Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC)

A method of preventing 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 R1 and R9 is independently —H, C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• each of R3NA and R3NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• each of R7NA and R7NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• 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).

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 R1 and R9 is independently —H, C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• each of R3NA and R3NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• each of R7NA and R7NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• 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).

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 R1 and R9 is independently —H, C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• each of R3NA and R3NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• each of R7NA and R7NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl;
• 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).