Hydroxamic acids substituted by heterocycles useful for inhibition of tumor necrosis factor

Abstract

Compounds of formula (I), wherein: n is 1 to 6; Het is a nitrogen containing ring fused to the benzene ring on two adjacent carbon atoms to form a bicyclic ring system which ring system may be optionally substituted; R 1 is hydrogen, C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, heterocyclylC 1-6 alkyl or C 3-8 cycloalkylC 1-6 alkyl; R 2 is C 1-6 alkyl, C 2-6 alkenyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl or the side-chain of a naturally occurring amino acid; R 3 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl or heterocyclylC 1-6 alkyl; R 4 is hydrogen or C 1-6 alkyl; or R 3 and R 4 together with the nitrogen atom to which they are joined form a heterocyclic ring; wherein any group or ring, in R 1 -R 4 , is optionally substituted; and pharmceutically acceptable salts and in vivo hydrolysable esters thereof, are described as inhibitors of the production of Tumour Necrosis Factor and/or one or more matrix metalloproteinase enzymes. Compositions containing them and their preparation are also described.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
         wherein: 
 n is 1 to 6;  
 Het is a nitrogen containing ring fused to the benzene ring on two adjacent carbon atoms to form a bicyclic ring system which ring system may be optionally substituted;  
 R 1  is hydrogen, C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, heterocyclylC 1-6 alkyl or C 3-8 cycloalkylC 1-6 alkyl;  
 R 2  is C 1-6 alkyl, C 2-6 alkenyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl or the side-chain of a naturally occurring amino acid;  
 R 3  is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl or heterocyclylC 1-6 alkyl;  
 R 4  is hydrogen or C 1-4 alkyl; or R 3  and R 4  together with the nitrogen atom to which they are joined form a heterocyclic ring;  
 wherein any group or ring, in R 1 -R 4 , is optionally substituted; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.  
 
       
     
     
         2 . A compound according to  claim 1  wherein Het is a 5- or 6-membered ring containing one or two ring nitrogen atoms.  
     
     
         3 . A compound according to  claim 1  wherein Het and the benzene ring to which it is fused forms a quinoline, isoquinoline, quinazoline, 1-methyl-2-oxo-1,2-dihydroquinoline, 2-methyl-4-hydroxyquinazoline or 2-methyl-4-hydroxy-7-bromoquinazoline bicyclic ring system.  
     
     
         4 . A compound according to  claim 1  wherein Het and the benzene ring to which it is fused forms a benzoxazole or 2-methylbenzothiazole bicyclic ring system.  
     
     
         5 . A compound of the formula (II):  
       
         
           
           
               
               
           
         
         wherein n is 1; Het is of the sub-formula (ii) or (iii):  
         
           
             
             
                 
                 
             
           
         
         wherein either of such rings is unsubstituted or substituted by one or two groups selected from halogen for example chloro, bromo or fluoro, C 1-6 alkyl for example methyl, isopropyl or tert-butyl, C 1-6 alkoxy for example methoxy, hydroxy, amino, C 1-6 alkylamino for example methylamino or di-C 1-6 alkylamino for example dimethylamino; R 1  is isobutyl; R 2  is isobutyl, tert-butyl or benzyl; R 3  is methyl, ethyl, n-propyl, isobutyl, tert-butyl, 2-dimethylaminoethyl or benzyl; and R 4  is hydrogen or methyl.  
       
     
     
         6 . A compound according to  claim 1  which is: 
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′-oxo-1′,2′-dihydroquinolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(quinolin-8′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(2′-methyl-4′-oxo-3′,4′-dihydroquinazolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(7′-bromo-2′-methyl-4′-oxo-3′,4′-dihydroquinazolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′-oxo-1′,2′-dihydroquinolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -dimethylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′-oxo-1′,2′-dihydroquinolin6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -(2-dimethylaminoethyl)amide;  
 N 2 -[4-(N-hydroxyamino)-2R-(4′-benzyloxy)butyl-3S-(1′-methyl-2′-oxo-1′,2′-dihydroquinolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(quinolin-8′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -dimethylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(quinolin-8′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -(2-dimethylaminoethyl)amide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(4′-oxo-3′,4′-dihydroquinazolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-(4′-benzyloxy)butyl-3S(quinolin-8′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-(3′-benzyloxy)propyl-3S-(2′-methyl-4′-oxo-3′,4′-dihydroquinazolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′-oxo-1′,2′-dihydroquinolin-7′-yl)methoxysuccinyl]L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(quinoxalin-5′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′-oxo-1′,2′-dihydroquinolin-5′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′,3′-dioxoindolin-5′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(1′-methyl-2′-oxo-1′,2′,3′,4′-tetrahydroquinolin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(quinoxalin-6′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(2,3-dihydro-4-methyl-3-oxo-1,4-benzoxazin-7-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(2′-oxo-1′,2′-dihydroquinolin-5′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(benzoxazol-5′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide;  
 N 2 -[4-(N-hydroxyamino)-2R-isobutyl-3S-(2′-methylbenzothiazol-5′-yl)methoxysuccinyl]-L-tert-leucine-N 1 -methylamide; or a pharmaceutically acceptable salt.  
 
     
     
         7 . A pharmaceutical composition which comprises a compound according to any one of  claims 1  to  6  and a pharmaceutically acceptable carrier.  
     
     
         8 . The use of a compound according to any one of  claims 1  to  6  for the manufacture of a medicament for treating disease conditions mediated by TNF.  
     
     
         9 . A process for preparing a compound according to any one of  claims 1  to  6  or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises 
 a) reacting a compound of the formula (III):  
                     
 wherein n, Het and R 1 -R 4  are as defined in  claim 1 , or an activated derivative thereof with hydroxylamine, O-protected hydroxylamine or a salt thereof; or  
 b) coupling a compound of the formula (IV) with a compound of the formula (V):  
                     
 wherein n, Het and R 1 -R 4  are as defined in  claim 1 , under standard peptide coupling conditions; or  
 c) reacting a compound of the formula (VI) with compound of the formula (Vll):  
                     
 wherein n, Het and R-R 4  are as defined in claim  1 :  
 wherein any functional group is protected, if necessary, and: 
 removing any protecting groups;  
 ii. optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.  
 
 
     
     
         10 . A compound of the formula (III) as defined in claim  9 .