Conjugated psychotropic drugs and uses thereof

Abstract

Novel chemical conjugates of psychotropic drugs and organic acids, uses thereof in the treatment of psychotic and/or proliferative disorders and diseases and as chemosensitizing agents, and their syntheses are disclosed. The organic acids are selected to reduce side effects induced by the psychotropic drugs and/or to exert an anti-proliferative activity.

1 . A chemical conjugate comprising a first chemical moiety being covalently linked to a second chemical moiety, wherein said first chemical moiety is a residue of fluphenazine and wherein said second chemical moiety is a residue of a γ-aminobutyric acid (GABA). 
     
     
         2 . The chemical conjugate of  claim 1 , comprising fluphenazine 4-aminobutyrate. 
     
     
         3 . The chemical conjugate of  claim 1 , wherein said second chemical moiety is covalently linked to said first chemical moiety via a carboxylic ester bond. 
     
     
         4 . A pharmaceutical composition comprising, as an active ingredient, the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         5 . The pharmaceutical composition of  claim 4 , being packaged in a packaging material and identified in print, on or in said packaging material, for use in the treatment of a psychotropic disorder or disease. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein said psychotropic disorder or disease is selected from the group consisting of schizophrenia, paranoia, childhood psychoses, Huntington's disease, Gilles de la Tourette's syndrome, depression, manic depression, anxiety, Parkinson disease, Alzheimer disease and epilepsy. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein said psychotropic disorder or disease is schizophrenia. 
     
     
         8 . The pharmaceutical composition of  claim 4 , being packaged in a packaging material and identified in print, on or in said packaging material, for use in the treatment of a proliferative disorder or disease. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said proliferative disorder or disease is selected from the group consisting of a brain tumor, a brain metastase and a peripheral tumor. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein said proliferative disorder is cancer. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein said cancer is a multidrug resistant cancer. 
     
     
         12 . The pharmaceutical composition of  claim 4 , being packaged in a packaging material and identified in print, on or in said packaging material, for use in chemosensitization, in combination with a chemotherapeutic agent and/or in a medical condition for which chemosensitization is beneficial. 
     
     
         13 . A method of treating a psychotropic disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chemical conjugate of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein said psychotropic disease or disorder is schizophrenia. 
     
     
         15 . The method of  claim 13 , wherein said chemical conjugate is administered intraperitoneally. 
     
     
         16 . The method of  claim 13 , wherein said chemical conjugate is administered orally. 
     
     
         17 . A method of treating a proliferative disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chemical conjugate of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein said proliferative disease or disorder comprises a brain tumor, a brain metastase and a peripheral tumor. 
     
     
         19 . The method of  claim 17 , wherein said proliferative disease or disorder is cancer. 
     
     
         20 . The method of  claim 19 , wherein said cancer is multidrug resistant cancer. 
     
     
         21 . A method of synthesizing the chemical conjugate of  claim 1 , the method comprising:
 reacting said γ-aminobutyric acid and said fluphenazine, so as to obtain said residue of said γ-aminobutyric acid covalently linked to said residue of said fluphenazine.   
     
     
         22 . The method of  claim 21 , wherein said residue of said γ-aminobutyric acid is covalently linked to said residue of said fluphenazine via a carboxylic ester bond, the method further comprising, prior to said reacting:
 converting said carboxylic group of said organic acid into an acyl chloride group. 
 
     
     
         23 . The method of  claim 22 , wherein said reacting is performed under basic conditions. 
     
     
         24 . The method of  claim 21 , further comprising:
 protecting an amino group of said γ-aminobutyric acid with a protecting group, prior to said reacting, so as to obtain by said reacting an amino-protected residue of said γ-aminobutyric acid covalently linked to said residue of said fluphenazine; and   removing said protecting group after obtaining said amino-protected residue of said γ-aminobutyric acid covalently linked to said residue of said fluphenazine.   
     
     
         25 . The method of  claim 24 , further comprising, after said protecting and prior to said reacting:
 converting said free carboxylic group in said γ-aminobutyric acid into an acyl imidazole group.