DE3344057A1 - A lactone compound and pharmaceutical compositions thereof, and processes for the preparation thereof - Google Patents

Abstract

A lactone compound of the 20-spiroxane series of the formula <IMAGE> and the corresponding 17 beta -hydroxy-17 alpha -pregn-4-ene-21-carboxylic acid and its salts have a high aldosterone-antagonistic activity and can be used as potassium-sparing diuretics in the therapy of various types of hyperaldosteronism. The compounds can be obtained by conventional processes of steroid chemistry.

Description

A new lactone compound and pharmaceutical compositions thereof, as well as processes for their preparation.

The invention relates to a new lactone compound of the steroid series with the structure of 20-spiroxan-21-one of the formula and also their open form, ie the corresponding 17β-hydroxy-17a-pregn-4-en-21-carboxylic acid of the formula and i: ire salts. The invention also relates to processes for producing these compounds and pharmaceutical compositions containing these compounds, as well as production processes for such compositions. The invention also relates to the therapeutic use of the compounds and compositions mentioned, in particular as aldosterone-antagonizing diuretics, and the corresponding medical method for treating warm-blooded animals, especially humans, with a therapeutically effective amount of such a compound alone or in the form of a pharmaceutical composition to remedy or alleviate pathological conditions associated with hyperaldosteronism.

Suitable salts of the abovementioned hydroxy acids of the formula IA are possible in particular physiologically compatible metal and ammonium salts, such as alkaline earth metal salts (e.g. calcium or magnesium salts) or especially alkali metal salts (e.g. sodium or potassium salts); the ammonium salts can be derived from ammonia or a suitable, derive preferably physiologically compatible, organic nitrogen-containing base. Both amines and lower alkylamines, in particular tri- (C -C -alkyl) amines, can be used as the base (e.g. triethylamine), hydroxy-14 lower alkylamines [e.g. 2-hydroxyethylamine, di- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine], cycloalkylamines (e.g. dicyclohexylamine), or benzylamines, (e.g. benzylamine and N, N'-dibenzylethylenediamine), as well as nitrogenous ones heterocyclic compounds such as those of aromatic character (e.g. pyridine or Quinoline) or those with an at least partially saturated heterocyclic Ring, (e.g. N-ethylpiperidine, morpholine, piperazine or N, N'-dimethylpiperazine) into consideration.

The compounds and pharmaceutical compositions according to the invention are characterized by favorable biological properties. In particular, wise They have a strong aldosterone antagonistic effect by acting as a result of aldosterone Reduce induced excessive sodium retention and potassium excretion. That's why they find an important application in therapy as potassium-sparing diuretics diseases associated with a disturbed mineral-water balance, e.g. in the treatment of heart failure, arrhythmias due to potassium deficiency, in cor pulmonale, liver cirrhosis, ascites prophylaxis, diabetes mellitus and hypertension.

As steroids with aldosterone-antagonizing effect are so far Spiroxane derivatives known, see e.g. Fieser and Fieser: Steroids; Page 708 (Reinhold Publ. Corp.,. New York, 1959) and British Patent No. 1,041,534; known are also correspondingly effective 17 P-hydroxy-21-carboxylic acids and their salts, see e.g. U.S. U.S. Patent 3,849,404.

Representative compounds of this type, which have also found a broader application in medical practice, are on the one hand 7a-acetylthio-17ß-hydroxy-3-oxo-17a-pregn-4-en-21-carboxylic acid lactone (7a-mercapto-20- spirox-4-en-3, 21-dione-7-acetate) of the formula on the other hand the potassium salt of 17ß-hydroxy-3-oxo-17a-pregna-4,6-diene-21-carboxylic acid of the formula which are also known under the generic names spironolactone or potassium canrenoate, see, for example, Merck Index, 9th Edition, page 1132 or 222; Publ. Merck &Co.> Inc., Rahway, NJ, USA, 1976. The compounds of this type used in therapy up to now have a considerable disadvantage, however, in that they always have a certain sex-specific activity, which is common with the usual long-term therapy sooner or later has a disruptive effect. Disturbances which can be attributed to the antiandrogenic effectiveness of the known antialdosterone preparations are particularly undesirable.

According to the U.S. Patent 4,150,127 by the Introduction of an oxygen function in position 19 of compounds with 20-spiroxan-3-one- and 20-spiroxane-3,21-dione structure are substantially fixed. E.g. with 19-hydroxy-7amercapto-20-spirox-4-en-3-one-7-acetate the antialdosterone effect from about 3 mg / kg orally (Kagawa test with adrenalectomized male rats) noticeable, whereas a demonstrable anti-androgenic effect only at doses of about 60 mg / kg orally [castrated rats treated with testosterone propionate] occurred.

Nonetheless, stick with the most effective compounds of the latter Type a disadvantage in appearance, which is also present with spironolactone and with some Is perceived as serious by the patient: as a result of the sulfur content (from the 7-mercapto group) the compounds have a characteristic odor that is also transmitted to the patient and possibly a trouble-free long-term Therapy stands in the way.

The compound of the formula I according to the invention, on the other hand, is both described Disadvantages free: on the one hand it is odorless, on the other hand it shows in comparison with spironolactone a significantly lower anti-androgenic effectiveness in both in vitro and in vivo, both compounds in the Kagawa test (rat, oral administration) an aldosterone-antagonizing activity of the same intensity (ED50 = 5 mg / kg).

The compound according to the invention of the formula given at the beginning I, as well as the corresponding 17-hydroxy-17a-pregnane-21-carboxylic acid and its salts, can be prepared according to methods of steroid chemistry known per se.

For example, the lactone of the formula I or the corresponding hydroxy acid of the formula IA can be obtained by in a corresponding compound with protected 3- and / or 2'-oxo group, the oxo protective group (s) with release of the corresponding oxo group (s) removed. (As the 2'-oxo group, that of the 7a-position becomes Acetonyl radicals). The derivatives with a protected 3-oxo group are 3-enamines, 3-enol ethers, 3-ketals and especially 3-thioketals into consideration. As enol ethers are Lower alkylenol ethers (i.e. compounds containing the 3-lower alkoxy-3,5-diene moiety) and in particular ethyl and methyl enol ethers are preferred. As 3-ketals are those preferred that differ from lower alkanols, such as methanol or methanol, and in particular of α- or ß-glycols, such as 1,2- or 1,3-propanediol, 1,2- or 2,3-butanediol, and mainly derive ethylene glycol. Those in particular come as 3-thioketals into consideration, which are derived from sulfur analogues of the glycols mentioned; particularly 3,3-ethylenedithio derivatives are preferred. The 3-pyrrolidino-3> 5-dienes are particularly suitable as 3-enamines to call. - In the 3-ketals, the double bond is usually in the 5,6-position, in contrast to the 3-thioketals in the 4,5-position; this location however, the double bond has no influence on the result of the release of the 3-oxo group, in which the 3-oxo-4-ene group is formed in each case. - Analog Protective groups are also suitable for the oxo group of the 7a-acetonyl radical one can also use one of the enol ethers Silyl ethers, such as a tri-lower alkyl silyl ether (e.g. especially trimethylsilyl ether).

These protective groups are split off in a manner known per se by hydrolysis, preferably under the general conditions of acid catalysis in the presence of water. In the case of thioketals, it is preferred to work with additives a sulfur binding compound, e.g.

a metal salt, in particular a heavy metal salt, such as cadmium carbonate and / or mercury (II) chloride. Because the latter means itself in the presence reacts strongly acidic from water, there is no additional acid when used necessary as a catalyst. The treatment is understood by acid catalysis in the presence of an inorganic acid, e.g. sulfuric acid, perchloric acid or a hydrohalic acid, such as hydrochloric, bromic or hydriodic acid, or in particular an organic acid, e.g. a sulphonic acid such as in particular p-toluenesulphonic acid, or a stronger carboxylic acid such as trifluoroacetic acid, Oxalic acid or formic acid. Silyl ethers and enamines may also work be cleaved with weaker carboxylic acids such as acetic acid or benzoic acid.

The starting materials for this process can be made using general methods of steroid chemistry known per se are obtained, e.g. as Intermediate products in the construction of the 7'-acetonyl radical or the lactone ring according to conventional methods Schemes. So you can e.g.

starting from 3,3-ethylenedithio- 3> 3-ethylenedithio-7a-formylmethyl-20-spirox-4-en-21-one by the Grignard reaction with methyl magnesium bromide or iodide and the following Chromium trioxide oxidation of the secondary 2'-hydroxyl group serving as the starting material 3,3-Ethylenedithio-7a-acetonyl-20-spirox-4-en-21-one was obtained. You can also e.g. to 21 2 ', 3-bis (ethylenedithio) -7a-propyl-20-spirox-4-en-21-one as the starting material get by in the 2 ', 3-bis- (ethylendithio-7a-propyl-androst-4-en-17P-ol the 17ß-hydroxyl group oxidized to the keto group and subsequently by means of a well-known method that builds up the lactone ring. For example, the androstene derivative is starting of 6-dehydrotestosterone through the addition of the 7a-allyl side chain, its catalytic Oxidation to the 7a-acetonyl side chain (see below) and thioketalization of both oxo groups accessible.

The lactone of the formula I or the corresponding hydroxy acid of the formula IA can also be obtained by using the corresponding 7a-allyl derivative of the formula respectively. or a salt of the compound of formula IIA, treated with oxygen or an oxygen donor in the presence of a noble metal catalyst.

Oxygen can be used in undiluted form (i.e. as elemental oxygen) or used in dilution with an inert gas (especially as air oxygen) will; as oxygen dunors e.g.

Hydrogen peroxide (especially as a 30-70% aqueous solution) or an organic hydroperoxide, such as in particular tert- Butyl hydroperoxide, into consideration.

A noble metal catalyst is derived from a metal or platinum in particular the palladium group, as from rhodium and especially from palladium, that as a complex, e.g. a complex with an alkyl hydroperoxide (such as the compound [CH, CO-Pd-O-O-tert-butyl] 4 or [CF3CO2-Pd-O-O-tert-butyl] 4), or as a salt an inorganic or organic acid, e.g. a halide (such as in particular Chloride) or an acetate or trifluoroacetate can be present.

Complex salts such as Na2PdC14 and salt-like salts also come into consideration Derivatives derived from "acidic carbon" organic compounds, e.g. Acetylacetone (2,4-pentanedione) or hexafluoroacetylacetone (1,1,1,5,5,5-hexafluoro-2,4-pentanedione) derive.

The reaction is usually carried out in an inert solvent or a mixture of solvents, the shortlist of which depends mainly on the type of solvent used Oxidizing agent -directs. For reaction with an oxygen donor of the type of an organic hydroperoxide, a tertiary aliphatic reaction medium is suitable Alcohol, especially tert-butyl alcohol, works particularly well; in the case of oxidation using hydrogen peroxide are lower alkanecarboxylic acids, especially acetic acid, and secondarily also tertiary ones aliphatic alcohols such as tert-butyl alcohol are preferred. Generally with Water-miscible organic solvents are preferred.

In a preferred variant of the oxidation process, in which the oxidation takes place with elemental oxygen or with atmospheric oxygen it is advantageous to thoroughly mix the gaseous and liquid phases conventional mechanical means such as finely distributing the gas as it passes through by porous materials, stirring and / or shaking. As a noble metal catalyst In this case, one can especially use a palladium salt of a hydrohalic acid (e.g. a bromide or, above all, a chloride), it being advantageous to add a copper salt, in particular a copper (I) halide, works. [A special one a preferred such catalyst is a mixture of palladium (II) chloride (PdCl2) and copper (I) chloride (Cu2C12.] The solvent used in oxygen oxidation with advantage a water-miscible, neutral organic solvent, which is inert to air oxidation. Suitable solvents are e.g. acetonitrile, Hexamethylphosphoric triamide (hexametapol% and amides of lower alkanoic acids (such as acetamide, Formamide, N, N-dimethylacetamide and especially N, N-dimethylformamide) into consideration. The water content of the reaction mixture is about 2-20, preferably about 5-15 Volume%. The reaction temperature is in the range from about -30 ° to + 50 °, preferably at room temperature. (In the case of hydrogen peroxide oxidation, preference is given to higher temperature, e.g. worked at around 40 ° to 800.) The starting material of the Formula II is a known compound which, for example, according to the European patent specification 18245 is accessible.

The compound of the formula I or IA can also be prepared by adding a compound of the formula wherein X is a removable, electron-withdrawing group, It, or in a salt of a compound of the formula IIIA, the group X removes.

Group X is one that is characterized by its strong negative I effect causes a slight detachment of the proton from the neighboring carbon atom and which can easily be detached from this carbon atom. One such group X is especially one in which the a atom (i.e. the one that has the free valence of the whole group carries) at least one oxo group. Group X is in primarily the carboxyl group, but also e.g. a sulfur-containing group of Partial formula R-S (= O) n-, where n is 1 or 2 and R is a di-lower alkylamino group or a hydrocarbyl radical with a maximum of 12 carbon atoms. (A lower alkylistein those with a maximum of 4 carbon atoms, such as, in particular, methyl.) The hydrocarbyl radical is preferably a lower alkyl as defined above or an aryl, e.g. in particular a phenyl, which is replaced by halogens (such as chlorine or bromine), nitro, lower alkyl (such as defined above) or lower alkoxy (such as methoxy) may be substituted. The number according to the O atoms, the above formula denotes sulfinyl (n = 1) or sulfonyl (n = 2); methylsulfinyl, methylsulfonyl and phenylsulfonyl are particularly preferred, as well as dimethylaminosulfonyl.

The group X is split off in a manner known per se, whereby one with advantage of each group X to be split off, the specific reaction conditions in each case adapts. - So the sulfur-containing residues are preferably split off reductively. For this purpose, for example, generally finely divided desulphurizing metals can be used the 1st transition group, especially nickel, especially as Raney nickel, and its Use alloys, such as a nickel-aluminum alloy, in common inert organic solvents (such as, in particular, lower alkanols (e.g. methanol, Ethanol or isopropyl alcohol), and in the case of the Ni-Al alloy in the presence dilute caustic soda, is working. Preferred reactants which are particularly characterized by their gentle action, includes e.g. aluminum amalgam, which in the presence of water and preferably in one miscible with water organic solvent (such as aqueous tetrahydrofuran) is used and in particular for splitting off all sulfinyl groups (especially the methylsulfinyl group), aliphatic sulfonyl groups (such as, in particular, the methylsulfonyl, i.e. the mesyl group), as well as di-lower alkylaminosulfonyl groups (such as in particular the dimethylaminosulfonyl group) suitable is. Arylsulfonyl groups are preferably combined with zinc (especially in Form of zinc dust) in acetic acid. The zinc reduction is expedient in dilution with common organic solvents that are subject to the reduction conditions are stable, including in particular those which are miscible with water, e.g. with lower alkanols, especially with methanol or ethanol; by the way, she is too well suited for the other groups containing sulfur.

The carboxyl group is also split off in a manner known per se, preferably in the form of carbon dioxide thermolytically, i.e. by heating to the Decomposition temperature 5 is preferably used in an organic solvent, such as a lower alkanol (e.g.

Methanol or ethanol) and optionally in the presence of a mineral acid, which further facilitates the elimination of carbon dioxide (decarboxylation) through acid catalysis. The decarboxylation usually takes place at a sufficient rate at room temperature.

The starting material of the formula III with the free carboxyl group can may also arise in situ, i.e. directly in the reaction mixture from a Pre-product, such as in particular a salt (e.g. a sodium or potassium salt) or an ester (i.e. a derivative where X is an esterified carboxyl group) are formed. The to it suitable starting materials, as well as the corresponding methodological process variants for their conversion are general known; the decarboxylation according to the invention usually takes place spontaneously and immediately following the release of the carboxyl group at the reaction temperature used, so that the starting material of the formula III or IIIA is usually isolated in State does not contain. -So you get the starting material with the free carboxyl group in situ from a corresponding salt by acidification, preferably to a pH below 5.0; The salt is advantageously also used in situ, e.g. by means of conventional basic Hydrolysis (preferably with a mild basic reagent of the alkali carbonate type or in particular hydrocarbonate, e.g. sodium or potassium hydrocarbonate) made from a corresponding ester. The in situ is obtained from an ester Starting material of the formula III with a free carboxyl group, advantageously by acid hydrolysis, e.g. in the presence of a catalytic amount of a strong mineral acid (e.g.

sulfuric acid, hydrochloric acid and especially 85% phosphoric acid) or a strong organic acid, e.g. a sulfonic acid (such as in particular a of the p-toluenesulfonic acid type) or trifluoroacetic acid, the acids at the same time also promote decarboxylation. Among the esters that cause hydrolytic cleavage (both the basic as well as the acidic) are particularly suitable, come in particular Lower alkyl esters into consideration, such as especially methyl and ethyl esters, as well as especially for acid hydrolysis, the tert-butyl ester. - The release of the Carboxyl group in situ can also be reductive with suitable esterified carboxyl groups take place, as is preferably the case with an optionally substituted benzyloxycarbonyl group (or an analogous group) by conventional hydrogenolysis, in the case of ß-halogenated Ethoxycarbonyl groups (e.g. the 2,2,2-trichloroethoxy, 2-bromoethoxy, 2-iodoethoxy or 2-chloroethoxycarbonyl group) by zinc reduction or electrolysis, or at Groups of the 2- (trimethylsilyl) ethoxycarbonyl group exposure to non-associated fluoride ions.

The starting materials of the formula III, or their precursors, in which X stands for an esterified carboxyl group, are also obtained in a manner known per se, for example by the Michael condensation of a corresponding 3-oxo-4,6-diene compound of the formula with a compound of the formula CH3COCH2X (V), in which X is O, which is analogous to the group X defined above, but in which an esterified carboxyl group is in place of the free carboxyl group. They can also be prepared by condensing the last-mentioned compound of the formula V in the form of an alkali metal salt with a corresponding 7-halo-3ß-hydroxy-5-ene steroid and the 313-hydroxy-5-ene grouping in the intermediate product formed oxidized to the 3-oxo-4-ene group.

The compound of the formula I or IA can also be obtained by converting a compound of the formula wherein one of the groups Y¹ and Y² represents a hydroxyl group together with a hydrogen atom, the other represents an oxo group or a hydroxyl group together with a hydrogen atom, and in which a double bond is in the 4,5- or 5,6-position, the hydroxyl group (n) oxidized to oxo group (s) and, if necessary, the 5,6 double bond isomerized in the 4,5-position.

The 3 and / or 2 'hydroxyl group is oxidized in a conventional manner known per se, e.g. with a compound of the 6-valent Chromium (such as chromium trioxide or chromic acid and their alkali metal salts), whereby one as the reaction medium lower alkanecarboxylic acids, such as acetic or propionic acid, or a ketone, such as acetone, or else pyridine, optionally with dilution with a halogenated lower alkane, such as methylene chloride or chloroform, used and the The reaction temperature is preferably kept below room temperature. A preferred one The variant is oxidation with a solution of chromium trioxide in aqueous sulfuric acid (Jones reagent), which is usually stored in acetone at a temperature between about -100 to about 250, preferably in the vicinity of the zero point.

For the starting material in which Y is the oxo group (and the 4,5 double bond is present), chromium (VI) oxidation is particularly advantageous. For compounds of the formula VI in which the hydroxyl group is in the 3-position (usually in the 313 position) and which have the 5,6-Do.ppel bond, Chromium (VI) oxidation can also be used, but offers no advantage because the double bond in most cases remains in the original 5,6-position and required to be isomerized to the 4,5-position afterwards, e.g. by treatment with a mineral acid such as sulfuric acid or hydrochloric acid, or an organic one Sulphonic acid, such as p-toluenesulphonic acid in a lower alkanol (e.g. methanol, ethanol or isopropyl alcohol) or a lower alkanoic acid (e.g. acetic or propionic acid). For the latter type of hydroxy compounds preferably the conventional Oppenauer oxidation in one of its usual in steroid chemistry Variants are used, regardless of whether the symbol Y2 is an oxo group or a hydroxyl group is available. The conventional way of working is with excess acetone or cyclohexanone worked in the presence of aluminum isopropoxide as a solvent usually toluene or xylenes are used. For the given case, this has Oxidation method still has the particular advantage that it contains the 5,6 double bond spontaneously migrated to the 4,5 position; In addition, one can also use it formed in situ Use hydroxy compounds produced by the action of said reagents on corresponding easily cleavable esters, such as chloroacetates and especially formates, were created under the conditions of the Oppenauer oxidation. - Is an allylic one Hydroxyl group present (as in 3-hydroxy-4-ene compounds) can be used as an oxidizing agent also manganese dioxide in an organic solvent, e.g. acetone, chloroform or Use dichloromethane in a manner known per se.

The starting materials of the formula VI are made by methods known per se produced, for example, by the above-mentioned condensation of a 7-halo-3ß-hydroxy-5-ene compound with an alkali metal salt of a compound of the formula V and the subsequent cleavage the group X 0 in the manner described above for starting materials of the formula III.

Compounds of the formula VI in which the hydroxyl group is in the 21-position is, for example, from corresponding compounds which are in the 7a-position a 2-oxoethyl group such as formylmethyl, chloroformylmethyl or an esterified one Have carboxymethyl, by treatment with a suitable organometallic Connection, e.g.

Methyl lithium, methyl magnesium bromide or iodide, dimethyl cadmium or dimethylzinc, can be obtained according to general methods known per se.

If desired, the end product obtained in the lactone form can be used the Formula I subsequently in the corresponding form of the hydroxycarboxylic acid of the form IA, or a salt thereof, in particular one of the abovementioned salts. This conversion is preferably carried out by hydrolysis, in particular by the conventional one basic hydrolysis using mild basic reagents, e.g. alkali carbonates and especially hydrocarbonates (such as sodium carbonate, sodium hydrocarbonate, potassium carbonate or potassium hydrocarbonate) in the presence of water in a water-miscible inert organic solvents such as a lower alkanol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran or dioxane), a lower alkanone such as acetone or 2-butanone, or a lower alkyl amide of lower aliphatic carboxylic acids (such as especially N, N-dimethylformamide), or a mixture thereof. - Preferably used you do not use more than an equivalent amount of base and avoid energetic reaction conditions, which could affect the 7-acetonyl group. The alkali metal thus obtained or alkaline earth metal salts can be converted into the corresponding free 17β-hydroxy-21-carboxylic acid be converted by a solution or suspension of a salt in water or is acidified with an organic solvent containing water. The free 17β-hydroxy-21-carboxylic acid can, if desired, be converted into salts by treatment with an appropriate base convert; in this way ammonium salts and salts become more organic advantageously Bases, e.g. those mentioned at the beginning.

The free 17β-hydroxy-21-carboxylic acid is unstable and passes over spontaneously into the lactone form. If desired, this lactonization can be carried out Acid catalysis and / or the use of dehydrating agents such as acetic anhydride, anhydrous copper sulfate, molecular sieves, or by azeotropic distillation support financially.

The 17-hydroxy-21-carboxylic acid of the formula IA and its salts on the one hand and the lactone of the formula I on the other hand, as well as intermediates constructed analogously, are so closely related (with the former merely represent the hydrated form of the latter) that the whole Descriptive text always refers to all the forms mentioned, unless there is a specific one There is a distinction.

Unless otherwise stated, the term "down" refers to used in connection with the definition of a compound or a substituent, to a compound or substituent containing no more than 4 carbon atoms.

The invention also relates to those embodiments of the above Process in which one of one obtainable at some stage as an intermediate Connection goes out and carries out the missing steps, or where a starting material is formed under the reaction conditions.

Containing the pharmaceutical preparations of the present invention the compound of the formula I or IA, or salts thereof, can in particular be used for treatment of hyperaldosteronism of various forms can be used. They contain an effective amount of the active ingredient alone or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers and, if desired, also with other pharmacologically or therapeutically valuable substances, and are particularly suitable for enteral, e.g.

oral or rectal, or for parenteral administration.

Without further specific information, the term "active ingredient" throughout the following text a compound of the formula I or IA, or a salt meant by it, as it is defined at the beginning.

The present invention particularly relates to pharmaceutical compositions Containing as active ingredient the compound of the formula 1 or IA according to the invention (including Salts) in the form of a sterile and / or isotonic aqueous solution, or else in a mixture with at least one solid or semi-solid carrier.

The present invention also relates to medicaments, as well as in particular Medicines in the form of dosage units which contain at least one of the Contain compounds alone or in a mixture with one or more carriers, especially those in solid form.

The invention relates in particular to medicaments in the form of tablets (including lozenges, granules and lozenges), coated tablets, capsules, pills, Ampoules, dry vials or suppositories containing the active ingredient defined above alone or in a mixture with one or more carriers.

As a special form of this pharmaceutical according to the invention Compositions and medicaments also come into consideration that, in addition to Aldosterone-antagonizing compound of the formula I or IA according to the invention, including salts (which is referred to in this context as component A), also contain a diuretic component B which is unspecific with regard to electrolytes.

As such, diuretic nonspecific with respect to electrolyte excretion Component B are conventional "classic" diuretics or mixtures thereof, which induces diuresis through both renal and extrarenal effects on tissue increase, especially substances with an inhibitory effect on reverse resoption in the Tubules such as saluretics or ethacric acid and their analogues. An in-depth compilation suitable diuretics of this type are found, for example, in U.S. Patent 4,261,985. Benzothiadiazine derivatives are particularly suitable as the electrolyte-unspecific component B, such as thiazides and hydrothiazides, also benzenesulfonamides, phenoxyacetic acids, benzofuran-2-carboxylic acids and 2,3-dihydro-benzofuran-2-carboxylic acids. The electrolyte-unspecific component B-can consist of a single active ingredient or an appropriate combination several There are active ingredients, the active ingredients also including several of the groups of substances mentioned can belong. - The following conventional ones are particularly useful as component B .Diuretics under consideration: l-oxo-3- (3-sulfamyl-4-chlorophenyl) -3-hydroxyisoindoline, 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, 3-cyclopentylmethyl-6-chloro- 7 -sulfamyl-3 2, 4-dihydro-l, 2,4-benzothiadiazine-l, 1-dioxide, 4- (2-methylenebutyryl) -2,3-dichloro-phenoxyacetic acid, 4-thenoyl-2,3-dichloro-phenoxyacetic acid, [1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid, 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide, 2-phenoxy-3-butyl amino-5-carb oxybenzene su 1-formamide and 2-phenoxy-3- [3- (1-pyrrolyl) propyl] -5-carboxybenzenesulfonamide.

In such pharmaceutical compositions according to the invention and drugs is the ratio of component A to component B, based to the respective mean effective dose, about 4: 1 to about 1: 4, preferably about 3: 2 to about 2: 3. As the mean effective dose of each specific component a known one or one that is easily ascertainable by known pharmacological test methods Value is easily possible for the person skilled in the art, within the abovementioned limits appropriate ratio of both components to each patient according to his specific Suffering, general health, individual responsiveness and age, as well as its gender.

For example, such combination preparations contain per dose unit 15 to 150 mg, in particular 20 to 100 mg of the compound of the formula I or one Salt of the corresponding hydroxy acid IA as component A and, as component B, for example 10-100 mg, in particular 25-50 mg of 2-chloro-5- [3-hydroxy-1-oxo-isoindolyl- (3)] -benzenesulfonamide or 4- (2-methylenebutyryl) -2,3-dichlorophenoxy acetic acid, 5-50 mg, especially 12-25 mg 6Chlor-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-l, l-dioxi-d or 2-chloro-4-furfurylamino -5-carboxybenzenesulfonamide, 2 - 20 mg, in particular 5-10 mg of 2-phenoxy-3- [3- (l-pyrrolyl) propyl] -5-carboxybenzenesulionamide, 0.1-1.0 mg, in particular 0.25-0.5 mg of 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide or 2-phenoxy-3-butylamino-5-carboxybenzenesulfonamide, 100-400 mg, in particular 200 mg of 4-thenoyl-2,3-dichloro-phenoxyacetic acid and 5 - 25 mg, especially 10 mg racemic (l-oxo-2-methyl-2-phenyl-6, 7-dichloro-5-indanyloxy) acetic acid, or half an amount of the laevo form of this acid.

For edema treatment in a moderate case, for example 1 - 3 dose units taken daily, which contain the active ingredients in amounts by weight, which at the higher limit of the above-mentioned particularly preferred dosage lie; a moderate case of essential hypertension is e.g. 1 - 3 Treated dose units whose active ingredient content at the lower particularly preferred Quantity limit lies.

The term "medicinal product" is used to denote individuals separate portions of uniform composition, which for medical Administration are suitable. The term "medicament in the form of dosage units" is used in this description to designate individual separated Servings of uniform composition intended for medical administration are suitable and each individually a specific amount of the active ingredient according to the invention contain the about 0.05 to about 2, preferably about 0.1 to about 1 daily dose is equivalent to.

The carriers for use in the pharmaceutical compositions (e.g. granules) for the production of tablets, coated tablets, capsules and pills e.g. the following: a) Diluents, e.g. starch, sugar (such as Lactose, glucose and sucrose) mannitol, sorbitol and silica, b) binders, e.g., carboxymethyl cellulose and other cellulose derivatives, alginic acid and its salts (such as sodium alginate) gelatin, and polyvinylpyrrolidone, c) moisture regulators, e.g. glycerine, d) disintegrants, e.g. agar-agar, calcium carbonate and sodium bicarbonate, e) Retarding agent to slow down the absorption of the active ingredient, e.g. paraffin, f) accelerators of absorption, e.g. quaternary ammonium compounds, g) surface-active Agents, e.g., cetyl alcohol and glycerol monostearate, h) adsorbents, e.g., kaolin and bentonite, i) flow regulators and lubricants, e.g. talc, calcium stearate, magnesium stearate and solid polyethylene glycols.

These and similar carriers or auxiliaries can also be several of the serve the purposes mentioned above.

The tablets, coated tablets, capsules and pills containing the above Pharmaceutical compositions according to the invention can be provided with the usual coatings and cladding materials, which, if desired, contain dyes or pigments, e.g. for identification or labeling purposes. These Coatings can also have such a composition that a slowed release the active ingredient enables; for this purpose, e.g. waxes and cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate are suitable.

These compositions can also be fabricated into the shape of the microcapsules will.

Medicines for parenteral administration are preferably ampoules containing a single dose of the active ingredient according to the invention, in particular of a water-soluble, physiologically acceptable salt, in the form of an aqueous one Solution, which is preferably sterilized and, if necessary, the usual buffering agents and / or neutral inorganic salts, such as sodium chloride, as adjustment auxiliaries of isotonicity with blood. Such an aqueous solution works well too for the production of injectable solid drug forms, such as dry vials, in which the amount of the solution corresponding to the single dose in the usual way, e.g. by lyophilization, is evaporated and the solid residue only immediately Is brought into the form of the solution for injection with sterile water before use.

As carriers for pharmaceutical compositions for processing the usual suppository bases are suitable for suppositories.

substances, e.g. natural or synthetic triglycerides, such as cocoa butter, Paraffinic hydrocarbons, polyethylene glycols and higher alkanols. Gelatin rectal capsules contain as base materials e.g.

liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

The pharmaceutical compositions according to the invention contain preferably from about 0.1 to about 99.5, especially from about 1 to about 90% by weight of the active ingredient.

The recommended daily dose of the active ingredient of the formula I or IA (including Salts) for a 75 kg warm-blooded animal is about 5-500 mg, preferably about 30-300 mg, but can vary widely depending on the species Age and individual responsiveness vary.

The production of the above-mentioned pharmaceuticals according to the invention Compositions, preparations, medicaments and medicaments in the form of dosage units takes place by means of conventional, per se known manufacturing processes of the pharmaceutical Industry, e.g.

by means of conventional mixing, granulating, tabletting, coating, dissolving and Lyophilization process, which, if desired, works under aseptic conditions or an intermediate product or a finished product is sterilized.

The present invention also relates to the use of the compound of the formula I or IA (including salts) for combating a wide variety of Forms of hyperaldosteronism in humans and other warm-blooded animals, as well as a corresponding one therapeutic method by administering an effective dose at least one of the active ingredients according to the invention alone or together with one or more Carriers or in a pharmaceutical form is characterized. The inventive Active ingredients are used enterally, e.g. rectally or especially orally, or parenterally, such as, in particular, administered intravenously. A special implementation of the present healing method according to the invention is characterized in that one according to the invention Compound of formula I or IA, or a salt thereof as the aldosterone-antagonizing Steroid component A, and one that is unspecific with regard to electrolyte excretion diuretic component (component B) simultaneously or together, in particular in the form of a corresponding pharmaceutical composition or a drug, administered.

In the following examples, which further illustrate the invention, without restricting them, the temperatures are given in degrees Celsius. All melting points are uncorrected.

Example 1: By a mixture of 52 mg (0.176 mmol) of 60% palladium chloride and 182 mg (1.83 mmol) of copper (I) chloride (Cu2C12) in 15 ml of dimethylformamide and 1.5 ml of water is passed in a stream of oxygen with stirring at room temperature. After 30 minutes, 670 mg (1.75 mmol) of 7a-allyl-20-spirox-4-ene-3,21-dione are added and the mixture in a closed vessel under an oxygen atmosphere at normal Stirred under pressure and room temperature for 24 hours. The reaction mixture is used for working up diluted with I-N hydrochloric acid and the product was taken up in 3 portions of ethyl acetate. The combined ethyl acetate extracts are successively with a half-saturated aqueous sodium hydrocarbonate solution and water, dried over sodium sulfate and evaporated. The residue, recrystallized from methylene chloride-ether, gives the desired 7a-acetonyl-20-spirox-4-en-3,20-dione of the formula defined at the outset I, m.p. 194-195.50.

The starting material is available, for example, as follows (see also EP 18 245): a) Manufacture of allyl triphenyl tin.

In a 1 1/2 1 three-necked flask with a reflux condenser and dropping funnel 24.3 g of magnesium turnings and 320 ml of tetrahydrofuran are presented under argon. To Addition of 2 ml of allyl bromide is carried out at reflux temperature while stirring within 3 1/2 Hours a solution of 96 g of triphenyltin chloride and 33 ml of allyl bromide in 240 mol Tetrahydrofuran was added dropwise. The reaction mixture is then 15 hours under Boiled to reflux, then cooled to room temperature, slowly with 500 ml of a saturated Ammonium chloride solution was added and poured into a separating funnel over glass wool. The aqueous phase is extracted twice with ether and the organic phase Washed 2 times with saturated ammonium chloride solution, dried and in a water jet vacuum evaporated. The crystalline residue is taken up in ether with a solution of 5 g of potassium fluoride in 50 ml Methanol and 500 ml of water, extracted once with ether, dried and evaporated in a water jet vacuum. The colorless crystalline residue is dissolved in approx. 100 ml of ligroin at 600 and cooled to about -15 ". The crystallized allyltriphenyltin is filtered off with suction and washed with cold ligroin, resulting in 79 g of a product of m.p. 74-750.

b) Preparation of a solution of phenyllithium in ether.

Lithium wire (14.7 g) in approx. 2 cm pieces is mixed with 250 ml of ether covered and with stirring and passing argon with about 50 drops of a A solution of 106 ml of bromobenzene in 500 ml of ether is added at room temperature. After approx. After a start-up time of 5 minutes, the temperature rises to boiling. For boiling and foaming The reaction mixture becomes the remainder within 30 minutes while being cooled with an ice bath added dropwise to the bromobenzene solution so that the temperature never falls below the boiling point, i.e. below 360, falls. The mixture is then taken for a further 30 minutes The cooled reaction solution is poured through glass wool into a brown, Pressed storage bottle flushed with nitrogen and stored in the refrigerator. To the Analysis is titrated 2 ml of the solution with 0.1 N hydrochloric acid. A consumption of 19.3 ml (with methyl orange as indicator) or 19.1 ml (with phenolphthalein as indicator) corresponds to the concentration of 0.96 N. The solution must be no later than the next Day to be used.

c) Preparation of 7a-allyl-20-spirox-4-en-3, 21-dione.

475 mg of copper (I) iodide are placed in a 25 ml Erlenmeyer flask (Cu2J2) and 0.875 ml of dibutyl sulfide were stirred for 10 minutes until a light brown color Solution results which, diluted with 10 ml of ether, give solution A. In one 100 ml of stirred flasks are 1.95 g of allyltriphenyltin at room temperature under argon (See paragraph a) dissolved in 11.5 ml of ether and with the help of a syringe with 5.19 ml of the under b) prepared 0.96 N-phenyllithium solution added, creating a white Precipitation occurs. After 15 minutes the reaction mixture is cooled to -300 and solution A is added within 10 minutes. To further 15 minutes at -30 ", 680 mg of 20-spiroxa-4,6-diene-3,21-dione, dissolved in 5 tl of tetrahydrofuran, are added dropwise. After a further 90 minutes, the cooling is removed and 15 ml of 2N hydrochloric acid are added and stirred for 2 hours; the colorless precipitate is suction filtered through kieselguhr and washed with ether, the filtrate washed with water, dried and in a water jet vacuum evaporated. The crude product is purified by chromatography and from methylene chloride-methanol recrystallized, whereby in a yield of 497 mg (65% of theory) the desired 7a-Allyl-20-spirox-4-en-3,21-dione, m.p. 189.5-190.5 °, results.

Example 2: Tablets containing approx. 50 mg of active ingredient, e.g. 7a-acetonyl-20-spirox-4-en-3,21-dione or the Na or K salt of the corresponding 17-hydroxy-21-carboxylic acid, are like made as follows: Composition for 1000 tablets active ingredient, finely ground 50.0 g powdered sugar (sucrose) 79.0 g gum arabic 4.75 g sorbitol 3.75 g talc 2t5 g magnesium stearate 4.9 g mineral oil 0.1 g carboxymethyl cellulose (Na salt) 5.0 g 150.0 g Manufacture The active ingredient is made with the powdered sugar and the Arabic Gum mixed, sieved and made using an approximately 35 percent aqueous sorbitol solution granulated. The granulate is driven through a sieve, dried and sieved again and with the other auxiliaries (talc, magnesium stearate, mineral oil and carboxymethyl cellulose sodium salt) intimately mixed. The mixture is compressed in the usual way to give tablets of 150 mg.

Example 3: Dragees containing approx. 50 mg of active ingredient, e.g. 7a-acetonyl-20-spirox-4-en-3,21-dione or the Na or K salt of the corresponding 17-hydroxy-21-carboxylic acid are as follows manufactured: Composition of a tablet core active ingredient, micronized 50.0 mg corn starch 90.0 mg tricalcium phosphate 100.0 mg polyvinylpyrrolidone K 25 15.0 mg magnesium stearate 2.0 mg sodium carboxymethyl cellulose 33.0 mg 290.0 mg Manufacture of 50,000 tablet cores The mixture of 2.5 kg of active ingredient, micronized, 4.5 kg of corn starch and 5 kg of tricalcium phosphate is distilled with a solution of 0.75 kg of polyvinylpyrrolidone K 25 in 5 kg Granulated water in the fluidized bed process. The one dried at 450C and through 0.1 kg of magnesium stearate are pressed through a sieve of 1 mm mesh size and 1.65 kg of sodium carboxymethyl starch mixed into convex tablets of 290 each mg pressed.

Production of 6.6 kg sugar coated tablets 6 kg of the coated tablet cores are used in a coating pan of 45 cm diameter with a sugar syrup (2 parts sugar and 1 part by weight of distilled water), in which 1.5% polyvinylpyrrolidone K25 and 1% polyethylene glycol 6000 are dissolved and 20% talc is suspended, up to one Weight of 360 mg coated in portions, with warm air of approx. 60 ° dried. Then sugar syrup (2 parts sugar and 1 part water) Applied in portions up to the final weight of 400 mg. The dragees will eventually glossed with a solution of 2% carnauba wax in trichlorethylene.

Example 4: Soft gelatin capsules containing 50 mg of active ingredient, e.g.

7a-Acetonyl-20-spirox-4-en-3,21-dione or the Na or K salt of corresponding 17-hydroxy-21-carboxylic acid are obtained as follows: Composition a soft gelatin capsule active ingredient, micronized 50.0 mg soy lecithin 1.5 mg beeswax 2.5 mg vegetable oil 110.0 mg vegetable oil, partially hydrogenated 54.0 mg 218.0 mg production of 100,000 soft gelatin capsules 5.0 kg of active ingredient, micronized, are in a Mixture made by melting 0.15 kg soy lecithin, 0.25 kg beeswax, 5.4 kg of partially hydrogenated vegetable oil and 11 kg of vegetable oil suspended and after brought into gelatin capsules using the punching process. The gelatine shell consists of approx. 71% gelatin, approx. 28% glycerine (85%) and approx. 1% titanium dioxide, as well as 0.3% p-hydroxybenzoic acid propyl ester. The capsule size is 4 minims (oblong shape).

Example 5: Film-coated tablets containing 100 mg of active ingredient, e.g. 7a-acetonyl-20-spirox-4-en-3,21-dione or the Na or K salt of the corresponding 17-hydroxy-21-carboxylic acid are as follows manufactured: Composition of a film tablet core active ingredient, micronized 100.0 polyethylene glycol 6000 52.0 mg colloidal silica 5.0 mg stearic acid 3.0 mg 160.0 mg Production of 10,000 cores 1.0 kg of active ingredient, micronized, is prepared with a melt of 0.52 kg of polyethylene glycol [with the addition of 0.05 kg of colloidal silica (specific surface 200 m² / g)] mixed and After cooling, pressed through a sieve with a mesh width of 1 mm. The granules will be 0.03 kg of powdered, pre-sieved stearic acid mixed in and too weak Compressed convex tablets of 160 mg each.

Production of 30,000 film dragees 4.8 kg cores are placed in a coating pan 45 cm in diameter with a solution of hydroxypropylmethylcellulose (viscosity 6 cP, 2% solution in water) in distilled water in which 2% talc is suspended is, continuously sprayed with warm air supply of 350 up to 5 mg on each core Paint is present.

Example 6: Tablets containing approx. 50 mg of component A and approx. 25 mg of component B are prepared as follows: Composition of a tablet Component A, micronized 50.0 mg Component B, micronized 25.0 mg corn starch 50.0 mg silica, colloidal 5.0 mg gelatin 5.0 mg cellulose microcrystalline 75.0 mg sodium carboxymethyl starch 20.0 mg magnesium stearate 1.5 mg 331.5 mg manufacture from 100,000 tablets 5 kg component A, micronized, and 2.5 kg component B, micronized, 5.0 kg of corn starch are mixed with 0.5 kg of colloidal silica and with a solution of 0.5 kg of gelatin in 5.0 kg of distilled water (30 "C) processed to a moist mass. This is through a sieve vatl 3 mm Driven mesh size and dried at 450C (fluidized bed dryer). The dry one Granules are pressed through a sieve with a mesh size of 0.8 mm, with one in front sieved mixture of 7.5 kg of microcrystalline cellulose and 2.0 kg of sodium carboxymethyl starch and 0.15 kg of magnesium stearate mixed and compressed to tablets of 331.5 mg weight.

Component A is 7a-acetonyl-20-spirox-4-en-3,21-dione or that Na or K salt of the corresponding 17-hydroxy-21-carboxylic acid, as component B 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine / l-dioxide used.

In an analogous manner, the following can also be used in the appropriate amounts Use active ingredients as component B: 2-chloro-5- (3-hydroxy-l-oxo-isoindolyl-3) -benzenesulfonamide or 4- (2-methylenebutyryl) -2,3-dichlorophenoxyacetic acid (50 mg each) 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (25 mg), 2-phenoxy-3-butylamino-5-carboxybenzo lsulfonamide (0.5 mg), (1-0xo-2-methyl-2-phenyl-6, 7-dichloro-indanyl-5-oxy) acetic acid (as racemate 20 mg, as the laevo form 10 mg) or 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5 mg).

Example 7: Soft gelatin capsules containing 50 mg of component A and 12.5 mg of component B are obtained as follows: Composition of a soft gelatin capsule Component A, micronized 50.0 mg Component B, micronized 12.5 mg soy lecithin 1.5 mg beeswax 2.5 mg vegetable oil 100.0 mg vegetable oil, partially hydrogenated 54.0 mg 220.5 mg Production of 100,000 soft gelatin capsules 6.25 kg a uniform mixture of components A and B in a weight ratio of 4: 1, micronized, are in the manner described in Example 4 with the same amounts of the carrier materials processed.

7a-Acetonyl-20-spirox-4-ene-3,21-dione is used as component A, as component B 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazinl, l-dioxide used.

In an analogous manner, the following can also be used in the appropriate amounts Use active ingredients as component B: 3-Cyclopentylmethyl-6-chloro-7-sulfamyl-3, 4-dihydro-1,2,4-benzothiadiazine-1,2-dioxide (0.25 mg), 4-thienyl-2,3-dichlorophenoxyacetic acid (125 mg), 2-chloro-5- (3-hydroxy-1-oxo-isoindolyl-3) -benzenesulfonamide (25 mg) or 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide (15 mg).

Example 8: Film-coated tablets containing 100 mg of component A and 10 mg Component B is produced as follows: Composition of a film tablet core Component A, micronized 100.0 mg Component B, micronized 10.0 mg polyethylene glycol 6000 52.0 mg Colloidal Silica 5.0 mg Stearic Acid 3.0 mg 170.0 mg Preparation from 10,000 cores 1.1 kg of an even mixture of components A and B in a weight ratio of 10: 1, micronized, with a melt of 0.52 kg of polyethylene glycol [prepared by adding 0.05 kg of colloidal silica (specific surface 200 m² / g)] mixed and after cooling through a sieve of 1 mm mesh width pressed.

0.03 kg of stearic acid in powder form, sieved in advance, are added to the granulate mixed in and compressed into slightly convex tablets of 170 mg each.

Production of 30,000 film coated tablets 5.1 kg of cores are placed in a coating pan 45 cm in diameter with a solution of hydroxypropylmethyl cellulose (viscosity 6 cP, 2% solution in water) in distilled water in which 2% talc is suspended is, continuously sprayed with hot air at 35 ° up to 5 mg on each core Paint is present.

7a-Acetonyl-20-spirox-4-ene-3,21-dione is used as component A, as component B 2-phenoxy-3- [3- (1-pyrrolyl) propyl] -5-carboxybenzenesulfonamide is used.

In an analogous manner, the following can also be used in the appropriate amounts Use active ingredients: As component A: the Na or K salt of the corresponding 17-hydroxy-21-carboxylic acid (100 mg); as component B: 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (25 mg), 2-chloro-5- (3-hydroxy-l-oxo-isoindolyl-3) -benzenesulfonamide (50 mg), 4- (2-methylenebutyryl) -2, 3-dichlorophenoxyacetic acid (50 mg), 2-chloro-4-furfurylamino-5-carboxybenzenesulfonamide (20 mg), 2-phenoxy-4-butylamino-5-carboxy-benzenesulfonamide (0.5 mg) or 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine -1,1-dioxide (0.5 mg).

Example 9: Dragees containing 40 mg of 7a-acetonyl-20-spirox-4-en-3,21-dione as component A and 10 mg of 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as component B.

Composition of a coated tablet core: 7a-acetonyl-20-spirox-4-en-3,21-dione 40 mg lactose 160 mg stearyl alcohol 77 mg polyvinylpyrrolidone 20 mg magnesium stearate 3 mg 300 mg protective varnish shell: 6-chloro-7-sulfamyl-3, 4-dihydro-1, 2,4-10 mg benzothiadiazine-l, l-dioxide Sugar, talc, color, 190 mg binder q.s. ad 500 mg Manufacture The steroid component and lactose are made with the stearyl alcohol and a concentrated polyvinylpyrrolidone solution granulated and dried. The mass obtained is sieved and made into pellets 300 mg weight pressed. These are covered with a protective lacquer layer and then with colored sugar syrup in which the diuretic component is dissolved, Coated up to a final weight of approx. 500 mg.

Example 10: Gelatin capsules containing approx. 50 mg 7a-acetonyl-20-spirox-4-en-3,21-dione as component A and 125 mg of 4-thenoyl-2,3-dichlorophenoxyacetic acid as component B are produced as follows: Composition of a desiccant capsule 7a-Acetonyt2t) -Spirox-4-en-3, 21-dione 50.0 mg 4-Thenoyl-2,3-dichlorophenoxyacetic acid 125.0 mg lactose 124.0 mg magnesium stearate 1.0 mg 350.0 mg Manufacture of 10 000 desiccant capsules 0.50 kg 7a-acetonyl-20-spirox-4-en-3,21-dione, finely ground, is intimately mixed with 1.25 kg of 4-thenoyl-2,3-dichlorophenoxyacetic acid and after If necessary, still grated, for this mixture 1.24 kg of finely ground lactose and 0.01 kg magnesium stearate added through a sieve and homogenized. The powder will sieved and filled in dry gelatin capsules in portions of 350 mg each.

In a manner analogous to that shown in the preceding Examples 2-10 the other active ingredients mentioned or mentioned in the description can also be used can be processed into analogous medicinal products.

Claims (8)

Claims A lactone of the 20-spiroxane series of the formula the corresponding 17p-hydroxy-17a-pregn-4-en-21-carboxylic acid of the formula and their salts. 2. A compound according to claim 1, which is 7a-acetonyl-20-spirox-4-ene-3,21-dione of formula I. 3. A compound according to claim 1, which is a sodium or potassium salt of 7a-acetonyl-17ß-hydroxy-3-oxo-17a-pregn-4-ene-21-carboxylic acid of formula IA. 4. Process for the preparation of a lactone of the 20-spiroxane series or the corresponding 17p-hydroxy-17a-pregn-4-en-21-carboxylic acid of the formulas or a salt of this acid, characterized in that a) in a corresponding compound with a protected 3- and / or 2'-oxo group, the oxo protective group (s) is removed with liberation of the corresponding oxo group (s), or b) the corresponding one 7a-allyl derivative of the formula or a salt of the compound of the formula IIA, treated with oxygen or an oxygen donor in the presence of a noble metal catalyst, or c) in a compound of the formula wherein X is a removable, electron-withdrawing group, or in a salt of a compound of the formula IIIA, the group X is removed, or d) in a compound of the formula wherein one of the groups Y and Y2 represents a hydroxyl group together with a hydrogen atom, the other represents an oxo group or a hydroxyl group together with a hydrogen atom, and in which a double bond is in the 4,5- or 5,6-position, the hydroxyl group (n) oxidized to oxo group (s) and, if necessary, the 5,6 double bond isomerized in the 4,5-position and e) if desired, the end product of the formula I obtained in the lactone form into the corresponding hydroxycarboxylic acid of the formula IA, or converts a salt thereof, and / or from an end product obtained as a salt releases the acid and / or lactonizes the free acid. 5. A compound according to any one of claims 1-3 as a diuretic. 6. A pharmaceutical composition containing as an active ingredient a the compounds defined in claims 1-3 and 5. 7. A pharmaceutical composition according to claim 6 containing in addition to an aldosterone-antagonizing compound designated as component A. according to one of claims 1-3 and 5, another one which is unspecific with regard to electrolytes diuretic component B. 8. A method for producing a pharmaceutical composition according to claim 6 or 7, characterized in that the active ingredient (s) is processed with at least one pharmaceutically usable carrier material in a non-chemical way. + rt4eapeutiche method; Combat ton lrlr Rfltj'mnFlln rr In Ulnr3 ai7peraldosteroni £ - mus in humans and other warm-blooded animals characterized by the administration of an effective dose of at least one of the in cont 1-3 and 5 defined active ingredients alone or together with one or according to several carriers or in the form of a composition Claim 6.> 10. A therapeutic method according to claim 9> characterized by draws that a connection defined in claims 1-3 or 5 formation of the formula I or 1 or a salt thereof as an aldosterone antagonizing St id component A, and one related to the Electrolyte exposure non-specific diuretic component (compo- nete B) at the same time or together, i.e. in the form of a corresponding the pharmaceutical composition according to claim 7, . vcrabrcicit, «