Metallo-b-lactamase inhibitors

Abstract

A new metallo-β-lactamase inhibitor which acts as a medicament for inhibiting the inactivation of β-lactam antibiotics and recovering anti-bacterial activities is disclosed. The maleic acid derivatives having the general formula (I) have metallo-β-lactamase inhibiting activities. It is possible to recover the anti-bacterial activities of β-lactam antibiotics against metallo-β-lactamase producing bacteria by combining the compound of the general formula (I) with β-lactam antibiotics.

1 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition comprising at least a compound represented by the following formula (I), or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         le represents a C 2-6  alkyl group, a C 3-7 cycloalkyl group, a hydroxymethyl group, a —C 1-3  alkylene-phenyl group, a —C 0-1  alkylene-heterocycle, a —O—C 1-6 alkyl group, or a —S—C 1-6 alkyl group, all of which may be substituted; 
         R 2  represents a C 1-6 alkyl group, a C 3-7  cycloalkyl group, a hydroxymethyl group, —C 1-3 alkylene-phenyl group, a —C 0-1 alkylene-heterocycle, a —O—C 1-6 alkyl group, or a —S—C 1-6 alkyl group, all of which may be substituted; and 
         each M 1  independently represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group which can be hydrolyzed in vivo, 
         a β-lactam antibiotic, 
         and a pharmaceutically acceptable carrier. 
       
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein said β-lactam antibiotic is a carbapenem antibiotic or a cephem antibiotic. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein said β-lactam antibiotic is selected from the group consisting of imipenem, meropenem, biapenem, doripenem, CS-023, ME1036, ceftriaxone, ceftadizime, cefotaxime, and cefepime. 
     
     
         24 . The pharmaceutical composition according to  claim 21 , further comprising a dehydropeptidase inhibitor and/or a β-lactamase inhibitor other than the compound of the formula (I). 
     
     
         25 . A compound represented by the following formula (II), or a salt thereof: 
       
         
           
           
               
               
           
         
         in which 
         R 3  represents a C 2-6  alkyl group, a C 3-7 cycloalkyl group, or a hydroxymethyl group, all of which may be substituted; 
         R 4  represents a C 1-6 alkyl group or a C 3-7  cycloalkyl group, all of which may be substituted; and 
         each M 2  independently represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group which may be hydrolyzed in vivo. 
       
     
     
         26 . A compound represented by the following formula (III), or a salt thereof: 
       
         
           
           
               
               
           
         
         in which 
         R 5  represents an ethyl group; 
         R 6  represents a C 1-3  linear alkyl group; and 
         each M 3  independently represents a pharmaceutically acceptable cation, or a pharmaceutically acceptable group which can be hydrolyzed in vivo. 
       
     
     
         27 . The compound according to  claim 26 , wherein R 5  and R 6  represent ethyl groups, and M 3  represents a sodium ion or a potassium ion. 
     
     
         28 . A compound represented by the following formula (IV), or a salt thereof: 
       
         
           
           
               
               
           
         
         in which 
         R 7  represents a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a —C 1-3 alkylene-phenyl group, a —C 1  alkylene-ring A, a —O—C 1-6  alkyl group, or a —S—C 1-6 alkyl group, all of which may be substituted; 
         R 8  represents a —C 1-3 alkylene-phenyl group, a —C 0-1 alkylene-ring A, a —O—C 1-6 alkyl group, or a —S—C 1-6  alkyl group, all of which may be substituted; 
         the ring A represents a five- to ten-membered mono- or bi-cyclic heterocyclic ring having 1-4 hetero atoms selected from nitrogen, oxygen and sulfur atoms; and 
         each M 4  independently represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group which can be hydrolyzed in vivo; 
         provided that when R 7  is a C 1-6 alkyl group, R 8  excludes dihydrofuran. 
       
     
     
         29 . The compound according to  claim 28 , wherein the ring A represents tetrahydrofuran, furan, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinuclidine, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, pteridine, or a salt thereof. 
     
     
         30 . A compound represented by the following formula (V), or a salt thereof: 
       
         
           
           
               
               
           
         
         in which 
         R 9  represents a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a —C 1-3 alkylene-phenyl group, a —C 0-1  alkylene-ring B, a —O—C 1-6 alkyl group, or, a —S—C 1-6  alkyl group, all of which may be substituted; 
         R 10  represents a —C 1-3  alkylene-phenyl group, a —C 0-1 alkylene-ring B, a —O—C 1-6  alkyl group, or a —S—C 1-6 alkyl group, all of which may be substituted; 
         ring B represents pyridine, piperidine, or tetrahydropyran; and 
         each M 5  independently represents a hydrogen atom, a pharmaceutically acceptable cation or a pharmaceutically acceptable group which may be hydrolyzed in vivo; 
         provided that the case when R 9  and R 10  represent pyridinium is excluded.