High-purity texaphyrin metal complexes
AssigneePharmacyclics, Inc.
InventorsHugo Madden, Greg Hemmi, Tarak Mody
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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.
Claims4
In a process for synthesizing a purified sample of a compound of Formula 1:
- wherein:
- M is Gd3+ or Lu3+;
- each X is independently selected from the group consisting of OH−, AcO−, Cl−, Br−, I−, F−, H2PO4−, ClO−, ClO2−, ClO3−, ClO4−, HCO3−, HSO4−, NO3−, N3−, CN−, SCN−, and OCN−;
- R4 and R7 are C3H6OH;
- R5 and R6 are C2H5;
- R3 and R8 are CH3;
- R1 and R2 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:
In a process for synthesizing a purified sample of a compound of Formula 1:
- wherein:
- M is Gd3+ or Lu3+;
- each X is independently selected from the group consisting of OH−, AcO−, Cl−, Br−, I−, F−, H2PO4−, ClO−, ClO2−, ClO3−, ClO4−, HCO3−, HSO4−, NO3−, N3−, CN−, SCN−, and OCN−;
- R4 and R7 are C3H6OH;
- R5 and R6 are C2H5;
- R3 and R8 are CH3;
- R1 and R2 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.
Dependencies are inferred from the claim text.