Indazolecarboxamide derivatives for the treatment and prevention of malaria

Abstract

The invention relates to methods of treating or preventing malaria which comprises administering to a patient in need thereof, an effective amount of a 1H-indazole-3-carboxamide derivative of general formula (I), in the form of a base or of an addition salt with an acid, or in the form of a hydrate or of a solvate of said base or acid addition salt.

1 . A method of treating malaria or inhibiting  Plasmodium falciparum  parasite in a patient in need thereof, which comprises administering to said patient an effective amount of a compound corresponding to general formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         R 1  represents a hydrogen or a halogen atom, or a group —NH 2 , —NHR 2 , —NHCOR 2 , —NO 2 , —CN, —CH 2 NH 2  or —CH 2 NHR 2 ; 
         or else R 1  represents a phenyl optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and C 1-6  alkyl, C 1-6 alkoxy, —OH, —NH 2 , —NHR 2  and —NR 2 R 3  groups; 
         or else R 1  represents a heteroaromatic group optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and heteroaromatic, C 1-6  alkyl, —OH, —NH 2 , —NHR 2 , —NHCOR 2 , —COOR 2 , —CONH 2 , —CONHR 2  and —CH 2 XR 2  groups, where X is chosen from O, NH and S; 
         Ar represents a phenyl group optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and C 1-6  alkyl, C 1-6  thioalkyl, C 1-6  alkoxy, —CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, —NH 2 , —NHR 2 , —NR 2 R 3 , —NHSO 2 R 2 , —CN, —SO 2 R 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —COOH, —COOR 2 , —CONH 2 , —CONHNH 2 , —CONHR 2 , —CH 2 NHR 2  and —CH 2 NR 2 R 3  groups; 
         or else Ar represents a heteroaromatic group optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and C 1-6  alkyl, C 1-6  thioalkyl, C 1-6  alkoxy, —CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, —NH 2 , —NHR 2 , —NR 2 R 3 , —NHSO 2 R 2 , —CN, —SO 2 R 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —COON, —COOR 2 , —CONH 2 , —CONHNH 2 , —CONHR 2 , —CH 2 NHR 2  and —CH 2 NR 2 R 3  groups; 
         R 2  and R 3 , which may be identical to or different from one another, represent a C 1-6  alkyl group optionally substituted with a —CONH 2  group, with a phenyl group or with a heteroaromatic group; 
         or else R 2  and R 3 , which may be identical to or different from one another, represent a phenyl group or a heteroaromatic group; and 
         n is equal to 0, 1, 2 or 3, 
         provided that when R 1  is a heteroaromatic group, then Ar is not a heteroaromatic group. 
         or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein the compound of general formula (I) is such that:
 R 1  represents a heteroaromatic group optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and heteroaromatic, C 1-6  alkyl, —NH 2  and —CONHR 2  groups.   
     
     
         3 . The method according to  claim 1 , wherein the compound of general formula (I) is such that:
 Ar represents a phenyl group optionally substituted with one or two substituents chosen, independently of one another, from —NHSO 2 R 2 , —CN, —SO 2 R 2 , —SO 2 NH 2 , —SO 2 NHR 2  and —CH 2 NHR 2  groups;   or else Ar represents a heteroaromatic group optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and C 1-6  alkyl, C 1-6  thioalkyl, C 1-6  alkoxy, —CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, —NH 2 , —NHR 2 , —NR 2 R 3 , —NHSO 2 R 2 , —CN, —SO 2 R 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —COON, —COOR 2 , —CONH 2 , —CONHNH 2 , —CONHR 2 , —CH 2 NHR 2  and —CH 2 NR 2 R 3  groups.   
     
     
         4 . The method according to  claim 1 , wherein the compound of general formula (I) is such that:
 R 2  and R 3 , which may be identical to or different from one another, represent a C 1-6  alkyl group optionally substituted with a —CONH 2  group; or else R 2  and R 3 , which may be identical to or different from one another, represent a phenyl group or a heteroaromatic group.   
     
     
         5 . The method according to  claim 1 , wherein the compound of general formula (I) is such that:
 n is equal to 0 or 1.   
     
     
         6 . The method according to  claim 1 , wherein R 1  represents a pyrazolyl, thiazolyl, tetrazolyl, oxazolyl, pyridinyl, isoquinolinyl or pyrrolo[2,3-c]pyridinyl group. 
     
     
         7 . The method according to  claim 1 , wherein Ar represents a phenyl group optionally substituted with one or two substituents chosen, independently of one another, from —NHSO 2 R 2 , —CN, —SO 2 R 2 , —SO 2 NH 2 , —SO 2 NHR 2  and —CH 2 NHR 2  groups;
 or else Ar represents a pyridinyl group optionally substituted with one or two substituents chosen, independently of one another, from halogen atoms and C 1-6  alkyl, C 1-6  thioalkyl, C 1-6  alkoxy, —CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, —NH 2 , —NHR 2 , —NR 2 R 3 , —NHSO 2 R 2 , —CN, —SO 2 R 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —COON, —COOR 2 , —CONH 2 , —CONHNH 2 , —CONHR 2 , —CH 2 NHR 2  and —CH 2 NR 2 R 3  groups. 
 
     
     
         8 . The method according to  claim 1 , wherein R 2  and R 3 , which may be identical to or different from one another, represent a methyl or ethyl group optionally substituted with a —CONH 2  group; or else R 2  and R 3 , which may be identical to or different from one another, represent a phenyl group or a heteroaromatic group.