High-purity texaphyrin metal complexes
View Patent ↗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. In a process for synthesizing a purified sample of a compound of Formula 1:
wherein:
M is Gd 3+ or 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 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; and
each x is independently selected from the group consisting of 1, 2, 3, 4, 5, and 6;
the improvement comprises synthesizing a purified sample of a compound of Formula 1 wherein each x is 3 in at least about 98.4% of compounds of Formula 1 in the purified sample;
the process comprising the steps of:
i. pegylating a compound of Formula 6 comprising reacting a compound of Formula 7
with an o-dihydroxybenzene of Formula 6:
in tetrahydrofuran to provide a compound of Formula 5 having the structure:
2. In a process for synthesizing a purified sample of a compound of Formula 1:
wherein:
M is Gd 3+ or 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 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; and
each x is independently selected from the group consisting of 1, 2, 3, 4, 5, and 6;
the improvement comprises synthesizing a purified sample of a compound of Formula 1 wherein each x is 3 in at least about 98.4% of compounds of Formula 1 in the purified sample;
the process comprising the steps of:
i. pegylating a compound of Formula 6 comprising reacting a compound of Formula 7
with an o-dihydroxybenzene of Formula 6:
in tetrahydrofuran to provide a compound of Formula 5 having the structure:
wherein the compound of Formula 5 is used directly in the next step without purification;
ii. nitration of the compound of Formula 5 to provide a compound of Formula 4 and having the structure:
iii. reduction of a compound of Formula 4 to provide a phenylenediamine of Formula 3a:
iv. condensation of a compound of Formula 3a with a compound of Formula 3b:
to provide a compound of Formula 2 and having the structure:
and
v. complexation of a compound of Formula 2 with a metal cation to provide a compound of Formula 1.
3. The method of claim 2 , wherein each X is AcO − .
4. The method of claim 2 , wherein each x is 3 in at least about 99.3% of the compounds of Formula 1 in the composition.