Methods of synthesis and/or purification of diaminophenothiazinium compounds

1. A method of treatment of a tauopathy 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. The method of claim 1 , wherein the tauopathy is selected from the group consisting of: Alzheimer's disease (AD); Pick's disease; Progressive Supranuclear Palsy (PSP); fronto-temporal dementia (FTD); parkinsonism linked to chromosome 17 (FTDP-17); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC); pallido-ponto-nigral degeneration (PPND); Guam-ALS syndrome; and cortico-basal degeneration (CBD).

12. The method of claim 1 , wherein the tauopathy is Alzheimer's disease (AD).

13. A method of treatment of a methemoglobinemia 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; and

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.

14. The method of claim 13 , wherein the high-purity diaminophenothiazinium compound has the formula:

15. The method of claim 14 , wherein the high-purity diaminophenothiazinium compound has a purity of greater than 99%.

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

17. The method of claim 16 , wherein the high-purity diaminophenothiazinium compound has less than 0.1% Azure B as impurity.

18. The method of claim 14 , 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).

19. The method of claim 14 , wherein the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.

20. The method of claim 19 , wherein 20 to 300 mg of the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.