Methods of synthesis and/or purification of diaminophenothiazinium compounds
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.
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 and at least one of the following:
(i) a chromium purity that is equal to or better than 100 μg/g;
(ii) a copper purity that is equal to or better than 300 μg/g;
(iii) an iron purity that is equal to or better than 200 μg/g.
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 characterized by a purity of greater than 99% and a chromium purity that is equal to or better than 10 μg/g.
4. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is characterized by a purity of greater than 99% and a copper purity that is equal to or better than 10 μg/g.
5. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is characterized by a purity of greater than 99% and an iron purity that is equal to or better than 100 μg/g.
6. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is characterized by a purity of greater than 99%, a chromium purity that is equal to or better than 100 μg/g, a copper purity that is equal to or better than 10 μg/g and an iron purity that is equal to or better than 100 μg/g.
7. The method of claim 1 , wherein the high-purity diaminophenothiazinium compound is characterized by a purity of greater than 99%, less than 0.15% Azure A as impurity, less than 0.15% Azure C as impurity, less than 0.05% Methylene Violet Bernthsen (MVB) as impurity, a chromium purity that is equal to or better than 100 μg/g, a copper purity that is equal to or better than 10 μg/g and an iron purity that is equal to or better than 100 μg/g.
8. A method of treating 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;
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 and at least one of the following:
(i) a chromium purity that is equal to or better than 100 μg/g;
(ii) a copper purity that is equal to or better than 300 μg/g;
(iii) an iron purity that is equal to or better than 200 μg/g.
9. The method of claim 8 , wherein the high-purity diaminophenothiazinium compound has the formula:
10. The method of claim 8 , wherein the high-purity diaminophenothiazinium compound is characterized by a purity of greater than 99%, a chromium purity that is equal to or better than 100 μg/g, a copper purity that is equal to or better than 10 μg/g and an iron purity that is equal to or better than 100 μg/g.
11. A method of treating Alzheimer's disease (AD) 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 and at least one of the following:
(i) a chromium purity that is equal to or better than 100 μg/g;
(ii) a copper purity that is equal to or better than 300 μg/g;
(iii) an iron purity that is equal to or better than 200 μg/g.
12. The method of claim 11 , wherein the high-purity diaminophenothiazinium compound has the formula:
13. The method of claim 11 , wherein the high-purity diaminophenothiazinium compound is characterized by a purity of greater than 99%, a chromium purity that is equal to or better than 100 μg/g, a copper purity that is equal to or better than 10 μg/g and an iron purity that is equal to or better than 100 μg/g.