NO127194B - - Google Patents

Description

Analogy method in the preparation of pharmacological

active 18-methyl-19-nor-17a-hydroxyprogesterones and their

esters.

The present invention relates to an analogous process for the production of new 18-methyl-19-nor-17a-hydroxyprogesterones and their -17-esters of the general formula

where R denotes hydrogen or an acyl residue with 1-11 C atoms in the ester residue, and C^ :.... Cy denotes a single or double carbon-carbon bond, which method is distinguished by reducing l8-methyl-19 -nor-A^'^-pregnatriene-3,17a-diol-20-one-3-alkylether-20-ketal according to Birch in liquid ammonia or electrolytically in an organic solvent, hydrolyzes the primary product in an acidic environment and optionally then converts the thus obtained 18-methyl-19-nor-17a-hydroxyprogesterone with a desired acid or a reactive acid derivative to the -17-ester and, if desired, introduces a double bond at the 6,7-position.

The alkyl group in the ether group in the 3-position of the starting material is a lower alkyl group, preferably -CH 2 or -C 2 H 2 -.

The compounds produced have a surprisingly strong progestagen effect. It was unexpected that these compounds, represented by 18-methyl-19-nor-17a-hydroxyprogesterone-17-acetate (VI) and 18-methyl-19-nor-17a-hydroxyprogesterone (VII), should prove to be better than e.g. the known, already highly progestogenic compounds I-V, as shown in the table below. The test results were obtained by subcutaneous administration in oil solution to rabbits in the usual Clauberg test, with the McPhail index being used as a comparison value.

For practical use, e.g. in progestagen therapy, the new active compounds are mixed with the usual carrier materials in galenic pharmacy and transferred to the usual administration forms, such as tablets, dragees, capsules, injection solutions, etc.

The production of the new compounds is carried out according to work methods known per se. For the reduction of the aromatic A ring, in addition to the commonly known chemical reduction according to Birch in liquid ammonia with preferably lithium, electrolytic reduction in a suitable solvent and in the presence of electrolyte salts is also suitable.

Solvents suitable for use during the electrolysis are preferably primary or tertiary alkylamines or also aliphatic amines with several amino groups. Particularly suitable are methylamine, ethylamine and ethylenediamine. If the solubility of the steroid used as starting material is too small in the aforementioned bases, solvents can also be added to the reaction mixture, e.g. ethers such as tetrahydrofuran, as co-solvent.

As electrolyte salts, such salts are used which dissociate well in the solvents or solvent mixtures used. Particularly suitable are alkali metal and alkaline earth metal halides, such as lithium chloride, potassium iodide, calcium iodide, etc.

The 20-ketal of the A'-3-alkyl ether obtained primarily by chemical or electrolytic reduction is hydrolyzed in the usual way to 18-methyl-19-nor-17a-hydroxyprogesterone, preferably with a strong acid.

Any subsequent esterification is carried out according to conventional methods. Examples include reaction with the anhydride or acid halide of the base acid in the presence of acidic or basic reagents, or esterification of the desired acid in the presence of trifluoroacetic anhydride.

Acids that can be used in the esterification are all acids which

are applicable in steroid chemistry. Preferred acids are aliphatic carboxylic acids, with from 1 to 11 carbon atoms in the acid radical, such as e.g. acetic acid, propionic acid, caproic acid, enanthic acid, undecyl acid, etc. Of course, the acids can also be unsaturated, branched, polybasic or substituted in the usual way. Examples include trimethyl-, dimethyl-, diethyl-. and t-butylacetic acid, 2,2-dimethylbutyric acid, phenyl or cyclohexylacetic acid, cyclopentylpropionic acid, haloacetic acid, aminoacetic acid, oxypropionic acid, benzoic acid, succinic acid and adipic acid.

The possibly subsequent introduction of the A^ double bond is likewise carried out in a manner known per se. As a dehydrating agent, e.g. chloranil or 2,5-dichloro-5,6-dicyano-benzoquinone are used.

However, the introduction of the A^ double bond can also be carried out on

known manner over the A^'^-3-alkyl ether with cleavage of an in 6-style

ling introduced halogen atom.

The 20,20-ethylenedioxy-18-methyl 1-19-nor-A1' 3»5 (10)_pregna-trien-3,17a-diol-3-methylethene used as starting material in the process according to the invention is likewise new and can is prepared according to the following, per se known method: 17a-ethynyl-18-methyl-A<1>'<3>'<5>^<10>^-estratriene-3,17p,diol-3 methyl ether (melting point 99>5 - 102°C; prepared from 3-methoxy-18-methyl-1,35(10)-estratrien-17p-ol- by oxidation with chromic acid and reaction of the obtained 17-ketone with melting point 144 - l45°C in ethylenediamine with acetylene in the presence of dissolved lithium) is obtained by in-

effect of POCl^ (8 hours at 70°C ) in the presence of 2,4-lutidin-17-ethi-nyl-18-methyl-A2 »3»5(10),16_estratraen_3_0i_3_methylethne (melt-

point 94 - 96°C), which by addition of water to the ethynyl group and epoxidation of the A^-double bond mec] H202/NaOH is transferred to 16a, 17a-oxido-18-methyl-19-nor-A1'^'^ (10 )-pregnatrien-3-ol-20-on-3-methylether (m.p. 109 - HO°C) over 18-methy1-19-nor-Al,3,5(10),<lD_>pregnatetraen_3_oi_20-on-3- methyl ether (142.5 - 143.5°C).

For the introduction of the 17a-hydroxy group, the oxidation ring is opened with HBr/ice-

vinegar, after which the simultaneously introduced 16-bromo atom is removed by reduction

tive in the presence of palladium and carbon. The 20-keto group in the 18-methyl-19-nor-A1'^'^ ^10^-pregnatrien-3,1/a-diol-20-one-3-methylether thus obtained (melting point 1/5 - 1/6 .5°C) is then finally ketalized with ethylene glycol in the usual way.

Example 1

A solution of 6 g of 20,20,ethylenedioxy-18-methy1-19-nor-A<1>'^'^(10)-pregnatriene-3,17a-diol is slowly added dropwise at -70°C to 600 ml of liquid ammonia -3-methyl ether in 350 ml of tetrahydrofuran, where-

after that it is flushed with 250 ml of absolute tetrahydrofuran. After the addition is complete, add 6 g of lithium in portions, after which the reaction mix-

is rotated for 2 hours at a temperature from -60° to -50°C, de-coloured by the careful addition of 240 ml of ethanol and then added

allowed to warm to room temperature. The mixture is then taken up in methylene chloride, and the organic phase is washed thoroughly with water. The solution dried over sodium sulfate is evaporated in vacuo under a nitrogen atmosphere. The remaining residue is dissolved in a mixture of 200 ml of methanol and 40 ml of methylene chloride, and the solution is added

30 ml of concentrated hydrochloric acid and 55 ml of ice water and stirred for two hours at 40°C. The mixture is then diluted with water and extracted with methylene chloride, and the organic phase is washed with water, sodium bicarbonate solution and then again with water to a neutral reaction and dried over sodium sulfate. The solvent is distilled off, and re-

the side is recrystallized from ethyl acetate over carbon. 3.25 g of 18-methyl-19-nor-α-pregnen-17α-ol-3,20-dione are obtained. Melting point 216-217°C; UV (methanol): e2/+0 = lb oOO.

Example 2

To a mixture of 0.3b ml of glacial acetic acid and 2.5 ml of absolute benzene

0.63 ml of trifluoroacetic anhydride is added at 0°C. After 10 minutes, 1.05 9 lo-methy1-lo-nor-A 4-pregnen-17a-ol-3,20-dione is added to this solution, and the mixture is stirred for 3 hours at room temperature under a nitrogen atmosphere and then for 2 hours at b0 °C. After to-

addition of 1 ml of methanol, the mixture is evaporated to dryness, after which 1.5 ml of methanolic hydrochloric acid is added to the residue (100 ml of methanol in

containing 0.6 ml of concentrated hydrochloric acid), and the mixture is heated at boiling point for 45 minutes. After cooling, the mixture is diluted with water, after which the substance is extracted with ether and the organic extracts are washed to a neutral reaction with water and sodium bicarbonate solution. After drying over sodium sulfate and distilling off the solvent, the crude product is chromatographed over 20 g of silicic acid

gel (deactivated with 10% water), with petroleum ether/acetone (from 0% to 20% acetone). 525 mg of 18-methyl-19-nor-α-pregnen-17α-ol-3,20-dione-17-acetate are obtained. Melting point 210-212°C (from acetone/hexane); UV

(methanol): ^40 = 1^ 10°*;Example 3 <->■<-->;A mixture of 5 g of ltt-methyl-19-nor-A^-pregnen-17a-pl-3,20- dione-17-acetate and 10 g of chloranil in 125 ml of ethyl acetate and 25 ml of glacial acetic acid I, heated at the boiling point for 20 hours under a nitrogen atmosphere.After cooling, the mixture is diluted with ether and it is terred with V"4jÉB g^Bgar-then it is washed with 1%-ig caustic soda until the organic phase has become colorless. After drying over sodium sulfate and removal of the solvent, the residue is chromatographed over silica gel. 2.3 g of ltt-methyl-19-npr-A^'<6->pregnadien-1 are retained -7a-ol-3v20-df^rl7-acetate. 'Illist f ;Example 4 ;To a solution of 4.7 g of 18-methyl-19-nor-A^-pregnen-1Jg-ol-3,20-dione -17-acetate in 25 ml abs. dioxane is added with stirring, 4 ml ethyl orthoformic acid and 1 ml of a solution of 2.5 ml conc. sulfuric acid in JO ml abs. dioxane. After 30 minutes of stirring at room temperature, the reaction mixture is added with 1 ml abs. pyridine, after which the mixture is evaporated in a rotary evaporates and the residue is triturated with acid-free methanol. The product is purified by recrystallization from methanol/methylene chloride. 4 g of 1S-methyl-19-nor-N-[alpha]-pregnadiene-3,17a-diol-20-one-3-ethylether-17a-acetate are obtained. A mixture of 86 ml of acetone, 0.6 ml of pyridine, 2.7 g of sodium acetate, 27 ml of water and 4,5 9 18-methyl-19-nor-αJ'-pregnadiene-3,17a-diol-20 -one-3-ethylether-17a-acetate is cooled to -5°C and, over the course of 20 minutes and thorough stirring, 2.2 g of N-bromosuccinimide and 2.7 ml of glacial acetic acid are added. After stirring for 1 1/2 hours while maintaining the temperature in the range from 0° to -5°C, it is extracted with ether, after which the organic phase is washed to a neutral reaction with water and dried. The solution of 6a-bromo-18-methyl-19-nor-A^-pregnen-1/a-ol-3,20-dione-17-acetate in ether is evaporated in vacuum to a small volume at a temperature below 20°C , after which 70 ml of dimethylformamide, 15 g of calcium carbonate and 7 9 of lithium bromide are added. Nitrogen is blown through the solution^ and this is heated somewhat to drive off residues of ether. Finally, the mixture is heated for half an hour at 120°C with stirring and under a nitrogen atmosphere. The calcium carbonate is then filtered off hot using a sintered glass filter, after which the solid residue is washed with hot dimethylformamide and the filtrates are combined and poured into ice water. After neutralization of the water sweep with sulfuric acid, the precipitate is filtered off. The residue is dissolved in methylene chloride and the solution is washed with water and dried. After distilling off the solvent, the crude product obtained is chromatographed over silica gel. 2.5 g of lb-methy 1-19-nor-H 3 -pregnadien-17a-ol-3,2o-dione-17-acetate are obtained. ;Example 5 ;From 700 ml of 18-methyl-19-nor-A^-pregnen-17a-ol-3,20-dione, 0.456 ml of caproic acid and 0.42 ml of trifluoroacetic anhydride in 2.5 ml. abs. benzene is prepared in a similar way as in example 2 350 mg 18-methyl-19-nor-α-pregnen-17a-ol-3,20-dione-17a-capronate. Melting point 109-110°C (ether/pentane); UV (methanol): £^39 = 17 300. ;Example 6. ;Through a solution of 14 g of 20,20-ethylenedioxy-18-methy1-19-nor-A"'"' -pre<g>natriene-3 ,17ct-diol-3-methylether and 75 g of lithium chloride in 15,000 ml of methylamine are passed for 12 hours under reflux and with stirring a direct current of 1.5 A and 35-<*>+0 V. The distance between the electrodes is 12.5 cm. After the reaction is complete, 50 ml of methanol is added, after which the methylamine is distilled off and the substance is precipitated in water. The skimming is filtered off and taken up in methylene chloride. The organic phase is washed to a neutral reaction with water and evaporated in a vacuum. The residue is dissolved in a mixture of <>>+00 ml of methanol and 80 ml of methylene chloride, and the solution is added to 60 ml. conc. hydrochloric acid and 100 ml of ice water and stirred for 2 hours at <1>+0°C. The mixture is then diluted with water, the substance is extracted with methylene chloride, and the organic phase is washed neutrally with water, sodium bicarbonate solution and then again with water and dried over sodium sulfate. The solution is evaporated to dryness. The residue is recrystallized from ethyl acetate over carbon. 6,3 and 18-methyl-19-nor-A<L>+--pregnen-17a-ol-3,20-dione are obtained. Melting point 216°C; UV (methanol): <£>2^0 <=> ^ 600.

Claims (3)

1. Analogous method for the production of pharmacologically active 18-methyl-19-nor-17ct-hydroxyprogesterones and their -17-esters of where R denotes hydrogen or an acyl residue with 1-11 carbon atoms in the ester residue and C> C„ denotes a single or double carbon-carbon bond, characterized in that 18-methyl-19-nor-A<1>'^'^( <10>)-pregnatriene-3,17a-diol-20-one-3-alkylether-20-ketal is reduced according to Birch in liquid ammonia or electrolytically, in an organic solvent and that the primary product is hydrolyzed in an acidic environment and that the thus obtained 18-methyl-19-nor-17a-hydroxyprogesterone is optionally reacted with a desired acid or a reactive acid derivative to -17-ester, and that, if desired, a double bond is introduced in the 6,7 position. 2. Analogous method according to claim 1, characterized in that 20,20,ethyleneoxy-18-methyl-19-nor-Al'^' (10')-pregnatriene-3,17a-diol-3-methylether is reduced after 3irch in liquid ammonia , after which the reaction product is hydrolysed in an acidic environment. 3. Analogous method according to claim 1, characterized in that 18-methyl-19-nor-17a-hydroxyprogesterone is reacted with glacial acetic acid in the presence of trifluoroacetic anhydride. h. Analogous method according to claim 1, characterized in that 18-methyl-19-nor-17a-hydroxyprogesterone is reacted with caproic acid in the presence of trifluoroacetic anhydride.