JPS6355488B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pharmaceutical compositions containing novel compounds with medicinal efficacy. More specifically, the present invention relates to new steroids useful in the treatment of androgen-induced skin diseases. Many skin disorders, such as acne and seborrhea, are believed to result from excessive secretion of sebum from the sebaceous glands under androgen stimulation. Testosteroid, the major circulating androgen, is now converted to 5α-dihydrotestosterone (DHT) in the androgen target cells, and thus the biologically active androgen responsible for this stimulation is
Believed to be DHT. The enzyme responsible for this conversion is Δ ⁴ -3-ketosteroid-5α-reductase. It therefore appears that compounds that can suppress the action of this enzyme on circulating testosterone, i.e. compounds that have anti-androgenic effects due to their ability to counteract DHT on target cells, would be useful in the treatment of the aforementioned skin disorders. Recognize. According to the present invention, certain new androstenes related to testosterone but in which the 16th position is disubstituted with a certain hydrocarbon group have 5α-reductase inhibitory activity and are equivalent to this. Androstane was found to be a weak anti-androgen due to its opposing effects to DHT on target cell locations. This androsten also has very weak anti-androgenic properties of this antagonist. These steroids are therefore useful in the treatment of the aforementioned skin disorders such as acne and seborrhea. It is believed that these steroids could be used in the treatment of other diseases derived from androgens bound to the skin and hair, such as hirsutism, androgenic alopecia, and androgenetic alopecia in women. W.Voigt and Fushia's paper
SLHsia, Endrocrinology, 1973 92, 1216~
1222) to formula (A) 4-androstene-3-one-17β shown as
-Carboxylic acid and its methyl ester are 5α-
Although known to have reductase inhibitory effects, these two compounds are structurally less related to the androstenes of the present invention than the standard reference androgen, testosterone. Also, from the specification of US Pat. No. 3,853,926, formula (B) 17β-hydroxy-16,16-dimethylestr-4-en-3-one represented by is an anti-androgen agent and is known to have an inhibitory effect on sebum secretion in rats. This steroid is esterene, whereas the unsaturated steroid of the present invention is androstene. 19-Norteron,
Clearly, esterene and most of its derivatives are gestagens and testosterone, and androstene is an androgen.
This shows that just because one class of steroid has a certain medicinal effect, it is not safe to predict that other types of steroids will have the same effect. According to the invention, the formula () (In the formula, R ₃ is a C _1-4 alkyl group, a C ₃ alkenyl group, or a benzyl group, R ₄ is a hydroxyl group, R ₅ is a methyl group or hydrogen, or R ₄
and R ₅ together with the carbon atom to which they are bonded represent a carbonyl group). In formula (), R ₃ is often a C ₁ -C ₄ alkyl group or a benzyl group. Suitable examples of R ₃ include methyl, ethyl, propyl, or benzyl groups. A preferred R ₃ is also an allyl group. More preferred R ₃ is methyl, ethyl, n-propyl or isopropyl group, most preferably
R ₃ is a methyl group. R ₄ is a hydroxyl group. R ₄ further OR ₆
It can also be based on Preferred R ₆ are, for example, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl, caproyl, heptanoyl, methyl, ethyl, n-propyl, isopropyl, n-butyl,
Isobutyl, t-butyl or benzyl.
The phenyl group in the benzyl group can also be substituted, for example with _C1 - _C4 alkyl, halogen or nitro groups. Preferred R ₅ is hydrogen or methyl group. Hydrogen is most suitable. Preferred R ₄ has a β-configuration. Therefore, a preferred class of compounds of formula () is formula () (In the formula, R ₇ is a hydroxyl group, R ₈ is hydrogen or a methyl group, or R ₇ and R ₈ together with the carbon atom to which they are bonded represent a carbonyl group, and R ₉ is a C ₁ to _C3 alkyl group)
It is a compound represented by Preferably R ₇ is in the β-configuration. Preferred R ₈ is hydrogen or methyl, with optimal
R ₈ is hydrogen. Preferred R ₉ is a methyl or ethyl group,
More preferred R ₉ is a methyl group. Among the compounds of formula (), a particularly preferred class of compounds is of formula () (wherein R ₁₀ is a hydroxyl group, R ₁₁ is hydrogen or a methyl group, or R ₁₀ and R ₁₁
together with the carbon atoms to which they are bonded represent a carbonyl group, and R ₁₂ is a methyl or ethyl group). Preferably R ₁₀ is in the β-configuration. Preferred R ₁₂ is a methyl group. One compound within formula () that is particularly useful due to its 5-α-reductase inhibiting action is androst-4-ene-16,16-dimethyl-17β-ol-3-one. According to the invention, the formula () (X is a protected carbonyl group, R ₃ ,
R ₄ and R ₅ have the meanings defined in formula ())
A method for producing a compound of formula () is obtained, which comprises reacting a compound represented by formula (2) to replace the protected carbonyl group X with a carbonyl group that does not have a protecting group. The double bond in the compound of formula () is rearranged during the deprotection reaction to become a double bond at the 4 and 5 positions in the product. The method of the present invention is a conventional reaction for deretention of a protected carbonyl group. Therefore, X is a ketalized carbonyl group, e.g. (wherein n is 2 or 3), or [wherein R'X is an alcohol or thiol residue (X is oxygen or sulfur, respectively), in which case the preferred deprotecting reaction is acid hydrolysis], or or Thioketalized carbonyl groups such as (in these formulas n is 2 or 3, suitable deprotection reactions in these cases are carried out using mercuric salts or likewise by acid hydrolysis) After this deprotection reaction, the following step may optionally be carried out depending on the case: (i) When R ₄ and R ₅ do not form a carbonyl group, R ₄ can be It can be converted with .
For example, the formula () where R ₄ is a hydroxyl group
A compound having an acylated or etherified hydroxy group can be prepared by acylation or etherification of the compound by conventional methods.
This type of reaction includes the reaction of a hydroxyl group with an acyl chloride or an acyl anhydride, such as acetyl chloride or acetic anhydride, to give an acyl derivative under anhydrous conditions, and the reaction of a sodium salt of a hydroxyl group with an alkyl halide to give an etherified derivative. be. (ii) Compounds of formula () having double bonds in the 4,5 positions can be converted to the corresponding saturated analogs by conventional reduction methods, such as hydrogenation using a palladium catalyst. The compounds of formula () are novel compounds and are useful as intermediate compounds for producing pharmaceutically active compounds of formula (), and the compounds themselves form part of the present invention. The compound of the formula () itself is the formula (), The 16th position of the compound represented by is substituted with the required R ₃ group,
The next step can be produced by a method comprising converting the carbonyl group at position 17 into other R ₄ and R ₅ by a conventional method, if necessary. Here R ₃ ,
R ₄ , R ₅ and X have the meanings defined in formula (). Although less preferred than this method, this reaction first isolates the 16-monosubstituted intermediate compound and then
Further substitutions can also be made at positions. Preferably, the substitution reaction can be carried out by reacting a selected compound of formula () with compound R ₃ Y in the presence of a strong base of low nucleophilicity. Preferred Y is halogen, tosyl group, mesyl group or azido group, the base is a hydride such as sodium hydride, and the reaction is carried out under anhydrous conditions. When converting the carbonyl group at position 17 to other R ₄ and R ₅ , the conversion can be carried out by a conventional method. Compounds in which R ₄ is a hydroxyl group and R ₅ is a hydrogen or methyl group are prepared from the corresponding 17-carbonyl compound by reduction or reaction with a methyl Grignard reagent or a methyl metal complex, preferably a methyllithium complex, respectively. be able to. Preferably, the reduction can also be carried out using lithium aluminum hydride, after which the hydroxyl group of R ₄ obtained as described above is itself subjected to the method described in (i) above. Thus, further R ₄ groups can also be acylated or etherified. A compound of formula () is a compound of formula () It can be produced by oxidizing the corresponding 17-hydroxyl compound shown under neutral or basic conditions. In formula (), X has the meaning defined in formula (). This reaction is conveniently carried out using silver carbonate supported on an inert support such as diatomaceous or Collins reagent, which is a mixture of chromium trioxide and pyridine in methylene dichloride. can. The compound of the formula () itself is the formula (), It can be produced by protecting the carbonyl group of the corresponding compound represented by This reaction is carried out under conventional conditions to obtain the desired protected carbonyl group X. For example, when a ketalized carbonyl group is to be produced, it is reacted with a suitable alcohol or thiol in the presence of a compound of formula (). In this way, for example, when using ethylene glycol, a 3,3-ethylenedioxycarbonyl protecting group is obtained. During this reaction, the double bond between the 4 and 5 positions is rearranged to become a double bond between the 5 and 6 positions. As can be seen from the foregoing description, a particularly preferred process for producing the compound of formula () is shown as follows. Compounds of formula () thus produced can optionally be subsequently converted into other compounds of formula () by steps (i) or (ii) as described above. According to the present invention, a pharmaceutical composition is obtained comprising a compound of formula () and a pharmaceutically acceptable carrier. A preferred pharmaceutical composition according to the invention is a pharmaceutical composition for topical administration to the skin, comprising a compound of formula () formulated in the form of a cream or ointment. Cream formulations or ointments which may be used for compounds of formula () are based on conventional formulations well known in the art, such as those published in standard textbooks on medicine and cosmetics, such as those published by Leonard Hill.
Harry's Cosmeticology) and the British Pharmacopoeia. Standard emulsifying ointment bases or anhydrous polyethylene glycols are simple examples of this type of formulation. Certain compounds of formula () appear to exhibit medicinal efficacy upon oral administration. Compounds of this type can therefore be formulated, with the addition of an inert carrier, into compositions conventionally used for oral administration, such as tablets, capsules, syrups and the like. The present invention also provides a method for treating skin abnormalities, which comprises administering to a patient with androgen-induced skin an effective amount of a compound of formula (). Compounds of formula () are particularly useful in the treatment of acne and seborrhea. In this case, the invention particularly provides a method for treating acne or seborrhea, which comprises administering to an acne or seborrhea patient an effective amount of a compound of formula (). Preferably, the compound of formula () is administered topically to affected skin. The effective amount will vary over a wide range depending on the area of skin affected, the location of the skin, the unique absorption capacity of the skin, and the severity of the condition being treated. The compounds of the present invention have the advantage of effectively treating androgen-induced skin abnormalities and exhibiting no harmful hormonal side effects. It is clear that one or more antimicrobial agents conventionally used to treat acne and seborrhea infections can be included in the compositions of the present invention and used in this type of treatment. The following production example shows a compound of formula () and an intermediate compound for producing the same. Manufacturing example 1 Androstane-5-ene-3,3-ethylenedioxy-17β-ol is prepared from androst-4-en-17β-3-one by the method of Campbell et al. (JA
Campbell, J.C.Babcock and JAHogg, J.Am.
Chem.Soc, 1958, 80, 4717-4721).
It was obtained as white fine needle-like crystals with a melting point of 185-186°C when recrystallized from methanol and water. Manufacturing example 2 20 g of silver carbonate supported on diatomaceous earth was dried by removing water by azeotropic distillation with benzene, suspended in 200 ml of dry benzene, and androst-5- in 50 ml of benzene was added to the suspension. En-
1 g of 3,3-ethylenedioxy-17β-ol was added and the mixture was heated under reflux for 4 hours, resulting in complete oxidation. The reaction mixture is filtered, the filtrate is evaporated, and the resulting residue is crystallized from methanol to give androst-5-ene-
0.95 g of white fine needle-like crystals of 3,3-ethylenedioxy-17-one was obtained. Complete oxidation was also obtained using a mixture of chromium trioxide and pyridine in methylene chloride. Manufacturing example 3 2.92 g of androst-5-ene-3,3-ethylenedioxy-17-one was dissolved in 60 ml of dry tetrahydrofuran, 2.92 g of sodium hydride and then 5 ml of methyl iodide were added and the reaction mixture was heated under reflux for 4 hours. . Tetrahydrofuran was evaporated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water, the ethyl acetate layer was washed again with water, dried over anhydrous MgSO ₄ and evaporated to dryness to yield 3.21 g of a solid. Recrystallizing this solid from methanol and water gives
Androst-5-ene-3, melting point 138-142℃
3-ethylenedioxy-16,16-dimethyl-17-
Obtained 2.4 g of colorless crystals of . The following compounds were similarly prepared. Production example 3a Androst-5-ene-3,3-ethylenedioxy-16,16-diallyl-17-one: Melting point when recrystallized from methanol: 100-101℃ Production example 3b Androst-5-ene -3,3-ethylenedioxy-16,16-dibenzyl-17-one White spongy, infrared carbonyl absorption band:
1725cm ^-1 Production example 3c Androst-5-ene-3,3-ethylenedioxy-16,16-d-n-butyl-17-one Melting point of product recrystallized from methanol: 165~
167℃ Production example 3d Androst-5-ene-3,3-ethylenedioxy-16,16-diethyl-17-one Melting point of product recrystallized from methanol: 146~
148℃ Production example 4 1.5 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one was dissolved in 100 ml of dry ether, 0.1 g of lithium aluminum hydride was added, and the reaction mixture was stirred at room temperature for 30 minutes. The excess hydride was destroyed by adding excess ethyl acetate. The mixture is shaken with a solution of potassium sodium tartrate and the organic layer is separated, washed with water and dried over anhydrous MgSO ₄ . After filtration and evaporation of the filtrate to dryness, the resulting residue is recrystallized from methyl acetate, melting point 178-179.
1.47 g of androst-5-ene-3,3-ethylene dioxide-16,16-dimethyl-17β-ol white powder was obtained. The following compounds were similarly prepared. Production example 4a Androst-5-ene-3,3-ethylenedioxy-16-16-diallyl-17βol Melting point 149-151℃ Production example 5 Dissolve 1 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17β-ol in 30 ml of methanol, add 5 ml of 2.5N hydrochloric acid,
The mixture was heated at reflux for 1 hour to obtain complete hydrolysis of the ketal. The reaction mixture was dissolved in excess ethyl acetate, washed with water until neutral, and the organic phase was dried.
Dry with _MgSO4 , filter and evaporate to dryness as a white solid.
0.88g was obtained. This was recrystallized from petroleum ether with a boiling point of 60 to 80℃ and ethyl acetate, and the melting point was 170 to 172℃.
Androst-4-ene-16,16-dimethyl-
0.76 g of white needle-like crystals of 17β-ol-3-one was obtained. Production example 5a Androst-4-ene-16,16-diallyl-
17β-ol-3-one Production example of viscous liquid showing infrared carbonyl absorption at 1680 cm ^-1 6 Dissolve 0.25 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one in 7.5 ml of methanol, and add 2.5N hydrochloric acid.
1.5 ml was added and the solution was heated at reflux for 30 minutes and after cooling excess ethyl acetate was added. The organic phase was washed with water until neutral, dried over anhydrous MgSO ₄ and evaporated to dryness to give 0.2 g of a white solid, which was recrystallized from petroleum ether with a boiling point of 60-80 °C and a melting point of 164-165. Androst-4-ene-16,16-dimethyl-
0.16 g of white needle-like crystals of 3,17-dione was obtained. The following compounds were also produced in the same manner. Production example 6a Androst-4-ene-16,16-diallyl-
3,17-dione Melting point of product recrystallized from petroleum ether with boiling point 60-80℃: 118-120℃ Production example 6b Androst-4-ene-16,16-dibenzyl-3,17-dione Boiling point 60-80℃ Melting point of product recrystallized from petroleum ether at 80°C: 150-152°C Production example 6c Androst-4-ene-16,16-d-n-butyl-3,17-dione Infrared irradiation at 1680 and 1720 cm ^-1 Example of producing a highly concentrated oily product that exhibits absorption 6d Androst-4-ene-16,16-diethyl-
3,17-dione Production example of semi-crystalline oil product showing infrared absorption at 1680 and 1720 cm ^-1 7 Androst-4-ene-16,16-dimethyl-
17β-ol-3-one 0.158g dried benzene 4
ml, add 0.14 g of dry pyridine and 0.12 g of acetyl chloride, and heat the mixture under reflux for 30 min.
After cooling, the mixture was poured into excess ethyl acetate. Wash the ethyl acetate solution with dilute hydrochloric acid, then with water, then dry it.
Dry with MgSO ₄ and evaporate the filtered filtrate to dryness. 0.156 g of the solid obtained is recrystallized from petroleum ether with a boiling point of 60-80°C. Androst-4-ene-16 with a melting point of 153-155°C ,16-dimethyl-17β-
White needle-like crystals of all-3-one acetate
0.100g was obtained. The following compounds were produced in the same manner. Production example 7a Androst-4-ene-16,16-dimethyl-
17β-ol-3-onehexanoate Melting point of product recrystallized from methanol: 105
~107℃ Production example 8 0.5 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one was dissolved in dry ether, kept under a nitrogen atmosphere, and a large excess of methyllithium (1.75 M solution in hexane) was dissolved in dry ether. 20
ml) was added over 10 minutes, resulting in an immediate precipitate. Stir the mixture at room temperature for 2 hours, then
The excess methyllithium was decomposed by careful addition of water, the product was extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous MgSO ₄ and evaporated to dryness to give 0.51 g of a white solid. This solid has a boiling point of 60~
When recrystallized from petroleum ether at 80°C, the melting point
Androst-5-ene-3,3- at 170-171℃
Ethylenedioxy-16,16,17α-trimethyl-
0.40 g of white crystals of 17β-ol was obtained. Manufacturing example 9 Dissolve 1.1 g of androst-5-ene-3,3-ethylenedioxy-16,16,17α-trimethyl-17β-ol in 50 ml of methanol, and add 2.5N hydrochloric acid 10
ml was added and the mixture was heated to reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water until neutral, dried over anhydrous MgSO ₂ , filtered and the filtrate was evaporated to dryness to yield 0.94 g of crude solid.
When this solid is recrystallized from petroleum ether with a boiling point of 60 to 80°C, flaky androst-4-ene-16,16,17α-trimethyl-
0.54 g of 17β-ol-3-one was obtained. Manufacturing example 10 5α-androstane-17β-all-3-one
8.34 g was dissolved in 375 ml of dry benzene, 5 g of ethylene glycol in 50 ml of dry benzene was added, then 0.10 g of toluene p-sulfonic acid was added and the mixture was refluxed for 10 hours with water removed using a Jean-Starck apparatus. Upon heating, ethyl acetate was added to the mixture, the mixture was shaken with a dilute solution of sodium bicarbonate, washed twice with ether, and dried over anhydrous _MgSO4 . The mixture is filtered, the filtrate is evaporated to dryness, and the resulting solid is recrystallized from methanol to give a melting point of
7.3 g of white crystals of 5α-androstane-3,3-ethylenedioxy-17β-ol were obtained at 170-172°C. Manufacturing example 11 2 g of 5α-androstane-3,3-ethylenedioxy-17β-ol is oxidized with silver carbonate supported on diatomaceous earth by heating under reflux in 350 ml of dry benzene for 4 hours, and the reaction mixture is filtered. The solid obtained by evaporating the filtrate to dryness was recrystallized from methanol to obtain 2 g of colorless crystals of 5α-androstane-3,3-ethylenedioxy-17-one with a melting point of 156-157.5°C. Manufacturing example 12 Using the method of Preparation Example 3, 5α-androstane-3,3- in 50 ml of dry tetrahydrofuran
2.4 g of ethylenedioxy-17-one is heated under reflux with 2 g of sodium hydride and 12 ml of methyl iodide for 4 hours, and the resulting 2.78 g off-white solid is recrystallized from methanol to give a product with a melting point of 153-155°C.
White crystals of 5α-androstane-3,3-ethylenedioxy-16,16-dimethyl-17-one 1.9
I got g. Manufacturing example 13 2 g of 5α-androstane-3,3-ethylenedioxy-16,16-dimethyl-17one is dissolved in 140 ml of dry ether and reduced with lithium sodium hydride using the method of Preparation Example 4, resulting in the main component and a small amount. 1.89 g of a crude white solid containing the following components was obtained. This mixture was subjected to column chromatography using silica, and the main component was recrystallized from petroleum ether with a boiling point of 60 to 80°C.
-Dimethyl-17β-ol colorless needle crystals 1.1g
I got it. Manufacturing example 14 Using the method of Production Example 5, 1.8 g of 5α-androstane-3,3-ethylenedioxy-16,16-dimethyl-17β-ol was mixed with 120 ml of methanol.
After heating under reflux with 16 ml of 2.5N hydrochloric acid for 1 hour, 1.56 g of the resulting crude solid is recrystallized from petroleum ether with a boiling point of 60-80°C to yield 5α-androstane-16,16-dimethyl-17β with a melting point of 184-185.5°C. -All-3
1.45 g of white crystals of -on were obtained. Manufacturing example 15 Using the method of Production Example 6, 0.5 g of 5α-androstane-3,3-ethylenedioxy-16,16-dimethyl-17-one was heated under reflux with 40 ml of methanol and 5 ml of 2.5N hydrochloric acid for 1 hour. The boiling point of the solid
Recrystallization from petroleum ether at 60-80°C yields pure 5α-androstane-16,16 with a melting point of 135-137°C.
-Dimethyl 3,17-dione white plate crystals 0.4g
I got it. Manufacturing example 16 5α-Androstane-16,16-dimethyl-17β
0.2 g of -ol-3-one was heated under reflux with 0.6 ml of heptanoyl chloride and 0.3 ml of pyridine in 7 ml of dry benzene for 1.5 hours, excess ether was added and the mixture was shaken twice with a dilute solution of sodium bicarbonate. Washed with water and dried with anhydrous _MgSO4 . Filter the mixture;
When the solid obtained by evaporating the filtrate to dryness is recrystallized from methanol and water, 5α with a melting point of 74.5-75.5℃ is obtained.
-White plate-like crystals of androstane-16,16-dimethyl-17β-ol-3-oneheptanoate
0.18g was obtained. Manufacturing example 17 A 1.75 M methyllithium solution in hexane was prepared by dissolving 0.25 g of 5α-androstane-3,3-ethylenedioxy-16,16-dimethyl-17-one in 20 ml of dry ether and using the method of Preparation Example 8. 20
0.25 g of crude solid obtained by processing ml with boiling point of 60~
Recrystallized from petroleum ether at 80℃, melting point 142
5α-androstane-3,3-ethylenedioxy-16,16,17α-trimethyl-17β- at ~144℃
0.17 g of white crystals of ol were obtained. Manufacturing example 18 Using the method of Production Example 3, 5α-androstane-3,3-ethylenedioxy-16,16,17α-
Trimethyl-17β-ol 0.75g methanol 55g
ml and 3 ml of 2.5N hydrochloric acid and heated under reflux for 10 minutes, and 0.5 g of the resulting crude solid was recrystallized from petroleum ether with a boiling point of 60-80°C to obtain 5α-androstane-16,16,17α with a boiling point of 152-153.5°C. -Trimethyl-17β-
0.4 g of white plate-like crystals of all-3-one were obtained. Example 1 Pharmacological data 1 Androgen-anabolic test and anti-androgen test The method used was basically the method of Hershber et al., with only slight modifications.
Geret al., Proc, Soc. Exp. Bicl. Med., 1953,
83.175). An immature male rat weighing 50 to 60 g was subjected to bilateral orchidectomy under Nembutal anesthesia.
Administration was carried out for 4 days starting from day 1, and the weight of the mice was recorded during the administration period. The mice were killed 10 days after removal, and the weights of the spermatozoa, abdominal wall prostate, levator muscle, and thymus were measured as well as the whole body weight. These data were compared to those of control animals. The test compound is prepared in solution or suspension in peanut oil and administered by subcutaneous injection. Androgen-anabolic test For this test, the test compound was administered by subcutaneous injection at a dose of 50 mg/Kg and the results were compared with those of control animals receiving testosterone at a dose of 1 mg/Kg. Each set of data was compared to that of a control animal that had both orchies removed and received no medication. Anti-Androgen Test For this test, the compound was administered by subcutaneous injection at a dose of 50 mg/Kg simultaneously with 1 mg/Kg of testosterone and 1 mg/Kg of testosterone (1
The degree of inhibition was measured in comparison with control animals subcutaneously injected with 10 mg/Kg). Data for each species were compared to data from biorchiectomized, non-medicated control animals.

Table 2. Androgen Replacement Test Compounds of the invention displace [ ³ H]-5α-dihydrotestrone from proteins that bind cytosolic androgens with high affinity isolated from murine prostate and epididymis. The ability to mainwaring etc. method (WIPMainwaring, FR
Mangan, PA Feherty and M. Freifield,
Molecular and Callular Endocrinology, 1974,
1,113-128), and was investigated in a test tube test. A sample of 0.1 ml of cytosol was mixed with 5 × 10 ^-10 M [ ³ H]
-5α-dihydrotestosterone (47Ci/mmol, obtained from The Radiochmicaj Ceutre, Amersham) alone or at 5×10 ⁻⁶ , 5×
10 ^-7 and 2.5 × 10 ^-7 M of the test compound, and the binding protein was incubated with [ ³ H]-5α.
-The ability to displace DHT was measured as the decrease in counts coming out of the supernatant.

[Table] 3 Inhibition of Testosterone 5α-Reductase The activity of this enzyme, △ ⁴ -3-ketosteroid 5α-reductase, can be determined by the methods such as WIPMainwaring and FR.
Mangan, J. Endocrinology, 1973, 59, 121~
139). With this test method, 5α from Testostron (T)
-The conversion rate to dihydrotestosterone (DHT) was 15-30% for various formulations. The conversion suppression rate is
Measured by the rate of decrease in cpm related to DHT. Conversion rate (%) = cpmDHT / cpmT + cpmDHT × 100% Inhibition rate % = Conversion rate when compound is not used (%) - Conversion rate when compound is used (%) / Conversion rate when compound is not used (%)

[Table] The numbers in brackets in the table represent the number of experiments. 4 Effect of Compounds on Testosterone-Induced Outgrowth of Flank Organs of Hamsters The growth of flank organs (sebaceous glands) is stimulated by topical application of testosterone in orchidectomized male hamsters or untreated female hamsters. Report by S. Takayashu and K.
Adachi, Endocriuology, 1972, 90, 73-80)
According to the authors, testosterone is converted in the sebaceous glands to 5α-dihydrotestosterone, which is currently considered to be the active androgen in the target organs responsible for most androgens. The ability of the compounds of the present invention to inhibit this stimulation is essentially based on the method of W.Voigt and SLHsia.
Endocrinology 1973, 92, 1216-1222). Adult male hamsters were subjected to incubation and both testicles were removed, and one week later the test animals were divided into groups of 4 animals each and treated as follows. The first group was left untreated and the second group received acetone alone in the left flank organ and acetone containing 4 mμ/day of testosterone in the right flank organ.
The third group received acetone alone in the left flank organ and acetone containing 4 mμ/day of testosterone and 400 mμ/day of the compound of the invention in the right flank organ. After 3 weeks of treatment, the hamsters were sacrificed and organs were measured and immersed in fixative for histological examination. An active compound should inhibit testosterone-induced flank organ growth.
Certain compounds of the invention, particularly those of Preparations 5, 6 and 9, were very effective in inhibiting sebaceous gland stimulation by testosterone. Histological examination confirmed a significant reduction in the size of the sebaceous glands in the flank organs. 5 Effect of Compounds on Sebum Secretion in Murines The ability of the compounds of the present invention to inhibit sebum secretion in rats essentially follows the method of Ebling (FJEbling,
J.of Investigative Derma tology1974, 62, 161
~171 and references cited in this paper). Compounds of Preparation Examples 5, 6 and 9, especially Preparation Example 1
Compounds such as 25 mg/Kg subcutaneously injected subcutaneously are very effective in inhibiting testosterone-stimulated sebum secretion in orchidectomized male rats, whereas 5α-dihydrotestosterone at the same dose It has no effect on suppressing sebum secretion stimulated by This seems to indicate that these compounds act via inhibition of 5α-reductase and not via the long-standing anti-androgenic mechanism. It will be done. 6. Toxicity When the compound of Preparation Example 5 was orally administered to mice in amounts up to 900 mg/Kg, no signs of toxicity were observed.

Claims (1)

[Claims] 1 Formula () (In the formula, R ₃ is a C _1-4 alkyl group, a C ₃ alkenyl group, or a benzyl group, R ₄ is a hydroxyl group, R ₅ is a methyl group or hydrogen, or R ₄
and R ₅ together with the carbon atom to which they are bonded represent a carbonyl group) and a pharmaceutically acceptable carrier for the treatment of skin diseases derived from androgens. 2. The pharmaceutical composition according to claim 1 for topical administration to the skin in the form of a cream or ointment.