (488 g) is obtained with a melting point of 205°-208°C. G 17β-N,N-diethylcarbamoyl-4-
Methyl-4-aza-5-androstene-3-
Condensate 200 ml of methylamine in a graduated cylinder kept in a dry ice bath and then add to it 1250 ml of ethylene glycol at room temperature with stirring. Capacity increases by 16%. This methylamine/ethylene glycol solution is added to 250 g of 17β-N,N-diethylcarbamoyl-5-oxo-3,5-secoandrostane-3-ouc acid in flask 3.
It becomes a solution in a few minutes. The reaction mixture is heated to 110°C for 40 minutes and heating is continued at a rate of 2°C per minute until the temperature reaches 180°C. Then stop heating. Total heating time is 70 minutes. The reaction mixture is quenched by pouring 10 parts of water into a milky solution, which is extracted 5 times with 2 parts of methylene chloride. Combine the organic solvent layers and acidify with concentrated hydrochloric acid.
of sodium bicarbonate solution and 3 times 4 times of water. The combined organic solvent layers are then dried over sodium sulfate, treated with 50 g of silicon dioxide, and then concentrated to dryness. 750 mg of cyclohexanone in n-hexane solution (750 ml) of the residue
and then aged overnight at room temperature with stirring. The product is filtered, washed with n-hexane and dried under vacuum. The final yield of product with a melting point of 115-118°C is 91% (226 g). H 17β-N,N-diethylcarbamoyl-4-
Methyl-4-aza-5α-androstane-3
-on A flask was charged with 150 g of 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one and 750 ml of glacial acetic acid, and the mixture was heated at 60°C under 45 p.si of nitrogen. Heat for 4 hours. The product overcake was washed with methylene chloride, and the liquid was concentrated to dryness. 750ml of residue
of methylene chloride, and diluted with 500 ml of 1N sulfuric acid.
Wash once with 500 ml of water, once with saturated sodium bicarbonate solution, and once with saturated saline solution. The solution is dried over magnesium sulfate, treated with 15 g of activated carbon and filtered through a 75 g silicon dioxide sieve. This filter cake was washed with 1 portion of methylene chloride and concentrated to dryness. The residue is dissolved in 450 ml of ethyl acetate and then aged for 1 hour at room temperature and 1 hour in an ice bath. The product is filtered, washed with 50 ml of ethyl acetate, then 100 ml of n-hexane and dried. The liquid was concentrated to dryness, dissolved in 100 ml of ethyl acetate, and aged at room temperature for 2 hours.
Filter and wash with 5 ml of ethyl acetate and 100 ml of n-hexane. The yield of product with a melting point of 172-174°C is 76.6% (115 g). Production example 13 N-methyl-N-[17β-(N′,N′-diethylcarbamoyl)-4-aza-4-methyl-5α
-androst-3-en-3-yl]amine hydrochloride 375 mg of 17β-N,N-diethylcarbamoyl-4 in 3 ml of methylene chloride at 0°C in a mixture of 160 mg of trimethyloxonium fluoroborate and 3 ml of methylene chloride. -Add methyl-4-aza-5α-androstane-3-one. 6 at 0°-5°C
After stirring for an hour, the mixture is left at room temperature overnight. Add diazabicyclo[5.4.0]undec-5-ene (160 mg), and dilute the organic solvent layer with anhydrous ether. Remove solid residue by centrifugation,
When the organic solvent layer is concentrated to dryness, Δ ₂ -lactiminomethyl ether remains. A mixture of this material and 1.0 g of methylamine in 5 ml of toluene was prepared at 100 ml in a sealed tube.
°C, heat for 24 hours. After cooling, the tube is opened and the solution is concentrated to dryness under a nitrogen stream. The residue was dissolved in 8 ml of ethyl acetate and bubbled with anhydrous hydrogen chloride gas at 0°C. The precipitated product was removed by centrifugation and diluted with ether.
After washing twice and drying under reduced pressure, N-methyl-N-
[17β-(N′,N′-diethylcarbamoyl)-4
-Aza-4-methyl-5α-androstane-3
-en-3-yl]amine hydrochloride is obtained.

Claims (1)

[Claims] 1 formula [In the formula, A is -CH ₂ -CH ₂ - or -CH=CH-; R ¹ is hydrogen or alkyl; X is [formula] or [formula] (provided that ], the carbonyl carbon is bonded to the nitrogen atom); and R ² is α-hydrogen, and R ³ is N-alkyl or N,N-dialkylcarbamoyl, lower alkanoyl, lower alkanoyloxy and lower alkoxycarbonyl, or R ²
and R ³ together are oxaspiro lower alkyl. However, when X is [Formula], R ³ is lower alkanoyloxy. ] A pharmaceutical composition for treating hyperandrogien symptoms, comprising a compound represented by the formula or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. 2 R ¹ is hydrogen or methyl, R ³ is selected from the group consisting of N-ethylcarbamoyl, N,N-diethylcarbamoyl, acetyl, acetyloxy and methoxycarbonyl, or R ² and R ³ The pharmaceutical composition according to claim 1, wherein are together spiro-2'-tetrahydrofuran. 3 R ¹ is methyl, R ³ is N,N-diethylcarbamoyl, and A is -CH ₂ -CH ₂ -
The pharmaceutical composition according to claim 1.