Methods of synthesis and/or purification of diaminophenothiazinium compounds

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).