JPS61178920A - Medicinal composition containing 4-ene-16, 16-disubstituted-3-one steroid - 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 pharmaceutical compositions containing novel compounds with medicinal efficacy.

More specifically, the present invention relates to a new steroid useful in the treatment of androgen-induced skin diseases.

Many skin abnormalities, such as acne and seborrhea, are believed to result from excessive secretion of sebum from the sebaceous glands under androgen stimulation. Currently, testosterone, the main circulating androgen, is converted to 5α-dihydrotestosterone (DHT) in androgen target cells.
It is therefore believed that the biologically active androgen responsible for this stimulation is DllT. The enzyme responsible for this conversion is Δ4-3-ketodes4ido-5α-reductase. Therefore, compounds that inhibit 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, may be useful in the treatment of the aforementioned skin abnormalities. I can see that it is possible.

The present invention has demonstrated that certain new androstenes, which are related to testosterone but are disubstituted with a certain hydrocarbon group at the 16th position, have 5α-reductase inhibitory effects, and that anthrostane, which is related to this, is a target. It was found to be a weak anti-androgen because it has an action that opposes DHT on cellular 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. Other diseases derived from androgens bound to the skin and hair may include the use of these steroids in the treatment of hirsutism, androgenic alopecia, and androgenetic alopecia in women.

Voigt and Fushia's paper (W. Voigt and Fushia)
d8, L, Hpia, Endrocrinology
% 1973 92.

1216-1222), it is known that 4-androsten-3-one-17β-carzenic acid represented by formula (A) and its methyl ester have a 5α-reductase inhibitory effect.
The species compounds are structurally less related to the androstenes of the present invention than the standard reference androgen, testosterone.

7β-hydroxy-t6. t6-dimethelestrol 4-en-3-one is an anti-androgen;
It is known to have an inhibitory effect on sebum secretion in rats. Whereas this steroid is estyrene,
The unsaturated steroid of the present invention is androstene. 1
Clearly, 9-noruterone, estyrene and most of its derivatives, gestagen and testosterone, androstene are androgens.
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 present invention, two m R.

υ (wherein R5 is a 01-4 alkyl group, 03 alkenyl group or benzyl group, R4 is a hydroxyl group, R5 is a methyl group or hydrogen, or R4 and R5
together with the carbon atoms to which they are bonded are cal/
(representing a nyl group) is obtained.

In formula (I), R3 is often a C1-C4 alkyl group or a hapensyl group.

Suitable examples of R3 include methyl, ethyl, propyl, or benzyl groups. A preferred R3 is an allyl group.

More preferred R and 3 are methyl, ethyl, n-propyl or impropyl groups, and most preferred R5 is methyl.

R4 is a hydroxyl group. R4 can also be an OR6 group. Preferred R6 is nine, for example acetyl,
lopropionil, impropionil.

n-butyryl, imbutyryl, t-butyryl, caproyl, heftanoyl, methyl, ethyl, n-zolobyl, impropyl, n-butyl, isobutyl, t-ethyl or quandyl. The phenyl group in the benzyl group may be substituted with an alkyl group of 01 to 04, and the halogen t7'c may be substituted with a nitro group.

Preferred R5 is hydrogen or methyl group. Hydrogen is most suitable.

Preferred R4 has a β-configuration.

A preferred class of compounds of formula (T) is therefore formula (Ir)
(In the formula, R7 is a hydroxyl group, R8 is hydrogen or a methyl group, or R7 and R8 together with the carbon atom to which they are bonded represent a carzenyl group, and R
q is a C7-C3 alkyl group).

Preferably R7 is in β-distribution.

Preferred R8 is hydrogen or methyl, most preferred R8 is hydrogen, preferred R7 is methyl or ethyl, and more preferred R7 is methyl.

Among the compounds of formula (Tl), a particularly preferred class of compounds is the compound of formula (1) (wherein R is a hydroxyl group, R4 is hydrogen or a methyl group, υ, or R7° and R11 are bonded to Together with the carbon atom, it represents a carzenyl group, and R12 is a methyl or ethyl group).

Preferably R4° is in the β-configuration.

Preferred R1□ is a methyl group.

One compound within formula (1) that is particularly useful due to its 5-α-reductase inhibitory action is androst-4-ene-
16,16-cymethyl-L7β-ol-3-one.

According to the invention, the formula (m (X is a protected car, 1-nyl group')), R3v
"4 and R5 have the meanings defined in formula (I))
A method for producing a compound of formula (1) is obtained, which comprises reacting a compound represented by formula (1) to replace the protected carzenyl group X with a carzenyl group that does not have a protecting group.

The double bond in the compound of formula (5) is rearranged during the deprotection reaction to become a double bond at position 4.5 in the product.

The method of the present invention is a conventional mixed group removal reaction of a protected carzenyl group. Therefore, X is a ketalized cardenyl group, 9 [wherein n is 2 or 3], or 8.X/ \ [wherein R'X is an alcohol or thiol residue (X is oxygen or sulfur, respectively) ), in which case the preferred deprotecting group reaction is acid hydrolysis], the next is a thioketalized carzenyl group such as or (in which n is 2 or 3, these A suitable deprotection reaction in the case is using mercuric salts.

or similarly carried out by acid hydrolysis].

After this deprotecting group reaction, the next step can optionally be carried out depending on the case.

(i) When R4 and R5 do not form a carsenyl group, R4 can be converted by conventional methods.

For example, compounds of formula (1) in which R4 is a hydroxyl group can be acylated or etherified by conventional methods to produce compounds in which R4 is an acylated or etherified hydroxyl group. 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.

(li)4. Compounds of formula H having a double bond in the s-position can be converted to the corresponding saturated analogs by conventional reduction methods, such as hydrogenation using a radium catalyst.

The compound of formula (5) is a novel compound and is useful as an intermediate compound for the preparation of the pharmaceutically active compound of formula (I), and the compound itself forms part of the present invention.

The compound of formula (IV) itself is obtained by substituting the 16th-position of the compound represented by formula 1 (g) with the required R3 group, and then substituting the 17th-position Cal 7j? as necessary. =R group by a conventional method
4 and R5. where R5, Ra, R5 and X have the meanings defined for formula You can also do that.

Preferably, the substitution reaction can be carried out by reacting the selected compound of formula (V) with compound R3Y in the presence of a strong base of low nucleophilicity. preferable! is halogen,
The base may be a hydride such as sodium hydride, and the reaction is carried out under anhydrous conditions.

When converting the car-7g-nyl group at position 17 to other R4 and R5, the conversion can be carried out by conventional methods.

Compounds in which R4 is a hydroxyl group and R5 is hydrogen or a methyl group can be prepared from the corresponding ehucarzenyl compound by reduction or reaction with a methyl Grignard reagent or a methyl metal complex, preferably a methyllithium complex, respectively. Preferably, the reduction can also be carried out using lithium aluminum hydride, after which, if necessary, the hydroxyl group of R4 obtained as described above is itself separated by the method described in (+) above. The R4 group of can also be acylated or etherified.

Compounds with a 2-closed structure can be made by oxidizing the corresponding 17-hydroxyproxyl compound of the formula (Vl) under neutral or basic conditions. It has a meaning.

This reaction can be carried out using either silver carbonate supported on an inert support such as diatomaceous material or the Choline reagent (Coff1ns), which is a mixture of chromium trioxide and pyridine in methylene dichloride.
reagent).

The compound VD itself can be made by protecting the calytnyl group of the corresponding compound of formula (H).

This reaction is carried out under conventional conditions to obtain the desired protected carzenyl group X. As a precaution, when a ketalized car-7d-nyl group is to be produced, it is reacted with a suitable alcohol or thiol in the presence of the compound of formula (a). In this way, for example, using ethylene glycol,
During the reaction to obtain the 3,3-ethylenedioxycar-nyl protecting group, 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 (I) is shown as follows.

: Carry out as necessary: Conversion of the Co group $ The compound of formula (I) thus prepared may be subsequently converted into another compound of formula (■) in step (1) or li) K, as the case may be, as described above. It can also be converted to .

According to the present invention, a pharmaceutical composition is obtained which comprises a compound of formula (1) and a carrier which can be used for pharmaceutical preparation. A preferred pharmaceutical composition according to the invention is a pharmaceutical composition for topical administration to the skin, comprising a compound of formula (I) formulated in the form of a cream or ointment.

Cream formulations or ointments which may be used for the compounds of formula (I) are conventional formulations well known in the art, such as standard textbooks on medicine and cosmetics, such as Harry's Cosmeticology, published by Leonard Hill Books. )
and prepared as described in the British Pharmacopoeia. Standard emulsifying ointment bases or anhydrous polyethylene glycols are simple examples of this type of formulation.

Certain compounds of formula (I) appear to exhibit medicinal efficacy upon oral administration. Compounds of this type can therefore be formulated with 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 an effective amount of a compound of formula (1) to a patient with androgen-induced skin.

Compounds of formula (1) are particularly useful in the treatment of seborrhea and seborrhea. In this case, the present invention is particularly suitable for patients with zatara or seborrhea.
A method of treating equilibrium or seborrhea is obtained comprising administering an effective amount of a compound of I).

Preferably, the compound of formula (T) is administered topically to affected skin. The effective amount varies over a wide range depending on the area of the affected skin, the position of the skin, differences in the unique absorption capacity of the skin, and the state of mind 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 of the antibacterial agents conventionally used to treat acne and seborrheic infections can be incorporated into the compositions of the present invention and used for this type of treatment.

The following Preparation Examples show the preparation of the compound of formula (I) and intermediate compounds in the t-a preparation thereof.

Expansion Example Eandrostan-5-ene-3,3-1: ethylene dioxy-17β-ol is
3-on to the method of Campbell et al. (J, A, Camb
ell, J, 0. Babcock and J.A.
, Hogg.

, 7- Am, C! hem, 8oc, 1958
, 80.4717-4721) t = melting point when used and recrystallized from methanol and water is 185-1
Obtained as white fine needle-like crystals at 86°C.

Production Example 2 Silver carbonate 209 supported on a diatomer was dried by distilling off water by azeotropic distillation with benzene, and KI! Cloudy.

A suspension of androst-5-nin-3,3-ethylenedioxy-17β-ol in 50 rnl of benzene is added to the suspension. was added and the mixture was heated at reflux for 4 hours to give the complete acid. The reaction mixture is filtered, the filtrate is evaporated and the resulting residue is crystallized from methanol, melting point 189-1.
0.95 f of white fine needle-like crystals of androst-5-ene-3,3-ethylenedioxy-17-one were obtained at 90°C.

Complete oxidation was also obtained using a mixture of chromium trioxide and lysine in methylene chloride.

Production Example 3 Androst-5-ene-3,3-ethylenedioxy-
Dry 17-one 2.929 m in tetrahydrofuran 60 m
2.9221 liters of sodium hydride and then 5 tul of methyl iodide were added and the reaction mixture was heated at reflux for 4 hours. Tetrahydrofuran was evaporated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed again with water, dried over anhydrous Mg80 a, and evaporated to dryness to yield solid 3.21 f. When this solid is recrystallized from methanol and water, androst-5-ene-3,3-ethylenedioxy-
16゜Colorless crystals of 16-cymethyl-7-one 2.4
I got 2.

The following compounds were similarly prepared.

Production Example 3a En-Prostau-5-ene-3,3-utelenedioxy-+6. ts-? Melting point when recrystallized from aryl-17-onimethanol: 1110~LOL°C Surface preparation example 3b androst-5-ene-3,3-ethylenedioxy-16,16-dibenzyl-1huon white spongy, by infrared radiation Calygnyl absorption band: 172
5 cm-' ゛El Example 3 c androst-5-ene-3,3
-ethylenedioxy-+6. +6-J-n-butyl-1
Melting point of product recrystallized from 7-one methanol: 165-167
C Production Example 3d Androst-5-; So-3,3-ethylenedioxy-x6. +6-ethyl-17-one Melting point of product recrystallized from methanol = 146-48C Production Example 4 H Androst-5-ene-3-ethylenedioxy-16
, 1.5 t of 16-dimethyl-1-phoon in 10 Q R1 of dry ether, 0.1 f of lithium aluminum hydride is added, the reaction mixture is stirred at room temperature for 30 minutes, and then excess ethyl acetate is added. Excess hydride was destroyed.

The mixture is shaken with a solution of potassium sodium tartrate and the organic layer is separated, washed with water and dried over anhydrous Mg804. After filtration and evaporation of the filtrate to dryness, the resulting residue was recrystallized from methyl acetate to give androst-5-ene-3,3-ethylene oxide-16 with a melting point of 178-179°C.
, 16-dimethyl-17β-ol white powder 1.479
I got it.

The following compounds were similarly developed.

JEHtr Example 4a Androst-5-ene-3,3
-ethyleneoxy-5-ts--) allyl-17βol Melting point 149-151°C Production Example 5 H Androst-5-ene-3,3-ethylenedioxy-
Dissolve 16,16-dimethyl-17β-ol IP in 30 g of methanol, add 2.5N hydrochloric acid sdi, and mix.
Heating at reflux for 1 hour resulted in complete hydrolysis of the ketal. The reaction mixture was dissolved in excess ethyl acetate, washed with water until neutral, the organic phase was dried over anhydrous Mg804, and the filtration was evaporated to dryness to yield 0.88 f of a white solid. This was recrystallized from petroleum ether with a boiling point of 60 to 80°C and ethyl acetate, and androst-4-ene with a melting point of 170 to 172°C was obtained.
White needle-like crystals o,'y6r2 of 16,16-dimethyl-17β-ol-3-one were obtained.

Production Example 5a 7ndrost 4-en-16゜16-
Production Example 6 of a viscous liquid exhibiting infrared carsenyl absorption in diallyl-17β-ol-3-one 16801M Androst-5-ene-3,3-ethylenedioxy-
0.252 of 16,16-dimethyl-1-fuon was dissolved in 7.5-methanol, 5 m/x of 2.5N hydrochloric acid was added, the solution was heated to reflux for 30 minutes, and after cooling, excess ethyl gold acetate was added. The organic phase was washed with water until neutral, dried over anhydrous Mg Day 04 and evaporated to dryness to give a white solid 0.29, which was recrystallized from petroleum ether with a boiling point of 60-80°C to give a melting point of 164. Androst-4-ene-1 at ~165°C
6,16-cymethyl-3. 0.169 white needle-like crystals of Airdione were obtained.

The following compounds were also produced in the same manner.

jlDtExample 6a ynodrost-4-ene-16゜1
6-diallyl-3,17-dione Melting point of a good product recrystallized from petroleum ether with a boiling point of 60 to 80°C: 118 to 120°C Production example 6b EnProstau 4-ene-16°16-dipendyl-3. Melting point of a good product recrystallized from petroleum ether with a boiling point of 60 to 80°C: 150 to 152°C
-J-n-butyl-3, Airdione 1680 and 1
Highly concentrated oily products exhibiting infrared absorption at 720 cIn ? Production Example 7 of a semi-crystalline oily product exhibiting infrared absorption at +1 t6-J methyl-17
β-ol-3-one 0.1589% dried benzene 4-
0.14 t of dry pyridine and 0.12 t of acetyl chloride are added, the mixture is heated to reflux for 30 minutes,
After cooling, the mixture was poured into excess ethyl acetate. The ethyl acetate solution was washed with dilute hydrochloric acid and then with water, dried over anhydrous Mg804, and the filtered filtrate was evaporated to dryness to give a solid of 0.156 cm.
When recrystallized from petroleum ether with a boiling point of 60-80°C, androst-4- with a melting point of 153-155°C
ene-16,+6--) methyl-17β-ol-3-
0.1009 of white needle-like crystals of onacetate were obtained.

The following compounds were prepared in the same way.

Preparation Example 7a Androst-4-ene-16゜16-dimethyl-17β-ol-3-one hexanoate Melting point of product recrystallized from methanol: 105-10
7℃ EnProstau 5-en-3,3-ethylenedioxy-
0.52 of the 16,16-dimethyl-1 phoon was dissolved in dry ether, kept under a nitrogen atmosphere, and dissolved in a large excess of methyllithium (2011 L of a 1.75 M solution in hexane).
was added over a period of 10 minutes, resulting in an immediate precipitate.

The mixture was stirred at room temperature for 2 hours, then the excess methyllithium was decomposed by carefully adding water, the product was extracted with ethyl acetate, the organic phase was washed with water and anhydrous Mg80
4 and evaporated to dryness to obtain 0.51 t of white solid. When this solid is recrystallized from petroleum ether with a boiling point of 60-80C, androstate with a melting point of 170-t'yiC is obtained.
5-ene-3,3-ethylenedioxy-16°16.1
White crystals of 7α-trimethyl-17β-ol 0.40
Get f.

Creation Example 9 H androst-5-ene-3,3-ethylenedioxy-
16,16,17α-trimethyl-17β-ol1.
Tokashi I P in methanol 50-, 2.5N salt *zo
mz was added and the mixture was heated to reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate, organic 1 was washed with water until neutral, dried over anhydrous MgF302, filtered and the filtrate was evaporated to dryness to yield 0.94 f of a crude solid. When this solid is recrystallized from petroleum ether with a boiling point of 60-80°C, flaky androst-4-
; No. 16.16.1 0.549 of α-trimethyl-17β-ol-3-one was obtained.

Production example 10 5α-antrostane-■7β-ol-3-one8.
34 ft - Trim 375 d of dry benzene, add 5 t of ethylene glycol in 50 d of dry benzene, then add 0.10 ff of toluene p-sulfonic acid, and remove the water from the mixture using a Jean-Starck apparatus. While doing 1
Heated at reflux for 0 h, 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 Mg804. The mixture is filtered, the filtrate is evaporated to dryness, and the resulting solid is recrystallized from methanol to give white crystals of 5α-eneProstan-3,3-ethylenedioxy-17β-ol 7 with a melting point of 170-172°C. I got .32.

Production Example 11 2 t of 5α-eneProstane-3,3-ethylenedioxy-7β-ol was heated under reflux in 350 d of dry benzene for 4 hours to oxidize it with silver carbonate supported on diatomite, and the reaction mixture was filtered. The filtrate was evaporated to dryness and the resulting solid was recrystallized from methanol, with a melting point of 156~
Colorless crystals of 5α-ene Prostan-3,3-ethylenedioxy-17-one at 157.5°C 2? Got nine.

Preparation Example 12 Using the method of Preparation Example 3, dry TetrahyP Lofuran 5
2.4f of 5α-antrostane-3,3-ethylenedioxy-17-one in 0d was heated under reflux for 4 hours with 2t of sodium hydride and 12p of methyl iodide, and the resulting off-white solid 2.782g was dissolved in methanol. Recrystallization from 5α-antrostane-3,3-ethylenedioxy-I6. with a melting point of 153-155°C. 1.9r of white crystals of t6--j methyl-17-one were obtained.

Production Example 13 0'H 5α-antrostane-3,3-ethylenedioxy-1
6,16-dimethyl-1 phon 2? Dry the ether 14
0 rfLg and reduction with sodium lithium hydride using the method of Group 1 Example 4 to give 1.89f of a crude white solid containing the main component and a small fraction. This mixture was subjected to column chromatography on silica, and the main component was recrystallized from petroleum ether with a boiling point of 60-80°C.
Colorless needle-like crystals of ethylenedioxy-16,16-dimethyl-17β-ol, 1? I got it.

Production Example 4 Using the method of Production Example 5, 5α-antrostane-3
,3-ethylenedioxy-to,to-dimethyl-17
β-ol t, St was heated under reflux for 1 hour with 120 methanol and 6 rnl of 2.5N hydrochloric acid.

1.56 t of the crude solid obtained is recrystallized from petroleum ether with a boiling point of 60-80°C, giving a melting point of 184-185.
1.45f of white crystals of 5α-antrostane-16,16-dimethyl-17β-ol-3-one were obtained.

Production Example 15 ■ Using the method of Production Example 6, 5α-antrostane-3
, 3-ethylenedioxy-16,16-dimethyl-1 phoon o, 5? 40ml of methanol and 5ml of 2.5N hydrochloric acid
The resulting solid was heated under reflux for 1 hour with a boiling point of 60-80.
When recrystallized from petroleum ether of c., melting point 135-1
White plate-like crystals of pure 5α-antrostane-16,16-dimethyl 3.17-dione at 37°C 0.4? I got it.

Production Example 16 000(OH2)50H3 ■ 5α-Anthrostane-r6. x6-) methyl-17β
- 0.22 of ol-3-one in dry benzene 7- with 0.6 d of heptanoyl chloride and 0.3 m of pyridine and 1.5
Heat at reflux for an hour, add excess
Dry with gBO4.

The mixture is filtered, the filtrate is evaporated to dryness, and the resulting solid is recrystallized from methanol and water, with a melting point of 74.5-7.
0.189 of white plate-like crystals of 5α-antrostane-16°16-dimether-17β-ol-3-oneheptanoate at 5.5°C were obtained.

Production Example 17 H 5α-antrostane-3,3-ethylenedioxy-t
6. t6-J methyl-17-o, 70.25 t dissolved in 20 ml of dry ether and using the method of Preparation Example 8,
1.75 M methyllithium solution in hexane 2nd
Crude solid obtained by treatment with 0.259 f boiling point 60 ~
Recrystallized from petroleum ether at 80°C, melting point 142~
Preparation Example 18 H Using the method of Preparation Example 3, 5α- Anthrostan-3,
3-C ethylenedioxy-16,16,17α-trimethyl-17β-ol 0.759 with methanol 55- and 2
．． Heating at reflux for 10 minutes with 3 WLt of 5N hydrochloric acid, 0.5 t of the resulting crude solid was recrystallized from petroleum ether with a boiling point of 60-80 C to give 5α- with a melting point of 152-153.5 C.
Anthrostane-16゜16.17a-)dimethyl-1
0.4 f of white plate-like crystals of fluor-β-ol-3-one were obtained.

Example 1 Pharmacological Data 1, Androgen-Assimilation Test and Anti-Endrogen Test The method used was basically the method of Hershber-geret et al. with slight modifications.
al,, Proc, Boc, Kxp+Bic
1. Med.

1953.83.175).

Immature male rats weighing 50 to 609 kg were anesthetized with Nembutal, and both ridges were removed. Starting from the 5th molar of the tube after removal, the drug was administered for 4 days, and the weight of the mice during the administration period was recorded. The mice were killed 10 days after removal, and the total weight was 1.
The weights of the 7c1 spermatozoa, abdominal wall prostate, single segment, and thymus were measured.

These data were compared to those of control animals.

The test compound is prepared in solution or suspension in peanut oil;
Administer by subcutaneous injection.

Androgen-anabolic test For this test, the test compound was administered by subcutaneous injection at a dose of 501n9/Kg, and the results
Results were compared to control animals treated with testosterone at Kq. Each set of data was compared with data from control animals in which the Ryōbimaru was removed and no drug was administered.

Anti-enzyme Progen Test For this test, compounds were administered by subcutaneous injection at a dose of 50 #/Kg at the same time as 1 #/Kg of testosterone (1 ~/Kg).
9)? Inhibition & was determined compared to control animals injected subcutaneously. Each set of data was compared to data from control animals that were enucleated and received no medication.

Table 1.2 Androgen Replacement Test This book replaces (3H)-5α-dihydrotestrone from the tongue protein, which binds with high affinity to cytosolic androgens isolated from the rat prostate and episternal glands. The ability of the compounds of the invention was evaluated by the method of Mainwaring et al.
, r , P , Ma inwar ing.

F, R, Mangan, P, A, Feherty an.
d M, Freifield.

Mo1ecular and Cal1ular En
docrinology.

1974.1, 113-1283, and was investigated in a test tube test.

A sample of 0.1 rnl of cytosol was mixed with 5XlO-''M (
3H)-5α-dihydrotestosterone (470i/mmol, The Radiochemicajceutr)
e.

(obtained from Amersha am) alone or in the presence of 5X10. 5X10 and 2.5X
After overnight incubation with the test compound in an amount of I 0-7 M, the ability to displace (3H)-5α-DHT Q from bound tannosoriplasm was measured as the decrease in counts emerging from the supernatant.

Table 2 Androgen-binding tannosori quality (7) (
3n)-sα-dihydrotestosterone substitution -5α-DHT 9 degrees 5X10-10M3,
Inhibition of Testosterone 5α-Reductase Determination of reductase activity is essentially performed by the method of Mainwarning et al.
, 1. P, Mainwaring and F.

R, Mangan, J, Endocrinolog
y, 1973, 59.

121-139).

In this test format, the conversion rate of Testostostrone (T) to 5α-dihydrotestosterone (DHT) was 15-30% for various formulations. Conversion suppression rate is DHTIICrJ
14% reduction in cpm; 1° inhibition rate - Conversion rate when no compound is used (@ - conversion rate when compound is used
Conversion rate (%) when no punitive compound is used The number in parentheses in Table 3 represents the number of experiments.

In hamsters, the growth of the flank organs (sebaceous glands) is stimulated by topical application of testosterone.

Indachi, Endocriuology, 19
72, 90, 73-80), testosterone is 5α in the sebaceous gland, which is currently considered to be the active androgen in most androgen-derived target organs.
-converted to dihydrotestosterone. The ability of the compounds of the present invention to inhibit this stimulation is essentially the method of Voigt et al. (W, Voigt and 8.L, Hsia.

Kndocrinology 1973, 92.121
Please be sure to measure using 6-12223. -fil? The male hamsters were subjected to incubation, and then both densities 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 gold containing testosterone 4 mμ/day in the right flank organ. The third group received acetone alone in the left flank organ and 4 mμ of testosterone in the right flank organ.
7 days and acetone containing 400 mμ/day of the compound of the invention.

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 the stimulation of sebaceous glands by testosterone. Histological examination confirmed that there was a significant reduction in the size of the sebaceous glands in the flank organs.

5. The ability of compounds to influence murine sebum secretion is essentially a method of nibbling (P,, r.

Ebling, J., of engineering research.
e Derma tology L974, 62. L6L
-171 and references cited in this report).

The compounds of Preparation Examples 5, 6 and 9, especially the compound of Preparation Example 1, are highly effective in inhibiting testosterone-stimulated sebum secretion in amphiectomized male rats given subcutaneous injection of 25/K9. Although effective, it is not effective in suppressing sebum secretion stimulated by 5α-dihydrotestosterone at the same dose. This seems to indicate that these compounds act through inhibition of 5α-reductase, but not through the entire anti-androgen mechanism, which has long been known. It will be done.

6. Toxicity No signs of toxicity were observed when the compound of Preparation Example 5 was orally administered to mice of Notes musculus in doses up to 900 ml/9.

Claims (2)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_3 is a C1-4 alkyl group, C_3 alkenyl group, or benzyl group, R_4 is a hydroxyl group, and R_5 is a a methyl group or hydrogen, or R_4 and R_5 together with the carbon atom to which they are attached represent a carbonyl group) and a pharmaceutically acceptable carrier for skin diseases originating from androgens. A pharmaceutical composition for the treatment of. (2) The pharmaceutical composition according to claim 1 for topical administration to the skin in the form of a cream or ointment.