IL41004A

IL41004A - 3'-(3-oxo-17beta-hydroxy-6,7-methylene-androsta-1,4-diene-17alpha-yl)-propionic acids and their salts,their preparation and aldosterone antagonist compositions containing them

Info

Publication number: IL41004A
Application number: IL41004A
Authority: IL
Original assignee: Merck & Co Inc
Priority date: 1972-12-05
Filing date: 1972-12-05
Publication date: 1977-02-28
Also published as: IL41004A0

Description

41004/2 , jn*n ai xn'3i»ana-( »K-17<*-?R»*i-4,1-»ee,»maR 3·-«.(3-Oxo-X7P-n These new steroids can be conveniently referred to as 3'-(3-oxo-17fi-hydroxy-6 ,7-methylene-androsta-l,4-diene-17a-yl) -propionic acid compounds. They are prepared by reacting the corresponding 6 ,7-methylene-20-spiroxa-l,4-diene-3 ,21-dione steroid lactone of the formula wherein Y is two hydrogen atoms, or a keto group; • -with an alkaline hydrolyzing agent thereby hydroly- 41004/2 zing the lactone ring of said steroid lactone and forming the desired 3'-(3-oxo-17B-hydroxy-6,7-niethylene-androsta- l,4-diene-17a-yl) -propionate compound.

The new compounds of this invention are potent aldosterone inhibitors. They block the salt-retaining effects of aldosterone and other salt-retaining steroids and are therefore useful in the alleviation of diseases such as congestive heart failure, nephrosis and cirrhosis of the kidney in which aldosterone secretion is increased.

The hereinabove-noted reaction of the 6,7-nethyl-ene-20-spiroxa-l,4-diene-3,21-dione steroid lactone with the alkaline hydrolyzing agent is conveniently conducted by dissolving the steroid in an alcohol such as ethanol, methanol, and the like, and heating the solution with the said aqueous alkaline hydrolyzing agent, as for example an aqueous alkali metal hydroxide such as aqueous sodium hydroxide, aqueous potassium hydroxide, and the like. The alcohol is then evaporated from the hydrolysis mixture, the residual aqueous solution is extracted with a water-immiscible organic solvent such as chloroform, and the aqueous solution is freeze-dried to give the hydrolyzed lactone, that is the salt of the corresponding 3'-(3-oxo-17β-hydroxy-6 , 7-methylene-androsta-1 ,4-diene-17a-y1) -propionic acid, in substantially quantitiative yield.

The steroid lactones used as starting materials a9 conveniently prepared by the introduction of a 1-double bond into the .corresponding 4-ene compounds. This is achieved, e.g. by the reaction of said 3-oxygenated-6 r7-methylene-20-spirox-4-ene-compound with 2,3-dichloro-5,6-dicyanobenzo-quinone. This reaction may be conducted by heating the reactants together in an organic solvent such as dioxane, preferably under substantially anhydrous conditions and under a nitrogen atmos¬ phere. When dioxane is used as the reaction solvent, the reaction is ordinarily carried out by heating the reaction mixture at a reflux temperature for a period of about 3 hours.

The resulting mixture is then diluted with a water-immiscible organic solvent such as ethyl acetate* the organic solution is washed with a dilute aqueous alkaline solution, then with water, dried and evaporated to dryness; the residual material is conveniently purified by chromatography using a silica gel column to produce the corresponding 3-oxygenated-6, 7-methyl- ene-20-spiroxa-l,4-diene product such as 6, 7-methylene-20-spiroxa-1 , 4-diene-3-one ; 6 ,7-methylene-20-spiroxa-l , 4-diene- 3,21-dione, and the like. * 4 The Δ -steroid lactones used as starting materials are conveniently prepared by reacting dimethyl-oxo-sulfonium methylide with a 3-oxygenated-20-spiroxa-4 , 6-diene , as for example 20-spiroxa-4 ,6-diene-3-one and 20-spiroxa-4 ,6-diene-3,21-dione; thereby forming the corresponding 6 , 7-methylene derivative. The reaction is conveniently conducted by bringing 41004/2 together, under nitrogen, a mineral oil dispersion of sodium Ψ j hydride and trimethyl sulfoxonium iodide and slowly adding thereto dry dimethyl sulfoxide whereupon reaction occurs with j the formation of dimethyl-oxo-sulfonium methylide. To the resulting mixture is then added an amount of the 3-oxygenated-20-spiroxa-4, 6-diene such that the molar ratio of dimethyl-oxo-sulfonium methylide to steroid is within the range of approximately 1:1 to 5:1. It is ordinarily preferred to use a molar ratio of about 1:1 where the 3-oxygenated-20-spiroxa- 4.6-diene starting steroid is a 20-spiroxa-4 , 6-diene-3 ,21-diqne The reaction is allowed to proceed for approximately 15 hours at about room temperature, and the steroid product is conveniently recovered from the reaction mixture by adding the reaction mixture to ice-water, extracting the steroid product with a water-immiscible organic solvent such as ether, evaporating the organic solvent, and purifying the residual material by chromatography over alumina. There is thus obtained the corresponding 3-oxygenated-6, 7-methylene-20- spirox -4-ene product such as 6, 7-methylene-20-spirox-4-ene-3-one; 6.7-methylene-2*0-spirox-4-ene-3,21-dione, and the like. 41004/2 When there is obtained, in accordance with the procedures hereinabove described, 6, 7-methylene-*20-spirox-4-ene (or.l, 4. -diene) -3-one steroid containing llfl-hydroxy substituent, this compound may be converted to the corres* ponding ll'-ketone by reaction with an oxidizing agent such as chromium trioxide-pyridine complex: the reaction is ordinarily conducted by adding a pyridine solution of the 11β-hydroxy steroid compound to the complex formed by adding chromium trioxide to excess pyridine, and allowing the oxidation reaction to proceed at approximately room temperature for a period of about 15 hours. The 11-keto steroid product is conveniently recovered from the reaction mixture by pouring the latter into water, extracting the aqueous mixture with a water-immiscible organic solvent such as ether, ethyl acetate, and the like; the organic solvent layer is then washed with dilute aqueous acid, then with water, dried and evaporated to dryness; the residual material is purified by crystallization from an organic solvent such as petroleum ether tcTgive the' "correspbhdihg 6-,T-meth-yTerie-20-spirox-4- ' ene (or 1,4-diene)- 3,11-dione steroid such as 6, 7-methylene- 20-spirox-4-ene-3, 11-dione; 6, 7-methylene-20-spirox-4-ene-3,11, 21-trionei 6 ,7-methylene-20-spiroxa-l,4-diene-3 , 11-dione; 6,7-methylene-20-spiroxa-l,4-diene-3,ll-21,trione; and the like. 41004/2 When there is obtained, in accordance with the procedures hereinabove described, a 6, 7-methylene-20-spirox-4-ene (or 1,4-diene) -3-one steroid which contains only hydrogen at C-21, such as 6, 7-methylene-20-spirox-4-ene-3-one, 6, 7-methylene-20-spirox-4-ene-3, 11-dione, and the like, this may be converted to the corresponding 21-ketone by reaction with an oxidizing agent such as t-butyl chromate . The t-butyl chromate is conveniently prepared by reacting chromium trioxide with butanol at about room temperature. The oxidation reaction is ordinarily conducted by adding an anhydrous carbon tetrachloride solution of t-butyl chromate, containing acetic anhydride and acetic acid, to a chloroform solution of the 6, 7-methylene-20-spirox-4-ene (or 1,4-diene) -3-one, and heating the resulting mixture, preferably under reflux, under which conditions the oxidation reaction to farm the C-21 ketone is substantially complete in about five hours. The 21-keto steroid product is conveniently recovered from the reaction mixture by adding a reducing agent such an aqueous oxalic acid to reduce excess t-butyl chromate, then extracting with carbon tetrachloride; the organic layer is then washed, dried and evaporated, and the residual material is conveniently purified by chromatography to give the corresponding 6, 7-methylene-20-spirox-4-ene- (or 1,4-diene) -3,21-dione steroid such as 6, 7-methylene-20-spriax-4-ene-3, 21-dione; 6, 7-methylene-20-spirox-4-ene-3, 11, 21-trione; 4100 /2 8 6 ,7-n»iethylene-20~spiroxa-l,4-diene-3#21-dione? 6 ,7-niethylene--20-spir©xa-l,4~diene-3 ,11,21-trione; Experimental details for the synthesis of these starting materials are set forth hereinbelow and designated Preparations 1-12, 6 , 7-methylene-9a-fluoro-20-spirox-4-ene-3 ,21-dione; 6 , 7-methylene-9a-fluoro-20-spirox-4-ene-3 ,11,21-trione; 6 , 7-methylene-20-spiroxa~l , 4-diene--3 , 21-dione ; 6 , 7-methylene-20-spiroxa-l , 4-diene-3 , 11 , 21-trione ; 6 , 7-methylene-9a-fluoro-20-spiroxa-l,4-diene-3 ,21-dione; 6 , 7-methylene-9a-fluoro-20-spiroxa-l , 4-diene-3 , 11,21-trione , and the like.

Experimental details for the synthesis of these starting materials are set forth hereinbelow and designated Preparations 1-12. f Preparation 1 To a thoroughly dry mixture of 1.8 g. of a 56.37% dispersion of sodium hydride in mineral oil (0.04246 moles) and 9.81 g. (0.04246 moles + 5% excess) of tri ethyl sulfoxonium iodide, maintained under a nitrogen atmosphere and cooled to a temperature of about 10°C, is slowly added 50 ml. of dry dimethyl sulfoxide at such a rate that foam-ing is not excessive. The resulting mixture is stirred at a temperature of about 20°C. for a period of about 2.5 hrs., or until all sodium hydride has reacted. To the thus formed dimethyl-oxo-sulfonium methylide reaction mixture, main-tained substantially anhydrous and under a nitrogen atmo-sphere, is added rapidly, with stirring at room temperature, a solution of 3.0 g. (0.0947 moles) of 20-spiroxa-4, 6-diene-3-one in 5 ml. of dimethyl sulfoxide. The reaction is allowed to proceed overnight at room temperature, and the reaction mixture is then added to about 100 ml. of an iee-water mixture. The resulting aqueous mixture is extracted with two 100 ml. -portions of ether, and the combined extracts are washed with three 25 ml. -portions of water.

The washed ethereal extract is dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The resulting yellow foam, approximately 3.9 is suspended in petroleum ether, and solution is effected by addition of benzene.

The resulting solution is chromatographed on an alumina column (ratio 30 parts by weight of alumina to 1 part by weight of crude reaction product) wet-packed with petroleum 4 petroleum ether until mineral oil is eluted. The propor-tion of ether in the eluting solvent is then raised by 10% increments until a 60:40 mixture of ether: petroleum ether is reached; evaporation of the 60:40 eluate gives 6a, 7a-methylene-20-spirox-4-ene-3-one which is obtained as an oil. Increasing concentrations of ether up to 100% ether are then used to elute the column. Evaporation of the 100% ether eluate gives substantially pure 6β, 7β-methylene-20-spirox-4-ene-3-one as crystalline material; each fraction from the chromatogram is seeded with this material; the fractions which partially or completely crystallize are combined to give approximately 900 mg. of 6β, 7β-ιηβί1^ΐ€ηβ-20-8ρίΓθ -4-βηβ-3-οηβ. Upon recrystalliza-tion once from ether, twice from hexane, and then from methanol, there is obtained analytically pure 6β, 7β-methylene-20-spirox-4-ene-3-one; m.p. 153-155°C.

In accordance with the foregoing procedure, but employing 20-spiroxa-4, 6-diene-3, 21-dione as steroid start-ing material (instead of 20-spiroxa-4, 6-diene-3-one) together with an approximately equimolecular proportion of dimethyl-oxo-sulfonium methylide, there are obtained 6β, 20-spirox-4-ene-3, 21-dione and 6a, 7a-methylene-20-spirox-4-ene-3, 21-dione.

Preparation 2 A mixture of 309 mg. (0.00131 moles) of 2,3-dichloro-5, 6-dicyanobenzoquinone, 14.4 ml. of dry dioxane - In accordance with the foregoing procedure, but employing 6β, 7p-methylene-20-spirox-4-ene-3-one as steroid starting material in place of the 6a, 7a-methylene-20-spirox-4-ene-3-one there employed, there is obtained 6β, 73-methylene-20-spiroxa-l, 4-diene-3-one.

Similarly, using as steroid starting material, 6a, 7a-methylene-20-spirox-4-ene-3,21-dione or 6β, 7β-methylene-20-spirox-4-ene-3,21-dione there is obtained, respectively, 6a, 7a-methylene-20-spiroxa-l, 4-diene-3, 21- 41004/2 Preparation 3 To a thoroughly dry mixture of 1.8 g. of a 56.37% dispersion of sodium hydride in mineral oil (0.0426 moles) and 9.81 g. (0.04246 moles + 5% excess) of trimethyl sul-foxonium iodide, maintained under a nitrogen atmosphere and cooled to a temperature of about 10°C, is slowly added 50 ml. of dry dimethyl sulfoxide at such a rate that foam-ing is not excessive. The resulting mixture is stirred at a temperature of about 20°C. for a period of about 2.5 hrs., or until all sodium hydride has reacted. To the thus formed dimethyl-oxo-sulfonium methylide reaction mixture, maintained substantially anhydrous and under a nitrogen atmosphere, is added rapidly, with stirring at room temperature, a solution of 3.0 g. (0.00947 moles) of 20-spiroxa-4, 6-diene-ll3-ol-3-one in 5 ml. of dimethyl sulfoxide. The reaction is allowed to proceed overnight at room temperature, and the reaction mixture is then added to about 100 ml. of an ice-water mix-ture. The resulting aqueous mixture is extracted with two 100 ml. -portions of ether, and the combined extracts are washed with three 25 ml. -portions of water. The washed ethereal extract is dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The resulting yellow foam, approximately 4 g. is suspended in petroleum ether, and solution is effected by addition of benzene. The resulting solution is subjected to chromatography on an alumina column to give 6β, 7P-methylene-20-spirox-4-ene-l^-ol-3-one and 6a, 7a-methylene-20-spirox-4-ene-l^-ol-3-one.

In accordance with the foregoing procedure, but employing 20-spiroxa-4, 6-diene-113-ol-3, 21-dione as steroid starting material (instead of 20-spiroxa-4, 6-diene-l^-ol-3-one) together with an approximately equimolecular pro-portion of dimethyl-oxo-sulfonium methylide, there are obtained 6β, 7p-methylene-20-spirox-4-ene-lip-ol-3,21-dione Preparation 3 A solution of 400 mg. of 6 , 7a-methylene-20-spirox-4-ene-lip-ol-3-one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room tempera-ture overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0°C, and then with water until neutral. The organic solvent layer is then dried, the solvent is evapo-rated therefrom in vacuo, and the residual material is purified by crystallization from petroleum ether to give 6α, 7a-methylene-20-spirox-4-ene-3, 11-dione.

In accordance with the foregoing procedure, but using 6β, 7 -methylene-20-spirox-4-ene-lip-ol-3-one as the steroid starting material, there is obtained 6β, 20-spirox-4-ene-3, 11-dione.

Similarly, using as steroid starting material, 6a, 7a-methylene-20-spirox-4-ene-l^-ol-3,21-dione or 6β, 7β-methylene-20-spirox-4-ene-l^-ol-3, 21-dione there is obtained, respectively, 6a, 7a-methylene-20-spirox-4-ene-3, 11, 21-trione or 6β, 7β-π^Ι¾τ1εηε-20-8ρίΓθχ-4-βηε-3, 11, 21- trione.

Preparation 8 A mixture of 309 mg. (0.00131 moles) of 2,3- . dichloro-5, 6-dicyanobenzoquinone, 14.4 ml. of dry dioxane and 309 mg. (0.0010 moles) of 6a, 7a-methylene-20-spirox-4-βηε-11β-ο1-3-οηβ, is heated at reflux temperature under a nitrogen atmosphere for a period of about 3 hours. The reaction mixture is cooled, diluted with about 15 ml. of ethyl acetate, and the ethyl acetate layer is separated and washed alternately with 1.0N aqueous sodium hydroxide solution, and with water until the sodium hydroxide wash solution remains clear. The washed ethyl acetate solution is dried over anhydrous sodium sulfate, and evaporated to give approximately 335 mg. of a red oil which is subjected to chromatography using a silica gel column to give 6a, 7a-methylene-20-spiroxa-l, 4-diene-l^-ol-3-one.

In accordance with the foregoing procedure, but employing 6β, 7β-π^1^1εηε-20-8ρίΓθχ-4-βηβ-11β-ο1-3-οηβ as steroid starting material in place of the 6a, 7a-methylene-20-spirox-4-ene-l^-ol-3-one there employed, there is obtained 6β, Similarly, using as steroid starting material, 6a, 7a-methylene-20-spirox-4-ene-l^-ol-3, 21-dione or 6β, 7β-methylene-20-spirox-4-ene- 11β-ο1-3, 21-dione, there is obtained, respectively, 6a, 7a-me hylene-20-spiroxa-l, 4- 1,4-άίβηβ-11β-ο1-3, 21-dione.

Preparation 6 A solution of 400 mg. of 6a,7a-methylene-20-spiroxa- 1, 4-diene-110-ol-3-one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium tri-oxide to 4 ml. of pyridine. The reaction r._Lxture is worked up in accordance with the method described in Preparation 9 to give 6a,7a-methylene-20-spiroxa-l,4-diene-3,ll--dione.

Similarly, using 60 , 70-methylene-2O-spiroxa-l,4r diene-lip-ol-3-one as the steroid starting material, there is obtained 60 ,70-methylene-2O-spiroxa-l,4-diene-3,ll-dione.

Similarly^ using as steroid^starting material, 6a, 7a-nethylene-2O-spiroxa-l,4-diene-110÷-0l-3,21-dione or 60,70-methylene-2O-spixoxa-l,4-diene-110-ol-3,21-dione there is obtained, respectively, 6a,7a-methylene-20-spiroxa-l,4- diene-3,ll,21-trione or 60 ,70-methylene-2O-spiroxa-l,4-diene- 3,11,21-trione.

Preparation 7 About 7.0 grams of chromium trioxide is added poutionwise with stirring to 18.7 ml. of t-butanol, while maintaining the temperature at about 25°C. The resulting solution is poured into 50 ml. of carbon tetrachloride, the two layers are separated, and the organic layer is dried, and then evaporated to a volume of about 40 ml. to give a solution of t-butyl chromate.

About 35 ml. of this t-butyl chromate in carbon tetrachloride, 8 ml. of acetic acid, and 4 ml. of acetic anhy-dirde are added to a solution of two grams of 60 ,70-methyl-ene-20-spirox-4-ene-3-one (prepared as described in Preparation 1 hereinabove) , and the resulting mixture is heated under reflux for a period of about five hours. 41004/2 To the reaction mixture is added a saturated aqueous solution of oxalic acid until the reddish color is diminished, and the mixture is then extracted with carbon tetrachloride. The organic layer is washed well with water, dried, and the solvent is evaporated. The residua"! material s purified by chromatography followed by recrystallization from aqueous methanol to give about 500 mg. of substantially pure 6B,7B-methylene-20-spirox-4-ene-3,21-dione ; m.p. 173-176°C In accordance with the foregoing procedure, but utilizing, as starting material, about 450 mg.of 6β,7β-methylene-20-spiroxa-l,4-diene-3-one, there are obtained approximately 150 mg. of 6β, 7fl-methylene-20-spiroxa-l,4- diene-3,21-dione ; m.p. 204~206°C.

EXAMPLE 1 To 176 mg. of 6fl,7e-methylene-20-spiroxa-l,4-diene-3,21-dione dissolved in 4 ml. of ethanol is added 4.5 ml. of a 0.1 M aqueous solution of sodium hydroxide. The mixture is warmed to reflux temperature, and heated under reflux for 4 hours. The ethanol is evaporated from the reaction mixture under vacuum, and the residual aqueous mixture is diluted with additional water. The resulting mixture is extracted with chloroform, and then with ether, and the residual aqueous solution (which contains the sodium salt of the hydrolyzed lactone) is freeze-dried to give - 16 - 41004/2 V sodium 3 (3-oxo-173-hydroxy-6e 7B-methylehe-androsta-l,4-diene-17a-yl) propionate; m.p. 185-193°C, with decomposition; and potassium 3 '-O-oxo-17/3-hydroxy, 60,70-raethylene-androsta-l,4-diene-17a-yl) propionate.

EXAMPLE 2 To 177 mg. of 6B , 7fi-methylene-20-spiroxa-l,4-diene- 3, 11, 21-triaie dissolved in 4 ml. of ethanol is added 4.5 ml of a O.lM aqueous solution of sodium hydroxide The alkaline mixture is warmed to reflux temperature, and heated under reflux for a period of about 4 hours . The ethanol is evap¬ orated from the reaction mixture under vacuum, and the re suiting mixture is diluted with -additional water:—The resulting mixture is extracted with chloroform, and then with ether, and the residual aqueous solution (which contains the sodium salt of the hydrolyzed lactone) is freeze-dried to give sodium 3 * - (3, ll-dioxo-17fl-hydroxy-6e, 76-methylene- androsta-l,4-diene-17a-yl) propionate in substantially quantitative yield.

In accordance with the foregoing procedure, but utilizing a O.lM aqueous solution of potassium hydroxide in place of the aqueous sodium hydroxide solution there employed, there is obtained, in substantially quantitative yield, potassium 3 * - (3, 11-dioxo - 17fl-hydroxy-6e, 7B-methylene- androsta-l,4-diene-17 -yl) propionate. 41004/2 f EXAMPLE 3 In accordance with the procedures of Examples 1 and 2 , but employing the following steroid starting materials: 1) 6a, 7a-niethylene-20-spiroxa-l, 4-diene-3 ,21-dione? 2) 6a,7a-meth lene-20-spiroxa~l,4-diene-3,11,21-trione ; there are obtained the sodium and potassium salts of the following propionic acid derivatives, respectively, which have been nunabered to correspond with that of the steroid starting material: 1) 3'- (3-oxo-17B-hydroxy-6ct,7 -methylene-androsta- 1, 4-diene-17a-yl) propionic acid; 2) 3'- {3 , 11-dioxo-170-hydroxy-6 , 7a-methylene- androsta-1, 4-diene-17a-yl) ropionic acidi - 18 -

Claims

41004/3 WHAT IS CLAIMED IS:

1. The process which comprises reacting a 6,7-nethylene-20-spiroxa-1^4-diene-3,21-dione steroid lactone having the formula wherein Y is two hydrogen atoms , or a keto group; • with an alkaline hydrolyzing agent thereby hydroly-zing the lactone ring of said steroid lactone and forming a 3 ' - (3-oxo~170-hydroxy-6 , 7-methylene-androsta-^l , 4-diene-17ot-yl) -propionate compound having the formula Oil wherein Y has the same meaning as above; and M is the cation component of the alkaline hydrolyzing agent; and acidifying this alkaline hydrolysis product to form the corresponding free propionic acid compounds.

2. · The process, as defined in Claim 1, character- \ ized in that the steroid lactone starting material is 6,7-methylene-20-spiroxa-l,4-diene-3 ,21-dione, and the hydrolysis product is 3 ' - (3-oxo-17/?-hydroxy-6 , 7-methylene-androsta-l , 4-diene-17a-yl) -propionic acid or salt thereof.

3. The process, as defined in Claim 2, characterized in that the alkaline hydrolyzing agent is an alkali metal hydroxide; the alkaline hydrolysis product is the corresponding alkali metal 3' (3-oxo-170-hydroxy-6 , 7-methylene-androsta-l , 4-diene-17a-yl)- . propionate; and the product obtained by acidification of the latter is 3 (3-oxo-170-hydroxy-6 , 7-methylene-androsta-l, 4-diene-17a-yl)*propionic acid.

4. The process, as defined in Claim 1, 2 or 3, characterized in that the steroid lactone starting material is 60,70-methylene-20-spiroxa-l,4-diene-3 ,21-dione; the alkaline hydrolyzing agent is sodium hydroxide in aqueous ethanolr the alkaline hydrolysis product is sodium 3 ' - (3-oxo-170-hydroxy- 60 ,70-methylene-androsta-l,4÷diene-17a-yl)-propionate; and the product obtained by acidification of the latter is 3'- (3--oxo-170-hydtfoxy-60 , 70-methylene-androsta-l, 4-diene-17a-yl) -propionic acid. 41004/3

5. The process, as defined in Claim 1, 2 or 3, characterized in that the steroid lactone starting material is 6β,7β- nethylene-20-spiroxa-l, 4-diene-3 ,21-dione; the alkalin hy^rolyzing agent is potassium hydroxide in aqueous ethanol; the alkaline hydrolysis product is potassium 31 - (3-oxo-170- hydroxy-60 ,7p-methylene-androsta-l,4-diene-17d-yl) -propionic acid.

6. · Tne process, as defined in Claim 1, characterized in that the steroid lactone starting material is 6,7- methylene-20-spiroxa-l, 4-diene-3 , 11 ,21-trione, and the hydrolysis product is 3 ' - (3 ,ll-dioxo-170-hydroxy-6 , 7-methyl- ene-androsta-l,4-diene-17a-yl)—propionic acid.

7. Λ 3'-(3-oxo-17p-hydroxy-6,7-methylene-androsta-l,4- diene-17o-yl) propionic acid compound having the formula OH CI CE COOZ wherein Y is two hydrogen atoms or a keto, group; Z is hydrogen or a pharmaceutically-acceptable salt-forming cation. 21 41004/2

8. . A propionic acid compound, as defined in Claim 7 having the chemical name 3 ' - ( 3-oxo-170-hydroxy-6,7-methylene~androsta-l,4-diene-17a-yl) propionic acid, and pharmaceutically acceptable salts thereof.

9. . Sodium 3 ' - (3-oxo-170 -hydroxy-6/3 , 70-raethylene-androsta-1, -diene-17a-yl) propionate.

10. · Potassium 3 *- (3-oxo-170-hydroxy-6/3 , 7/3-m»2thyl-ene-androsta -1 , 4-diene-17fc-yl) propionate.

11. A propionic acid compound, as defined in Claim J , having the chemical name 3 ' - (3 ,11-dioxo-170-hydroxy 6 , 7-methylene-androsta-l , 4-diene-17a-yl) propionic acid, and pharmaceutically acceptable salts thereof.

12. Sodium 3 ' - (3 ,ll-dioxo-170-hydroxy-60 , 70-methyl ene-androst-l,4-diene-17a-yl) propionate.

13. An aldosterone-inhibiting composition for pharmaceutical use, containing as active ingredient a compound as claimed in any one of claims 7 to 13 together with a pharmaceutical excipient.