DE3242894A1 - 17 alpha -Substituted equilenin derivatives, processes for their preparation and pharmaceuticals containing these - Google Patents

Abstract

The invention relates to 17 alpha -substituted equilenin derivatives of the general formula I <IMAGE> in which n denotes the numbers 0 or 1 to 3 and R<1> represents a hydrogen atom or a C1-4-acyl radical. These compounds have a potent inhibitory effect on progesterone biosynthesis and can be used for postcoital fertility control.

Description

17a-Substituted Equilenin-

derivatives, processes for their production and pharmaceuticals containing them description The invention relates to new 17α-substituted equilenin derivatives and methods for their production and medicaments containing them according to the claims.

Hydroxyl protective groups are to be understood as meaning the intermediate protection of free hydroxyl groups by groups that can easily be split off again. Protection with dihydropyran, methyl vinyl ether, formaldehyde dimethylacetal or 1-chloromethoxy-2-methoxyethane1, where the radicals R and R represent a hydroxyl protective group, may be mentioned in particular -CH2-O-CH3 or -CH20CH2CH20CH3 means.

The new compounds according to the invention have the property that Inhibit progesterone biosynthesis from pregenolone. As the endogenous progesterone concentration to maintain a pregnancy do not fall below a certain value may be done by administering compounds with a progesterone synthesis inhibiting effect affect and interrupt pregnancy.

Substances of this type are therefore used for post-coital fertility control suitable.

Steroid compounds with an inhibitory effect on progesterone biosynthesis are known and described, for example, in US Pat. No. 4,160,027 such as, for example Trilostane (4 ", 5z-epoxy-17R-hydroxy-3-oxo-5a-androstane-2a-carbonitrile) and 4,17-dimethyltrillostan (4β, 17a-Dimethyl-4a, 5a-epoxy-17R-hydroxy-3-oxo-5a-androstane-2a-carbonitrile) The Compounds according to the invention are in their inhibitory effect on progesterone biosynthesis superior to the cited compounds of the prior art, such as the following Table shows: Table 1 shows the percentage inhibitory effects on progesterone biosynthesis at the same concentration of trilostane, 4,17-dimethyltrilostane and the Compound according to the invention 17a- (3-hydroxypropyl) -1,3,5,6,8-estrapentaen-3,17β-diol (Compound A) compared.

The compounds according to the invention prove to be as in the example the compound A shown - at each concentration compared to the comparison compounds than more effective.

Table 1 Concentration% inhibition (Moles / 1) Trilostane 4,17-dimethyl compound A Trilostane 5x10-7 79.2 81.6 94.8 1x10-7 57.1 84.0 93.1 5x10-8 45.7 37.0 86.4 1x10-8 24.0 22.4 54.3 1x10-9 15.1 17.9 23.4 The inhibitory effect of the test substance to be examined can be determined by two methods; Both methods use the reaction equation of the dehydration of pregnenolone with NAD) (nicotinamide adenine dinucleotide) to progesterone, whereby the equivalent amount of NADH + (reduced nicotinamide adenine dinucleotide) arises: One of the two measurement methods makes use of the fact that the amount of NADH produced is proportional to the amount of progesterone produced; the increase in WADH is determined by measuring the absorbance at 340 nm.

Leaving the reaction in the presence of radiolabelled 1t- or 3H-pregnenolone are going on, the increase in C- or 3H-progesterone can be measured will.

By comparison with the results of the corresponding reaction without The percentage of inhibition values is obtained by adding an inhibiting substance.

The invention also relates to a method of making compounds of the general formula I according to claim 5.

For the preparation of the compounds according to the invention of the general Formula I, in which n = 0 and R 1 has the meaning given in claim 1, is the oxirane of the general formula II in a suitable polar solvent such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone- (2) dissolved and after adding a dilute aqueous alkali metal hydroxide solution at a Temperature from 500C to 1200C, preferably 900C to 1100C, stirred and the progress the reaction was followed by thin layer chromatography.

After the reaction has ended, the mixture is cooled and by adding a organic acid or mineral acid such as acetic acid, hydrochloric acid, dilute sulfuric acid or trifluoroacetic acid is neutralized and worked up.

If one proceeds for the preparation of the compounds according to the invention according to of process variant b), the starting compound of the general formula is dissolved III in an aprotic, dry solvent such as tetrahydrofuran, Dioxane, diethyl ether or toluene and reduced by adding a complex metal hydride such as LiAlH4 or diisobutylaluminum hydride at a temperature of OOC to 200C, preferably at OOC to 50C. When the reaction is complete, the Worked up in a manner known to those skilled in the art by carefully adding water and diluted aqueous alkali hydroxide such as sodium hydroxide drips until formed a precipitate, which is filtered off and with organic solvent is washed. The filtrate is concentrated and the reaction product is worked up.

If one proceeds according to process variant c), the starting material becomes of the general formula IV in a solvent suitable for the hydrogenation such as Dissolved methanol, ethanol, tetrahydrofuran or ethyl acetate and, after adding a Noble metal catalyst such as palladium, palladium on barium sulfate or palladium / carbon shaken in a hydrogen atmosphere until hydrogen uptake ceases is.

The catalyst is then filtered off and the reaction product is concentrated by evaporation obtain.

Contain the products obtained according to the three process variants or hydroxyl protective groups, these will be used following the reactions described removed by acid hydrolysis according to methods known to the person skilled in the art.

For example, the solution of the compound of the general formula is stirred wherein n has the meaning given in claim 1 and X and Y are identical or different and are hydrogen or a hydroxyl protecting group, in methanol, ethanol or aqueous dioxane with an aqueous solution of a mineral acid such as dilute hydrochloric acid, dilute sulfuric acid or at a temperature of 200 up to the boiling point of the solvent and controls the reaction by thin layer chromatography. Then it is neutralized by adding bases such as aqueous solutions of sodium bicarbonate, sodium hydroxide or potassium carbonate, mixed with ethyl acetate, methylene chloride or ether, extracted and worked up. If the compounds of the formula I according to the invention with n as defined in claim 1 and R as a C1-4 acyl radical are obtained, the compounds of formula I with n as defined above and R1 as a hydrogen atom are obtained acylated by methods known to those skilled in the art. For example, the compound to be acylated in a suitable solvent such as dimethylformamide or dimethylacetamide in the presence of a base such as pyridine, trimethylamine or 4-dimethylaminopyridine with an acid anhydride (acyl) 20 or an acid halide acyl-Hal with Hal meaning chlorine or bromine Allow to react at 100 ° to 300 ° C. until the reaction has ended according to thin-layer chromatographic control. This reaction can also be carried out without a solvent only in the presence of the base, which then serves as the solvent. After the reaction has ended, it is diluted with ice water and worked up.

The starting compounds required for the production process according to the invention can be prepared by methods known to those skilled in the art.

The following work instructions are intended to describe these procedures in greater detail explain: 3-tetrahydropyranyloxy-spiro-, 3,5,6,8-estrapentaen-17ß, 2'-oxirai7 a) A suspension of 5 g equilenin in 50 ml methylene chloride and 5 ml dihydropyran 50 mg of p-toluenesulfonic acid are added while cooling with ice, and the mixture is stirred at 250C for 16 h. It is then diluted with ethyl acetate and washed with sodium bicarbonate solution and narrowed. 6.1 g of 3-tetrahydropyranyloxy-1,3,5,6,8-estrapentaen-17-one are obtained as a crude product, which is used in the next stage without further purification.

b) A solution of 1.0 g of the tetrahydropyranyl ether obtained under a) 874 mg of trimethylsulfonium iodide are added to 10 ml of dimethylformamide. Under Ice-cooling, 513 mg of potassium tert-butoxide are added in portions and the mixture is stirred for 15 Minutes after. The reaction solution is stirred into ice water, the precipitate filtered off and dried. Recrystallization of the crude product thus obtained Diisopropyl ether gives 970 mg of 3-tetrahydropyranyloxy-spiro-r1,3,5,6,8-estrapentaen-17ß, 1'-oxirane] of melting point 160-162 ° C, [α] D20 -136.60 (CHCl3, c = 0.5).

17a-ethoxycarbonylmethyl-3-methoxymethyl-1, 3,5,6,8-estrapentaen 17β-ol a) A suspension of 5 g of equilenin in 60 ml of formaldehyde dimethyl acetal and 60 ml of methylene chloride is successively mixed with 5.0 g of Celite at room temperature and 2.5 g of P4 010 are added and the mixture is then vigorously stirred for 4 hours at 250C. Thereafter the reaction solution is filtered and the filter residue with methylene chloride thorough washed. After adding 2 ml of triethylamine, the filtrate becomes in a water-jet vacuum constricted.

Chromatography of the crude product over silica gel with hexane / acetone gives 4.5 g of 3-methoxymethyl-1,3,5,6,8-estrapentaen-17-one with a melting point of 112-114 ° C.

b) A solution of 1.45 g of the product obtained under a) in 20 ml 3 g of zinc shavings and a grain of iodine are added to absolute THF. To do this, drips a solution of 3 ml of ethyl bromoacetate in 10 ml of absolute THF, so that the internal temperature does not exceed 400C. The mixture is then stirred for 5 hours at 40 ° C. filtered ', dilute the filtrate with ethyl acetate, wash with NaH2PO4 solution and water and constricts. Chromatography of the crude product over silica gel with hexane / ethyl acetate gives 1.45 g of 17α-ethoxycarbonylmethyl-3-methoxymethyl-1,3,5,6,8-estrapentaen-17β-ol of m.p. 70-720C, [α] D20 27.80 (CHCl3, C = 0.5).

17a- (3-tetrahydropyranyloxypropin-1-yl) -1,3,5,6,8-estrapentaen-3,17β-diol a) A solution of 9.4 g of propargyl alcohol tetrahydropyranyl ether in 200 ml of absolute Tetrahydrofuran is added dropwise with 38.5 ml of a 15% solution while cooling with ice mixed with n-butyllithium in hexane.

A solution of 5.0 g equilenin in 100 ml is then added dropwise Section. THF to it and stir for 16 hours at room temperature. After that, it is poured into saturated Ammonium chloride solution and extracted with methylene chloride.

17a- (3-Tetrahydropyranyloxy-propyn-1-yl) 1,3,5,6,8-estrapentaen-3,17-diol is obtained as a raw product.

The invention also relates to medicaments according to claim 6, which at least a compound of the general formula I according to claims 1 to 4 contain.

The pharmacologically active compounds of the formula according to the invention I can use galenical methods known per se to produce drugs, in particular for oral application.

The dosage of the compound according to the invention or of the mixture of several of these compounds of general formula I is included in humans 50-300 mg / day total amount of active ingredient.

The following examples are intended to illustrate the process according to the invention explain: Example 1 570 mg of 3-tetrahydropyranyloxy-spiro1,3,5,6,8estrapentaene 17β, 2'-oxirane7 are dissolved in 25 ml of dimethylformamide and, after adding 1.2 g Potassium hydroxide and 2.7 ml of water were stirred for 8 hours at 1000C. After cooling down it is diluted with ethyl acetate, washed with saturated sodium chloride solution and concentrated. The crude product obtained in this way (680 mg) becomes tetrahydropyranyl ether cleavage without further purification used by dissolving it in 17 ml of methanol and after adding 3.4 ml of 1N sulfuric acid 30 min.

stirs at 250C. Then neutralize by adding 1 n Sodium hydroxide, diluted with ethyl acetate and washes neutral. The crude product (330 mg) is purified by preparative layer chromatography (chloroform / acetone). Crystallization of the main fraction from ethyl acetate / diisopropyl ether gives 100 mg 17α-hydroxymethyl-1,3,5,6,8-estrapentaen-3,17β-diol, melting point 242-2440C.

Example 2 100 mg of 17a-ethoxyearbonylmethyl-3-methoxymethyl-1,3,5,6,8-estrapentaen-17β-ol are dissolved in 2 ml of absolute tetrahydrofuran and, while cooling with ice water, with 39 mg lithium aluminum hydride added. The mixture is stirred at room temperature for 3 hours carefully add 0.1 ml of water and 0.1 ml of 2N sodium hydroxide, filter, wash the filter residue with tetrahydrofuran and the filtrate is concentrated. The thus obtained The crude reduction product (106) is crystallized from ethanol, and 17a- (2-hydroxyethyl) -3-methoxymethyl-1,3,5,6,8-estrapentaen-17β-ol is obtained; Melting point 167-169 ° C.

A solution of 100 mg of the product obtained in 5 ml of ethanol and 0.5 ml of 1N sulfuric acid is refluxed for 3 hours. After cooling down it is diluted with ethyl acetate, washed with water and concentrated. After crystallization 62 mg of 17- (2-hydroxyethyl) -1,3,5,6,8-estrapentaen-3,17β-diol are obtained from ethanol of melting point 2.88-2900C.

Example 3 A solution of 3.3 g of 17a- (3-tetrahydropyranyloxy-propyn-1-yl) -1,3,5,6,8-estrapentaen-3,17β-diol in 100 ml of ethanol after addition of 330 mg of palladium carbon (10% Pd) at room temperature and normal pressure hydrogenated. After uptake of 515 ml of hydrogen (1.5 hours) filtered off from the catalyst and concentrated. The crude product thus obtained is in 50 ml of methanol added and after the addition of 10 ml of 2N sulfuric acid for 2 hours Stirred at 250C. The reaction solution is then stirred into ice water and filtered and dries the precipitate. Crystallization of the crude product from ethanol results 1.6 g of 17a- (3-hydroxypropyl) -1,3,5,6,8-estrapentaen-3,17β-diol, melting point 213-2150C.

Example 4 2 g of 17a- (3-hydroxypropyl-E12-1,3,5,6,8-estrapentaen-3,17ßdiol are stirred in 20 ml of acetic anhydride and 10 ml of pyridine for 2 hours at 250C. The batch is then poured into ice water and extracted with ethyl acetate.

The extract is dried and evaporated, the residue from ethyl acetate recrystallized. 1.82 g of 3-acetoxy-17a- (3-acetoxypropyl-C1-1, 3,5,6,8-estrapentaen-17β-ol; Melting point 118-1190C.

Claims (6)

Claims 1. 17α-Substituted equilenin derivatives of the general formula I. where n is the numbers 0 or 1 to 3 and R is a hydrogen atom or a C1-4 acrylic radical. 2. 17α-hydroxymethyl-1,3,5,6,8-estra-pentaene-3,17β-diol. 3. IYa- (2-hydroxyethyl) -1,3,5,6,8-estrapentaen-3,17β-diol. 4. 17α- (3-hydroxypropyl- [1]) - 1,3,5,6,8-estrapentaen-3, 17β-diol. 5. Process for the preparation of 17-substituted equilenin derivatives of the general formula I. in which n is the numbers 0 or 1 to 3 and R1 is a hydrogen atom or a C1 4 acyl radical, characterized in that in a manner known per se, a) for the preparation of the compound of the formula I with n = 0 and R 1 in the above mentioned meaning an oxirane of the general formula II wherein R2 represents a hydrogen atom or a hydroxyl protective group, hydrolyzed under alkaline conditions and, if necessary, cleaves off the hydroxyl protective group and, if desired, acylates free primary and secondary hydroxyl groups or b) for the preparation of the compound of the formula I with n = 1 and R in the abovementioned meaning a 17a-lower alkoxy carbonyl methyl compound of the general formula III where R2 has the abovementioned meaning and R3 can be a C1 4 -alkyl radical, reduced with a complex alkali metal hydride and, if necessary, splitting off the hydroxyl protective group and, if desired, acylating free primary and secondary hydroxyl groups, or c) for the preparation of the compound of the formula I with n = 2 or 3 and R1 in the abovementioned meaning is a 17a-alkynyl compound of the general formula IV where R has the abovementioned meaning, m is 1 or 2 and R4 is a hydrogen atom or a hydroxyl protective group, hydrogenated with catalytically activated hydrogen and, if necessary, cleaves off the hydroxyl protective groups present in the molecule and, if desired, acylates free primary and secondary hydroxyl groups 6. Medicaments containing at least one of the compounds according to the claims 1 to 4.