EP0053017A1 — Amide derivatives

Claim 1

Independent Claim 756 words

An amide derivative of the formula:- wherein either R is hydrogen, or alkyl of up to 15 carbon atoms which is unsubstituted, or which bears one substituent selected from amino, benzyloxycarbonylamino, hydroxy, alkoxy, alkylthio and alkoxycarbonyl each of up to 5 carbon atoms, and aryl, aryloxy, arylthio and heterocyclic substituents; or which bears two or three substituents one of which is aryl,another of which is aryl, hydroxy, amino, benzyloxycarbonylamino, trifluoromethyl, aryloxy or alkoxy of up to 5 carbon atoms and the third of which, if present, is aryl or trifluoromethyl; or R 1 is aryl or, when Y is carbonyl or thiocarbonyl, is aryloxy, alkoxy or arylalkoxy wherein the alkoxy part has up to 5 carbon atoms; or R 1 is halogenoalkyl of up to 6 carbon atoms or is alkenyl, halogenoalkenyl or cycloalkyl each of up to 6 carbon atoms which is unsubstituted or which bears an aryl substituent; or R 1 is a substituent of the formula R 8 CONHCHR 9 - or R 8 COCH 2 CHR 9 - wherein R 8 is alkyl or cycloalkyl each of up to 10 carbon atoms, or aryl and R 9 is hydrogen, or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent, or R 9 is a group other than those stated above such that the compound H 2 NCHR 9 COOH would be a common amino acid; or R 1 is heterocyclic; wherein R 2 is hydrogen, alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent, or aryl; wherein R 3 is alkyl or alkenyl each of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent; or R 3 is aryl or indolylmethyl or R 3 is alkyl of up to 5 carbon atoms which is substituted by heterocyclic, other than methyl substituted by indolyl; provided that when R 1 is other than heterocyclic or alkyl substituted by heterocyclic, R 3 must be alkyl substituted by heterocyclic other than methyl substituted by indolyl. wherein R 4 is hydrogen or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent; wherein either R 5 is hydrogen or aryl, or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent; or R 5 is joined together with R 6 as defined below; wherein either R 6 is hydrogen, aryl or heterocyclic, or alkyl of up to 5 carbon atoms which is unsubstituted or which bears a hydroxy, aryl or heterocyclic substituent; or R 6 and R 5 are joined together to form alkylene or alkenylene of 2 to 5 carbon atoms; or an oxa-, thia-or aza-derivative of said alkylene or alkenylene; or a hydroxy- or oxo-substituted derivative of said alkylene or alkenylene; or R 6 and R 16 , or R 6 , R 16 and R 5 , or R 6 and R 10 are joined together as defined below; wherein R16 is hydrogen or alkyl of up to 5 carbon atoms; or R 6 and R16 are joined together to form alkylene of 2 to 5 carbon atoms (that is, to form a spirocycloalkyl group); or R 16 together with the first carbon atom of R 6 form a double bond wherein R 6 is otherwise alkyl, or wherein R 6 is otherwise substituted alkyl as defined above, or wherein R 6 and R 5 are otherwise joined together as defined above (that is, so that R 5 , R 6 and R 16 together form alkylidene); wherein Q is carbonyl (-CO-) or methylene (-CH 2 -); and wherein either R 10 is hydroxy, amino, aryloxy, arylthio, alkoxy, cycloalkoxy, alkylamino, dialkylamino, cyclic amino, hydroxyalkoxy, acyloxyalkoxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, cyclic aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, cyclic aminoalkylamino or arylalkoxy wherein each alkyl or alkoxy has up to 5 carbon atoms and wherein cyclic amino has up to 6 carbon atoms; or wherein R 10 and R 6 are joined together such that R 10 is oxygen (-O-) joined to the terminal carbon atom of R 6 when it is alkyl; wherein R 11 is hydrogen or alkyl of up to 3 carbon atoms; wherein X is carbonyl (-CO-),hydroxymethylene (-CHOH-), thiocarbonyl (-CS-) or oximinomethylene (-C=N-OR20, wherein R 20 is hydrogen or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent); and wherein Y is carbonyl, thiocarbonyl, sulphonyl (-S0 2 -) or amido (-NHCO-); or a salt thereof where appropriate.

Claim 2

Dependent Claim 756 words

An amide derivative of the formula:- wherein either R is hydrogen, or alkyl of up to 15 carbon atoms which is unsubstituted, or which bears one substituent selected from amino, benzyloxycarbonylamino, hydroxy, alkoxy, alkylthio and alkoxycarbonyl each of up to 5 carbon atoms, and aryl, aryloxy, arylthio and heterocyclic substituents; or which bears two or three substituents one of which is aryl,another of which is aryl, hydroxy, amino, benzyloxycarbonylamino, trifluoromethyl, aryloxy or alkoxy of up to 5 carbon atoms and the third of which, if present, is aryl or trifluoromethyl; or R 1 is aryl or, when Y is carbonyl or thiocarbonyl, is aryloxy, alkoxy or arylalkoxy wherein the alkoxy part has up to 5 carbon atoms; or R 1 is halogenoalkyl of up to 6 carbon atoms or is alkenyl, halogenoalkenyl or cycloalkyl each of up to 6 carbon atoms which is unsubstituted or which bears an aryl substituent; or R 1 is a substituent of the formula R 8 CONHCHR 9 - or R 8 COCH 2 CHR 9 - wherein R 8 is alkyl or cycloalkyl each of up to 10 carbon atoms, or aryl and R 9 is hydrogen, or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent, or R 9 is a group other than those stated above such that the compound H 2 NCHR 9 COOH would be a common amino acid; or R 1 is heterocyclic; wherein R 2 is hydrogen, alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent, or aryl; wherein R 3 is alkyl or alkenyl each of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent; or R 3 is aryl or indolylmethyl or R 3 is alkyl of up to 5 carbon atoms which is substituted by heterocyclic, other than methyl substituted by indolyl; provided that when R 1 is other than heterocyclic or alkyl substituted by heterocyclic, R 3 must be alkyl substituted by heterocyclic other than methyl substituted by indolyl. wherein R 4 is hydrogen or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent; wherein either R 5 is hydrogen or aryl, or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent; or R 5 is joined together with R 6 as defined below; wherein either R 6 is hydrogen, aryl or heterocyclic, or alkyl of up to 5 carbon atoms which is unsubstituted or which bears a hydroxy, aryl or heterocyclic substituent; or R 6 and R 5 are joined together to form alkylene or alkenylene of 2 to 5 carbon atoms; or an oxa-, thia-or aza-derivative of said alkylene or alkenylene; or a hydroxy- or oxo-substituted derivative of said alkylene or alkenylene; or R 6 and R 16 , or R 6 , R 16 and R 5 , or R 6 and R 10 are joined together as defined below; wherein R16 is hydrogen or alkyl of up to 5 carbon atoms; or R 6 and R16 are joined together to form alkylene of 2 to 5 carbon atoms (that is, to form a spirocycloalkyl group); or R 16 together with the first carbon atom of R 6 form a double bond wherein R 6 is otherwise alkyl, or wherein R 6 is otherwise substituted alkyl as defined above, or wherein R 6 and R 5 are otherwise joined together as defined above (that is, so that R 5 , R 6 and R 16 together form alkylidene); wherein Q is carbonyl (-CO-) or methylene (-CH 2 -); and wherein either R 10 is hydroxy, amino, aryloxy, arylthio, alkoxy, cycloalkoxy, alkylamino, dialkylamino, cyclic amino, hydroxyalkoxy, acyloxyalkoxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, cyclic aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, cyclic aminoalkylamino or arylalkoxy wherein each alkyl or alkoxy has up to 5 carbon atoms and wherein cyclic amino has up to 6 carbon atoms; or wherein R 10 and R 6 are joined together such that R 10 is oxygen (-O-) joined to the terminal carbon atom of R 6 when it is alkyl; wherein R 11 is hydrogen or alkyl of up to 3 carbon atoms; wherein X is carbonyl (-CO-),hydroxymethylene (-CHOH-), thiocarbonyl (-CS-) or oximinomethylene (-C=N-OR20, wherein R 20 is hydrogen or alkyl of up to 5 carbon atoms which is unsubstituted or which bears an aryl substituent); and wherein Y is carbonyl, thiocarbonyl, sulphonyl (-S0 2 -) or amido (-NHCO-); or a salt thereof where appropriate.

Claim 3

Dependent Claim 29 words

An amide derivative as claimed in claim 1 wherein X, Y and Q are all carbonyl and R 2 and R 11 are both hydrogen, or a salt thereof.

Claim 4

Dependent Claim 140 words

An amide derivative of the formula:- wherein R 1 is methyl, benzyl, β-phenylethyl, benzyloxy, phenoxymethyl, phenylthiomethyl, phenyl, tolyl, methoxyphenyl, methylthiophenyl, monochlorophenyl, dichlorophenyl, fluorophenyl, iodophenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl, acetamidophenyl, acetylphenyl, methanesulphonylphenyl, biphenylyl, naphthyl, benzamidomethyl, cyclopentanecarbonamidomethyl or β-benzoylethyl; R 3 is methyl substituted by a 5- or 6-membered. fully- unsaturated heterocyclic ring containing 1 or 2 hetero- atoms selected from oxygen, nitrogen and sulphur, which ring may optionally contain a methyl substituent or be fused to a benzene ring, provided that R 3 is not indolyl-methyl; R 4 is hydrogen or methyl; R 5 is hydrogen or methyl and R 6 is hydrogen, benzyl or indol-3-ylmethyl, or R 5 and R 6 together form trimethylene, tetramethylene, pentamethylene, 2-hydroxytrimethylene, 2-thiatrimethylene, 3-thiatetramethylene, 3-oxatetramethylene, 3-methyl-3-azatetramethylene; and R 10 is hydroxy, amino,alkoxy of up to 5 carbon atoms, S-dimethylaminoethoxy, β-morpholinoethoxy or benzyloxy, or a salt thereof.

Claim 5

Dependent Claim 140 words

An amide derivative of the formula:- wherein R 1 is methyl, benzyl, β-phenylethyl, benzyloxy, phenoxymethyl, phenylthiomethyl, phenyl, tolyl, methoxyphenyl, methylthiophenyl, monochlorophenyl, dichlorophenyl, fluorophenyl, iodophenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl, acetamidophenyl, acetylphenyl, methanesulphonylphenyl, biphenylyl, naphthyl, benzamidomethyl, cyclopentanecarbonamidomethyl or β-benzoylethyl; R 3 is methyl substituted by a 5- or 6-membered. fully- unsaturated heterocyclic ring containing 1 or 2 hetero- atoms selected from oxygen, nitrogen and sulphur, which ring may optionally contain a methyl substituent or be fused to a benzene ring, provided that R 3 is not indolyl-methyl; R 4 is hydrogen or methyl; R 5 is hydrogen or methyl and R 6 is hydrogen, benzyl or indol-3-ylmethyl, or R 5 and R 6 together form trimethylene, tetramethylene, pentamethylene, 2-hydroxytrimethylene, 2-thiatrimethylene, 3-thiatetramethylene, 3-oxatetramethylene, 3-methyl-3-azatetramethylene; and R 10 is hydroxy, amino,alkoxy of up to 5 carbon atoms, S-dimethylaminoethoxy, β-morpholinoethoxy or benzyloxy, or a salt thereof.

Claim 6

Dependent Claim 60 words

An amide derivative as claimed in claim 3 wherein R l is phenyl, R 3 is methyl substituted by 3-thienyl, 5-methyl-2-furyl, 2-pyridyl, 3-pyridyl, 4-thiazolyl, 4-imidazolyl, 3-isoxazolyl or 2-benzimidazolyl, R 4 is hydrogen or methyl, R 5 and R 6 together form trimethylene and R 10 is hydroxy, alkoxy of up to 5 carbon atoms or benzyloxy, or a salt thereof.

Claim 7

Dependent Claim 136 words

An amide derivative of the formula:v ; wherein R 1 is a 5- or 6-membered, fully-unsaturated heterocyclic ring containing 1 or 2 hetero-atoms selected from oxygen, nitrogen and sulphur, which ring may optionally contain a methyl substituent or be fused to a benzene ring; R 3 is benzyl which is unsubstituted or bears a methyl, t-butyl, methoxy, fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amino, acetamido, methanesulphonamido, trifluoromethanesulphonamido or phenyl substituent, or R 3 is 3-phenylpropyl or 3-phenylprop-2-enyl; R 4 is hydrogen or methyl; R 5 is hydrogen or methyl and R 6 is hydrogen, benzyl or indol-3-ylmethyl, or R 5 and R 6 together form trimethylene, tetramethylene, pentamethylene, 2-hydroxytrimethylene, 2-thiatrimethylene, 3-thiatetramethylene, 3-oxatetramethylene or 3-methyl -3-azatetramethylene; and R 10 is hydroxy, amino, alkoxy of up to 5 carbon atoms, β-dimethylaminoethoxy, β-morpholinoethoxy or benzyloxy, or a salt thereof.

Claim 8

Dependent Claim 136 words

An amide derivative of the formula:v ; wherein R 1 is a 5- or 6-membered, fully-unsaturated heterocyclic ring containing 1 or 2 hetero-atoms selected from oxygen, nitrogen and sulphur, which ring may optionally contain a methyl substituent or be fused to a benzene ring; R 3 is benzyl which is unsubstituted or bears a methyl, t-butyl, methoxy, fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amino, acetamido, methanesulphonamido, trifluoromethanesulphonamido or phenyl substituent, or R 3 is 3-phenylpropyl or 3-phenylprop-2-enyl; R 4 is hydrogen or methyl; R 5 is hydrogen or methyl and R 6 is hydrogen, benzyl or indol-3-ylmethyl, or R 5 and R 6 together form trimethylene, tetramethylene, pentamethylene, 2-hydroxytrimethylene, 2-thiatrimethylene, 3-thiatetramethylene, 3-oxatetramethylene or 3-methyl -3-azatetramethylene; and R 10 is hydroxy, amino, alkoxy of up to 5 carbon atoms, β-dimethylaminoethoxy, β-morpholinoethoxy or benzyloxy, or a salt thereof.

Claim 9

Dependent Claim 52 words

An amide derivative as claimed in claim 5 wherein R 1 is 2-furyl, 2-thienyl, 2-pyridyl or 2-thienylmethyl, R 3 is benzyl, R 4 is hydrogen or methyl, R 5 and R 6 together form triemthylene and R 10 is hydroxy or alkoxy of up to 5 carbon atoms, or a salt thereof.

Claim 10

Dependent Claim 11 words

The compound N-[2-methyl-4-oxo-6-phenyl-5-(2- thenoylamino)hexanoyl]-L-proline; N-[5-(2-furoylamino)-4-oxo-6-phenylhexanoyl]-L-proline isobutyl ester; N-[5- benzamido-4-oxo-6-(pyrid-3-y1)hexanoyl]-L-proline or N-[5-benzamido-6-(imidazol-4-yl)-4-oxohexanoyl]-L-proline.

Claim 11

Dependent Claim 11 words

The compound N-[2-methyl-4-oxo-6-phenyl-5-(2- thenoylamino)hexanoyl]-L-proline; N-[5-(2-furoylamino)-4-oxo-6-phenylhexanoyl]-L-proline isobutyl ester; N-[5- benzamido-4-oxo-6-(pyrid-3-y1)hexanoyl]-L-proline or N-[5-benzamido-6-(imidazol-4-yl)-4-oxohexanoyl]-L-proline.

Claim 12

Dependent Claim 35 words

A salt of an amide derivative, claimed in any of claims 1 to 7 wherein R 10 is hydroxy which is an alkali metal or alkaline earth metal salt, or an ammonium or dicyclohexylamine salt.

Claim 13

Dependent Claim 585 words

A process for the manufacture of an amide derivative or a salt thereof, claimed in any of claims 1 to 8, which comprises (a) the reaction of an acid of the formula:- wherein R 1 , R 2 , R 3 , R 4 , R 11 , X and Y have the meanings stated in any of claims 1 to 5, or of a reactive derivative thereof, with an amine of the formula:- wherein R 5 , R 6 , R 16 and Q have the meanings stated in any of claims 1 to 5 and wherein R 12 has any of the meanings stated in claims 1 to 5 for R 10 except those containing a free hydroxy or amino group; or (b) for the manufacture of an amide derivative wherein R 2 is hydrogen and X is carbonyl or thiocarbonyl, the reaction of an amine of the formula: wherein R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 16 , Q and 1 have the meanings stated above, with a compound of the formula R 1 -Y-Z 1 , wherein R 1 and Y have the meanings stated above and wherein Z 1 is a displaceable halogen, alkanesulphonyl or arensulphonyl group, or Z 1 is hydroxy (in which case the reaction is carried out in the presence of a carbodiimide or an alkyl chloroformate), or, when Y is amido, with a compound of the formula R 1 NCO, or, when Y is thiocarbonyl, with a compound of the formula R1CS-SCH2COOH; or (c) for the manufacture of an amide derivative wherein R 2 is hydrogen and X is a carbonyl, the reaction of a compound of the formula:- wherein R 4 , R 5 , R 6 , R 11 , R 12 , R 16 , and Q have the meanings stated above and Z 2 is a displaceable halogen atom, with a compound of the formula wherein R 1 and R 3 have the meanings stated above, followed by hydrolysis of the oxazolone ring; whereafter an amide derivative wherein R 2 is alkyl, arylalkyl or aryl (and R 10 is R 12 ) may be obtained by reacting the corresponding amide derivative wherein R 2 is hydrogen (and R 10 is R 12 ) with a compound of the formula R 2 Z, wherein R 2 has the meaning stated above and Z is a displaceable halogen alkanesulphonyl or arenesulphonyl group; or whereafter an amide derivative wherein R 3 is unsubstituted or substituted alkyl may be obtained by the hydrogenation of the corresponding compound wherein R 3 is unsubstituted or substituted alkenyl; or whereafter an amide derivative wherein R 10 is other than hydroxy (that is, wherein-Q-R 10 forms an ester or amide group) may be obtained from the corresponding acid wherein-Q-R 10 is -COOH by conventional means of ester or amide formation; or whereafter an amide derivative wherein Q is carbonyl and R 10 is hydroxy may be obtained by the hydrolysis of the corresponding amide derivative wherein R 10 is alkoxy, or, when R 10 is t-butoxy, by the acid-catalysed cleavage of said compound; or whereafter an amide derivative wherein X is hydroxymethylene may be obtained by the reduction of the corresponding amide derivative wherein X is carbonyl; or whereafter an amide derivative wherein X is oximinomethylene may be obtained by the reaction of the corresponding amide derivative wherein X is carbonyl with hydroxylamine or an O-substituted hydroxylamine derivative.

Claim 14

Dependent Claim 34 words

lO. A pharmaceutical composition comprising as active ingredient at least one amide derivative, or a salt thereof, claimed in any of claims 1 to 8, in association with a pharmaceutically-acceptable diluent or carrier therefor.

Amide derivatives

Abstract

Inventors

Bibliographic Details

Claims Analysis

References Cited (Backward Citations)

USPTO Annuity & Maintenance Windows

Assigned Categories & Tags

Assign Category Tag