BG61244B2 - 4-AZA-17BETA-SUBSTITUTED-5ALPHA-ANDROSTANE-3-OH-REDUCTASE INHIBITORS - Google Patents

Abstract

1. Compounds of general formula such as formula i may also have the structure of fragments ii and/or iii in which a denotes (1) -cn 2 -cn 2 -; (2) -sn=sn-; (3) or (4) in means (1) (2) z means (1) -hydrogen or -hydroxyl and (a) (2) or ch-alk-or12 in which alk is present or absent, (3) in wherein the dotted bond replaces 17 hydrogens, (4) -hydrogen and wherein r13 is (a) C1-12 alkyl or (c) nr9r10, (5) -hydrogen and cyano, or (6) -hydrogen and tetrazolyl, and pharmaceutically acceptable salts of the indicated compounds. 19 claims

Description

The invention relates to novel 4-aza17p-substituted-5a-androstan-3-ones and their A-homologs and their use as 5α-reductase inhibitors.

Some undesirable physiological manifestations such as acne vulgaris, seborrhea, female hair and male pattern baldness and mild (benign) prostatic hypertrophy are known to result from hyperandrogenic stimulation caused by excessive accumulation of testosterone or similar metabolic hormones. Early attempts to provide a chemotherapeutic agent to eliminate the undesirable effects of hyperandrogenism led to the discovery of several steroidal anti-androgens that exhibited their own unwanted hormonal effects. Estrogens, for example, not only counteract the androgen effect, but also exert a feminizing effect. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethylisobutyranilide. See Neri et al., Endo, Vol. 91, No. 2 (1972). These compounds, although devoid of hormonal effects, are peripherally active, competing with natural naturally occurring androgens for receptor sites, and thus tend to feminize the male set or the male germ in the female set.

Recently, it has become known that the major mediator of the androgenic activity of certain organs is 5α-dihydrotestosterone and that it is locally formed in a specific organ by the action of testosterone 5α-reductase. It is therefore understood and demonstrated that testosterone-5 α-reductase inhibitors serve to prevent or reduce the symptoms of hyperandrogenic stimulation. Nayfen et al., Steroids, 14, 269 (1969) have demonstrated in vitro that methyl 4-androsten-3-one-17β-carboxyl is a testosterone 5 α-reductase inhibitor. Later, Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Patent No. 970 692, demonstrated that the above ester and the free acid, 4-androsten-3-one 17P-carboxylic acid, were active inhibitors of testosterone 5a-reductase IVF. External administration of both testosterone and 5α-dihydrotestosterone increase the weakening organ of female hamsters, an androgen-dependent fat structure. Thus, concomitant administration of 4-androsten-3-one-17P carboxylic acid or its methyl ester inhibits testosterone-induced effects but does not inhibit 5 α-dihydrotestosterone effects. These results indicate that the compounds are antiandrogenic due to their ability to inhibit testosterone 5α-reductase.

The novel compounds of the invention are potent anti-androgens due to their ability to specifically inhibit testosterone-5α-reductase.

The use of 4-aza-17substituted-5a-androstan-3-ones is not known to treat hyperandrogenic conditions, although Selly in Belgian Patent No. 775,919 describes such a compound and a number of other compounds additionally having one or more carbonitrile substituents, as catatoxic compounds useful in the treatment of other conditions of prostate hypertrophy.

A large number of 4-aza steroid compounds are known. For example, US Patent Nos. 2,227,876, 3,239,417, 3,246,301 and 3,285,918, French Patent No. 1,465,544, Doorebos and Solomons, J. Pharm. Sci. 62, 4 pp. 638-640 (1973), Doorebos and Brown, J. Pharm. Sci. 60, 8, pp. 1234-1235 (1971), and Doorens and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974). None of the known compounds suggest the 4-aza compounds of the invention and their use in the treatment of hyperandrogenic conditions.

The invention relates to novel anti-androgen 4-aza-17P-substituted-5a-androstan-3-ones, their A-homoanalogues, certain isosters and their derivatives, a method for their preparation, pharmaceutical forms of administration containing, as active ingredient, the novel compounds, and a method for inhibiting 5 α-reductase and treating hyperandrogenic conditions with new compounds or pharmaceutical compositions containing them. The invention relates to novel compounds of formula 5

(II) (III) in which formula I may also have the structure of partial formulas II and / or III in which

A is 1 / -CH ₂ -CH ₂ -, 25

2 / -CH = CH-,

3 / CH ₃ - C - CH ₂ -; 1 2 30 CH _? —CH --- CH— 4 /

Bel / in which R ¹ is

a) hydrogen, c) methyl or ethyl, c) ethenyl, d) ethynyl, is (NR ² R ³ ) in which R ² and R ³ are hydrogen or 45 methyl or f / cyano, or

2 /

wherein X is any anion and R ⁴ is a / OR ⁵ in which R ⁵ is C _1-4 alkyl, or in / NR ⁶ R ⁷ in which R ⁶ and R ⁷ are hydrogen, methyl, ethyl, hydroxyl or one of them may be missing, in which case the nitrogen atom is bonded by a double bond to the unloaded A-ring,

R 'is hydrogen or methyl,

R ”is hydrogen or β-methyl,

R '' - β-methyl or hydroxyl,

Z is 1 / oxo,

2 / β-hydrogen or α-hydroxyl, 3 / α-hydrogen or α-hydroxyl, and α /

O ¹¹ alkyl-C-k in which alkyl may or may not be present and has a straight or branched hydrocarbon chain of from 1 to 12 carbon atoms, and R ⁸ is

1 / hydrogen,

II / hydroxyl,

III / C _2-4 alkyl,

IV / NR'R ¹⁰ in which R 'and R ^{10 are} each independently selected from hydrogen, C ₁₄ straight or branched alkyl, C ₃₆ cycloalkyl, phenyl, or R' and R ¹⁰ taken together with the nitrogen atom to which they are attached, represent a 5-6 membered saturated ring joining any other heteroatom selected from oxygen and nitrogen, or V / OR ¹¹ in which R 'is M, where M is hydrogen or an alkali metal, or C _{( 18} straight or branched alkyl;

B / alk-OR ¹² , where A1k is always present and has the same meaning as above, and

R ¹² is

I / phenyl C alkylcarbonyl,

II / C ₅₁₀ cycloalkylcarbonyl,

III / benzoyl, or

IV / C _{] 8} alkoxycarbonyl;

V / amino or C] _lg alkyl substituted amino, carbonyl, or

VI / hydrogen, with the proviso that A1k is a branched C ₃ chain;

4 / o A ¹¹

CH-Aak-CR ⁸ or CH-alk-OR ' ² in which alk. is present or absent and has the same meaning as above, and R ⁸ and R ¹² have the same meaning as above, and R ¹² is also hydrogen or C ₁₂₀ alkylcarbonyl;

in which the link indicated by the dashed line replaces 17hydrogen;

6 / α-hydrogen and in which R ^'3 is a / C _{[| 2} alkyl, or / NR'R ^10;

7 / α-hydrogen and cyano, or

8 / α-hydrogen and tetrazolyl, and pharmaceutically acceptable salts of the above compounds.

Unless otherwise noted, both stereo configurations a and β are considered for the different substituents.

The anion, X _o, A-ring quaternary nitrogen compounds described above may be any suitable pharmaceutically acceptable anion, for example, as described below with regard to pharmaceutically acceptable salts.

The compounds of formulas I, II and III can be used as salts derived from inorganic or organic acids. These include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, cyclopentan propionate, digluconate, dodecyl sulfate, furan , hydrobromide, hydrogen iodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2naphthalenesulfonate, nicotinate, oxalate, ramoate, rectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, propionate, propionate, propinate In addition, the major nitrogen-containing groups can be quaternized with such compounds as lower alkyl halides, for example methyl, ethyl, propyl and butyl chloride, bromides and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulphate halogens for example, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl 5 and phenethyl bromides, etc. Water or oil-soluble or dispersible products are thus obtained.

The new compounds have the following preferred structural formula I wherein R ¹ is 10 hydrogen, methyl or amino, and T is CONHCH ₂ CH ₃ , CHCHCH 3, ----, θ <..! ^sos * “ ^s - ° ^ch >

Even more preferred form of the novel compounds is that in which R ¹ is methyl and T CONHCH ₂ CH ₃ or con / ch ₂ ch _3/2.

Representative compounds of the invention include, but are not limited to:

17 p-N, N-diethylcarbamoyl-4-methyl-4aza-5 α-androstan-3-one

RM, N-diethylcarbamoyl-4-aza-5a-androstan-3-one

17β-N, N-diethylcarbamoyl-4-amino-425 aza-5 α-androstan-3-one

4-aza-5a-20-spiroxan-3-one 4-methyl-4-aza-5a-20-spiroxan-3-one p-N-ethylcarbamoyl-4-methyl-4-aza-5 a-androst-3 -on

4-methyl-4-aza-5a-pregnan-3,20-dione

4-ethyl-4-aza-5a-20-spiroxan-3-one p-carbomethoxy-4-methyl-4-aza-5a-androstan-3-one

The new compounds of formula I according to the invention 35 may be prepared by a method comprising the steps of:

1. Treatment of a 4-androsten-3-one derivative with an oxidizing agent such as ozone at reduced temperatures from about -70 to

-80 ° C to form 5-oxo-3,5-secoandrostan-3-oic acid compound.

2. Reaction of the product of the secoandrostanoic acid compound from step I with a suitable amine to form a 4-substituted-4-aza-5-androsten-3-one compound.

3. Reaction of 4-aza-5-androsten-3-one with hydrogen in the presence of a catalyst for the formation of a 4-aza-5 α-androstane-3-one compound of formula I. These reactions are presented schematically as follows chart:

The new compounds of formula I which incorporate in their structure the structure of the partial formula II according to the invention, i. A-homo analogs can be obtained by a method comprising the steps of:

1. Reaction of testosterone with ethanedithiol in the presence of boron trifluoride etherate to form a 3-dithioketal derivative of testosterone.

2. Impact on product from stage

1. with sodium and liquid ammonia to remove the 3-dithioketal substituent.

3. Impact on stage product

2. with dihydropyran in the presence of p-toluenesulfonyl chloride to form a 17-tetrahydropyranyloxy derivative.

4. Reaction of the product from step 3. with borane and then with sodium hydroxide and hydrogen peroxide to form a 4-hydroxy-5? -Hydrogen compound.

5. Reaction of the product of step 4. with chromium trioxide to give 4-ketone compound.

6. Treatment of the product of step 5. with acid to remove the 17-tetrahydropyranyl protecting group and to form a 17-hydroxy compound.

7. Reaction of the product of step 6. with benzoyl chloride to give 17-benzoate.

8. Reacting the product of step 7. with hydroxylamine hydrochloride to give a 4oxime compound.

9. Reacting the product of step 8. with thionyl chloride and then with potassium to give a compound of formula II, an A-homo-4-aza-compound. The reactions listed are schematically presented in the following diagram:

V

The new compounds of formula I which include the structure of the partial formula III according to the invention, i. D-Homo analogues can be prepared by a number of known methods, including. those described in J. Steroid Biochem., Vol.5, No. 4, p. 298 (June) 1974 by Alig et al. and Kerb et al., and in Helv. Chim. Acta, Vol. 23, pp. 376-384 and 840-845 by Goldberg and Mannier.

Novel compounds of the invention with a 1,2 α-methylene substituent, i. where A is

SI _? * h —s ——— 'ss — can be obtained according to conventional methods, i. e. described in Chemical and Industry, p. 1710 (October 10, 1964) by Loev et al.

New compounds of the invention which are Δ1, i. wherein A is -CH = CH-, and in which the 4-nitrogen atom bears a substituent other than hydrogen, can be prepared according to the method described in Example 15, which follows. The new compounds in which the 4-nitrogen atom is only replaced by hydrogen can be prepared according to the method described in Example 16. The preferred method of preparing 17βΝ, Ν-diethyl carbamoyl-4-methyl-4-aza-5a-androstane The -3-one, a particularly preferred compound according to the invention, comprises the following steps: a) pregnenolone (V), accessible starting material, is treated by King's halogenated reaction with iodine and pyridine to form the 20-pyridine iodide derivative of pregnenolone (VI). ; c) the pyridine iodide derivative (VI) is hydrolyzed to the 17-carboxypregnenolone methyl ester (VII) with sodium methylate and methanol, the ester form being preferred for carrying out the next Openhower reaction; c) the 17-carboxy pregnenolone methyl ester (VII) is treated with aluminum isopropylate and cyclohexanone in a suitable solvent such as toluene to give methyl 4-androsten-3-one-17carboxylate (VIII); d) the methyl-4-androsten-3-one-17-carboxylate (VIII) thus obtained is hydrolyzed to 17-acid (IX) under acidic conditions in solvent methanol: water in proportions, approximately 4: 1; f) The 17th acid (IX) is then treated with oxalic chloride: pyridine complex in proportions of approximately 1: 1 in toluene or other suitable solvent, e.g. xylene to form the chloride of the 17th acid (X); f) the 17-acid chloride (X) is treated in situ with excess diethylamine and forms 173-1 N, N-diethylcarbamoyl-4-androsten-3-one (XI); g (the 4androsten-3-one thus obtained (XI) is oxidized by treatment with sodium periodate and potassium permanganate, using the tert-butanol and water system as solvent, to the corresponding 5-oxo-3,5secoandrostan-3 acid / XII /; And (secoandrostanoic acid (XII) is then converted to the corresponding 4-aza compound (XIII) when treated with methylamine in ethylene glycol for about 1 hour, during which period the temperature of the reaction mixture rises to about 140-180 ° C and maintains from 0.5 to 5min; i) then the resulting 17β-Ν, Ν-ethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one (XIII) is hydrogenated by treatment with hydrogen at room temperature to 60 ° C or high temperature, such as is used as a platinum oxide catalyst until 17β is formed

-N, N-diethylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one (XIV) final product, which is separated and purified.

The above reactions are presented schematically in the following diagram:

UNEP,

sn.

(XIV)

The compounds of the invention prepared according to the method described are potent antiandrogenic agents by virtue of their ability to specifically inhibit testosterone-5α-reductase.

The invention relates to a method for the treatment of hyperandrogenic conditions of acne vulgaris, seborrhea and female hair by external application and to a method for treating these conditions, as well as benign prostatic hypertrophy, by parenteral administration of the new compounds according to the invention.

The invention also relates to the preparation and provision of suitable pharmaceutical forms for external and parenteral administration for use in the new treatment methods according to the invention.

Compositions containing the compounds of the invention as the active ingredient for use in the treatment of benign prostatic hypertrophy can be administered in a wide variety of therapeutic dosage forms in conventional carriers for systemic administration, such as for oral administration in the form of tablets, capsules, solutions or suspensions, or by intravenous injection. The daily dosage of the products can range from 50 to

2000 mg. The compositions are generally formulated as labeled tablets containing 5,10,25,50,100,150,250 and 500 mg of the active ingredient for symptomatic dose adjustment in relation to the patient being treated. An effective amount of the drug is usually delivered at a dose level of about 1 mg to about 50 mg / kg body weight per day. Preferably, this size is from about 1 mg to 7 mg / kg body weight per day. These doses are well below the toxic doses of the product. Capsules containing the product according to the invention are prepared by mixing the active compound of the invention with lactose and magnesium stearate, starch, talc or other carriers and placing the mixture in a gelatin capsule. The tablets are made by mixing the active ingredient with conventional tablet ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate. Liquid forms are suitably tasteful suspension and dispersing agents such as synthetic and natural resins, for example, tragacanth, acacia, methylcellulose and the like. similar. Other dispersible substances that may be used include glycerol and the floor. Suspensions and solutions for parenteral use must be sterile. When intravenous administration is desired, isotonic preparations, which usually contain preservatives, are used.

For the treatment of acne vulgaris, seborrhea, and women's hair, the compounds of the invention are administered in the form of pharmaceutical compositions containing the active ingredient in combination with a pharmacologically acceptable excipient. These pharmaceutical forms for external use may be in the form of a cream, ointment, gel or aerosol dispenser suitable for application to the skin. These topical pharmaceutical forms containing the compounds of the invention typically contain about 0.1 to 15%, preferably about 5% of the active compound in a mixture of about 95% of the carrier.

The process for the preparation of the new compounds of the invention described in general terms above is explained by the following examples.

Example 1. 17p-N, N-diethylcarbamoyl-4 methyl-4-aza-5a-androstan-3-one

A. 3-Oxo-N, N-diethyl-4-ethienamide g sodium 3-oxo-4-ethienate are suspended in 360 ml of dry benzene and 0.13 ml of pyridine and cooled to 14 ° C. The suspension was treated with 20 ml of oxalic chloride and stirred at 15 ° C for 15-20 minutes. The suspension was evaporated to dryness and then suspended in 125 ml of dry tetrahydrofuran. This suspension was then added to a solution of 25 ml diethylamine and 125 ml tetrahydrofuran and stirred at room temperature for 1 h, after which the mixture was poured into 4 l ice water. A semi-crystalline precipitate was obtained, which was extracted with ethyl acetate, washed with water and then with saturated brine, dried, evaporated to 25.7 g of product yield. The product was recrystallized from ethyl ether, the first yield of 10 g having m.p. 127-129 ° C, second yield 3.1 g, m.p. 114-119 ° C.

B. 17p-N, N-diethylcarbamoyl-5-oxo-

3,5-secoandrostan-3-acid acid g of the product from step A was dissolved in 150 ml of dichloromethane and 75 ml of methanol and cooled to -78 ° C, then ozone was bubbled through the solution until a consistent blue color appeared. The reaction mixture was then warmed to room temperature and purged with nitrogen, then evaporated to dryness at 35 ° C. The residue was dissolved in benzene and extracted three times with 2.5 N NaOH. The waters of these basic washes were collected and acidified with concentrated HCl, extracted with benzene, washed, dried and evaporated to 11.5 g of white crystalline solid. The product was recrystallized from ethyl acetate to give a substance, m.p. 205-208 ° C.

C. 17P-> 1, N-diethylcarbamoyl-4-aza-4methyl-5-androsten-3-one

To 190 ml of ethanol was added 26.3 g of the product from step B to form a solution. The solution was cooled in an ice bath and saturated with methylamine, then heated at 180 ° C for 8 hours. The reaction mixture was then cooled to room temperature and evaporated to give 22.3 g of a yellowish solid. After chromatography and recrystallization from ethyl ether, the final product has m.p. 120-122 ° C.

D. 17P-1H, N-diethylcarbamoyl-4-methyl4-aza-5a-androstan-3-one

36.5 g of the product from step C were added to 1 L of glacial acetic acid to form a solution. The solution was then treated with 3.5 g of platinum oxide catalyst and hydrogenated at 40 psi at room temperature for 8 h. The reaction mixture was then filtered and evaporated to dryness. The residue was dissolved in chloroform and washed with bicarbonate solution, brine and then dried and evaporated to dryness. The product was recrystallized from ethyl ether to yield 30.65 g of a white crystalline final product, m.p. Mp 168-170 ° C.

Examples 2-27. Following the method described in Example 1, but replacing the 3-oxo-4-ethylene in step A by an equimolar amount of other readily available or prepared 3-

oxo-Δ ⁴ compounds, or substitution of a dietary lamina by an equimolar amount of another suitable amine, yields the compounds of formula 1 according to the invention given in the following table. Table R ¹ ιΑζ-Η for OH) R | (IX) Ex- ample No. | 7α R ¹ R> rap. R CO

2 Η H CONtCHiCHjh H 263-265 3 - H H 283-285 F [o · * . 4 - CHj H 136-140

5 H H COCHj * H 272-275 6 H CHj COCHj H ^ 18-220 1 H CHj CONHCHjCHj H 249-251 « H H COOCHj Η 300-302 9 H CHj NHCOCHj H 284-287 10 H CHj CH, Η 162-165 CHCOOCHj 11 H CHj CHj H 307-309 CHCOOH 12 H CHj CONHj H 246-248 13 H CHj CONH (CHj) jCHj H (lass

(mass spectra M ⁺ 444)

14 H CHj CON (CHj) j H 240-242 15 Η CHj CHj CON (CH) j 1 CHj H 181-183 16 Η CHj UNC H > 300 17 Η CHj COOCHj H 133-135 18 Η CHj CHj CH (CH ₂ hCON (CjHj) j H 165-167 19 Η CHj CHj CH (CHjhCOOH and 256-258 20 Η CHj V CHJ CHCON (CiHjh H 216-218 21 Η CHj CHJ CHJCHihCOOCHj H 95-97 22 N NHCHj H 227-229 23 Η CHj CHjCON (CjHj) j Η 159-162 24 Η CHj CHjCOCXCjHj) H 55-57 25 26 - CHjCHj CHj D-I r — r ο,> · H CHj (lass 115-119 27 CHj CH-OH H 2? Η eH, H 194- no

snnrn

Example 28. 17P-benzoyloxy-4a-aza-5aA-homoandrostan-4-one

A. 17P-hydroxy-4-androstene-3-thioketal

A solution of 7.5 g of testosterone, 37.5 ml of glacial acetic acid, 4.5 ml of ethanedithiol and 3.0 ml of borane trifluoride etherate at 0 ° C was prepared. The mixture was brought to room temperature and maintained for 1.5 h. The mixture was then diluted with water, extracted with chloroform and washed with 5% sodium bicarbonate, then several times with water and then with saturated sodium chloride solution. The mixture was then dried and evaporated to give a white solid which was crystallized from methanol to yield 9.0 g of the final product (95% yield), m.p. 160-162 ° C.

B. 17p-hydroxy-4-androstene

To 60 ml of anhydrous liquid ammonia was added 1.2 g of metallic sodium. To the solution was added 1.0 g of thioketal in 10 ml of dry tetrahydrofuran and the solution was refluxed for 20 min. The solution was saturated with several milliliters of ethanol and evaporated at room temperature. It is then diluted with water, extracted with dichloromethane, washed with water, HCl, again water and dried and evaporated to give a white solid, m.p. 149152 ° C (609 mg, 81% yield).

C. 17P-tetrahydropyranyloxy-4-androstene

To 30 ml of dihydropyran containing 450 mg of p-toluenesulfonyl chloride were added 6.0 g of the product from step B and the solution was stirred at room temperature for 1 h. The solution was diluted with ethyl ether and washed with 20% pyridine-water mixture twice, then with water, brine, dried and evaporated to give a pale yellow oil, which crystallized (8.5 g) and m.p. 92-96 ° C.

D. 17β-tetrahydropyranyloxy-4β-hydroxy-5OC-androstane

To a cooled solution (0 ° C) of 5 ml of 1M borane in tetrahydrofuran in 2.7 ml of dry tetrahydrofuran was added 500 mg (1.4 mmol) of the product from step C in 2.0 ml of dry tetrahydrofuran. The clear solution was stirred for 1 h at room temperature and then cooled to 0 ° C and treated with 5 ml.

2.5 N sodium hydroxide solution followed by 4 ml of 30% hydrogen peroxide. The solution was stirred for 1 h at room temperature, diluted with water and extracted with ethyl ether, washed with water, brine, dried and evaporated to an oil crystalline solid. The product was washed with cold methanol and dried to 175 mg of the final product, m.p. 167-170 ° C.

E. 17P-tetrahydropyranyloxy-5α-androstan-4-one

0.264 g of chromium trioxide was slowly added to 0.42 ml of dry pyridine and 6.3 ml of dry dichloromethane and the mixture was stirred at room temperature for 15 minutes. A solution of 175 mg of the product from step D in 0.7 ml of dichloromethane was added to the mixture and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was diluted with water, extracted with ethyl ether and washed with 2.5 N sodium hydroxide, water and brine. The mixture was dried and evaporated to a clear oil.

F. 17P-hydroxy-5a-androstan-4-one

2.32 g of the product from step E are added to 75 ml of ethanol, a solution is formed, which is treated with 5 ml of 2.5 N hydrochloric acid and heated in a steam bath for 40 min to give 2.1 g crystalline product, m.p. 123-126 ° C.

G. 17P-Benzyloxy-5-oct-androstan-4-one

To 12 ml of dry pyridine and 6 ml of benzoyl chloride was added 2.0 g of the product from step F, forming a solution which was heated in a steam bath for 30 min and then poured into 175 ml of ice water and stirred until decomposed. excess chloride. The reaction mixture was filtered, washed with water and dried under high vacuum at 50 ° C, yielding 1.7 g of the final product.

Η. 173-benzyloxy-5α-androstane-4-oxime

To 125 ml of ethanol and 30 ml of dry pyridine was added 2.0 g of the product from step G, a solution was obtained, which was treated with 420 mg of hydroxylamine hydrochloride and stirred at room temperature. The reaction mixture was chromatographed by thin layer chromatography on silica gel in 20% ethyl acetate / benzene overnight. The product was concentrated to a small volume at 30-40 ° C under high vacuum, slowly diluted with water to form a white crystalline material, which was filtered, washed with water, dissolved in ethyl ether, dried and recrystallized from ethyl ether .

I. 17P-Benzyloxy-4a-aza-5a-A-homoandrostan-4-one

To 3.3 ml of distilled thionyl chloride was added at -78 ° C 500 mg of the product from step H and the resulting solution was stirred for 1-2 min, then slowly added to 50 ml of 4N potassium base at 20 ° C. A solid precipitate formed which was filtered off and washed thoroughly with water and then with ethyl ether. The product was recrystallized from ethyl acetate, washed with ethyl acetate, ethyl ether and dried to give 210 mg of the final product.

Example 29. 17P-1H, N-dibutylcarbamoyl4-methyl-4-aza-5a-androst-1-en-3-one

A solution of 0.20 g of anhydrous diisopropylamine with 5.0 ml of anhydrous tetrahydrofuran was treated under nitrogen at -78 ° C with 0.9 ml of 2.2 M butyllithium. After 20 min, a solution of 388 mg of 17P-N, N-dibutylcarbamoyl-4methyl-4-aza-5a-androstan-3-one in 3 ml of tetrahydrofuran was added dropwise to the reaction mixture at -78 ° C. After stirring for 30 minutes at -78 ° C, a solution of 440 mg of phenyldisulfide in 1 ml of tetrahydrofuran was slowly added to the reaction mixture. After stirring for 10 min at -78 ° C, the reaction mixture was warmed to room temperature. The mixture was added to water and the product was extracted with ethyl acetate. The organic layer is washed with a dilute sodium hydroxide solution, then with water, with dilute hydrochloric acid and finally with a solution (saturated) of sodium chloride. The solution was dried over calcium sulfate and then concentrated to a crude solid. Elution through 30 g of silica gel with increasing amounts of ethyl acetate in hexane gave the 2-phenylthio derivative as a visible mixture of two isomers. The material suspended in 5 ml of 20% aqueous methanol is treated with a solution of 225 mg of sodium metaperiodate in 2 ml of water. After stirring for 16 h, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated to leave crude sulfur dioxide. A solution of this substance in 5 ml of toluene was refluxed for 30 minutes. The solvent was removed and the residue was chromatographed on 20 g of silica gel, eluting with increasing amounts of ethyl acetate in ether. The final product crystallizes after trituration with ether.

Example 30 A solution of 291 mg of 17β-Ν, diethylcarbamoyl-4-aza-5a-androstan-3-one in 3 ml of methylene chloride was added at 0 ° C to a solution of 117 mg of trimethyloxonium fluoroborate in methylene chloride. The mixture was stirred at 0 ° C for 6 h and then treated with 125 mg 1.5 diazobicyclo 5,4,0 undec-5-ene. Stirring was continued for 2 h and the reaction mixture was diluted with anhydrous ether. The organic solution was separated from the residue and concentrated under reduced pressure to leave the crude lactam ether. The material was converted to the corresponding Δ1 compound according to the procedures described in Example 29.

Example 31. 17p-N, N-diethylcarbamoyl3-metimino-4-methyl-4-aza-5a-androstane

A mixture of 195 mg of 17P-N, N-dimethylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one and 70 mg of dimethyl sulfate in 1.0 ml of chloroform was heated under nitrogen in a bath maintained at 75 ° C. . The mixture was heated overnight, the condensate was removed and the chloroform was allowed to distill off. The resulting resin (under nitrogen vapor) was heated at 75 ° C for 3 hours, then cooled and released with the solvent under reduced pressure (5 mm Hg, room temperature). The product is adhesive and proves to be hygroscopic. It was dissolved in 3 ml of anhydrous methanol and brought to reflux while during that time methyl gas was purged into the mixture. The treatment was continued for 3 h, after which the methylamine was removed by distillation with methanol and the mixture concentrated to a thick sticky residue. A mixture (6 ml) of ethyl acetate: ether 1: 1 was added to the material and triturated until the solid was completely separated. The layers were separated by centrifugation and the solid was washed with ether. The solid was dried in vacuo and then washed twice with 4 ml of water each. The residue was dried and crystallized from ethyl acetate, leaving 62 mg of product, m.p. Mp 184-187 ° C. After recrystallization, m.p. mp 183-186 ° C.

Example 32 4-Methyl-3-oxo-4-aza-5pregn-17/20 / -en-21-acid

A. 4-Methyl-4-aza-5a-androstane-3,17-dione

A sample of 1.5 g of 17-hydroxy-4-methyl-4aza-5a-androstan-3-one was partially dissolved in 75 ml of acetone, stirred vigorously and treated with 3.6 ml of 8 N Jones reagent. The mixture was stirred at room temperature for 15 min and then saturated with a few drops of methanol. The mixture was filtered through silica gel and evaporated to dryness. The residue was dissolved in chloroform and passed through a thin layer of silica gel. The product was chromatographed and recrystallized from ether to give 806 mg.

B. Ethyl-4-methyl-3-oxo-4-aza-5a-pregn 17/20 / -en-21-at

A sample of 800 mg (2.64 mmol) of the product of step A was suspended in 1.46 ml (1.67 g, 7.92 mmol) of methyl diethylphosphonoacetate. Subsequently, a solution of sodium ethylate prepared from 190 mg of sodium in 3.3 ml of distilled ethanol was added dropwise over a 20 minute period. The addition was carried out at room temperature, after which the reaction was continued under reflux. After 7 h, the starting material disappears. The reaction mixture was evaporated to dryness, diluted with water, acidified with acetic acid, extracted with ether and washed with water, saturated bicarbonate, water and saturated brine. The reaction mixture was then dried and evaporated until spontaneous crystallization occurred. The product was recrystallized from ether to yield 461 mg of white crystals, m.p. 150-152 ° C.

C. 4-Methyl-3-oxo-4-aza-5a-pregn-17/20 / -en-21-acid

A sample of 265 mg of the product from step B was dissolved in 10 ml of methanol and 1 ml of water, treated with 200 mg of potassium carbonate and refluxed for 1 h. Silica gel thin layer chromatography in 1: 1 ethyl acetate / acetone shows the predominance of the starting material and the reaction mixture is refluxed overnight. The reaction mixture was evaporated to a thick solution, diluted with water, extracted with ethyl acetate, acidified, filtered and a white precipitate was dried, which was dried to 206 mg, m.p. 285288 ° C (dec.).

Example 33. 17P-N, N-Diethylcarbamoyl4-methyl-4-aza-5a-androst-1-en-3-one

A solution of 1.164 g of 17P-N, N-fluoroacapamoyl-4-methyl-4-aza-5a-androstan-3-one in 12 ml of THF was treated at -78 ° C with 6 ml of lithium diisopropylamide solution and then cooled to 0 ° C. The resulting solution was added at 0 ° C to a solution of 900 mg diphenyl sulfide in 5 ml tetrahydrofuran for 5 min with stirring. It is then left to stand for 1.5 h at room temperature and then treated with water. The mixture was extracted with ethyl acetate and the organic layer was washed sequentially with 5% sodium hydroxide solution, water, 2.5 N hydrochloric acid, water, saturated sodium chloride solution and finally dried over calcium sulfate and concentrated to a residue of 1. 68 g. This residue was triturated with 50 ml hexane, cooled and dissolved in about 8 ml ethyl acetate. The solution of the residue was saturated with phenyl sulfide and the crystalline material obtained was separated and washed with ether to give 282 mg. The combined mother liquors were obtained on 6 x 2000μ layers, eluting with 30% hexane / ethyl acetate. Two layers were isolated: the main layer (the bottom layer) was the desired product (crystalline) and when combined with the first product gave 995 mg.

A solution of the monophenylthio-construct (990 mg) in 15 ml of methanol was treated with very vigorous stirring with a solution of 700 mg of sodium metaperiodate in 3 ml of water. The reaction mixture was stirred at room temperature overnight and clouded by a solid precipitate.

The crude sulfone (about 950 mg) was dissolved in 15 ml of toluene and refluxed for 2 hours. Dilute with ethyl acetate and extract with 5% sodium hydroxide solution, water and saturated sodium chloride solution. The reaction mixture was dried and concentrated to a semi-crystalline mass, which was recrystallized from ethyl acetate by the addition of hexane to give 235 mg of the expected product, m.p. 202205 ° C. One part was recrystallized from ethyl acetate to give an analytical sample of m.p. 200-202 ° C.

Example 34

1. Tablets - 10,000 labeled tablets for oral use, each containing 500 mg of the active ingredient, are made from the following ingredients:

Mr Rücker

17β-N, N-diethylcarbamoyl-4-methyl- til-4-a-5a-androstan-3-one 5000 Starch, USP 350 Talc, USP 250 Calcium stearate 35

The active ingredient is granulated at 4% w / v. aqueous methylcellulose USP solution (1500 drops). A mixture of the rest of the ingredients is added to the dried granules and the final mixture is compressed into tablets of a certain weight.

2. Capsules - 10,000 capsules of hard gelatin in two parts for oral use, each containing 250 mg of the active ingredient, are made from the following ingredients:

Mr Rücker

17P-N, N-diethylcarbamoyl-4-methyl- til-4-aza-5a-androstan-3-one 2500 Lactose, USP 1000 Starch, USP 300 Talc, USP 65 Calcium stearate 25

The active ingredient is mixed with the starch-lactose mixture, followed by talc and calcium stearate. The final mixture is then encapsulated as usual. Capsules containing 10, 25, 50 and 100 mg of the active ingredient are also prepared, replacing the indicated 2500 g in the above formulation with 100, 250, 500 and 1000 g.

3. Soft elastic capsules - soft elastic capsules of one part for oral use, each containing 500 mg of the active substance, are prepared in the usual way, first by dispersing the active substance in enough corn oil to make the material fit for use. encapsulation.

4. Aqueous suspensions - an aqueous suspension for oral use containing in each 5 ml of 0.25 g of the active ingredient is made from the following ingredients:

Mr Rücker

17p-1H, N-diethylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one 500

Methylparaben (paraaminobenzoic acid), USP 7,5

Propyl parabenic acid, USP 2.5

Saccharin sodium 12,5

Glycerin 3000

Powder tragant 10

Orange flavored oil 10

F.D. &. C. orange paint 7.5

Deionized water, up to 10,000 ml g.s.

5. Gel

0.1 mg disodium edetate (ethylenediaminetetraacetate)

1.30 mg of purified water

300 mg isopropanol mg hydroxypropylcellulose mg 17P-N, N-diethyl-carbamoyl-4-methyl-4-aza-5a-androstan-3-one g propylene glycol g.s.a.d.

6. Ointment mg wool alcohols B.P.

150 mg of amihol C

350 mg white wax mg 17P-N, N-diethyl-carbamoyl-4-methyl-4-aza-5a-androstan-3-one g isopropyl myristate g.s.a.d.

Claims (19)

1. 4-aza-17β-substituted-5α-androstan-3-ones and their A-homologues of general formula I in which formula I may also have the structure of fragments II and/or III, in which A represents 1/ -CH ₂ -CH ₂ -; 2/ -CH=CH-; photo ₃ 3/ - s - sn ₂ - 1 2 or 4/ are you _? * h —sn—-sn— B means 1/ R' in which R ¹ is a/ hydrogen; b/ methyl or ethyl; with/ ethenyl; d/ ethynyl e/ NR ² R ^{3 * 5 6} , in which R ² and R ³ are hydrogen or methyl; or f/ cyano; or 2/ I With in which X® denotes any anion and R ⁴ is a/OR ⁵ , in which R ⁵ is C _1-4 alkyl; or b/ NR ⁶ R ⁷ , in which R ⁶ and R ⁷ are hydrogen or methyl; R' is hydrogen or methyl; R” - hydrogen or β-methyl; R'” - hydrogen, β-methyl or hydroxyl; Z stands for 1 / α-hydrogen or α-hydroxyl and a/ O Alk-CR ⁸ in which Alk is present or absent and represents a straight or branched hydrocarbon chain containing from 1 to 12 carbon atoms; and R ⁸ is I/ hydrogen, II/ hydroxyl, III/ C, , alkyl, IV/ NR ⁹ R ¹⁰ , in which each of the radicals R' and R ¹⁰ is independently selected from hydrogen, C] _g straight or branched alkyl chain, C ₃ cycloalkyl, phenyl; or R' and R ¹⁰ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring, joined to any other heteroatom selected from oxygen and nitrogen; or V/ OR ¹¹ , in which R ¹¹ is M, where M is hydrogen or an alkali metal or C _1-18 straight or branched alkyl, benzyl; or b/ Alk-OR ¹² , in which Alk is always present and has the above meaning, and R ¹² is I/ phenyl C ₁₆ alkylcarbonyl, II/ C ₅₁₀ cycloalkylcarbonyl, 111/ benzoyl, or IV/ C, _g alkoxycarbonyl, V/ amino or C alkyl substituted amino, carbonyl, or VI/ hydrogen, provided that Alk is C ₃ -C ₈ branched chain; 2/ o CH-Aak-CR ⁸ or CH-Alk-OR ¹² , in which Alk is present or absent and has the same meaning as above, R ⁸ and R ¹² have the above meaning, and R ¹² is also hydrogen or C _1-20 alkylcarbonyl; 3/ in which the dotted bond replaces the 17a-hydrogen; 4/ a-hydrogen and o HYS- wherein R ¹³ is a/C _1-12 alkyl; or b/ NR'R ¹⁰ ; 5/ α-hydrogen and cyano; or 6/ α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 2. A compound according to claim 1 with in which R ¹ represents hydrogen, methyl or amino; and T is CONHCH ₂ -CH ₃ , CH,CH, ------ fl ^sg> '-'sn/.n ₃ · > ^sosn » ^s -° ^sn > 3. A compound according to claim 2, wherein R ¹ is methyl and T is CONHCH ₂ CH ₃ or CON(CH ₂ CH ₃ ) ₂ . 4. A compound according to claim 1, wherein the compound is 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one. 5. A compound according to claim 1, wherein the compound is 17β-N,N-diethylcarbamoyl-4-aza-5α-androstan-3-one. 6. A compound according to claim 1, wherein the compound is 173-N,N-diethylcarbamoyl-4-amino-4-aza-5a-androstan-3-one. 7. A compound according to claim 2, wherein the compound is 4-aza-5a-20-spiroxan3-one. 8. A compound according to claim 2, wherein the compound is 4-methyl-4-aza-5a-20-spiroxan-3-one. 9. A compound according to claim 1, wherein the compound is 17[3-[beta]-ethylcarbamoyl-4methyl-4-aza-5a-androstan-3-one. 10. A compound according to claim 2, wherein the compound is 4-methyl-4-aza-5-pregnane-3,20-dione. 11. A compound according to claim 2, wherein the compound is 20-hydroxymethyl-4-methyl-4-aza-5a-pregnan-3-one. 12. A compound according to claim 1, wherein the compound is 17β-carbomethoxy4-methyl-4-aza-5α-androstan-3-one. 13. A compound according to claim 1, wherein the compound is 17β-N-octylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one. 14. A method for treating hyperandrogenic conditions of acne vulgaris, seborrhea, increased hirsutism in women and benign prostatic hypertrophy, characterized in that a therapeutically effective amount of a compound of formula is parenterally administered to a patient in need of such treatment. in which formula I may also have the structure of fragments II and/or III, in which A means: 1/ -CH ₂ -CH ₂ -; 2/ -CH=CH-; 9H ₃ 3/ — s — sn ₂ — 1 2 or sn _? 4/ / \ —sn—sn— In means 1/ R ¹ in which R ¹ is a/ hydrogen; b/ methyl or ethyl; with/ ethenyl; d/ ethynyl; e/ NR ² R ³ , where R ² and R ³ are hydrogen or methyl; or f/ cyano; or 2/ I C in which X® represents any anion and R ⁴ is a/OR ⁵ , where R ⁵ is C alkyl; or b/ NR ⁶ R ⁷ , where R ⁶ and R ⁷ are hydrogen or methyl; R' is hydrogen or methyl; R” - hydrogen or β-methyl; R’” - hydrogen, β-methyl or hydroxyl; Z means 1/ α-hydrogen or α-hydroxyl and α/ o Alk-C—R ⁸ in which Alk is present or absent and represents a straight or branched hydrocarbon chain containing from 1 to 12 carbon atoms; and R* is I/ hydrogen, II/ hydroxyl, III/ C, ₄ alkyl, IV/ NR'R ¹⁰ , where each of the radicals R ⁹ and R” is independently selected from hydrogen, C] straight or branched alkyl chain, C cycloalkyl, phenyl; or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached represent a 5-6-membered saturated ring, joined to any other heteroatom selected from oxygen and nitrogen; or V/ OR ¹¹ , where ReM, where M is hydrogen or an alkali metal or C _(1g) straight or branched alkyl, benzyl, or b/ Alk-OR' ² , in which Alk is always present and has the same meaning as above, and R ¹² is I/ phenyl C ₍₆ alkylcarbonyl, II/ C ₅₁₀ cycloalkylcarbonyl, III/ benzoyl, or IV/ C, ₈ alkoxycarbonyl, V/ amino or _C18 alkyl substituted amino, carbonyl, or VI/ hydrogen, provided that Alk is C ₃ -C ₈ branched chain; 2/ o CH-Aak-CR ⁸ or CH-Alk-OR ¹² , in which Alk is present or absent and has the above meaning, R ⁸ and R ¹² have the same meaning as above, and R ¹² is also hydrogen or C ₍₂₀ alkylcarbonyl; 3/ in which the dotted bond replaces the 17a hydrogen; 4/ α-hydrogen and o II and J/HC—R° in which R ¹³ is a/C] ₁₂ alkyl; or b/ NR'R ¹⁰ ; 5/ α-hydrogen and cyano; or 6/ α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 15. A method according to claim 14, characterized in that a compound of formula is used in which R ¹ represents hydrogen, methyl or amino; and T is /CH 2 CH 3 »----» ° ^CON -CH _I CH _S · ^cosn > - «-oxy· 16. A method for inhibiting testosterone-5α-reductase in a patient in need of such inhibitory treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula in which formula I may also have the structure of fragments II and/or III, in which A represents 1/ -CH ₂ -CH ₂ -; 2/ -CH=CH-; <t ⁿ z 3/ — s — sn ₂ — 1 2 OR SN _? 4/ / \ —sn—sn— In means 1/ R' in which R ¹ is a/ hydrogen; b/ methyl or ethyl; with/ ethenyl; d/ ethynyl; e/ NR ² R ³ , where R ² and R ³ are hydrogen or methyl; or f/ cyano; or 2/ 1 C in which X° represents any anion and R ⁴ is a/OR ⁵ , where R ⁵ is C 1-4 alkyl; or b/ NR ⁶ R ⁷ , where R ⁶ and R ⁷ are hydrogen or methyl; R' is hydrogen or methyl; R” - hydrogen or β-methyl; R’” - hydrogen, β-methyl or hydroxyl; Z means 1/ α-hydrogen or α-hydroxyl and α/ O Alk—C—R ⁸ in which Alk is present or absent and represents a straight or branched hydrocarbon chain containing from 1 to 12 carbon atoms; and R ⁸ is I/ hydrogen, II/ hydroxyl, III/ C _1-4 alkyl, IV/ NR'R ¹⁰ , where each of the radicals R' and R ¹⁰ is independently selected from hydrogen, C] ₄ straight or branched alkyl chain, C _{J 6} cycloalkyl, phenyl; or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring, joined to any other heteroatom selected from oxygen and nitrogen; or V/OR, where R is M, where M is hydrogen or an alkali metal or C, _]g straight or branched alkyl; benzyl or b/ Alk-OR ¹² , in which Alk is always present and has the above meaning, and R ¹² is I/ phenyl C alkylcarbonyl, II/ C _{5 [0} cycloalkylcarbonyl, III/ benzoyl, or IV/ C( _g alkoxycarbonyl, V/ amino or C 1 - _g alkyl substituted amino, carbonyl, or VI/ hydrogen, provided that Alk is C ₃ -C ₈ branched chain 2/ o CH-Alk-CR ⁸ or CH-Alk-OR ¹² , in which Alk is present or absent and has the meaning indicated above, R ⁸ and R ¹² have the meaning indicated above, and R ¹² is also hydrogen or C _1-20 alkylcarbonyl; 3/ in which the dotted bond replaces the 17a-hydrogen; 4/ α-hydrogen and o wherein R ¹³ is, a/C _1-12 alkyl; or b/ NR ⁹ R'°; 5/ α-hydrogen and cyano; or 6/ α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 17. A method according to claim 16, characterized in that a compound of formula is used. wherein R ¹ represents hydrogen, methyl or amino; and T is CHgCH3 |1 y ^co <cn ₂ chn ₃ - J - ^COCH 3 -« C-OCH3 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula wherein formula I may also have the structure of fragments II and/or III, wherein A represents: 1/ -CH ₂ -CH ₂ -; 2/ -CH=CH-; CH ₃ 3/ — C — CH ₂ — 1 2 or sn ₂ 4/ / \ —CH--CH— In means 1/ R* in which R ¹ is a/ hydrogen b/ methyl or ethyl c/ ethenyl d/ ethynyl e/ NR ² R ³ , where R ² and R ³ are hydrogen or methyl; or f/ cyano; or 2/ I In which Xθ denotes any anion and R ⁴ is a/OR ⁵ , where R ⁵ is C _1-4 alkyl; or b/ NR ⁶ R ⁷ , where R ⁶ and R ⁷ are hydrogen or methyl; R' is hydrogen or methyl; R” - hydrogen or β-methyl; R'” - hydrogen, β-methyl or hydroxyl; Z stands for 1/ α-hydrogen or α-hydroxyl and α/ O Alk—C—R ⁸ in which Alk is present or absent and represents a straight or branched hydrocarbon chain containing from 1 to 12 carbon atoms; and R ⁸ is I/ hydrogen, II/ hydroxyl, III/ C] ₄ alkyl, IV/ NR'R ¹⁰ , where each of the radicals R' and R ¹⁰ is independently selected from hydrogen, C j straight or branched alkyl chain, C cycloalkyl, phenyl; or R' and R ¹⁰ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring, joined to any other heteroatom selected from oxygen and nitrogen; or V/ OR ¹¹ , where R ¹¹ is M, where M is hydrogen or an alkali metal or C _1-18 straight or branched alkyl, benzyl; or b/ Alk-OR ¹² , where Alk is always present and has the above meaning, and R ¹² is I/phenyl C] ₆ alkylcarbonyl, II/ C ₅ cycloalkylcarbonyl, III/ benzoyl, or IV/ C] ₈ alkoxycarbonyl, V/ amino or C1, alkyl substituted amino, carbonyl, or VI/ hydrogen, provided that Alk is C ₃ -C ₈ branched chain; 2/ O CH-Aλκ—CR ⁸ or CH-Alk-OR ¹² , in which Alk is present or absent and has the same meaning as above, R ⁸ and R ¹² have the above meaning, and R ¹² is also hydrogen or C _1-20 alkylcarbonyl; 3/ [—[ in which the dotted bond replaces 5 17a hydrogen; 4/ α-hydrogen and o J/HC—R° 10 in which R ¹³ is a/C, ₁₂ alkyl; or b/ NR'R ¹⁰ ; 5/ α-hydrogen and cyano; or 6/ α-hydrogen and tetrazolyl, and pharmaceutically acceptable salts of the above compounds. 19. A composition according to claim 18, characterized in that it uses a compound of formula wherein R ¹ represents hydrogen, methyl or amino; and T is conC CH ₂ CH ₃ oh II COCH3 or C-OCH3