Methods of synthesis and/or purification of diaminophenothiazinium compounds
Disclosed are methods of synthesis and/or purification of certain 3,7-diamino-phenothiazin-5-ium compounds (“diaminophenothiazinium compounds”) including Methylthioninium Chloride (MTC) (Methylene Blue), and the resulting high purity characterized by a purity greater than 98%, and very low levels of heavy metals and organic impurities Azure A, B, C and MVB. Also disclosed are methods of treatment of a tauopathy or methemoglobinemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the high-purity diaminophenothiazinium compound.
1. A method of treatment of malaria in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a high-purity diaminophenothiazinium compound of the following formula:
wherein:
each of R 1 and R 9 is independently —H, C 1-4 alkyl, C 2-4 alkenyl, or halogenated C 1-4 alkyl;
each of R 3NA and R 3NB is independently C 1-4 alkyl, C 2-4 alkenyl, or halogenated C 1-4 alkyl;
each of R 7NA and R 7NB is independently C 1-4 alkyl, C 2-4 alkenyl, or halogenated C 1-4 alkyl; and
X is one or more anionic counter ions to achieve electrical neutrality;
wherein high-purity is characterized by:
a purity of greater than 98%;
less than 1% Azure B as impurity;
less than 0.15% Azure A as impurity;
less than 0.15% Azure C as impurity; and
less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.
2. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound has the formula:
3. The method of claim 2 , wherein the high-purity diaminophenothiazinium compound has a purity of greater than 99%.
4. The method of claim 2 , wherein the high-purity diaminophenothiazinium compound has less than 0.5% Azure B as impurity.
5. The method of claim 2 , wherein the high-purity diaminophenothiazinium compound has less than 0.1% Azure B as impurity.
6. The method of claim 2 , wherein the high-purity diaminophenothiazinium compound has:
less than 100 μg/g Aluminium (Al);
less than 1 μg/g Cadmium (Cd);
less than 100 μg/g Chromium (Cr);
less than 300 μg/g Copper (Cu);
less than 10 μg/g Tin (Sn);
less than 200 μg/g Iron (Fe);
less than 10 μg/g Manganese (Mn);
less than 1 μg/g Mercury (Hg);
less than 10 μg/g Molybdenum (Mo);
less than 10 μg/g Nickel (Ni);
less than 10 μg/g Lead (Pb); and
less than 100 μg/g Zinc (Zn).
7. The method of claim 2 , wherein the high-purity diaminophenothiazinium compound has:
less than 50 μg/g Aluminium (Al);
less than 0.5 μg/g Cadmium (Cd);
less than 50 μg/g Chromium (Cr);
less than 150 μg/g Copper (Cu);
less than 5 μg/g Tin (Sn);
less than 100 μg/g Iron (Fe);
less than 5 μg/g Manganese (Mn);
less than 0.5 μg/g Mercury (Hg);
less than 5 μg/g Molybdenum (Mo);
less than 5 μg/g Nickel (Ni);
less than 5 μg/g Lead (Pb); and
less than 50 μg/g Zinc (Zn).
8. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.
9. The method of claim 8 , wherein the high-purity diaminophenothiazinium compound is administered as a tablet or capsule comprising 20 to 300 mg of the diaminophenothiazinium compound.
10. The method of claim 9 , wherein the pharmaceutical tablet or capsule comprises 30 to 200 mg of the diaminophenothiazinium compound.
11. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is administered in combination with one or more other antimicrobial agents.
12. The method of claim 11 , wherein the one or more antimicrobial agents comprise one or more of chloroquine, atovaquone, quinine, primethamine, sulfadiazine, or primaquine.
13. The method of claim 11 , wherein the one or more antimicrobial agents comprise chloroquine.
14. A method of treatment of a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a high-purity diaminophenothiazinium compound of the following formula:
wherein:
each of R 1 and R 9 is independently —H, C 1-4 alkyl, C 2-4 alkenyl, or halogenated C 1-4 alkyl;
each of R 3NA and R 3NB is independently C 1-4 alkyl, C 2-4 alkenyl, or halogenated C 1-4 alkyl;
each of R 7NA and R 7NB is independently C 1-4 alkyl, C 2-4 alkenyl, or halogenated C 1-4 alkyl; and
X is one or more anionic counter ions to achieve electrical neutrality;
wherein high-purity is defined by:
at least 98% pure;
less than 1% Azure B as impurity;
less than 0.15% Azure A as impurity;
less than 0.15% Azure C as impurity; and
less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.
15. The method of claim 14 , wherein the high-purity diaminophenothiazinium compound has the formula:
16. The method of claim 15 , wherein the high-purity diaminophenothiazinium compound is at least 99% pure.
17. The method of claim 15 , wherein the high-purity diaminophenothiazinium compound has less than 0.5% Azure B as impurity.
18. The method of claim 17 , wherein the high-purity diaminophenothiazinium compound has less than 0.1% Azure B as impurity.
19. The method of claim 15 , wherein the high-purity diaminophenothiazinium compound has:
less than 100 μg/g Aluminium (Al);
less than 1 μg/g Cadmium (Cd);
less than 100 μg/g Chromium (Cr);
less than 300 μg/g Copper (Cu);
less than 10 μg/g Tin (Sn);
less than 200 μg/g Iron (Fe);
less than 10 μg/g Manganese (Mn);
less than 1 μg/g Mercury (Hg);
less than 10 μg/g Molybdenum (Mo);
less than 10 μg/g Nickel (Ni);
less than 10 μg/g Lead (Pb); and
less than 100 μg/g Zinc (Zn).
20. The method of claim 15 , wherein the high-purity diaminophenothiazinium compound has:
less than 50 μg/g Aluminium (Al);
less than 0.5 μg/g Cadmium (Cd);
less than 50 μg/g Chromium (Cr);
less than 150 μg/g Copper (Cu);
less than 5 μg/g Tin (Sn);
less than 100 μg/g Iron (Fe);
less than 5 μg/g Manganese (Mn);
less than 0.5 μg/g Mercury (Hg);
less than 5 μg/g Molybdenum (Mo);
less than 5 μg/g Nickel (Ni);
less than 5 μg/g Lead (Pb); and
less than 50 μg/g Zinc (Zn).
21. The method of claim 14 , wherein the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.
22. The method of claim 21 , wherein the high-purity diaminophenothiazinium compound is administered as a tablet or capsule comprising 20 to 300 mg of the diaminophenothiazinium compound.
23. The method of claim 22 , wherein the pharmaceutical tablet or capsule comprises 30 to 200 mg of the diaminophenothiazinium compound.
24. The method of claim 14 , wherein the viral infection is selected from the group consisting of: Hepatitis C virus (HCV), human immunodeficiency virus (HIV), and West Nile virus (WNV).
25. The method of claim 14 , wherein the viral infection is Hepatitis C virus (HCV).
26. The method of claim 14 , wherein the viral infection is human immunodeficiency virus (HIV).
27. The method of claim 14 , wherein the viral infection is West Nile virus (WNV).