Use of quinoline derivatives with anti-integrase effect and applications thereof

Abstract

The invention relates to the use of 8-hydroxyquinoline 7-carboxylic acid derivatives in order to produce integrase inhibiting medicaments, capable of blocking viral replication in the stages preceding integration, and if appropriate, at the level of this integration stage, these medicaments being usable for the treatment of retroviral pathologies, in particular for the treatment of AIDS.

1 . A method for inhibiting integrase and blocking viral replication, comprising administering to an animal or human in need thereof a 8-hydroxyquinoline 7-carboxylic acid derivative of formula I, a pharmaceutically acceptable salt thereof, a diastercoisomer thereof, or an enantiomeric form thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         Rb is H or Rb represents one or more substituents occupying any position on the rings, each Rb independently selected from the group consisting of —(CH 2 ) n′ Y, and —CH═CH—Y; 
         Rc is selected from the group consisting of —(CH 2 ) n —Y and —CH═CH—Y; 
         Z is an aryl radical or a heterocyclic radical; 
         X is a double bond, a —(CH 2 ) n′ — group, or a —CH(Rd)—CH(Re)— group; 
         Y is a halogen atom, —OH, —OR, —CHO, —COR, —COOH, —COOR, —CONH 2 , —CONR x R y , —CH═NOH, —CO—CH═NOH, —NH 2 , —NR x R y , —NO 2 , —PO(OR) 2 , —SH, —SR, —SO 2 R, —SO 2 NHR, or CN; 
         R is an alkyl radical having 1 to 8 carbon atoms, an aryl radical, or a heterocyclic radical; 
         R x  and R y , are independently an alkyl radical with 1 to 5 carbon atoms; 
         Rd and Re are independently a hydrogen, a halogen atom, a hydroxy, or an epoxy group; 
         n is zero or an integer from 1 to 5; and 
         n′ is an integer from 1 to 5; 
         with the proviso that when Y in Rc is a —COOH or —COOR group, and when Z is an aryl group, Z comprises at least 3 substituents, or the quinoline nucleus is tri-substituted. 
       
     
     
         2 . The method according to  claim 1 , wherein said derivative is 8-hydroxy-2-[2-[3,4-dihydroxy-5-methoxyphenyl)ethenyl]]-7-quinoline carboxylic acid. 
     
     
         3 . The method according to  claim 1 , wherein said derivative is 8-hydroxy- 2- [2-[3,4-dihydroxyphenyl)ethenyl]]-7-quinoline carboxylic acid. 
     
     
         4 . The method according to  claim 1 , for the treatment of a retroviral pathology selected from the group consisting of HIV-1, HIV-2, SIV, and RSV pathologies. 
     
     
         5 . The method according to  claim 1 , for the treatment of AIDS. 
     
     
         6 . The method according to  claim 1 , wherein said derivatives are administered in multitherapies. 
     
     
         7 . A method for inhibiting integrase nuclear import, comprising administering an animal or human in need thereof with a derivative of formula I, a pharmaceutically acceptable salt thereof, a diastereoisomer thereof, or an enantiomeric form thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         Rb is H or Rb represents one or more substituents occupying any position on the rings, each Rb independently selected from the group consisting of —(CH 2 ) n— Y, and —CH═CH—Y; 
         Rc is selected from the group consisting of —(CH 2 ) n —Y and —CH═CH—Y; 
         Z is an aryl radical or a heterocyclic radical; 
         X is a double bond, a —(CH 2 ) n′ — group, or a —CH(Rd)—CH(Re)— group; 
         Y is a halogen atom, —OH, —OR, —CHO, —COR, —COOH, —COOR, —CONH 2 , —CONR x R y , —CH═NOH, —CO—CH═NOH, —NH 2 , —NR x R y , —NO 2 , —PO(OR) 2 , —SH, —SR, —SO 2 R, —SO 2 NHR, or CN; 
         R is an alkyl radical having 1 to 8 carbon atoms, an aryl radical, or a heterocyclic radical; 
         R x  and R y , are independently an alkyl radical with 1 to 5 carbon atoms; 
         Rd and Re are independently a hydrogen, a halogen atom, a hydroxy, or an epoxy group; 
         n is zero or an integer from 1 to 5; and 
         n′ is an integer from 1 to 5; 
         with the proviso that when Y in Rc is a —COOH or —COOR group, and when Z is an aryl group, Z comprises at least 3 substituents, or the quinoline nucleus is tri-substituted. 
       
     
     
         8 . The method according to  claim 7 , wherein said derivative is 8-hydroxy-2-[2-[3,4-dihydroxy-5-methoxyphenyl)ethenyl]]-7-quinoline carboxylic acid. 
     
     
         9 . The method according to  claim 7 , wherein said derivative is 8-hydroxy-2-[2-[3,4-dihydroxyphenyl)ethenyl]]-7-quinoline carboxylic acid. 
     
     
         10 . The method according to  claim 7 , wherein said derivative is administered in multitherapies.