Antibacterial substituted 7-acylamino-3-(methylhydrazono) methyl-cephalosporins and intermediates

Abstract

A compound of formula wherein W, V, R 1 , R 5 , R 2 , R 3 and R 4 have various meanings, a process for their production and their use as a pharmaceutical.

1 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  denotes hydrogen, acyl, carboxyl, or alkyl;  
 R 2  and R 3  are the same or different and independently of each other denote hydrogen, cycloalkyl, alkyl, alkenyl or alkinyl;  
 R 4  denotes hydrogen or a group of formula  
                     wherein R 6  denotes amino, hydrazino aminoalkylamino, alkoxy, aryl, cycloalkyl, aryloxy, heterocyclyl, alkyl, alkenyl, alkinyl;    Z denotes O, S or NR 7 , wherein R 7  is as defined as R 2 ;    
 R 5  denotes hydrogen or an ester moiety; W denotes CH or N;  
 V denotes CH or N—O;  
 with the proviso that not all of R 2 , R 3  and R 4  denote hydrogen; and  
 if R 4  denotes hydrogen, R 1  is other than h or CH 3 .  
 
     
     
         2 . A compound of formula  
       
         
           
           
               
               
           
         
         wherein W and R 5  are as defined in  claim 1 ,  
         R′ 1  denotes hydrogen or alkyl,  
         R′ 2  and R′ 3  are the same or different and independently of each other denote hydrogen; alkenyl, or alkyl, and  
         R′ 4  denotes hydrogen or a group of formula  
         
           
             
             
                 
                 
             
           
         
         wherein  
         Z′ denotes O or NR′ 7 , wherein R′ 7  denotes hydrogen or alkyl; and  
         R′ 6  denotes amino; aminoalkylamino; hydrazino; alkoxy; unsubstituted aryl or substituted aryl; cycloalkyl; a 5 to 6 membered, heterocycle containing 1 to 3 nitrogen and/or sulphur- and/or oxygen atoms; unsubstituted alkyl, or substituted alkyl, e.g. one or several-fold; by unsubstituted aryl, or substituted aryl by hydroxy, alkoxy, phenoxy; aryloxy; amino; hydroxy; carboxy; guanidino or nitroguanidino; or a heterocyclyl-carboximino group with the proviso that not all of R′ 2 , R′ 3  and R′ 4  denote hydrogen.  
       
     
     
         3 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 5  is as claimed in  claim 1;   
 R 2s  and R 3s  independently of each other denote alkyl, aralkyl, alkenyl, or alkinyl; and R 3s  additionally denotes hydrogen.  
 
     
     
         4 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein R 5  is as defined in  claim 1 .  
     
     
         5 . A compound of formula  
       
         
           
           
               
               
           
         
         wherein R 1 , R 5 , W and V are as defined in  claim 1 ,  
         R 2p  and R 3p  are the same or different and independently of each other denote hydrogen, cycloalkyl, or alkyl substituted by halogen or hydroxy,  
         R 6p  denotes amino, unsubstituted or substituted alkylamino or dialkylamino, alkoxy, aryl, cycloalkyl, aryloxy, an unsubstituted 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms, a substituted 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms by amino, hydroxy, alkoxy, acyloxy, carboxy or mercapto, cycloalkyl or unsubstituted straight chain or branched (C 1-20 )alkyl, (C 1-20 )alkenyl or (C 1-20 )alkinyl, which may be interrupted by N, S and/or O; once or several times substituted straight chain or branched (C 1-20 )alkyl, (C 1-20 )alkenyl or (C 1-20 )alkinyl which may be interrupted by N, S and/or O, by hydroxy, alkoxy, aryloxy, acyloxy, carbamoyloxy, amino, alkylamino, dialkylamino, trialkylammonium, acylamino, ureido, oximino, imino, carboxy, oxo, halogen, nitro, a carboxylic acid derivative, a sulphonic acid derivative, an unsubstituted 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms; or a substituted 5- or 6-membered, saturated, partially saturated or unsaturated heterocycle which may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms by amino, hydroxy, alkoxy, acyloxy, carboxy or mercapto; and Z p  denotes oxygen or NR 7p , wherein R 7p  is as defined R 2p .  
       
     
     
         6 . A compound of formula  
       
         
           
           
               
               
           
         
         wherein W and R 5  are as defined in  claim 1 ,  
         R 1p  denotes hydrogen or CH 2 F, and  
         R′ 6p  denotes hydrogen, (C 1-20 )alkyl, one or two fold substituted (C 1-20 )alkyl by phenyl, phenoxy, amino, hydroxyphenyl, hydroxy, carboxyl, guanidino or nitroguanidino, unsubstituted phenyl or substituted phenyl by acetoxy, pyrrolidinyl; or a compound of formula  
         
           
             
             
                 
                 
             
           
         
       
     
     
         7 . A compound of any preceding claim in the form of a salt and/or in the form of a solvate.  
     
     
         8 . 7-(((5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl)amino)-3(E)-((imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylic acid in the form of a hydrochloride.  
     
     
         9 . 7-(((5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl)amino)-3(E)-((imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylic acid in the form of a trihydrochloride.  
     
     
         10 . A compound selected from 
 1-[(1-Methylhydrazino)iminomethyl]piperazine    1-[(1-Ethylhydrazino)iminomethyl]piperazine    1-[(1-Allylhydrazino)iminomethyl]piperazine    1-[(1-(4-Methoxybenzyl)hydrazino]iminomethyl]piperazine    1-[(1-(3,4,5-Trimethoxybenzyl)hydrazino]iminomethyl]piperazine    1-[(1-Methylhydrazino)(methylimino)methyl]piperazine    1-[(1-Methylhydrazino)(ethylimino)methyl]piperazine    Glycin-(4-hydrazinoiminomethyl)piperazide    1-(R)-(Amino(4-hydroxyphenyl)acetyl)4-(hydrazinoiminomethyl)piperazine    1,4-bis-(Hydrazinoiminomethyl)piperazine, or    1-(Hydrazinoiminomethyl)4-[ethylimino) [3-dimethylaminopropyl)amino]methyl]-piperazine.    
     
     
         11 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein R 5  is as defined in  claim 1 , and R Int  denotes a group  
       
         
           
           
               
               
           
         
       
       which is formed by a bond of the terminal amine group of the hydrazino group of a compound of  claim 10  and wherein the —N— group is substituted according to a compound of  claim 10 .  
     
     
         12 . A process for the production of a compound of formula I, as defined in  claim 1   a) Reacting a compound of formula                        wherein W, V and R 1  are as defined in  claim 1  and wherein 
 α) R b  denotes hydroxy and R c  and R d  together denote a bond, or  
 β) R d  denotes hydrogen, a cation, an ester moiety or a silyl group and R b  and R c  denote the oxo group  
   with a compound of formula                          wherein R 2 , R 3  and R 4  are as defined in  claim 1 ,      b) for the production of a compound of formula                        wherein W, V, Z, R 1 , R 2 , R 3 , R 5  and R 6  are as defined in  claim 1 , acylating a compound of formula                          wherein Z, R 2 , R 3 , R 5  and R 6  are as defined in  claim 1 , with a compound of formula                          wherein V, W and R 1  are as defined above and X denotes a leaving group; or reacting a compound of formula                          wherein R 1 , R 2 , R 3 , R 5 , V and W are as defined in  claim 1 , with a compound of formula                          wherein R 6  and Z are as defined in  claim 1  and X denotes a leaving group.      
     
     
         13 . A pharmaceutical composition comprising a compound of formula I according to  claim 1  in the form of a pharmaceutically acceptable salt or in free form in association with at least one pharmaceutical carrier or diluent.  
     
     
         14 . A compound of  claim 1  or a composition of  claim 13  for use as a pharmaceutical.  
     
     
         15 . A method of treatment of microbial diseases which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.