JPS60222497A - 17 beta-n-monosubstituted carbamoyl or 17 beta-acyl-4-aza-5 alpha-androst-1-en-3-one as 5 alpha reductase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to rubamoyl or 17β-acyl-4-aza-5α-andoester 1-en-3-one compounds and the use of such compounds as testosterone-5α-reductase inhibitors.

Certain undesirable physiological symptoms such as acne vulgaris, seborrhea, female baldness, male roughness, and prostatic hyperplasia are caused by hyperandrogenic conditions due to an excess of testosterone or similar androgenic hormones in the metabolic system. It is known to those skilled in the art that this is the result of stimulation accumulation. Early attempts to prepare chemotherapeutic agents to treat the undesirable consequences of androgen excess led to the discovery of several steroidal antiandrogens that themselves have undesirable hormonal activities. For example, estrogen
It not only suppresses the effects of androgens, but also has the effect of turning women into women. Non-steroidal anti-androgens have also been developed, such as Example 1f4'12tro3'1trifluoromethylisobutylanilide. For example, Neri
et al., Endo. , 9 Volume 1, No. 2 (1972). However, although these products do not have hormonal effects, they are peripherally active and have the same receptor organs as natural androgens, and therefore tend to feminize male patients and male fetuses. Ta.

More recently, it has been shown that the main mediator of androgenic activity in the target organs of some species is 5α-dihydrotestosterone, and that this compound is formed locally in the target organs by the action of testosterone-5α-reductase. It has become known to those skilled in the art that

Therefore, inhibitors of testosterone-5α-reductase were hypothesized to prevent or alleviate the symptoms of hyperandrogenism, and this has been shown to be the case. Nayfe et al. (Steroids, vol. 14, 269
(1969) showed that methyl 4-androsten-3-one 17β-carboxylate is an inhibitor of testosterone-5α-reductase in vitro. Next, VO4gt and Hs ia (Endo
crinology.

Volume 92, page 1216 (1973), Power Patent No. 97
No. 0,692) is the above ester and its original free acid, 4-
Androsten-3-one-17β-carboxylic acid, both of which have been shown to be active inhibitors of testosterone-5α-reductase in vitro. They further showed that topical application of testosterone or 5α-dihydrotestosterone causes enlargement of the flank organs of female hamsters, which are androgen-dependent sebaceous structures.

However, coadministration of 4-androsten-3-one-17β-carboxylic acid or its methyl ester blocked the response produced by testosterone, but not 5α-dihydrotestosterone. These results are explained as indicating that these compounds are anti-androgenic due to their ability to inhibit testosterone-5α-reductase.

A large number of 4-azasteroid compounds are known. For example, U.S. Pat. No. 2,227,876, 3,239,4
No. 17, 3,264.30' No. 1, and 3,285,
No. 918, French Patent No. 1.465,544, Do
arenboS and 3o1omons1J, Phar
m, Sci, Vol. 62, No. 4, pp. 638-640 (1
973); Doorenbos and BrOwn;
J, Pharm.

Sci, Vol. 60, No. 8, pp. 1234-1235 (19
71) + Doorenbos and Kin, J.
, Pharm, Sci, Vol. 63, No. 4, 620-6
See page 22 (1974).

Additionally, Rasmussen et al., U.S. Pat. No. 4,377.
584 and 4,220,775, 4-aza-17 is said to be useful in the treatment of hyperandrogenism.
A group of β-substituted-5α-antrostan-3-ones has been described. However, none of these references cite the novel 17β-N-(monosubstituted)carbamoyl or 17β-acyl-4-aza-5α-androsten-1-en-3-one potent testosterone -5
It has not been shown to be an α-reductase inhibitor.

The present invention provides novel 17β-N- (monosubstituted) or 17β-
Acyl-carbamoyl-4-aza-5α-androsten-1-en-3-one compounds, processes for their preparation, pharmaceutical compositions containing this new compound as an active ingredient, methods for inhibiting testosterone-5α-reductase, The present invention relates to methods of treating hyperandrogenism with novel compounds or pharmaceutical formulations thereof.

The present invention relates to compounds of structural formula: However, in the formula, R is hydrogen, methyl or ethyl.

R2 represents straight-chain and branched alkyl of 1-12 carbon atoms, optionally one or more alkyl substituents of 1-2 carbon atoms, and/or one or more halogen (α
, F or Br) is a hydrocarbon group selected from monocyclic aryl containing a substituent.

R' is hydrogen or methyl.

R" is hydrogen or β-methyl.

R/// is hydrogen, α-methyl or β-methyl.

A preferred specific example of the novel compound of the present invention has the following structural formula: 0%Formula% where R is hydrogen, methyl or ethyl, and R3 is a branched chain alkyl of 4-8 carbon atoms.

Representative compounds of the present invention include the following: 17β-(N-
tertiary butylcarbamoyl)-4-aza-4-methyl-5
α-Androst-1-en-3-one, 17β-(N-isobutylcarbamoyl)-4-aza-
4-Methyl-5α-androst-1-en-3-one, 17β-(N-tertiary octylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one, 17β -(N-octylcarbamoyl)-4-aza-4
-Methyl-5α-androst-1-en-3-one, 17β-(n-1,1-diethylbutylcarbamoyl)
-4-aza-4-methyl-5α-androst-1-en-3-one, 17β-(N-neopentylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3 -one, 17β-(N-tertiary-amylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one, 17β-(N-tertiary-hexylcarbamoyl)-4 -aza-4-methyl-5α-androst-1-ene-3-
and corresponding compounds in which the 4-methyl substituent in these compounds is replaced with hydrogen or an ethyl group.

Further representative compounds include N-branched alkyl substituents in the above compounds: methyl, ethyl, propyl, isopropyl, butyl, phenyl; 2,3. or 4-tolyl, xylyl, 2-bromo or 2-chlorophenyl, 2,6-
Included are those substituted with dichloro or 2,6-dibromophenyl substituents.

The novel compound of formula (1) of the present invention can be prepared by a method starting from a known steroid ester of structural formula, 17β-(carbomethoxy)-4-aza-5α-antrostan-3-one. This method is 1
) dehydrogenating the starting material to form the corresponding compound having a knee bond at the 1,2-position of the 8-ring; 2) converting the 17-carbomethoxy substituent to an N-monosubstituted carbamoyl substituent; , and if desired, 3) alkylating the nitrogen of the A-ring to introduce an N-methyl or 4-ethyl substituent on the A-ring. In carrying out the process of the present invention, the dehydrogenation of the 1,2-position of the steroid hemocycle in step 1 is carried out to form a 4-aza-5α-antholyte having no substituent other than hydrogen on the nitrogen of A′Jj. It is essential to use a rostan-3-one compound. Step 2 may consist of one or more chemical reaction steps and may occur before step (1) or after step (1) or (3) if desired.

According to the process of the present invention, the product of the present invention comprises: 1) 17β-alkoxycarbonyl-4-aza-5α-antrostan-3-one compound ■ in refluxing chlorobenzene is converted into penzeneselenic anhydride 17β-Flucooxycarbonyl-4-aza-5α- by heating with a dehydrogenating agent such as
forming anthrostan-1-en-3-one, 2
) 5α-androsta-1-ene-3 produced in step 1
-one rl:, the compound is reacted with sodium hydride under anhydrous conditions in a neutral solvent such as dimethylformamide, and 3) this reaction mixture is reacted with an alkyl iodide (methyl or ethyl) to form the corresponding 17β-alkoxycarbamoyl-4-alkyl-4-aza-5α-androst-1-en-3-one, 4) then the 17β-flucooxycarbonyl-4-alkyl-4-aza- 5α-androst-1-en-3-one is hydrolyzed with a strong base such as aqueous methanolic potassium hydroxide at reflux temperature and then acidified to give the resulting steroid acid, 17β-carboxy-4- Full Kill-4-
Aza-5α-androster-1-en-3-one, ■,
5) The steroid is then dissolved in triphenylphosphine 7 in an inert solvent such as toluene. ,2
'-Dipyridyl disulfide is converted to its corresponding 2-pyridylthioester by refluxing and the product 17β-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5α-androsta-1- The en-3-one, ■, was isolated by silica gel chromatography, 6) and the pyridylthioester was then reacted with ethylamine in tetrahydrofuran to yield the desired product 1.
7β-N-Ethylcarbamoyl-4-furkyl-4-aza-5α-androst-1-en-3-one, 1, is prepared by isolation by silica gel chromatography. Formula R2 in place of ethylamine
When the above reaction is carried out using the amine of NH, the corresponding 17
β-(N-R2-carbamoyl)-4-alkyl-4-
Aza-5α-androst-1-en-3-one is prepared.

Following our inventive process, the corresponding 17β-(N-R
2-carbamoyl)-4-aza-5α-androsta-
1-en-3-one, x■, can be converted to 17β-(alkoxycarbonyl)-4-aza-5α-antrostan-3-one,
It is easily prepared from However, in this case, the sodium amide of 4-aza-5α-androst-1-en-3-one via the above reaction 2, intermediates ① and XI,
and the subsequent treatment with methyl iodide or ethyl iodide is omitted.

According to yet another method of preparing compounds of our invention having hydrogen as the only substituent on the nitrogen of the A ring, Am
The double bond is introduced at a later stage of the process. For example, 17β-flucooxycarbonyl-4-aza-5α
-Anthrostan-3-one, ■, is hydrolyzed to the corresponding steroid acid, ■, 17β-carboxy-4-aza-5α-antrostan-3-one, which is then converted to the corresponding pyridylthioester, 17β-( 2-pyridylthiocarbonyl)-4-aza-5α-antrostane-3
-one, x, and then convert this ester to formula R2-
Treatment with amine of NH2 (R2 is as defined above) gives 17β-(N-R2-carbamoyl)-
4-Aza-5α-antrostan-3-one, Xl, is formed and this compound is dehydrogenated as described above to form the compound, 17β-(N-R2゛-carbamoyl)-4-
7 Zarandrostar 1-en-3-one is prepared.

17β-(N-R”-carbamoyl) substituent with formulas ■, ■
Or, in another method of introducing 17β-carboxyanthrostane compounds, these compounds can be introduced into steroids, 3
5, β3. March 1980, pages 1-7, treated with dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, 17
β-(1-heditriazoleoxycarbonyl)-4
-Aza-5α-androster-1-en-3-one, ■
, X■, or let

The above reaction is illustrated in the structural scheme below.

The present invention provides 17β-acyl-4-aza-5α-androsta-1 of structural formula E.
-en-3-one compound. However, in the formula, R is hydrogen, methyl, ethyl, and R2 is a linear or branched alkyl consisting of 1-12 carbons, optionally 1-2
aralkyl selected from monocyclic aryl, benzyl and phenethyl, containing one or more lower alkyl substituents consisting of carbon atoms and/or one or more halo (α or Br) substituents, 2- or 4-pyridyl,
It is a monovalent group selected from a heterocycle selected from 2-pyrrolyl, 2-furyl or thiophenyl, and R', R'' and R''/ are each selected from hydrogen and methyl.

Preferred specific examples of the novel 17β-acyl compound of the present invention are represented by the following structural formula. In the formula, R is hydrogen, methyl, or ethyl.
R3 is a branched alkyl of 4-8 carbons or cycloalkyl.

Representative compounds of the present invention include the following.

17β-(t-butylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one, 17β-(isobutylcarbonyl)-4-aza-4-methyl-5α-androsta- 1-en-3-one, 17β-(inoctylcarbonyl)-4-aza-4-
Methyl-5α-androst-1-en-3-one, 17β-(n-octylcarbonyl)-4-aza-4-
Methyl-5α-androst-1-en-3-one, 17β-(1,1-diethylbutylcafflebonyl)-4
-aza-4-methyl-5α-androst-1-ene-
3-one, 17β-(neopentylcarbamoyl)-4-aza-4
-Methyl-5α-androst-1-en-3-one, 17β-(tertiary-amylcarbonyl)-4-aza-4-
Methyl-5α-androst-1-en-3-one, 17β-(tertiary-hexylcarbonyl)-4-aza-4
-Methyl-5α-androst-1-en-3-one, 17β-(5-butylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one, and in the above compounds corresponding compounds in which the 4-methyl group of is replaced by a hydrogen or ethyl group.

Further representative compounds include those in which the alkyl of the alkylcarbonyl substituent is methyl, ethyl, propyl, impropyl, butyl, phenyl, 2-13- or 4-tolyl, xylyl, 2-bromo or 2-chlorophenyl, 2,6 −
Mention may be made of the above compounds substituted with a dichloro or 2,6-dibromophenylcarbonyl substituent, or a heterocyclic substituent selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or 2-thiophenyl.

The novel compounds of formula I of the present invention are prepared by a process starting from known steroid esters having the structural formula C00CH3H-one. This method consists of (1) dehydrogenating the starting material to prepare a corresponding compound having a double bond at the 1, 2-positions of the A ring, and (2) replacing the 17-carbomethoxy substituent with 17β- It consists of steps of converting to an acyl substituent and, if desired, (3) alkylating the nitrogen of the hexacycle to introduce 4-methyl or 4-ethyl on the hexacycle. When carrying out the process of the invention, steroid A-i in step (1)
Dehydrogenation at the 1,2-positions of 4-aza-5α-androstene-3-
It is essential to carry out using one compound. step(
2) may consist of a one-step or multi-step reaction,
If desired, before step (1) or after (1),
Alternatively, it may be performed after step (3).

According to the process of the present invention, the product of the present invention comprises: (1) converting the 17β-alkoxycarbonyl-4-aza-5α-antrostane-3-one compound ■ in refluxing chloropenvin to benzeneselenic anhydride; 17β~alkoxycarbonyl-4-aza-5α- by heating with a dehydrogenating agent such as
forming androster-1-en-3-one (2
) reacting the 5α-androst-1-en-3-one compound produced in step jV (1) with sodium hydride under anhydrous conditions in a neutral solvent such as dimethylformamide; (3) reacting the reaction mixture with sodium hydride; is reacted with an alkyl iodide (methyl or ethyl) to form the corresponding 17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one (V),
4) Then the 17β-flucooxycarbonyl-4-
Al Lord Lu 4-Aza-5α-Androsta-1-En-
3-one is hydrolyzed with a strong base such as aqueous methanolic potassium hydroxide at reflux temperature and then acidified to produce the steroid acid, 17β-carboxy-4-alkyl-4-aza-5α-androsta. -1-en-3-one (b) by isolating (5) then refluxing the steroid with triphenylphosphine and 2,2'-dipyridyl disulfide in an inert solvent such as toluene. Converted to its corresponding 2-pyridylthioester, the product 17β-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5α-androsta-1
The -en-3-one (4) was isolated by silica gel chromatography (6) and the pyridylthioester was then isolated in atrahydrofuran with R2M9X (X =
α, Br) compound to produce the desired product 17β-
(Secondary-)ethylcarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one (■) is then isolated by silica gel chromatography. The above reaction was carried out using R2M9X instead of 2-butylmagnesium chloride.

or when carried out with R2-Li compounds, the corresponding 17β-(acyl)-4 where the acy9 group is R2 carbonyl
-Alkyl-4-aza-5α-androst-1-en-3-one is prepared.

According to the method of the present invention, by repeating the above-mentioned series of reactions, the corresponding 17β-acyl-4 -Aza-5α-androstal 1-nin-3-one (XV) is easily produced by A.

However, the reaction in step 2, in which 4-aza-5α-androster 1-en-3-one is treated with sodium amide and then with methyl iodide or ethyl iodide, is omitted.

According to yet another method of preparing compounds of the invention having only hydrogen as a substituent on the nitrogen of term A, the introduction of the double bond into A-31 is carried out in the final step of the process. For example, 1
7β-alkoxycarbonyl-4-aza-5α-antrostan-3-one (III) was hydrolyzed to the corresponding steroid acid, 17β-carboxy-4-aza-5α-antrostan-3-one (X). , which was then converted into the corresponding thio-pyridyl ester, 17β-(2-pyridylthiocarbonyl)-4-aza-5α-antrostane-
1-one (X) and then convert this ester into R2M
gX spanning R2Li (R2 is as defined above)
to produce 17β-(acyl)-4-aza-5α-antrostan-3-one (XI), which is dehydrogenated as described above to yield the compound iXN, 17β-(acyl)- 4-aza-5α-androsta-1-ene-3
− Generate on.

A 16-methyl derivative in which R/// is methyl is, for example, 4,16β-dimethyl-17β-acetyl-4-aza-
Known 16- such as 5α-antrostan-3-one
Methyl-17-acyl-4-methyl-4-aza-5α-
From anthrostan-3-ones, the corresponding 4,16β-dimethyl-17β-7 cetyl-4-aza-5α-androsta-1 -en-3-one.

The reaction described above is illustrated in the diagram below.

In the formula, X is a 2-thiocarbonyl substituent and R2 is as defined above.

The compounds of the invention prepared on the basis of the above-described method are, as already explained, potent anti-androgens due to their ability to specifically inhibit testosterone-5α-reductavi.

Accordingly, the present invention particularly relates to a method of treating hyperandrogenism such as acne vulgaris, seborrhea and female hair loss by topically administering the novel compounds of the invention, and all the pathologies mentioned above and The present invention relates to a method for treating benign prostatic hyperplasia by parenteral methods.

The invention therefore also relates to topical and parenteral pharmaceutical formulations for use in the new treatment methods of the invention.

Compositions for the treatment of benign prostatic hyperplasia containing a compound of the invention as an active ingredient can be administered systematically in a wide variety of therapeutic dosage forms, such as tablets for oral administration, formulated with conventional excipients. It can be administered as a capsule, solution, or suspension for intravenous injection. The daily dosage of this product will vary over a wide range from 50 to 2.000 η.

5.10.25.50.100.150.250.5 so that the composition can be varied according to the condition of the patient being treated.
Preferably, the tablets are supplied as numbered tablets containing the active ingredient from 0.00 to 0.00. Effective amounts of this drug are usually at dosage levels of from about 1 to about 50·cm per cod body weight per day. The preferred range is about 1 to 7 m per day per body weight.
I? It is. These dosages are well below the toxic levels of this product. Capsules containing the compounds of the invention may be prepared by combining the active compounds of the invention with lactose, magnesium stearate, calcium stearate, starch 1. It can be prepared by mixing with talc, or a carrier, and placing the mixture in a gelatin capsule. The active ingredients can also be mixed with tabletting agents such as calcium phosphate, lactose, corn starch or magnesium stearate to form tablets.

Liquid forms include those dissolved in suitably flavored suspending or dispersing agents, such as synthetic and natural gums such as tragacanth and acacia, methylcellulose, and the like. Other dispersants that may be used include glycerin and the like. For parenteral administration, sterile suspensions and solutions are preferred. When intravenous administration is desired, isotonic preparations that generally contain suitable preservatives are employed.

For the treatment of acne vulgaris, seborrhea, and hair loss in women, the compounds of the invention may be used in pharmaceutical compositions consisting of the active ingredient in combination with a pharmacologically acceptable carrier suitable for parenteral administration. administered in the form of These parenteral pharmaceutical compositions can be creams, ointments, gels or aerosols suitable for dermal administration. These topical pharmaceutical compositions containing the compounds of this invention usually contain about 0.1% to 15%, preferably about 5% active compound and about 95% vehicle.

The process for preparing the novel 17β-N-mono-substituted or 17β-acylcarbamoyl compounds of the present invention, already described in general form, is explained in more detail in the following examples.

Example 1 837 g of methyl 3-
A suspension of oxo-4-aza-5α-antrostane-17-carboxylate and 126.5 g of pemboselenic anhydride was refluxed for 2 hours. The reflux condenser was replaced with a distillation column and the mixture was gradually distilled to remove water produced during the reaction (2 hours). The solution was evaporated to give 198 g of wet residue.

The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCOa and saturated brine, then dried and evaporated to 172.
Obtained 4g of substance. This was chromatographed on 2.5 f3 kg of silica gel, eluting first with methylene chloride (51) and then with 4:1 methylene chloride-acetone. The desired product appeared after 81 elutions and weighed 53.4 g. When this was washed with diethyl ether and dried, it weighed 495g, melting point 278-280.
°C, obtained.

Similarly, the following compounds were converted to their corresponding derivatives of 1.

HH Melting point Ia R=CONHC(CJ(3)3252-254℃
lb = C0NHC(CH3)2CH2C(CH3)3
224-226゜RasmussOn JohnstO
n and Arth, U.S. Pat. No. 4,377,584, 1
March 22, 983.

Example 2 25 g of the product of Example 1 and 2.25 g of sodium hydride in 500° dry dimethylformamide were stirred under nitrogen for 15 minutes. Methyl iodide (15rnl) was added dropwise to U7, and the mixture was stirred at room temperature for 30 minutes.Moreover, methyl iodide (5-) was added, and the mixture was stirred at 50°C.
Heated for 2 hours. After cooling, it was diluted with 21 parts of water. After cooling, the solid was separated. Its weight is 25.49. Melting point 1
59-161℃.

Similarly, the following compounds were converted to their corresponding 4-methyl derivatives.

RR Melting point 2a R=C0NHC(CH3)2cH2c(CH3)
3148-150°C Anthrostane 2b =C0NHC(CH3)3:Δl-Androstene 153-155°2c =C0NHC(CH3)2
CIhC(CH+)3 168-170° Δ1-Androstene Example 3 A suspension of 25 g of the product of step 2 in methanol at 125° KOH (12,5 g) in 12.5 rnl water
treated with a solution of After refluxing for 4 hours, the solution was diluted with 6NH (
Acidified with J and diluted with water. The crude product acid (23
,32,! 9) was separated and dried, the melting point was 300°C.
Met.

The dried crude acid (23I), triphenylphosphine (36.45 g), and 2°2'-dipyridyl disulfide (30.41) were suspended in 138-dipyridyl disulfide and stirred at room temperature for 3 hours. The reaction solution was directly chromatographed on 4.5 ml silica gel and eluted with 9:1 ethyl acetate-acetone to give the desired product, 20.49 ml, mp 218-220°C.

Continued elution with acetone yielded the methanol adduct of 5.2.9, 5-(2-pyridyl) 1α-methoxy-4-
Methyl-3-oxo-4-aza-5α-antrostane-17β-thiocarboxylate, melting point 221-223
°C was obtained as a by-product.

3 A. Similarly, the product of Example 1 was converted to 5-(2-pyridyl) 3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate, mp 230
-23'2°C.

3B, similarly methyl 3-oxo-4-aza-5
α-Anthrostane-17β-carboxylate with 5-
(2-pyridyl) 3-oxo-4-aza-5α-antrostane-17β-thiocarboxylate, melting point 23
2-234°C.

Example 4 2 obtained in Example 3 in 70°C of tetrahydrofuran
Anhydrous ethylamine was bubbled into the suspension of pyridylthioester of 5I for 30 minutes. After 60 minutes, the resulting solution was evaporated and the residue was chromatographed on 125 g of silica gel. Ethyl acetate-methylene chloride (20:
Elution with 1) gave 1.5I product. Melting point 240-242°C.

This example was repeated using the appropriate amine and the appropriate pyridylthioester to give the following product.

4b: N-octyl 4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, melting point 106-108°C.

4c: N-t-butyl 4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, melting point 152-1
54℃.

4d: N-ethyl 3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, mp 257-259°C.

4e: N-butyl 3-oxo-4-aza-5α-antrostane-17β-carboxamide, melting point 275-276°C 0 4f: N-(2,4,4-trimethyl-2-pentyl)4-methyl-3 -Oxo-4-aza-5α-androst-1-ene-17β-carboxamide, melting point 168-170°C.

Example 5 Monodioic acid To a solution of 20051 3-oxo-4-ethene-20-acid in 3.51 t-butanol was added 474 m
A solution of 198.4 g of sodium bicarbonate in water was added. A warm solution (65°C) of 948.5g of sodium metaperiodate and 695g of permanganic acid in 3.51ml of water was added at a rate such that the temperature of the reaction was 80°C. After the addition, the mixture was refluxed for 1 hour. The reaction solution was left at room temperature overnight. The inorganic salts were removed and the cake was washed with 225ml of water.

A 5% sodium bisulfite solution was added to reduce the remaining return element. The t-butanol was removed under reduced pressure and the aqueous residue was acid-tetrified with concentrated hydrochloric acid. The separated gummy material was extracted with methylene chloride, washed with 5% sodium bisulfite, saturated brine, then dried and concentrated to give an off-white residue (214p). This was suspended in ether and diluted with hexane to give crystallized material 152, mp 189-192°C.

Example 5B - 6 obtained in step 5 in ethylene glycol with 350 m of acid
A suspension of 47 g of diacid was treated with 80 d of liquid ammonia. The resulting solution was heated at a rate of 3° per minute to 180° C. and held at this temperature for 15 minutes. After cooling, 11 water was added and the mixture was adjusted to pH 1 with 10% hydrochloric acid.
, I gave it a 5. After removing the product, washing with water and air drying, 57.5! ! A product with a melting point of 310° C. was obtained.

Example 5C 3-oxo-4-aza-5α-ethian-20-acid 16
A solution of 136 g of the Δ5-acid obtained in run 5B in acetic acid of 32-
from O2) in the presence of Jf! E2.81KMaGl(40
psig) and 60° C. for 3 hours. The catalyst was removed and the solution was concentrated to yield 128.2 g of product. This material was washed thoroughly with 31 g of water, then filtered and air dried to yield 125y, a white solid, mp 310°C.

This material was prepared as methyl 3-oxo-4-aza-5α-antrostane-1 in 7% methanolic potassium hydroxide.
It was also obtained by saponifying and then acidifying 7β-carboxylate (methyl 3-oxo-4-aza-5α-ethien-20-oate).

Example 5D The product of Example 5c in 500-methylene chloride 5.
A solution of 0 g, dicyclohexylcarbodiimide, 3.35 g, and 1-hydroxybenztriazole, 3.18 g, was stirred at room temperature overnight. 2.4.
Treated with 4-trimethyl-2-pentylamine (t-octylamine). This solution was allowed to stand at room temperature for 64 hours, a small amount of solid matter was removed, and the solution was washed successively with 10% sodium hydroxide, water, 10% hydrochloric acid and saturated saline. After drying and concentration, the crude product was chromatographed on 240 g of silica gel and acetone-methylene chloride (3N)
55 g of product, mp 250-251°C.
was gotten.

Example 5E 2.2. Example 5D is repeated using t-butylamine in place of 4-t-riftyl-2-pentylamine.
N-t-butyl 3-oxo-4-aza-5α-antrostane-17β-carboxamide, melting point 274-27
6°C is obtained.

Example 6゜2887! of 7.2 g of 5-(
To a solution of 2-pyridyl)-3-oxo-4aza-5α-androst-1-ene-17β-thiocarboxylate at -78°C was added 1.3 M 5-butylmagnesium chloride at -78°C. added. After 30 minutes at -78°C, the solution was returned to room temperature and treated with saturated saline. The product was extracted with methylene chloride, saturated brine, 10
% NaOH water, then dried and concentrated. The residue was chromatographed on 430S silica gel, eluting with methylene chloride-acetone (9:1) to yield 4.5I.
A product of 246-249 DEG C. was obtained.

Repeating the same procedure using the following reagents gives the product as described.

Example 7 A solution of 21.9 of 22-methyl-4-aza-21-true 5α-furan-3,20-dione (Step 1) and 29.49 g of pemboselenic anhydride in 552 degrees of chlorobenzene. was refluxed for 4 hours with separation of water. After concentration, the residue was redissolved in methylene chloride. After washing with 10% aqueous sodium hydroxide, 10% aqueous hydrochloric acid, and then saturated brine, the solution was dried and concentrated to yield 45 g of a yellow residue.

This was chromatographed on silica gel packed with methylene chloride and eluting with ethyl acetate.
．． 6 g of product, melting point 248-251°C, were obtained.

When the same procedure is repeated using 23-methyl-4-aza-21-true 5α-furan-3,20-dione as starting material, the product obtained is 23-methyl-4-aza-21- True 5α-col-1-ene-3,20-dione, melting point 283-286°C.

Applicant Merck End Company, Inc. Continued from page 1 Priority claim [Phase] February 27, 1984 [Phase] United States (U.S.
S) [Stock] 584062 @ Inventor Glenn F., Ray 7 United States of America.

Zulu Yield, Edge 07090 252 West Flood Avenue, New Jersey

Claims (1)

[Claims] 1 Structural formula (wherein R is hydrogen, methyl or ethyl, R2 is a straight or branched alkyl of 1-12 carbon atoms, optionally 1-2 carbon atoms) is a hydrocarbon group selected from monocyclic aryl having one or more alkyl substituents and/or one or more halogen substituents, R′ is hydrogen or methyl, R “ is hydrogen or β-methyl, R〃 is hydrogen, α-methyl, β-methyl, or R′, R”, Rtry are each selected from hydrogen or methyl), or the structural formula ( where R is hydrogen, methyl and ethyl; R2 is straight or branched alkyl of 1-12 carbon atoms, optionally substituted with one or more alkyls of 1-2 carbon atoms; and/or monocyclic aryl having one or more halogen (α, F or Br) substituents, aaralkyl selected from benzyl and phenethyl, and 2- or 4-pyridyl, 2-pyrroli JL, 2 - A monovalent group selected from a heterocycle selected from furyl or thiophenyl, and R', R'', and R/// are each selected from hydrogen and methyl.) 2. Structural formula Structural formula. having a compound according to Range 1 (wherein R is hydrogen, methyl, or ethyl; R3 is 4-8
branched alkyl or cycloalkyl having carbon atoms). 3. The compound is 17β(N-ethylcarnocumoyl)-4
-Methyl-4-aza-5α-anFroster 1-en-3-one. 4. The compound is 17β (N-ethylcaffreno(moyl)-
The compound according to claim 1, which is 4-aza-5α-androst-1-en-3-one. 5. The compound is 17β(N-t-butylcarbamoyl)-
4-Methyl-4-aza-androst-1-ene-3-
The compound according to claim 1, which is 6. The compound is 17β(N-t-butylcarbamoyl)-
A compound according to claim 1 which is 4-aza-androst-1-en-3-one. 7 The compound is 22-methyl-4-aza-21-true5
The compound according to claim 1, which is α-col-1-ene-3,20-dione. 8. The compound is 17β-pyrrolylcarbonyl-4-aza-
The compound according to claim 1, which is 5α-androst-1-en-3-one. 9. The compound is 4,22-dimethyl-4-aza-21-
2. A compound according to claim 1 which is true 5α-fluor 1-en-3-one. 10. The compound according to claim 1, wherein the compound is 4-methyl-17β-(2-pyrrolylcarbonyl)-4-aza-5α-7androster-1-en-3-one. 11. Structural formula (wherein R is hydrogen, methyl or ethyl, R2 is a straight or branched alkyl of 1-12 carbon atoms, or optionally of 1-2 carbon atoms) A hydrocarbon group selected from monocyclic aryl containing one or more lower alkyl substituents or one or more halogen substituents, R' is hydrogen or methyl, R" is hydrogen or β -methyl, R111 is hydrogen, α-methyl or β-methyl) or the structural formula % (wherein R is hydrogen, methyl or ethyl and R2 is 1-12 carbon atoms) a straight or branched chain alkyl consisting of atoms, or a unit optionally containing one or more substituents and/or one or more halo (α, F or Br) substituents of 1-2 carbon atoms; cyclic aryl, aralkyl selected from benzyl and phenethyl, 2- or 4-
A monovalent group selected from a heterocycle selected from pyridyl, 2-pyrrolyl, 2-furyl, or thiophenyl, and R
', R'', R/// are each selected from hydrogen and methyl) for the treatment of androgen excess conditions such as acne vulgaris, seborrhea, female hair loss, and benign prostatic hyperplasia. 12. A pharmaceutically acceptable carrier and a compound according to paragraph 1, 1 (wherein R is Hydrogen, methyl, ethyl, R3 is 4-
a branched alkyl of 8 carbon atoms).