Medical methods utilising high purity diaminophenothiazinium compounds

Patent metadata

Field	Value
Publication number	US-9801890-B2
Application number	US-201715419763-A
Country	US
Kind code	B2
Filing date	Jan 30, 2017
Priority date	Sep 23, 2004
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

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 recrystallization (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

We claim:

1. A method of treating methemoglobinemia, urinary tract infection, or kidney stones in a patient, comprising administering to said 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 characterised by a purity of greater than 98% and one or more of the following:
(i) less than 2% Azure B as impurity;
(ii) less than 0.13% Methylene Violet Bernthsen (MVB) as impurity; or
(iii) an elementals purity better than the European Pharmacopoeia (EP) limits of 100 μg/g Aluminium (Al), 10 μg/g Chromium (Cr), 10 μg/g Zinc (Zn), 10 μg/g Copper (Cu), 100 μg/g Iron (Fe), 10 μg/g Manganese (Mn), 10 μg/g Nickel (Ni), 10 μg/g Molybdenum (Mo), 1 μg/g Cadmium (Cd), 1 μg/g Tin (Sn), and 10 μg/g Lead (Pb).

2. The method of claim 1 wherein the high-purity diaminophenothiazinium compound has the formula:

3. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.

4. A method of treating kidney stones in a patient,
comprising administering to said 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 characterised by a purity of greater than 98% and one or more of the following:
(i) less than 2% Azure B as impurity;
(ii) less than 0.13% Methylene Violet Bernthsen (MVB) as impurity; or
(iii) an elementals purity better than the European Pharmacopoeia (EP) limits of 100 μg/g Aluminium (Al), 10 μg/g Chromium (Cr), 10 μg/g Zinc (Zn), 10 μg/g Copper (Cu), 100 μg/g Iron (Fe), 10 μg/g Manganese (Mn), 10 μg/g Nickel (Ni), 10 μg/g Molybdenum (Mo), 1 μg/g Cadmium (Cd), 1 μg/g Tin (Sn), and 10 μg/g Lead (Pb).

5. The method of claim 4 wherein the high-purity diaminophenothiazinium compound has the formula:

6. The method of claim 4 , wherein the high-purity diaminophenothiazinium compound is administered with a pharmaceutically acceptable carrier, diluent, or excipient.

7. A method of identifying tissue at a surgical site of a patient, comprising administering to the patient an 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 characterised by a purity of greater than 98% and one or more of the following:
(i) less than 2% Azure B as impurity;
(ii) less than 0.13% Methylene Violet Bernthsen (MVB) as impurity; or
(iii) an elementals purity better than the European Pharmacopoeia (EP) limits of 100 μg/g Aluminium (Al), 10 μg/g Chromium (Cr), 10 μg/g Zinc (Zn), 10 μg/g Copper (Cu), 100 μg/g Iron (Fe), 10 μg/g Manganese (Mn), 10 μg/g Nickel (Ni), 10 μg/g Molybdenum (Mo), 1 μg/g Cadmium (Cd), 1 μg/g Tin (Sn), and 10 μg/g Lead (Pb).

8. The method of claim 7 wherein the high-purity diaminophenothiazinium compound has the formula:

9. A method of diagnosing urinary function in a patient comprising administering to the patient an effective amount of a high purity diaminophenothiazinium compound, and monitoring the appearance of the compound in the urine, wherein the compound has 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 characterised by a purity of greater than 98% and one or more of the following:
(i) less than 2% Azure B as impurity;
(ii) less than 0.13% Methylene Violet Bernthsen (MVB) as impurity; or
(iii) an elementals purity better than the European Pharmacopoeia (EP) limits of 100 μg/g Aluminium (Al), 10 μg/g Chromium (Cr), 10 μg/g Zinc (Zn), 10 μg/g Copper (Cu), 100 μg/g Iron (Fe), 10 μg/g Manganese (Mn), 10 μg/g Nickel (Ni), 10 μg/g Molybdenum (Mo), 1 μg/g Cadmium (Cd), 1 μg/g Tin (Sn), and 10 μg/g Lead (Pb).

10. The method of claim 9 wherein the high-purity diaminophenothiazinium compound has the formula:

Assignees

• Wista Lab Ltd

Inventors

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

Classifications

• A61P31/18

  for HIV · 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title