Hydroxyphenyl derivatives and biological applications thereof

Abstract

The invention relates to hydroxyphenyl derivatives of formula (I); and uses thereof as anti-bacterial and/or anti-parasitic agents.

We claim: 
     
         1 . Hydroxyphenyl derivatives of the invention of formula (I) 
       
         
           
           
               
               
           
         
         R1 is a 6 membered monocyclic nitrogenous heteroaryl of formula 
       
       
         
           
           
               
               
           
         
       
       Z4, Z5, Z6, Z7 and Z8 are independently C or N with a maximum of three N, R1 being possibly substituted by 1 to 3 R identical or different, R being selected from the group comprising H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 5 or 6 membered monocyclic heteroaryl or aliphatic heterocycle containing 1 to 3 heteroatoms selected from N, O and S, COOR a , COR a , CONR a R b , OCOR a , CN, OR a , NR a R b , CR a ═NOR b , NR a COR b , NR a COOR b , OCONR a R b , NR a CONR b R c , SR a , SO 2 R a , SO 2 NR a R b , NR a SO 2 R b  and NR a C(S)NR b R c , all being possibly substituted by R′, or R is C 1 -C 4 fluoro-alkyl, or R is halogeno,
 R2 is phenyl, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 1 -C 4 fluoro-alkyl, C 2 -C 4 fluoro-alkenyl, OR a , SR a , all being possibly substituted by 1 to 3 identical or different R′, 
 R a , R b  and R c , identical or different, are selected from the group consisting of H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, phenyl, heteroaryl and aliphatic heterocycle as defined above for R2, the heteroaryl and the heterocycle being possibly formed with the carbon and nitrogen atoms to which R a , R b  and R c  are linked, 
 R′ is selected from the group comprising heteroaryl and aliphatic heterocycle as defined above for R2, C 1 -C 8  alkyl, CH 2 CO 2 R″, CO 2 R″, COR″, CONR″R″′, OCOR″, OR″, NR″R″′, NR″COR″′, NR″COOR″′, OCONR″R″′, NR″CONR″R″′, NR″SO 2 R″′, SO 2 R″, NR″SO 2 R″′, halogen and CN, R″ and R″′, identical or different, are H, C 1 -C 8  alkyl or form together a 4 to 6 membered heterocycle with 1 to 3 heteroatoms selected from N, O and S, 
 Y represents H or a labile chemical group able to regenerate in vivo the free phenol selected from the group consisting of C(O)R a , C(O)OR a , C(O)NR a ,R b , P(O)(OH) 2  and COCHR a NR b R c , 
 Z1 and Z3, identical or different, are halogen or H, 
 Z2 is fluor or H, 
 
       provided that
 either Z2 is fluor and all the other definitions are as defined above, 
 or Z6 is a carbon atom substituted by R as defined above, R being different from H, alkyl, halogen, NH 2 , OH, CONH 2  or fluoro alkyl and all the other definitions are as defined above, 
 or Z4 or Z5, or Z7 or Z8 are carbon atoms substituted by NR a R b  or OR a , OR a  being different from OH and all the other definitions are as defined above, 
 or Z5, or Z7, is a carbon atom substituted by R, R being different from H and all the other definitions are as defined above, 
 or R2 is a C 1 -C 8 alkyl-heteroaryl radical or a C 1 -C 8 alkyl-OR a  radical, OR a  being different from OH and all the other definitions are as defined above, 
 and the pharmaceutically acceptable organic and mineral salts, as well as the racemic derivatives and each unique not racemic derivatives, in case the derivatives of formula (I) have one or more chiral centers, both the cis (Z) and trans (E) isomers, in cases the derivatives of formula (I) have unsaturated carbon=carbon double bonds, and any N-oxide form of the derivatives. 
 
     
     
         2 . The derivatives according to  claim 1 , wherein R1 is a 6 membered monocyclic heteroaryl with 1 or 3 nitrogen atoms selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. 
     
     
         3 . The derivatives according to  claim 1 , wherein R1 is substituted by 1 to 3 substituents selected from the group comprising F, COR a , OR a , NR a R b , alkynyl, SO 2 R a , NR a SO 2 R b , SO 2 NR a R b , NR a COOR b  and CR a ═NOR b . 
     
     
         4 . The derivatives according to  claim 1 , wherein Z2 is fluor. 
     
     
         5 . The derivatives according to  claim 1 , wherein Z6 is a carbon atom substituted by R as defined in  claim 1 , R being different from H, alkyl, halogen, NH 2 , OH, CONH 2  or fluoro alkyl. 
     
     
         6 . The derivatives according to  claim 1 , wherein Z4 or Z5, or Z7 or Z8, are carbon atoms substituted by NR a R b  or OR a . 
     
     
         7 . The derivatives according to  claim 1 , wherein, Z5 or Z7 is a carbon atom substituted by R as defined in  claim 1 , R being different from H. 
     
     
         8 . The derivatives according to  claim 1 , wherein R2 is a C 1 -C 8 alkyl-heteroaryl or C 1 -C 8 alkyl-OR a . 
     
     
         9 . The derivatives according to  claim 1 , wherein Y represents H. 
     
     
         10 . The derivatives according to  claim 1 , wherein Y represents a labile chemical group selected from the group consisting of C(O)R a , CO(O)R a , C(O)NR a R b , P(O)(OH) 2  and COCHR a NR b R c . 
     
     
         11 . A process for making a derivative according to  claim 1 , comprising the steps of
 a) reacting with AR1, a phenol derivative of formula (II)   
       
         
           
           
               
               
           
         
       
       wherein R1, R2, Z1, Z2 and Z3 are as defined in  claim 1 , R3 represents an alkyl group, and A is a reactive group capable of reacting with the OH group of (II), under basic conditions, to give a derivative of formula (III) 
       
         
           
           
               
               
           
         
         b) reacting the derivative of formula (III) with a Lewis acid to give the desired derivative of formula (I). 
       
     
     
         12 . The process according to  claim 11 , wherein to obtain derivative with R2 representing a functional group, the desired function is introduced prior removal of R3. 
     
     
         13 . A process for making a derivative according to  claim 1 , comprising the steps of
 a) reacting the protected phenol derivative of formula (II) with TosCl to give a derivative of formula (IV)   
       
         
           
           
               
               
           
         
         wherein R2, Z1, Z2 and Z3 are as defined in  claim 1  and R3 represents an alkyl group 
         b) reacting the derivative of formula (IV) with a Lewis acid to give a derivative of formula (V) 
       
       
         
           
           
               
               
           
         
         c) treating the derivative of formula (V) under basic or acidic conditions, to introduce R4, R4 being a protecting group selected from the group consisting of benzyl, BOM, SEM, MOM, MEM, TBDMS, THP and analogs, to obtain a derivative of formula (VI), 
       
       
         
           
           
               
               
           
         
         d) reacting said derivative of formula (VI) under basic conditions or with Mg in an alcohol, to remove the Tos group, to obtain a derivative of formula (VII) 
       
       
         
           
           
               
               
           
         
         e) reacting the derivative of formula (VII) with AR1 to obtain a product of formula (III′) 
       
       
         
           
           
               
               
           
         
         wherein A is a reactive group capable of reacting with the OH group of (VII) and R1 is as defined in  claim 1 , 
         f) deprotecting the phenol group to obtain the desired derivative of formula (I) with Y representing H. 
       
     
     
         14 . A process for making the derivatives according to  claim 1  wherein Z2 is fluor, comprising the steps of
 a) reacting the bromophenol of formula (VIII): 
 
       
         
           
           
               
               
           
         
         with AR1, in the presence of a base to obtain the compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein R3 represents an alkyl group, A is a reactive group capable of reacting with the OH group of (VII) and R1 is as defined in  claim 1 , 
         then reacting the compound of formula (IX) with a palladium catalyst in the presence of a base and a boronic reactant of formula R2B, R2 is as defined in  claim 1  and B is a boronic ester residue, to obtain a derivative of formula (X), 
       
       
         
           
           
               
               
           
         
         b) alternatively protecting the compound of formula (VIII), with a benzyl group prior to reacting it with a palladium catalyst in the presence of a base and a boronic reactant of formula R2B, to obtain the benzylated derivative (XI), 
       
       
         
           
           
               
               
           
         
         debenzylating it with palladium on charcoal and hydrogen to obtain the free phenol of formula (XII) 
       
       
         
           
           
               
               
           
         
         and reacting (XII) with AR1 to generate the derivative of formula (X) 
         wherein A is a reactive group capable of reacting with the OH group of (VII) and R1 is as defined in  claim 1 , 
         c) Dealkylalating the compound of formula (X) by reacting the compound of formula (X) with a Lewis acid to generate the derivative of formula (I). 
       
     
     
         15 . A process according to  claim 11 , wherein a compound of formula (III), (VI), (VII), (X) or (I) is obtained from a compound of formula (XIII) 
       
         
           
           
               
               
           
         
         in which R5 is H, by hydrogenation with palladium on charcoal to give the corresponding ethyl compound derivative (XIV) 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . A process according to  claim 11 , wherein a derivative of formula (I) in which Y═H is converted into a compound in which Y is C(O)R a , CO(O)R a , C(O)NR a , R b , P(O)(OH) 2 , and COCHR a NR b R c . 
     
     
         17 . A pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of a derivative of formula (I) as defined in  claim 1 , in combination with a pharmaceutically acceptable carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17 , which is formulated to be administered under oral, injectable, parental routes, to a patient. 
     
     
         19 . A method for treating human or animal infections by microbial pathogens comprising  E. coli, S. aureus, M. tuberculosis, H. pylori  or  Plasmodium falciparum,  said method comprising administering to a patient in need thereof an effective amount of a hydroxyphenyl derivative as defined in  claim 1 .