DK143757B - ANALOGY PROCEDURE FOR THE PREPARATION OF 16,16-DISUBSTITUTED 3-OXOANDROSTEN - Google Patents

Description

(19) DENMARK (^)

| J | 02) PRESENTATION WRITING ου 143757 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 1234/76 (51) (^ .α.3 C 07 J 1/00 (22) Filing Day ^ 9 · ♦ 1 97 6 (24) Race Day 19 * ®ar. 1976 (41) Aim. available 22 p. 1976 (44) Submitted 5 · Oct. 1981 (86) International Application no.

(86) International Filing Day (85) Continuation Day “(62) Application No. ~

(30) Priority Mar 21 1975, 1986/75, GB

(71) Applicant BEECHAM GROUP LIMITED, Brentford, GB.

(72) Inventor Frederick £ asfsidy, GB.

(74) Plougmann & Vingtoft Patent Tur eau.

(54) Analogous procedure for the preparation of 1 6.1 6-disubstituted 3-oxoandrostens.

The present invention relates to an analogous process for the preparation of novel compounds having a pharmaceutical effect, namely 16,16-disubstituted 3-oxoandrostenes, which can be used to treat androgen-dependent skin disorders.

Many skin disorders, e.g. acne and seborrhoea, are believed to occur due to unusually large sebum secretion from the sebaceous glands

Mk U under androgenic stimulation. It is now believed that testosterone, D the major circulating androgen, is converted to 5α-dihydrotestosterone (DHT) on androgen receptor cells, and that DHT is therefore the biologically active androgen causing this stimulation. The enzyme ιέ 2 2 t43757 4 that induces this conversion is Δ -3-ketosteroid-5α reductase.

Therefore, it is clear that a compound which can inhibit the action of this enzyme on circulating testosterone, or which has anti-androgenic effect by virtue of its ability to compete with DHT for the receptor positions, can be used to treat the aforementioned skin disorders.

It has now been found that certain novel androstens which are related to testosterone but di-substituted at the 16-position with certain hydrocarbon groups have 5α-reductase inhibitory effect and that the corresponding androstanes are weak anti-androgens in effect. of their ability to compete with DHT for the receptor positions. These androstenes also have a very weak anti-androgenic effect of this competing species. These steroids can therefore be used to treat the above-mentioned skin disorders, e.g. acne and seborrhoea. It is believed that treatment for other androgen-dependent disorders associated with the skin and hair follicles, e.g. hirsutism in women, androgenic alopecia and masculine baldness pattern in women are also possible with these steroids.

It is known (W. Voigt and S.L. Hsia, Endrocrinology, 1973, 92, 1216 -1222) that 4-androsten-3-one-17β-carboxylic acid of formula A and its methyl ester listed below has 5α-reductase inhibitory effect.

^^ COOH

However, these two compounds are structurally less closely related to the androstens produced by the process of the present invention than testosterone used as the standard reference androgen.

It is also known from United States Patent No. 3,853,926 that 173-hydroxy-16,16-dimethyl-estr-4-en-3-one of formula B

3 143767

OH

is an anti-androgen and can suppress sebum secretion in rats.

The steroid B is an ester, while the unsaturated steroids produced by the method of the invention are androstenes. The fact that 19-nor-testosterone, an ester, and most of its derivatives are progestogens, and that testosterone, an androsterone, is an androgen, clearly shows that there is no certainty of predictable pharmacological action from one to the other. second class of steroids.

The present invention relates to an analogous process for the preparation of compounds of general formula I

wherein R is alkyl having 1-5 carbon atoms, alkenyl having 3-6 carbon atoms or phenylalkyl, wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is optionally substituted with alkyl 4 having 1-4 carbon atoms, halogen or nitro; R represents hydroxy 6 or a group OR, wherein R represents acyl of 2-7 carbon atoms, alkyl of 1-4 carbon atoms or optionally in the phenyl nucleus of alkyl of 1-4 carbon atoms, halogen or nitro substituted benzyl; R represents hydrogen or alkyl of 1 to 5 carbon atoms; Or R and R together with the carbon atom to which they are attached form a carbonyl group.

In formula I, R will often be an alkyl group having 1 to 5 carbon atoms or a phenylalkyl group wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl group is optionally substituted.

3

Suitable examples of R are the following groups: methyl, ethyl, propyl, benzyl and phenylethyl. The phenyl moieties of the benzyl and phenylethyl groups may be substituted by an alkyl group of 1-4 carbon atoms, halogen or a nitro group. R can also conveniently be an allyl or butenyl group. Preferably, R- is a methyl, ethyl or n or isopropyl group, especially a methyl group.

4 o 4

It is particularly convenient that R is a hydroxy group. When R imide is a group OR, suitable examples of R are the following groups: acetyl, n- and isopropionyl, n-, sec- and tert-butyl, caproyl, heptanoyl, methyl, ethyl, n- and isopropyl and n-, sec- and t-butyl and benzyl. The phenyl moiety of the benzyl group may be substituted by alkyl of 1-4 carbon atoms, halogen or nitro.

Suitable examples of r ~ * are hydrogen, methyl, ethyl, n- and isopropyl and n-butyl. Preferably, R 5 is hydrogen or methyl, especially hydrogen.

Within the compounds of formula I, a particularly preferred class of compounds are those having the general formula III

* lc 11 L ~ - -r11 \ ch. wherein R 10 represents hydroxy optionally acylated with acyl of 2 to 7 carbon atoms, R 2 represents hydrogen or methyl, or R 10 and R 2 together with the carbon atom to which they are attached form a carbonyl group .

R "may be, for example, hydroxy, acetoxy, n- or isopropionyloxy, ca-proyloxy and heptanoyloxy.

Preferably, R 5 is a hydroxy group.

Preferably, R 11 is hydrogen or methyl, or R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group. R 2 is a hydrogen atom in particular.

Due to the particularly good action exhibited by such compounds, a preferred embodiment of the process of the invention is to prepare a compound of general formula III wherein R 10 represents hydroxy or caproyloxy and R 5 represents hydrogen.

A compound which has the general formula III and which is particularly useful by virtue of its 5-α-reductase inhibitory effect is androst-4-ene-16,16-dimethyl-173-ol-3-one.

The process of the invention for the preparation of compounds of general formula I is characterized in that 1 is a compound of general formula IV 4

IV

Where X represents protected carbonyl and R, R and R have the meaning set forth in formula I, the protecting group is removed to form an unprotected carbonyl group at the 3-position f 4 and then, if desired, a hydroxy group R is converted to a group OR6 by acylation or etherification in a manner known per se.

The bond of formula IV is rearranged during the reaction to remove the protection to give the desired 4.5 bond in the product.

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The method of the invention is a conventional removal of the protection from a protected carbonyl group. The group X may thus be a ketalized carbonyl group, e.g. O (CHO) C, where n is 2 n / 2 or 3, or R'X ^ C, where R'X is an alcohol or thiol residue (X is oxygen or sulfur, respectively), in which case the removal of the protection conveniently carried out by acid hydrolysis; or it may be a thioketalized carbonyl group, e.g.

/ ° \ (CH-),; C or (CHO) x C, where n is 2 or 3, in which case the 2 n \ X 2 X / s xs trap removal of the protection can conveniently be performed using mercuric salts or by acid hydrolysis.

After removing the protection, the following optional steps can be performed: o 4 5 4 When R and R do not form a carbonyl group, the group R can be varied in the usual manner. Eg. For example, compounds of formula I wherein 4 R is an acylated or etherified hydroxy group may be prepared by conventional acylation or etherification of compounds of formula 4 I wherein R is a hydroxy group. Such reactions include reacting the hydroxy group with acyl chlorides or acyl anhydrides such as acetyl chloride or acetic anhydride under anhydrous conditions to form acyl derivatives, and reacting a sodium salt of the hydroxy group with an alkyl halide to form an etherified derivative.

The compounds of formula IV are novel and can be used as intermediates to form the pharmaceutically active compounds of formula I.

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The compounds of formula IV, in turn, can be prepared by a process consisting of the fact that in the 16-position of a compound of the general formula V

3 is substituted with the desired groups R and then, if desired, the 17-4 carbonyl group is converted to other groups R and R in the usual .45 way. R and R have the meaning given in formula IV. Less preferably, the 16-mono-substituted intermediates can first be isolated and then further substituted at the 16-position.

The substitution reaction may conveniently be carried out by reacting 3 the selected compound of formula V with a compound R Y in the presence of a strong base which is only slightly nucleophilic. It is convenient that Y is a halide, tosylate, mesylate or azide, that the base is a hydride such as sodium hydride and that the reaction is carried out under anhydrous conditions.

The optional conversion of the 17-carbonyl group to other groups 45 R and R can be carried out using conventional methods. Eg.

45, compounds wherein R is hydroxy and R is either hydrogen or alkyl of 1 to 5 carbon atoms can be prepared from the corresponding 17-carbonyl compound either by reduction or by reaction with a C 1-6 alkyl-Grignatd reagent or a C ^, alkyl alkyl-metal complex (conveniently a C15 alk alkyl lithium complex). The reduction may conveniently be carried out using lithium aluminum hydride. Subsequently, the R hydro hydroxy group thus formed can, if desired, be itself acylated or etherified to form another group R as described above.

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The compounds of formula V can be prepared by oxidation of the corresponding 17-hydroxy compounds of general formula VI

OH

where X has the meaning given in the formula V, under neutral or basic conditions.

This reaction is conveniently carried out using either silver carbonate on an inert carrier such as diatomaceous earth or using Collins reagent, which is a mixture of chromium trioxide and pyridine in methylene dichloride.

The compounds of formula VI can be prepared by protecting the carbonyl group of the corresponding compound of formula VII

VI1

This reaction is carried out under usual conditions to form the desired protected carbonyl group X. If a ketalized carbonyl group is to be prepared, the compound of formula VII is reacted with a suitable alcohol or thiol in the presence of acid. In this way, use of e.g. ethylene glycol to a 3,3-ethylenedioxy carbonyl protecting group.

4.5- The bond is rearranged during the reaction to form a 5.6 bond.

It can be seen from the above that a particularly suitable preparative route for compounds of formula I is as shown in the diagram below:

OH

VI1 protection. v

OH

^ VI

oxidation

16,16 disubstitution 'V

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Continued R4 3 3 optional carbonyl conversion removing protection

The compound of formula I thus prepared can then, if desired, be converted to another compound of formula I as described above.

With the compounds of the process of the present invention, a pharmaceutical composition can be prepared which contains a compound of formula I together with a pharmaceutically tolerable carrier.

The present compounds will usually be formulated into a cream or ointment for topical administration to the skin. Therefore, a preferred composition is a pharmaceutical composition for topical administration to the skin which contains a compound of formula I which has been formulated into a cream or ointment.

Cream or ointment preparations which can be used for compounds of formula I are conventional compositions known in the art, e.g. preparations described in standard pharmaceutical and cosmetic works, e.g. Harry's Cosmeticology, published by Leonard Hiil Books, and British Pharmacopoeia. Simple examples of suitable formulations are those containing a standard emulsifying base ointment or anhydrous polyethylene glycol.

It is believed that some of the compounds of formula I are active when taken orally. Such compounds can therefore be formulated together with inert carriers for preparations which are usual for administration in this manner, e.g. tablets, capsules and syrups.

By administering an effective amount of a compound of formula I, androgen-dependent skin disorders can be treated.

The compounds of formula I are particularly valuable for the treatment of acne and seborrhoea.

Preferably, the compounds of formula I are topically administered to the affected skin.

The compounds of formula I have the advantage of providing effective relief in the treatment of androgen-dependent skin disorders, while apparently not having harmful hormonal side effects.

It is to be understood that one or more of the antibacterial agents commonly used in the treatment of acne and seborrhoea infections may be incorporated into the present compositions when these preparations are to be used for such treatment.

The process of the invention for the preparation of the compounds of formula I and the preparation of their intermediates for use therewith as well as pharmacological tests are further illustrated below:

Example 1.

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OH

Androstan-5-ene-3,3-ethylenedioxy-173-ol is prepared from androst-4-ene-173 ~ ol-3-one and is obtained in the form of fine white needles, melting point 185 - 186 ° C (of methanol / water ) using that of YES Campbell, J.C. Babcock and J.A. Hogg in J. Am. Chem. Soc., 1958, 80, 4717 - 4721 disclosed method.

Example 2.

ISLAND

20 g of silver carbonate on diatomaceous earth is dried by azeotropic distillation of any moisture present by means of benzene. The oxidizing agent is suspended in 200 ml of dry benzene and 1 g of androst-5-ene-3,3-ethylenedioxy-173 ° Ol is added to 50 ml of benzene and the mixture is refluxed for 4 hours. Complete oxidation is obtained. The reaction mixture is filtered and the filtrate is evaporated to give 0.95 g of androst-5-ene-3,3-ethylenedioxy-17-one in the form of fine white needles which after crystallization of methanol melt at 189 - 190 ° C.

13 143757

Complete oxidation can also be obtained using chromium trioxide and pyridine in ethylene chloride.

Example 3

2.92 g of androst-5-ene-3,3-ethylenedioxy-17-one is dissolved in 60 ml of dry tetrahydrofuran. 2.92 g of sodium hydride is added followed by 5 ml of methyl iodide and the reaction mixture is refluxed for 4 hours. The tetrahydrofuran is evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate phase is washed again with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 3.21 g of solid. This solid is recrystallized from methanol / water to give 2.4 g of androst-5-en-3,3-ethylenedioxy-16,16-dimethyl-17-one in the form of colorless crystals, mp 138 - 142 ° C.

Similarly, the following compounds are prepared:

Example 3a.

Androst-5-ene-3,3-ethylenedioxy-16,16-diallyl-17-one, m.p. 100-101 ° C (of methanol).

Example 3b.

Androst-5-ene-3,3-ethylenedioxy-16,16-dibenzyl-17-one, in the form of a white foam (infrared carbonyl absorption at 1725 cm 2).

Example 3c.

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Androst-5-ene-3,3-ethylenedioxy-16,16-di-n-butyl-17-one, mp 165 - 167 ° C (of methanol).

Example 3d.

Androst-5-ene-3,3-ethylenedioxy-16,16-diethyl-17-one, mp 146 -148 ° C (of methanol).

Example 4

OH

CH3 1.5 g of androst-5-ene-3-ethylenedioxy-16,16-dimethyl-17-one is dissolved in 100 ml of dry ether and 0.1 g of lithium aluminum hydride is added. The reaction mixture is stirred at room temperature for 30 minutes, after which the excess amount of hydride is decomposed by adding an excess of ethyl acetate. The mixture is then shaken with a solution of potassium sodium tartrate and the organic phase is separated and washed with water before being dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate to dryness afforded 1.47 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-173-ol in the form of a white powder which after crystallization of ethyl acetate melts at 178 - 179 ° C.

Similarly, the compounds listed below are prepared:

Example 4a.

Androst-5-ene-3,3-ethylenedioxy-16,16-diallyl-178-ol, m.p. 149 -151 ° C.

Example 5

Dissolve 1 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17i3-ol in 30 ml of methanol and add 5 ml of 2.5N hydrochloric acid solution. The mixture is refluxed for 1 hour to achieve complete hydrolysis of the ketal. The reaction mixture is taken up in excess ethyl acetate and washed with water for neutral reaction. The organic phase is dried over magnesium sulfate and filtered, and the filtrate is evaporated to dryness to give 0.88 g of a white solid. Recrystallization of petroleum ether (boiling range 60 -80 ° C) / ethyl acetate gives 0.76 g of androst-4-ene-16,16-dimethyl-17 | 3-ol-3-one in the form of white needles, melting point 170 - 172 ° C.

Similarly, the following compound is prepared:

Example 5a.

Androst-4-ene-16,16-diallyl-17 | 3-ol-3-one, which is a thick oil with infrared carbonyl absorption at 1680 cm ”1.

Example 6

ISLAND

ch3 16 1 * 3? " Dissolve 0.25 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one in 7.5 ml of methanol and add 1.5 ml of 2.5N hydrochloric acid solution. The solution is refluxed for 30 minutes and, after cooling, an excess of ethyl acetate is added. The organic phase is washed with water for neutral reaction, dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.2 g of a white solid which is recrystallized from petroleum ether (boiling range 60 - 80 ° C) to give 0 16 g of androst-4-ene-16,16-dimethyl-3,17-dione in the form of white needles, mp 164 - 165 ° C.

Similarly, the compounds listed below are prepared:

Example 6a.

Androst-4-ene-16,16-diallyl-3,17-dione, m.p. 118-120 ° C (of petroleum ether with boiling range 60 - 80 ° C).

Example 6b.

Androst-4-ene-16,16-dibenzyl-3,17-dione, m.p. 150 - 152 ° C (of petroleum ether with boiling range 60 - 80 ° C).

Example 6c.

Androst-4-ene-16,16-di-n-butyl-3,17-dione, in the form of a thick oil with infrared carbonyl absorptions at 1680 and 1720 cm

Example 6d.

Androst-4-ene-16,16-diethyl-3,17-dione, in the form of a semi-crystallized oil with infrared carbonyl absorptions at 1680 and 1720 cm 17

Example 7 · OCOCH 2 O 0.158 g of androst-4-ene-16,16 * -dimethyl-17 | 3-ol-3-one is dissolved in 4 ml of dry benzene and 0.14 g of dry pyridine and 0.12 are added. g of acetyl chloride. The mixture is refluxed for 30 minutes, cooled and poured into an excess of ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and then with water before being dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate to dryness afforded 0.156 g of a solid which was recrystallized from petroleum ether (boiling range 60 - 80 ° C) to give 0.100 g of androst-4-ene-16,16-dimethyl-17 | 3-ol-3-one acetate in the form of white needles, m.p. 153 - 155 ° C.

Similarly, the following compound is prepared:

Example 7a.

Androst-4-ene-16,16-dimethyl-17β-ol-3-one-hexanoate, mp 105 -107 ° C (of methanol).

Example 8.

CH3 0.5 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one is dissolved in dry ether and kept under a nitrogen atmosphere. A large excess of methyl lithium (20 ml of a 1.75M solution in hexane) is added over 10 minutes. A precipitate is formed immediately. The mixture is stirred for 2 hours at room temperature before the excess amount of methyl lithium is decomposed by gentle addition of water. The product is extracted with ethyl acetate and the organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.51 g of a white solid. This solid is recrystallized from petroleum ether (boiling range 60 - 80 ° C) to give 0.40 g of androst-5-ene-3,3-ethylenedioxy-16,16,17a-trimethyl-17β-ol in the form of white crystals, melting point 170 - 171 ° C.

Example 9. OH

Dissolve 1.1 g of androst-5-ene-3,3-ethylenedioxy-16,16,17a-trimethyl-173-ol in 50 ml of methanol and add 10 ml of 2.5N hydrochloric acid solution. The mixture is refluxed for 15 minutes. The product is extracted with ethyl acetate and the organic phase is washed to neutral with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate is evaporated to dryness to give 0.94 g of a crude solid. This solid is recrystallized from petroleum ether (boiling range · 60 - 80 ° C) to give 0.54 g of androst-4-ene-16,16,17a-trimethyl-170-ol-3-one in the form of white flakes with mp 165 - 166 ° C.

19 1437 57

Pharmacological description.

1. Androgenic / Anabolic Test and Anti-Androgenic Test.

The method used was basically that of Hershberger et al. in Proc.

Soc. Exp. Biol. Med., 8_3, 175, (1953), with minor modifications.

Non-sexually mature male rats weighing 50 - 60 g were castrated under nembutal anesthesia.- The animals were given medication for 4 days beginning on the 5th day after castration. The body weight of the animals was measured during the period of drug administration. On the 10th day after castration, the animals were killed and the weight of the sperm bladder, ventral prostate, levator ani muscle and thymus was measured, as was the whole body weight.

These data were then compared with data from control animals. The compounds were formulated as solutions or suspensions in arachis oil and administered subcutaneously.

Androgenic / anabolic experiment.

For this experiment, the compounds were given at a dose of 50 mg / kg subcutaneously, and the results were compared with control animals given subcutaneously with testosterone at a dose of 1 mg / kg. Both rows of data were compared with data from castrated control animals that did not receive medication.

Anti-androgenic trial.

For this experiment, the compounds were administered at a dose of 50 mg / kg subcutaneously equivalently with testosterone at a dose of 1 mg / kg subcutaneously to determine the degree of inhibition compared to control animals receiving testosterone at a dose of 1 mg / kg subcutaneously. Both rows of data were compared with data from castrated control animals that did not receive medication. The results are given in Table I below.

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Table I

Compound Androgenic Response, Anti-Androgenic Data, Percent Percent Inhibition Prepared Strength According to Test Specimen No. Ron Sperm Prostate Sperm Prostate 5 0.15 0.36 12.1 14.4 6. - 17, 8 35.0 9 - 6.5 19.7 cyproterone acetate 20 mg / kg - - 54.0 56.5 2. Androgen displacement test.

3

The ability of the compounds to displace [H] -5α-dihydrotestosterone from high affinity cytosol androgen binding proteins isolated from rat prostate and epididymis was investigated in vitro using that of W.I.P. Mainwaring, F.R. Manganese, P.A. Feherty and M. Freifeld in Molecular and Cellular Endocrinology, 1974, 1, 113 -128.

0.1 ml of cytosol samples were incubated overnight in the presence of -in in 5 x 10 M [H] -5α-dihydrotestosterone (47 Ci / millimole, The Radiochemical Center, Amersham), either alone or in conjunction with the compound to be was tested, at a concentration of 5 x 10 -7 -5 x 10 and 2.5 x 10 M. The ability of the compounds to displace 3 [H] -5a-DHT from the binding proteins could be seen as a decrease in the number of pulses that was bound in the supernatant fluid. The results are given in Table II below.

Table II

3

Percent displacement of [H] -5α-dihydrotestosterone from androgen-binding proteins 3-10

[H] -5a-DHT concentration 5 x 10 M

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Compound 2.5 x 10 5.0 x 10 5.0 x 1Q-Sl prosta-epi-pro-epi-pro-epi-didy-state didy-state didy-mis mis 5 36 0 50 4 81 64 6 16 0 27 0 80 48 9 32 0 46 4 88 81 DHT 86 72 86 75 90 83 3. Inhibition of testosterone 5α reductase.

4

The determination of the activity of this enzyme (β-ketosteroid-5α-reductase) was performed essentially as described by W.I.P. Mainwaring and F.R. Mangan, J. Endocrinology, 1973, 5JJ, 121-139.

The percentage conversion of testosterone (T) to 5α-dihydrotestosterone (DHT) in this system ranged from 15 to 30%, depending on the different formulations. Inhibition of the conversion was found by a reduction in the number of pulses per second. minute associated with DHT.

% conversion = -CP11), D.HT- x10%

cpm T + cpm DHT

% conversion without connection -% conversion with fc? r-% inhibition = --- ffXa & Slae% conversion without connection (cpm = number of pulses per minute)

The results are shown in Table III and Table IV below.

Table III

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Compound% inhibition of 5α-reductase -5

compound in 1 x 10 M

30.0 (3) 6 23.1 (2) 9 27.3 (2)

Table IV

Compound% inhibition of 5α-reductase -4

concentration 1 x 10 M

androst-4-ene-16,16-dimethyl-170-ol-3-one 58.0 (7) androst-4-ene-16,16-dimethyl-3,17-dione 56.8 ( 3) androst-4-ene-16,16,17a-trimethyl-17β-ol-3-one 48,9 (3) andro-t-4-ene-16,16-dimethyl-17β-α1-3 -οη-17-methyl ether 52,7 (3) androst-4-ene-16,16-dimethyl-173-ol-3-one-17-benzyl ether 41,2 (3) androst-4 -en-16,16-dimethyl-173-ol-3-one-17-hexanoate 65,4 (3) androst-4-ene-16,16-diethyl-173-ol-3-one 44 , 7 (3) 23 143757

Table IV continued androst-4-en-16,16-diethyl-3.17-dione 28.1 (3) androst-4-en-16,16-diallyl-17β-ο1-3-οη 27,6 (3) androst -4-en-16,16-diallyl-3.17-dione 15.0 (3) androst-4-en-16,16-dibenzyl-3.17-dione 26.4 (3) () The numbers in the parentheses indicate the number of attempts .

4. The effect of the compounds on the testosterone-induced growth of an organ on the side of a hamster.

In castrated male hamsters or unoperated female hamsters, the flank organ (a sebaceous gland) can be stimulated for growth by topical application of testosterone. Testosterone is converted in this gland to 5α-dihydrotestosterone (S. Takayashu and K. Adachi, Endocrinology, 1972, 90 73-80), which is now believed to be the active androgen in most androgen-dependent receptor organs. The ability of the compounds to inhibit this stimulation was examined essentially using that of W. Voigt and S.L. Hsia, Endocrinology, 1973, 92, 1216 - 1222, stated method.

Adult male hamsters were castrated by the scrotal pathway. 1 week later, they were divided into groups of 4 animals and treated as follows: one group was not treated. Another group received only acetone on the flank of the animal on the left side and acetone containing 4 µg of testosterone per day. day on the right flank organ. Other groups received acetone alone on the left side flank and acetone containing 4 µg testosterone plus 4 µg / µg compound per day. day on the right flank.

After 3 weeks of treatment, the animals were killed and the organs measured and placed in fixative for histological examination. >

Claims (4)

An active compound could inhibit the testosterone-induced growth of the flank organ. Some of the compounds, especially compounds 5, 6 and 9, were very effective in inhibiting the glandular stimulation induced by testosterone. Histological examination confirmed that there was a significant reduction in flank organ sebaceous size. 5. The effect of the compounds on rat sebum secretion. The ability of the compounds to inhibit sebum secretion in rats was determined essentially by that of F.J. Ebling, J. of Investigative Dermatology, 1974, 62, 161 - 171 and references thereto, method cited. Some of the compounds, e.g. Compounds 5, 6 and 9, especially Compound 5, were very effective in inhibiting testosterone-stimulated sebum secretion in castrated male rats when given at a dose of 25 mg / kg subcutaneously, but were unable to inhibit 5α-dihydrotestosterone-stimulated sebum secretion at the same dose level. This could indicate that such compounds act via 5α-reductase inhibition and not via a classical anti-androgenic mechanism. 6. Toxicity. Toxic symptoms were not found when compound 5 to mice was given at doses up to 900 mg / kg orally. Claims. An analogous process for the preparation of 16,16-disubstituted 3-oxoandrostenes of the general formula I wherein R represents alkyl of 1-5 carbon atoms, alkenyl of 3-6 carbon atoms or phenylalkyl 3 carbon atoms and the phenyl moiety is optionally substituted by alkyl 4 with 1-4 carbon atoms, halogen or nitro; R represents hydroxy 6 or a group OR, wherein R represents acyl of 2-7 carbon atoms, alkyl of 1-4 carbon atoms or optionally in the phenyl nucleus of alkyl of 1-4 carbon atoms, halogen or nitro substituted benzyl; R represents hydrogen or alkyl of 1 to 5 carbon atoms; 45 or R and R together with the carbon atom in which they are attached form a carbonyl group, characterized in that in a compound of the general formula IV in IV x 3 4 5 where X represents protected carbonyl and R R and R are as defined in formula I, the protecting group is removed to form an unprotected carbonyl group at the 3-position, whereupon, if desired, a hydroxy group R4 is converted to a group OR ^ by acylation or etherification per se known way.