New compounds for the treatment and/or prevention of parasitic diseases and method of production of thereof

Abstract

Disclosed are new compounds for treating, preventing or inhibiting a parasitic disease, preferably toxoplasmosis in a subject, the method for preparing thereof.

1 . Compound of formula (I′): 
       
         
           
           
               
               
           
         
         wherein: 
         n is a natural number chosen from 0, 1, and 2, 
         X is chosen from 
       
       
         
           
           
               
               
           
         
         Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, which is a fluor atom, a thiazolyl, or a group chosen from: —OR 1  in meta position, —R 2 —O—R 1 , wherein R 1  represents a C1-C 8 -alkyl, which is eventually substituted by a halogen, R 2  represents a C 1 -C 8  alkylene group eventually substituted by a halogen, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . Compound of formula (I′) according to  claim 1 , wherein Ar is chosen from
 i) a phenyl substituted at the meta-, para-, or ortho-position by a fluor or a thiazolyl, or 
 ii) a benzyl substituted at the meta-position by an C1 to C4 alkoxy group. 
 
     
     
         3 . Compound of formula (I′) according to  claim 1 , wherein
 n is a natural number chosen from 0, 1, and 2, 
 X is chosen from 
 
       
         
           
           
               
               
           
         
         Ar is a benzyl substituted at the meta-position by a methoxy group, 
       
       said compound corresponding to formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         4 . Compound of formula (Ia) according to  claim 3 ,
 wherein either n is 0 and X is   
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ia1),
 or wherein n is 1 and X is 
 
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ia2). 
     
     
         5 . Compound of formula (I′) according to  claim 1 , wherein
 n is a natural number chosen from 0, 1, and 2, 
 X is chosen from 
 
       
         
           
           
               
               
           
         
         Ar is a phenyl substituted at the meta-position by a fluor, 
       
       said compound corresponding to formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         6 . Compound of formula (Ib) according to  claim 5 ,
 wherein either n is 1 and X is   
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ib1),
 or wherein n is 0 and X is 
 
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ib2),
 or wherein n is 1 and X is 
 
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ib3),
 or wherein n is 0 and X is 
 
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ib4). 
     
     
         7 . Compound of formula (I′) according to  claim 1 , wherein
 n is a natural number chosen from 0, 1 and 2, 
 X is chosen from 
 
       
         
           
           
               
               
           
         
         Ar is a phenyl substituted at para position by 
       
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ic): 
       
         
           
           
               
               
           
         
       
     
     
         8 . Compound of formula (Ic) according to  claim 7 ,
 wherein either n is 1 and X is   
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ic1),
 or wherein n is 0 and X is 
 
       
         
           
           
               
               
           
         
       
       said compound corresponding to formula (Ic2). 
     
     
         9 . A method for treating, inhibiting or preventing a parasitic disease in a mammalian subject, including human, cat or dog, comprising applying an effective amount of the compound of formula (I′) of  claim 1  in the form of a pharmaceutical drug. 
     
     
         10 . The method of  claim 9 , wherein the parasitic disease is caused by a protozoan parasite of the family of the Trypanosomatidae selected from the genus  Trypanosoma  or the genus  Leishmania , or the parasite  Toxoplasma gondii.    
     
     
         11 . A method for treating toxoplasmosis, comprising applying an effective amount of the compound of formula (Ia1) of  claim 4  in the form of a pharmaceutical drug. 
     
     
         12 . A pharmaceutical composition comprising a compound of formula (I′) according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient. 
     
     
         13 . A pharmaceutical composition comprising:
 a compound of formula (I′) according  claim 1 , or a pharmaceutically acceptable salt thereof, and   at least one anti-parasitic compound, selected from the group comprising: miltefosin, antimony based drugs, like meglumine antimoniate or sodium stibogluconate, amphotericin B, benzimidazol, nifurtimox, paromomycin, pentamidin and its derivatives, arsenic derivatives, melarsoprol and difluoromethylornithin.   
     
     
         14 . Method for preparing a compound of formula (I′) according to  claim 1 , comprising the following steps:
 (i) the reaction between a compound of formula II′ 
 
       
         
           
           
               
               
           
         
         wherein n is a natural number chosen from 0, 1 and 2, 
         with a compound of formula III′: Ar—X—Cl, wherein
 X is chosen from 
 
       
       
         
           
           
               
               
           
         
         
           
             Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, which is a fluor atom, a thiazolyl, or a group chosen from: —OR 1  in meta position, —R 2 —O—R 1 , wherein R 1  represents a C 1 -C 8 -alkyl, which is eventually substituted by a halogen, R 2  represents a C 1 -C 8  alkylene group eventually substituted by a halogen, 
           
         
         to obtain a compound of formula IV′ 
       
       
         
           
           
               
               
           
         
         wherein:
 n is a natural number chosen from 0, 1 and 2, 
 X is chosen from 
 
       
       
         
           
           
               
               
           
         
         
           
             Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, which is a fluor atom, a thiazolyl, or a group chosen from: —OR 1  in meta position, —R 2 —O—R 1 , wherein R 1  represents a C 1 -C 8 -alkyl, which is eventually substituted by a halogen, R 2  represents a C 1 -C 8  alkylene group eventually substituted by a halogen, 
           
         
         (ii) the reaction between the compound of formula IV′ and a base to obtain a compound of formula V′ 
       
       
         
           
           
               
               
           
         
         wherein n, X and Ar respectively has the same definition of that for formula IV′, said compound of formula V′ is eventually acidified, 
         and M +  represents a metallic cation; 
         (iii) the reaction between the compound of formula V′ and hydroxylamine to obtain the compound of formula I′. 
       
     
     
         15 . A method for treating, inhibiting or preventing a parasitic disease in a mammalian subject, including human, cat or dog, comprising applying an effective amount of a pharmaceutical drug comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 n is a natural number chosen from 0, 1 and 2, 
 X is chosen from 
 
       
         
           
           
               
               
           
         
         Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, a thiazolyl, or a group chosen from: —R 1 , —OR 1 , —R 2 —O—R 1 , wherein R 1  represents a C 1 -C 8 -alkyl, which is eventually substituted by a halogen, R 2  represents a C 1 -C 8  alkylene group eventually substituted by a halogen, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound of  claim 1 , wherein Ar is a phenyl. 
     
     
         17 . The compound of  claim 1 , wherein Ar is a benzyl. 
     
     
         18 . The compound of  claim 1 , wherein the halogen is a fluor atom. 
     
     
         19 . The compound of  claim 1 , wherein the halogen is a thiazolyl. 
     
     
         20 . The compound of  claim 2 , wherein the C1 to C4 alkoxy group is a methoxy group.