DE1121610B - Process for the preparation of alkanoyl thiosteroids - Google Patents

Description

Process for the production of alkanoyl thiosteroids The invention relates to a process for the production of a new group of alkanoylthio-17a-carboxy-ethyl-17ß-oxyandrosten-3-one-lactones, alkanoylthio-17cc-carboxy-ethyl-3,17fl-dioxyandrosten-lactones and the corresponding 19-nor compounds that have the following general structural formulas correspond, in which E 'is an ethylene, vinylene or alkanoylthioethylene radical and R is hydrogen or a methyl radical, unless E' is a vinylene radical, in which case R is only a methyl radical.

In the present context, “alkanoylthio” is understood to mean a radical which has the following formula: in which the alkyl component is, for example, a methyl, ethyl, propyl, isopropyl, butyl or hexyl radical with fewer than 9 carbon atoms. The alkanoylthioalkyl radical denoted by E ' is limited to those radicals which enable the sulfur-containing side chain to assume the Lx position.

The lactones which can be prepared according to the process can also be in the form of the corresponding oxyacids and their alkali metal salts, which have the following general formulas: in which E ' and R are as defined above and M is hydrogen, an alkali metal or the ammonium radical.

The aforementioned lactones, oxy acids and salts are useful because of their valuable pharmacological properties. Among other things, they are diuretic agents and can inhibit the effects of deoxycorticosterone acetate on the sodium and potassium in the urine.

The compounds that can be prepared according to the invention. are by methods known per se by mixing a thioalkanoic acid of the general formula with a corresponding: steroid of the general formulas, in which Z is an ethylene or vinylene radical and R has the meaning given above, and heating the solution or irradiating the same with ultraviolet light are obtained. In the case of 3,17-dioxy compounds, the thioalkanoyl radical is bonded to the carbon atom in the 7-position, and the double bond of the A-ring shifts into the 5 (6) position.

The 3,17ß-dioxy compounds obtained according to the process can with Chromium trioxide in a known manner in a neutral or weakly basic solvent, such as B. acetone, to alkanoylthio-17a- (2-earboxyethyl) 17ß-oxyandrost-4-en-3-one-lactones are oxidized.

The lactones described can be treated with aqueous Convert alkali into the salts of the corresponding oxyacids, from which the free Acids can be obtained by briefly treating them with an H + ion implements the supplying means. A longer treatment in turn leads to lactone formation.

The following examples explain the process according to the invention. In these examples the relative amounts of material are in parts by weight and the Pressures given in mm Hg.

Example 1 A mixture of 1 part of 17 x, (2-carboxyethyl) -17fl-oxyandrosta-1,4-dien-3-one lactone and 1 part of thioacetic acid /, heated for 1 hour to about 90'C. Most of the excess thioacetic acid is then evaporated under nitrogen and the residue is recrystallized from a mixture of ethyl acetate and ether. Recrystallization from ethyl acetate gives la-acetylthio-17x- (2-carboxyethyl) -17fl-oxyandrost-4-en-3-one-lactone, which melts with decomposition at about 199 to 200-'C.

Example 2 A mixture of 7 parts of 17a- (2-carboxyethyl) -17β-oxyandrosta-1,4-dien-3-one-lactone and 10 parts of thiopropionic acid is heated to about 90 ° C. for 1 hour. Ethyl acetate and a sufficient amount of hexane are added to cause crystallization and the product which separates out is further purified by recrystallization from a mixture of benzene and hexane. The 17cc- (2-carboxyethyl) -17fl-oxy- 1 -prionylthioandrost-4-en-3-one-lactone obtained in this way melts with decomposition at 176 to 178 ° C.

Example 3 17x- (2-carboxyethyl) -17fl-oxyandrosta-4,6-dien-3-one lactone A mixture of about 11 parts and 10 parts of thioacetic acid is heated for 1 / hour to 85 to 95'C. At this point most of the excess thioacetic acid is removed by vacuum distillation and the residue is diluted with methanol. The desired 7, x-acetylthio-17, x- (2-carboxyethyl) -17fl-oxyandrost-4-en-3-one-lactone, which melts at about 134 to 135 ° C., crystallizes out. If the product is heated above this melting point, it solidifies and melts again with decomposition at 201 to 202 ° C. 7x-Acetylthio-17x- (2-carboxyethyl) -17ß-oxyandrost-4-en-3-one-lactone has the following formula: Example 4 A mixture of 13 parts of 17 x, (2-carboxyethyl) -17fl-oxyandrosta-4,6-dien-3-one lactone and 10 parts of thiopropionic acid is / are heated hour to 900C. 1 Treatment according to the method described in detail above in Example 3 gives 17cc- (2-carboxyethyl) -17β-oxy-7, x-propionylthioandrost-4-en-3-one-lactone, which melts at 192.5 to 194 ° C.

Example 5 Thiocaprylic acid is prepared by slowly introducing hydrogen sulfide into 102 parts of caprylic anhydride over 48 hours with stirring. After 48 hours the solution shows a weight gain of about 12 parts. The thiocaprylic acid is distilled off from the mixture at 0.5 mm / Hg and has a boiling point of 60 to 64 ° C.

A solution of 1 part of thiocaprylic acid and 1 part of 17a- (2-carboxyethyl) -17β-oxyandrost-4,6-diene-3-one lactone is heated on a steam bath for 2 hours. The reaction mixture is then taken up in benzene and applied to a chromatographic column containing silica gel (silica gel). The column is developed with benzene solutions containing increasing amounts of ethyl acetate. After elution with a 511 /, weight ethyl acetate solution in benzene and evaporation is 7x Caprylthio-17 "X (2-carboxyethyl) - 1 7fl-oxyandrost-4-en-3-one lactone as an oil The compound has a. Absorption maximums in the ultraviolet range at 237.5 m # L and an extinction coefficient of 18.750. Infrared maxima were found at 5.65, 5.95, 6.17, 6.80 and 10.25 #t.

Example 6 A mixture of 5 parts of 17-, x- (2-carboxyethyl) -17fl-oxyandrosta-1,4,6-trieii-3-one-lactone monomethanolate and 10 parts of thioacetic acid is heated to 85 to 95 ° C. for 1 hour . The excess thioacetic acid is then removed by vacuum distillation. The residue is chromatographed on silica gel using benzene and ethyl acetate as developing solvents. The desired 1, 7oc-diacetylthio-17-x- (2-carboxyethyl) -17β-oxyandrost-4-en-3-one-lactone is obtained from an eluate of 1511 / jgem ethyl acetate in benzene. The product is characterized by a maximum in the ultraviolet spectrum at 236.5 iril.L and maxima in the infrared absorption spectrum at 3.4, 5.65, 5.9, 6.0, 6.2, 7.4, 8.5, 8.8 and 10.5 #L. The use of an equimolar amount of thiopropionic acid in place of the thioacetic acid in the previous paragraph of the present example gives Ix, 7x-dipropionylthio-17 "x- (2-carboxyethyl) -17fl-oxyandrost-4-en-3-oii-lactone.

Example 7 A solution of 10 parts of 17 - # - (2-carboxyethyl) -17 ' ß-oxyandrosta-1,4,6-trien-3-one-lactone monomethanolate in a mixture of 3 parts of thioacetic acid and 750 parts of chloroform is irradiated with ultraviolet light for 3 hours. The chloroform is then distilled off under nitrogen. The residue is dissolved in benzene and chromatographed on a column over 300 parts of silica gel. The column is washed successively with benzene and 5, 8 and 10 1) 1 "solutions of ethyl acetate in benzene and then eluted with 12, 15 and 200% solutions of ethyl acetate in benzene. From the first eluates is obtained on evaporation of the solvent 1 -x - acetylthio -17a- (2-carboxyethyl) - 17fl-oxyandrosta-4, 6-dien-3-one lactone, which is characterized by an absorption maximum in the ultraviolet spectrum at 287 m 1 u. From the later eluates, when the solvent evaporates, 7-N-acetylthio-17x- (2-carboxyethyl) -17fl-oxyandrosta-1,4-dien-3-one-lactone is obtained, which has an absorption maximum in the ultraviolet spectrum at 239 m # t has.

If an equimolar amount of thiopropionic acid is used in place of the thioacetic acid in the previous paragraph of the preceding example, a mixture of 1 x-propionyl-thio-17x- (2-carboxyethyl) - 17 # - oxyandrosta-4,6 - diene- is obtained 3- onlactone and 7.x-propionyl-thio-17.x- (2-carboxyäthvl) -17ß-oxyandrosta-1,4-dien-3-one-lactone. This mixture is also separated by chromatography.

Example 8 To a solution of 820 parts of chloranil in 87,000 parts of xylene containing 1 part of p-toluenesulfonic acid monohydrate, 1000 parts of 17x (2-carboxyethyl) -17β-oxy-19-norandrost-4-en- 3-on-lactone given. The lactone dissolves. The resulting solution is refluxed for 1 hour, then cooled and chromatographed on silica gel using benzene and ethyl acetate as developing agents. In this way, the desired 17 # x - (2 - carboxyethyl) - 17 fl - oxy - 19 - norandrosta -4,6-dien-3-one-lactone is obtained, which melts after recrystallization from ethyl acetate at 235 to 239 ° C .

A mixture of 47 parts of 17cc- (2-carboxyethyl) -17 # -oxy-19-norandrosta-4,6-dien-3-one-lactone and 100 parts of thioacetic acid is heated to 80 to 95 ° C. for several hours. The material is then taken up in benzene and chromatographed on silica gel using benzene and ethyl acetate as developing agents. In this way, pure 7, x-acetylthio-17x- (2-carboxyethyl) -17fl-oxy-19-norandrost-4-en-3-one-lactone is obtained, the absorption maximum of which in the ultraviolet spectrum is 236.5m # £ . The product melts at 111 to 113 # -C.

If one uses an equimolar amount of thiopropionic acid instead of the Thioacetic acid in the previous paragraph of the present example is obtained 7 # x-Propionylthio-17-x- (2-carboxyethyl) -17fl-oxy-19-norandrost-4-en-3-one-lactone.

Example 9 To a stirred solution of 0.6 parts of 17 # x- (2-carboxyethyl) - 17FL-oxyandrosta- 4,6-dien-3-onlacton in 55 parts of 2-propanol is added a solution of 0.5 parts of sodium borohydride in Given 15.7 parts of 2-propanol. After about 35 minutes, a solution of 8.4 parts of glacial acetic acid in 30 parts of water is added. The mixture is concentrated to half its volume, diluted with about 300 parts of water, cooled and filtered. The filter cake is then washed with water. This product is 17-x- (2-carboxyethyl) -3,17fl-dioxyandrosta-4,6-diene-lactone, which is used immediately in the next stage without being purified.

A solution of 2 parts of 17-x- (2-carboxyethyl) -3,17fl-dioxyandrosta-4,6-diene-lactone in 2 parts of thioacetic acid is irradiated with ultraviolet light for 1 hour. The excess thioacetic acid is removed by vacuum distillation and the residue is diluted with methanol. The solution is concentrated and the residue obtained is 7x-acetylthio-17N- (2-carboxyethyl) -3.17 # -dioxyandrost- 5 (6) -enlactone.

A solution is slowly added to a stirred solution of 1 part 7.N-Acetylthio-17-x- (2-carboxyäthvl) -3,17fl-dioxy-androst-5 (6) -enlactone in 79 parts of acetone, which by dissolving of 26.7 parts of chromium trioxide in 43.5 parts of concentrated sulfuric acid and dilution to 100 parts by means of water. The chromium trioxide solution is added until a red color remains and the mixture is stirred for about 5 minutes. Then a few drops of a methanolic hydrogen chloride solution are added and the mixture is stirred for a further hour. The solution is then diluted with 400 parts of water and filtered. The crude product is recrystallized from methanol and gives 7-, c-acetylthio-17 x - (2 - carboxyethyl) - 17fl - oxyandrost - 4 - en -3-one-lactone. which melts at about 134 to 135 ° C and then again with decomposition at 201 to 202 ° C.

Claims (1)

PATENT CLAIM. Process for making alkanoyl thiosteroids of the following general formulas: in which E 'is an ethylene, vinylene or alkyl-CO-S-CH-CHj radical and R is hydrogen or a methyl radical, unless E' is a vinylene radical, in which case R is only a methyl radical, characterized in that a thioalkanoic acid is mixed with a corresponding steroid of the following general formulas by methods known per se in which Z is an ethylene or vinylene radical and R has the meaning given above, the mixture is mixed and the solution is heated or irradiated with ultraviolet light and any 3-hydroxy compounds obtained are oxidized with chromic acid in a manner known per se. Contemplated publications: USA. Patents No. 2837535, 2859222..