Certain N-substituted butyramide derivatives

Claim 2

A compound of the formula I wherein X and Y independently represent hydroxymethyl; cyano;- carboxy; functionally modified carboxy selected from esterified carboxy, carbamoyl, and N-substituted carbamoyl; 5-tetrazolyl; 2-oxazolyl, 4,5-dihydro-2-oxazolyl, or each said grouping substituted by lower alkyl; R and Ro independently represent lower alkyl, (C 3 -C 7 )-cycloalkyl-lower alkyl, or aryl-lower alkyl; A represents methylene; or A represents methylene substituted by lower alkyl, by lower alkylthio-lower alkyl, by aryl-lower alkylthio-lower alkyl, by arylthio-lower alkyl, by hydroxy-lower alkyl, by acyloxy-lower alkyl, by lower alkoxy-lower alkyl, by aryl-lower alkyloxy-lower alkyl, by aryloxy-lower alkyl, by amino-lower alkyl, by acylamino-lower alkyl, by guanidino-lower alkyl, by (C 3 -C 7 )-cycloalkyl, by (C 3 -C 7 )-cycloalkyl-lower alkyl, by aryl or aryl-lower alkyl; or a pharmaceutically acceptable ester or amide derivative of any said compound having a free carboxy group; or a pharmaceutically acceptable salt of any said compound with a salt-forming group.

Claim 3

A compound according to claim 1 of the formula II wherein R 1 and R 2 independently represent lower alkyl, (C 3 -C 7 )-cycloalkyl-lower alkyl, or aryl-lower alkyl; A represents methylene; or A represents methylene substituted by lower alkyl, by lower alkylthio-lower alkyl, by hydroxy-lower alkyl, by acyloxy-lower alkyl, by lower alkoxy-lower alkyl, by aryl-lower alkylthio-lower alkyl, by aryl-lower alkyloxy-lower alkyl, by aryloxy-lower alkyl, by arylthio-lower alkyl, by amino-lower alkyl, by acylamino-lower alkyl, by guanidino-lower alkyl, by (C 3 -C 7 )-cyeloalkyl-lower alkyl, or by aryl-lower alkyl; a mono- or bis-carboxylic acid derivative thereof in which the derivative is selected from an unsubstituted amide or mono- or di-(C l -C 2 o)-alkylamide; a tertiary lower alkylene, oxalkylene or azaalkylene amide wherein the lower alkylene, oxalkylene or azaalkylene group together with the amide nitrogen forms a 5-, 6- or 7-membered ring, or said lower alkylene, oxalkylene or azaalkylene amide is substituted on the ring by lower alkyl, hydroxy-lower alkyl or by lower alkanoyloxy-lower alkyl; an arylamide, an aryl-lower alkylamide; an (amino or acylamino)-lower alkylamide; a (C l -C 2 . 0 )-alkyl ester; an (amino, acylamino, mono- or di-lower alkylamino, carboxy or lower alkoxycarbonyl)-substituted lower alkyl ester; an aryl-lower alkyl ester; a lower alkanoyloxy-lower alkyl ester; a 3-phthalidyl or (lower alkyl, lower alkoxy or halogen)-substituted 3-phthalidyl ester; a (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethyl ester; a bicycloalkyloxycarbonyl-lower alkyl ester; a hydroxyamide; a lower alkylsulfonylamide; a 1-(lower alkoxycarbonyloxy)-lower alkyl ester; a 3-cholestanyl or 3-cholestenyl ester; a monosaccharidyl or protected monosaccharidyl ester being an ester incorporating as the alcohol portion a monosaccharide or protected monosaccharide, as a free or protected aldopentose or aldohexose in straight chain or cyclic furanose or pyranose form, or a free or protected glyconic acid of 5 or 6 carbon atoms or a lactone thereof; a polyhydroxy-lower alkyl or protected polyhydroxy-lower alkyl ester being an ester incorporating as the alcohol portion a polyhydroxy-lower alkane or protected polyhydroxy-lower alkane, being a free or protected-glycerol or erythritol; or a pharmaceutically acceptable salt of any said compound with a salt-forming group.

Claim 4

A compound according to claim 1 of the formula III wherein R 1 ' and R 2 ' independently represent aryl-(C1-C4)-alkyl in which aryl represents phenyl or phenyl mono- or di-substituted by halogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl or cyano; A represents methylene monosubstituted by lower alkyl, by phenyl-lower alkyl, by (halogen, lower alkyl, hydroxy, trifluoromethyl or lower alkoxy)-mono- or di-substituted phenyl-lower alkyl, by lower alkylthio-lower alkyl, by hydroxy-lower alkyl, by lower alkoxy-lower alkyl, by amino-lower alkyl or by acylamino-lower alkyl; by guanidino-lower alkyl; by aryl-lower alkylthio-lower alkyl or aryl-lower alkyloxy-lower alkyl in which aryl represents indolyl, pyridyl, phenyl or phenyl mono- or disubstituted by halogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl or cyano; the groups COR 3 and COR 4 independently represent carboxy, carboxy esterified in form of a pharmaceutically acceptable ester, carbamoyl or N-substituted carbamoyl in which R 3 and R 4 independently represent hydroxy, lower alkoxy; (amino, acylamino, mono- or di-lower alkylamino)-lower alkoxy; carboxy-lower alkoxy; lower alkoxycarbonyl-lower alkoxy; aryl-lower alkoxy in which aryl represents phenyl, pyridyl or (halogen, lower alkyl, hydroxy or lower alkoxy)-mono- or di-substituted phenyl or pyridyl; (hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxymethoxy; bicyclo[2,2,l]-heptyloxycarbonyl-lower alkoxy; cholestan-3-oxy or cholest-5-en-3-oxy; 3-phthalidoxy or (lower alkyl, lower alkoxy or halogen)-substituted 3-phthalidoxy; monosaccharidyloxy or protected monosaccharidyloxy representing glucosyloxy, galactosyloxy, mannosyloxy, sorbosyloxy, allosyloxy, ribosyloxy, arabinosyloxy, ribonyloxy, gluconyloxy, or cyclic pyranose, furanose or lactone forms thereof, wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; polyhydroxy-lower alkoxy or protected polyhydroxy-lower alkoxy representing dihydroxypropyloxy or trihydroxybutyloxy wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; 1-(lower alkoxycarbonyloxy)-lower alkoxy; amino; mono- or di-lower-alkylamino; morpholino; N-lower alkylpiperazino; pyrrolidino; piperidino; perhydroazepino; (amino or lower alkanoylamino)-lower alkylamino; hydroxyamino; or lower alkylsulfonylamino; or a pharmaceutically acceptable salt of any said compound with a salt forming group.

Claim 5

A compound according to claim 3 of the formula III, wherein R 1 ' and R z ' independently represent aryl-(C 1 -C 4 )-alkyl in which aryl represents phenyl or phenyl mono- or di-substituted by halogen, lower alkyl, hydroxy, lower alkoxy or trifluoromethyl; A represents methylene substituted by lower alkyl, by phenyl-lower alkyl, by lower alkylthio-lower alkyl, by lower alkyloxy-lower alkyl, by phenyl-(lower alkylthio-lower alkyl or lower alkyloxy-lower alkyl), by pyridyl-(lower alkylthio-lower alkyl or lower alkyloxy-lower alkyl), by amino-lower alkyl, by acylamino-lower alkyl or by guanidino-lower alkyl; R 3 and R 4 independently represent hydroxy; lower alkoxy; (amino, mono- or di-lower alkylamino)-lower alkoxy; alpha-carboxy-lower alkoxy; alpha-lower alkoxycarbonyl-lower alkoxy; aryl-methoxy in which aryl represents phenyl, pyridyl, or (halogen, lower alkyl or lower alkoxy)-monosubstituted phenyl or pyridyl; (lower alkanoyloxy or lower alkoxy)-methoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-ethoxymethoxy; bicyclo[2,2,l]heptyl- oxycarbonylmethoxy; 1-(lower alkoxycarbonyloxy)-lower alkoxy; 3-phthalidoxy or (lower alkyl, lower alkoxy, or halogen)-substituted 3-phthalidoxy; cholestan-3-oxy or cholest-5-en-3-oxy; monosaccharidyloxy or protected monosaccharidyloxy selected from glucosyloxy, galactosyloxy, mannosyloxy, sorbosyloxy, allosyloxy, ribosyloxy, arabinosyloxy, ribonyloxy, gluconyloxy, or cyclic pyranose, furanose or lactone forms thereof, wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; polyhydroxy-lower alkoxy or protected polyhydroxy-lower alkoxy selected from dihydroxypropyloxy or trihydroxybutyloxy wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; amino; mono- or di-lower alkylamino; morpholino; N-methylpiperazino; piperidino; perhydroazepino; amino-lower alkylamino; (aryl or aryl-lower alkyl)-amino in which aryl represents pyridyl, phenyl or phenyl substituted by lower alkyl, halogen or trifluoromethyl; or lower alkylsulfonylamino; or a pharmaceutically acceptable salt of any said compound with a basic or acidic salt-forming group.

Claim 6

A compound according to claim 3 of the formula III, wherein R 3 and R 4 independently represent hydroxy, lower alkoxy, pivaloyloxymethoxy, bornyloxycarbonylmethoxy, benzyloxy, pyridylmethoxy, alpha-carboxyethoxy, alpha-lower alkoxycarbonylethoxy, 3-phthalidoxy, furthermore monosaccharidyloxy or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are free or hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; amino, mono- or di-lower alkylamino, morpholino, or lower alkylsulfonylamino; or a pharmaceutically acceptable salt of any said compound with a basic or acidic salt-' forming group.

Claim 7

A compound according to any of claims 3-5 of the formula III, wherein the groups COR 3 and COR 4 independently represent carboxy or carboxy esterified in form of a pharmaceutically acceptable ester wherein R 3 and R4 independently represent hydroxy, lower alkoxy, benzyloxy, pyridylmethoxy, pivaloyloxymethoxy, 3-phthalidoxy, monosaccharidyloxy or protected monosaccharidyloxy.

Claim 8

A compound according to any of claims 3-5 of the formula III, wherein the groups wherein one of R 3 and R 4 represents hydroxy and the other of R 3 and R 4 represents lower alkoxy, pivaloyloxymethoxy or protected monosaccharidyloxy.

Claim 9

A compound according to claim 1 of the formula IV wherein m and n independently represent an integer from 1 to 4; R 3 ' and R 4 ' represent hydroxy; Rs and R 6 independently represent hydrogen, halogen, hydroxy, lower alkoxy, lower alkyl or trifluoromethyl; R 7 represents lower alkyl, aryl-C l -C 4 -alkyl, (C 5 -C 7 )-cycloalkyl-C l -C 4 -alkyl, amino-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, guanidino-C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy-C 1 -C 4 - alkyl, aryl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkyloxy-C 1 -C 4 - alkyl in which definitions aryl represents phenyl, pyridyl, indolyl, imidazolyl, or phenyl mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; or a pharmaceutically acceptable mono- or di-ester derivative thereof; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt-forming group.

Claim 10

A compound according to claim 8 of the formula IV, wherein m, n, Rs, R 6 and R 7 are as defined therein and wherein either one or both of R 3 ' and R 4 ' represent lower alkoxy of 1 to 4 carbon atoms, 3-pyridylmethoxy, benzyloxy, pivaloyloxymethoxy, 3-phthalidoxy, bornyloxycarbonylmethoxy, 1-(ethoxycarbonyloxy)-ethoxy or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; and at most one of R 3 ' and R 4 ' represents hydroxy; or a pharmaceutically acceptable salt thereof.

Claim 11

A compound according to claim 8 of the formula IV, wherein m and n represent the integer 1; R 3 ' and R 4 ' independently represent hydroxy, lower alkoxy, pivaloyloxymethoxy, pyridylmethoxy, benzyloxy, 3-phthalidoxy, or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; Rs and R 6 represent hydrogen; and R 7 represents phenyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 - alkylthio-C l -C 4 -alkyl, phenyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl or guanidino-C 1 -C 4 - alkyl; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt forming group.

Claim 12

The threo racemate of a compound of claim 2.

Claim 13

A compound of claim 2 in the enantiomeric form depicted in formula IIa

Claim 14

A compound according to claim 10 of the formula IVa wherein R 3 ', R 4 ', R 5 , R 6 , R7, m and n have meaning as defined in said claim; or a pharmaceutically acceptable salt thereof of any said compound with a free carboxy group or basic salt forming group.

Claim 15

A compound according to claim 10 being N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-0-benzyl-(L)-serine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Claim 16

A compound according to claim 10 being N-[(S,S)-2,4-dibenzyl-4-carboxybutyryll-(L)-homophenylalanine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Claim 17

A compound according to claim 10 being N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-benzyl-(L)-cysteine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Claim 18

A compound according to claim 10 being N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-(2-pyridylmethyl)-(L)-cysteine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Claim 19

A compound of the formula I according to claim 1, wherein X and Y independently represent hydroxymethyl; cyano; carboxy; functionally modified carboxy selected from esterified carboxy, carbamoyl, and N-substituted carbamoyl; 5-tetrazolyl; 2-oxazolyl, 4,5-dihydro-2-oxazolyl, or each said grouping substituted by lower alkyl; R and Ro independently represent lower alkyl, (C 3 -C 7 )-cycloalkyl-lower alkyl, or aryl-lower alkyl; A represents methylene; or A represents methylene substituted by lower alkyl, by lower alkylthio-lower alkyl, by aryl-lower alkylthio-lower alkyl, by arylthio-lower alkyl, by hydroxy-lower alkyl, by acyloxy-lower alkyl, by lower alkoxy-lower alkyl, by aryl-lower alkyloxy-lower alkyl, by aryloxy-lower alkyl, by amino-lower alkyl, by acylamino-lower alkyl, by (C 3 -C 7 )-cycloalkyl, by (C 3 -C 7 )-cycloalkyl-lower alkyl, by aryl or aryl-lower alkyl; or a pharmaceutically acceptable ester or amide derivative of any said compound having a free carboxy group; or a pharmaceutically acceptable salt of any said compound with a salt-forming group.

Claim 20

A compound according to claim 18 of the formula IV shown in claim 8, wherein m and n independently represent an integer from 1 to 4; R 3 ' and R 4 ' represent hydroxy; R 5 and R 6 independently represent hydrogen, halogen, hydroxy, lower alkoxy, lower alkyl or trifluoromethyl; R 7 represents lower alkyl, aryl-C 1 -C 4 -alkyl, (C 5 -C 7 )-cycloalkyl-C 1 -C 4 -alkyl, amino- or hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, C I -C 4 -alkyloxy-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl in which definitions aryl represents phenyl, pyridyl, indolyl, imidazolyl, or phenyl mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; or a pharmaceutically acceptable mono- or di-ester derivative thereof; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt-forming group.

Claim 21

A compound according to claim 19 of the formula IV shown in claim 8, wherein m and n represent the integer 1; R 3 ' and R 4 ' independently represent hydroxy, lower alkoxy, pivaloyloxymethoxy, pyridylmethoxy, benzyloxy, 3-phthalidoxy, or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; R 5 and R 6 represent hydrogen; and R 7 represents phenyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkyl, pyridyl-C l -C 4 - alkylthio-C 1 -C 4 -alkyl or pyridyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt forming group.

Claim 22

Pharmaceutical preparations containing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

Claim 23

A compound of the formula I according to claim 1 of a pharmaceutically acceptable salt thereof for use in a method for the prophylactic and/or therapeutic treatment of the animal or human body.

Claim 24

A compound of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof as antihypertensive.

Claim 25

A compound of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof as diuretic.

Claim 26

Use of a compound of the formula I according to claim 1 or of a pharmaceutically acceptable salt thereof for the manufacture of a medicament with antihypertensive and/or diuretic activity.

Claim 27

Process for the manufacture of compounds of the formula I according to claim 1, or salts thereof, which comprises: condensing a compound of formula V wherein A and X have meaning as defined under formula I, in temporarily protected form if required, with a compound of formula VI or a reactive functional derivative thereof, wherein R, R and Y have meaning as defined under formula I, in temporarily protected form if required; and, if temporarily protecting any interfering reactive group(s), removing said protecting group(s); and, if desired, condensing a diacid of formula I obtained, wherein X and Y are carboxy, or a mono ester derivative thereof, with an esterifying agent of the formula VII wherein Z represents hydroxy or a reactive esterified hydroxyl group; and Ra represents any of the ester radicals defined for formula I in order to obtain a mono- or bis-functional derivative of said diacid of formula I wherein either one or both carboxy groups are esterified by identical or different radicals; and, if desired, converting a resulting compound of the invention into another compound of the invention, and/or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and/or, if desired, separating a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained into the optical antipodes.

Claim 28

Claims for the Contracting States: AT, ES, GR 1. A process for the manufacture of a compound of the formula I wherein X and Y independently represent hydroxymethyl; cyano; carboxy; functionally modified carboxy selected from esterified carboxy, carbamoyl, and N-substituted carbamoyl; 5-tetrazolyl; 2-oxazolyl, 4,5-dihydro-2-oxazolyl, or each said grouping substituted by lower alkyl; R and Ro independently represent lower alkyl, (C 3 -C 7 )-cycloalkyl-lower alkyl, or aryl-lower alkyl; A represents methylene; or A represents methylene substituted by lower alkyl, by lower alkylthio-lower alkyl, by aryl-lower alkylthio-lower alkyl, by arylthio-lower alkyl, by hydroxy-lower alkyl, by acyloxy-lower alkyl, by lower alkoxy-lower alkyl, by aryl-lower alkyloxy-lower alkyl, by aryloxy-lower alkyl, by amino-lower alkyl, by acylamino-lower alkyl, by guanidino-lower alkyl, by (C 3 -C 7 )-cycloalkyl, by (C 3 -C 7 )-cycloalkyl-lower alkyl, by aryl or aryl-lower alkyl; or a pharmaceutically acceptable ester or amide derivative of any said compound having a free carboxy group; or a pharmaceutically acceptable salt of any said compound with a salt-forming group, which comprises: condensing a compound of formula V wherein A and X have meaning as defined under formula I, in temporarily protected form if required, with a compound of formula VI or a reactive functional derivative thereof, wherein R, R and Y have meaning as defined under formula I, in temporarily protected form if required; and, if temporarily protecting any interfering reactive group(s), removing said protecting group(s); and, if desired, condensing a diacid of formula I obtained, wherein X and Y are carboxy, or a mono ester derivative thereof, with an esterifying agent of the formula VII wherein Z represents hydroxy or a reactive esterified hydroxyl group; and Rs represents any of the ester radicals defined for formula I in order to obtain a mono- or bis-functional derivative of said diacid of formula I wherein either one or both carboxy groups are esterified by identical or different radicals; and, if desired, converting a resulting compound of the invention into another compound of the invention, and/or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and/or, if desired, separating a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained into t'ie optical antipodes.

Claim 29

A process according to claim 1, characterized in that a compound cf the formula II wherein R 1 and R 2 independently represent lower alkyl, (C 3 -C 7 )-cycloalkyl-lower alkyl, or aryl-lower alkyl; A represents methylene; or A represents methylene substituted by lower alkyl, by lower alkylthio-lower alkyl, by hydroxy-lower'alkyl, by acyloxy-lower alkyl, by lower alkoxy-lower alkyl, by aryl-lower alkylthio-lower alkyl, by aryl-lower alkyloxy-lower alkyl, by aryloxy-lower alkyl, by arylthio-lower alkyl, by amino-lower alkyl, by acylamino-lower alkyl, by guanidino-lower alkyl, by (C 3 -C 7 )-cycloalkyl-lower alkyl, or by aryl-lower alkyl; a mono- or bis-carboxylic acid derivative thereof in which the derivative is selected from an unsubstituted amide or mono- or di-(Ci-C z o)-alkylamide; a tertiary lower alkylene, oxalkylene or azaalkylene amide wherein the lower alkylene, oxalkylene or azaalkylene group together with the amide nitrogen forms a 5-, 6- or 7-membered ring, or said lower alkylene, oxalkylene or azaalkylene amide is substituted on the ring by lower alkyl, hydroxy-lower alkyl or by lower alkanoyloxy-lower alkyl; an arylamide, an aryl-lower alkylamide; an (amino or acylamino)-lower alkylamide; a (C l -C ZO )-alkyl ester; an (amino, acylamino, mono- or di-lower alkylamino, carboxy or lower alkoxycarbonyl)-substituted lower alkyl ester; an aryl-lower alkyl ester; a lower alkanoyloxy-lower alkyl ester; a 3-phthalidyl or (lower alkyl, lower alkoxy or halogen)-substituted 3-phthalidyl ester; a (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethyl ester; a bicycloalkyloxycarbonyl-lower alkyl ester; a hydroxyamide; a lower alkylsulfonylamide; a 1-(lower alkoxycarbonyloxy)-lower alkyl ester; a 3-cholestanyl or 3-cholestenyl ester; a monosaccharidyl or protected monosaccharidyl ester being an ester incorporating as the alcohol portion a monosaccharide or protected monosaccharide, as a free or protected aldopentose or aldohexose in straight chain or cyclic furanose or pyranose form, or a free or protected glyconic acid of 5 or 6 carbon atoms or a lactone thereof; a polyhydroxy-lower alkyl or protected polyhydroxy-lower alkyl ester being an ester incorporating as the alcohol portion a polyhydroxy-lower alkane or protected polyhydroxy-lower alkane, being a free or protected glycerol or erythritol; or a pharmaceutically acceptable salt of any said compound with a salt-forming group is manufactured.

Claim 30

A process according to claim 1, characterized in that a compound of the formula III wherein R 1 ' and R z ' independently.represent aryl-(C 1 -C 4 )-alkyl in which aryl represents phenyl or phenyl mono- or di-substituted by halogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl or cyano; A represents methylene monosubstituted by lower alkyl, by phenyl-lower alkyl, by (halogen, lower alkyl, hydroxy, trifluoromethyl or lower alkoxy)-mono- or di-substituted phenyl-lower alkyl, by lower alkylthio-lower alkyl, by hydroxy-lower alkyl, by lower alkoxy-lower alkyl, by amino-lower alkyl or by acylamino-lower alkyl; by guanidino-lower alkyl; by aryl-lower alkylthio-lower alkyl or aryl-lower alkyloxy-lower alkyl in which aryl represents indolyl, pyridyl, phenyl or phenyl mono- or disubstituted by halogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl or cyano; the groups COR 3 and COR 4 independently represent carboxy, carboxy esterified in form of a pharmaceutically acceptable ester, carbamoyl or N-substituted carbamoyl in which R 3 and R 4 independently represent hydroxy, lower alkoxy; (amino, acylamino, mono- or di-lower alkylamino)-lower alkoxy; carboxy-lower alkoxy; lower alkoxycarbonyl-lower alkoxy; aryl-lower alkoxy in which aryl represents phenyl, pyridyl or (halogen, lower alkyl, hydroxy or lower alkoxy)-mono- or di-substituted phenyl or pyridyl; (hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxymethoxy; bicyclo[2,2,1]-heptyloxycarbonyl - lower alkoxy; cholestan-3-oxy or cholest-5-en-3-oxy; 3-phthalidoxy or (lower alkyl, lower alkoxy or halogen)-substituted 3-phthalidoxy; monosaccharidyloxy or protected monosaccharidyloxy representing glucosyloxy, galactosyloxy, mannosyloxy, sorbosyloxy, allosyloxy, ribosyloxy, arabinosyloxy, ribonyloxy, gluconyloxy, or cyclic pyranose, furanose or lactone forms thereof, wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; polyhydroxy-lower alkoxy or protected polyhydroxy-lower alkoxy representing dihydroxypropyloxy or trihydroxybutyloxy wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; 1-(lower alkoxycarbonyloxy)-lower alkoxy; amino; mono- or di-lower-alkylamino; morpholino; N-lower alkylpiperazino; pyrrolidino; piperidino; perhydroazepino; (amino or lower alkanoylamino)-lower alkylamino; hydroxyamino; or lower alkylsulfonylamino; or a pharmaceutically acceptable salt of any said compound with a salt forming group is manufactured.

Claim 31

A process according to claim 3, characterized in that a compound of the formula III, wherein R l ' and R 2 ' independently represent aryl-(C I -C 4 )-alkyl in which aryl represents phenyl or phenyl mono- or di-substituted by halogen, lower alkyl, hydroxy, lower alkoxy or trifluoromethyl; A represents methylene substituted by lower alkyl, by phenyl-lower alkyl, by lower alkylthio-lower alkyl, by lower alkyloxy-lower alkyl, by phenyl-(lower alkylthio-lower alkyl or lower alkyloxy-lower alkyl), by pyridyl-(lower alkylthio-lower alkyl or lower alkyloxy-lower alkyl), by amino-lower alkyl, by acylamino-lower alkyl or by guanidino-lower alkyl; R 3 and R 4 independently represent hydroxy; lower alkoxy; (amino, mono- or di-lower alkylamino)-lower alkoxy; alpha-carboxy-lower alkoxy; alpha-lower alkoxycarbonyl-lower alkoxy; aryl-methoxy in which aryl represents phenyl, pyridyl, or (halogen, lower alkyl or lower alkoxy)-monosubstituted phenyl or pyridyl; (lower alkanoyloxy or lower alkoxy)-methoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-ethoxymethoxy; bicyclo[2,2,1]-heptyloxycarbonylmethoxy; 1-(lower alkoxycarbonyloxy)-lower alkoxy; 3-phthalidoxy or (lower alkyl, lower alkoxy, or halogen)-substituted 3-phthalidoxy; cholestan-3-oxy or cholest-5-en-3-oxy; monosaccharidyloxy or protected monosaccharidyloxy selected from glucosyloxy, galactosyloxy, mannosyloxy, sorbosyloxy, allosyloxy, ribosyloxy, arabinosyloxy, ribonyloxy, gluconyloxy, or cyclic pyranose, furanose or lactone forms thereof, wherein hydroxy groups are free or one or more are protected in form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; polyhydroxy-lower alkoxy or protected polyhydroxy-lower alkoxy selected from dihydroxypropyloxy or trihydroxybutyloxy wherein hydroxy groups are free or one or more are protected in -form of a lower alkanoyl or a benzoyl ester, in form of a lower alkyl or benzyl ether, or, in case two vicinal hydroxy groups are involved, in the form of a lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene derivative; amino; mono- or di-lower alkylamino; morpholino; N-methylpiperazino; piperidino; perhydroazepino; amino-lower alkylamino; (aryl or aryl-lower alkyl)-amino in which aryl represents pyridyl, phenyl or phenyl substituted by lower alkyl, halogen or trifluoromethyl; or lower alkylsulfonylamino; or a pharmaceutically acceptable salt of any said compound with a basic or acidic salt-forming group is manufactured.

Claim 32

A process according to claim 3, characterized in that a compound of the formula III, wherein R 3 and R 4 independently represent hydroxy, lower alkoxy, pivaloyloxymethoxy, bornyloxycarbonylmethoxy, benzyloxy, pyridylmethoxy, alpha-carboxyethoxy, alpha-lower alkoxycarbonylethoxy, 3-phthalidoxy, furthermore monosaccharidyloxy or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are free or hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; amino, mono- or di-lower alkylamino, morpholino, or lower alkylsulfonylamino; or a pharmaceutically acceptable salt of any said compound with a basic or acidic salt-forming group is manufactured.

Claim 33

A process according to any of claims 3-5, characterized in that a compound of the formula III, wherein the groups COR 3 and COR 4 independently represent carboxy or carboxy esterified in form of a pharmaceutically acceptable ester wherein R 3 and R 4 independently represent hydroxy, lower alkoxy, benzyloxy, pyridylmethoxy, pivaloyloxymethoxy, 3-phthalidoxy, monosaccharidyloxy or protected monosaccharidyloxy is manufactured.

Claim 34

A process according to any of claims 3-5, characterized in that a compound of the formula III, wherein the groups wherein one of R 3 and R 4 represents hydroxy and the other of R 3 and R 4 represents lower alkoxy, pivaloyloxymethoxy or protected monosaccharidyloxy is manufactured.

Claim 35

A process according to claim 1, characterized in that a compound of the formula IV wherein m and n independently represent an integer from 1 to 4; R 3 ' and R 4 ' represent hydroxy; Rs and R 6 independently represent hydrogen, halogen, hydroxy, lower alkoxy, lower alkyl or trifluoromethyl; R 7 represents lower alkyl, aryl-C 1 -C 4 -alkyl, (C 5 -C 7 )-cycloalkyl-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, hydroxy-C l -C 4 -alkyl, guanidino - C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy-C 1 -C 4 - alkyl, aryl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkyloxy-C 1 -C 4 - alkyl in which definitions aryl represents phenyl, pyridyl, indolyl, imidazolyl, or phenyl mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; or a pharmaceutically acceptable mono- or di-ester derivative thereof; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt-forming group is manufactured.

Claim 36

A process according to claim 8, characterized in that a compound of the formula IV, wherein m, n, R 5 , R 6 and R 7 are as defined therein and wherein either one or both of R 3 ' and R 4 ' represent lower alkoxy of 1 to 4 carbon atoms, 3-pyridylmethoxy, benzyloxy, pivaloyloxymethoxy, 3-phthalidoxy, bornyloxycarbonylmethoxy, l-(ethoxycarbonyloxy)-ethoxy or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4- lactone)-yloxy, wherein hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; and at most one of R 3 ' and R 4 ' represents hydroxy; or a pharmaceutically acceptable salt thereof is manufactured.

Claim 37

A process according to claim 8, characterized in that a compound of the formula IV, wherein m and n represent the integer 1; R 3 ' and R 4 ' independently represent hydroxy, lower alkoxy, pivaloyloxymethoxy, pyridylmethoxy, benzyloxy, 3-phthalidoxy, or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; R 5 and R 6 represent hydrogen; and R 7 represents phenyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl or guanidino-C I -C 4 -alkyl; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt forming group is manufactured.

Claim 38

A process according to claim 2, characterized in that the threo racemate of a compound of claim 2 is manufactured.

Claim 39

A process according to claim 2, characterized in that a compound of claim 2 in the enantiomeric form depicted in formula IIa is manufactured.

Claim 40

A process according to claim 10, characterized in that a compound of the formula IVa wherein R 3 ', R 4 ', Rs, R 6 , R 7 , m and n have meaning as defined in said claim; or a pharmaceutically acceptable salt thereof of any said compound with a free carboxy group or basic salt forming group is manufactured.

Claim 41

A process according to claim 10, characterized in that N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-O-benzyl-(L)-serine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof is manufactured.

Claim 42

A process according to claim 10, characterized in that N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-(L)-homophenylalanine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof is manufactured.

Claim 43

A process according to claim 10, characterized in that N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-benzyl-(L)-cysteine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof is manufactured.

Claim 44

A process according to claim 10, characterized in that N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-(2-pyridylmethyl)-(L)-cysteine, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof is manufactured.

Claim 45

A process according to claim 1, characterized in that a compound of the formula I, wherein X and Y independently represent hydroxymethyl; cyano; carboxy; functionally modified carboxy selected from esterified carboxy, carbamoyl, and N-substituted carbamoyl; 5-tetrazolyl; 2-oxazolyl, 4,5-dihydro-2-oxazolyl, or each said grouping substituted by lower alkyl; R and R o independently represent lower alkyl, (C 3 -C 7 )-cycloalkyl-lower alkyl, or aryl-lower alkyl; A represents methylene; or A represents methylene substituted by lower alkyl, by lower alkylthio-lower alkyl, by aryl-lower alkylthio-lower alkyl, by arylthio-lower alkyl, by hydroxy-lower alkyl, by acyloxy-lower alkyl, by lower alkoxy-lower alkyl, by aryl-lower alkyloxy-lower alkyl, by aryloxy-lower alkyl, by amino-lower alkyl, by acylamino-lower alkyl, by (C 3 -C 7 )-cycloalkyl, by (C 3 -C 7 )-cycloalkyl-lower alkyl, by aryl or aryl-lower alkyl; or a pharmaceutically acceptable ester or amide derivative of any said compound having a free carboxy group; or a pharmaceutically acceptable salt of any said compound with a salt-forming group is manufactured.

Claim 46

A process according to claim 18, characterized in that a compound of the formula IV shown in claim 8, wherein m and n independently represent an integer from 1 to 4; R 3 ' and R 4 ' represent hydroxy; R 5 and R 6 independently represent hydrogen, halogen, hydroxy, lower alkoxy, lower alkyl or trifluoromethyl; R 7 represents lower alkyl, aryl-C 1 -C 4 -alkyl, (C 5 -C 7 )-cycloalkyl-C l -C 4 -alkyl, amino- or hydroxy-C 1 -C 4 -alkyl, Ci-C 4 -alkylthio-C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl in which definitions aryl represents phenyl, pyridyl, indolyl, imidazolyl, or phenyl mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; or a pharmaceutically acceptable mono- or di-ester derivative thereof; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt-forming group is manufactured.

Claim 47

A process according to claim 19, characterized in that a compound of the formula IV shown in claim 8, wherein m and n represent the integer 1; R 3 ' and R 4 ' independently represent hydroxy, lower alkoxy, pivaloyloxymethoxy, pyridylmethoxy, benzyloxy, 3-phthalidoxy, or protected monosaccharidyloxy selected from glucofuranosyloxy, glucopyranosyloxy, galactopyranosyloxy, allofuranosyloxy, mannofuranosyloxy, ribofuranosyloxy, sorbofuranosyloxy, arabinofuranosyloxy and ribono-(1,4-lactone)-yloxy, wherein hydroxy groups are protected in form of a lower alkanoyl ester, in form of a benzyl ether or in form of an isopropylidene, a benzylidene or cyclohexylidene derivative; R 5 and R 6 represent hydrogen; and R 7 represents phenyl-C 1 -C 4 - alkyl, phenyl-C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, phenyl-C I -C 4 -alkyloxy-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkyl, pyridyl-C 1 -C 4 -alkylthio-C 1 -C 4 - alkyl or pyridyl-C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl; or a pharmaceutically acceptable salt of any said compound with a free carboxy group or basic salt forming group is manufactured.

Claim 48

A process for the manufacture of a pharmaceutical preparation, characterized in that a compound obtainable according to any one of the claims 1 - 20 is processed with a pharmaceutical carrier.

Claim 49

A process for the manufacture of a pharmaceutical preparation, characterized in that a compound obtainable according to any one of the claims 1 - 20 is incorporated into said preparation, thereby forming a portion of 0.1 to 75 weight % of the total preparation.