Wista Laboratories Ltd.

Other

Taurx Therapeutics Management Ltd.

John Mervyn David Storey

Claude Michel Wischik

James Peter Sinclair

Colin Marshall

Thomas Craven Baddeley

Charles Robert Harrington

Janet Elizabeth Rickard

David Horsley

Scott Clunas

Damon Jude Wischik

Craig Williamson

Christopher Paul Larch

Han Wan Tan

Michael Simpson

Karrar Ahmad Khan

Björn Olaf Schelter

Barry Alan Wood

Yin Sze Loh

Sarah Louise Nicoll

Ahtsham Ishaq

Steven John Kemp

Tobias Heinrich

Helen Sarah Gibbard

Lynda Jane Storey

Michel Wischik Claude

Tobias Kerst Heinrich

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

The invention provides novel regimens for treatment of neurodegenerative disorders utilising methylthioninium (MT)-containing compounds. The regimens are based on novel findings in relation to the dosage of MT compounds, and their interaction with symptomatic treatments based on modulation of a acetylcholinesterase levels.

Administration and dosage of diaminophenothiazines

The invention provides novel regimens for treatment of neurodegenerative disorders utilising methylthioninium (MT)-containing compounds. The regimens are based on novel findings in relation to the dosage of MT compounds, and their interaction with symptomatic treatments based on modulation of acetylcholinesterase levels.

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

The invention describes improved treatments for Frontotemporal dementia based on the use of a methylthioninium compound in combination with a compound which directly modifies synaptic neurotransmission in the brain, such as a symptomatic Alzheimer's disease treatment (e.g. acetylcholinesterase and/or memantine).

Treatment of dementia

Growing community of inventors

Old Aberdeen, United Kingdom

John Mervyn David Storey