USE OF PHTHALIMIDE AND/OR SULPHONAMIDE DERIVATIVES IN THE TREATMENT OF DISEASES WHICH REQUIRE REDUCING THE TNF-alpha LEVELS AND AN EXOGENOUS SOURCE OF NITRIC OXIDE, PHTHALIMIDE DERIVATIVES, SULPHONAMIDE DERIVATIVES, AND A METHOD FOR OBTAINING A SULPHONAMIDE DERIVATIVE

Abstract

The present invention refers to the use of phthalimide and/or sulphonamide derivatives with nitric oxide donor properties, which have important activities in increasing the gamma-globin gene expression and anti-inflammatory and analgesic activities, effective in the treatment of hematologic diseases which require reducing the TNF-α levels and an exogenous source of nitric oxide. More particularly, the present invention describes the use of such phthalimide and/or sulphonamide derivatives for the treatment of sickle-cell disease. The invention also has as a novel characteristic the disclosure of new functionalized phthalimide derivatives designed from the prototypes thalidomide and hydroxyurea, and designed rationally through the strategy of molecular hybridization for the treatment of said diseases. The invention still discloses a new method for obtaining a specific sulphonamide derivative which can be used in the preparation of a drug for the treatment of diseases which require reducing the levels of the TNF-α factor and an exogenous source of nitric oxide.

1 . Use of a compound of general formula (I) 
       
         
           
           
               
               
           
         
         Where: 
         W═H, halogen, NO 2 , NH 2 , OH, C 1 -C 6  alcoxy, C 1 -C 6  haloalcoxy, C 1 -C 6  haloalkyl; R corresponds to C 1 -C 7  alkyl, 2-phenyl, 3-phenyl, 4-phenyl, 2-benzyl, 3-benzyl, 4-benzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, benzyl, thiophene, furan, pyrrole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, pyrimidine, benzothiophene, benzofuran, indole, quinoline, isoquinoline, naphthalene, CH 2 -2-thiophene, CH 2 -3-thiophene, CH 2 -2-furan, CH 2 -3-furan, CH 3 CH 2 -2-thiophene, CH 3 CH 2 -3-thiophene, CH 3 CH 2 -2-furan, CH 3 CH 2 -3-furan; R′ corresponds to O—NO 2   −  or SO 2 NHOH or furoxan or any pharmaceutically-acceptable salt thereof, characterized by being for the preparation of a drug for the treatment of diseases which require reducing the levels of the TNF-α factor and an exogenous source of nitric oxide. 
       
     
     
         2 . Use according to  claim 1 , characterized by the compound being of formula (IA) 
       
         
           
           
               
               
           
         
       
     
     
         3 . Use according to  claim 1 , characterized by the compound being of formula (IB) 
       
         
           
           
               
               
           
         
       
     
     
         4 . Use according to  claim 1 , characterized by the compound being of formula (IC) 
       
         
           
           
               
               
           
         
       
     
     
         5 . Use according to  claim 1 , characterized by the compound being of formula (ID) 
       
         
           
           
               
               
           
         
       
     
     
         6 . Use according to  claim 1 , characterized by the compound being of formula (IE) 
       
         
           
           
               
               
           
         
       
     
     
         7 . Use of a compound of general formula (II)
   W—R 1 —SO 2 NHR 2    II
   wherein W═H, halogen, NO 2 , NH 2 , OH, C 1 -C 6  alcoxy, C 1 -C 6  haloalcoxy, C 1 -C 6  haloalkyl , R 1  corresponds to 2-phenyl, 3-phenyl, 4-phenyl, 2-benzyl, 3-benzyl, 4-benzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, benzyl, thiophene, furan, pyrrole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, pyrimidine, benzothiophene, benzofuran, indole, quinoline, isoquinoline, naphthalene, CH 2 -2-thiophene, CH 2 -3-thiophene, CH 2 -2-furan, CH 2 -3-furan, CH 3 CH 2 -2-thiophene, CH 3 CH 2 -3-thiophene, CH 3 CH 2 -2-furan, CH 3 CH 2 -3-furan; R 2  corresponds to OH, H, C(═O)NHOH, C(═S)NHOH, C(═O)NOH (C 6 H 5 ); or any pharmaceutically acceptable salt thereof, characterized by being for the preparation of a drug for the treatment of diseases which require reducing the levels of the TNF-α factor and an exogenous source of nitric oxide.   
     
     
         8 . Use according to  claim 7 , characterized by the compound being of formula (IIA) 
       
         
           
           
               
               
           
         
       
     
     
         9 . Use according to  claim 1 , characterized by being for the treatment of sickle-cell disease. 
     
     
         10 . Pharmaceutical composition for the treatment of diseases which require reducing the levels of the TNF-α factor and an exogenous source of nitric oxide characterized by comprising the compound as defined in  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         11 . Method for obtaining the compound of formula (IIA) 
       
         
           
           
               
               
           
         
         Characterized in that it comprises the following steps: 
         a) mixing, in a suitable container, hydroxylamine hydrochloride, sodium bicarbonate and water; 
         b) adding ethanol to the mixture obtained in step a; 
         c) adding 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzenesulphonyl chloride to the mixture obtained in step b. 
       
     
     
         12 . Method for obtaining according to  claim 11 , characterized in that the addition of ethanol in step b) occurs only after the elimination of the CO 2  released in step a). 
     
     
         13 . Method for obtaining according to  claim 11 , characterized in that after step c), the solvent is evaporated and the obtained product is washed with hot dichloromethane. 
     
     
         14 . Compound characterized by being of formula (IC) 
       
         
           
           
               
               
           
         
       
     
     
         15 . Compound characterized by being of formula: