Novel substituted omega-aroyl(propionyl or butyryl)-L-prolines, pharmaceutical compositions containing them and processes for their preparation

Claim 2

A compound selected from the group consisting of those of the formulae: wherein n is zero or one; R 1 is hydrogen or alkyl having up to 3 carbon atoms; R 2 is hydrogen, phenyl or alkyl having up to 3 carbon atoms; R 3 is mercapto, formylthio, benzoylthio, alkanoylthio having from 2 to 4 carbon atoms or moieties of the formulae: and wherein R 9 is phenyl or substituted phenyl; R 4 is hydrogen, phenyl or alkyl having up to 4 carlon atoms; R 5 is hydrogen or alkyl having up to 4 carbon atoms; and ARYL is selected from the group consisting of 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 5,6,7,8-tetrahydro-l-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 4-methoxy-1-naphthyl, 5-acenaphthyl, 4-biphenylyl, 5- indanyl, 4-indanyl and moieties of the formula: wherein R 6 is selected from the group consisting of hydrogen, fluoro, chloro, bromo trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohex y lphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylamino having up to 4 carbon atoms, alkanoylamino having from 2 to 4 carbon atoms and alkoxycarbonyl having from 2 to 4 carbon atoms, R 7 is selected from the group consisting of chloro, fluoro, bromo, alkyl having up to 4 carbon atoms and alkoxy having up to 4 carbon atoms, and m is zero, one or two; and the pharmacologically acceptable cationic salts thereof when R 5 is hydrogen.

Claim 3

A compound according to Claim 1, formula (I) thereof, which is: 1-[2-acetylthio-3-(1-naphthoyl)propionylj-L-proline; 1-[2-benzoylthio-3-(2-naphthoyl)propionyl]-L-proline; or 1-[2-mercapto-3-(benzoyl)propionyl]-L-proline.

Claim 4

A compound according to Claim 1, formula (II) thereof, which is: [S-(R*, [3-acetylthio-4-(benzoyl)-2-methylbutyryl]-L-proline; [S-(R*, S*)-1-[3-acetylthio-4-(3-fluorobenzoyl)-2-methylbutyryl]-L-proline; [S-(R',S*)]-1-[3-acetylthio-4-(2-naphthoyl)-2-methylbutyryl]-L-proline; or [S(R*, S*)]-1-[3-acetylthio-4-(4-chlorobenzoyl)-2-methylbutyryl]-L-proline.

Claim 5

A compound according to Claim 1, formula (III) thereof, which is: 1-[3-acetylthio-3-(4-biphenylcarbonyl) propionyl]-L-proline; 1-[3-acetylthio-3-(4-chlorobenzoyl)-2-methylpropionyl]-L-proline; 1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline; 1-[3-acetylthio-3-(4-chloro-1-naphthoyl)propionyl]-L-proline; 1-(3-acetylthio-3-[4-(4-chlorophenoxy)benzoyl]propionyl)-L-proline; 1-[3-acetylthio-3-(3,4-dichlo-robenzoyl)-2-methylpropionyl]-L-proline; 1-[3-benzoylthio-3-(3-fluoro-4-methoxybenzoyl) propionyl]-L-proline; 1-[3-acetylthio-3-(3,4,5-trimethoxy- benzoyl)propionyl]-L-proline; 1-[3-acetylthio-3-(3-trifluoromethylbenzoyl)-2-methylpropionyl]-L-proline; [S-(R*,S*]-1-[3-(acetylthio)-3-(benzoyl)-2-methylpropionyl]-L-proline; [S-(R*,S*)]-1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline; [S-(R*, S*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline; [S-(R*,R*)]-1- [3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline; [S-(R*,S*)]-1-[3-acetylthio-3-(4-chlorobenzoyl)-2-methylpropionyl]-L-proline; [S-(R*,R*)]-1-[3-acetylthio-3-(4-chlorobenzoyl)-2-methy]propionyl] -L-proline; [S-(R*,S*)] [3-acetylthio-3-(2-naphthoyl)-2-methylpropionyl]-L-proline; [S-(R*, R*)]-1-[3-acetylthio-3-(benzoyl)-2-methylpropionyl]-L-proline; or [S-(R*,R*)] -1- [3-acetylthio-3-(3-fluorobenzoyl) -2-methylpropionylJ-L-proline.

Claim 6

A composition comprising a compound of any preceding Claim in an amount sufficient to reduce blood pressure by inhibiting the conversion of angiotensin I to angiotensin II, and a pharmacologically acceptable vehicle therefor.

Claim 7

A process for preparing a compound of the formula: wherein n is zero or one; R 3 is mercapto, formylthio, benzoylthio, alkanoylthio having from 2 to 4 carbon atoms or moieties of the formulae: having up to 3 carbon atoms; R 9 is phenyl or substituted phenyl; R 4 is hydrogen, phenyl or alkyl having up to 4 carbon atoms; R 5 is hydrogen or alkyl having up to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-l-naphthyl, 5-acenaphthyl, 4-methoxy-l-naphthyl, 4-biphenylyl, 5-indanyl, 4-indanyl, 5,6,7,8-tetrahydro-l-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl or a group of the formula: wherein R 6 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylamino having up to 4 carbon atoms, alkanoylamino having from 2 to 4 carbon atoms or alkoxycarbonyl having from 2 to 4 carbon atoms; R 7 is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; and m is zero; one or two; .........characterized by condensing a compound of the formula: wherein n, R 4 and ARYL are as defined above; X is chloro, bromo, iodo, -SR, or -SO 2 R wherein R is alkyl having up to 4 carbon atoms, phenyl, p-tolyl, benzyl or p-methoxybenzyl; and Y is the carbonyl activating residue of a peptide coupling reagent, chloro, bromo or a group of the formulae: wherein R' is hydrogen, alkyl having up to 4 carbon atoms, phenyl, p-tolyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, trimethylsilyl, 2-trimethylsilylethyl and R 5 is as defined above; .........with the anion of a thiolating reagent of formula H-R 3 wherein R 3 is as defined above to give an intermediate of the formula: wherein n, R 3 , R 4 , ARYL, and Y are as defined above, .........and, if desired, removing the thioprotecting group to give a mercapto group; .........and, if desired, converting Y to chloro, bromo or iodo when Y is hydroxy; .........and, if desired, condensing an intermediate of the formula: wherein Z is chloro, bromo or the carbonyl activating residue of a peptide coupling reagent with L-proline or an L-proline alkyl (C 1 -C 4 ) ester or an L-proline derivative of the formula: wherein R' is as defined above and removing the R' group; .........and, if desired, forming the cationic salts of the compounds of formula (III) when R 5 is hydrogen.

Claim 8

A process for preparing a compound of the formula: wherein n is zero or one; R 3 is mercapto, formylthio, benzoylthio, alkanoylthio having from 2 to 4 carbon atoms or moieties of the formulae: having up to 3 carbon atoms; R 9 is phenyl or substituted phenyl; R 4 is hydrogen, phenyl or alkyl having up to 4 carbon atoms; R 5 is hydrogen or alkyl having up to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-l-naphthyl, 5-acenaphthyl, 4-methoxy-l-naphthyl, 4-biphenylyl, 5-indanyl, 4-indanyl, 5,6,7,8-tetrahydro-l-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl or a group of the formula: wherein R 6 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylamino having up to 4 carbon atoms, alkanoylamino having from 2 to 4 carbon atoms or alkoxycarbonyl having from 2 to 4 carbon atoms; R 7 is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; and m is zero; one or two; .........characterized by condensing a compound of the formula: wherein n, R 4 and ARYL are as defined above; X is chloro, bromo, iodo, -SR, or -SO 2 R wherein R is alkyl having up to 4 carbon atoms, phenyl, p-tolyl, benzyl or p-methoxybenzyl; and Y is the carbonyl activating residue of a peptide coupling reagent, chloro, bromo or a group of the formulae: wherein R' is hydrogen, alkyl having up to 4 carbon atoms, phenyl, p-tolyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, trimethylsilyl, 2-trimethylsilylethyl and R 5 is as defined above; .........with the anion of a thiolating reagent of formula H-R 3 wherein R 3 is as defined above to give an intermediate of the formula: wherein n, R 3 , R 4 , ARYL, and Y are as defined above, .........and, if desired, removing the thioprotecting group to give a mercapto group; .........and, if desired, converting Y to chloro, bromo or iodo when Y is hydroxy; .........and, if desired, condensing an intermediate of the formula: wherein Z is chloro, bromo or the carbonyl activating residue of a peptide coupling reagent with L-proline or an L-proline alkyl (C 1 -C 4 ) ester or an L-proline derivative of the formula: wherein R' is as defined above and removing the R' group; .........and, if desired, forming the cationic salts of the compounds of formula (III) when R 5 is hydrogen.

Claim 9

A process for preparing a compound of the formula: wherein n is zero or one and wherein A is when n is zero and A is when n is one; R 1 is hydrogen or alkyl having up to 3 carbon atoms; R 2 is hydrogen, phenyl or alkyl having up to 3 carbon atoms; R 3 is mercapto, formylthio, benzoylthio, alkanoylthio having from 2 to 4 carbon atoms or moieties of the formulae: and wherein R 9 is phenyl or substituted phenyl; R 5 is hydrogen or alkyl having up to L carbon atoms and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 4-methoxy-l-naphthyl, 5-acenaphthyl, 4-biphenylyl, 5-indanyl, 4-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl or moieties of the formula: wherein R 6 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylamino having up to 4 carbon atoms, alkanoylamino having from 2 to 4 carbon atoms or alkoxycarbonyl having from 2 to 4 carbon atoms; R 7 is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; and m is zero, one or two; .......characterized by adding a thiolating reagent of the formula H-R 3 wherein R 3 is as hereinabove defined; ........to a compound of the formula: wherein A i ' s a moiety of the formulae: or R 1 , R 2 , and ARYL are as defined above and Y is chloro, bromo, the carbonyl activating residue of a peptide coupling reagent, or a group of the formulae: wherein R' is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, p-tolyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, trimethylsilyl, 2-trimethylsilylethyl and R 5 is as defined above to give a compound of formula (I or II) or an intermediate of the formula: wherein A is a moiety of the formulae and Z is chloro, bromo, or the carbonyl activating residue of a peptide coupling reagent; ........and condensing a thus obtained intermediate of formula (E) with L-proline, an L-proline alkyl (C l -C 4 ) ester or an L-proline derivative of the formula wherein R' is as defined above and removing the R' group; ..........and if desired, forming the cationic salts of the compound of formula (I or II) when R 5 is hydrogen.

Claim 10

A process for preparing a compound of the formula: wherein n is zero or one and wherein A is when n is zero and A is when n is one; R 1 is hydrogen or alkyl having up to 3 carbon atoms; R 2 is hydrogen, phenyl or alkyl having up to 3 carbon atoms; R 3 is mercapto, formylthio, benzoylthio, alkanoylthio having from 2 to 4 carbon atoms or moieties of the formulae: and wherein R 9 is phenyl or substituted phenyl; R 5 is hydrogen or alkyl having up to L carbon atoms and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 4-methoxy-l-naphthyl, 5-acenaphthyl, 4-biphenylyl, 5-indanyl, 4-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl or moieties of the formula: wherein R 6 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylamino having up to 4 carbon atoms, alkanoylamino having from 2 to 4 carbon atoms or alkoxycarbonyl having from 2 to 4 carbon atoms; R 7 is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; and m is zero, one or two; .......characterized by adding a thiolating reagent of the formula H-R 3 wherein R 3 is as hereinabove defined; ........to a compound of the formula: wherein A i ' s a moiety of the formulae: or R 1 , R 2 , and ARYL are as defined above and Y is chloro, bromo, the carbonyl activating residue of a peptide coupling reagent, or a group of the formulae: wherein R' is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, p-tolyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, trimethylsilyl, 2-trimethylsilylethyl and R 5 is as defined above to give a compound of formula (I or II) or an intermediate of the formula: wherein A is a moiety of the formulae and Z is chloro, bromo, or the carbonyl activating residue of a peptide coupling reagent; ........and condensing a thus obtained intermediate of formula (E) with L-proline, an L-proline alkyl (C l -C 4 ) ester or an L-proline derivative of the formula wherein R' is as defined above and removing the R' group; ..........and if desired, forming the cationic salts of the compound of formula (I or II) when R 5 is hydrogen.