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

Abstract

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

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof with a base or acid:  
     
       
         
         
             
             
         
       
     
     in which: 
 n is 2;  
 R 1  is selected from the group consisting of hydrogen, alkyl having up to 8 carbon atoms and (CH 2 ) n′ R o   1  in which n′ is 0 or 1 and R o   1  is selected from the group consisting of aryl having up to 12 carbon atoms; heteroaryl having up to 15 carbon atoms and at least one heteroatom selected from N, S, and O; COR′; CONR′R″; CSNR′R″; COCOOR′; SO 2 NR′R″; SO 2 R′; CO 2 R′ and CN;  
 R′ is selected from the group consisting of hydrogen, alkyl having up to 8 carbon atoms, alkenyl having up to 8 carbon atoms, aralkyl having up to 12 carbon atoms and aryl having up to 12 carbon atoms;  
 R″ is selected from the group consisting of hydrogen; alkyl having up to 8 carbon atoms; aryl having up to 12 carbon atoms; aralkyl having up to 12 carbon atoms; SO 2 —R′ and COR′; in each case R′ being independently selected from the group consisting of hydrogen, alkyl having up to 8 carbon atoms, alkenyl having up to 8 carbon atoms, aralkyl having up to 12 carbon atoms and aryl having up to 12 carbon atoms;  
 R2 is selected from the group consisting of hydrogen, halo, alkyl, OH, Oalkyl, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , NHCOalkyl, NHSO 2 alkyl, CONHalkyl, SO 2 NHalkyl, COOH, COOalkyl, CN, OSO 2 alkyl, NHCONHalkyl and COalkyl; said alkyl having up to 8 carbon atoms;  
 X is a divalent group —C(O)—N(OR 3 )— connected to the ring nitrogen atom via its carbonyl carbon atom and to the ring carbon atom via its nitrogen atom, in which R 3  is selected from the group consisting of hydrogen and the R, Y, Y 1 , Y 2  and Y 3  moieties defined below;  
 R is selected from the group consisting of alkyl having up to 6 carbon atoms, optionally substituted by pyridyl or carbamoyl; alkenyl having up to 8 carbon atoms; aryl having up to 12 carbon atoms; and aralkyl having up to 12 carbon atoms; each said aryl group optionally being substituted by an —OH, —NH 2 , —NO 2 , alkyl having up to 8 carbon atoms, an alkoxy having up to 8 carbon atoms or by one or more halogens;  
 Y is selected from the group consisting of COR, COOH, COOR, CONHR, CONHOH, CONHSO 2 R, CH 2 COOH, CH 2 COOR, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, CH 2  (protected tetrazole), CH 2 SO 3 H, CH 2 SO 2 R, CH 2 PO(OR) 2 , CH 2 PO(OR)(OH), CH 2 PO(R)(OH) and CH 2 PO(OH) 2 , wherein R is as defined hereinabove;  
 Y 1  is selected from the group consisting of SO 2 R, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR and SO 3 H, wherein R is as defined hereinabove;  
 Y 2  is selected from the group consisting of PO(OH) 2 , PO(OR) 2 , PO(OH)(OR) and PO(OH)(R), wherein R is as defined hereinabove;  
 Y 3  is selected from the group consisting of tetrazole, tetrazole substituted by R, squarate, NRtetrazole, NRtetrazole substituted by R, and NRSO 2 R, wherein R is as defined above, including the pure enantiomers thereof, in the R, S or RS configuration, as well as any racemic mixture of said enantiomers.  
 
   
   
       2 . A compound as claimed in  claim 1 , wherein R 2  is hydrogen.  
   
   
       3 . A compound as claimed in  claim 1 , wherein R 1  is hydrogen, alkyl having up to 8 carbon atoms or (CH 2 ) n , R o   1  wherein n′ is 0 or 1 and R o   1  is aryl having up to 12 carbon atoms; heteroaryl having up to 15 carbon atoms and at least one heteroatom selected from N, S, and O; CONR′R″; CSNR′R″; COCOOR′; SO 2 NR′R″; SO 2 R′ or CO 2 R′; R′ and R″ being as defined in  claim 1 .  
   
   
       4 . A compound as claimed in  claim 1 , wherein X is a divalent group —C(O)—N(OR 3 )— in which R 3  is selected from the group consisting of hydrogen and the R, Y and Y 1  radicals, R, Y and Y 1  being as defined in  claim 1 .  
   
   
       5 . A compound of formula (I) as defined in  claim 1 , selected from the group consisting of: 
 [[1,5-dihydro-1-(methylsulfonyl)-3-oxo-2,5-methano-2-H-1,2,4-benzotriazepin-4(3H)-yl]oxy]acetic acid,    [[1-[(benzoylamino)carbonyl]-1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl]oxy]acetic acid,    [[1,5-dihydro-3-oxo-1-[(phenylsulfonyl)aminocarbonyl]-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl]oxy]acetic acid,    [(1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl)oxy]acetic acid,    4,5-dihydro-1-methyl-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzotriazepin-3(1H)-one,    4,5-dihydro-4-(2-propenyloxy)-1-(3-pyridinylmethyl)-2,5-methano-2H-1,2,4-benzotriazepin-3(1H)one,    4,5-dihydro-3-oxo-N-(phenylsulfonyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepine-1(3H)-carboxamide,    N-benzoyl-4,5-dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepine-1(3H)-carboxamide,    ethyl 4,5-dihydro-α,3-dioxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepine-1(3H)-acetate,    ethyl 4,5-dihydro-3-oxo-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzo-triazepine-1(3H)-acetate,    and their salts and enantiomers as defined in  claim 1 .    
   
   
       6 . A process for the preparation of a compound as claimed in  claim 1 , which process comprises: 
 a) a first stage during which a compound of formula (II):                          in which:    R′ 1  is R 1  or a precursor thereof, R 2  is R 2 , and R 2  and n are as defined in  claim 1  and R′ 3  is selected from the group consisting of a protective group for hydroxyl, Rp, Yp, Y 1 p, Y 2 p and Y 3 p, which, respectively, correspond to R, Y, Y 1 , Y 2  and Y 3  as defined in  claim 1 , in which the possible reactive functional groups present are, if appropriate, protected, is reacted with a carbonylating agent, if appropriate in the presence of a base, for the purpose of obtaining an intermediate compound of formula (III):                          in which:    R′ 1  and R 2  are as defined above, and R2 and n are as defined in  claim 1  and either (1) X 1  is hydrogen and X 2  represents an —N(OR′ 3 )—CO—X 3  group, wherein R′ 3  is as defined above and X 3  is the residue of the carbonylating agent, or (2) X 2  is —NH—OR′ 3  and X 1  is CO—X 3  group, X 3  being as defined above; and    b) a second stage during which the intermediate of formula III obtained above is cyclized, in the presence of a base.    
   
   
       7 . The process of  claim 6  further comprising, either before stage a) or after stage b), as appropriate: 
 c) one or more of the following reactions, in an appropriate order: 
 protection of the reactive functional groups,  
 deprotection of the reactive functional groups,  
 esterification,  
 saponification,  
 sulfonation,  
 phosphatation,  
 amidation,  
 acylation,  
 sulfonylation,  
 alkylation,  
 formation of a urea group,  
 introduction of a tetrazole group,  
 reduction of carboxylic acids,  
 dehydration of amide to nitrile,  
 salification,  
 exchange of ions,  
 separation of enantiomers,  
 nitration,  
 reduction of a nitro to an amino,  
 halogenation,  
 carbamoylation,  
 introduction of a cyano group.  
   
   
   
       8 . The process as claimed in  claim 6 , wherein the carbonylating agent is selected from the group consisting of phosgene, diphosgene, triphosgene, aryl, aralkyl, alkyl and alkenyl chloroformates, alkyl dicarbonates, carbonyldiimidazole and their mixtures.  
   
   
       9 . The process as claimed in  claim 6 , wherein the carbonylation reaction takes place in the presence of a base.  
   
   
       10 . The process as claimed in  claim 6 , wherein, in stage b), the base is selected from the group consisting of amines, alkali metal hydrides, alkoxides, amides and carbonates and alkaline earth metal hydrides, alkoxides, amides and carbonates.  
   
   
       11 . The process as claimed in  claim 10 , wherein the base is an amine.  
   
   
       12 . The process as claimed in  claim 6 , wherein the compound of formula (II) is obtained by a process wherein a compound of formula (IV):  
     
       
         
         
             
             
         
       
       in which R′ 1 , R 2  and n are as defined in  claim 6 , R 2  is selected from the group consisting of hydrogen, halo, alkyl, OH, Oalkyl, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , NHCOalkyl, NHSO 2 alkyl, CONHalkyl, SO 2 NHalkyl, COOH, COOalkyl, CN, OSO 2 alkyl, NHCONHalkyl and Coalkyl, said alkyl having up to 8 carbon atoms, n is 2, and A is hydrogen or a protective group for the nitrogen, is treated with a reducing agent, to obtain a compound of formula (V):  
       
         
           
           
               
               
           
         
       
       in which A is defined above in  claim 6 , R′ 1  and R 2  are as defined in  claim 6 , and R 2  and n are as defined above, and in which process, if appropriate, the OH group is replaced by a leaving group, to obtain a compound of formula (VI):  
       
         
           
           
               
               
           
         
       
       in which A is defined above, R′ 1  and R 2  are as defined in  claim 6 , and R 2  and n are as defined above and B represents a leaving group, which compound of formula VI is then treated with a compound of formula NH 2 —OR′ 3 , R′ 3  being as defined in  claim 6 , and then, if appropriate, with an appropriate deprotecting agent for the nitrogen atom.  
     
   
   
       13 . The process as claimed in  claim 12 , wherein the compound of formula (II) is obtained by a process wherein a compound of formula (IV) as defined in  claim 12  is treated with a compound of formula H 2 N—OR′ 3 , to obtain a compound of formula (VI):  
     
       
         
         
             
             
         
       
       in which A is as defined in  claim 12 , and R′ 1 , R 2 , n and R′ 3  are as defined in  claim 12 , which compound of formula VII is then reacted with a reducing agent, to obtain a compound of formula (VIII):  
       
         
           
           
               
               
           
         
       
       in which A, R′ 1 , R 2 , n and R′ 3  are as defined in  claim 12 , which compound of formula VIII is then treated, if appropriate, with an appropriate deprotecting agent for the nitrogen atom.  
     
   
   
       14 . A pharmaceutical composition comprising the compound as defined in  claim 1  in combination with a pharmaceutically acceptable carrier.  
   
   
       15 . A pharmaceutical composition comprising the compound as defined in  claim 6  in combination with a pharmaceutically acceptable carrier.  
   
   
       16 . A compound of general formula (III) or one of its salts with an acid, in particular its hydrochloride and its trifluoroacetate:  
     
       
         
         
             
             
         
       
       in which:  
       R′ 1 , R 2 , X 1 , X 2  and n are as defined in  claim 6 .  
     
   
   
       17 . A compound of general formula (II) or one of its salts with an acid, in particular its hydrochloride and its trifluoroacetate: 
 in which R′ 1 , R 2 , R′ 3  and n are as defined in  claim 6 .                          
   
   
       18 . A compound selected from the compounds of formulas (IV) and (V) or a salt thereof with an acid:  
     
       
         
         
             
             
         
       
       in which A, R 2  and n have the same meanings as in  claim 12  and R′ 1  is (CH 2 ) n ′R o   1  in which n′ is 0 or 1 and R o   1  is selected from the group consisting of heteroaryl containing up to 15 carbon atoms and one or more heteroatoms selected from nitrogen, sulfur and oxygen, COR′, CONR′R″, CSNR′R″, COCOOR′, SO 2 NR′R″, SO 2 R′, CO 2 R′ and CN, R′ is hydrogen, alkyl or alkenyl containing up to 8 carbon atoms, aralkyl containing up to 12 carbon atoms or aryl containing up to 12 carbon atoms, and R″ is hydrogen, alkyl containing up to 8 carbon atoms, aryl containing up to 12 carbon atoms, aralkyl containing up to 12 carbon atoms, SO 2 —R′ or COR′, R′ being as defined above.  
     
   
   
       19 . A compound of formula (VI) or one of its salts with an acid:  
     
       
         
         
             
             
         
       
       in which A, R′ 1 , R 2 , B and n are as defined in  claim 12 .  
     
   
   
       20 . A compound of formula (VII) or (VIII) or one of its salts with an acid:  
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       in which A, R′ 1 , R 2 , n and R′ 3  are as defined in  claim 13 .  
     
   
   
       21 . A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an antibacterially effective amount of a compound of  claim 1 .  
   
   
       22 . A method of treating an infection or infection-causing condition in a mammal that is due to the presence of bacteria that generate beta-lactamases, which comprises administering to a mammal in need thereof an amount of a compound of  claim 1  that is effective to inhibit beta-lactamase in said mammal.