US3597453A - Mineralocorticoidal 3-ethers - Google Patents

Abstract

AS STEROIUS EXHIBITING STRONG MINERALOCOTICOIDAL ACTIVITIES AND WEAK GLUCOCORTICOIDAL ACTIVITIES, ARE COMPOUNDS OF THE FORMULA:

3-R1-O-,4-R2-,5-R3-,21-R4-PREGNAN-20-ONE

WHEREIN R1 IS LOWER ALKYL OR CYCLO ALKYL; R2 AND R3 REPRESENT HYDROGEN OR TOGETHER A DOUBLE BOND; AND R4 IS A FREE OR ESTERIFIED HYDROXY GROUP.

Description

United States Patent Office 3,597,453 Patented Aug. 3, 1971 US. Cl. 260397.47 7 Claims ABSTRACT OF THE DKSCLOSURE As steroids exhibiting strong m ineralocorticoidal activities and Weak glucocorticoidal activities, are compounds of the formula:

wherein R is lower alkyl or cyclo alkyl;

R and R represent hydrogen or together a double bond;

and

R is a free or esterified hydroxy group,

BACKGROUND OF THE INVENTION This invention relates to steroids, and in particular to those exhibiting mineralocorticoidal activity.

It is known that the natural mineralocorticoids, such as desoxycorticosterone and aldosterone, are orally inactive. There are, however, certain synthetic corticosteroids, such as 9a-fiuorohydrocortisone and derivatives thereof, which are orally active mineralocorticoidal agents, but they also exhibit deleteriously strong glucocorticoid side eiiects. Accordingly, these known orally active synthetics must be administered with caution and only to certain patients.

SUMMARY OF THE INVENTION An object of this invention is to provide steroids having a high index of mineralocorticoidal to glucocorticoidal activities.

Another object is to provide novel steroids, processes for their preparation, and intermediates for such processes.

Other objects include pharmaceutical compositions and methods of administration for effecting mineralocorticoidal activities.

Upon further study of the specification and claims, other objects and advantages of the present invention will become apparent.

To attain the objects of this invention, there are pro vided compounds of Formula I, as follows:

C.7H R C 0 '5 R10 NW IIt Rs 2 (I) wherein R is lower alkyl or cycloalkyl;

R and R represent hydrogen or together a double bond;

and

R represents a free or esterified hydroxy group, as well as ester salts of the acidic or basic 21-esters thereof.

These compounds exhibit, upon oral administration, high mineralocorticoidal activities without the occurrence of appreciable glucocorticoid side effects. Thus, for example, 306 methoxy-Zl-hydroxy-4-pregnen-20=one possesses a sodium-retaining and diuresis-inhibiting activity approximating that of 9oc fill0i0h1YdI'OCOI'liiS0l'16, but without effecting a thymus involution.

Consequently, the compounds of Formula I are valuable drugs, and, in particular, can be administered to animals without danger for combating Addisons disease and hypotonia.

In addition to the aforementioned activities, the compounds exhibit a blood pressure elevating activity.

It is also to be noted that the compounds of Formula I are suitable as intermediates for the preparation of other pharmacologically effective compounds.

For example, by ether cleavage and subsequent oxidation, followed by esterification, compounds such as 21- hydroxy-Sfl-pregnan-3,2O-dione-2'l-hemisuccinate can be obtained which are active on the central nervous system. Furthermore, a series of conventional reaction steps including the introduction of a 14,61 hydoxy group, Reformatskij reaction of the 20-keto group and lactonization furnishes the known digitoxigenin acetate.

To prepare the compounds of Formula 1, several alternative processes can be used, to wit:

(1) a 3-hydroxy-steroid of Formula II CH R4 wherein R to R, have the above-indicated meanings, or a derivative of such a 3-hydroxy-steroid reactively esterified in the 3-position, can be reacted with an alcohol of the formula R OH or with a reactive derivative of such an alcohol;

a compound of the general Formula III (llHgR CO I -orar RiO g I R R, 3

R to R have the above-indicated meanings, and can be reacted with zinc in aqueous acetic acid to remove the 17oc-OH group;

(3) a functionally modified 20-ketoand/or 21-R group in a steroid otherwise corresponding to Formula I can be liberated by solvolysis, preferably by acidic or alkaline hydroylsis, or by hydrogenolysis;

(4) a free hydroxy group can be esterified in the 21- position;

(5) an acidic or basic 21-ester can be converted into the ester salt thereof; and

(6) a double bond present in the 4(5)-position can be catalytically hydrogenated.

In Formulae I-III, the wavy lines in the 3- and 5- positions mean that the substituents in these positions can be Ot-POSltlOIlGd or ,B-positioned. Accordingly, the formulae encompass the corresponding 5a: and 55-H- pregnanes and 4-pregnenes.

(III) wherein DETAILED DISCUSSION OF THE INVENTION In the formulae, R represents alkyl groups advantageously of 1-10, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and furthermore also sec.-butyl, tert.-butyl, n-amyl, isoamyl, nhexyl, n-octyl, and n-decyl; or cycloalkyl groups of especially 3-7, preferably 5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

R represents a free or esterified hydroxy group. In the esters, the acid residues are those derived from saturated or unsaturated aliphatic or cycloaliphatic, aromatic or heterocyclic carboxylic acids of respectively l-18 carbon atoms in total, examples including, but not limited to:

formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, the valeric acids, such as n-valeric acid or trimethylacetic acid, the caproic acids, such as B-trimethylpropionic acid or diethylacetic acid, the enanthic, caprylic, pelargonic, capric or undecylic acids, the undecylenic acids, the lauric, myristic, palmitic or stearic acids, oleic acid, cyclopropy1-, cyclobutyl-, cyclopentyland cyclohexyl-carboxylic acids, cyclopropyl-methylcarboxylic acid, cyclobutylmethylcarboxylic acid, cyclopentylethylcarboxylic acid, cyclohexylethylcarboxylic acid, the cyclopentyl-, cyclohexylor arylacetic acids or propionic acids, e.g. phenylacetic acid or 3-phenylpropionic acid, benzoic acid, phenoxyalkanoic acids, such as phenoxyacetic acid, as well as halocarboxylic acids, such as chloroacetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, ether acids, such as 4-tert.-butylphenoxyacetic acid, 3-phenoxypropionic acid, 4-phenoxybutyric acid, heterocyclic acids, such as furan-Z-carboxylic acid, 5-tert.-butylfuran-2-carboxylic acid, S-bromofuran-Z-carboxylic acid, nicotinic acid or isonicotinic acid, fi-ketocarboxylic acids, e.g. acetoacetic acid, propionylacetic acid, butyrylacetic acid or capronoylacetic acid, or amino acids, such as diethylaminoacetic acid or aspartic acid.

In place of the carboxylic acid residues, residues of sulfonic, phosphoric, sulfuric or hydrohalic acids can also be used.

Of particular importance are those esters containing a group which imparts water-solubility to the compound, such as a hydroxyl, carboxyl or amino group, since they can be employed for the preparation of aqueous solutions. Such esters are derived from dicarboxylic acids of preferably 2-10 carbon atoms, examples of such acids including, but not limited to: oxalic, succinic, maleic, glutaric, dimethylglutaric, pimelic, acetonedicarboxylic, acetylenedicarboxylic, phthalic, tetrahydrophthalic, hexahydrophthalic, endomethylenetetrahydrophthalic, endomethylenehexahydrophthalic, endoxyhexahydrophthalic or endoxytetrahydrophthalic acid, camphoric acid, cyclopropanedicarboxylic acid, cyclobutanedicarboxylic acid, diglycolic acid, ethylenebisglycolic acid, polyethylenebisglycolic acids, thioglycolic acid, furan-, dihydrofuranand tetrahydrofuran-dicarboxylic acids, quinolinic acid (2,3- pyridinedicarboxylic acid), cinchomeronic acid (3,4-pyridinedicarboxylic acid), the polyethyleneglycol-monoalkylether mono-esters of the above dicarboxylic acids. Additional acids include amino-, alkylaminoor dialkylaminocarboxylic acids, and polybasic inorganic acids, such as sulfuric or phosphoric acids. By using these acids, the corresponding esters can be produced, including, but not limited to, for example: oxalates, succinates, maleates or the acid addition salts of aminocarboxylic acid esters, e.g. the esters of aspartic acid or diethylaminoacetic acid.

Typical ester salts of the acidic 21-esters, e.g. the sulfuric and phosphoric acid esters and the 2l-mono-esters of dibasic carboxylic acids are, in particular, the alkali salts, preferably the salts of alkali metals, particularly the sodium salts; the ammonium salts; and the ethanolammonium, diethanolamrnonium and triethanolammonium salts. Characteristic ester salts of the basic 21-esters are the acid addition salts, especially the hydrohalogenides, e.g. the hydrochlorides and hydrobromides of 21-(aminocarboxylic acid)-esters.

With respect to the preparation of the final compounds of Formula I, starting compounds of Formula II are, in particular, those wherein the optionally esterified hydroxy group in the 3-position is more reactive than the hydroxy or ester group in the 21-position. Examples of suitable starting compounds include, but are not limited to: 3ocand 3fl-chloro-2l-hydroxy-5aand Sfl-pregnan-ZO- one, 311- and 3p-bromo-21-hydroXy-5otand Sflregnan- 20-one and the corresponding 3-sulfonic acid esters, e.g. the 3-methancsulfonates, 3-benzenesulfonates and 3-ptoluenesulfonates of 30;,21- and of 35,21-dihydroxy-5aand 5fl-pregnan-20-one, and the derivatives of these compounds which are not reactively esterified in the 21-position, for example, the 21-acylates pertaining thereto, especially the Zl-acetates, e.g. 3a,21- and 3,8,21-dihydroxy- 5aand Sfi-pregnan-ZO-one-Zl-acetate and also the 4(5)- dehydro-derivatives of the above-mentioned compounds, such as 3aand 3fl-chloro-Z1-hydroxy-4-pregnen-20-one or 30:,21- or 3 8,2l-dihydroxy-4-pregnen-20-one-2 l-acetate.

Alcohols of the formula R OH suitable for the etherification are preferably methanol and ethanol, but, of course, all other species of R OH can also be used, e.g. propanol, isopropanol, butanol, isobutanol, cyclopropan01, cyclobutanol, cyclopentanol, cyclohexanol and cycloheptanol. Reactive derivatives of these alcohols are the corresponding chlorides, bromide, iodides, sulfates and sulfonic acid esters, particularly the esters of methanesulfonic, benzenesulfonic and p-toluenesulfonic acid, such as, e.g. methyl chloride, methyl bromide and methyl iodide, dimethyl sulfate, methylmethanesulfonate, -benzenesulfonate and -p-toluenesulfonate. Reactive derivatives along the lines of the present invention are also the corresponding diazoalkanes, e.g. diazomethane and diazoethane.

The compounds of Formulae II and R OH (or the reactive derivatives thereof) are reacted in accordance with methods known from the literature and dependent on the nature of the corresponding starting materials. Thus, it is possible, for example, to employ in the reaction one of the two reactants in the form of a reactive ester (halogenide or sulfonic acid ester), and the other in the form of the free alcohol or of an alcoholate, e.g. of the associated sodium or potassium alcoholate. Thus, for producing a 3-methoxy compound, it is possible, for example, to react a 3-chloroor 3-bromo-steroid or the 3-sulfonic acid ester of a 3-hydroxy-steroid of Formula II with methanol and catalytic amounts of an acid, e.g. p-toluenesulfonic acid, or instead with sodium methylate. However, the sodium compound of a S-hydroxy-steroid of Formula II can also be made to react with methyl iodide, methyl bromide or with the methyl ester of a sulfonic acid.

Insofar as the solvent employed in the above method is not an excess of the etherification agent, for example, the alcohol R OH (such as methanol or ethanol), the re action is normally conducted in the presence of an additional inert solvent, suitable solvents in this connection being, for instance, hydrocarbons, such as hexane, benzene, toluene; or ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane. The reaction is conducted at temperatures preferably between C. and the boiling point of the solvent employed. The reaction times range generally between 1 and 48 hours.

Another method resides in reacting a compound of Formula II containing a free 3-hydroxy-group with a diazoalkane, such as diazomethane, in the presence of a Lewis acid, such as aluminum chloride or boron trifluoride. Suitable solvent are especially ethers, such as the ones enumerated above.

In a further method, it is possible to react the two components II and R OH in the form of the free alcohols in the presence of a strong acid, such as hydrogen chloride or sulfuric acid, and optionally in the presence of an inert solvent.

The starting compounds of Formula II are obtainable, for example, by reducing the 3-keto-group of the desoxycorticosterone (optionally after first etherifying or esterifying the 2l-hydroxy-group and/or blocking the -ketogroup) selectively to a mixture of the 3aand 3B-hydroxy compounds, with the aid of a suitable reducing agent, such as lithium-tri-tert.-butoxyaluminum hydride or sodium borohydride. The resulting mixture is separated, if desired (for example, by chromatography), and any protective groups present can then be cleaved, for example, by alkaline or acidic hydrolysis. The mixture (or the individual epimers) can be converted with thionyl chloride or phosphorus pentachloride into the 3m and BB-chloro-compounds; with phosphorus pentabromide or triphenylphosphine dibromide into the 304- and 3,8bromo-compounds; or with the corresponding sulfonic acid chlorides into the B-methanesulfonates, 3-benzenesulfonates and 3-p-toluenesulfonates.

The corresponding derivatives saturated in the 4-position are obtainable by catalytic heydrogenation of the unsaturated starting compounds or the intermediate products thereof. The hydrogenated intermediates can then be converted into the above-mentioned saturated starting materials in analogous reaction sequences.

The starting substances of the saturated series can also be produced by selectively reducing pregnane-3,20-dione into a mixture of cand 3B-hydroxypregnan-ZO-one, acetoxylating this mixture in the 2-position, and optionally halogenating same in the 3-position, as described above, or reacting same with a sulfonic acid chloride, as likewise set forth in the foregoing.

The compounds of Formula I can also be produced by reductively removing the 17u-hydroxy-group in steroids of Formula III, by treating the latter with zinc in aqueous acetic acid. Preferably, a large excess of zinc dust is employed, and the reaction mixture is heated for /2 to 4 hours in boiling 50% acetic acid. Suitable starting materials are, for example, 3ocand 3,B-methoxy-, -ethoxy-, -propoxy-, -cyclopentyloxyand cyclohexyloxyl7a, 21- dihydroxy-4-pregnen-20-one, as well as the corresponding 6 5aand SB-pregnane derivatives saturated in the 4(5)- position. These starting compounds can be produced from cortexolone (Reichstein substance S), the dismethylenedioxy derivative of which is reduced with a complex metal hydride, e.g. sodium borohydride, to a mixture of the epimeric 3-hydroxy compounds. After the protective group has been split oif, for example, by the effect of formic acid or hydrofluoric acid, an etherification in the 3-position is conducted. A separation of the 3-epimers and/or, if desired a hydrogenation of the 4(5)-double bond, can be conducted at various stages.

Another process for obtaining the products of Formula I comprises converting a functionally modified ZO-ketogroup in a steroid otherwise corresponding to Formula I into a free 20-keto-group by solvolysis, preferably by acidic or alkaline hydrolysis.

The functionally modified 20-keto-group is preferably present as the ethylene ketal or the semicarbazone. Additional suitable functional derivatives are other ketals, e.g. the dimethyl, diethyl, and propylene ketals, as well as hemithioketals (ethylene-, propylene-, dimethyland diethylhemithioketals), thioketals (ethylene, pr0pylene-, dimethyland diethylthioketals), enol ethers, thioenol ethers, cyanohydrins, oximes, phenylhydrazones and Girard derivatives (for example, the Girard-T derivative).

The solvolysis of the above-mentioned 20 keto-deriva tives is conducted in the conventional manner described in the literature. The ketals are preferably split by treatment with dilute acids. Suitable acids are, for example, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, p-toluenesulfonic acid, oxalic acid, acetic acid, as Well as Lewis acids, such as boron trifluoride etherate. Ordinarily, an inert solvent is employed, such as methanol, ethanol, acetone, dioxane, ether, tetrahydrofuran, benzene, chloroform or methylene chloride or mixtures of these solvents, optionally with the addition of water. Acetic acid can simultaneously serve as the reactant and the solvent. The splitting takes place readily at room temperature, but it is also possible to conduct the process at temperatures up to the boiling point of the solvent employed, if splitting of the ether group in the 3-position is avoided, which latter measure does not entail any difficulties. Depending on the conditions employed, the reaction is terminated after a few minutes up to after 24 hours.

Thioketals and thioenol ethers are suitably split by treatment with mercury chloride/cadmium carbonate at room temperature or under heating, preferably in aqueous acetone, but also by hydrolysis with dilute hydrochloric acid or sulfuric acid. Hemithioketals are split by employing the same acids, with mercury chloride or with Raney nickel, e.g. in acetic acid in the presence of sodium acetate. Also semicarbazones, oximes, phenylhydrazones and Girards T derivatives can be split in an acidic medium, but the cyanohydrin is split with bases, such as methanolic potassium methylate or pyridine.

It is also possible to conduct the splitting operation in the presence of a carbonyl compound, which, in turn, reacts with the liberated reactant With the formation of the corresponding derivative. Thus, the semicarbazone is converted into the free keto compound in a particularly advantageous manner by treatment with pyruvic acid. This reaction is conducted, for example, in aqueous dioxane or aqueous acetic acid at room temperature or, more suitably, at elevated temperatures up to the boiling point of the solvent.

The ZO-keto-derivatives to be employed as the starting materials can be obtained, for instance, from desoxycorticosterone, the latter being first partially functionalized in the 20-position, e.g. ketalized. The thus-obtained derivative is thereafter reduced in the 3-position, optionally after first separating the isomers and by-products; the reduction process is preferably conducted with a complex metal hydride, such as lithium aluminum hydride or sodium borohydride. Saturated starting. substances are produced by catalytically hydrogenating the 4(5)-double bond.

It is also possible, under solvolysis conditions, to simultaneously liberate the functionalized keto-group in the -position and accomplish the etherification in the 3-position; this is done, for example, by treating the ethylene ketal of 3,8,21-dihydroxy-4-pregnen-20-one with p-toluenesulfonic acid and R OH; the alcohol R OH serves at the same time as the solvent and as the etherification agent.

The ethers of the general Formula I can also be obtained by converting a functionally modified 2'1-R -group in a steroid otherwise corresponding to Formula I into an R -group by solvolysis. Thus, 21-hydroxy-steroids of Formula I can be liberated from the 21-esters or 21-ethers thereof. Characteristic starting steroids are those wherein the 21-hydroxy-group is present in the form of a readily splittable ester, for example, as the acetate or benzoate, or a readily splittable ether. In the last-mentioned case, the 21-ether-group must be more easily splittable than the ether group in the 3-position. 21-ethers suitable for this purpose are the benzyl, diphenylmethyl (benzhydryl), triphenylmethyl and tetrahydropyranyl ethers. Accordingly, suitable starting substances are the following, for example: 3a and 3fi-methoxy-2l-acetoxy-5otand -55- pregnan-ZO-one, 3aand 3B-methoxy-2l-benzoyloxy-5aand -5,8-pregnan-20-one, 3aand -methoxy-21-benzyloxy-5aand Sfl-pregnan-ZO-one, 341- and 3,8-methoxy-2ltriphenylmethoxy-5uand -5fl-pregnan-20-one, as well as the corresponding 4(5)-dehydro-derivatives, e.g. 30:- and 3fi-methoxy-21-acetoxy-4-pregnen-20-one and the analogous 3-ethoxy, 3-propoxy, 3-isopropoxy, 3-butoxy, 3-cyclopentyloxy and 3-cyclohexyloxy compounds.

The Ill-esters are preferably converted into the free 21- hydroxy-compounds by alkaline or also by acidic hydrolysis. Thus, it is possible, for example, to react these compounds with sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate; in this connection, suitable solvents are lower alcohols, such as methanol, ethanol, or isopropanol, or mixtures thereof with water.

The saponification is generally conducted at temperatures between room temperature and the boiling point of the solvent, the reaction times ranging between 1 and 48 hours. An acidic saponification of the 21-ester-group can be accomplished with the aid of mineral acids, such as hydrochloric or sulfuric acid; however, owing to the vulnerability of the ether group in the 3-position, alkaline saponification is preferred.

The splitting of the 21-ester-groups is preferably conducted in an acidic medium; in this connection, the conditions must be selected so that the ether group in the 3- position is not affected. When employing readily splittable 21-ethers, this is normally possible without difiiculties. Of particular suitability are the triphenylmethyl (trityl) ether, tetrahydropyranyl ether, tert.-butyl ether and methoxymethyl ether, which are split in an organic solvent with the addition of a mineral acid. Thus, it is possible, for example, to split the 2'1-trityl ether of a steroid in chloroform saturated with hydrogen chloride, or the 21- methoxymethyl ether in 50% aqueous acetic acid with 0.5% sulfuric acid added thereto, into the 21-hydroxycompounds.

21-ethers, such as 21-benzyl ether, 21-benzhydryl ether and 21-trityl ether can also be split by catalytic hydrogenation. Suitable catalysts are, for example, noble metal, nickel and cobalt catalysts. The noble metal catalysts can be employed in the form of supported catalysts, such as, for example, palladium on charcoal, calcium carbonate or strontium carbonate; as oxide catalysts, such as platinum oxide, for instance; or as finely divided metal catalysts. Nickel and cobalt catalysts are suitably employed as Raney metals, and nickel is also used supported on kieselguhr or pumice; palladium (5-10%) on charcoal is preferred. The hydrogenation can be conducted at room temperature and under normal pressure, or also at elevated temperature and/ or under elevated pressure. Preferably, the process is conducted at pressures between 1 and 100 atmospheres and at temperatures between and +150 C. Suitably, the reaction is carried out in the presence of a solvent, e.g. methanol, ethanol, isopropanol, tert.-butanol, dioxane, glacial acetic acid, tetrahydrofuran or Water, the preferred solvent being ethyl acetate. In some cases, the addition of catalytic amounts of a mineral acid is advisable, for example, hydrochloric or sulfuric acid.

As still another process, 21-halosteroids which otherwise correspond to Formula I can be converted into the corresponding 2l-acylates by reaction with an alkali salt of a fatty acid. Thus, the acetoxy compounds corresponding to Formula I can be obtained, for example, by treating the 21-bromides with anhydrous potassium acetate in acetone. The reaction requires temperatures ranging preferably from room temperature to the boiling point of the solvent and is terminated after 1 to 48 hours.

It is also possible to employ starting compounds simultaneously containing a functionally modified 20-ketogroup and a functionally modified 21-R -group, insofar as both protective groups can be split off under the same reaction conditions. Thus, a derivative of a compound of Formula I ketalized in the 20-position and etherified in the 21-position can be hydrolyzed under the acidic conditions set forth hereinabove, wherein simultaneously the keto-group in the 20-position and the hydroxy group in the 21-position are liberated.

In the compounds of Formula I, a free 21-hydroxy group can be esterified, if desired. Suitable esterification agents are all those acids or the derivatives thereof suitable for esterification which yield physiologically compatible esters; for example, the above-listed acids or the derivatives thereof suitable for esterification can be employed in this connection. As esterification agents, the halogenides and anhydrides of the above-mentioned acids can be employed, for example. For interesterification methods, the lower alkyl esters thereof are suitable. The esterification is normally conducted in the presence of an organic base, such as pyridine. Whereas the base can also serve as the solvent, an additional inert solvent can also be employed. The esterification is generally conducted at temperatures between room temperature and the boiling point of the solvent employed and lasts normally between /2 and 12 hours.

In an interesterification, the 2l-hydroxy-steroid to be esterified is dissolved in an excess of another ester of that acid with which the steroid is to be esterified (in order to produce 21-acetoxy-steroids, for example, in ethyl acetate); as the catalyst, a small amount of a strong base is utilized, such as sodium methylate or potassium tert.- butylate.

For the production of the sulfuric acid esters, the reaction is preferably conducted with the aid of sulfamic acid. In this connection, the process is conducted by mixing a steroid of Formula I (R =OH) in equal parts with sulfamic acid; introducing the mixture at temperatures between 100 and +110 C., preferably at G, into absolute pyridine; and heating the mixture for a rather long period of time (15 minutes up to 3 days) to C. After the usual working-up operation has been conducted, the corresponding sulfuric acid esters are obtained, which can be converted into the sodium salts with pyridine and 12% aqueous sodium hydroxide solution.

A double bond in the 4(5)-position present in the compounds of Formula I can be catalytically hydrogenated, if desired. The hydrogenation is conducted under the above-described conditions. In starting materials containing simultaneously a group which can be hydrogenolyzed in the 21-position (eg. a benzyloxy or trityloxy group) and a 4(5)-double bond, it is possible to remove this group by hydrogenolysis and to hydrogenate the double bond, at the same time.

Referring now to Formula I, the following subgeneric groups of compounds are preferred, as well as the ester salts of the acidic or basic 2l-esters thereof:

(A) Compounds wherein:

R and R have the previously indicated meanings;

R represents alkyl of 1-4 carbon atoms or cycloalkyl of 3-7 carbon atoms; and

R is hydroxy or O-acyl wherein acyl is the residue of a carboxylic acid of up to 11 carbon atoms, or a phosphoric or sulfuric acid residue;

(B) compounds wherein R and R have the previous ly indicated meanings, and

R and R represent hydrogen;

(C) compounds wherein R and K, have the previously indicated meanings, and

R and R together represent a double bond 4(5);

(D) compounds wherein:

R and R represent hydrogen, and

R and R have the same meanings as in subgeneric e p( (E) compounds wherein:

R and R represent a 4(5)-double bond, and

R and R have the same meanings as in subgenerlc group (F) compounds wherein:

R and R have the previously indicated meanings;

R, has the same meaning as in subgeneric group (A) and R is methyl or ethyl;

(G) compounds wherein:

R and R have the previously indicated meanings; R represents methyl or ethyl; and

R represents hydroxyl or acetoxy.

The novel compounds of this invention can be employed in mixture with conventional pharmaceutical excipients. Carrier substances can be such organic or inorganic substances suitable for parenteral, enteral, or topical application, and which, of course, do not delete riously react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, benzyl alcohol, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc.

For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. Ampoules are convenient unit dosages.

For enteral application, particularly suitable are tablets or dragees which are also characterized by talc and/or a carbohydrate carrier or binder or the like, the cabohydrate carrier being preferably lactose and/or corn starch and/ or potato starch. A syrup or the like can also be used wherein a sweetened vehicle is employed.

For topical application, viscous to semisolid forms are used such as liniments, salves or creames, which are, if desired, sterilized, or mixed With auxiliary agents, such as preservatives, stabilizers, or Wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.

The substances of this invention are generally administered to animals, including, but not limited to, mammals and avians, e.g. cattle, cats, dogs, and poultry. A daily dosage of the compounds of Formula I comprises about 0.1-100, preferably 1-10 mg. together with 1-5000 mg. of pharmaceutically acceptable carriers and/or excipients. The dose can be administered all at once or as divided dosages throughout the day. In general, the mg./ kg. ratio is preferably about 0.001 to 1 mg. to kg. of body weight.

Oral administration is preferred, the compounds of Formula I being particularly valuable in the treatment of patients who cannot tolerate the glucocorticoidal side efiects.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description,

10 utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the specification and claims in any Way whatsoever.

EXAMPLE 1 (a) 100 mg. of 304,2l-dihydroxyl-pregnen-ZO-oneimono-p-toluenesulfonate is allowed to stand in 5 ml. of methanol in the presence of 10 mg. of p-toluenesulfonic acid for 24 hours. Then, 5 ml. of water is added, the reaction mixture is extracted several times with ether, the ether extracts are Washed with water, dried over sodium sulfate, evaporated, and the residue is chromatographed in chloroform on silica gel. 3or-m6thOXY-21-hYdfOXY-4- pregnen-ZO-one, M.P. 143-145" C. is obtained.

(b) 500 mg. of 3a-methoxy-2l-hydroxy-4-pregnen-20- one is dissolved in 3 ml. of pyridine and mixed with 3 ml. of acetic anhydride. The reaction mixture is agitated at room temperature for 3 hours, poured into water, and then extracted with chloroform. The combined chloroform extracts are washed neutral, dried over sodium sulfate and evaporated, thus obtaining 3a:-methoxy-21-acetoxy-4- pregnen-ZO-one.

The starting material is obtained by selective reduction of the 3-keto-group of desoxycorticosterone with sodium borohyride in isopropanol; separation of the thus-obtained 304- and S/E-hydroxy-steroids by chromatography; and reaction of the 3a-isomer with p-toluenesulfonyl chloride/ pyridine.

EXAMPLE 2 100 mg. of Son-methoxy-17a,2l-dihydroxyl-pregnen- 20 one is dissolved in 5 ml. of acetic acid, mixed with 5 ml. of water and 1 g. of zinc dust and refluxed for minutes. The mixture is filtered, and the Zinc is washed with methanol. The filtrate is mixed with ice, almost neutralized with 3 N sodium hydroxide solution and extracted several times with ether. The ether extracts are washed with water, dried over sodium sulfate, evaporated, and the thus-obtained crude product is purified by chromatographing same in chloroform on silica gel. 30:- methoxy-Zl-hydroxy-4-pregnen-20-one, M.P. l43145 C., is produced.

The starting material is obtained by converting Cor texolon into the bismethylenedioxy derivative (M.P. 255257 C.), reduction with lithium aluminum hydride to produce the 3-hydroxy-compound, M.P. 153155 C., removing the bismethylenedioxy group by hydrolysis, tosylation in the 3-position, methanolysis and chromatographic separation of the thus-obtained 3aand 3,8-1nethoxy-epimers.

EXAMPLE 3 (a) 2.6 g. of 20,20-ethylenedioxy-4-pregnene-3[3,21-diol is dissolved, together with 230 mg. of p-toluenesulfonic acid, in 1.3 l. of methanol and allowed to stand at room temperature for 8 hours. Thereafter, the reaction solution is poured into 1.3 l. of Water, extracted several times with ether, the ether extracts washed with water, dried over sodium sulfate and concentrated by evaporation. The residue (1.7 g.) is dissolved in 15 ml. of chloroform and separated by layer chromatography on three plates coated with silica gel of a length of cm. There are obtained 3 B methoxy 21-hydroxy-4-pregnen-20-one, M .P. 101-103 C. and 3a-methoxy-21--hydroxy-4-pregnen-20- one, M.P. 143l45 C.

The starting material is produced as follows:

30 g. of desoxycorticosterone is ketalized in the conventional manner with ethylene glycol in the presence of p-toluenesulfonic acid in boiling benzene (6 hours), thus obtaining a mixture of desoxycorticosterone with the three possible ketals. \By separation by means of layer chromatography in chloroform on silica gel, 7 g. of a resinous 20,20-ethylenedioxy-2l-hydroxy 4 pregnen-3- one is isolated.

This substance is dissolved in a mixture of 200 m1. of absolute tetrahydrofuran, as well as 200 ml. of absolute ether, and is stirred during the course of 20 minutes under ice cooling and a purge stream of nitrogen into a suspension of 4 g. of lithium aluminum hydride in 1 l. of absolute ether. After another two hours of agitation at room temperature, the reaction mixture is decomposed in the customary manner first with ethyl acetate and then With water, and worked up. The thus-obtained crude product is recrystallized from methanol and yields 20,20- ethylenedioxy-4-pregnene-35,2l-diol, M.P. 208-210 C.

(b) 0.37 g. of 3B-methoxy-Z1-hydroxy-4-pregnen-20- one is hydrogenated in ml. of ethyl acetate of .50 mg. of platinum dioxide at room temperature until 1 molar equivalent of hydrogen has been absorbed. The reaction mixture is filtered off, the filtrate is concentrated by evaporation, and a mixture of 3,8 methoxy-21-hydroxy-5apregnan--one and 3B-methoxy-2l-hydroxy-SB-pregnan- 20-one is obtained, which is separated by chromatography on silica gel.

EXAMPLE 4 (a) 300 mg. of the 21-trityl ether of 3[5'-methoxy-21- hydroxy-4-pregnen-20-one is dissolved in ml. of 95% acetic acid and 10 ml. of glacial acetic acid and allowed to stand at 30 C. for 7 hours. The acetic acid is removed under reduced pressure and replaced by benzene. The solution is chromatographed on silica gel in order to remove the concomitantly produced triphenylcarbinol. By elution with chloroform and subsequent concentration, 3 ,B-methoxy-Z1-hydroxy-4-pregnen-ZO-one, M.P. l01-103 C., is obtained.

The starting material is produced as follows:

10 g. of desoxycorticosterone is converted into the 21- trityl-ether by reaction with trityl chloride in pyridine (yield: 6.7 g., M.P. 157-160" C.).

6 g. of the trityl ether is partially reduced in the 3- position with lithium-tri-tert.-butoxyaluminum hydride. The oily crude product (5.5 g.) is subjected to solvolysis in methanol in the presence of patoluenesulfonic acid, thus obtaining a mixture of 3B- and 3ot-methoxy-2l-hydroxy- 4-pregnen-20one-2l-trityl ether, which mixture is separated by plate chromatography. The 21-trityl ether of 3,8-methoxy-21-hydroxy-4-pregnen-20-one is obtained in the form of a yellowish oil.

(b) 2.28 g. of 3,!3-methoxy-21-hydroxy-4-pregnen-20- one and 2.28 g. of sulfamic acid are dissolved in 17 m1. of pyridine and agitated on a steam bath under the exclusion of moisture for 1.5 hours. After cooling, the reaction mixture is vacuum-filtered, and the residue is extracted with ml. of pyridine. The filtrate and the Washing liquid are shaken out with ether, and the pyridine phase is subsequently concentrated. The residue is taken up in 20 ml. of pyridine and 27 ml. of 12% sodium hydroxide solution, agitated for 10 minutes and then again extracted with ether. The combined ether phases are dried over sodium sulfate and evaporated, thus obtaining the sodium salt of 3,8-methoxy-21-hydroxy-4-pregnen20-one- 21-sulfate.

(c) A solution of 0.34 g. of 3fl-methoxy-21-hydroxy- 4-pregnen-20-one in 8 ml. of dioxane is mixed with 0.1 ml. of absolute pyridine and 0.1 ml. of chloroacetyl chloride. The reaction mixture is allowed to stand for 3 days at room temperature, poured into Water, and 0.33 g. of crude 3fi-methoxy-21-chloroacetoxy-4-pregnen-20 one is thus obtained; the last-mentioned compound is boiled for 1 hour with 3.3 g. of diethylamine in 25 ml. of acetone and 2 ml. of water and is then evaporated. The residue is taken up in 20 ml. of chloroform, the mixture is shaken with sodium bicarbonate solution and with water, dried, evaporated, and 3fl-rnethoxy-21-diethylaminoacetoxy-4- pregnen-ZO-one is obtained.

EXAMPLE 5 250 mg. of 35,21-dihydroxy-4-pregnen-20-one is dissolved in 130 ml. of methanol and allowed to stand at room temperature for 10 hours with 23 mg. of p-toluenesulfonic acid. The reaction mixture is poured into 200 ml. of Water, extracted with ether, the ether solution Washed with water, dried over sodium sulfate and evaporated. A mixture of 3,8-methoxy-21hydroxy-4-pregnen-20-one and 3ot-methoxy-21-hydroxy 4 pregnen-ZO-one is obtained Which is separated by chromatography as described in Example 3.

The starting material is produced from 20,20-ethylenedioxy-4pregnene3fi,2l-diol with 20% aqueous-ethanolic oxalic acid solution.

EXAMPLE 6 575 mg. of 35 methoxy 21 triphenylmethOXy-Sapregnan-ZO-one is dissolved in 60 ml. of ethyl acetate and hydrogenated at room temperature after the addition of 350 mg. of 5% palladium-charcoal. The catalyst is fi1 tered off, and the filtrate is evaporated, thus obtaining 3B-methoxy-21-hydroxy-5a-pregnan-20-one.

In order to produce the starting material, 21-hydroxy- 50c pregnane-3,20-dione is converted into the 2l-tritylether and selectively reduced in the 3-position with tritert.-butoxylithiumaluminum hydride to 3 ,8 hydroxy-2ltrityloxy-5a-pregnan 20 one; etherification with methanol/p-toluenesulfonic acid results in 3,8-methoxy-21-trityloxy-5ot-pregnan-20-one.

EXAMPLE 7 388 mg. of 2l-acetoxy-35-methoxy-4-pregnen-20-one is dissolved in 12 ml. of methanol, mixed with a solution of 93 mg. of sodium bicarbonate in 2 ml. of water and boiled for 10 minutes. The mixture is poured into ml. of water and extracted with chloroform. The combined chloroform extracts are dried over sodium sulfate and evaporated; the thus-obtained 3,8-methoxy-2l-hydroxy-4-pregnen-20-one is recrystallized from methanol, M.P. 101 103 C.

In order to prepare the starting material, the 2l-acetate of ll-desoxycorticosterone is ketalized selectively in the 20-position with ethylene glycol; the ZO-ketal is reduced in the 3-position with sodium borohydride in methanol, and the thus-produced 21-acetoxy-20,20-ethylenedioxy- 4-pregnen-3fl-ol is simultaneously deketalized in the 20-positi0n and etherified in the 3-position with methanol/ p-toluenesulfonic acid. The mixture of 3u-methoxy-21- acetoxy-4-pregnen-20-one and 3,8-methoxy-21-acetoxy-4- pregnen-20-one obtained in this manner is separated by chromatography.

EXAMPLE 8 Analogously to Example 3, the following compounds are produced by splitting the corresponding 20,20-ethylenedioxy-compounds:

3vt-methoxy-21-hydroxy-5a-pregnan-20-one 3 ot-methoxy-2l-hydroxy-5,B-pregnan-20-one 3,8-methoxy-21-hydroxy-5a-pregnan-20-one 3fi-methoxy-21-hydroxy-5,8-pregnan-20-one 3a-eth0Xy-21-hydroxy-5a-pregnan-20-one 3ot-ethoxy-21-hydroxy-5/i-pregnan-20-one 3,8-ethoxy-21-hydroxy-5a-pregnan-ZO-One 3B-ethoxy-21-hydroxy-SB-pregnan-ZO-one 3a-ethoxy-Zl-hydroxy-4-pregnen-20-one 3B-ethoxy-21-hydroxy-4-pregnen-20=one 3a-propoxy-21hydroxy-5a-pregnan-20-one 3oc-p1'OpOXY-21-hYdrOXY-5 ,B-pregnan-ZO-one 3,8-propoxy-21-hydroxy-5u-pregnan-ZO-One 3B-propoxy-21-hydroxy-5/3-pregnan-20-one 3ot-propoxy-21-hydroxy-4-pregnen-20-one 3 p-propoxy-21-hydroxy-4-pregnen-20-one 3a-cyclopentyloxy-2l-hydroxy-Sa-pregnan-ZO-One 3 a-cyclopentyloxy-21-hydroxy-5p-pregnan-20-one 3 fi-cyclopentyloxy-Z1-hydroxy-5ot-pregnan-20-one 3 p-cyclo pentyloxy-2l-hydroxy-5 8-pregnan-20-one 3ot-cyclopentyloxy-21-hydroxy-4-pregnen-20-one 3 fi-cyclopentyloxy-Z1-hydroxy-4-pregnen-20-one 13 3a-cyclohexyloxy-2I-hydrOXy-Sa-pregnan-20-one 3ot-cyclohexyloxy-21-hydroxy-Sfi-pregnanQO-one 3/8-cyclohexyloxy-21-hydroxy-5a-pregnan-ZOone 3/8-cyclohexyloxy-21-hydroxy-5 3-pregnan-20-one 3u-cyclohexyloxy-21-hydroxy-4-pregnen-20-one 3/3-cyclohexyloxy-21-hydroxy-4-pregnen-20-one.

The following examples include pharmaceutical com positions of the novel compounds:

EXAMPLE A: Tablets Each tablet contains:

3a-methoxy-21-hydroxy-4-pregnen-20-one '2 Lactose 70 Wheat starch 18 Talc 10 EXAMPLE B: Coated tablets Each tablet contains:

3u-methoxy-21-hydroxy-4-pregnen-20-one 3 Lactose 80 Potato starch 15 Magnesium stearate 2 The coating (150 mg.) is a conventional mixture of corn starch, sugar, talc, and tragacanth.

EXAMPLE C: Solution for injection A solution of 2 g. of 3a-methoxy-21-hydroxy-4-pregnen- 20-one in 998 ml. of sesame oil is prepared and filled into ampoules in such a manner that each ampoule contains 2 mg. of said sodium salt.

Instead of 3a methoxy-Zl-hydroxy-4-pregnen-20-one, other compounds covered by Formula I can be incorporated into similar compositions.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

1. A member selected from the group consisting of a compound of the following formula, physiologically acl4 ceptable salt of an acidic 21-ester thereof and a physiologically acceptable salt of a basic 21-ester thereof:

OH R;

wherein R is lower alkyl or cycloalkyl of 3-7 carbon atoms;

R and R each represent hydrogen or together a double bond; and

R is hydroxy or O-acyl wherein acyl is the residue of a carboxylic acid of up to 11 carbon atoms, or a phosphoric or sulfuric acid residue.

2. A member as defined by claim 1 wherein R and R have the previously indicated meanings, and

R and R represent hydrogen.

3. A member as defined in claim 1 wherein R and R have the previously indicated meanings, and

R and R together represent a double bond 4(5).

4. A member as defined by claim 1 wherein R R and R have the previously indicated meanings;

R is methyl or ethyl.

5. A member as defined by claim 1 wherein R and R have the previously indicated meanings;

R represents methyl or ethyl; and

R represents hydroXyl or acetoxy.

6. A member as defined in claim 1 wherein said member is 3a-methoxy-21-hydroxy-4-pregnene-20-one.

7. A member as defined by claim 1 wherein said member is 3fi-methoXy-2l-hydroxy-4-pregnene-20-one.

No references cited.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 597, 453 Dated August 3, 1971 Inventor(s) Klaus Irmscher et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Claims:

Claim 1, in the formula, line 2, "CH" should be --CO---.

Signed and sealed this 27th day of June 1972.

(SEAL) Attest ROBERT GOTTSCHALK EDHARD M.FLETGHER,JR. Attestinp; Officer Commissioner of Patents LISCOMM-DC BOS'IG PGD FORM PD-IOSO (10-69) h u,s. sovrmmrm' nmmns OFFICE: 190 o-au-an