Methods of synthesis and/or purification of diaminophenothiazinium compounds

Patent metadata

Field	Value
Publication number	US-2016296531-A1
Application number	US-201615185803-A
Country	US
Kind code	A1
Filing date	Jun 17, 2016
Priority date	Jul 11, 2006
Publication date	Oct 13, 2016
Grant date	—

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 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.

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

• A61P31/14

  for RNA viruses · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P33/02

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

• A61P31/18

  for HIV · CPC title