Water-soluble porphyrin derivatives and methods of their preparation

Abstract

The invention relates to the chemistry of biologically active compounds, namely, to a new method to prepare water-soluble porphyrin derivatives, particularly chlorin derivatives having general formulae (1). The compounds of the present invention are useful as photosensitizers for the photodynamic therapy of cancer, of infectious and other diseases, as well as for light irradiation treatments in other cases. where: R 1 ═—CH═CH 2 , —CH(OAlk)CH 3 , —CHO, —C(O)CH 3 ; —CH 2 CH 3 ; —CH(Alk)CH(COAlk) 2 , —CH 2 CH(COAlk) 2 , —CH(Alk)CH 2 COAlk, —CH(Alk)CH 2 CH(OH)CH 3 , —CH 2 CH 2 CH(OH)CH 3 R 2 ═—CH 3 , —CHO, —CH(OH)Alk, —CH═CHAlk, CH 2 OH, CH 2 OAlk; R 3 ═H or lower allyl; G=hydrophilic organic amine (f. ex. N-methyl-D-glucamine and other amino-group containing carbohydrate derivatives, TRIS, aminoacids, oligopeptides). Alk=alkyl substituent.

We claim:  
     
         1 . A method to prepare water-soluble porphyrin derivatives, comprising steps of 
 a) a direct acidic alcoholysis of biological raw material giving crystalline alkyl pheophorbide;    b) conversion of the obtained alkyl pheophorbide into an acidic porphyrin in an aqueous-based solution;    c) interaction of the acidic porphyrin in the aqueous-based solution with a hydrophilic organic amine.    
     
     
         2 . A method of  claim 1 , wherein said biological raw material is selected from the group, comprising naturally occurring plants, algae, blood components, insect excretions.  
     
     
         3 . A method of  claim 2 , wherein naturally occurring plants and algae comprise  Spirulina Platensis, Spirulina maxima , Chlorella, nettle and spinach.  
     
     
         4 . A method of  claim 1 , wherein said direct acidic alcoholysis is preferably selected from the group methanolysis or ethanolysis.  
     
     
         5 . A method of  claim 1 , wherein said hydrophilic organic amine is selected from the group, comprising N-methyl-D-glucamine, amino alkyl glycosides, TRIS and derivatives thereof, aminoacids and oligopeptides and preferably is N-methyl-D-glucamine.  
     
     
         6 . A method of  claim 1 , wherein said aqueous-based solution is a solution in water.  
     
     
         7 . A method of  claim 1 , wherein said aqueous-based solution is an aqueous organic solution.  
     
     
         8 . A method to prepare water-soluble porphyrin derivatives, comprising the step of interaction of the acidic porphyrin in an aqueous-based solution with a hydrophilic organic amime.  
     
     
         9 . A method of  claim 8 , wherein said hydrophilic organic amine is selected from the group, comprising N-methyl-D-glucamine, amino alkyl glycosides, TRIS and derivatives thereof, aminoacids and oligopeptides, and preferably is N-methyl-D-glucamine. A method to prepare water-soluble porphyrin derivatives, comprising the steps of 
 a) a direct acidic alcoholysis of biological raw material giving crystalline alkyl pheophorbide;    b) conversion of the obtained alkyl pheophorbide into an acidic porphyrin in an aqueous-based solution;    c) interaction of the acidic porphyrin in the aqueous-based solution with a hydrophilic organic amine; and    d) purification of a water-soluble porphyrin derivative by reversed phase chromatography with the use of volatile solvents.    
     
     
         11 . A method of  claim 10 , wherein said biological raw material is selected from the group, comprising naturally occurring plants, algae, blood components, insect excretions.  
     
     
         12 . A method of  claim 11 , wherein naturally occurring plants and algae comprise  Spirulina Platensis, Spirulina maxima , Chlorella, nettle and spinach.  
     
     
         13 . A method of  claim 10 , wherein the direct acidic alcoholysis is preferably selected from the group: methanolysis or ethanolysis.  
     
     
         14 . A method of  claim 10 , wherein said hydrophilic organic amine is selected from the group, comprising N-methyl-D-glucamine, amino alkyl glycosides, TRIS and derivatives thereof, aminoacids and oligopeptides and preferably is N-methyl-D-glucamine.  
     
     
         15 . A method to prepare water-soluble porphyrin derivatives, comprising the steps of: 
 a) interaction of the acidic porphyrin in an aqueous-based solution with a hydrophilic organic amine,    b) purification of a water-soluble porphyrin derivative by reversed phase chromatography with the use of volatile solvents.    
     
     
         16 . A method of  claim 15 , wherein said hydrophllic organic amine is selected from the group, comprising N-methyl-D-glucamine, amino alkyl glycosides, TRIS and derivatives thereof, aminoacids and oligopeptides and preferably is N-methyl-D-glucamine.  
     
     
         17 . Water-soluble porphyrin derivatives according to formula 1 useful for medical applications and prepared by a method selected from the group:  claim 1 ,  claim 7 ,  claim 10  and  claim 15 .  
     
     
         18 . Defined mixtures of different water-soluble porphyrin derivatives of  claim 17  useful for medical applications.  
     
     
         19 . The use of water-soluble porphyrin derivatives of  claim 17  and  18  for photodynamic therapy of cancer, other hyperproliferative diseases and infections.  
     
     
         20 . Water-soluble porphyrin derivatives of  claim 17  and  18  in pharmaceutically active preparations.