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 - 15 . (canceled)  
   
   
       16 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen, acyl, carboxyl, or alkyl;  
 R 2  and R 3  are the same or different and independently of each other are hydrogen, cycloalkyl, alkyl, alkenyl, or alkinyl;  
 R 4  is hydrogen or a group of the formula  
                     wherein R 6  is amino, hydrazino, aminoalkylamino, alkoxy, aryl, cycloalkyl, aryloxy, heterocyclyl, allyl, alkenyl, or alkinyl; and    Z is O, S, or NR 7 , wherein R 7  is as defined as R 2 ;    
 R 5  is hydrogen or an eater moiety;  
 W is CH or N; and  
 V is CH or N—O;  
 with the proviso that not all of R 2 , R 3 , and R 4  denote hydrogen and that if R 4  denotes hydrogen, then R 1  other than hydrogen or CH 3 ; and  
 with the further proviso that compounds of formula I wherein 
 a) V is N—O, W is CH, R 1  is CH 3 , R 2  is H, R 3  is CH 3 , and R 4  is H;  
 b) V is N—O, W is CH, R 1  is CH 3 , R 2  is H, R 3  is H, and R 4  is H;  
 c) V is N—O, W is CH, R 1  is CH 3 , R 2  is CH 3 , R 3  is H, and R 4  is H;  
 d) V is N—O, W is CH, R 1  is H, R 2  is H, R 3  is H, and R 4  is H;  
 e) V is N—O, W is CH, R 1  is H, R 2  is CH 3 , R 3  is H, and R 4  is H; and  
 f) V is N—O, W is N, R 1  is CH 2 F, R 2  is H, R 3  is H, and R 4  is H; are excluded.  
 
 
   
   
       17 . A compound of  claim 16  of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 R′ 1  is hydrogen or alkyl;  
 R′ 2  and R′ 3  are the same or different and independently of each other are hydrogen, alkenyl, or alkyl; and  
 R′ 4  is hydrogen or a group of the formula  
                     
 wherein  
 Z′ is O or NR′ 7 , wherein R′ 7  is hydrogen or alkyl; and  
 R′ 6  is 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; alkyl, one or several-fold substituted by unsubstituted aryl, or by aryl which is in turn substituted by hydroxy, alkoxy, phenoxy, aryloxy, amino, hydroxyl, 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 and that if R′ 4  denotes hydrogen, then R′ 1  is other than hydrogen or CH 3 ; and  
 with the further proviso that compounds of formula Ia wherein 
 a) W is CH, R′ 1  is CH 3 , R′ 2  is H, R′ 3  is CH 3 , and R′ 4  is H;  
 b) W is CH, R′ 1  is CH 3 , R′ 2  is H, R′ 3  is H, and R′ 4  is H;  
 c) W is CH, R′ 1  is CH 3 , R′ 2  is CH 3 , R′ 3  is H, and R′ 4  is H;  
 d) W is CH, R′ 1  is H, R′ 2  is H, R′ 3  is H, and R′ 4  is H;  
 e) W is CH, R′ 1  is H, R′ 2  is CH 3 , R′ 3  is H, and R′ 4  is H; and  
 f) W is N, R′ 1  is CH 2 F, R′ 2  is H, R′ 3  is H, and R′ 4  is H; are excluded.  
 
 
   
   
       18 . A compound of  claim 16  of the formula  
     
       
         
         
             
             
         
       
     
   
   
       19 . A compound of  claim 16  of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 R 2p  and R 3p  are the same or different and independently of each other are hydrogen, cycloalkyl, or alkyl substituted by halogen or hydroxyl;  
 R 6p  is amino; unsubstituted or substituted alkylamino or dialkylamino; alkoxy; aryl; cycloalkyl; aryloxy; and 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 substituted by amino, hydroxy, alkoxy, acyloxy carboxy or mercapto; unsubstituted straight chain or branched (C 1-20 )alkyl, (C 2-20 )alkenyl or (C 2-20 )alkinyl, wherein said (C 1-20 )alkyl may be interrupted by S and/or O and said C 2-20 )alkenyl or (C 2-20 )alkinyl be interrupted by N, S, and/or O; once or several times substituted straight chain or branched (C 1-20 )alkyl, (C 2-20 )alkenyl or (C 2-20 )alkinyl, wherein said (C 1-20 )alkyl may be interrupted by S and/or O and said (C 2-20 )alkenyl or (C 2-20 )alkinyl be interrupted by N, S, and/or O, and which is substituted by hydroxy, by, by alkoxy, by aryloxy, by acyloxy, by carbamoyloxy, by amino, by alkylamino, by dialkylamino, by trialkylammonium cation, by acylamino, by ureido, by oximino, by imino, by carboxy, by oxo, by halogen, by nitro, by a carboxylic acid derivative, by a sulphonic acid derivative, by 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 by 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 which is substituted by amino, hydroxy, alkoxy, acyloxy, carboxy, or mercapto; and  
 Z p  is oxygen or NR 7p , wherein R 7p  is as defined for R 2p .  
 
   
   
       20 . A compound of  claim 16  of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1p  is hydrogen or CH 2 F; and  
 R′ 6p  is (C 1-20 )alkyl, (C 1-20 )alkyl one or two fold substituted by phenyl, phenoxy, amino, hydroxyphenyl, hydroxy, carboxyl, guanidino or nitroguanidino, unsubstituted phenyl or phenyl substituted by acetoxy, or pyrrolidinyl; or a moiety of the formula  
                     
 
   
   
       21 . A compound of  claim 16  in the form of a salt and/or in the form of a solvate.  
   
   
       22 . 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; and    1-(hydrazinoiminomethyl)-4-[ethylimino)[3-dimethylaminopropyl)amino]methyl]-piperazine.    
   
   
       23 . (canceled)  
   
   
       24 . A process for the production of a compound of  claim 16 , which comprises 
 a) reacting a compound of the formula                          wherein 
 α) R b  is hydroxy and R c  and R d  together are a bond, or  
 β) R d  is hydrogen, a cation, an ester moiety, or a silyl group and R b  and R c  together are oxo with a compound of the formula  
                     
   
   
   
       25 . (canceled)  
   
   
       26 . A pharmaceutical composition comprising a compound of  claim 16  in the form of a pharmaceutically acceptable salt or in free form in association with at least one pharmaceutical carrier or diluent.  
   
   
       27 . A method of treating microbial diseases which comprises administering to a subject in need of such treatment an effective amount of a compound of  claim 16 .  
   
   
       28 . A process for the production of a compound of  claim 16  of the formula  
     
       
         
         
             
             
         
       
     
     which comprises: 
 a) acylating a compound of the formula  
                     
 with a compound of the formula  
                     
 wherein X is a leaving group; or  
 b) reacting a compound of the formula  
                     
 with a compound of the formula  
                     
 wherein X is a leaving group.  
 
   
   
       29 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 R 5  is hydrogen or an ester moiety and R int  is a group of the formula  
                     
 which is formed by a bond of the terminal amine group of the hydrazino group of a compound of  claim 22  and wherein the —N— group is substituted according to a compound of  claim 22.