NO130190B - - Google Patents

Description

Analogy method of manufacture

of new, therapeutically active A-furan-

steroids.

The present invention relates to an analogue process for the production of new, therapeutically active A-furan steroids of the general formula I

in which stands for hydrogen or acetyl, and the peculiarity of the analogous procedure is that a steroid of the general formula II in which R-^ has the above-mentioned meaning is reduced with an aluminum compound of the general formula III

where M stands for an alkali metal and R stands for a lower alkyl radical or a lower alkoxy radical, n is 0 or 1,

and m is an integer from 0-3 when n is 0, and m is an integer from 0-4 when n is 1. The method is described in British Patent No. 1,081,647 (Shionogi & Co.Ltd.).

The starting compound can be prepared from the corresponding 19-nor-3-oxo-4-ene-steroid by oxidation and decarboxylation to form 5-oxo-A-dinor-2,5-seco-19-norsteroid-2-carboxylic acid, which sequentially subjected to Grignard reaction, dehydration and oxidation to form 5-oxo-A-dinor-2,5-seco-19-nor-steroid-2-carboxylic acid and then enol-lactonized to give the desired starting compound of formula II.

An active aluminum compound is used as a reducing agent

with the general formula III. A reaction according to the invention can be carried out within a wide temperature range, even at -80°C, depending on the compound used to give the desired A-furan-steroid compounds of formula I.

The reaction between the starting compounds and the active reducing agent can be carried out in an inert solvent, e.g. a liquid hydrocarbon such as petroleum ether, benzine, naphtha, benzene or toluene, or an ether such as e.g. diethyl ether, dipropyl ether, dibutyl ether, diglyme (diethylene glycol dimethyl ether), tetrahydrofuran, tetrahydropyran and dioxane. Although the method can be carried out within a wide temperature range, it is preferred to carry out the reaction between -50°C and 0°C when the reducing agent is dialkyl aluminum hydride or lithium aluminum hydride.

Agitation and replacement of air with an inert gas such as e.g. nitrogen or argon is preferably used during the reaction.

In many cases the desired furan compound can be prepared using these reducing agents in almost quantitative yield. After the reaction, the reaction mixture is mixed with water or an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, benzenesulfonic acid or acetic acid to cleave the adduct and excess reducing agent.

It is then extracted with a suitable solvent to isolate the desired A-furan-steroid compounds.

The present A-furan-steroid compounds have useful pharmacological properties and can be used as agents for regulating the physiological functions. In particular, the A-furanoostran-17(3-ol) derivatives show antideciduomatogenic activity, antiuterotropin activity, antianabolic activity, antiandrogen activity, uterotropic activity, antiestrogenic activity, contragestive activity and lipid-converting activity. It should be noted that almost all of these effects are antihormonal activity. When these new compounds, 3-oxa-A-norostra-1,5(10)-dien-173-ol and its acetate, are administered subcutaneously and they completely block progesterone-induced decidual growth Subcutaneous administration of 3-oxa -A-norostra-1,5(10)-dien-17(3)ol prevented the growth of the seminal vesicle and the levator ani muscle produced by testosterone propionate to an extent of 10 to 30%.

Additional trial data:

Anti-deciduomatoa effect: Complete blocking of decidual growth, induced by progesterone, at a dose of 0.8 mg administered subcutaneously to mice for 9 days.

Anti-implantation: Efficacy equal to 20% at a dose of 1 mg administered subcutaneously to mice for 6 days.

Anti-anabolic; Effect equal to 78% of testosterone propionate with

a dose of 1 mg, which is administered subcutaneously to mice for 10 days.

Anti-estrogen; Effect equal to 44% of Ostradiol added in one dose

of 0.3 mg, which is administered subcutaneously to mice, when the mice are examined by vaginal TTC reduction.

Anti-androgen: Effect equal to 39% increase in seminal vesicle weight induced by testosterone propionate with a dose of 1 mg, which is administered subcutaneously for 10 days.

From the "Journal of the Medicinal Chemistry" there are known A-saturated 19-methyl steroids, which are analogous to the androgens and which thus differ from the present A-aromatic steroids, which are analogous to the estrogens.

The aforementioned 19-methyl steroids also have only a weak androgen

and anti-androgenic effect.

The. the following examples further illustrate the invention:

Example 1

To a solution of 517 mg of 17 (3-acetyloxy-3-oxa-A-norostra-1(10)-en-2-one in 14 ml of tetrahydrofuran, cooled to -20°C to

-25°C, a solution of 0.8 g diisobutylaluminum hydride in 4.7 ml tetrahydrofuran is added dropwise. The resulting mixture is stirred for 20 min at the same temperature and excess diisobutylaluminum hydride is decomposed by adding a few drops of 10% sulfuric acid, water is added to the reaction mixture and extraction is carried out with methylene chloride. The extract is washed with water, dried and evaporated. Recrystallization of the crude product from a mixture of acetone and hexane yields 294 mg

3-oxa-A-norostra-1, 5 (10 )-dien-17[3-ol with melting point 137.5

to 139.5°C. IR: V <C>^<1>4 3628, 1505, 902 cm<-1>. Thin layer chromatography: Rf 0.52 (silica gel: cyclohexane ethyl acetate (1:1)).

Example 2

To a solution of 10 mg of 17(3-acetyloxy-3-oxa-A-nor6stra-1(10)-en-2-one in 10 ml of tetrahydrofuran, cooled to -20° to -25°C, is added dropwise a solution of 15 mg of diisobutyl aluminum hydride in 1 ml of tetrahydrofuran. The resulting mixture is stirred for 10 minutes at the same temperature and the excess of the reaction component is decomposed by adding a few drops of 10% sulfuric acid. The reaction mixture is diluted with water and extracted with methylene chloride. The extracted solution washed with water, dried and evaporated. Thin-layer chromatography gives 3-oxa-A-norostra-1, 5 (10 )-dien-17(3-ol with m.p. 139°C, and the acetate thereof with IR:^ max 1740 ' 1502' 1243 cm •' Thin-layer chromatogram Rf 0.80 (silica gel: cyclohexane-ethyl acetate (1:1)). The acetate is identical to the acetylation product of the 17(3-ol compound, which is identical to the product from example 1.

(the yield of the 17|3-ol compound and its acetate was approx

2 mg and 1 mg).

Claims (1)

Analogous process for the preparation of new, therapeutically active A-furan steroids of the general formula I in which R^ stands for hydrogen or acetyl, characterized in that a steroid of the general formula II, in which R^ has the above meaning, is reduced with an aluminum compound of the general formula III, in which M stands for an alkali metal and R a lower alkyl radical or a lower alkoxy radical, n is 0 or 1, and m is an integer from 0-3 when n is 0, and m is an integer from 0-4 when n is 1.