Synthesis of chlorins and phorbines with enhanced red spectral features

Abstract

The present invention provides compounds of the general Formula DI: along with methods of making such compounds, formulations containing the same, and methods of using the same (e.g., in photodynamic therapy, for the production of solar cells, etc.).

1 . A compound of Formula DI: 
       
         
           
           
               
               
           
         
       
       wherein:
 M is a metal or is absent; 
 X 1 , X 2 , X 3  and X 4  are each independently selected from the group consisting of Se, NH, CH 2 , O and S; 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 21 , R 22 , R 31  and R 32  are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, aryloxy, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, acyl, formyl, carboxylic acid, acylamino, ester, amide, hydroxyl, nitro, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acyloxy, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, aminoacyloxy, linking groups, surface attachment groups, bioconjugatable groups, targeting groups, and water soluble groups; 
 wherein each pair of R 1  and R 2 , R 3  and R 4 , R 11  and R 12 , R 13  and R 14 , R 21  and R 22 , or R 31  and R 32 , can together form ═O; 
 wherein each of R 1  and R 2 , R 3  and R 4 , R 11  and R 12 , or R 13  and R 14 , can together form spiroalkyl; 
 wherein R 2  and R 3  can together form a double bond; and wherein R 12  and R 13  can together form a double bond; 
 or a salt thereof; 
 subject to the proviso that: neither R 1  nor R 2  is H; or neither R 3  nor R 4  is H; or neither R 11  nor R 12  is H; or neither R 13  nor R 14  is H. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 R 1  and R 2  are both independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, and linking groups; or   R 3  and R 4  are both independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, and linking groups; or   R 11  and R 12  are both independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, and linking groups; or   R 13  and R 14  are both independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, and linking groups.   
     
     
         3 . The compound of  claim 1 , wherein:
 R 1  and R 2  are both independently selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, and linking groups; or   R 3  and R 4  are both independently selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, and linking groups; or   R 11  and R 12  are both independently selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, and linking groups; or   R 13  and R 14  are both independently selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, and linking groups.   
     
     
         4 . A method of making a compound of Formula DI: 
       
         
           
           
               
               
           
         
       
       wherein:
 M is a metal or is absent; 
 X 1 , X 2 , X 3  and X 4  are each independently selected from the group consisting of Se, NH, CH 2 , O and S; 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 21 , R 22 , R 31  and R 32  are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, aryloxy, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, acyl, formyl, carboxylic acid, acylamino, ester, amide, hydroxyl, nitro, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acyloxy, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, aminoacyloxy, linking groups, surface attachment groups, bioconjugatable groups, targeting groups, and water soluble groups; 
 wherein each pair of R 1  and R 2 , R 3  and R 4 , R 11  and R 12 , R 13  and R 14 , R 21  and R 22 , or R 31  and R 32 , can together form ═O; 
 wherein each of R 1  and R 2 , R 3  and R 4 , R 11  and R 12 , or R 13  and R 14 , can together form spiroalkyl; 
 wherein R 2  and R 3  can together form a double bond; and wherein R 12  and R 13  can together form a double bond; 
 said method comprising 
 (a) providing a compound of Formula DII: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is H or halo; and 
 M, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 31  and R 32  are as given above; 
 (b) cyclizing said compound of Formula DII by an intramolecular alpha arylation to produce a cyclized product; and 
 (c) optionally deoxygenating said product; and then 
 (d) optionally metalating said product to produce said compound of Formula DI. 
 
     
     
         5 . The method of  claim 4 , wherein R 31  and R 32  are each independently H, alkyl, or aryl;
 or one of R 31  and R 32  is H and the other is cyano;   or one of R 31  and R 32  is H and the other is ester.   
     
     
         6 . The method of  claim 4 , wherein R 31  and R 32  are each independently H or alkyl. 
     
     
         7 . The method of  claim 4 , wherein Z is halo. 
     
     
         8 . The method of  claim 4 , wherein Z is bromo. 
     
     
         9 . The method of  claim 4 , wherein said cyclizing step is carried out in an organic solvent. 
     
     
         10 . The method of  claim 4 , wherein said cyclizing step is carried out with a palladium catalyst in the presence of a base. 
     
     
         11 . The method of  claim 9 , wherein said palladium catalyst is (PPh 3 ) 2 PdCl 2 . 
     
     
         12 . The method of  claim 10 , wherein said base is Cs 2 CO 3 . 
     
     
         13 . The method of  claim 4 , wherein said compound of Formula DI has the structure of Formula DI′: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 4 , wherein Z is halo and said compound of Formula DII is produced by halogenating a compound of Formula DIII: 
       
         
           
           
               
               
           
         
       
       wherein M, X 1 , X 2 , X 3  X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 31  and R 32  are as given above. 
     
     
         15 - 29 . (canceled) 
     
     
         30 . A composition comprising:
 (a) an aqueous solvent; and   (b) from 1 microMolar to 500 milliMolar of a compound of claim  28  solubilized in said aqueous solvent.   
     
     
         31 . A pharmaceutical formulation comprising:
 (a) a pharmaceutically acceptable carrier; and   (b) a compound of claim  28  in said carrier.   
     
     
         32 . A method for treating a target in a subject in need thereof, comprising: (i) administering to said subject the compound of claim  28  or a pharmaceutically acceptable conjugate thereof that preferentially associates with the target, and (ii) irradiating the target with light of a wavelength and intensity sufficient to treat said target. 
     
     
         33 . In a light harvesting rod, the improvement comprising utilizing a compound of claim  28  as at least one chromophore therein. 
     
     
         34 . In a solar cell, the improvement comprising utilizing a compound of claim  28  as a chromophore or photosensitizer therein.