DE1793055C3 - 18 Methyl-1,4-androstadienes, process for their production and pharmaceuticals containing them - Google Patents

Description

OR ¹

/ ■■■ ·

wherein R is a methyl, ethyl, vinyl or ethynyl radical and R ^{1 is} hydrogen or an aliphatic carboxylic acid radical having 1 to 12 carbon atoms, characterized in that corresponding steroids saturated in the 1,2-position are dehydrated in a manner known per se and If desired, a free 17-hydroxy group present in the primary product is then acylated or, if appropriate, a 17-acyloxy group is saponified.

The invention relates to IS-methyl-M-androstadienes of the general formula I.

O =

wherein R is a methyl, ethyl, vinyl or ethynyl radical and R ^{1 is} hydrogen or an aliphatic carboxylic acid radical having 1 to 12 carbon atoms.

Possible acyl ^{radicals R 1} are radicals which are derived from acids which are usually used for esterifications in steroid chemistry. The acids can also be unsaturated, branched, polybasic or substituted in the usual way, for example by hydroxyl, amino groups or halogen atoms.

Preferred acids for forming the acyl radical R ¹ include, for example: acetic acid, propionic acid, caproic acid, undecylic acid, trimethylacetic acid, chloroacetic acid, dichloroacetic acid, dialkylaminoacetic acid, succinic acid, and the like.

The new 18-methyl-1,4-androstadienes of the general formula 1 have valuable pharmacological properties Properties. They are, for example, by a surprisingly favorable ratio of anabolic main to androgenic side effect excellent. The table below shows the superiority of the new Active ingredients using the example of 17 / J-hydroxy-l7a, 18-dimethyl-l, 4-androstadien-3-one (I) in comparison to the commercial preparations 17 /? - Hydroxy-17 "-methyl-1,4-androstadien-3-one (11) and 17 "-Methyl-5a-androstano- [3,2-c] -l'H-pyrazol-17j3-ol (Androstanazole) (III). The results given in the table were obtained on castrated male rats after oral administration determined in the usual levator ani / seminal vesicle test.

table

Serial No. Tested substance dose Lev. ani weight Seminal vesicles Weight in mg in mg in mg I. 17p-hydroxy-.17ix, 18-di- 1 mg 27 9 methyl-1,4-androstadien-3-one Il l7 / f-Hydroxy-I7Ä-methyl- 1 mg 29 27 1,4-androstadien-3-one III 17fX-methyl-5a-androstano- 1 mg 19th 15th [3,2-c] -l'H-pyrazole- 17 / f-ol (androstanazole)

The active ingredients according to the invention should be used in combination with the additives known and customary in galenical pharmacy for the production of anabolic drugs. For example
the following preparations in question:

come

Γ / 93

a) tablets of 5 mg 17 ^ -hydroxy-17 (X, i8-dimelhyl-

1,4-androstadien-3-one
Composition for 1 tablet:

5 mg 17/3-hydroxy-17 «, 18-dimethyl-1,4-androsta-

dien-3-one (micronized)
105 mg milk sugar (DAB 6)

8 mg corn starch (USP XVI)

1 mg magnesium sterate (USP XVI)

1 mg talc (DAB 6)
120 mg

The tablets are produced in the usual way on a tablet press.

Diameter: 7 mm with a break notch, height: 2.7-2.8 mm, hardness: about 4-5 kg

The tablets disintegrate in the gastric juice at 37 ° C in about 15 seconds.

b) Capsules of I mg 17 / J-Hydroxy-17rx, 18-dimethyll, 4-androstadien-3-one

Composition for one capsule

Quinone is also expediently carried out at the boiling point of the solvent used.

Examples of suitable solvents are: alcohols such as ethanol, butanol and tert-butanol, acetic acid esters, Glacial acetic acid, benzene, dioxane, tetrahydofuran etc. To accelerate the reaction, small amounts can be used Nitrobenzene or p-nitrophenol can be added. The reaction times are between 5 and 50 hours.

The dehydration in the 1,2-position can except by

ίο chemical also through microbiological processes respectively. For microbiological dehydration, microorganisms can be used that are used for Examples include the following genera: Calonectria, Colletotrichum, Didymella, Fusarium, Septomyxa, Vermicularia, Acetobacter, Aerobacter, Alcaligenes, Bacillus (especially Bacillus lentus MB 284), Corynebacterium (especially Corynebacterium simplex), Mycobacterium, Nocardia, Protaminobacter, Pseudomonas, Streptomyces etc.

The starting compounds of the general formula 11 not previously described

1.0mg ^ / Mlydroxy- ^ ftJS-dimeihyl-l ^ -androsta-

dien-3-one (micronized)
66.5 mg MiIChZUCkCr (DAB 6)
67.5 mg

As usual, the substance comes in hard gelatine capsules bottled.

The new active ingredients can be used for all indications in which protein cultivation is promoted is required. Such indications are, for example: convalescence, reduced general condition, consuming Illnesses, cachectic conditions, radiation and cytostatic therapy, in advanced Breast and genital cancer as additional treatment, anemia, long-term treatment with corticosteroids, osteoporosis, chronic liver and kidney diseases, hyperthyroidism, muscular dystrophy, in poorly thriving and dyslrophic infants, in cases of impaired wakefulness and others. The dosage is based on Severity of the illness and is about 2 to 25 mg per day.

The invention also relates to a process for the preparation of the new 18-methyl-l, 4-androstadienes general formula I, characterized in that corresponding steroids saturated in the 1,2-position dehydrated in a manner known per se and, if desired, then one present in the primary product free 17-hydroxy group aeylated or optionally a 17-acyloxy group saponified.

The dehydration according to the invention takes place according to methods as are known to be used in steroid chemistry to introduce a ^ '- double bond into a / 4 ⁴ -3-ketosteroid.

For example, chemical dehydrogenation using selenium dioxide or quinones, such as 2,3-dichloro-5,6-dicyanobenzoquinone.

When using selenium dioxide, the solvents are, for example, tert-butanol and tert-amyl alcohol or acetic acid ester suitable. The conversion can be accelerated by adding small amounts of glacial acetic acid and succeeds by heating the reaction mixture under reflux. The implementation is after about Finished 10 to 50 hours.

When using 2,3-dichloro-5,6-dicyan-benzo-

(II)

where R ^{2 is} a methyl, ethyl, vinyl or ethynyl radical and R ^{1 is} hydrogen or an aliphatic carboxylic acid radical having 1 to 12 carbon atoms, can be prepared, for example, as follows: 3-methoxy-17 / J-acetoxy-18-methyl- 1,3,5 (10), 8,14-oestrapentaene is hydrogenated, subjected to Birch reduction, reacetylated in the 17-position and the 3-methoxy-2,5 (10) -17 / 9-acetoxy compound is cleaved from the enol ether subject. The 17-acetoxy-18-methyl-5 (10) -estren-3-one (melting point 145-146 ° C.) obtained in this way is reduced with sodium borohydride in hydrous tetrahydrofuran. The 17 / i-acetoxy-18-methyl-5 (10) -estren-30-ol separated from the epimer mixture is methylenated according to Simmons and Smith with methylene iodide and zinc-copper to give ^ jS-acetoxy-IS-methyl-S.lOß -methylene-sweet-stran-30-ol (m.p. 128.5-129.5 ° C). After oxidation to the corresponding 3-ketone (temperature 141-144 ° C) the metal ring of ^ ß-acetoxy-IS-methyl-S.lOß-methylene-50-estran-3-one is heated by heating the substance in acetic acid / conc . Hydrochloric acid (3: 1) split and the 17ß-acetoxy group saponified. The resulting 17ß-hydroxy-18-methyl-4-androsten-3-one (R ² = H, R '= H; F. 176.5-177.5 ° C) is heated by heating with ethylene glycol in the presence of p- Toluenesulfonic acid is ketalized in benzene in the 3-position and then oxidized in the 17-position by treatment with chromic acid solution. Depending on the meaning, the R ² is supposed to have in the final product, the obtained 3,3-ethylenedioxy-18-methyl-5-androsti; on-NL7 (.F. 197-200 ⁰ C) are reacted for example with lithium acetylide or Methylmagiiesiumjodid. After ketal cleavage is obtained ^ jJ-hydroxy ^ a.ie-dimethyl ^ - androsten-3-one of melting point 182.5 to 189 ⁰ C büw. 17 /? - Hydroxy-18-methyi-17a-ethinyl-4-androsten-3-one with a melting point of 232-234 ° C. To produce the 17a-vinyl and 17'-ethyl compounds, the 17a-ethynyl compound is hydrogenated before the ketal cleavage. One receives, for example, 170-hydroxy-18-methyl-17 <x-ethyl-4-an-

drosten-3-one with a melting point of 132-133 ° C. To prepare the compounds of the general formulas I and II with R ¹ meaning an aliphatic carboxylic acid radical having 1 to 12 carbon atoms, the corresponding 17 /? -Hydroxy compounds can be esterified in a manner known per se. The conversion ml ·: acid anhydride or halide in the presence of acidic or basic reagents and the conversion with the desired acid in the presence of trifluoroacetic anhydride may be specifically mentioned.

example 1

1.25 g of nß-hydroxy- ^ a.ie-dimethyl- ^ androsten-3-one and 375 mg of selenium dioxide are in 62.5 ml of abs. tert-butanol and 0.63 ml of glacial acetic acid were refluxed under nitrogen for 24 hours. Another 375 mg of selenium dioxide are added and the mixture is heated again for 24 hours under nitrogen and reflux. The precipitate is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, the solution is washed successively with aqueous sodium hydrogen carbonate solution and water and dried over sodium sulfate. The solvent is evaporated off in vacuo and the residue is chromatographed on 100 g of silica gel. After gradient elution with pentane / 15 ° / o acetone and recrystallization from hexane / Accton one erhät 705 mg 17 / f-hydroxy-17ix, 18-dimethyl-l, 4-androstadien-3-one of melting point 150-151 ⁰ C. ; UV (Me; hand): / 244 = 15 500.

Example 2

Analogously to Example 1, 800 mg of 17 /? - Hydroxy-18-methyl-17ix-a'ihinyl-4-androsten-3-one in 40 ml of abs. tert-butanol, which contains 0.4 ml of glacial acetic acid, heated with 2 × 250 mg of selenium dioxide for 48 hours under nitrogen and reflux. After appropriate work-up, chromatography on silica gel and recrystallization from hexane / acetone to obtain 400 mg of 17/3-hydroxy-18-methyl-17aälhinyl-l, 4-androstadien-3-one of melting point 162- 63 ⁰ C!; UV (methanol): F244 = 14,900.

Example 3

Analogously to Example 1, 800 mg of 17 /? - Hydroxy-18-metby] -17a-ethyl-4-androsten-3-one in 40 ml of abs. tert-butanol, which contains 0.4 ml of glacial acetic acid, is dehydrated with 2 × 250 mg of selenium dioxide. After appropriate work-up of the reaction mixture, chromatography of the crude product obtained on silica gel and recrystallization from diisopropyl ether, 232 mg of 17/3-hydroxy-18-methyl-17a-ethyl-1,4-androstadien-3-one with a melting point of 178-181 are obtained ⁰ C; UV (methanol): fi245 = 14

Claims (3)

Patent claims: 1. 18-methyl-1,4-androstadienes of the general formula I. (I) where R is a methyl, ethyl, vinyl or ethynyl radical and R ^{1 is} hydrogen or an aliphatic carboxylic acid radical having 1 to 12 carbon atoms. 2. Medicines based on active ingredients according to claim 1. 3. Process for the preparation of new 18-methyl-1,4-androstadienes of the general formula I.