Cytostatic agents

Abstract

This invention provides a method of inhibiting proliferation of tumor cells in a subject by administering to the subject an effective amount of ester and thioester compounds containing an N-formyl hydroxylamine group. The compounds with which this invention is concerned thus represent a selection of a subclass from the compounds known in the art as MMP inhibitors, for a specific and previously unrecognized pharmaceutical utility in the inhibition of proliferation of rapidly dividing cells, including such tumor cells as lymphoma, leukemia, myeloma, adenocarcinoma, carcinoma, mesothelioma, teratocarcinoma, choriocarcinoma, small cell carcinoma, large cell carcinoma, melanoma, retinoblastoma, fibrosarcoma, leiomyosarcoma or endothelioma cells by a mechanism other than MMP inhibition.

1 . The use of a compound of formula (I) or a pharmaceutically acceptable salt hydrate or solvate thereof in the preparation of a pharmaceutical composition for inhibiting proliferation of tumour cells in mammals:  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen or (C 1 -C 6 )alkyl:  
 R 1  is hydrogen; 
 (C 1 -C 6 )alkyl or fluoro-substituted (C 1 -C 6 )alkyl;  
 (C 2 -C 6 )alkenyl;  
 phenyl or substituted phenyl;  
 phenyl(C 1 -C 6 )alkyl or substituted phenyl(C 1 -C 6 )alkyl;  
 phenyl(C 2 -C 6 )alkenyl or substituted phenyl(C 2 -C 6 )alkenyl heterocyclyl or substituted heterocyclyl;  
 heterocyclyl(C 1 -C 6 )alkyl or substituted heterocyclyl(C 1 -C 6 )alkyl;  
 a group BSO n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C 1 -C 6 ) alkyl, phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C 1 -C 6 )acyl, phenacyl or substituted phenacyl group, and A represents (C 1 -C 6 )alkylene;  
 amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or carboxy(C 1 -C 6 ) alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl- group amidated;  
 lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino;  
 a cycloalkyl, cycloalkenyl, cycloalkyl(C 1 -C 6 alkyl), cycloalkenyl(C 1 -C 6 alkyly or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, halo, cyano (—CN), —CO 2 H, —CO 2 R, —CONH 2 , —CONHR, —CON(R) 2 , —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO 2 R wherein R is C 1 -C 6  alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;  
 
 R 2  is a C 1 -C 12  alkyl, 
 C 2 -C 12  alkenyl,  
 C 2 -C 12  alkynyl,  
 phenyl(C 1 -C 6  alkyl),  
 heteroaryl(C 1 -C 6  alkyly,  
 phenyl(C 2 -C 6  alkenyly,  
 heteroaryl(C 2 -C 6  alkenyly,  
 phenyl(C 2 -C 6  alkynyly,  
 heteroaryl(C 2 -C 6  alkynyly,  
 cycloalkyl(C 1 -C 6  alkyly,  
 cycloalkyl(C 2 -C 6  alkenyly,  
 cycloalkyl(C 2 -C 6  alkynyly,  
 cycloalkenyl(C 1 -C 6  alkyl),  
 cycloalkenyl(C 2 -C 6  alkenyl),  
 cycloalkenyl(C 2 -C 6  alkynyl),  
 phenyl(C 1 -C 6  alkyl)O(C 1 -C 6  alkyl), or  
 heteroaryl(C 1 -C 6  alkyl)O(C 1 -C 6  alkyl) group,  
 any one of which may be optionally substituted by 
 C 1 -C 6  alkyl,  
 C 1 -C 6  alkoxy,  
 halo,  
 cyano (—CN),  
 phenyl or heteroaryl, optionally ring-substituted by 
 C 1 -C 6  alkyl,  
 C 1 -C 6  alkoxy,  
 halo, or  
 cyano (—CN);  
 
 
 
 R 3  is the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected; and  
 R 4  is an ester or thioester group.  
 
     
     
         2 . A method for inhibiting proliferation of tumour cells in mammals, comprising administering to a mammal suffering such cell proliferation an amount of a compound of general formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, sufficient to inhibit such proliferation.  
     
     
         3 . The use as claimed in  claim 1 , or a method as claimed in  claim 2  wherein in formula (I) the stereochemical configuration of the carbon atom carrying the groups R 3  and R 4  is S.  
     
     
         4 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 1  is: 
 hydrogen, methyl, 3,3,3-trifluoropropyl, n-propyl, n-butyl, isobutyl, allyl, cyclopentylmethyl, phenylpropyl, cyclopropylmethyl, phenylprop-2-enyl, thienylsulphanylmethyl, thienylsulphinylmethyl, or thienylsulphonylmethyl; or  
 C 1 -C 4  alkyl, eg methyl, ethyl n-propyl or n-butyl, substituted by a phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1,2,4-oxadiazolyl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidinyl or 2,6-dioxopiperidinyl, 5,5-dimethyl-2,4-dioxo-3-oxazolidinyl, hexahydro-1,3-dioxopyrazolo[1,2,a][1,2,4]-triazol-2-yl, or a naphththalimido (ie 1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl), 1,3-dihydro-n-oxo-2H-benz[f]isoindol-2-yl, 1,3-dihydro-1,3-dioxo-2H-pyrrolo[3,4-b]quinolin-2-yl, or 2,3-dihydro-1,3-dioxo-1H-benz[d,e]isoquinolin-2-yl group; or  
 cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydropyranyl or morpholinyl.  
 
     
     
         5 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 1  is hydrogen, cyclopropylmethyl, n-propyl, 3,3,3-trifluoropropyl or allyl.  
     
     
         6 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 2  is: 
 C 1 -C 12  alkyl, C 3 -C 6  alkenyl or C 3 -C 6  alkynyl;  
 cycloalkyl(C 1 -C 6  alkyl)-;  
 phenyl(C 1 -C 6  alkyl)-, phenyl(C 3 -C 6  alkenyl)- or phenyl(C 3 -C 6  alkynyl)- optionally substituted in the phenyl ring;  
 heteroaryl(C 1 -C 6  alkyl)-, heteroaryl(C 3 -C 6  alkenyl)- or heteroaryl(C 3 -C 6  alkynyl)- optionally substituted in the heteroaryl ring;  
 4-phenylphenyl(C 1 -C 6  alkyl)-, 4-phenylphenyl(C 3 -C 6  alkenyl)-, 4-phenylphenyl(C 3 -C 6  alkynyl)-, 4-heteroarylphenyl(C 1 -C 6  alkyl)-, 4-heteroarylphenyl(C 3 -C 6  alkenyl)-, 4-heteroarylphenyl(C 3 -C 6  alkynyl)-, optionally substituted in the terminal phenyl or heteroaryl ring; or  
 phenoxy(C 1 -C 6  alkyl)- or heteroaryloxy(C 1 -C 6  alkyl)- optionally substituted in the phenyl or heteroaryl ring.  
 
     
     
         7 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 2  is methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-nonyl, n-decyl, benzyl, cyclopentylmethyl, cyclopropylmethyl, prop-2-yn-1-yl, 3-phenylprop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, benzyl phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, phenoxybutyl, 3-(4-pyridylphenyl)propyl-, 3-(4-4-pyridyl)phenyl)prop-2-yn-1-yl, 3-(4-phenylphenyl)propyl-, 3-(4-phenyl)phenyl)prop-2-yn-1-yl or 3-[(4-chlorophenyl)phenyl]propyl-.  
     
     
         8 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 2  is benzyl, n-butyl, iso-butyl, n-hexyl, cyclopentylmethyl, cyclopropylmethyl, or 3-(2-chlorophenyl)prop-2-yn-1-yl.  
     
     
         9 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is C 1 -C 6  alkyl, phenyl, 2,-3-, or 4-pyridyl, 2- or 3-thienyl, 2,- 3-, or 4-hydroxyphenyl, 2,-3-, or 4-methoxyphenyl, 2,-3-, or 4-pyridylmethyl, benzyl, 2,- 3-, or 4-hydroxybenzyl, 2,-3-, or 4-benzyloxybenzyl, 2,-3-, or 4-C 1 -C 6  alkoxybenzyl, or benzyloxy(C—C 6 alkyl).  
     
     
         10 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is the characterising group of a natural α-amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated.  
     
     
         11 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is a group -[Alk] n R 6  where Alk is a (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more —O—, or —S— atoms or —N(R 7 )— groups [where R 7  is a hydrogen atom or a (C 1 -C 6 )alkyl group], n is 0 or 1, and R 6  is an optionally substituted cycloalkyl or cycloalkenyl group.  
     
     
         12 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is a benzyl group substituted in the phenyl ring by a group of formula —OCH 2 COR 8  where R 8  is hydroxyl, amino, (C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, phenyl(C 1 -C 6 )alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and asparfic acid.  
     
     
         13 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is a heterocyclic(C 1 -C 6 )alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )alkanoyl, trifluoromethyl (C 1 -C 6 )alkyl, hydroxy, formyl, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, mercapto, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylphenylmethyl.  
     
     
         14 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is a group —CR a R b R c  in which: 
 each of R a , R b  and R c  is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl; or  
 R c  is hydrogen and R a  and R b  are independently phenyl or heteroaryl such as pyridyl; or  
 R a  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, and R a  and R b  together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5 to 6-membered heterocyclic ring; or  
 R a , R b  and R c  together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or  
 R a  and R b  are each independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or a group as defined for R c  below other than hydrogen, or R a  and R b  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R c  is hydrogen, —OH, —SH, halogen, —CN, —CO 2 H, (C 1 -C 4 )perfluoroalkyl, —CH 2 OH, —CO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 2 -C 6 )alkenyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 ) alkyl, —S(C 2 -C 6 )alkenyl, —SO(C 2 -C 6 )alkenyl, —SO 2 (C 2 -C 6 )alkenyl or a group -Q-W wherein Q represents a bond or —O—, —S—, —SO— or —SO 2  and W represents a phenyl, phenylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylalkyl, (C 4 -C 8 )cycloalkenyl, (C 4 -C 8 )cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, —CN, —CO 2 H, —CO 2 (C 1 -C 6 )alkyl, —CONH 2 , —CONH(C 1 -C 6 )alkyl, —CONH(C 1 -C 6 alkyl), —CHO, —CH 2 OH, (C 1 -C 4 )perfluoroalkyl, —O(C 1 -C 6 )alkyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —NO 2 , —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NHCO(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, phenyl or benzyl.  
 
     
     
         15 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is benzyl, phenyl, cyclopentylmethyl, cyclohexylmethyl, pyridin-3-ylmethyl, 2- or 3-thienyl, 3-, or 4-methoxyphenyl, tert-butoxymethyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 
 1-methylthio-1-methylethyl, or 1-mercapto-1-methylethyl.  
 
     
     
         16 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is phenyl, 3-, or 4-methoxyphenyl, benzyl, tert-butoxymethyl, iso-propyl or iso-butyl.  
     
     
         17 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 3  is R 4  is a group of formula —(C═O)OR 9 , —(C═O)SR 9 , —(C═S)SR 9 , and —(C═S)OR 9  wherein R 9  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, cycloalkyl, cycloalkyl(C 1 -C 6 )alkyl-, phenyl, heterocyclyl, phenyl(C 1 -C 6 )alkyl-, heterocyclyl(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, any of which may be substituted on a ring or non-ring carbon atom or on a ring heteroatom, if present.  
     
     
         18 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 4  is a group of formula —(C═O)OR 9  wherein R 9  is methyl, ethyl, n-and iso-propyl, n-, sec- and tert-butyl, 1-ethyl-prop-1-yl, 1-methyl-prop-1-yl, 1-methyl-but-1-yl, cyclobutanyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, allyl, phenyl, benzyl, 2-, 3- and 4-pyridylmethyl, N-methylpiperidin-4-yl, 1-methylcyclopent-1-yl, adamantyl, tetrahydrofuran-3-yl, tetrahydropyranyl or methoxyethyl.  
     
     
         19 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 4  is a carboxylate ester of formula —(C═O)OR 9 , wherein R 9  is benzyl, cyclopentyl, or isopropyl.  
     
     
         20 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R is hydrogen.  
     
     
         21 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in  claim 3  wherein R 1  is hydrogen, cyclopropylmethyl, n-propyl, 3,3,3-trifluoropropyl or allyl, R 2  is benzyl, n-butyl, iso-butyl, n-hexyl, cyclopentylmethyl, cyclopropylmethyl, or 3-(2-chlorophenyl)prop-2-yn-1-yl, R 3  is phenyl, 3, or 4-methoxyphenyl, benzyl, tert-butoxymethyl, iso-propyl or iso-butyl, R 4  is a group of formula —(C—O)OR 9  wherein R 9  is benzyl, cyclopentyl, or isopropyl and R is hydrogen.  
     
     
         22 . The use as claimed in  claim 1  or method as claimed in  claim 2  or the use or method as claimed in any of  claims 3  to  21  wherein the cell proliferation treated is proliferation of lymphoma, leukemia, myeloma, adenocarcinoma, carcinoma, mesothelioma, teratocarcinoma, choriocarcinoma, small cell carcinoma, large cell carcinoma, melanoma, retinoblastoma, fibrosarcoma, leiomyosarcoma, glioblastoma or endothelioma cells.  
     
     
         23 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen or (C 1 -C 6 )alkyl;  
 R 1  is hydrogen; 
 (C 1 -C 6 )alkyl or fluoro-substituted (C 1 -C 6 )alkyl;  
 (C 2 -C 6 )alkenyl;  
 phenyl or substituted phenyl;  
 phenyl (C 1 -C 6 )alkyl or substituted phenyl(C 1 -C 6 )alkyl;  
 phenyl (C 2 -C 6 )alkenyl or substituted phenyl(C 2 -C 6 )alkenyl heterocyclyl or substituted heterocyclyl;  
 heterocyclyl(C 1 -C 6 )alkyl or substituted heterocyclyl(C 1 -C 6 )alkyl;  
 a group BSO n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C 1 -C 6 ) alkyl, phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C 1 -C 6 )acyl, phenacyl or substituted phenacyl group, and A represents (C 1 -C 6 )alkylene;  
 amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or carboxy(C 1 -C 6 ) alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl- group amidated;  
 lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino;  
 a cycloalkyl, cycloalkenyl, cycloalkyl(C 1 -C 6 alkyl)-, cycloalkenyl(C 1 -C 6 alkyl)- or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, halo, cyano (—CN), —CO 2 H, —CO 2 R, —CONH 2 , —CONHR, —CON(R) 2 , —OH, —OR, oxo, —SH, —SR, —NHCOR, and —NHCO 2 R wherein R is C 1 -C 6  alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;  
 
 R 2  is a C 1 -C 12  alkyl, 
 C 2 -C 12  alkenyl,  
 C 2 -C 12  alkynyl,  
 phenyl(C 1 -C 6  alkyly,  
 heteroaryl(C 1 -C 6  alkyl),  
 phenyl(C 2 -C 6  alkenyl),  
 heteroaryl(C 2 -C 6  alkenyly,  
 phenyl(C 2 -C 6  alkynyly,  
 heteroaryl(C 2 -C 6  alkynyl),  
 cycloalkyl(C 1 -C 6  alkyl),  
 cycloalkyl(C 2 -C 6  alkenyly,  
 cycloalkyl(C 2 -C 6  alkynyl),  
 cycloalkenyl(C 1 -C 6  alkyly,  
 cycloalkenyl(C 2 -C 6  alkenyly,  
 cycloalkenyl(C 2 -C 6  alkynyly group, 
 any one of which may be optionally substituted by C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, cyano (—CN), or phenyl or heteroaryl optionally ring-substituted by C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, or cyano (—CN);  
 
 
 R 3  is the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected; and  
 R 4  is an ester or thioester group,  
 or a pharmaceutically acceptable salt, hydrate or solvate thereof, PROVIDED THAT (i) R 3  is not a bicyclicarylmethyl group or (ii) R 2  is not a C 1 -C 12  alkyl, C 2 -C 12  alkenyl, or C 2 -C 12  alkynyl group substituted by a C 1 -C 6  alkoxy group.  
 
     
     
         24 . A compound as claimed in  claim 23  wherein in formula (I) the stereochemical configuration of the carbon atom carrying the groups R 3  and R 4  is S.  
     
     
         25 . A compound as claimed in  claim 23  wherein R 1  is: 
 hydrogen, methyl, trifluoropropyl, n-propyl, 3,3,3-trifluoropropyl, n-butyl, isobutyl, allyl, cyclopentylmethyl, phenylpropyl, cyclopropylmethyl, phenylprop-2-enyl, thienylsulphanylmethyl, thienylsulphinylmethyl, or thienylsulphonylmethyl; or  
 C 1 -C 4  alkyl, eg methyl, ethyl n-propyl or n-butyl, substituted by a phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1,2,4-oxadiazolyl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidinyl or 2,6-dioxopiperidinyl, 5,5-dimethyl-2,4-dioxo-3-oxazolidinyl, hexahydro-1,3-dioxopyrazolo[1,2,a][1,2,4]-triazol-2-yl, or a naphththalimido (ie 1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl), 1,3-dihydro-1-oxo-2H-benz[f]isoindol-2-yl, 1,3-dihydro-1,3-dioxo-2H-pyrrolo[3,4-b]quinolin-2-yl, or 2,3-dihydro-1,3-dioxo-1H-benz[d,e]isoquinolin-2-yl group; or  
 cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydropyranyl or morpholinyl.  
 
     
     
         26 . A compound as claimed in  claim 23  wherein R 1  is hydrogen, cyclopropylmethyl, n-propyl, 3,3,3-trifluoropropyl, trifluoropropyl or allyl.  
     
     
         27 . A compound as claimed in any of  claims 23  to  26  wherein R 2  is: 
 C 1 -C 12  alkyl, C 3 -C 6  alkenyl or C 3 -C 6  alkynyl;  
 cycloalkyl(C 1 -C 6  alkyl)-;  
 phenyl(C 1 -C 6  alkyl)-, phenyl(C 3 -C 6  alkenyl)- or phenyl(C 3 C 6  alkynyl)- optionally substituted in the phenyl ring;  
 heteroaryl(C 1 -C 6  alkyl)-, heteroaryl(C 3 -C 6  alkenyl)- or heteroaryl(C 3 -C 6  alkynyl)- optionally substituted in the heteroaryl ring; or  
 4-phenylphenyl(C 1 -C 6  alkyl)-, 4-phenylphenyl(C 3 -C 6  alkenyl)-, 4-phenylphenyl(C 3 -C 6  alkynyl)-, 4-heteroarylphenyl(C 1 -C 6  alkyl)-, 4-heteroarylphenyl(C 3 -C 6  alkenyl)-, 4-heteroarylphenyl(C 3 -C 6  alkynyl)-, optionally substituted in the terminal phenyl or heteroaryl ring.  
 
     
     
         28 . A compound as claimed in any of  claims 23  to  26  wherein R 2  is methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-nonyl, n-decyl, benzyl, cyclopentylmethyl, cyclopropylmethyl, prop-2-yn-1-yl, 3-phenylprop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, benzyl phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, phenoxybutyl, 3-(4-pyridylphenyl)propyl-, 3-(4-(4-pyridyl)phenyl)prop-2-yn-1-yl, 3-(4-phenylphenyl)propyl-, 3-(4-phenyl)phenyl)prop-2-yn-1-yl or 3-[(4-chlorophenyl)phenyl]propyl-.  
     
     
         29 . A compound as claimed in any of  claims 23  to  26  wherein R 2  is benzyl, n-butyl, iso-butyl, n-hexyl, cyclopentylmethyl, cyclopropylmethyl, or 3-(2-chlorophenyl)prop-2-yn-1-yl.  
     
     
         30 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is C 1 -C 6  alkyl, phenyl, 2,-3-, or 4-pyridyl, 2- or 3-thienyl, 2,-3-, or 4-hydroxyphenyl, 2,-3-, or 4-methoxyphenyl, 2,-3-, or 4-pyridylmethyl, benzyl, 2,-3-, or 4-hydroxybenzyl, 2,-3-, or 4-benzyloxybenzyl, 2, -3-, or 4-C 1 -C 6  alkoxybenzyl, or benzyloxy(C 1 -C 6 alkyly)-.  
     
     
         31 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is the characterising group of a natural α-amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated.  
     
     
         32 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is a group -[Alk] n R 6  where Alk is a (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more —O—, or —S— atoms or —N(R 7 )— groups [where R 7  is a hydrogen atom or a (C 1 -C 6 )alkyl group], n is 0 or 1, and R 6  is an optionally substituted cycloalkyl or cycloalkenyl group.  
     
     
         33 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is a benzyl group substituted in the phenyl ring by a group of formula —OCH 2 COR 8  where R 8  is hydroxyl, amino, (C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, phenyl(C 1 -C 6 )alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid.  
     
     
         34 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is a heterocyclic(C 1 -C 6 )alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )alkanoyl, trifluoropropyl, (C 1 -C 6 )alkyl, hydroxy, formyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, mercapto, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 5 )alkyl or (C 1 -C 6 )alkylphenylmethyl.  
     
     
         35 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is a group —CR a R b R c  in which: 
 each of R a , R b  and R c  is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl; or  
 R c  is hydrogen and R a  and R b  are independently phenyl or heteroaryl such as pyridyl; or  
 R c  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, and R a  and R b  together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or  
 R a , R b  and R c  together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or  
 R a  and R b  are each independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or a group as defined for R c  below other than hydrogen, or R a  and R b  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R c  is hydrogen, —OH, —SH, halogen, —CN, —CO 2 H, (C 1 -C 4 )perfluoroalkyl, —CH 2 OH, —CO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 2 -C 6 )alkenyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 ) alkyl, —S(C 2 -C 6 )alkenyl, —SO(C 2 -C 6 )alkenyl, —SO 2 (C 2 -C 6 )alkenyl or a group -Q-W wherein Q represents a bond or —O—, —S—, —SO— or —SO 2 — and W represents a phenyl, phenylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylalkyl, (C 4 -C 8 )cycloalkenyl, (C 4 -C 8 )cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, —CN, —CO 2 H, —CO 2 (C 1 -C 6 )alkyl, —CONH 2 , —CONH(C 1 -C 6 )alkyl, —CONH(C 1 -C 6 alkyl) 2 , —CHO, —CH 2 OH, (C 1 -C 4 )perfluoroalkyl, —O(C 1 -C 6 )alkyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —O 2 (C 1 -C 6 )alkyl, —NO 2 , —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NHCO(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, phenyl or benzyl.  
 
     
     
         36 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is cyclopentylmethyl, cyclohexylmethyl, pyridin-3-ylmethyl, 2- or 3-thienyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, or 1-mercapto-1-methylethyl.  
     
     
         37 . A compound as claimed in any of  claims 23  to  29  wherein R 3  is phenyl, 3-, or 4-methoxyphenyl, benzyl, tert-butoxymethyl, iso-propyl or iso-butyl.  
     
     
         38 . A compound as claimed in any of  claims 23  to  37  wherein R 4  is a group of formula —(C═O)OR 9 , —(C═O)SR 9 , —(C═S)SR 9 , and —(C═S)OR 9  wherein R 9  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, cycloalkyl, cycloalkyl(C 1 -C 6 )alkyl-, phenyl, heterocyclyl, phenyl(C 1 -C 6 )alkyl-, heterocyclyl(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, any of which may be substituted on a ring or non-ring carbon atom or on a ring heteroatom, if present.  
     
     
         39 . A compound as claimed in any of  claims 23  to  37  wherein R 4  is a group of formula —(C═O)OR 9  wherein R 9  is methyl, ethyl, n-and iso-propyl, n-, sec- and tert-butyl, 1-ethyl-prop-1-yl, 1-methyl-prop-1-yl, 1-methyl-but-1-yl, cyclobutanyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, allyl, phenyl, benzyl, 2-, 3- and 4-pyridylmethyl, N-methylpiperidin-4-yl, 1-methylcyclopent-1-yl, adamantyl, tetrahydrofuran-3-yl, tetrahydropyranyl or methoxyethyl.  
     
     
         40 . A compound as claimed in any of  claims 23  to  37  wherein R 4  is a carboxylate ester of formula —(C═O)OR 9 , wherein R 9  is benzyl, cyclopentyl, or isopropyl.  
     
     
         41 . A compound as claimed in any of  claims 23  to  40  wherein R is hydrogen.  
     
     
         42 . A compound as claimed in  claim 23  or  claim 24  wherein wherein R 1  is hydrogen, cyclopropylmethyl, n-propyl, trifluoropropyl, 3,3,3-trifluoropropyl or allyl, R 2  is benzyl, n-butyl, iso-butyl, n-hexyl, cyclopentylmethyl, cyclopropylmethyl, or 3-(2-chlorophenyl)prop-2-yn-1-yl, R 3  is phenyl, 3-, or 4-methoxyphenyl, benzyl, tert-butoxymethyl, iso-propyl or iso-butyl, R 4  is a group of formula —(C═O)OR 9  wherein R 9  is benzyl, cyclopentyl, or isopropyl and R is hydrogen.  
     
     
         43 . A compound as claimed in  claim 23  selected from the group consisting of 
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-3,3-dimethyl butyric acid cyclopentyl ester,  
 S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-2-phenyl acetic acid methyl ester,  
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-3-phenylpropionic acid tert-butyl ester,  
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-2-phenyl acetic acid ethyl ester,  
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-3,3-dimethyl butyric acid cyclobutyl ester,  
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-3,3-dimethyl butyric acid cyclohexyl ester,  
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-3,3-dimethyl butyric acid cyclopentylmethyl ester,  
 2S-[2-(R,S)-Benzyl-34-formyl-hydroxy-amino)-propionylamino]-3-phenyl-propionic acid cyclopentyl ester,  
 2S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-3,3-dimethyl butyric acid isopropyl ester,  
 S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-2-phenyl acetic acid iso propyl ester,  
 S-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoylamino}-2-phenyl acetic acid cyclopentyl ester,  
 2S-[2R-Benzyl-3S-(formyl-hydroxy-amino)-hexanoylamino]-3-tert-butoxypropionic acid cyclopentyl ester,  
 S-[3S-(Formyl-hydroxy-amino)-2R-isobutyl-hexanoylamino]-phenyl-acetic acid cyclopentyl ester  
 and pharmaceutically acceptable salts, hydrates and solvates thereof.  
 
     
     
         44 . A pharmaceutical composition for inhibiting proliferation of tumour cells in mammals, comprising a compound as claimed in any of  claims 23  to  43  together with a pharmaceutically acceptable carrier.