High-purity texaphyrin metal complexes
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.
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 − , CO − , 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 phophoramide.
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 9 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.