N-formyl hydroxylamine derivatives as inhibitors of bacterial polypeptide formylase for treating microbial infections

Abstract

Compounds of formula (I) are antibacterial or antiprotozoal agents for treatment of infections in humans and non-human mammals, wherein: Z represents a radical of formula —N(OH)CH(═O) or formula C(═O)NH(OH); R 1 represents hydrogen, methyl or trifluoromethyl, or except when Z is a radical of formula —N(OH)CH(═O), a hydroxy, halo or amino group; R 2 represents a group R 10 —(X) n -(ALK) m — wherein R 10 , ALK, X, m and n are as defined in the specification; R 3 represents hydrogen, (C 1 -C 6 ) alkyl or phenyl(C 1 -C 6 )alkyl-; and R 5 and R 6 are as defined in the specification.

1 - 16 . (canceled) 
   
   
       17 . A method for the treatment of bacterial or protozoal infections in humans and non-human mammals, which comprises administering to a subject suffering such infection an antibacterially or antiprotozoally effective dose of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof: 
     
       
         
         
             
             
         
       
       wherein: 
       Z represents a radical of formula —N(OH)CH(═O) or formula —C(═O)NH(OH); 
       R 1  represents hydrogen, methyl or trifluoromethyl, or, except when Z is a radical of formula —N(OH)CH(═O), a hydroxy, halo or amino group; 
       R 2  represents a group R 10 —(X) n -(ALK) m — wherein
 R 10  represents hydrogen, or a C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, mercapto, (C 1 -C 6 )alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH 2 , —COOR A , —NHCOR A , —CONHR A , —NHR A , —NR A R B , or —CONR A R B  wherein R A  and R B  are independently a (C 1 -C 6 )alkyl group and 
 ALK represents a straight or branched divalent C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene radical, and may be interrupted by one or more non-adjacent —NH—, —O— or —S— linkages, 
 X represents —NH—, —O— or —S—, and m and n are independently 0 or 1; 
 R 3  represents the characterizing 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; or 
 a group [Alk] n R 9  where Alk is a (C 1 -C 6 )alkylene or (C 2 -C 6 )alkenylene group optionally interrupted by one or more —O—, or —S—, atoms or —N(R 12 )— groups, where R 12  is a hydrogen atom or a (C 1 -C 6 )alkyl group, n is 0 or 1, and R 9  is hydrogen or an optionally substituted phenyl, aryl, heterocyclyl, cycloalkyl or cycloalkenyl group or (only when n is 1) R 9  may additionally be hydroxy, mercapto, (C 1 -C 6 )alkylthio, amino, halo, trifluoromethyl, nitro, —COOH, —CONH 2 , —COOR A , —NHCOR A , —CONHR A , —NHR A , —NR A R B , or —CONR A R B  wherein R A  and R B  are independently a (C 1 -C 6 )alkyl group; or 
 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; or 
 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; or 
 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, —SO(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; and 
       R 4  represents hydrogen, (C 1 -C 6 )alkyl or phenyl(C 1 -C 6 )alkyl-; and 
       (a) R 5  and R 6  independently represent:
 hydrogen, halogen, trifluoromethyl, or 
 (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heterocyclyl, aryl(C 1 -C 6 )alkyl-, or heterocyclyl(C 1 -C 6 )alkyl-, any of which may be optionally substituted by
 (C 1 -C 6 )alkyl, halogen, trifluoromethyl, cyano, nitro, oxo, 
 phenoxy or phenylthio-, 
 —OR A , —SR A , —NHR A , —NR A R B , —NHCOR A —CONHR A , —CONR A R B , or —COOR A , wherein
 R A  and R B  are independently hydrogen or (C 1 -C 4 )alkyl, 
 or in the case where R A  and R B  are attached to a nitrogen atom then R A  and R B  taken together with the nitrogen atom to which they are attached form a monocyclic 5-7 membered ring; or 
 
 
 
       (b) R 5  and R 6  taken together with the carbon atoms to which they are attached form a fused monocyclic or bicyclic carbocyclic or heterocyclic ring which may be further substituted with any of the substituent groups listed under (a). 
     
   
   
       18 . A method as claimed in  claim 17  wherein R 2  is:
 optionally substituted C 1 -C 8  alkyl, C 3 -C 6  alkenyl, C 3 -C 6  alkynyl or cycloalkyl;   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;   cycloalkyl(C 1 -C 6  alkyl)-, cycloalkyl(C 3 -C 6  alkenyl)- or cycloalkyl(C 3 -C 6  alkynyl)-optionally substituted in the cycloalkyl ring;   heterocyclyl(C 1 -C 6  alkyl)-, heterocyclyl(C 3 -C 6  alkenyl)- or heterocyclyl(C 3 -C 6  alkynyl)-optionally substituted in the heterocyclyl ring; or   CH 3 (CH 2 ) p —O—(CH 2 ) q — or CH 3 (CH 2 ) p S(CH 2 ) q —, wherein p is 0, 1, 2 or 3 and q is 1, 2 or 3.   
   
   
       19 . A method as claimed in  claim 17  wherein R 2  is methyl, ethyl, n- or iso-propyl, n- and iso-butyl, n-pentyl, iso-pentyl, 3-methyl-but-1-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl, methylsulfanylethyl, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxymethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl, prop-2-yn-1-yl, 3-phenylprop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, but-2-yn-1-yl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-ylmethyl, furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, or 4-methoxybenzyl. 
   
   
       20 . A method as claimed in  claim 17  wherein R 2  is n-propyl, n-butyl, n-pentyl, or cyclopentylmethyl. 
   
   
       21 . (canceled) 
   
   
       22 . A method as claimed in  claim 17  wherein R 3  is methyl, ethyl, benzyl, 4-chlorobenzyl, 4-hydroxybenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridin-3-ylmethyl, tert-butoxymethyl, naphthylmethyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro-1-methylethyl, hydroxymethyl, 2-hydroxethyl, 2-carboxyethyl, 2-methylcarbamoylethyl, 2-carbamoylethyl, or 4-aminobutyl. 
   
   
       23 . A method as claimed in  claim 17  wherein R 3  is tert-butyl. 
   
   
       24 . A method as claimed in  claim 17  wherein R 4  is hydrogen or methyl. 
   
   
       25 . A method as claimed in  claim 17  wherein R 5  and R 6  are independently hydrogen, methyl, trifluoromethyl, phenyl, bromo, chloro, fluoro, methoxy, hydroxymethyl, dimethylaminomethyl-, ethoxymethyl-, 4-methyl-piperazine-1-carbonyl-, 4-methyl-piperazin-1-ylmethyl-, morpholin-4-ylmethyl-, methoxycarbonyl, thiazol-2-yl-, phenoxymethyl-, pyrrolidin-1-ylmethyl-, piperidin-1-ylmethyl-, —C(O)NH 2 , (CH 2 ) 2 CO 2 CH 3 , —CH(OH)CH(CH 3 ) 2 , —CH(OH)CH 3 , or —CH(OH)Ph; or wherein R 5  and R 6  taken together with the carbon atoms to which they are attached form a fused benzo, naphtho or pyrido ring, which may be substituted. 
   
   
       26 . A method as claimed in  claim 25  wherein R 1  is hydrogen, R 2  is n-propyl, n-butyl, n-pentyl, or cyclopentylmethyl, R 3  is tert-butyl, and R 4  is hydrogen or methyl.