Methods of synthesis and/or purification of diaminophenothiazinium compounds

Patent metadata

Field	Value
Publication number	US-9382220-B2
Application number	US-201313890607-A
Country	US
Kind code	B2
Filing date	May 9, 2013
Priority date	Jul 11, 2006
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

Described are methods of synthesis and/or purification of certain 3,7-diamino-phenothiazin-5-ium compounds (referred to herein as “diaminophenothiazinium compounds”) including Methylthioninium Chloride (MTC) (also known as Methylene Blue), the resulting (high purity) compounds, compositions comprising such compounds (e.g., tablets, capsules), and the use of such high purity compounds. The compounds are useful in inactivating pathogens, and methods of medical treatment, prophylaxis, and diagnosis of diseases including a tauopathy, related neurological and infectious diseases.

First claim

The invention claimed is:

1. A diaminophenothiazinium composition comprising a 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 the composition is characterised by the following by weight in the composition:
at least 98% of the diaminophenothiazinium compound;
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. A diaminophenothiazinium composition comprising a diaminophenothiazinium compound of the following formula:

wherein the composition is characterised by the following by weight in the composition:
at least 98% of the diaminophenothiazinium compound;
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.

3. The diaminophenothiazinium composition of claim 2 , having at least 99% of the diaminophenothiazinium compound by weight.

4. The diaminophenothiazinium composition of claim 2 , having at least 99.5% of the diaminophenothiazinium compound by weight.

5. The diaminophenothiazinium composition of claim 2 , having at least 99.6% of the diaminophenothiazinium compound by weight .

6. The diaminophenothiazinium composition of claim 2 , having at least 99.7% of the diaminophenothiazinium compound by weight.

7. The diaminophenothiazinium composition of claim 2 , having less than 0.5% Azure B as impurity by weight.

8. The diaminophenothiazinium composition of claim 2 , having less than 0.1% Azure A as impurity by weight.

9. The diaminophenothiazinium composition of claim 2 , having less than 0.05% Azure A as impurity by weight.

10. The diaminophenothiazinium composition of claim 2 , having less than 0.1% Azure C as impurity by weight.

11. The diaminophenothiazinium composition of claim 2 , having less than 0.05% Azure C as impurity by weight.

12. The diaminophenothiazinium composition of claim 2 , having less than 0.02% MVB as impurity by weight.

13. The diaminophenothiazinium composition of claim 2 , having:
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).

14. The diaminophenothiazinium composition of claim 2 , having:
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).

15. The diaminophenothiazinium composition of claim 1 , wherein the diaminophenothiazinium compound is obtained by a method of synthesis comprising the steps of, in order:
(a) purifying a corresponding acylated reagent compound the following formula, wherein R 10 is independently saturated aliphatic C 1-5 alkyl, phenyl, p-methoxyphenyl, or p-nitrophenyl:

(b)(i) deacylating the acylated reagent compound to give a corresponding deacylated compound of the following formula:

(b)(ii) optionally purifying the deacylated compound;
(c)(i) oxidizing the deacylated compound to give the diaminophenothiazinium compound; and
(c)(ii) optionally purifying the diaminophenothiazinium compound.

16. The diaminophenothiazinium composition of claim 2 , obtained by a method of synthesis comprising the steps of, in order:
(a) purifying 3,7-di(dimethylamino)-10-acetyl-phenothiazine;
(b)(i) deacylating the 3,7-di(dimethylamino)-10-acetyl-phenothiazine by reaction with hydrochloric acid to give 3,7-di(dimethylamino)-10H-phenothiazine;
(b)(ii) optionally purifying the 3,7-di(dimethylamino)-10H-phenothiazine;
(c)(i) oxidizing the 3,7-di(dimethylamino)-10H-phenothiazine by reaction with FeCl 3 to give methylthioninium chloride; and
(c)(ii) optionally purifying the methylthioninium chloride.

17. The composition of claim 1 , obtained by a method of synthesis comprising the steps of, in order:
(a) acylating a corresponding non-acylated precursor of a corresponding acylated reagent compound to give the corresponding acylated reagent compound, wherein the non-acylated precursor is a compound of the following formula:

and wherein the acylated reagent compound is a compound of the following formula, wherein R 10 is independently saturated aliphatic C 1-5 alkyl, phenyl, p-methoxyphenyl, or p-nitrophenyl:

(b) purifying the acylated reagent compound;
(c)(i) deacylating the purified acylated reagent compound to give a corresponding deacylated compound of the following formula:

(c)(ii) optionally purifying the deacylated compound;
(d)(i) oxidizing the deacylated compound to give the diaminophenothiazinium compound; and
(d)(ii) optionally purifying the diaminophenothiazinium compound.

18. The diaminophenothiazinium composition of claim 2 , obtained by a method of synthesis comprising the steps of, in order:
(a) acylating 3,7-di(dimethylamino)-10H-phenothiazine by reaction with (CH 3 CO) 2 O in a basic solvent to give 3,7-di(dimethylamino)-10-acetyl-phenothiazine;
(b) purifying the 3,7-di(dimethylamino)-10-acetyl-phenothiazine;
(c)(i) deacylating the 3,7-di(dimethylamino)-10-acetyl-phenothiazine by reaction with hydrochloric acid to give 3,7-di(dimethylamino)-10H-phenothiazine;
(c)(ii) optionally purifying the 3,7-di(dimethylamino)-10H-phenothiazine;
(d)(i) oxidizing the 3,7-di(dimethylamino)-10H-phenothiazine by reaction with FeCl 3 to give methylthioninium chloride; and
(d)(ii) optionally purifying the methylthioninium chloride.

19. The diaminophenothiazinium composition of claim 1 , obtained by a method of synthesis comprising the steps of, in order:
(a)(i) reducing a corresponding oxidized precursor of a corresponding non-acylated precursor of a corresponding acylated reagent compound to give the non-acylated precursor of the acylated reagent compound, wherein the oxidized

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

• A61P33/06

  Antimalarials · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P31/18

  for HIV · CPC title