Cephem compounds

Abstract

The present invention relates to a compound of the formula [I]: wherein R<SUP>1 </SUP>is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and R<SUP>2 </SUP>is hydrogen or amino protecting group, or R<SUP>1 </SUP>and R<SUP>2 </SUP>are bonded together and form lower alkylene or lower alkenylene; R<SUP>3 </SUP>is hydrogen or lower alkyl; R<SUP>4 </SUP>is R<SUP>5 </SUP>is carboxy or protected carboxy; and R<SUP>6 </SUP>is amino or protected amino, or a pharmaceutically acceptable salt thereof, a process for preparing a compound of the formula [I], and a pharmaceutical composition comprising a compound of the formula [I] in admixture with a pharmaceutically acceptable carrier.

1 . A compound of the formula [I]:  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is lower alkyl, hydroxy (lower) alkyl or halo (lower) alkyl, and  
         R 2  is hydrogen or amino protecting group, or  
         R 1  and R 2  are bonded together and form lower alkylene or lower alkenylene;  
         R 3  is hydrogen or lower alkyl;  
         R 4  is  
         
           
             
             
                 
                 
             
           
           wherein  
           A is  
           
             
               
               
                   
                   
               
             
             wherein X is O or NH,  
           
           R 7  is hydrogen, lower alkyl or amino protecting group,  
           R 8  is hydrogen or hydroxy,  
           R 9  is amino, mono or di (lower) alkylamino, protected amino, guanidino, protected guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or protected amino,  
           k, m, n and q are independently 0 or 1, and  
           p is 0, 1, 2 or 3;  
         
         R 5  is carboxy or protected carboxy; and  
         R 6  is amino or protected amino, or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The compound of  claim 1  wherein 
 R 1  is lower alkyl or hydroxy(lower)alkyl, and    R 2  is hydrogen or amino protecting group, or    R 1  and R 2  are bonded together and form lower alkylene;    R 3  is hydrogen;    A is                        wherein X is O or NH;      R 7  is hydrogen or amino protecting group;    R 9  is amino or protected amino; and    p is 0, 1 or 2,    or a pharmaceutically acceptable salt thereof.    
     
     
         3 . The compound of  claim 2  wherein R 8  is hydrogen, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The compound of  claim 1  wherein 
 R 1  is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and    R 2  is hydrogen, aryl(lower)alkyl or acyl, or    R 1  and R 2  are bonded together and form lower alkylene or lower alkenylene;    R 5  is carboxy or esterified carboxy;    R 6  is amino or acylamino;    R 7  is hydrogen, lower alkyl or acyl; and    R 9  is amino, mono or di(lower)alkylamino, acylamino, guanidino, acylguanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or acylamino,    or a pharmaceutically acceptable salt thereof.    
     
     
         5 . The compound of  claim 4  wherein 
 R 1  is lower alkyl or hydroxy(lower)alkyl, and    R 2  is hydrogen, aryl(lower)alkyl or acyl, or    R 1  and R 2  are bonded together and form lower alkylene;    R 5  is carboxy or esterified carboxy;    R 6  is amino or acylamino;    R 7  is hydrogen or acyl; and    R 9  is amino or acylamino,    or a pharmaceutically acceptable salt thereof.    
     
     
         6 . The compound of  claim 5  wherein 
 R 1  is lower alkyl or hydroxy(lower)alkyl, and    R 2  is hydrogen, aryl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, or    R 1  and R 2  are bonded together and form lower alkylene;    R 5  is carboxy or lower alkoxycarbonyl;    R 6  is amino, lower alkanoylamino or lower alkoxycarbonylamino;    R 7  is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and    R 9  is amino, lower alkanoylamino or lower alkoxycarbonylamino,    or a pharmaceutically acceptable salt thereof.    
     
     
         7 . The compound of  claim 6  wherein 
 R 1  is lower alkyl or hydroxy(lower)alkyl, and    R 2  is hydrogen, or    R 1  and R 2  are bonded together and form lower alkylene;    R 5  is carboxy;    R 6  is amino;    R 7  is hydrogen or lower alkanoyl; and    R 9  is amino,    or a pharmaceutically acceptable salt thereof.    
     
     
         8 . The compound of  claim 1  wherein 
 R 4  is selected from the group consisting of                          wherein R 7 , A, m, p and q are each as defined in  claim 1 ,    R 14  is amino, mono or di(lower)alkylamino or protected amino,    R 15  is guanidino or protected guanidino, and    R 16  is saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or protected amino,    or a pharmaceutically acceptable salt thereof.    
     
     
         9 . The compound of  claim 1  wherein 
 R 4  is selected from the group consisting of                          wherein    p is 0, 1 or 2,    q is 0 or 1,    R 7  is hydrogen or amino protecting group, and    R 9  is amino or protected amino,    or a pharmaceutically acceptable salt thereof.    
     
     
         10 . The compound of  claim 9  wherein 
 R 7  is hydrogen, lower alkanoyl or lower alkoxycarbonyl; and    R 9  is amino, lower alkanoylamino or lower alkoxycarbonylamino,    or a pharmaceutically acceptable salt thereof.    
     
     
         11 . The compound of  claim 10  wherein 
 R 7  is hydrogen or lower alkanoyl; and    R 9  is amino,    or a pharmaceutically acceptable salt thereof.    
     
     
         12 . A process for preparing a compound of the formula [I]:  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is lower alkyl, hydroxy(lower)alkyl or halo(lower)alkyl, and  
         R 2  is hydrogen or amino protecting group, or  
         R 1  and R 2  are bonded together and form lower alkylene or lower alkenylene;  
         R 3  is hydrogen or lower alkyl;  
         R 4  is  
         
           
             
             
                 
                 
             
           
           wherein  
           A is  
           
             
               
               
                   
                   
               
             
             wherein X is O or NH,  
           
           R 7  is hydrogen, lower alkyl or amino protecting group,  
           R 8  is hydrogen or hydroxy,  
           R 9  is amino, mono or di(lower)alkylamino, protected amino, guanidino, protected guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms optionally substituted by amino or protected amino,  
           k, m, n and q are independently 0 or 1, and  
           p is 0, 1, 2 or 3;  
         
         R 5  is carboxy or protected carboxy; and  
         R 6  is amino or protected amino,  
         or a salt thereof, which comprises 
 (1), reacting a compound of the formula [II]:  
                     
 
         wherein R 1 , R 2 , R 3  and R 4  are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula [III]:  
         
           
             
             
                 
                 
             
           
         
         wherein R 5  and R 6  are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the formula [I]:  
         
           
             
             
                 
                 
             
           
         
         wherein R 1  , R 2 , R 3 , R 4 , R 5  and R 6  are each as defined above, or a salt thereof, or 
 (2) subjecting a compound of the formula [Ia]:  
                     
 
         wherein R 1  , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , A, k, m, n, p and q are each as defined above, and R 9 a is protected amino, protected guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by protected amino, or a salt thereof to elimination reaction of the amino protecting group to give a compound of the formula [Ib]:  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , A, k, m, n, p and q are each as defined above, and R 9 b is amino, guanidino or saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms substituted by amino, or a salt thereof, or 
 (3) reacting a compound of the formula [VI]:  
                     
 
         wherein R 5  and R 6  are each as defined above, R 10 , is protected carboxy, and Y is a leaving group, or a salt thereof with a compound of the formula [VII]:  
         
           
             
             
                 
                 
             
           
         
         wherein R 1  , R 2 , R 3  and R 4  are each as defined above, or a salt thereof to give a compound of the formula [VIII]:  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 10  are each as defined above, and Z {circle around (−)}  is an anion, or a salt thereof, and subjecting the compound of the formula [VIII] or a salt thereof to elimination reaction of the carboxy protecting group, to give a compound of the formula [I]:  
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each as defined above, or a salt thereof.  
       
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.  
     
     
         14 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof for use as a medicament.  
     
     
         15 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof for use as an antimicrobial agent.  
     
     
         16 . Use of a compound of  claim 1  or a pharmaceutically acceptable salt thereof for manufacture of a medicament for treating infectious diseases.  
     
     
         17 . A method for the treatment of infectious diseases which comprising administering a compound of  claim 1  or a pharmaceutically acceptable salt thereof to human or animals.