Novel heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors

Abstract

The invention relates to novel heterocyclic compounds of general formula (I), and their salts with a base or an acid: The invention also relates to a method for preparing these compounds, and to their use as medicaments, in particular as antibacterials and β-lactamase inhibitors.

1 . A compound of general formula (III) or one of its salts comprising: 
     
       
         
         
             
             
         
       
       wherein R′ 1  selected from the group consisting of H, CN, protected COOH, COOR 9 , (CH 2 ) n′ R′ 5 , CONR 6 R 7 , and 
     
     
       
         
         
             
             
         
       
       wherein R 9  is selected from the group consisting of alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl; —CH 2 -alkenyl containing in total from 3 to 9 carbon atoms; aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the aryl or aralkyl being optionally substituted with a substituent selected from the group consisting of NO 2 , protected OH, protected NH 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms, 
       n′ is equal to 1 or 2, 
       R′ 5  is selected from the group consisting of protected OH, CN, protected NH 2 , CO—NR 6 R 7 , protected COOH, COOR 9 , and OR 9 , R 9  being as defined above, 
       R 6  and R 7  are individually selected from the group consisting of hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms, an aralkyl radical containing from 7 to 11 carbon atoms and an alkyl radical containing from 1 to 6 carbon atoms which is substituted with a pyridyl radical; 
       R′ 2  is selected from the group consisting of hydrogen, halogen, R 9 , S(O) m R 9 , OR 9 , NHCOH, NHCOR 9 , NHCOOR 9  and NHSO 2 R 9 , R 9  being as defined above and m being 0, 1 or 2, 
       R′ 4  represents a hydrogen atom or (CH 2 ) n′     1   R′ 5 , n′ 1  being 0, 1 or 2 and R′ 5  being as defined above; 
       wherein R 3  and R′ 4  or R′ 1  and R 3  together with the carbon atoms to which they are attached, form a phenyl or an aromatic heterocycle containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and substituted with one or more groups selected from the group consisting of —(CH 2 ) b -phenyl and —(CH 2 ) b -aromatic heterocycle, where b is an integer from 0 to 6 and each of said phenyl and heterocycle are optionally substituted with one or more substituents selected from halogen, alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and CF 3 ; 
       X 1  is hydrogen and X 2  is-Z-CO—X 3  or X 2  is -ZH and X 1  is CO—X 3 , where X 3  represents the residue of the carbonylating agent, ZH is selected from the group consisting of HNR′ 8 —(CH 2 ) n″ —, where n″ is 0 or 1 and R′ 8  is selected from the group consisting of hydrogen, R 9 , protected OH, OR 9 , Y′ 1 , OY′, Y′ 1 , OY′ 1 , Y′ 2 , OY′ 2 , Y′ 3 , O—CH 2 —CH 2 —S(O) m —R″, SiRaRbRc and OSiRaRbRc, each of Ra, Rb and Rc individually being a linear or branched alkyl containing from 1 to 6 carbon atoms or an aryl containing from 6 to 10 carbon atoms, R 9  and m being as defined above, 
       Y′ is selected from the group consisting of COH, COR 9 , COOR 9 , CONH 2 , CONHR 9 , CONHSO 2 R 9 , CH 2 COOR 9 , protected CH 2 tetrazole, CH 2 SO 2 R 9 , CH 2 PO(OR 9 ) 2 , protected CONHOH, protected CH 2 COOH, protected CH 2 CONHOH, protected CH 2 SO 3 , protected CH 2 PO(OR)(OH), protected CH 2 PO(R)(OH) and protected CH 2 PO(OH) 2 , 
       Y′ 1  is selected from the group consisting of SO 2 R 9 , SO 2 NHCOH, SO 2 NHCOR 9 , SO 2 NHCOOR 9 , SO 2 NHCONH 2 , SO 2 NHCONHR 9  and protected SO 3 H, 
       Y′ 2  is selected from the group consisting of PO(OR 9 ) 2 , protected PO(OH) 2 , protected PO(OH)(OR) and protected PO(OH)(R), 
       Y′ 3  is selected from the group consisting of protected tetrazole, tetrazole substituted with R 9 , protected squarate, protected NHtetrazole, protected NR 9 tetrazole, protected NH, NR 9 tetrazole substituted with R 9 , NHSO 2 R 9  and NSO 2 R 9 , 
       R is selected from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl radical; a —CH 2 -alkenyl radical containing in total from 3 to 9 carbon atoms; a (poly)alkoxyalkyl group containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms; an aryl radical containing from 6 to 10 carbon atoms or an aralkyl radical containing from 7 to 11 carbon atoms, the aryl or aralkyl radical being optionally substituted with a radical selected from the group consisting of OH, NH 2 , NO 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms; 
       R″ being selected from alkyl radicals containing from 1 to 6 carbon atoms substituted with one or more radicals selected from hydroxy, protected hydroxy, oxo, halogen and cyano radicals; and 
       n is 1. 
     
   
   
       2 . A compound of  claim 1  wherein said salt is a hydrochloride or trifluoroacetate. 
   
   
       3 . A compound of  claim 1  having said general formula (III) or one of its salts with an acid: 
     
       
         
         
             
             
         
       
     
     wherein R′ 1  is CONR 6 R 7  in which R 6  or R 7  is an alkoxy radical containing from 1 to 6 carbon atoms and R′ 2 , R 3 , R′ 4 , X 1 , X 2 , n, and all other values are as defined in  claim 1 . 
   
   
       4 . A compound of  claim 3  wherein said salt is a hydrochloride or trifluoroacetate. 
   
   
       5 . A compound of general formula (II) or one of its salts with an acid comprising: 
     
       
         
         
             
             
         
       
       wherein R′ 1  selected from the group consisting of H, CN, protected COOH, COOR 9 , (CH 2 ) n′ R′ 5 , CONR 6 R 7 , and 
     
     
       
         
         
             
             
         
       
       wherein R 9  is selected from the group consisting of alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl; —CH 2 -alkenyl containing in total from 3 to 9 carbon atoms; aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the aryl or aralkyl being optionally substituted with a substituent selected from the group consisting of NO 2 , protected OH, protected NH 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms, 
       n′ is equal to 1 or 2, 
       R′ 5  is selected from the group consisting of protected OH, CN, protected NH 2 , CO—NR 6 R 7 , protected COOH, COOR 9 , and OR 9 , R 9  being as defined above, 
       R 6  and R 7  are individually selected from the group consisting of hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms, an aralkyl radical containing from 7 to 11 carbon atoms and an alkyl radical containing from 1 to 6 carbon atoms which is substituted with a pyridyl radical; 
       R′ 2  is selected from the group consisting of hydrogen, halogen, R 9 , S(O) m R 9 , OR 9 , NHCOH, NHCOR 9 , NHCOOR 9  and NHSO 2 R 9 , R 9  being as defined above and m being 0, 1 or 2, 
       R′ 4  represents a hydrogen atom or (CH 2 ) n′     1   R′ 5 , n′ 1  being 0, 1 or 2 and R′ 5  being as defined above; 
       wherein R 3  and R′ 4  or R′ 1  and R 3  together with the carbon atoms to which they are attached, form a phenyl or an aromatic heterocycle containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and substituted with one or more groups selected from the group consisting of —(CH 2 ) b -phenyl and —(CH 2 ) b -aromatic heterocycle, where b is an integer from 0 to 6 and each of said phenyl and heterocycle are optionally substituted with one or more substituents selected from halogen, alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and CF 3 ; 
       ZH is selected from the group consisting of HNR′ 8 —(CH 2 ) n″ —, where n″ is 0 or 1 and R′ 8  is selected from the group consisting of hydrogen, R 9 , protected OH, OR 9 , Y′, OY′, Y′ 1 , OY′ 1 , Y′ 2 , OY′ 2 , Y′ 3 , O—CH 2 —CH 2 —S(O) m —R″, SiRaRbRc and OSiRaRbRc, each of Ra, Rb and Rc individually being a linear or branched alkyl containing from 1 to 6 carbon atoms or an aryl containing from 6 to 10 carbon atoms, R 9  and m being as defined above, 
       Y′ is selected from the group consisting of COH, COR 9 , COOR 9 , CONH 2 , CONHR 9 , CONHSO 2 R 9 , CH 2 COOR 9 , protected CH 2 tetrazole, CH 2 SO 2 R 9 , CH 2 PO(OR 9 ) 2 , protected CONHOH, protected CH 2 COOH, protected CH 2 CONHOH, protected CH 2 SO 3 , protected CH 2 PO(OR)(OH), protected CH 2 PO(R)(OH) and protected CH 2 PO(OH) 2 , 
       Y′ 1  is selected from the group consisting of SO 2 R 9 , SO 2 NHCOH, SO 2 NHCOR 9 , SO 2 NHCOOR 9 , SO 2 NHCONH 2 , SO 2 NHCONHR 9  and protected SO 3 H, 
       Y′ 2  is selected from the group consisting of PO(OR 9 ) 2 , protected PO(OH) 2 , protected PO(OH)(OR) and protected PO(OH)(R), 
       Y′ 3  is selected from the group consisting of protected tetrazole, tetrazole substituted with R 9 , protected squarate, protected NHtetrazole, protected NR 9 tetrazole, protected NH, NR 9 tetrazole substituted with R 9 , NHSO 2 R 9  and NSO 2 R 9 , 
       R is selected from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl radical; a —CH 2 -alkenyl radical containing in total from 3 to 9 carbon atoms; a (poly)alkoxyalkyl group containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms; an aryl radical containing from 6 to 10 carbon atoms or an aralkyl radical containing from 7 to 11 carbon atoms, the aryl or aralkyl radical being optionally substituted with a radical selected from the group consisting of OH, NH 2 , NO 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms; 
       R″ being selected from alkyl radicals containing from 1 to 6 carbon atoms substituted with one or more radicals selected from hydroxy, protected hydroxy, oxo, halogen and cyano radicals; and 
       n is 1. 
     
   
   
       6 . A compound of  claim 5  wherein said salt is a hydrochloride or trifluoroacetate. 
   
   
       7 . A compound of  claim 5  wherein R′ 1  is CONR 6 R 7  in which R 6  or R 7  is an alkoxy radical containing from 1 to 6 carbon atoms, wherein all the other values are as defined in  claim 5 . 
   
   
       8 . A compound of  claim 7  wherein said salt is a hydrochloride or trifluoroacetate. 
   
   
       9 . A compound selected from the compounds having general formulas (IV), (V), or (VI) or one of their salts: 
     
       
         
         
             
             
         
       
     
     wherein R′ 1  selected from the group consisting of H, CN, protected COOH, COOR 9 , (CH 2 ) n′ R′ 5 , CONR 6 R 7 , and 
     
       
         
         
             
             
         
       
       wherein R9 is selected from the group consisting of alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl; —CH 2 -alkenyl containing in total from 3 to 9 carbon atoms; aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the aryl or aralkyl being optionally substituted with a substituent selected from the group consisting of NO 2 , protected OH, protected NH 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms, 
       n′ is equal to 1 or 2, 
       R′ 5  is selected from the group consisting of protected OH, CN, protected NH 2 , CO—NR 6 R 7 , protected COOH, COOR 9 , and OR 9 , R 9  being as defined above, 
       R 6  and R 7  are individually selected from the group consisting of hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms, an aralkyl radical containing from 7 to 11 carbon atoms and an alkyl radical containing from 1 to 6 carbon atoms which is substituted with a pyridyl radical; 
       R′ 2  is selected from the group consisting of hydrogen, halogen, R 9 , S(O) m R 9 , OR 9 , NHCOH, NHCOR 9 , NHCOOR 9  and NHSO 2 R 9 , R 9  being as defined above and m being 0, 1 or 2, 
       R′ 4  represents a hydrogen atom or (CH 2 ) n′     1   R′ 5 , n′ 1  being 0, 1 or 2 and R′ 5  being as defined above; 
       wherein R 3  and R′ 4  or R′ 1  and R 3  together with the carbon atoms to which they are attached, form a phenyl or an aromatic heterocycle containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and substituted with one or more groups selected from the group consisting of —(CH 2 ) b -phenyl and —(CH 2 ) b -aromatic heterocycle, where b is an integer from 0 to 6 and each of said phenyl and heterocycle are optionally substituted with one or more substituents selected from halogen, alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and CF 3 ; 
       A represents hydrogen or a group protecting the nitrogen; 
       R 11  represents a leaving group; and 
       n is 1. 
     
   
   
       10 . A compound of  claim 9  wherein said salt is a hydrochloride or trifluoroacetate. 
   
   
       11 . A compound selected from the compounds having general formulas (VII), (VIII) and (VIII′) or one of its salts comprising: 
     
       
         
         
             
             
         
       
       wherein R′ 1  selected from the group consisting of H, CN, protected COOH, COOR 9 , (CH 2 ) n′ R′ 5 , CONR 6 R 7 , and 
     
     
       
         
         
             
             
         
       
       wherein R 9  is selected from the group consisting of alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl; —CH 2 -alkenyl containing in total from 3 to 9 carbon atoms; aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the aryl or aralkyl being optionally substituted with a substituent selected from the group consisting of NO 2 , protected OH, protected NH 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms, 
       n′ is equal to 1 or 2, 
       R′ 5  is selected from the group consisting of protected OH, CN, protected NH 2 , CO—NR 6 R 7 , protected COOH, COOR 9 , and OR 9 , R 9  being as defined above, 
       R 6  and R 7  are individually selected from the group consisting of hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms, an aralkyl radical containing from 7 to 11 carbon atoms and an alkyl radical containing from 1 to 6 carbon atoms which is substituted with a pyridyl radical; 
       R′ 2  is selected from the group consisting of hydrogen, halogen, R 9 , S(O) m R 9 , OR 9 , NHCOH, NHCOR 9 , NHCOOR 9  and NHSO 2 R 9 , R 9  being as defined above and m being 0, 1 or 2, 
       R′ 4  represents a hydrogen atom or (CH 2 ) n′     1   R′ 5 , n′ 1  being 0, 1 or 2 and R′ 5  being as defined above; 
       wherein R 3  and R′ 4  or R′ 1  and R 3  together with the carbon atoms to which they are attached, form a phenyl or an aromatic heterocycle containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and substituted with one or more groups selected from the group consisting of —(CH 2 ) b -phenyl and —(CH 2 ) b -aromatic heterocycle, where b is an integer from 0 to 6 and each of said phenyl and heterocycle are optionally substituted with one or more substituents selected from halogen, alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and CF 3 ; 
       R′ 8  is selected from the group consisting of hydrogen, R 9 , protected OH, OR 9 , Y′ 1 , OY′ 1 , Y′ 1 , OY′ 1 , Y′ 2 , OY′ 2 , Y′ 3 , O—CH 2 —CH 2 —S(O) m —R″, SiRaRbRc and OSiRaRbRc, each of Ra, Rb and Rc individually being a linear or branched alkyl containing from 1 to 6 carbon atoms or an aryl containing from 6 to 10 carbon atoms, R 9  and m being as defined above; 
       Y′ is selected from the group consisting of COH, COR 9 , COOR 9 , CONH 2 , CONHR 9 , CONHSO 2 R 9 , CH 2 COOR 9 , protected CH 2 tetrazole, CH 2 SO 2 R 9 , CH 2 PO(OR 9 ) 2 , protected CONHOH, protected CH 2 COOH, protected CH 2 CONHOH, protected CH 2 SO 3 , protected CH 2 PO(OR)(OH), protected CH 2 PO(R)(OH) and protected CH 2 PO(OH) 2 , 
       Y′ 1  is selected from the group consisting of SO 2 R 9 , SO 2 NHCOH, SO 2 NHCOR 9 , SO 2 NHCOOR 9 , SO 2 NHCONH 2 , SO 2 NHCONHR 9  and protected SO 3 H, 
       Y′ 2  is selected from the group consisting of PO(OR 9 ) 2 , protected PO(OH) 2 , protected PO(OH)(OR) and protected PO(OH)(R), 
       Y′ 3  is selected from the group consisting of protected tetrazole, tetrazole substituted with R 9 , protected squarate, protected NHtetrazole, protected NR 9 tetrazole, protected NH, NR 9 tetrazole substituted with R 9 , NHSO 2 R 9  and NSO 2 R 9 , 
       R is selected from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl radical; a —CH 2 -alkenyl radical containing in total from 3 to 9 carbon atoms; a (poly)alkoxyalkyl group containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms; an aryl radical containing from 6 to 10 carbon atoms or an aralkyl radical containing from 7 to 11 carbon atoms, the aryl or aralkyl radical being optionally substituted with a radical selected from the group consisting of OH, NH 2 , NO 2 , alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms; 
       R″ being selected from alkyl radicals containing from 1 to 6 carbon atoms substituted with one or more radicals selected from hydroxy, protected hydroxy, oxo, halogen and cyano radicals; 
       A represents hydrogen or a group protecting the nitrogen; and 
       n is 1. 
     
   
   
       12 . A compound of  claim 11  wherein said salt is a hydrochloride or trifluoroacetate.