# US 4,396,614 A · Novel steroids > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,396,614 A - Document ID: US4396614A - Status: Granted - Kind: A - Application number: 06/332,842 - Filed: 1981-12-21 - Granted: 1983-08-02 - Earliest claimed: 1980-12-23 - Assignees: Roussel Uclaf - Inventors: Lucien Nedelec; Vesperto Torelli; Daniel Philibert - Web page: https://patentgrep.com/patent/US4396614A ## CPC - C07J 41/0088: {containing unsubstituted amino radicals} - A61P 7/10: Antioedematous agents; Diuretics - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/12: Antihypertensives - C07J 1/0033: {substituted in position 17 alfa and 17 beta} - C07J 1/0081: {Substituted in position 17 alfa and 17 beta} - C07J 21/003: {at position 17} - C07J 51/00: Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 - C07J: STEROIDS (seco-steroids C07C) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Novel steroids of the formula ##STR1## wherein R is selected from the group consisting of R.sub.1 and R.sub.2, R.sub.1 is selected from the group consisting of alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms R.sub.2 is --(CH.sub.2).sub.n --R.sub.3, n is an integer from 1 to 8 and R.sub.3 is selected from the group consisting of free or protected --OH, free or protected --NH.sub.2, monoalkyl and dialkylamino with 1 to 6 carbon atoms, a free, esterified or salified --COOH and halogen X and Y together form ##STR2## or X is OH and Y is --CH.sub.2 --CH.sub.2 --COOM, M is selected from the group consisting of hydrogen, an alkali metal and --NH.sub.4, Ra is selected from the group consisting of hydrogen and methyl, the dotted line in the I(2)-position indicates the optional presence of a double bond and the wavy line indicates that R may be in the .alpha.- or .beta.-position, with the proviso that R is not R.sub.1 or R.sub.2 when n is 1 and R.sub.3 is halogen, when the 1(2) bond is a simple bond and when Ra is --CH.sub.3, R.sub.3 is not a free carboxyl when Y is --CH.sub.2 --CH.sub.2 --COOM in which M is an alkali metal or --NH.sub.4 and R.sub.3 is not a salified carboxyl when Y is --CH.sub.2 --CH.sub.2 --COOH having aldosterone antagonistic properties and increases aqueous sodium diuresis while conserving organic potassium without secondary hormonal effects and their preparation. ## Claims ### Claim 1 A steroids of the formula ##STR27## wherein R is selected from the group consisting of R.sub.1 and R.sub.2, R.sub.1 is selected from the group consisting of alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms R.sub.2 is --(CH.sub.2).sub.n --R.sub.3 n is an integer from 1to 8 and R.sub.3 is selected from the group consisting of free or protected --OH, free or protected --NH.sub.2, monoalkyl and dialkylamino with 1 to 6 carbon atoms, a free, esterified or salified --COOH and halogen X and Y together form ##STR28## or X is OH and Y is --CH.sub.2 --CH.sub.2 --COOM, M is selected from the group consisting of hydrogen, an alkali metal and --NH.sub.4, Ra is selected from the group consisting of hydrogen and methyl, the dotted line in the 1(2)-position indicates the optional presence of a double bond and the wavy line indicates that R may be in the .alpha.- or .beta.-position, with the proviso that R is not R.sub.1 or R.sub.2 when n is 1 and R.sub.3 is halogen, when the 1(2) bond is a simple bond and when Ra is --CH.sub.3, R.sub.3 is not a free carboxyl when Y is --CH.sub.2 --CH.sub.2 --COOM in which M is an alkali metal or --NH.sub.4 and R.sub.3 is not a salified carboxyl when Y is --CH.sub.2 --CH.sub.2 --COOH. ### Claim 2 (depends on 1) A compound of claim 1 wherein Ra is methyl. ### Claim 3 (depends on 1) A compound of claim 1 wherein Ra is methyl, R is R.sub.2 and the bond in the 1(2)-position is a single bond. ### Claim 4 (depends on 1) A compound of claim 1 wherein Ra is hydrogen and the bond in the 1(2)-position is a single bond. ### Claim 5 (depends on 1) A compound of claim 1 wherein the bond in the 1(2)-position is a double bond. ### Claim 6 (depends on 1, 3, 4, 5) A compound of claim 1,3,4 or 5 wherein X and Y are the group ##STR29## ### Claim 7 (depends on 1, 3, 4, 5) A compound of claim 1,3,4 or 5 wherein X is --OH and Y is --CH.sub.2 --CH.sub.2 --COOK. ### Claim 8 (depends on 1) A compound of claim 1 wherein R is in the .alpha.-position. ### Claim 9 A compound of cliam 1,2,4,5,6,7 or 8 wherein R is selected from the group consisting of propyl, butyl, isobutyl or butenyl. ### Claim 10 (depends on 1) A compound of claim 1 wherein R is selected from the group consisting of chloropropyl, hydroxypropyl, carboxyethyl and methoxycarbonylethyl. ### Claim 11 (depends on 1) A compound of claim 1 selected from the group consisting of .gamma.-lactone 7.alpha.-propyl-17.alpha.-.DELTA..sup.1,4 -pregnadiene-17.beta.-ol-3-one-21-carboxylic acid and potassium 7.alpha.-propyl-17.alpha.-.DELTA..sup.1,4 -pregnadiene-17.beta.-ol-3-one-21-carboxylate. ### Claim 12 (depends on 1) A process for the preparation of a compound of claim 1 wherein Ra is methyl comprising reacting a compound of the formula ##STR30## with either a compound of the formula R.sub.4 --(CH.sub.2).sub.n --MgX' III.sub.1 in the presence of a copper salt wherein X' is a halogen and R.sub.4 is selected from the group consisting of protected --OH, protected amino and monoalkylamino and dialkylamino and n is 1 to 8 or with a compound of the formula [R.sub.4 --(CH.sub.2).sub.n ].sub.2 Cu Li III.sub.1 ' wherein R.sub.4 and n have the above definitions to obtain after treatment with an acid a compound of the formula ##STR31## in the form of a mixture of 7.alpha.- and 7.beta.-isomers which, if desired, may be separated and, if desired, each isomer or the mixture thereof when R.sub.4 is protected --OH or protected amino may be treated with a hydrolysis agent to obtain a compound of the formula ##STR32## wherein R.sub.4 ' is selected from the group consisting of --OH and --NH.sub.2 and when R.sub.4 ' is --OH, reacting the compound of formula I.sub.B " with an oxidizing agent to obtain a compound of the formula ##STR33## which may be esterified or salified by known methods or when n is other than 1, the compound of formula I.sub.B " is reacted with a halogenation agent to obtain a compound of the formula ##STR34## wherein n.sub.1 is a integer from 2 to 8 Hal is a halogen and, if desired, the compounds of formulae I.sub.A ", I.sub.B ", I.sub.C " or I.sub.D " in their 7.alpha.- or 7.beta.-isomer form or mixtures thereof may be reacted with an alkali metal hydroxide or ammonium hydroxide to obtain a compound of the formula ##STR35## wherein R.sub.3 ' is R.sub.3 other than free carboxy and M' is an alkali metal or --NH.sub.4 in the form of its 7.alpha.- or 7.beta.-isomers or mixtures thereof which, if desired, may be separated and then reacting the same with an acid agent to obtain a compound of the formula ##STR36## wherein R.sub.3 " is R.sub.3 other than salified carboxy. ### Claim 13 (depends on 1) A process for the preparation of a compound of claim 1 wherein Ra is hydrogen comprising reacting a compound of the formula ##STR37## with either a compound of the formula R.sub.5 --Mg--X' III.sub.2 in the presence of a copper salt wherein R.sub.5 is R.sub.1 or R.sub.4 --(CH.sub.2).sub.n -- and X' is a halogen or with a compound of the formula (R.sub.5).sub.2 CuLi III.sub.2 ' to obtain after treatment with an acid a compound of the formula ##STR38## in the form of its 7.alpha.- and 7.beta.-isomers which, if desired, may be separated and, if desired, each isomer or a mixture thereof when R.sub.5 is --(CH.sub.2).sub.n --R.sub.4 and R.sub.4 is a protected amino or protected --OH reacted with a hydrolysis agent to obtain a compound of the formula ##STR39## wherein R.sub.4 ' is --OH or --NH.sub.2 and reacting a compound of formula I.sub.B.sbsb.1 " wherein R.sub.4 is --OH with either an oxidation agent when n is greater than 1 to obtain a compound of the formula ##STR40## which is optionally esterfied or salified by known methods or reacting the compound of formula I.sub.B.sbsb.1 " with a halogenation agent to obtain a compound of the formula ##STR41## wherein Hal is a halogen and, if desired, reacting the compounds of formulae I.sub.A.sbsb.1 ", I.sub.B.sbsb.1 ", I.sub.C.sbsb.1 " or I.sub.D.sbsb.1 " in the form of their 7.alpha.- or 7.beta.-isomers or mixtures thereof with an alkali metal hydroxide or ammonium hydroxide to obtain a compound of the formula ##STR42## wherein R.sub.5 ' has the definition of R.sub.1 or is --(CH.sub.2).sub.n --R.sub.3 ' wherein R.sub.3 ' is R.sub.3 with the exception of free carboxyl and M' is alkali metal or --NH.sub.4 ' or the form of its 7.alpha.- or 7.beta.-isomers or mixtures thereof which can be separated into its isomers if desired and subjecting the compound of formula I.sub.T.sbsb.1 " to an acid agent to obtain a compound of the formula ##STR43## wherein R.sub.5 " is R.sub.1 or --(CH.sub.2).sub.n --R.sub.3 " and R.sub.3 " is R.sub.3 except for salified carboxy. ### Claim 14 (depends on 1) A process for the preparation of a compound of claim 1 wherein the bond in the 1(2)-positon is a double bond comprising reacting a compound of the formula ##STR44## wherein R is R.sub.1 or R.sub.2 and Ra, R.sub.1 and R.sub.2 have the above definitions in the form of its 7.alpha.- or 7.beta.-isomers or mixtures thereof with a dehydrogenation agent to obtain a compound of the formula ##STR45## in the form of its 7.alpha.- or .beta.-isomers or mixtures thereof which an optionally be separated and reacting the latter with an alkali metal hydroxide or ammonium hydroxide to obtain a compound of the formula ##STR46## wherein M' is an alkali meta or --NH.sub.4 and R' is R except for free carboxy in the form of its 7.alpha.- or 7.beta.-isomers or mixtures thereof which, if desired, may be separated and subjecting the latter to an acid agent to form a compound of the formula ##STR47## wherein R" is R except for (CH.sub.2).sub.n --R.sub.3 and R.sub.3 is salified carboxy. ### Claim 15 A composition for treating cardiac insufficiency and arterial hypertension comprising an amount of at least one compound of clam 1 sufficient to combat arterial hypertension and cardiac insufficiency and an inert pharmaceutical carrier. ### Claim 16 (depends on 15) The compositions of claim 15 wherein Ra is methyl. ### Claim 17 (depends on 15) The composition of claim 15 wherein Ra is methyl, R is R.sub.2 and the bond in the1(2)-position is a single bond. ### Claim 18 (depends on 15) The composition of claim 15 wherein Ra is hydrogen and the bond in the 1(2)-position is a single bond. ### Claim 19 (depends on 15) The composition of claim 15 wherein the bond in the 1(2)-position is a double bond. ### Claim 20 (depends on 15) The composition of claim 15 wherein X and Y are the group ##STR48## ### Claim 21 (depends on 14) The composition of claim 14 wherein X is --OH and Y is --CH.sub.2 --CH.sub.2 --COOK. ### Claim 22 (depends on 14) The composition of claim 14 wherein R is in the .alpha.-position. ### Claim 23 (depends on 14) The composition of claim 14 wherein R is selected from the group consisting of propyl, butyl, isobutyl and butenyl. ### Claim 24 (depends on 14) The composition of claim 14 wherein R is R.sub.2 which is selected from the group consisting of chloropropyl, hydroxypropyl, carboxyethyl and methoxycarbonylethyl. ### Claim 25 (depends on 15) A composition of claim 15 wherein the compound is selected from the group consisting of .gamma.-lactone of 7.alpha.-propyl-17.alpha.-.DELTA..sup.1,4 -pregnadiene-17.beta.-ol-3-one-21-carboxylic acid and potassium 7.alpha.-propyl-17.alpha.-.DELTA..sup.1,4 -pregnadiene-17.beta.-ol-3-one-21-carboxylate. ### Claim 26 (depends on 1) A method of treating cardiac insufficiency and arterial hypertension in warm-blooded animals comprising administering to warm-blooded animals an amount of at least one compound of claim 1 sufficient to treat arterial hypertension and cardiac sufficiency. ### Claim 27 (depends on 26) The method of claim 26 wherein Ra is methyl. ### Claim 28 (depends on 26) The method of claim 26 wherein Ra is methyl, R is R.sub.2 and the bond in the 1(2)-position is a single bond. ### Claim 29 (depends on 26) The method of claim 26 wherein Ra is hydrogen and the bond in the 1(2)-position is a single bond. ### Claim 30 (depends on 26) The method of claim 26 wherein the bond in the 1(2)-position is a double bond. ### Claim 31 (depends on 26) The method of claim 26 wherein X and Y are the group ##STR49## ### Claim 32 (depends on 26) The method of claim 26 wherein X is --OH and Y is --CH.sub.2 --CH.sub.2 --COOK. ### Claim 33 (depends on 26) The method of claim 26 wherein R is in the .alpha.-position. ### Claim 34 (depends on 26) The method of claim 26 wherein R is selected from the group consisting of propyl, butyl, isobutyl and butenyl. ### Claim 35 (depends on 26) The method of claim 26 wherein R is R.sub.2 which is selected from the group consisting of chloropropyl, hydroxypropyl, carboxyethyl and methoxycarbonylethyl. ### Claim 36 (depends on 26) The method of claim 26 wherein the compound is selected from the group consisting of the .gamma.-lactone of 7.alpha.-propyl-17.alpha.-.DELTA..sup.1,4 -pregnadiene-17.beta.-ol-3-one-21-carboxylic acid and potassium 7.alpha.-propyl-17.alpha.-.DELTA..sup.1,4 -pregnadiene-17.beta.-ol-3-one-21-carboxylate.