Medical methods utilising high purity diaminophenothiazinium compounds

Patent metadata

Field	Value
Publication number	US-11116772-B2
Application number	US-201916697907-A
Country	US
Kind code	B2
Filing date	Nov 27, 2019
Priority date	Sep 23, 2004
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

This disclosure pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7 diamino-phenothiazin-5-ium compounds (referred to herein as “diaminophenothiazinium compounds”) including Methythioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: nitrosylation (NOS); nitrosyl reduction (NR); thiosulfonic acid formation (TSAF); oxidative coupling (OC); Cr(VI) reduction (CR); isolation and purification of zwitterionic intermediate (IAPOZI); ring closure (RC); chloride salt-formation (CSF); one of: sulphide treatment (ST); dimethyldithiocarbamate treatment (DT); carbonate treatment (CT); ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction (OE); and recrystallisation (RX). Also disclosed resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment and diagnosis, etc., for example, for tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral diseases, bacterial diseases, or protozoal diseases.

First claim

The invention claimed is:

1. A high purity diaminophenothiazinium compound of the following formula:

wherein:
each of R 1 and R 9 is independently selected from —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
each of R 3NA and R 3NB is independently selected from C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
each of R 7NA and R 7NB is independently selected from C 1-4 alkyl, C 2-4 alkenyl, and 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 97% and an elementals purity better than the European Pharmacopoeia (EP) limits of 100 μg Aluminium (Al), 10 μg Chromium (Cr), 10 μg Zinc (Zn), 10 μg Copper (Cu), 100 μg Iron (Fe), 10 μg Manganese (Mn), 10 μg Nickel (Ni), 10 μg Molybdenum (Mo), 1 μg Cadmium (Cd), 1 μg Tin (Sn) and 10 μg/g Lead (Pb).

2. The high purity diaminophenothiazinium compound according to claim 1 , having the following formula:

3. The high purity diaminophenothiazinium compound according to claim 1 , having an elementals purity better than 0.5 times the European Pharmacopoeia (EP) limits.

4. The high purity diaminophenothiazinium compound according to claim 1 , having an elementals purity better than 0.1 times the European Pharmacopoeia (EP) limits.

5. The high purity diaminophenothiazinium compound according to claim 1 , having less than 2% Azure B as impurity.

6. The high purity diaminophenothiazinium compound according to claim 1 , having less than 0.13% MVB as impurity.

7. A pharmaceutical composition comprising a high purity diaminophenothiazinium compound according to claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.

8. The pharmaceutical composition according to claim 7 , which is a dosage unit comprising 20 to 300 mg or 30 to 200 mg of the high purity diaminophenothiazinium compound, and a pharmaceutically acceptable carrier, diluent, or excipient.

9. The pharmaceutical composition according to claim 8 , which is a tablet or capsule.

10. A method for the treatment of a tauopathy comprising administering to a patient in need thereof a pharmaceutically effective amount of the high purity diaminophenothiazinium compound according to claim 1 .

11. The method according to claim 10 , wherein the tauopathy is Alzheimer's disease (AD).

12. A method for the treatment of a viral, bacterial or protozoal disease, skin cancer, melanoma, Hepatitis C, HIV, or West Nile Virus A, comprising administering to a patient in need thereof a pharmaceutically effective amount of the high purity diaminophenothiazinium compound according to claim 1 .

13. A method of inactivating a pathogen in sample, comprising introducing into the sample the high purity diaminophenothiazinium compound according to claim 1 and exposing the sample to light.

14. A pharmaceutical composition comprising the high purity diaminophenothiazinium compound according to claim 2 , and a pharmaceutically acceptable carrier, diluent, or excipient.

15. The pharmaceutical composition according to claim 14 , which is a dosage unit comprising 20 to 300 mg or 30 to 200 mg of the high purity diaminophenothiazinium compound, and a pharmaceutically acceptable carrier, diluent, or excipient.

16. The pharmaceutical composition according to claim 15 which is a tablet or capsule.

17. A method for the treatment of a tauopathy comprising administering to a patient in need thereof a pharmaceutically effective amount of the high purity diaminophenothiazinium compound according to claim 2 .

18. The method according to claim 17 , wherein the tauopathy is Alzheimer's disease (AD).

19. A method for the treatment of a viral, bacterial or protozoal disease, skin cancer, melanoma, Hepatitis C, HIV, or West Nile Virus A, comprising administering to a patient in need thereof a pharmaceutically effective amount of the high purity diaminophenothiazinium compound according to claim 2 .

20. A method of inactivating a pathogen in sample comprising introducing into the sample the high purity diaminophenothiazinium compound according to claim 2 and exposing the sample to light.

Assignees

• Wista Lab Ltd

Inventors

• Storey John Mervyn David
• Sinclair James Peter
• Marshall Colin
• Tan Han Wan
• Wischik Claude Michel

Classifications

• C07D279/18

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61K49/006

  Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title