Methods of synthesis and/or purification of diaminophenothiazinium compounds

Patent metadata

Field	Value
Publication number	US-9980971-B2
Application number	US-201715619199-A
Country	US
Kind code	B2
Filing date	Jun 9, 2017
Priority date	Jul 11, 2006
Publication date	May 29, 2018
Grant date	May 29, 2018

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 mild cognitive impairment (MCI) 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.

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 is at least 99% pure.

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 4 , 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. A method of treatment of a synucleinopathy 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.

12. The method of claim 11 , wherein the high-purity diaminophenothiazinium compound has the formula:

13. The method of claim 12 , wherein the high-purity diaminophenothiazinium compound is at least 99% pure.

14. The method of claim 12 , wherein the high-purity diaminophenothiazinium compound has less than 0.5% Azure B as impurity.

15. The method of claim 14 , wherein the high-purity diaminophenothiazinium compound has less than 0.1% Azure B as impurity.

16. The method of claim 12 , 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).

17. The method of claim 12 , 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).

18. The method of claim 11 , wherein the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.

19. The method of claim 18 , wherein the high-purity diaminophenothiazinium compound is administered as a tablet or capsule comprising 20 to 300 mg of the diaminophenothiazinium compound.

20. The method of claim 19 , wherein the pharmaceutical tablet or capsule comprises 30 to 200 mg of the diaminophenothiazinium compound.

21. The method of claim 11 , wherein the synucleinopathy is selected from the group consisting of: Parkinson's Disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), drug-induced parkinsonism, and pure autonomic failure (PAF).

22. The method of claim 11 , wherein the synucleinopathy is Parkinson's Disease (PD).

23. The method of claim 11 , wherein the synucleinopathy is dementia with Lewy bodies (DLB).

24. The method of claim 11 , wherein the synucleinopathy is multiple system atrophy (MSA).

25. The method of claim 11 , wherein the synucleinopathy is drug-induced parkinsonism.

26. The method of claim 11 , wherein the synucleinopathy is pure autonomic failure (PAF).

Assignees

• Wista Lab Ltd

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title