Wista Laboratories Ltd.

Other

James Peter Sinclair

John Mervyn David Storey

Colin Marshall

Claude Michel Wischik

Thomas Craven Baddeley

Charles Robert Harrington

Janet Elizabeth Rickard

David Horsley

Han Wan Tan

Scott Clunas

Christopher Paul Larch

Michael Simpson

John Mervyn Storey

Karrar Ahmad Khan

Craig Williamson

Yin Sze Loh

Sarah Louise Nicoll

Barry Alan Wood

Ahtsham Ishaq

Steven John Kemp

Helen Sarah Gibbard

John M D Storey

Michel Wischik Claude

Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula: wherein: Rand Rare independently selected from: —H; Calkyl; Calkenyl; and halogenated Calkyl; each of Rand Ris independently selected from: —H; Calkyl; Calkenyl; and halogenated Calkyl; each of Rand Ris independently selected from: —H; Calkyl; Calkenyl; and halogenated Calkyl; each of HXand HXis independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These methods are particularly useful for producing stable reduced forms, and with high purity. The stability and purity are especially relevant for pharmaceutical compositions for the treatment of disease. The compounds are useful for treatment of e.g. tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs.

3, 7-diamino-10H-phenothiazine salts and their use

Disclosed are compounds of general formula (I): and pharmaceutically acceptable salts thereof, formulations, methods and uses in, for example, the treatment of disease.

Phenothiazine diaminium salts and their use

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.

Methods of synthesis and/or purification of diaminophenothiazinium compounds

Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula: wherein: Rand Rare independently selected from: &#x2014;H; Calkyl; Calkenyl; and halogenated Calkyl; each of Rand Ris independently selected from: &#x2014;H; Calkyl; Calkenyl; and halogenated Calkyl; each of Rand Ris independently selected from: &#x2014;H; Calkyl; Calkenyl; and halogenated Calkyl; each of HXand HXis independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These methods are particularly useful for producing stable reduced forms, and with high purity. The stability and purity are especially relevant for pharmaceutical compositions for the treatment of disease. The compounds are useful for treatment of e.g. tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs.

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.

Medical methods utilising high purity diaminophenothiazinium compounds

The present invention pertains generally to the field of chemical synthesis, and more particularly to methods for the chemical synthesis of a thiosulfonic acid of Formula (1) by a step of periodate mediated oxidative coupling of a thiosulfonic acid of Formula (2) with an aniline of Formula (3), as described herein. The present invention also relates to such methods which incorporate one or more additional (subsequent and/or preceding) steps, for example, to prepare compounds of Formula (5) from compounds of Formula (1); to prepare compounds of Formula (6) from compounds of Formula (5); and to prepare compounds of Formula (2) from compounds of Formula (4), as described herein. 

Synthesis of a thiosulfonic acid by a step of periodate mediated oxidative coupling of a thiosulfonic acid with an aniline

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 'diaminophenothiaziniumcompounds') 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.

Methods of synthesizing and purifying certain 3,7-diamino-phenothiazin-5-ium compounds (referred to herein as 'diaminophenothiazinium compounds') including Methylthioninium Chloride (MTC) (also known as Methylene Blue) are provided. 

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

The present invention pertains generally to the field of chemical synthesis, and more particularly to methods of chemical synthesis which include the step of preparing a substituted 10H-phenothiazine-3,7-diamine compound of Formula (1) by a step of selective alkylation by reductive amination, in which the corresponding unsubstituted diamine of Formula (4) is reacted with aldehyde/ketone, under reductive amination conditions. The present invention also relates to such methods which incorporate additional subsequent and/or preceding steps, for example, to prepare compounds of Formulae (2) and (3) from compounds of Formula (1), and to prepare compounds of Formula (4) from, for example, compounds of Formulae (5), (6), (7), (8), and (9). Compounds of Formula (1), Formula (2), and Formula (3) are useful, for example, in the treatment of diseases of protein aggregation, such as Alzheimer's disease.

Methods of chemical synthesis of substituted 10H-phenothiazine-3,7-diamine compounds

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) are provided. 

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Old Aberdeen, United Kingdom

James Peter Sinclair