Methods of synthesis and/or purification of diaminophenothiazinium compounds

Patent metadata

Field	Value
Publication number	US-11045477-B2
Application number	US-201916685420-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Jul 11, 2006
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

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.

First claim

What is claimed is:

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).

Assignees

• Wista Lab Ltd

Inventors

• Wischik Claude Michel
• Storey John Mervyn David
• Marshall Colin
• Sinclair James Peter
• Baddeley Thomas Craven

Classifications

• C09B67/0097

  Dye preparations of special physical nature; Tablets, films, extrusion, microcapsules, sheets, pads, bags with dyes · CPC title

• C09B21/00

  Thiazine dyes · CPC title

• C09B67/0096

  Purification; Precipitation; Filtration · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• C07D279/18

  [b, e]-condensed with two six-membered rings · CPC title