NO119467B - - Google Patents

Description

Process for the preparation of easily soluble steroid 21-esters and their alkali and alkaline earth salts.

The invention relates to a method for producing new esters of retrocortin with polybasic carboxylic acids, as well as salts of such esters. These compounds have cortisone activity, but differ from cortisone in having no appreciable sodium or water retention, and yet having the advantageous property of being readily soluble in water. These acid esters of retrocortin are particularly effective in the treatment of arthritis and related diseases, because one can make use of their cortisone effect, and avoid the adverse impact on the metabolism, e.g. edema, which cortisone induces due to sodium and water retention.

These esters of retrocortin can be shown chemically as follows:

where R is a carboxyacyloxy radical. These esters are produced according to the invention by reacting a 21-oxy steroid (retrocortin) with the following general formula

with an anhydride or a halide of a polybasic carboxylic acid, in an organic solvent consisting of or containing

a tertiary amine. If desired, the 21-esters thus obtained can then be prepared

alkali metal salts by reacting them with a basic alkali metal compound in aqueous solution.

When carrying out the invention, it is generally preferred as the acid anhydride to use a polybasic carbonic anhydride, e.g. an aliphatic dicarboxylic anhydride, succinic anhydride, glutaric anhydride,

maleic anhydride, ' adipic anhydride

or the like, or an aromatic dicarboxylic acid anhydride such as phthalic anhydride and the like.

As an organic solvent, you can use e.g. pyridine, or benzene or chloroform with a content of a tertiary amine.

The ester of retrocortin and carboxylic acid can be recovered by evaporation of the organic solvent. When pyridine is used as a solvent, it is generally preferred to add dilute hydrochloric acid to the reaction mixture, whereby the ester is precipitated and can be recovered by filtration or centrifugation. If desired, the ester can be purified in the usual way, e.g. by recrystallization in a solvent such as methanol, acetone-petroleum ether and the like.

Using this method, acidic retrocortin esters such as retrocortin-21-hemisuccinate, retrocortin-21-hemiphthalate, retrocortin-21-maleate and the like have been produced. The acid ester of retrocortin can be reacted with a preferably aqueous solution of a basic alkali metal or alkaline earth metal compound, to produce the corresponding salt of the acid retrocortin ester. As a basic alkali or alkaline earth compound, an alkali carbonate or alkaline earth carbonate, an alkali hydroxide, an alkaline earth hydroxide and the like are most often used. In general, an aqueous solution of the carbonate of the alkali or alkaline earth metal is used, whereby an aqueous solution of the corresponding alkali salt of the acidic retrocortin ester is obtained.

The reaction to prepare the salts is advantageously carried out with the addition of a lower aliphatic alcohol to the aqueous solution of the alkali metal compound to facilitate the dissolution of the acidic retrocortin ester. The solution is then heated to approx. 40-50° C, whereby an aqueous solution of the components is formed. The water is conveniently removed from the solution by freeze-drying, whereby the desired salt of the acidic retrocortin ester is usually obtained as an amorphous material.

These esters of retrocortin with carboxylic acids can be used in the treatment of patients who have rheumatic arthritis (arthritis) and who also suffer from kidney and heart diseases, as these new esters are relatively free of side effects, such as e.g. sodium and water retention which is characteristic of adrenocortical hormones such as e.g. cortisone. The acid esters of retrocortin, and especially their alkali and alkaline earth salts, have the particular advantage that they are much more easily soluble in water than cortisone or hydrocortisone or their acetates, which are generally used in the treatment of rheumatic arthritis.

In the following, some embodiments of the method according to the invention are described as examples.

Example 1.

A portion of succinic anhydride is dissolved in five

parts freshly distilled pyridine, and half a part of retrocortin is added to the solution. This is allowed to stand at room temperature for approx. 24 hours during occasional shaking. The solution is added dropwise while stirring to 50 parts of cold hydrochloric acid diluted with water (approx. 3 per cent). The precipitate, which is retrocortin-21-hemisuccinate, is filtered off, washed with water and dried. It can then, if desired, be recrystallized from acetone-petroleum ether.

Example 2.

One part of retrocortin is dissolved in ten parts of pyridine, two parts of maleic anhydrin are added and the solution is left to stand at room temperature under nitrogen gas for approx. 16 hours. The reaction mixture is then poured with stirring into 100 parts of ice-cold dilute hydrochloric acid, and the aqueous solution

extracted repeatedly with ether.

The ether extracts are combined and washed with water until the wash water becomes neutral, and dried with anhydrous sodium sulphate. The ether solution is evaporated to dryness, and the residue is recrystallized from acetone-petroleum ether. Pure retrocortin 21-hemimaleate is obtained.

Example 3.

One part of retrocortin is added to a solution of 0.8 parts of phthalic anhydride in five parts of pyridine. The mixture is set aside for approx. 24 hours, and the almost colorless solution is poured into ice water containing hydrochloric acid. The precipitate is filtered off, washed well with cold water and then with hot water, to remove traces of phthalic acid, which is formed by the excess of the phthalic anhydride used in the reaction. After drying, the washed substance is recrystallized from aqueous methanol and pure retrocortin-21-phthalate is obtained.

The retrocortin that is used as starting material in the previous examples can be prepared in the following way: 39.6 g of bromine dissolved in 300 ml of acetic acid is added to a solution of 100 g of 3.11.20-triketo-17a-hydroxy-21-acetoxy-pregnane in 1500 ml of acetic acid. When the reaction is practically finished, the solution is immediately poured into water and the resulting suspension is extracted with chloroform. The chloroform extract is washed with water, evaporated to dryness and the solids recrystallized from acetone-ether. A pure crystalline substance is obtained which is 4-bromo-3,11,20-triketo-17α-hydroxy-21-acetoxypregnane.

The mother liquor from the recrystallization is dissolved in benzene and chromatographed with acid-washed alumina. The column is eluted with a mixture of ether and chloroform. The eluate is evaporated to dryness, and the crystallized substance is recrystallized from ethyl acetate. 2-bromo-3,11,20-triketo-17-a-hydroxy-21-acetoxy-pregnane is obtained. A solution of 900 mg of this 2-bromo-3,11,20-triketo-17a-hydroxy-21-acetoxy-pregnane in 15 ml of collidone is heated with a reflux condenser for one hour and the collidine is evaporated in vacuo. The dry substance is dissolved in chloroform and the solution is washed with dilute hydrochloric acid and then with water, dried and evaporated in vacuo to dryness. The residue is recrystallized from ethyl acetate and pure A1-3,11,20-triketo-17a-hydroxy-21-acetoxy-pregnane is obtained. Melting point 244-246° C.

400 mg of A1-3,11,20-triketo-17a-hydroxy-21-acetoxy-pregnane is dissolved in 50 ml glacial acetic acid which contains three drops of a 30% solution of bromic acid in glacial acetic acid. While stirring, add during 10 min. 0.61 ml (190 mg) of bromine in 5 ml of glacial acetic acid. Five minutes after the bromine has been added, the reaction mixture is poured into 400 ml of ice water, and the aqueous mixture is extracted three times with chloroform. The chloroform extracts are combined, washed with a sodium bicarbonate solution and then with water, dried and evaporated to dryness in vacuo. A1-4 bromo-3,11,20-tri-keto-17a-hydroxy-21-acetoxy-pregnane is obtained.

500 mg of A1-4-bromo-3,11,20-triketo-17a-hydroxy-21-acetoxy-pregnane are heated under reflux and with 10 ml of collidine for one hour, the mixture is cooled and treated while stirring with 35 ml 2 N sulfuric acid. The aqueous solution is extracted three times with chloroform. The combined chloroform extracts are dried and the chloroform is evaporated in vacuo. The residue is dissolved in benzene and chromatographed over 15 g of acid-washed alumina. The column is eluted with a mixture of ether and chloroform and the eluates obtained are evaporated to dryness. The crystalline solid is recrystallized from ethyl acetate. Pure retrocortin-21-acetate (A1,4-3,1l,20-triketo-17a-hydroxy-21-acetoxy-pregnadiene) is obtained; melting point 116 -228° C.

100 mg of retrocortin-21-acetate is dissolved in a mixture of 1.0 ml of benzene and 1.0 ml of 1.1 N potassium hydroxide in methanol and the solution is allowed to stand at room temperature for approx.

10 minutes The solution is acidified with acetic acid, benzene is evaporated in a vacuum and resi-

the duet is recrystallized from ethyl acetate. Pure retrocortin (A1,4-3,11,20-triketo-17n,21-dihydroxy-pregnadiene) is obtained; melting point 207-214° C.

Claims (2)

1. Process for the preparation of readily soluble steroid 21-esters and their alkali and alkaline earth salts, which esters have cortisone action without causing any appreciable sodium or water retention, and of the general formula where R denotes a carboxy-acyloxy radical, characterized by reacting a 21-oxy-steroid (retrocortin) with the following general formula: with an anhydride or a halide of a polybasic carboxylic acid in an organic solvent consisting of or containing a tertiary amine, optionally with subsequent preparation of the alkali metal salts of the obtained 21-esters by reacting said esters with a basic alkali metal compound in aqueous solution. 2. Process according to claim 1 for the production of retrocortin-21-hemisuccinate, characterized in that succinic anhydride is used as the acid anhydride and pyridine is used as the organic solvent.