High-purity texaphyrin metal complexes

Abstract

Disclosed herein are the methods and compositions for the improved synthesis of texaphyrin metal complexes. The improved synthesis results in high-purity compositions of texaphyrin metal complexes in which more than about 98% of the texaphyrin metal complexes in the composition have the same structure and/or the same molecular weight. Further described herein are pharmaceutical compositions comprising such high-purity compositions, and the use of such high-purity compositions in the treatment of cancer and cardiovascular diseases and disorders.

What is claimed is: 
     
         1 . A high-purity composition comprising a compound according to Formula 1 
       
         
           
           
               
               
           
         
       
       wherein: M is a trivalent metal cation selected from the group consisting of Gd +3 , and Lu +3 ; each X is independently selected from the group consisting of OH − , AcO − , Cl − , Br − , I − , F − , H 2 PO 4   − , ClO − , ClO 2   − , ClO 3   − , ClO 4   − , HCO 3   − , HSO 4   − , NO 3   − , N 3   − , CN − , SCN − , and OCN −  R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently H, OH, C n H (2n+1) O y  or OC n H (2n+1) O y  and R 1 , R 2  are independently H or C 1 -C 6  alkyl where
 at least one of R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is C n H (2n+1) O y  or OC n H (2n+1) O y , having at least one hydroxyl substituent; 
 n is a positive integer from 1 to 11; y is zero or a positive integer less than or equal to n; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; 
 wherein at least about 98.4% of compounds of Formula 1 in the composition have the same structure. 
 
     
     
         2 . The composition of  claim 1  wherein M is Gd +3 . 
     
     
         3 . The composition of  claim 2  wherein R 4  and R 7  are C 3 H 6 OH; R 5  and R 6  are C 2 H 5 ; R 3  and R 8  are CH 3 ; R 1  and R 2  are H. 
     
     
         4 . The composition of  claim 3  wherein each x is 3. 
     
     
         5 . The composition of  claim 4  wherein each X is AcO − . 
     
     
         6 . The composition of  claim 1  wherein at least about 99.3% of the compounds of Formula 1 in the purified composition have the same molecular weight. 
     
     
         7 . The composition of  claim 1  wherein at least about 99.3% of the compounds of Formula 1 in the purified composition have the same structure. 
     
     
         8 . A method for synthesizing a purified sample of a compound of Formula 4 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently H or C 1 -C 6  alkyl; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; and wherein at least about 99% of the compounds of Formula 4 in the purified sample have the same structure 
       comprising:
 reacting a compound of Formula 5 
 
       
         
           
           
               
               
           
         
       
       with about 90% HNO 3  in AcOH at about 0-5° C. for at least 30 minutes, wherein at least about 99% of the compound of Formula 4 formed in the purified sample has the same molecular weight. 
     
     
         9 . The method of  claim 8  wherein each x is 3. 
     
     
         10 . The method of  claim 8  wherein at least about 99.3% of the compounds of Formula 4 in the purified sample have the same structure. 
     
     
         11 . The method of  claim 8 , wherein the compound of Formula 5 is provided as a purified sample synthesized by a method comprising:
 reacting tosylated compound of Formula 7   
       
         
           
           
               
               
           
         
       
       with o-dihydroxybenzene of Formula 6 
       
         
           
           
               
               
           
         
       
       in the presence of K 2 CO 3  and an aprotic solvent and heating the mixture at about 65° C. for about 24 hr, wherein at least about 98.4% of the compounds of Formula 5 formed in the purified sample have the same structure. 
     
     
         12 . The method of  claim 11  wherein said aprotic solvent is selected from the group consisting of aldehydes, ketones, dimethyl sulfoxide, dimethyl formamide, pyridine, diethyl ether, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetonitrile, benzonitrile, sulfur dioxide, tetrahydrofuran, and hexamethyl phosphoramide. 
     
     
         13 . The method of  claim 12  wherein said aprotic solvent is tetrahydrofuran. 
     
     
         14 . The method of  claim 11  wherein each x is 3. 
     
     
         15 . The method of  claim 11  wherein at least about 99.3% of the compounds of Formula 5 in the purified sample have the same structure. 
     
     
         16 . A pharmaceutical composition comprising a compound according to Formula 1 
       
         
           
           
               
               
           
         
       
       wherein: M is a trivalent metal cation selected from the group consisting of Gd +3 , and Lu +3 ; each X is independently selected from the group consisting of OH − , AcO − , Cl − , Br − , I − , F − , H 2 PO 4   − , ClO − , ClO 2   − , ClO 3   − , ClO 4   − , HCO 3   − , HSO 4   − , NO 3   − , N 3   − , CN − , SCN − , and OCN − ; R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently H, OH, C n H (2n+1) O y  or OC n H (2n+1) O y  and R 1 , R 2  are independently H or C 1 -C 6  alkyl where
 at least one of R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is C n H (2n+1) O y  or OC n H (2n+1) O y , having at least one hydroxy substituent; 
 n is a positive integer from 1 to 11; y is zero or a positive integer less than or equal to n; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; 
 
       and a pharmaceutically acceptable carrier, wherein at least about 98.4% of the compounds of Formula 1 in the pharmaceutical composition have the same structure. 
     
     
         17 . The pharmaceutical composition of  claim 16  wherein M is Gd +3 . 
     
     
         18 . The pharmaceutical composition of  claim 17  wherein R 4  and R 7  are C 3 H 6 OH; R 5  and R 6  are C 2 H 5 ; R 3  and R 8  are CH 3 ; R 1  and R 2  are H. 
     
     
         19 . The pharmaceutical composition of  claim 18  wherein each x is 3. 
     
     
         20 . The pharmaceutical composition of  claim 19  wherein each X is AcO − . 
     
     
         21 . The pharmaceutical composition of  claim 16  wherein at least about 99.3% of the compounds of Formula 1 in the pharmaceutical composition have the same molecular weight. 
     
     
         22 . The pharmaceutical composition of  claim 16  wherein at least about 99.3% of the compound of Formula 1 in the pharmaceutical composition have the same structure. 
     
     
         23 . The pharmaceutical composition of  claim 16  wherein the pharmaceutically acceptable carrier is suitable for parenteral administration. 
     
     
         24 . A method of treating a cancer comprising administering to a human patient in need thereof an effective amount of a purified composition comprising a compound of Formula 1 
       
         
           
           
               
               
           
         
       
       wherein: M is a trivalent metal cation selected from the group consisting of Gd +3 , and Lu +3 ; X is independently selected from the group consisting of OH − , AcO − , Cl − , Br − , I − , F − , H 2 PO 4   − , ClO − , ClO 2   − , ClO 3   − , ClO 4   − , HCO 3   − , HSO 4   − , NO 3   − , N 3   − , CN − , SCN − , and OCN − ; R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently H, OH, C n H (2n+1) O y  or OC n H (2n+1) O y  and R 1 , R 2  are independently H or C 1 -C 6  alkyl where
 at least one of R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is C n H (2n+1) O y  or OC n H (2n+1) O y , having at least one hydroxyl substituent; 
 n is a positive integer from 1 to 11; y is zero or a positive integer less than or equal to n; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; and wherein at least about 98.4% of the compounds of Formula 1 in the purified composition have the same molecular weight; 
 
       or a pharmaceutically acceptable salt, solvate, isomers, tautomers, metabolites, analogs, or prodrugs thereof. 
     
     
         25 . The method of  claim 24  wherein M is Gd +3 . 
     
     
         26 . The method of  claim 25  wherein R 4  and R 7  are C 3 H 6 OH; R 5  and R 6  are C 2 H 5 ; R 3  and R 8  are CH 3 ; R 1  and R 2  are H. 
     
     
         27 . The method of  claim 26  wherein each x is 3. 
     
     
         28 . The method of  claim 27  wherein each X is AcO − . 
     
     
         29 . The method of  claim 24  wherein at least about 99.3% of the compounds of Formula 1 in the purified sample have the same molecular weight. 
     
     
         30 . The method of  claim 24  wherein at least about 99.3% of the compounds of Formula 1 in the purified sample have the same structure. 
     
     
         31 . The method of  claim 24  further comprising providing to the human patient an additional therapy selected from the group consisting of surgery, radiation therapy, chemotherapy, gene therapy, immunotherapy, or a combination thereof. 
     
     
         32 . The method of  claim 24  wherein the cancer is metastatic brain cancer.