DE2101813C3 - New 17alpha- (2 ', 3'-difluoromethylene prop-1' -en-1 '-yl) -östra-4-en-3-ones, processes for their preparation and agents containing them - Google Patents

Description

F F

wherein R _{1 is} H or an acyl group having fewer than 12 carbon atoms.

2. Process for the preparation of the compounds of claim 1, characterized in that the corresponding 17 <i- (propadien-I'-yI) compound in one step with a difluorocarbene precursor implemented in a manner known per se, whereupon if necessary

a) a 17 / i-acyl compound obtained in a conventional manner Way saponified and / or

b) a 17 / i-hydroxy compound obtained according to a) or directly acylated in the usual way.

3. Medicaments containing a compound according to claim 1 and customary auxiliaries and carriers.

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The present invention relates to steroids of the general formula

OR ¹

: CH = C CH, ^4S

in which R _{1 stands} for H or an acyl group with fewer than 12 carbon atoms.

The acyl groups can be straight or branched or cyclic or in their chain structure be cyclic-aliphatic. The groups can be saturated, unsaturated or aromatic and with functional Groups such as hydroxyl groups, alkoxy groups with up to 5 carbon atoms, acyloxy groups with up to 12 carbon atoms, nitro groups, amino groups, halogen groups, etc., may be substituted. Typical esters are e.g. B. the acetate, propionate. oenanthate, benzoate, trimethyl acetate, tert-butyl acetate, Phenoxyacetate, cyclopentylpropionate, aminoacetate, / i-chloropropionate, adamantoate or dichloroacetate.

The new compounds show a progestatic, anti-oestrus and pituitary inhibitory efficacy; they are suitable for treating various menstrual disorders and for the control and regulation of fertility. You can in the doses corresponding to the disease to be treated in the usual pharmaceutical preparations administered.

The new connections are created by adding the corresponding 17a- (propadien-I'-yl) -östra-4-en-3-one implemented in one stage with a difluorocarbene precursor.

The starting materials used are described in US Pat. No. 3,392,166.

The difluorocarbenes can be used in any suitable and known manner, such as. B. from alkali metal salts corresponding trihaloacetic acids, e.g. B. the sodium chlorodifluoroacetate, dissolved in a suitable solvent. Another suitable one Difluorocarbene precursor is e.g. B. Trimethyl (trifluoromethyl) tin sodium iodide.

The reaction to introduce the carbene takes place under anhydrous conditions in an inert Solvent. The precursor is mixed with a suitable solvent and applied to the Reaction temperature heated steroid added. The steroid can also become a solution from precursors and solvent are added and the mixture is then heated. The special solvent as well as the reaction temperature will depend on the particular carbene precursor selected. the different precursors release the carbene under different conditions.

The alkali metal salts of trihaloacetic acid set the carbene through thermal decarboxylation free. The metal salt is in a suitable solvent, such as diethylene glycol dimethyl ether, diglyme, Triethylene glycol dimethyl ether, etc., dissolved, the steroid is added and the mixture to the appropriate Temperature heated. In the case of diglyme, the saline solution is based on the presence of the steroid 120 to 165 "C. The temperatures at which the other solvents mentioned above are expedient heated, can be found in the literature or can easily be determined by routine experiments. The trimethyl (trifluoromethyl) tin precursor forms the carbene when it is in a suitable Solvents such as benzene, toluene, etc., dissolve and reflux in the presence of sodium iodide. Other suitable precursors for the formation of carbenes are described in J. Am. Chem. Soc, Vol. 82, p. 1188 (1960), and Kirmse, "Carbene Chemistry" Vol. 1, Academic Press, pp. 145-169 (1964). Other precursors are also known. Usually 1 to 10 molar equivalents of the carbene precursor in a suitable solvent with the 17u-Propadienylsteroid implemented. However, one can up to 20 and even 50 molar equivalents of the carbene precursor use.

Preferably the 17 ^ -hydroxy compound is produced, by reacting a corresponding 17 / <- acylated compound with the carbene precursor and then saponified to the free 17 / y-hydroxy compound. Out the free 17 / y-hydroxy compound can then optionally the other 17/1 acyl compounds by conventional acylation.

The following examples illustrate the present invention without restricting it.

21 Ol

example

a) From a solution of 3.4 g (20 millimoles) of sodium difluorothloroacetate in 30 ecm diglyme (distilled over potassium hydroxide tablets) about 10 ecm of the diglyme were distilled off at 30 to 40 ° C under vacuum. The remaining solution was transferred to a dropping funnel which was attached to a three-necked flask. In the flask, 700 mg (2 millimoles) of 17 / i-acetoxy-17 «- (propadien-l'-yl) -estr-4-en-3-one were dissolved in 17 ecm diglyme and heated to the boil. The sodium salt solution was added dropwise over the course of an hour, a total of 40 ecm of diglyme being distilled off from the reaction mixture under normal pressure. The reaction mixture was refluxed for 10 minutes, cooled, filtered and evaporated. The crude product was separated by preparative chromatography in hexane / ethyl acetate. About 300 mg of 1 Tfi - acetoxy -1 Tu - (2 ', 3' - difluoromethylene prop - Γ - enl'-yl) oestra-4-en-3-one (m.p. = 135 to 141 "C) and 110 were obtained mg of crude, unconverted 17'-propadiene. The difluoromethylene propenylestrenone was recrystallized from acetone / water.

b) Similarly, 17 / i-Hydroxy-17a- (propadien-l'-yl) -estr-4-en-3-one implemented.

15th

c) 1 g of the 17p'-acetoxy-1 la - (T, y - difluoromethylene prop - 1 '- en -1' - yl) - oestr-4-en-3-one prepared according to a) was used at room temperature for 15 hours Ig potassium bicarbonate in 10 ecm water and 90 ecm methanol left to stand. After this time the methanol was evaporated under reduced pressure and the residue extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts gave 17 / i-hydroxy-17r; - (2 ', 3' - difluoromethylene prop -1 '- en -1' - yl) - oestr-4-en-3-one, which was filtered off and recrystallized from acetone / hexane.

d) The 17 / i-hydroxyestrenone obtained according to c) was dissolved in 60 ecm of anhydrous tetrahydrofuran, then 1.2 molar equivalents of ethylmagnesium bromide in ether were added. After a few minutes, 1.2 molar equivalents of propionyl chloride were added. The mixture was allowed to stand at room temperature for 15 hours, diluted with water and extracted with methylene chloride. The extracts were washed neutral with water, dried and evaporated. The residue was chromatographed on neutral alumina, eluting with ether / hexane; 17 / i-propionoxy- ¹ .7u- (2 ', 3'-difluoromethylene-prop-1' -en-1 '-yl) -ostr-4-en-3-one was obtained in this way.

Claims (1)

21 Ol patent claims: 1. 17u- (2'.3'-difluoromethylene prop- Γ-εη- Γ-yl) -östra-4-en-3-ones the general formula H, C CH = C- -CH,