Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs

Abstract

The invention relates to a method for improving the bioavailability of pharmaceutical substances and for allowing the pharmaceutical substances to permeate the blood-brain barrier, the pharmaceutical substances having at least one or more amidine, guanidine, N-hydroxyamidine (amidoxime) or N-hydroxyguanidine functions. The invention also relates to medicaments containing the correspondingly modified pharmaceutical substances.

1 . A method comprising using a partial structure forming formula (I) or formula (II), 
       
         
           
           
               
               
           
         
       
       as a constituent of the overall structure of a prodrug that is a prodrug for a medicinal substance, wherein n=0, . . . , 12 and R1 is selected from the group consisting of hydrogen, an alkyl radical and aryl radical. 
     
     
         2 . The method according to  claim 1 , wherein the partial structure of formula (I) or (II) is used as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of the prodrug for improving the solubility, bioavailability and/or capacity of the medicinal substance to pass the blood-brain barrier. 
     
     
         3 . The method according to  claim 1 , wherein the medicinal substance is selected from the group consisting of protease inhibitors, DNA-intercalating compounds, RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists. 
     
     
         4 . The method according to  claim 3 , wherein the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII or all of the proteases of the coagulation cascade, or a matriptase inhibitor. 
     
     
         5 . The method according to  claim 3 , wherein the DNA-intercalating or RNA-intercalating compound is pentamidine, diminazene or isometamidium. 
     
     
         6 . The method according to  claim 3 , wherein the inhibitor of viral enzymes is a neuraminidase inhibitor. 
     
     
         7 . The method according to  claim 1 , wherein the overall structure of the prodrug comprises a plurality of at least one of the partial structures of formula (I) and formula (II). 
     
     
         8 . The method according to  claim 1 , wherein the medicinal substance is configured for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2 nd  phase of trypanosomiasis, or pneumonia caused by  pneumocystis carinii , for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, or for combating viral infections. 
     
     
         9 . The method according to  claim 1 , wherein the prodrug is pentamidine succinic acid ester. 
     
     
         10 . A prodrug comprising a partial structure having the formula (I) or (II), 
       
         
           
           
               
               
           
         
       
       wherein n=0, . . . , 12, and R 1  is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical, the prodrug is a prodrug for a medicinal substance, and the medicinal substance is selected from the group consisting of protease inhibitors, DNA-intercalating compounds, RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists. 
     
     
         11 . The prodrug according to  claim 10 , wherein the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII or all of the proteases of the coagulation cascade, or a matriptase inhibitor. 
     
     
         12 . The prodrug according to  claim 10 , wherein the DNA-intercalating or RNA-intercalating compound is pentamidine, diminazene or isometamidium. 
     
     
         13 . The prodrug according to  claim 10 , wherein the inhibitor of viral enzymes is a neuraminidase inhibitor. 
     
     
         14 . The prodrug according to  claim 10 , wherein the medicinal substance is configured for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2 nd  phase of trypanosomiasis, or pneumonia caused by  pneumocystis carinii , for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, and for combating viral infections. 
     
     
         15 . The prodrug according to  claim 10 , wherein the overall structure of the prodrug comprises a plurality of at least one of the partial structures of formula (I) and formula (II). 
     
     
         16 . The prodrug according to  claim 10 , wherein the prodrug is pentamidine succinic acid ester.