DE1493318C - 3 beta, 17 alpha dihydroxy 6 alpha methyl 4 pregnen 20 on 3 sodium succinate 17 acetate and 3beta, 17 alpha dihydroxy 6 methyl 16 methylene 4,6 pregnadiene 20 on 3 sodium succinate 17 acetate and processes for the production of these compounds - Google Patents

Description

The invention relates to 3 / i, 17a-dihydroxy- 6 (i- methyl-4-pregnen-20-one-3-sodium succinate-17-acetate of the formula

CH ₃

and 3 //, l Ta-dihydroxy-o-methyl-lo-methylene-'l.o-pregnadiene-2 () - one-3-sodium succinate-17-acetate the formula

RO-

CH ₃

where R is the radical NaOOC-CH ₂ -CH ₂ -CO-, and a process for the preparation of these compounds.

The inventive method consists in that one in a known manner a corresponding 3-Hydroxy compound reacts with an agent introducing the succinic acid residue and that obtained hemisuccinate converted into the sodium salt.

The compounds of the invention are therapeutic and provide fertility Decreasing, estrus-regulating, progestatic and pregnancy-maintaining Agents with an improved therapeutic index. They are also suitable for the treatment of inflammatory conditions, especially for the treatment of inflammatory processes of the skin, eyes and ears as well as for the treatment of contact dermatitis, anaphylaxis and other allergic symptoms.

They can be administered in the usual dosage forms, e.g. B. in the form of pills, Tablets, capsules, syrups or emulsions for oral administration or in liquid form like them is known for natural and synthetic corticoid hormones for parenteral administration. You can Also administer locally in the form of ointments, creams, lotions and the like, if necessary together with other antibiotics, germicides, etc.

The compounds of the invention are the first progestins that are easily found in water and Dissolve aqueous buffer solutions and are therefore injected intravenously to achieve high progestin levels be able. The inhibition of uterine activity achieved with them corresponds to that with a microcrystalline Suspension of 6'-methyl-17a-hydroxyprogesterone-17-acetate (Medroxyprogesterone Acetat, Provera) achieved. However, intravenous injection of a microcrystalline suspension is dangerous. It always carries the risk of blockage of the blood vessels and a pulmonary embolism. With the

It is the first time compounds according to the invention It has become possible, through intravenous injection, to rapidly reach high progestin levels which block uterine activity to generate and thus to prevent an impending abortion.

The aqueous solutions of the compounds according to the invention can be used to achieve a rapid and strong effects can of course also be used intra-amniotic and orally.

A preparation to be administered intravenously can be prepared in such a way that powdered 3 β, 17α - dihydroxy - 6α - methyl - 4 - pregnen 20-one-3-sodium succinate-17-acetate is sterilized with ethylene oxide gas and it is then sterilized in quantities of 100 mg aseptically filled into sterile 5 cm ^J -ampules. If there is a risk of abortion, sterile sodium chloride injection solution is added until a volume of 2 ml is achieved. The solution can be administered intravenously or intramuscularly.

Acylation with the succinic acid residue

.10 introducing agent is carried out using the acylating agent as a solvent, preferably in the presence of a suitable other inert solvent, such as benzene, toluene, xylene, dioxane, Methylene chloride, dimethylformamide, ether and the like, especially if the acylating agent is a solid, furthermore often in the presence of a catalyst, such as p-toluenesulfonic acid, or an amine, preferably Pyridine. Depending on the temperature and solvent, the reaction time is a few minutes

4c 24 hours. If the acylating agent is the free Acid is used, the reaction is preferably carried out in the presence of an esterification catalyst, such as p-toluenesulfonyl chloride, trifluoroacetic anhydride, p-Toluenesulfonic acid, tritluoroacetic acid, sulfuric acid or the like.

If the esterification does not proceed completely at room temperature, temperatures of up to 90 "C, preferably of about 65 "C. The progress of the reaction becomes appropriate followed by thin layer chromatography over clay or synthetic magnesium silicate ("Florisil").

The acylation product is isolated from the reaction mixture in a manner known per se, e.g. B. by Precipitation with water or dilute inorganic acid and filtration or extraction with one water-immiscible solvents such as methylene chloride, ethyl acetate, benzene, ether, etc., direct crystallization, chromatography, counter-

^fo electricity extraction or a combination of these measures.

For the subsequent salt formation, the 3-acylate can also be used in its raw form.

The conversion into the sodium salt /. takes place after

⁶ S methods known per se, / .. B. according to the method described in US Pat. No. 3,025,311. The following examples explain this process according to the invention:

Claims (3)

B eis ρ ie 1 1 a) 3 / (, l 7 (x-Dihydroxy-6 «-methyl-4-pregnen-20-one-3-hemisuccinate-17-acetate To a solution of 2.5 g 3 /) ', 17 "-Dihydroxy-6u-methyl-4-pregnen-20-one-l 7-acetate (prepared from 17 (i-hydroxy-6fi-methyl-4-pregnen-3,20-dione-l 7-acetate by reduction with lithium aluminum tri-tert-butoxyhydride) in 25 ml of pyridine, 2.5 g of succinic anhydride were added.The reaction mixture was kept at room temperature for about 16 hours and then heated for about 12 hours to 60 ° to 70 ° C. The succinic acid ester appeared on thin-layer chromatography The reaction mixture was poured into ice water containing 30 ml of concentrated hydrochloric acid, the precipitate formed was collected, washed well with water, dried and slurried in 100 ml of water containing a slight amount of water 60 ml of 0.1 η sodium hydroxide solution were then slowly added in order to dissolve the precipitate. Filtering through a layer of diatomaceous earth removed a small amount of insoluble material. The product was precipitated from the filtrate by adding 3N hydrochloric acid dropwise. The precipitate was collected, washed with water and dried. 2.7 g of a product containing 3 / i, 17u-dihydroxy-6-i-methyl-4-pregnen-20-one-3-hemisuccinate-l 7-acetate, which was processed further without purification, were obtained. b) 3 / ;, 17a-dihydroxy-6a-methyl-4-pregnen-20-one-3-sodium succinate-17-acetate To a solution of 1.0 g of the product obtained above in 50 ml of acetone, the equivalent amount ( 0.177 g) sodium bicarbonate in 8 ml of water. Water was added from time to time while removing the acetone on a rotary evaporator. After the acetous had been removed, a clear solution was obtained which was diluted with about 15 ml of water and frozen in a 1-1 round bottom flask with stirring. The frozen product was lyophilized. A fluffy amorphous powder was obtained which was dissolved in water and filtered through a layer of diatomaceous earth. The filtrate was freeze-dried again, whereupon 1.0 g of 3 / i, 17ii-dihydroxy-6-i-methyl-4-pregnen-20-one-3-sodium succinate-17-acetate was obtained as an amorphous solid, the intense IR Absorption bands at 1725 (C = C)) and 1245 (CO-) cm "1. The molecular weight determined by titration was 529 (theoretical value 510). 3 / i, 17 <t-dihydroxy-6 (i - methyl - 4 - pregnen - 20 - on - 3 - nutriumsuccinut 17-acetate has a half-life of significantly more than one hour at a pH value of 9 at 25 ". It is a light white powder without a defined melting point. Analysis: Calculated .. .C 65.86, H 7.70, Na 4.50; found C 65.95, H 7.92, Na 4.53. '.: "·" "-. 285 ιημ 2 a) 3 /), 17a-dihydroxy-6-methy 1-16-methylene-4,6-pregnadien-20-one-3-hemisuccinate-17-acetate A solution of 1 g 3 /}, 17 (£ - Dihydroxy-6-methyl-16 - methylene -4,6 - pregnadiene - 20- one -17-acetate (made from 17 "-hydroxy-6-methyl-16-methylene-4,6-pregnadiene-3.20- dion-l 7-acetate through Reduction with lithium aluminum tri-tert-butoxyhydride), 1 g of succinic anhydride and 10 ml of pyridine were left to stand for about 8 hours at 70 to 80 ° C. and then poured into ice water. The precipitated product was extracted with methylene chloride, and the extract was washed with dilute acid and water, dried and evaporated. Crystals of 3 / U7 <z-dihydroxy-6-methyl-16-methylene-4,6-pregnadien-20-one-3-hemisuccinate-17-acetate were obtained. The product can be purified by dissolving it in cold sodium bicarbonate solution, filtering off the foreign matter and reprecipitating the 3-hemisuccinate with dilute cold hydrochloric acid. b) 3 / i, 17u-dihydroxy-6-methyl-16-methylene-4,6-pregnadien-20-one-3-sodium succinate-l 7-acetate 1.0 g 3 / i, 17 (t-dihydroxy 6-methyl-16-methylene-4,6-pregnadien-20-one-3-hemisuccinate-l 7-acetate was dissolved in 25 ml of acetone and filtered through a medium-pore glass filter. The resulting solution was cooled in an ice bath and filtered with a A filtered aqueous solution of 1 equivalent (0.177 g) sodium bicarbonate was added, the solution obtained was concentrated in vacuo at a temperature not exceeding 250 ° C. to remove the acetone and lyophilized in a high vacuum -methyl-lo-methylene ^^ - pregnadien ^ O-one- 3-sodium succinate-l 7-acetate as an amorphous white powder; molecular weight 515 determined by titration in a non-aqueous medium; calculated molecular weight 520.59; AiVI '° "= 235 πιμ; t = 20 650; A ^ "" = 241.5; f = 24 400. The compound has no defined melting point. Infrared absorption: C- OΙ 735, 1715 cm - '; / ° ■ C1580 cm "1; \) C— Ο- 1240, 1200, 1160, 1040, 1017 and 965 cm "'. Claims: 1. 3 /) ', 17α - dihydroxy - 6u - methyl - 4 - pregnen 20-one-3-sodium succinate-17-acetate. 2. 3 / ί, 1 la - dihydroxy - 6 - methyl -16 - methylene-4,6-pregnadien-20-one-3-sodium succinate-l 7-acetate. 3. Process for the preparation of the steroids according to claims 1 and 2, characterized in that a corresponding 3-hydroxy compound with a succinic acid radical is used in a manner known per se importing agent converts urd the obtained succinate into the sodium sulfate.