Compounds derived from artesunate, preparation process, pharmaceutical composition and use of the respective medicine

Abstract

The present invention refers to new compounds represented by the general formula (I) where X is represented by the general formula (II) and Y is represented by the general formula (III). The relation X to Y may vary from 1:1 to 1:7. The radicals R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 in formula (II) are represented by: R 1 ═H, CF 3 , CH 3 , OCH 3 , NH 2 , halogen; R 2 ═H, CH 3 , NH 2 , halogen, NH—CHCH 3 (CH 2 ) 3 N(C 2 H 5 )(CH 2 CH 2 OH), CH(OH)-2(C 5 H 11 N), NH—R 7 —N—(C 2 H 5 ) 2 ; R 3 ═H, m-OC 6 H 4 CF 3 , NH 2 ; R 4 ═H, CH 3 , OCH 3 , NH 2 , halogen; R 5 ═H, CH 3 , CF 3 , NH 2 , halogen; R 6 ═H, CF 3 , CH 3 , NH 2 , halogen, NH—R 8 —N—(C 2 H 5 ) 2 , NHCH(CH 3 )(CH 2 ) 3 NH 2 ; R 7 ═(CH 2 ) 2 , (CH 2 ) 3 , CHCH 3 CH 2 , (CH 2 ) 4 , (CH 2 ) 5 , CHCH 3 (CH 2 ) 3 , (CH 2 ) 6 , (CH 2 ) 8 , (CH 2 ) 10 , (CH 2 ) 12 ; R 8 ═CHCH 3 (CH 2 ) 3 , CHCH 3 (CH 2 )CHCH 3 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 6 , (CH 2 ) 3 O(CH 2 ) 3 . This invention also refers to a process of preparation of these compounds (formula I), and antiparasitic pharmaceutical compositions thereof.

1 . A compound derived from artesunate salts, characterized by the fact that it is represented by the general formula 1:
   X + Y −     
       where X is represented by the general formula II: 
       
         
           
           
               
               
           
         
       
       and Y is represented by the general formula III: 
       
         
           
           
               
               
           
         
       
       wherein R 1 ═R 2 ═R 3 ═R 5 ═H; R 4 ═OCH 3  and R 6 ═NHCH(CH 3 )(CH 2 ) 3 NH 2 ; and X to Y equals 1:1. 
     
     
         2 . Preparation process of the artesunate derived compound, as defined by  claim 1 , characterized by the fact it comprises the following stages:
 a) solubilization of primaquine, represented by the general formula II, wherein R 1 ═R 2 =R 3 ═R 5 =H; R 4 ═OCH 3  and R 6 ═NHCH(CH 3 )(CH 2 ) 3 NH 2 , as a free base form in organic solvents;   b) solubilization of artesunate, represented by the general formula III, in organic solvents;   c) addition of the artesunate solution (stage b) to the primaquine solution (stage a) in order to obtain derivatives of artesunate salts of primaquine;   d) solvent evaporation for salt precipitation;   e) salt filtration in order to obtain derivatives of artesunate salts of primaquine as a solid product.   
     
     
         3 . Preparation process according to  claim 2 , characterized by the fact that base-free primaquine may be obtained through the following stages:
 i) solubilization of primaquine salt in selected polar solvents such as water, water/aliphatic alcohol from C 1  to C 6  and ether;   ii) primaquine conversion into base-free salt, using a saturated aqueous solution of inorganic base;   iii) extraction of primaquine in base-free form using organic solvents;   iv) drying of the organic phase with desiccant agents;   v) organic solvent evaporation to obtain primaquine in base-free form.   
     
     
         4 . Preparation process according to  claim 3 , characterized by the fact that stage (i) ether may be selected among diethylether, t-butylmethylether, tetrahydrofuran, and 1,2-dimetoxyethane. 
     
     
         5 . Preparation process according to  claim 3 , characterized by the fact that in the conversion of primaquine in its base-free form, stage (ii), it is employed an inorganic base selected among sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, and sodium bicarbonate. 
     
     
         6 . Preparation process of compounds derived from artesunate and primaquine according to  claim 3  characterized by the fact that in the organic phase drying, stage (iv), desiccant agents may be selected among anhydrous sodium sulphate, anhydrous magnesium sulphate, and calcium chloride. 
     
     
         7 . Preparation process of compounds derived from artesunate and primaquine according to  claim 2  characterized by the fact that the organic solvents of stages (a), (b) and (iii) are selected among ethers, halogenide solvent and alcohols. 
     
     
         8 . Preparation process of compounds derived from artesunate according to  claim 7 , characterized by the fact that ethers may be selected among diethylether, t-butylmethylether, tetrahydrofuran and 1,2-dimetoxyethanol. 
     
     
         9 . Preparation process of compounds derived from artesunate according to  claim 7 , characterized by the fact that halogenide solvents may be either dichlorometan or chloroform. 
     
     
         10 . Preparation process of compounds derived from artesunate according to  claim 7 , characterized by the fact that alcohols may be aliphatic from C 1  to C 6 . 
     
     
         11 . Pharmaceutical composition characterized by an active ingredient, present in an effective amount of one of the derivatives of artesunate salts with primaquine as defined in  claim 1  and an acceptable pharmaceutical vehicle. 
     
     
         12 . Pharmaceutical composition according to  claim 11 , characterized by the fact that the active ingredient ranges from 0.1 to 99% of composition weight. 
     
     
         13 . Pharmaceutical composition according to  claim 12 , characterized by the fact that the active ingredient may be in a concentration that ranges from 0.25 to 99% of the composition weight. 
     
     
         14 . Pharmaceutical composition according to  claim 13 , characterized by the fact that it is employed in the treatment or prevention of malaria. 
     
     
         15 . Method of treatment, prevention or inhibition of malaria characterized by the use of a therapeutically effective amount of a general formula I compound of  claim 1  for the human being, who needs the referred treatment, prevention or inhibition. 
     
     
         16 . A compound according to  claim 1 , characterized by the fact that the compounds are employed in the treatment or prevention from malaria.