DE1044076B - Process for the production of cortisone-active derivatives from cortisone substances - Google Patents

Description

Process for the production of cortisone-active derivatives from cortisone substances It is known that cortisone and its related 21-hydroxypregnene or pregnadienes are one have a beneficial effect on patients suffering from nervous shock. at the treatment of such diseases, however, it is desirable that the effect occurs quickly. A quick effect of these substances is made possible by the fact at risk that they are only sparingly soluble in water and so in the bloodstream cannot be introduced directly in the form of aqueous solutions.

It was therefore common to use the cortisone and related substances in ethanol to dissolve and the solution thus obtained intravenously in a suitably diluted state inject. However, this approach has significant drawbacks, especially when considering the large amount of fluid that is necessary. Also, such an injection can usually not be done outside of the hospital, although this is in many cases it would be desirable, e.g. B. at an accident site.

For this and other purposes it would be good to have solutions available to have in which the necessary dose in a few milliliters of a liquid which can be injected into the blood and is in such a form that the active substances are sufficiently quickly accessible to the requirements of the organism are.

Compounds of cortisone substances found in aqueous fluids are more soluble than the cortisone substances themselves, but not necessarily very much must be easily soluble can also be used for other purposes, e.g. B. for the production of ointments with cortisone action for dermatological purposes.

It has now been found that previously unknown compounds of cortisone substances, which are 21-hydroxypregnenes or -pregnadienes, by introducing the group - O - CS - S H in the 21 position of the cortisone substance, with xanthates or Xanthogenic acids, which contain the alcohol residue of the steroid in question, form, can be produced and that these compounds with bases in water are soluble.

The compounds obtained by this process can be used as esters of diethyl carbonic acid. The acid sulfhydryl group is in these esters of diethyl carbonic acid, and therefore they are soluble in aqueous bases and form xanthates, the solubility of which depends on the nature of the base. It was found that the xanthates very quickly in the presence of water at almost neutral Hydrolyze pH values, releasing the cortisone substance. With intravenous The use of xanthates in the human organism shows up very quickly a cortisone effect.

Based on biological assessment of the glucocorticoid effect in rats show the new substances the same effect as a corresponding steroid hormone. Because of the rapid hydrolysis of the xanthate solutions, the new substances must for therapeutic use either in the form of a dry substance that can be dissolved in water, administered or in the form of free xanthogenic acid, which are mixed with an aqueous solution of a base immediately before use can be, or in the form of ointments, which are a more or less soluble xanthate and are intended for external use.

The - O - CS - SH group can pregnen in the 21-position of 21-hydroxy or -pregnadienes in a known manner by reaction in a liquid medium with an alkali hydroxide and carbon disulfide.

In this way xanthogenic acids of 44-3,20-diketo-17a, 21-dihydroxypregnate and -pregnadienes are made from the corresponding cortisone substances, not only including 44-pregnene-3,11,20-triketo-17a, 21-diol-21-xanthogenic acid and d4-pregnen-3,20-diketo-11,17a, 21-triol-21-xanthogenic acid (in which the 11-hydroxy group a- or ß-position), but also including the 41> 4-pregnadiene-3,11,20-triketo-17a, 21-diol-21-xanthogenic acid and Ai, 4-pregnadiene-3,20-diketo-11,17a, 21-triol-21-xanthogenic acid (in which the 11-hydroxy group can be α or β), and related compounds. as Examples of related compounds of the present invention can be compounds mentioned which correspond to those listed above and those in the a-position by methyl are substituted. Xanthogenic acids can even be made from such related compounds and xanthates can be prepared in the same manner while maintaining the improved cortisone effect, which is characteristic of substituted in this way Cortisone substances is.

When carrying out the method according to the invention, various Reactants can be used provided that the steroid is soluble in them and that they do not react with alkali and carbon disulfide to form xanthates themselves to build. Solvents containing alcohol groups are therefore generally available out of question. It has also been found that the reactant has some miscibility with water, preferably such that it is at least 5 to 10 0o water solves. When i # ethyl isobutyl ketone is used as the reactant, the is Only one yield of xanthate under otherwise essentially similar conditions Third of the yield that is obtained, run e.g. B. dioxane is used accordingly the lower miscibility of the former solvent with water. As examples for reactants that can be used in place of those already mentioned, are mentioned: acetone and other ketones, e.g. B. methyl ethyl ketone and dimethylformamide. Acetone and dimethylformamide yield in all cases where an attempt is made with them yields as good as dioxane.

The reaction is preferably carried out by the solution of the Steroids in the selected organic solvent, which at least partially with Water is miscible, is treated with an All-.alihydroxyd and the resulting Alcoholate is reacted with carbon disulfide; then the formed xanthate or (after adding an acid) separating the free xanthogenic acid from the solution. The reaction is preferably cooled, if necessary at temperatures near the freezing point of the solvent. The Allkahhydroxyd can first in aqueous Solution can be added. After the two phases have been mixed for a short time, may be carbon disulfide or a solution thereof in the same solvent as for the dissolution of the steroid was used, or in another solvent, that has similar properties. When the carbon disulfide some Time has reacted, the xanthate forms and the aqueous phase can be removed will. The organic phase can then be treated in various ways to separate either the xanthate of the base in question or the free xanthogenic acid. In the former case, the solution can be dried and evaporated to dryness, or it can be a solvent that increases the solubility of the xanthate in the mixture reduced, added, e.g. B. ether, which separates the xanthate. In the latter case, a strong acid, such as hydrochloric acid or sulfuric acid, and a solvent can be added, and then the aqueous phase is removed again the organic phase can be evaporated to dryness Water is dried off if necessary to avoid hydrolysis). It can also a solvent, e.g. B. acetone, can be added to separate the free acid. The separated xanthate or xanthic acid can be recrystallized, and salts can be prepared from the acid by dissolving it in the corresponding base earth.

The free xanthogenic acids are moderately soluble in water, but they are many Salts are easily soluble. Because of this, and because of their deliquescence, it can be difficult be able to produce them in a purely crystalline state. This is how the sodium salts dissolve light, whereas the potassium salts, although also very easily soluble, more easily can be obtained in the pure state. Even the calcium salts and the zinc salts can easily be made in solid form, but certain amine salts can despite their good solubility can be obtained particularly easily in pure crystalline form, z. B. the salts of ethanolamine, diethylamine and N-ethylpiperidine salts. Even quaternaries Ammonium salts can be made.

The following are examples of sparingly soluble amine salts: Diisopropylamine salts and the salts of diethylaminopropylamine, n-butylamine and Triethanolamine.

To determine the solubility of a number of soluble salts, especially the Amine salts, to illustrate, will hereinafter be the amount of an aqueous solution different bases in which 50 mg of hydrocortionic-21-xanthogenic acid are found Dissolve formation of salts, indicated: 0.5 ml of a 1.10 /, aqueous solution of ethylamine 1.0 ml of a 1.2% aqueous solution of triethylamine 0.5 ml of a 2.7% aqueous solution Solution of ß-diethylaminoethanol 0.5 ml of a 3.0 aqueous solution of ß-dimethylaminoethanol 1.0 ml of a 0.85% aqueous solution of tert. Butylamine 0.5 ml of a 2.5 aqueous Solution of 1-amino-2-propanol 0.5 ml of a 3.0% aqueous solution of 1-diethylamino-2-propanol 0.5 ml of a 0.6% aqueous solution of ammonia 1.0 ml of a 0.5 aqueous solution of sodium hydroxide The production of xanthogenic acids and various salts is illustrated below by a number of examples. Example 1 d4-Pregnen-3,11,20-trione-17a, 21-diol- 21-xanthogenic acid 3.00g of cortisone are heated in 90 ml of peroxide-free dioxane is dissolved, and the solution is in a mixture of ice and water cooled to the freezing point of the dioxane. Then a previously cooled A solution of 3.0 g of K OH in 30 ml of water was added with vigorous stirring. The stirring and cooling is continued for 5 minutes, after which 3.0 g of C S2 in 5 ml of dioxane are added added in a proportion. After stirring for an additional 15 minutes, the reaction mixture becomes diluted with 200 ml of benzene and acidified by adding 9 ml of concentrated hydrochloric acid. The aqueous phase is removed and the benzene solution is washed three times with water. After drying with Nag S 04, the solution becomes in vacuo at room temperature Evaporated dry and the residue crystallized by adding acetone. the Crystals are filtered, spread into a thin layer, and exposed to air dried at room temperature. Yield of dried product: 2.55 g. The substance melts at 127 to 130 ° C, but with further heating it solidifies and melts then at 230 to 232 ° C.

Example 2 44-Pregnen-3,20-dione-11β, 17a, 21-triol-21-xanthogenic acid 3.00 g of hydrocortisone are treated as described in Example 1, with the only one Difference that the reaction mixture with 300 ml of ether instead is diluted with 200 ml of benzene. By washing the solution with water, the hydrocortisone-21-xanthogenic acid becomes failed. The precipitate is filtered off, washed with ether and allowed to air dried at room temperature. 3.00 g of the desired substance are obtained in this way. The product melts at 110 to 113 ° C, but further heating will solidify it and then melts at 210 to 213 "C. Example 3 Ai, 4-pregnadiene-3,11,20-trione-17a, 21-diol-21-xanthogenic acid 3.00 g of 1-dehydrocortisone are dissolved in 180 ml of dioxane and the solution is cooled to the freezing point of the dioxane. After that, under strong Stirring a solution of 3.0 g of K O H in 60 ml of water was added. Stirring is 5 Minutes continued, after which a solution of 3.0 g of CS, in 5 ml of dioxane in one portion is admitted. After stirring for a further 15 minutes, the reaction mixture is with Diluted 300 ml of ether and acidified by adding 9 ml of concentrated hydrochloric acid. The aqueous phase is removed and the ether phase is washed three times with water. After drying with Na .. S O4, the solution is in vacuo at room temperature Evaporated dry, and 9 ml of acetone are added to the residue. After standing for some time at 0'C, the crystals of xanthogenic acid are filtered off and air dried at room temperature. Yield 1.95g. The product melts at 120 to 122 ° C, but with further heating it solidifies and then melts at 222 to 224 ° C with decomposition.

Example 4 41.4-Pregnadiene-3,20-dione-11β, 17a, 21-triol-21-xanthogenic acid 3.00 g of prednisolone are removed by gentle heating in 90 ml of dioxane, which is free from Peroxide is dissolved and the solution in a mixture of ice and water until Chilled the freezing point of the dioxane. After that, a previously cooled solution of 3.0 g of K O H in 30 ml of water were added with vigorous stirring. The stirring and cooling will be Continued for 5 minutes, after which a solution of 3.0 g CS, in 5 ml: dioxane in one Proportion is added. After stirring for a further 15 minutes, the mixture becomes 500 ml of ether and acidified by adding 9 ml of concentrated hydrochloric acid. The aqueous phase is removed and the ether phase is washed three times with water. After standing for a short time, the prednisolone-21-xanthogenic acid precipitates. The precipitation is filtered off, washed with ether and air-dried at room temperature. 2.1 g of the desired substance are obtained in this way. The product melts at 127 to 128'C, but after further heating it solidifies and then melts at 227 to 228'C.

Example 5 4 4-pregnen-3,20-dione-11a, 17a, 21-triol-21-xanthogenic acid 5 g of d4-pregnen-3,20-dione-11a, 17a, 21-triol are converted into 150 ml of dioxane is dissolved, and the solution is cooled in a mixture of ice and water to near the freezing point of dioxane. A previously cooled solution of 4 g of Na OH in 50 ml of water is added with vigorous stirring. Stirring and cooling is continued for 5 minutes and then a solution of 8 ml of CS in 10 ml of dioxane is added in one portion. After stirring for a further 15 minutes, the reaction mixture is diluted with 850 ml of ether and acidified by adding 15 ml of concentrated hydrochloric acid. The aqueous phase is removed and the ether phase is washed twice with water. This causes the 21-xanthogenic acid to precipitate, and after standing briefly at O ' C the precipitate is filtered off, washed with ether and air-dried at room temperature. Yield: 3.5 g. The product melts at 135 to 137 ° C, but after further heating it solidifies and then melts at 216 to 217 ° C.

Example 6 44-Pregnen-3,11-20-trione-17a, 21-diol-21-xanthogenic acid 1.0 g of cortisone is dissolved by heating in 200 ml of methyl isobutyl ketone and the Solution cooled to room temperature. 1 ml CS, and 1 g KOH, dissolved in 10 ml water, are added with vigorous stirring. Stirring is continued for 45 minutes. The lower phase is removed and the methyl isobutyl ketone phase with 1N hydrochloric acid washed. The methyl isobutyl ketone phase is dried with Na, SO4, filtered and Petroleum ether added. After the solution has stood at 0 ° C for some time, it is filtered to remove the crystals formed therein, and the crystals are air-dried at room temperature. There are 0.3 g of the desired Obtain xanthogenic acid. Example 7 The potassium salt of 6a-methylcortisone-21-xanthogenic acid 3 g of 6a-methylcortisone are dissolved in 9 ml of dimethylformamide. A solution of 3 g of K OH in 2.3 ml of water and then 3 ml of CS. "are at room temperature under strong Stirring added. Stirring is continued for 45 minutes. The lower phase will removed, and ether is added to the remaining dimethylformamide phase. A precipitate separates out and, after standing for a short time, the ether becomes by decantation removed. Acetone is added to the precipitate remaining after decanting, the mixture is filtered and the mother liquor is again precipitated with ether. The educated Precipitate is removed by filtering, washed with ether and at room temperature dried in vacuo over P.05. 2.7 g of the desired potassium salt are obtained.

The ultraviolet spectrum shows maxima at 244 mu. (E = 15 100) and at 304 mt, (s = 13,500) in a freshly prepared solution in water.

Example 8 Potassium salt of hydrocortisone-21-xanthogenic acid 3 g of hydocortisone are dissolved in 9 ml of dimethylformamide. A solution of 3 g of K O H in 2.3 ml of water is added with vigorous stirring at room temperature. Then 3 ml of CS, admitted. Stirring is continued for 45 minutes. The lower phase is removed and ether added to the dimethylformamide phase. A precipitate forms from which the ether is removed by decanting after standing for a short time. To the precipitation acetone is added, the mixture is filtered off and the mother liquor again precipitated with ether. The precipitated substance is filtered off with ether washed and dried at room temperature in vacuo over P.05. 2.7 is obtained g of the desired potassium salt.

Example 9 Potassium salt of prednisolone-21-xanthogenic acid 620 mg K O H in powder form and 2 ml of C S, become a mixture of 2 g of prednisolone and 60 ml of acetone added. After stirring for 10 minutes, the Reaction mixture filtered off and added to ether. A precipitate forms, which through Removed filtration, washed with ether and vacuumed over at room temperature P205 is dried. 2.1 g of the desired potassium set are obtained.

Example 10 Potassium set of cortisone-21-xanthogenic acid 3.00 g of cortisone are, as described in Example 1, in a dried solution of xanthogenic acid converted to benzene. The solution is 30 minutes at Zir, .rr.ertcmperatur below Vacuum applied to remove excess CS2. Then 42 ml of a 1.6 ° Qigcn alcoholic solution of KOH added. According to the Will stand for some time the precipitated substance is filtered off, washed well with benzene and without heating air dried. This gives 2.4 g of the desired substance with a melting point from 165 to 167 ° C (decomposition) and 13.60 °; o S (calculated: 13.51 ° i, S).

Example 11 Potassium set of hydrocortisone-21-xanthogenic acid 1.50 g Hydrocortisone-21-xanthogenic acid are mixed with 10 ml of a 2% alcoholic solution mixed by KOH. The substance dissolves. After the mixture has stood for a while has, the potassium set begins to deposit, and after further. Standing during For some time the salt is filtered off, washed with ether and dried. Yield: 1.30 g, 8.12 l) /, K (calculated: 8.20a K).

Example 12 Potassium set of prednisolone-21-xanthogenic acid 1.50 g of prednisolone-21-xanthogenic acid -, verden with 10 ml of a 2% alcoholic solution of K O H mixed. The substance dissolves. When the mixture has stood for a while, the potassium set begins to separate, and after a short standing the salt is filtered off, washed with ether and dried. Yield: 1.40 g.

The ultraviolet spectrum shows maxima at 244 mu, e = 15,200, and at 304 mu, a = 13,400 (water). Example 13 Ethanolamine Salt of Hydrocortisone-21-xanthogenic Acid To -1.0 g of freshly prepared hydrocortisone-21-xanthogenic acid are added 20 ml of a 3.1% solution of ethanolamine in 99 °; oigem ethanol added. The xanthogenic acid is dissolved in this way and a precipitate forms after a few minutes. After a while, the precipitate is filtered off, washed well with 990% strength ethanol and then with ether, and dried in vacuo over P. 05. 2.7 g of the desired salt are obtained. Its ultraviolet spectrum shows', laxima at 245 m # t (a = 17500) and at 304 mu (f = 14-100) in a freshly prepared, aqueous solution. Example 14 Diethylamine salt of hydrocortisone-21-xanthogenic acid 27 ml of a 2.5% solution of diethylamine in 990% ethanol are added to -1.0 g of freshly prepared hydrocortisone-21-xanthogenic acid. The xanthogenic acid dissolves and a precipitate forms. After the mixture has stood for a while, the precipitate is filtered off, washed thoroughly with 990% strength ethanol and then with ether and dried in vacuo over P205. 3.5 g of the desired salt are obtained. Its ultraviolet spectrum shows maxima at 246 mp. (8 = 18,200) and 304 mu (a = 14,400) in freshly prepared, aqueous solution.

Example 15 Tetraethylammonium salt of hydrocortisone-21-xanthogenic acid 5.0 g of tetraethylammonium iodide are dissolved in 80 ml of methanol and add 1 ml to the solution Water and 3.5 g Ag20 were added. After stirring for 3 hours, the mixture is filtered and the filtrate is diluted to 100 rr.l with methanol. To 4.0 g of hydrocortisone-21-xanthogenic acid 48 ml of the diluted filtrate are added. The xanthogenic acid dissolves, and after a few minutes, ether is added. An oily precipitate forms, the liquid is decanted off and the precipitate is dissolved in acetone. It will added ether again and filtered off the precipitated substance, thoroughly washed with ether and dried in vacuo over P205. 2.8 g of the desired are obtained Salt. Its ultraviolet spectrum shows maxima at 245 mu (s = 17 500) and at 303 mu (s = 14,000) in freshly prepared, aqueous solution.

Example 16 N-ethylpiperidine salt of hydrocortisone-21-xanthogenic acid To 4.0 g of freshly prepared hydrocortisone-21-xanthogenic acid are 4.0 g of N-ethylpiperidine, dissolved in 20 ml of 990% ethanol was added. This dissolves the xanthogenic acid, and after a few minutes a precipitate forms. This precipitate will filtered off, washed with ether and dried in vacuo over P205. You get 4.4 g of the desired salt. Its ultraviolet spectrum shows maxima at 246 mu (s = 17,600) and at 303 mu (a = 13,800) in freshly prepared, aqueous solution. Example 17 Calcium Salt of Hydrocortisone-21-xanthogenic Acid To 85 mg of calcium hydroxide 1 g of freshly prepared hydrocortisone-21-xanthogenic acid and Added 10 ml of 99% ethanol. The mixture is processed with a pestle for 5 minutes and then filtered. The solid substance is washed with 99% ethanol, then with ether and then dried in vacuo at room temperature over P205. You get 1.0 g of the desired salt. Its ultraviolet spectrum shows maxima at 245 mu (a = 30,000) and at 304 mu (a = 22,000) in freshly prepared, aqueous solution.

Example 18 Zinc Salt of Hydrocortisone-21-xanthogenic Acid At 452 mg Zinc hydroxide in a mortar is 40 ml of 99% ethanol and 4.0 g of freshly prepared Hydrocortisone-21-xanthogenic acid given. The mixture is made with a pestle for 5 minutes processed and then filtered. The solid substance is with 990 /, ethanol and then washed with ether and finally dried in vacuo over P205. You get 3.9 g of the desired salt. Its ultraviolet spectrum shows maxima at 245 must (e = 30 400) and at 304 mu (a = 28 100) in freshly prepared, aqueous 0.1 n-Na 0 H solution.

Aqueous solutions of the salts, e.g. B. the potassium salts or the diethanolamine salts, are rapidly hydrolyzed, the half-life period in the case of the salts mentioned at a px value of 7.2 and at 37 ° C 15 minutes. Through this the steroid hormone in question, e.g. B. Hydrocortisone, free. If solutions of this Salts, dissolved in a small amount of water, will be injected intravenously the hydrocortisone or - generally speaking - those contained in the xanthate Free of cortisone substances in the blood in a short time.

Claims (2)

PATENT CLAIMS: 1. Process for the production of cortisone-active substances Derivatives of cortisone substances, the 21-hydroxy-pregnene or 21-hydroxy-pregnadienes These derivatives are more soluble in water and bases than the cortisone substances itself, characterized in that the group -O-CS-SH in a known manner in the Introduced 21-position of the cortisone substance and optionally the 21-xanthogenic acid obtained is converted in a known manner into the salt of a base. 2. The method according to claim 1, characterized in that the reaction in the presence of a solvent that is at least partially miscible with water and does not contain any alcohol groups, in particular Acetone, dioxane or dimethylformamide.