JPS6361315B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel 4-aza-17-substituted-5a-
The present invention relates to androstan-3one, its A-ring homolog, and a method for producing the same. Some unfavorable physiological symptoms, such as acne vulgaris, seborrhea, female baldness, male-pattern baldness, and benign prostatic hypertrophy, are caused by the metabolic system being affected by testosterone or similar androgenetic conditions. It is well known to those skilled in the art that this is due to hyperandrogien stimulation caused by excessive accumulation of diene 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, 4'-nitro-3'-trifluoromethylbutylanilide. Neri
other. , Endo Vol. 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 5a-dihydrotestosterone, which is produced locally in the target organ by testosterone-5a-reductase. . It has therefore been hypothesized, and has been shown, that inhibitors of testosterone-5a-reductase would reduce or prevent the symptoms of hyperandrogenic stimulation. Nayfeh et al.
Methyl 4-androstene-3-
showed that on-17β-carboxylate is an inhibitor of testosterone-5a-reductase (Steroids, vol. 14, p. 269, 1969). Voigt and Haia also describe the above-mentioned ester and its free acid, i.e., 4-androstene-
It has been shown that 3-one-17β-carboxylic acid is active as an inhibitor of testosterone-5a-reductase in vitro (Endocrinology, Vol. 92, p. 1216, No. 1973, Canadian Patent No. 970,692). They further showed that topical administration of testosterone or 5a-dihydrotestosterone increases androgen-derived adipose structures in the flank organs of female hamsters. However, 4-androsten-3-one-17β
- Co-administration of a carboxylic acid or its methyl ester inhibits the response induced by testosterone, but not by 5a-dihydrotestosterone. These results are explained by the fact that these compounds possess anti-androgien activity through their ability to inhibit testosterone-5a-reductase. The new compounds of the invention are therefore testosterone-
It is a selective anti-androgien substance with the ability to specifically inhibit 5a-reductase. To date, 4
-aza-17-substituted-5a-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 suggest the 4-aza compounds of the present invention or their use in hyperandrodiene conditions. The present invention relates to novel anti-androgienes, 4-aza-17β-substituted-5a-androstan-3ones, their A-ring homologs, some isosteres and derivatives thereof, and the preparation of these compounds. The method, i.e., the present invention, is based on the formula [In the formula, A is -CH ₂ -CH ₂ - or -CH=CH-R
, R' is hydrogen or alkyl, and X is

[Formula] or

[Formula] (where X is

the carbonyl carbon is bonded to the nitrogen atom), and Z consists of α-hydrogen and N-alkyl or N,N-dialkylcarbamoyl, lower alkanoyl, lower alkanoyloxy, and lower alkoxycarbonyl. or Z is oxaspiro lower alkyl. However, if X

In the case of [Formula], Z is α-hydrogen and alkylcarbonyloxy) and pharmaceutically acceptable salts. and pharmaceutically acceptable salts of the compounds described above. 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. where R ¹ is hydrogen, methyl or amino,
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 −
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 Structural formula of the present invention and A novel compound having a structural formula with a partial structure is produced by a method including 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 compound of 5-oxo-3,5-seco-androstane-3-oic acid is obtained. (2) By treating the product of step (1) with an amine represented by the structural formula R′NH ₂ , 4-aza-5-androstene-3 substituted with R′ at the 4-position is obtained.
-one compound is obtained. (3) By reacting the product of step (2) with hydrogen in the presence of a catalyst, B is

The present compound having 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 is -CH=CH- in the structural formula, 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 a 1,2-saturated compound with lithium diisopropylamide. (2) The enolate of step (1) is treated with diphenyl disulfide in situ to obtain the corresponding α-phenylthio compound. (3) Oxidize the compound of step (2) to obtain the corresponding sulfoxide compound. (4) Heat the product of step (3), and remove A from -
A compound of CH=CH- is obtained. A typical method for producing this type of compound is shown in the example below.
This will be explained in Section 10. 17β-N, which is a particularly preferred compound of the present invention,
A preferred method of producing N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one includes the following method. (a) 20-pyridinium iodide derivative of pregnenolone (20-pyridinium iodide) is obtained by subjecting the available starting material pregnenolone (2018) to a haloform King reaction with iodine and pyridine.
get. (b) This pyridinium iodide derivative ()
is subjected to methanolysis 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 produce methyl-4-androsten-3-one-17-carboxynote (). get. (d) Methyl-4-androsten-3-one-17-carboxylate thus obtained ()
is hydrolyzed under acidic conditions in a solvent of about 4:1 methanol:water to give 17-acid (). (e) 17 by reacting the 17-acid () with a complex of about 1:1 oxalyl chloride:pyridine in a suitable solvent such as toluene or xylene.
- Obtain acid chloride. (f) React this 17-acid chloride () with an excess amount of diethylamine on the spot.
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 give the corresponding 5-oxo-3,5-seco Androstane-3-oic acid (XII) is obtained. (h) This secoandrostanic acid (XII) was heated in ethylene glycol from 140° to 180°C while maintaining the temperature for 0.5 minutes to 5 minutes, and reacted with methylamine for about 1 hour to form the corresponding 4-aza compound ( ). (i) Obtained 17β-N,N-diethyl-carbamoyl-4-methyl-4-methyl-4-aza-
17β-N,
N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one () is obtained as the final product, which is separated and purified. The above reaction is detailed in Example 12 and shown in the figure below.
Represent diagrammatically. The A-homologue of the present invention is produced by a method including the following steps. (1) Testosterone is reacted with ethanedithiol in the presence of boron trifluoride esterate to obtain a 3-dithioketal derivative of testosterone. (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), reacting the product of step (3) with borane, then reacting with sodium hydride and hydrogen peroxide, 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 compound of step (5) with an acid
Removal of the 17-tetrahydropyranyl protecting group yields the 17-hydroxy compound. (7), reacting the product of step (6) 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 Example 9 below,
It is also shown schematically in the figure below. A novel compound of the present invention in which Δ1, that is, A is -CH=CH and the nitrogen at the 4-position has a substituent other than hydrogen, is produced according to the method shown in Example 10 below. When nitrogen at the 4-position is replaced only with hydrogen, it is produced according to the method shown in Example 11 described below. The compound of the present invention produced by the above-mentioned method is a specific inhibitor of testosterone-5α-reductase, as mentioned above, and is therefore a potent anti-androgien agent. Therefore, the novel compounds of the present invention can be administered topically for hyperandrogenic symptoms of acne vulgaris, seborrhea, male pattern baldness, female baldness, for the above-mentioned conditions and for benign conditions by parenteral administration. prostate enlargement,
It can be used for administration to breast cancer and 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 a compound of the invention as an active ingredient 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 It can be administered in a wide range of clinical dosages (intravenous suspensions). The daily dosage of this compound is 250
It varies over a wide range from mg to 2000 mg. 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 compounds of the invention are prepared by mixing the active substances of the invention with lactose, magnesium stearate, calcium stearate, starch, talc, and other excipients and filling this mixture into gelatin capsules. Ru. 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 compounds of the invention may be administered in a form containing the active substance together with a pharmaceutically acceptable excipient suitable for topical administration. be done. 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 preparation of the novel compounds of the invention as already described in general form is further illustrated in the following examples. 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 is treated with 20 ml of oxalyl chloride and stirred for 15-20 minutes. The suspension is evaporated to dryness and then suspended in 125 ml of dry tetrahydrofuran. This suspension was then mixed with 125 ml of tetrahydrofuran and 25 ml of
of diethylamine and stirred for 1 hour at room temperature, after which the mixture was poured into ice water. A semi-crystalline precipitate forms which is extracted with ethyl acetate, washed with water and then with saturated saline, dried and evaporated to give 25.7 g of product. The product is recrystallized from ethyl ether; the first 10.0 g has a melting point of 127-129°C, the second 3.1 g has a melting point of 114
~119℃. B 17β-N,N-diethylcarbamoyl-5
-oxo3,5-secoandrostane-3-
Dissolve 15 g of the product of Step A in 150 ml of methylene chloride and 75 ml of methanol, cool to -78°C,
This solution is then bubbled with ozone until a blue color remains. 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, acidified with concentrated hydrochloric acid, extracted with benzene, washed, dried, and evaporated to yield 11.5 g of a white crystalline solid. Recrystallization of this product from ethyl acetate gives a material with a melting point of 205-208°C. C17β-N,N-diethylcarbamoyl-4
-aza-4-methyl-5-androstene-
Add 26.3 g of the product from Step B to 190 ml of 3-one ethanol to form a solution. The solution is cooled in an ice bath to saturate the methylamine and then heated 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-androstan-3-one 36.5 g of the product of Step C is dissolved in 1 part of glacial acetic acid. The solution is then treated with 3.5 g of platinum oxide catalyst and hydrogenated at room temperature under a pressure of 40 psi for 8 hours. The reaction mixture is then filtered and evaporated to dryness. The residue is dissolved in chloroform and washed with bicarbonate solution, salt, then dried and evaporated to dryness. When this product is reconstituted from ethyl acetate, its melting point is
30.65g of the final product in white crystals with a temperature of 168-170℃
is obtained. Examples 2-8 Using equimolar amounts of other available or easily prepared 3-oxo-Δ4 compounds in place of 3-oxo- ^4- ethienate in Step A, or in place of diethylamine, etc. Following the method described in Example 1 above using molar amounts of other appropriate amines, the formula compounds of the invention listed in the table below are prepared.

[Table] Example 9 17β-acetoxy-4a-aza-5α-A-homoandrostan-4-one A 17β-hydroxy-4-androsten-
3-thioketal 7.5g testosterone, 37.5ml glacial acetic acid, 4.5
A solution consisting of 3.0 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. The mixture is then diluted with water, extracted with chloroform, washed with 5% aqueous sodium bicarbonate, then several times with water, and then with saturated saline. The mixture was then dried and evaporated to give a white solid, which was reconstituted from methanol to give the final product with a melting point of 160-162 °C (yield 95
%) 9.0g is obtained. B 17β-Hydroxy-4-androstene Add 1.2 g of sodium metal to 60 ml of anhydrous liquid ammonia. To this solution is added 1.0 g of thioketal in 10 ml of dry tetrahydrofuran and the solution is refluxed for 20 minutes. Stop the reaction by adding a few ml of ethanol and dry at room temperature. This solution was then diluted with water, extracted with methylene chloride, and diluted with water,
Wash with HCl then water, dry and evaporate to melting point
A white solid (609 mg, yield 81%) is obtained at 149-152°C. C 17β-tetrahydropyranyloxy-4-
Androstene 6.0 g of the product of Step B in 30 ml of dihydropyran containing 450 mg of p-toluenesulfonyl chloride
is added and the solution is stirred at room temperature for 1 hour. The solution is then diluted with ethyl acetate, washed twice with a 20% pyridine/water mixture, then water, then brine, dried and evaporated to give a pale yellow oil. It is crystallized (8.5 g) and has a melting point of 92-96°C. 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 500 mg (1.4 mmol) of the product of Step C in 2.0 ml of dry tetrahydrofuran. .
The clear solution is stirred at room temperature for 1 hour, then cooled to 0° C. and treated with 5 ml of 2.5N sodium hydroxide and then 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. This product was washed with cold methanol and pump dried to a melting point of 167
175 mg of final product at -170°C is obtained. E 17β-tetrahydropyranyloxy-5α-
Androstan-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 and the mixture is stirred for 15 minutes at room temperature. to this mixture
Product of Step D dissolved in 0.7 ml methylene chloride
Add 175 mg of solution and stir the resulting mixture at room temperature for 20
Stir for a minute. 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-one A solution of 2.32 g of the product of step E in 75 ml of ethanol, which is subsequently treated with 5 ml of 2.5N hydrochloric acid and heated on a steam bath for 40 minutes gives a melting point of 123-
2.1 g of crystalline product at 126° C. are obtained. G 17β-acetoxy-5α-androstane-
4-one A solution of 2.0 g of the product of step F in 12 ml of dry pyridine and 6 ml of acetic anhydride is heated on a steam bath for 30 minutes, then poured into 175 ml of ice water and stirred to remove excess. Decomposes acetic anhydride. Filtering the reaction mixture, washing with water and pump drying at 50°C under high vacuum yields a final product with a melting point of 160-163°C.
1.7g is obtained. 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 made.
Treat with 420 mg of hydroxyamine hydrochloride and stir at room temperature. The reaction mixture is purified by thin layer chromatography on silica gel (20% ethyl acetate/benzene) overnight. Product under high vacuum
When concentrated to a small amount at 30-40℃ and diluted with water, a white crystalline substance is produced. 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−
It has a temperature of 224℃. I 17β-acetoxy-4aaza-5α-A-homoandrostan-4-one In 3.3 ml of distilled thionyl chloride at -78°C Step H
Add 500 mg of the product, stir the resulting solution for 1-2 minutes, and then slowly add to 50 ml of 4N sodium hydroxide solution at 20°C. 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 melting point of
210 mg of final product at 232-235°C are obtained. 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 is Treat with 0.9 ml of 2.2M butyllithium at 78°C under nitrogen. After 20 minutes at -78°C, 388 mg of 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α- in 3 ml of tetrahydrofuran
Add the androstan-3-one solution dropwise to the reaction mixture. 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 at °C, 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. When eluted from 30 g of silica gel by increasing the proportion of ethyl acetate in hexane, 2
-Phenylthio derivatives are obtained as a mixture of two distinct 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. toluene 5
A solution of this substance in ml 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) Example 11 291 mg of 17β-N,N in 3 ml of methylene chloride
-Diethylcarbamoyl-4-aza-5α-androstan-3-one solution is added to a solution of 117 mg of trimethyloxonium fluoroborate in methylene chloride at 0°C. The mixture is then stirred for 6 hours at 0 DEG C. and then treated 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 by the method described in Example 10 above. (Melting point 275°-277.5°C) Example 12 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstane-3-
A (3β-Hydroxypregn-5-en-20-one-21-yl)pyridinium iodide 1 Kg (3.16 mol) of pregnenolone was added to the pyridine of 2, and the mixture was heated at 90-95°C with gentle stirring. All pregnenolone dissolves when heated to . Total of 866.1g in this mixture
(3.41 mol) of iodine is carefully added over 15-20 minutes. The temperature of the reaction mixture is observed to rise to 120°C. The mixture is stirred at 100° C. or higher for 1 hour, then slowly cooled over 1 hour, then placed in a cold water bath to cool to room temperature. The product was collected on a medium porosity silica gel funnel and found to be rubbery and gel-like. Assist the filtration by adding pyridine and reduce the filtration product to 300
Wash 6 times with 300 ml of pyridine, then 6 times with 300 ml of ether, then air dry. Melting point 228-230℃
A product with a yield of 99% (1635.8 g) is obtained. B Methyl 5-androsten-3β-ol-17βcarboxylate A flask was charged with 2.7 Kg (5.177 mol) of (3β-hydroxypregn-5-en-20-one-21-yl)pyridium iodide, 13.5 methanol and 900g
of sodium methylate. The mixture was refluxed for 1 hour, then cooled to about 53°C and then 24°C.
The reaction is stopped by adding 100 ml of ice and 200 ml of water, and the temperature of the reaction solution is brought to 5°C. Then add to this mixture
Add 2100ml of 1:1 solution of hydrochloric acid and water to neutralize and adjust the pH.
to 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-androsten-3β-ol-17β-carboxylate in flask, 2.4
Add toluene dried with a molecular sieve and 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 320ml
88 g of aluminum isopropoxide in dry toluene is added as a slurry all at once. The reaction mixture was brought to reflux for about 1 hour.
Remove 800ml of toluene. The mixture is then cooled to 25° C. and 40 g of diatomaceous earth are added followed by 80 ml of water. The mixture is stirred for 10 minutes, filtered through diatomaceous earth, then washed three times with 300 ml of toluene, concentrated to near dryness, and then cooled 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 product is 83.6% (133g) and the melting point is 130-132°C. D 4-androsten-3-one-17β-carboxylic acid 2.462 Kg methyl 4- in 24.6 methanol
Add 1.23 Kg of potassium hydroxide dissolved in 4.9 parts of water to the androsten-3-one-17β-carboxylate. The reaction mixture is refluxed under nitrogen for 6 hours, then cooled overnight at room temperature. this mixture
Acidify with 3200 ml of 6N hydrochloric acid. Most of the product precipitates as thin crystals. Then add 14 pieces of water
All the product precipitates out after 30 minutes of flowing down. The mixture is aged for 4 hours at 30° C. with stirring. The mixture is filtered through a funnel with a lid and washed with water until the washings become neutral. The product is dried in an oven at 50° C. overnight. melting point 245
The product at -248°C is obtained in 98% yield (2.313 g). E 17β-N,N-diethylcarbamoyl-4-
Androsten-3-one 700 g of 4-androsten-3 in a flask
-one-17β-carboxylic acid and 11.6 azeotropically dried benzene are introduced. 226 to this mixture
ml of pyridine dried through molecular sieves is added followed by the careful addition of 250 ml of oxalyl chloride in 250 ml of dry toluene over 20 minutes. The reaction mixture was aged for 1 hour at room temperature and then
Cool to 10°C. Then, add the dried diethylamine through molecular sieves mixed with an equal volume of dry toluene.
Add enough until the pH is permanently alkaline. Approximately 2.4 volumes of solution are required. 30% reaction mixture
Aginate for 16 min, then add 16 ml of ice water to stop the reaction. It will separate into two layers, so separate it and divide the water layer into 4 layers.
Extract three times with ethyl acetate. Combine the organic solvent layers and wash with water and hydrochloric acid (8) to make the solution acidic (PH3).
Next, 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, hexane (4) was added to this liquid, and the mixture was cooled at 0-5°C for 1 hour. Collect the product and wash it three times with a small amount of cold hexane.
It is then dried overnight at 40-50°C in an air oven.
A product with a melting point of 119 DEG-121 DEG C. is obtained in a yield of 75% (616.5 g). F 17β-N,N-diethylcarbamoyl-5
-oxo-3,5-secoandrostane-3
- Eutsuk acid A flask containing 600 g of 17β-N,N-diethylcarbamoyl-4-androsten-3-one and
Add 18 tertiary butanol to make a solution. Then add 258 g of sodium carbonate solution dissolved in 1200 ml of water. Next, 2.4Kg dissolved in 18 water
of sodium periodate is added over 1.5 hours while maintaining the color of the reaction mixture while simultaneously adding 1340 ml of 2% potassium permanganate. 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 the aqueous solution remains to remove the tertiary butanol, then cool to 10°C and acidify (PH3) with 110 ml of 50% sulfuric acid. This aqueous solution was extracted three times with 6 ethyl acetate. Combine the ethyl acetate washes, add 4 parts of 5% sodium bisulfate solution, then 2 parts of 5% sodium bisulfate solution.
Wash 4 times with 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-on graduated cylinder maintained in dry ice bath
200 ml of methylamine are condensed and then 1250 ml of ethylene glycol are added to this at room temperature while stirring. Capacity increases by 16%. This methylamine/ethylene glycol solution was added to 250 g of 17β-N,N-diethylcarbamoyl-5-oxo-3,5-secoandrostane-3 in 3 flasks.
-Add to Oytsk Assid. 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. 10% reaction mixture
The reaction is stopped by pouring it into water to obtain a milky solution, which is extracted five times with 2 methylene chloride. The organic solvent layers were combined and added with water from 4 acidified with concentrated hydrochloric acid, sodium bicarbonate solution from 4 and sodium bicarbonate solution from 3.
Wash with water 4 times. The combined organic solvent layers are then dried over sodium sulfate, treated with 50 g of silicon dioxide, and then concentrated to dryness. The residue was dissolved in a solution of 750 mg of cyclohexanone in n-hexane (750 mg
ml) 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-androstan-3-one In a flask, add 150 g of 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one and 750 ml of glacial acetic acid. and heat the mixture to 60° C. under 45 psi nitrogen for 4 hours. The product is filtered, the percake is washed with methylene chloride, and the liquid is concentrated to dryness. The residue was dissolved in 750 ml of methylene chloride and diluted twice 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 was dried over magnesium sulfate, treated with 15 g of activated carbon,
Pass through a 75 g silica gel 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. Filter the product and add 50ml of ethyl acetate then
Wash with 100ml of normal hexane and dry. The filtrate was concentrated to dryness, dissolved in 100 ml of ethyl acetate, aged for 2 hours at room temperature, filtered, and washed with 15 ml of ethyl acetate and 100 ml of n-hexane. Melting point 172−
The yield of product at 174° C. is 76.6% (115 g). Example 13 N-Methyl-N-[17β-(N′,N′-diethylcarbamoyl)-4-aza-4-methyl-5α-androst-3-en-3-yl]amine hydrochloride 160 mg trimethyl To a mixture of oxonium fluoroborate and 3 ml of methylene chloride is added 375 mg of 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one in 3 ml of methylene chloride at 0°C. 6 at 0°-5°C
After stirring for an hour, the mixture is left at room temperature overnight. Diazabicyclo [5.4.0] Undese-5
-ene (160 mg) was added, and the organic solvent layer was diluted with anhydrous ether. The solid residue is removed by centrifugation and the organic solvent layer is concentrated to dryness, leaving Δ ² -lactiminomethyl ether. A mixture of this material and 1.0 g of methylamine in 5 ml of toluene is heated in a sealed tube at 100° C. 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 anhydrous hydrogen chloride gas was blown into the solution at 0°C. The precipitated product was removed by centrifugation, washed twice with ether, and dried under reduced pressure to give N-methyl-N-[17β-(N',N'-diethylcarbamoyl).
-4-aza-4-methyl-5α-androstan-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, and X is [formula] or [formula] (provided that X is [formula] ), then the carbonyl carbon is bonded to the nitrogen atom), and Z is α-
hydrogen and N-alkyl or selected from the group consisting of N,N-dialkylcarbamoyl, lower alkanoyl, lower alkanoyloxy, and lower alkoxycarbonyl, or Z is oxaspiro-lower alkyl. However, when X is [Formula], Z is α-hydrogen and alkylcarbonyloxy. ] and pharmaceutically acceptable salts. 2 R' is hydrogen or methyl, Z is selected from the group consisting of α-hydrogen and N-ethylcarbamoyl, N,N-diethylcarbamoyl, acetyl, acetyloxy, and methoxycarbonyl, or Z is spiro The compound according to claim 1, which is -2'-tetrahydrofuran. 3. The compound according to claim 1, wherein the compound is 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one. 4 (1) Treat pregnenolone with iodine and pyridine to form the corresponding 20-pyridinium iodide derivative of pregnenolone; (2) Methanolyse the product of step (1) to form the methyl ester of 17-carboxyandrostenol; ( 3) Treating the product of step (2) with aluminum isopropoxide and cyclohexanone to yield 4-androsten-3-one-17-carboxylic acid methyl ester; (4) Hydrolyzing the product of step (3) and the corresponding 17−
(5) treating the product of step (4) with an oxalyl chloride:pyridine complex to form the corresponding 17-acid chloride; (6) treating the product of step (5) with its diethylene amine; 17β-N,N-diethylcarbamoyl-
4-androsten-3-one; (7) The product of step (6) is oxidized with sodium periodate and potassium permanganate in a t-butanol:water solvent system to give the corresponding 5-oxo- 3, 5
(8) Treat the product of step (7) with methylamine in ethylene glycol to obtain 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5. -androsten-3-one; (9) Hydrogenate the product of step (8) by treating it with hydrogen in the presence of a catalyst to form the final product 17β-
N,N-diethylcarbamoyl-4-methyl-
4-aza-5a-androstan-3-one; the following formula consisting of each step: A method for producing a compound represented by 5 (1) 4-androsten-3-one-17β-
Treatment of the carboxylic acid with oxalyl chloride;pyridine complex to give the corresponding 17-acid chloride; (2) Treatment of the product of step (1) in situ with diethylamine to give the 17β-N,N-diethylcarbamoyl -4-androsten-3-one; (3) The product of step (2) is oxidized with sodium periodate and potassium permanganate in a t-butanol:water solvent system to give the corresponding 5-oxo-4-androsten-3-one; -3, 5
(4) Treat the product of step (3) with methylamine in ethylene glycol to obtain 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5- androsten-3-one; (5) Hydrogenate the product of step (4) by treating it with hydrogen in the presence of a catalyst to obtain the final product, 17β
-N,N-diethylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one; The following formula consisting of each step: A method for producing a compound represented by