DE2036380A1 - 18 methyl 17 alpha athmyl testosterone ester - Google Patents

Description

SCEEElfG AG

Patent division

'"Berlin, July 16, 19? O

18-methyl-17a-ethmnyl-teEt oster-on-ester

The invention "relates to IS-methyl-IFoc-ethinyl-testosterone ester of the general formula I.

* ^ * where

R means a residue of debris.

As acid-resistant acids, those of physiologically compatible acids come into question * Preferred acids are organic carboxylic acids with up to 15 carbon atoms. The acids can also be unsaturated, branched, polybasic or substituted in the usual way, for example by hydroxyl, oxo or amino groups or halogen atoms. Are also suitable
cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which can likewise be substituted in a suitable manner.

Such acids are, for example, formic acid, acetic acid, propionic acid, butyric acid, aleric acid, caproic acid,

109885/1819

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Oenanthate saturation> lndecylic acid *! Erimethyiessigsätare ,; Mlthyle ssi gsäure »t ~ butyl essi gsäur e ,, phenyl acetic acid _f öycl opentylpropioi £ _t säiire oleic acid * Hileiisatire ,, Hoiiö-, bi- HBD TricMoressigsänre, iaainoessigsäöre, MätttylamdBO- _s piperidino Iind _{Morpholinoessigsäiire%} Bernsteinsätire _f adipic acid _t Benzoessrare ,. Kicotinsäare * learner take the common inorganic acids such as sulfuric and phosphoric acid into consideration.

For the production of water-soluble preparations, substituted aminoacylates such as diethylamine, piperidino- and morpholino acetates in the acid addition salts and the sulfuric and phosphoric acid esters in the Alkali metal salts are transferred.

The invention also relates to a process for the production of 18-Hethyl-17a-äthinyl-testosteroneesters general formula I, characterized in that 17ß-hydroxy-18-methyl-17a-ethinyl-4 ~ androsten-5-one in itself esterified in a known way.

The esterification of the 17β-position hydroxyl group takes place after Methods as are generally known to the person skilled in the art.

109885/1819

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For example, esterification with an acid or a reactive acid derivative v. ^T he acid anhydride or halide or mixtures thereof in the presence of a strongly acidic esterification catalyst such as p-toluenesulfonic acid, perchloric acid or trifluoroacetic acid or in the presence of a basic esterification catalyst vrie pyridine, collidine, quinoline, etc. "at temperatures - preferably above room temperature.

The used as starting material: β-Hydroxy-18-niethyl-17a-äthinyl-4-androsten-3-one is after Baddeley et. al. - (J.Crg.Chem.] 51 (1966) Io26).

The compounds according to the invention have valuable pharmacological ones Properties and are characterized by a superior level of anti-ovulatory and gestagenic insufficiency Compared to known compounds of analogous structure. So is 17ß-Aceto ^ r-18-methyl-17ö-äthinyl-4-androsten-3-one the corresponding 18-desmethyl compound, dem. 17 ß-acetoxy-17ot-äthinyl - ^ - andrösten-J-on ", in the inhibition of ovulation and in the gestagenic effectiveness - by an order of magnitude consider, as can be seen from the following table .

■ - 4 -

109 88 5/1819

SCHERING AG

0? a b e 1 1 e

link Inhibition of ovulation
SC Clauberg test
* sc 17ß-Aceto2cy-17a-
äthinyl-4- andr ο st en-
3-on
17β-acetoxy-18-
methyl-17a-ethinyl-
4-androsten-3-one Dose inhibition
(mg) (%) Dose of McPhail
(mg) 3, o 4o
1, ο inactive
l, o · loo
o, 3 4-0
o, l inactive o, 3 inactive
o, 3 3.3
o, l 1.5
ο, o3 1.1

The ovulation-inhibiting effect was tested on rats with a Minimum weight of lj? O g checked in the tube inspection test. The percentage of animals in the dose groups is determined in which ovulation was inhibited.

The gestagenic effect was reduced in the usual Clauberg test Using the McPhail scale

It is surprising that the effectiveness of 17ß-acetoxy-18-iaethyi-17a-äthinyl-4-androsten ~ 3-one is greater than that of 17ß-acetoxy-17a-äthinyl-4-andi'osten-3-one, since it is known that the activities in the 18-rMethyl-lj3,5 (lo) -estratriene series (Recent-Progress in Hormone Research, G ₀ Pincus, Academic Press 1966, p. 328),

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SGHERING AG - 5 -

18-methyl-pregnane and 18-methyl-androstane series (Strike et. al., J. Med. Chem. Lo (1967) 446) compared to the corresponding 18 ~ desmethyl compounds are often even significantly lower »

The compounds according to the invention have the advantage that due to the lo-methyl group in the organism they do not * can be metabolized to estrogens as it is by 19-nor ~ steroids is known.

The compounds according to the invention are used for production of drugs and can be used successfully to treat the following gynecological disorders: Primary and secondary amenorrhea, endometriosis, hypoplasia uteri, functional bleeding, glandular-cystic hyperplasia, sterility in the case of inadequate corpus luteum function and cycle fluctuations.

The new connections can also be used if a concept is to be avoided.

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The dosage is based on the severity of the illness. Generally one administered between 5 and loo mg of active ingredient daily. Strong menstrual swan Cuts can be regulated, for example, through cycle-appropriate treatment with daily dosages of Io mg., Bei Use of the compounds according to the invention as contra · zeptisom-, if necessary together with a suitable one estrogen, the dosage is οςΊ to 5 ^ g daily.

The pharmaceutical specialties are produced in the usual way by adding the active ingredients to the carrier substances, diluents, and flavoring agents customary in pharmaceutical pharmacy in the desired application form, such as tablets, coated tablets, capsules, solutions, etc. , convicted. The active ingredient concentration in the thus-formulated medicines, is dependent on the form of the application, a tablet preferably o, l contains -. Io mg \ Solutions for parenteral administration contain 1 - 2o mg / ml solution.
The following examples explain the invention:

Example 1 :

A solution of 91o mg of 17β-Hydro3 £ y-18-methyl-17a-ethinyl-4 androsten-3-one in 19 ml of collidine and 6 ml of acetic anhydride

_ π -
109885/1819

ZU3638Q

SCHERING AG. - 7 -

is heated to boiling under nitrogen for 5 hours. After cooling, it is poured into ice water and extracted with methylene chloride. The extract is washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water, dried and evaporated in vacuo. The residue is chromatographed on silica gel. With 5-7 % acetone-hexane, after recrystallization from acetone-hexane, 556 mg of 17β-acetoxy-18-methyl-17a-ethinyl- ^i- androsten-3-one vom

° C βΰψ = + 25 °

Cutting point 122.8 ° C. βΰψ = + 25 ° (chloroform).

Example 2 ;

1 x 7 g of 17β-Hydroxy-18-methyl-17a-ethinyl-4-androsten-3-one 25 mg of p-toluenesulfonic acid monohydrate are added to 25 ml of acetic anhydride and heated to 90 ° C. for 1 hour. After cooling, it is poured into 100 ml of water and 25 minutes touched. After neutralization with 25 g of sodium hydrogen carbonate is extracted with methylene chloride, the extract is washed with water, dried and concentrated in vacuo. The crude product is dissolved in 100 ml of methanol, with the addition of 10 ml of water and 1 g of sodium hydrogen carbonate. One stirs 6 hours at room temperature and pour into ice water. The resulting precipitate is filtered off, washed and dried and uncrystallized from Diisopropylätlier.

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Yield: 91o mg ^ ß-acetoxy-IS-methyl- ^ cc-äthinyl ^ - androsten ~ 3-one with a melting point of 119.8 ° C. Πΰψ = + 24 ° (chloroform). UV: Cp ^, = 16,9oo (methanol).

Example 3 :

2.0 g of 17β-hydroxy-18 ~ methyl-17a-ethinyl-4-androsten-3-one are dissolved in 25 ml of pyridine and 25 ml of enanthic anhydride and heated to 160 ° C. for 6 hours in a sealed tube. After cooling, the reaction mixture is treated with steam. The crude product is isolated from the residue of the steam distillation by extraction with methylene chloride and this is then chromatographed on silica gel. With 4-7% acetone-hexane, 1.6 g of 17β- • heptanoyloxy-18-methyl-17a-ethinyl-4-androsten-3-one are obtained as a colorless oil.

ψ = + 23 ° (chloroform). UV: ε _24ο = 17 2oo (methanol).

- 9 τ

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Claims (7)

SCHERING AG
Patent department Berlin, July 16, 1970 Claims II, method of making IS testosterone esters the general formula OR wherein R is an acid residue, characterized in that 18-Hethyl-17cc-äthinyl-testosterone is known per se Esterified way. 2. 18-Methyl-17c £ -äthinyl-testosteroneester of the general formula OR where R is an acyl radical. - 1 ο -109885/1819 SCHERING AG. wuou 3. ^ ß-Aeetoxy-IS-methyl- ^ cc-äthinyl ^ -androsten-J-one. 4. 17-heptanoyloxy-18-m "ethyl-17o £ · -ätlliIιyl-4-androsten-3-one. 5. Medicines based on active ingredients according to. Claim 2-4. . 6. Use of pharmacologically active compounds according to claims 2-4 for the treatment of gynecological ones Disruptions. 7. Use of pharmaceutically active compounds according to claims 2-4 for contraception. 109885 / Ί819