Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
wherein: R1 and R9 are independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R3NA and R3NB is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R7NA and R7NB is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of HX1 and HX2 is 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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
C07D 279/22 - [b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
The invention provides novel dosing regimens for Leuco-Methylthioninium (LMT) compounds which maximise the proportion of subjects in which the MT concentration will exceed concentrations in which therapeutic efficacy in relation to treatment of neurodegenerative disorders such as Alzheimer's disease and rontotemporal dementias can be achieved, while maintaining a desirable clinical profile. Also provided are LMT-containing dosage units and other compositions.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A23L 33/00 - Modifying nutritive qualities of foodsDietetic productsPreparation or treatment thereof
A23L 33/105 - Plant extracts, their artificial duplicates or their derivatives
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
3.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A23L 33/105 - Plant extracts, their artificial duplicates or their derivatives
A23P 10/28 - TablettingMaking food bars by compression of a dry powdered mixture
A23P 10/30 - Encapsulation of particles, e.g. foodstuff additives
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
B65D 75/36 - Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages
4.
METHYLENE BLUE CONTAINING COMPOUNDS FOR THE TREATMENT OF METHAEMOGLOBINAEMIA
The invention provides novel methods of treating methaemoglobinaemia orally in a subject, which methods comprise orally administering to said subject a methylthioninium (“MT”) containing salt of the following formula: wherein each of HnA and HnB (where present) are protic acids which may be the same or different, and wherein p=1 or 2; q=0 or 1; n=1 or 2; (p+q)×n=2, or a hydrate or solvate thereof. The administration should provide a total daily oral dose of 4 mg to 60 mg of MT to the subject per day.
The invention provides novel methods of treating methaemoglobinaemia orally in a subject, which methods comprise orally administering to said subject a methylthioninium (“MT”) containing salt of the following formula: wherein each of HnA and HnB (where present) are protic acids which may be the same or different, and wherein p=1 or 2; q=0 or 1; n=1 or 2; (p+q)×n=2, or a hydrate or solvate thereof. The administration should provide a total daily oral dose of 4 mg to 60 mg of MT to the subject per day.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 9/00 - Medicinal preparations characterised by special physical form
A61P 7/00 - Drugs for disorders of the blood or the extracellular fluid
5.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
A method for predicting a patient or patient cohort's cognition score on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). The method comprises obtaining data relating to a plurality of patients or patient cohorts, the data including information relating to the longitudinal trajectories of the plurality of patients', or patient cohorts', ADAS-Cog score over time, each patient or patient cohort having undergone a treatment plan selected from a plurality of treatment plans; encoding the data into a tensor across patients or patient cohorts, time and treatment plan; generating a synthetic model of a target patient or target patient cohort using a machine learning process and the tensor; and predicting an ADAS-Cog score of the target patient or target patient cohort under a target treatment plan selected from the plurality of treatment plans, using the synthetic model.
G16H 50/50 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders
A61B 5/00 - Measuring for diagnostic purposes Identification of persons
G16H 10/20 - ICT specially adapted for the handling or processing of patient-related medical or healthcare data for electronic clinical trials or questionnaires
G16H 50/70 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
7.
DIAMINOPHENOTHIAZINE FOR THE TREATMENT OF MICROVASCULAR BRAIN DISEASE DISEASE
The invention provides a method of therapeutic or prophylactic treatment of microvascular brain disease in a subject, which method comprises orally administering to said subject reduced form of a methylthioninium (MT)-containing compound, wherein said administration provides a total daily dose of between 8 and 200 mg of MT to the subject per day, optionally split into 2 or more doses.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
8.
3, 7-diamino-10H-phenothiazine salts and their use
Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
2 is 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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
C07D 279/22 - [b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
The invention provides different types of floating composition of diaminophenothiazine (DAPTZ) compounds such as methylene blue, which provide rapid-release in the stomach, or are gastro-retained. They further provide methods of making and using the same in the treatment and/or prevention of diseases. In one embodiment the invention provides an oral pharmaceutical composition which is a film-coated solid tablet comprising a DAPTZ compound as active ingredient in a gastro-retentive platform. In another embodiment the invention provides an oral pharmaceutical composition comprising an elongate hollow cylindrical capsule containing a weighting agent which is retained at one end, the capsule being buoyant and self-orientating, wherein the capsule is coated with an inner sustained release layer comprising a DAPTZ compound as active ingredient, and a further protective outer layer.
A61K 9/48 - Preparations in capsules, e.g. of gelatin, of chocolate
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
11.
THIAZOLE DERIVATIVES AS TAU AGGREGATION INHIBITORS
The present invention provides compounds of general formula (I): or pharmaceuticaly acceptable salts, solvates or hydrates thereof, wherein RNis independently -H or - Me; RX1-41-4 alkyl, optionaly substituted with halo or hydroxy; -NHRN1, wherein RN11-4 5-105-10 heteroaryl; RY5-10 5-10 heteroaryl, optionaly substituted with methyl, halo or phenyl; or neopentyl. The compounds are of use as tau aggregation inhibitors (TAIs).
C07D 277/56 - Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
C07D 417/14 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing three or more hetero rings
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Diagnosis of dementia A method for diagnosing dementia subtypes is described. The method comprises obtaining brain imaging data relating to one or more patients, analysing the data using a deep learning model and classifying the one or more patients between a plurality of classes comprising a first class of patients having a first subtype of dementia and a second class of patients having a second subtype of dementia, using the deep learning model. The deep learning model has been trained using brain imaging data from patients, the brain imaging data comprising a first set of images showing evidence of temporo-parietal hypo-metabolism, and a second set of images showing evidence of hypo-metabolism in regions of the brain other than the temporal and parietal regions instead or in addition to the temporal and parietal regions, wherein the first set of images is labeled as associated with the first subtype of dementia and the second set of images is labeled as associated with the second subtype of dementia. Related systems and methods are also described.
The invention provides methods of treatment of a neurodegenerative disease in a subject, which methods comprise orally administering to said subject a methylthioninium (MT) containing compound, wherein said administration is at a dosage frequency of less than once daily; and wherein said administration provides an amount of MT to the subject that corresponds to an average of between 0.05 mg and 30 mg MT per day, preferably between 0.1 mg and 20 mg MT per day. The invention further provides related compositions and kits of parts for use in the method.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
14.
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 a acetylcholinesterase levels.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A23L 33/105 - Plant extracts, their artificial duplicates or their derivatives
A23P 10/28 - TablettingMaking food bars by compression of a dry powdered mixture
A23P 10/30 - Encapsulation of particles, e.g. foodstuff additives
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
B65D 75/36 - Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages
15.
METHYLENE BLUE CONTAINING COMPOUNDS FOR THE TREATMENT OF METHAEMOGLOBINAEMIA
The invention provides novel methods of treating methaemoglobinaemia orally in a subject, which methods comprise orally administering to said subject a methylthioninium ("MT") containing salt of the following formula: wherein each of HnA and HnB (where present) are protic acids which may be the same or different, and wherein p = 1 or 2; q = 0 or 1; n = 1 or 2; (p + q) × n = 2, or a hydrate or solvate thereof. The administration should provide a total daily oral dose of 4 mg to 60 mg of MT to the subject per day.
A61P 7/00 - Drugs for disorders of the blood or the extracellular fluid
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A method for predicting a patient or patient cohort's cognition score on the Alzheimer's Disease Assessment Scale – cognitive subscale (ADAS-Cog). The method comprises obtaining data relating to a plurality of patients or patient cohorts, the data including information relating to the longitudinal trajectories of the plurality of patients', or patient cohorts', ADAS-Cog score over time, each patient or patient cohort having undergone a treatment plan selected from a plurality of treatment plans; encoding the data into a tensor across patients or patient cohorts, time and treatment plan; generating a synthetic model of a target patient or target patient cohort using a machine learning process and the tensor; and predicting an ADAS-Cog score of the target patient or target patient cohort under a target treatment plan selected from the plurality of treatment plans, using the synthetic model.
G16H 50/20 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
G16H 50/30 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indicesICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for individual health risk assessment
G16H 50/50 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders
G16H 10/20 - ICT specially adapted for the handling or processing of patient-related medical or healthcare data for electronic clinical trials or questionnaires
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 31/4706 - 4-Aminoquinolines8-Aminoquinolines, e.g. chloroquine, primaquine
18.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A23L 33/105 - Plant extracts, their artificial duplicates or their derivatives
A23P 10/28 - TablettingMaking food bars by compression of a dry powdered mixture
A23P 10/30 - Encapsulation of particles, e.g. foodstuff additives
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
B65D 75/36 - Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages
19.
METHYLTHIONINIUM COMPOUNDS FOR USE IN THE TREATMENT OF COVID-19
A61K 31/54 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 33/00 - Medicinal preparations containing inorganic active ingredients
A61P 7/00 - Drugs for disorders of the blood or the extracellular fluid
21.
Optimised dosage of diaminophenothiazines in populations
The invention provides novel dosing regimens for Leuco-Methylthioninium (LMT) compounds which maximise the proportion of subjects in which the MT concentration will exceed concentrations in which therapeutic efficacy in relation to treatment of neurodegenerative disorders such as Alzheimer's disease and rontotemporal dementias can be achieved, while maintaining a desirable clinical profile. Also provided are LMT-containing dosage units and other compositions.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A23L 33/00 - Modifying nutritive qualities of foodsDietetic productsPreparation or treatment thereof
A23L 33/105 - Plant extracts, their artificial duplicates or their derivatives
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
The present invention relates generally to methods of treatment of Alzheimer's Disease or Mild Cognitive Impairment which are adapted to avoid negative interactions between combinations of therapeutics. In particular there are disclosed such methods of treatment in which the order of therapeutics is actively controlled to mitigate homeostatic downregulation prior to administration of active, for example disease modifying, therapeutic agents. In certain embodiments therapy with symptomatic treatments (such as modifiers of the activity of acetylcholine or glutamate neurotransmitters) may subsequently be combined with the disease modifying or other active treatment. The invention also applies the findings in relation to homeostatic downregulation to novel methods of clinical trial design.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
23.
METHYLTHIONINIUM FOR USE IN THE TREATMENT OF SYNAPTOPATHIES
The present invention relates generally to methods and materials for treating synaptopathies, based on the use of Leu-co-methylthioninium acid salts, which are disclosed herein to increase synaptophysin levels in various brain regions at therapeutically relevant doses both in animal models of neurodegenerative disease, and in normal animals.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
A61K 31/27 - Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, e.g. meprobamate, carbachol, neostigmine
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
24.
METHYLTHIONINIUM AS ENHANCERS OF THE COGNITIVE FUNCTION
The present invention relates generally to nootropic compositions comprising Leuco-methylthioninium acid salts and their uses for cognitive enhancement in normal (non-demented) individuals.
B65D 75/36 - Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages
25.
3, 7-diamino-10H-phenothiazine salts and their use
Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
2 is 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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
C07D 279/22 - [b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
Disclosed are compounds of general formula (I):
and pharmaceutically acceptable salts thereof, formulations, methods and uses in, for example, the treatment of disease.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 9/00 - Medicinal preparations characterised by special physical form
A61L 2/00 - Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lensesAccessories therefor
C07C 303/32 - Preparation of esters or amides of sulfuric acidsPreparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
C07C 309/04 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
C07C 309/05 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
C07C 309/30 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
B65D 75/36 - Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages
28.
METHODS OF PROVIDING MODULATORS OF TAU AGGREGATION
The present invention relates generally to methods for selecting or designing a compound for modulating the aggregation of a Tau protein. The method comprising using computer- implemented molecular modelling means to compare the three-dimensional structure of a candidate compound with a three-dimensional structure of at least a part of the Tau protein comprising amino acids 315-378 and determine whether the candidate compound is able to simultaneously form non-covalent interactions with two or more of Leu315, Ser341, Glu342, Lys343, Phe346, Lys347, Val350, Ser352, Ile354, Lys369, Ile371, Glu372, Phe378 and Thr373. A candidate compound that is able to form said interactions is predicted to modulate the aggregation of the Tau protein or truncated form thereof. Methods using a three- dimensional structural model of at least a part of the Tau protein comprising amino acids 315-378, wherein the model is an intermediate in the aggregation process of the part of the Tau protein with a paired helical filament (PHF) are also described, as are computing systems and products.
The present invention provides a system for the study of tau protein aggregation in neuronal cells in vitro which can be used to screen agents for therapeutic effectiveness against aggregates of tau protein or fragments thereof.
The invention relates to specific binding molecules, such as antibodies, directed to key epitopes of tau. The specific binding molecules of the invention find applications in diagnostics and therapeutics of tauopathies including Alzheimer's disease.
C07K 16/18 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 39/00 - Medicinal preparations containing antigens or antibodies
31.
METHYLTHIONINIUM COMPOUNDS FOR USE IN THE TREATMENT OF COVID-19
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 31/4706 - 4-Aminoquinolines8-Aminoquinolines, e.g. chloroquine, primaquine
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 33/00 - Medicinal preparations containing inorganic active ingredients
A61P 7/00 - Drugs for disorders of the blood or the extracellular fluid
A61P 11/00 - Drugs for disorders of the respiratory system
A61P 43/00 - Drugs for specific purposes, not provided for in groups
34.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
35.
Optimised dosage of diaminophenothiazines in populations
The invention provides novel dosing regimens for Leuco-Methylthioninium (LMT) compounds which maximise the proportion of subjects in which the MT concentration will exceed concentrations in which therapeutic efficacy in relation to treatment of neurodegenerative disorders such as Alzheimer's disease and rontotemporal dementias can be achieved, while maintaining a desirable clinical profile. Also provided are LMT-containing dosage units and other compositions.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A23L 33/00 - Modifying nutritive qualities of foodsDietetic productsPreparation or treatment thereof
A23L 33/105 - Plant extracts, their artificial duplicates or their derivatives
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
36.
METHYLTHIONINIUM AS ENHANCERS OF THE COGNITIVE FUNCTION
The present invention relates generally to nootropic compositions comprising Leuco-methylthioninium acid salts and their uses for cognitive enhancement in normal (non-demented) individuals.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
37.
METHYLTHIONINIUM FOR USE IN THE TREATMENT OF SYNAPTOPATHIES
The present invention relates generally to methods and materials for treating synaptopathies, based on the use of Leuco-methylthioninium acid salts, which are disclosed herein to increase synaptophysin levels in various brain regions at therapeutically relevant doses both in animal models of neurodegenerative disease, and in normal animals.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
The present invention relates generally to methods of treatment of Alzheimer's Disease or Mild Cognitive Impairment which are adapted to avoid negative interactions between combinations of therapeutics. In particular there are disclosed such methods of treatment in which the order of therapeutics is actively controlled to mitigate homeostatic downregulation prior to administration of active, for example disease modifying, therapeutic agents. In certain embodiments therapy with symptomatic treatments (such as modifiers of the activity of acetylcholine or glutamate neurotransmitters) may subsequently be combined with the disease modifying or other active treatment. The invention also applies the findings in relation to homeostatic downregulation to novel methods of clinical trial design.
A61K 31/27 - Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, e.g. meprobamate, carbachol, neostigmine
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
39.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
Disclosed are compounds of general formula (I):
and pharmaceutically acceptable salts thereof, formulations, methods and uses in, for example, the treatment of disease.
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 9/00 - Medicinal preparations characterised by special physical form
C07C 309/04 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
C07C 309/05 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
C07C 309/30 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
C07C 303/32 - Preparation of esters or amides of sulfuric acidsPreparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
41.
Synthesis of a thiosulfonic acid by a step of periodate mediated oxidative coupling of a thiosulfonic acid with an aniline
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.
A method of determining patient response to a neuropharmacological intervention, a method of determining a patient's likelihood of developing one or more neurological disorders, and systems for the same. The method of determining a patient's likelihood of developing one or more neurological disorders, comprising the steps of: obtaining data indicative of electrical activity within the brain of the patient; generating a network, based at least in part on the obtained data, said network comprising a plurality of nodes and directed connections between nodes,wherein the network is indicative of a flow of the electrical activity within the brain of the patient; calculating, for each node, a difference in a number and/or strength of connections into the node and a number and/or strength of connections out of the node; and determining, using the calculated differences, the patient's likelihood of developing one or more neurological disorders.
G16H 50/20 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
43.
OPTIMISED DOSAGE OF DIAMINOPHENOTHIAZINES IN POPULATIONS
The invention provides novel dosing regimens for Leuco-Methylthioninium (LMT) compounds which maximise the proportion of subjects in which the MT concentration will exceed concentrations in which therapeutic efficacy in relation to treatment of neurodegenerative disorders such as Alzheimer's disease and rontotemporal dementias can be achieved, while maintaining a desirable clinical profile. Also provided are LMT- containing dosage units and other compositions.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
44.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
B65D 75/36 - Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages
A23P 10/30 - Encapsulation of particles, e.g. foodstuff additives
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).
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 9/48 - Preparations in capsules, e.g. of gelatin, of chocolate
A61K 31/136 - Amines, e.g. amantadine having aromatic rings, e.g. methadone having the amino group directly attached to the aromatic ring, e.g. benzeneamine
A61K 31/165 - Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Disclosed are compounds of general formula (I):
and pharmaceutically acceptable salts thereof, formulations, methods and uses in, for example, the treatment of disease.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07C 309/04 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
C07C 309/05 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
C07C 309/30 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
C07C 303/32 - Preparation of esters or amides of sulfuric acidsPreparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
47.
Methods of chemical synthesis of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
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.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
49.
Methods of chemical synthesis of substituted 10H-phenothiazine-3,7-diamine compounds
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.
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.
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).
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 31/136 - Amines, e.g. amantadine having aromatic rings, e.g. methadone having the amino group directly attached to the aromatic ring, e.g. benzeneamine
A61K 31/165 - Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61K 9/48 - Preparations in capsules, e.g. of gelatin, of chocolate
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
52.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
53.
Methods of chemical synthesis of Diaminophenothiazinium compounds including methylthioninium chloride (MTC)
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.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
55.
METHODS OF CHEMICAL SYNTHESIS OF SUBSTITUTED 10H-PHENOTHIAZINE-3,7-DIAMINE COMPOUNDS
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.
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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
57.
Methods of chemical synthesis of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
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.
Disclosed are compounds of general formula (I):
and pharmaceutically acceptable salts thereof, formulations, methods and uses in, for example, the treatment of disease.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 9/00 - Medicinal preparations characterised by special physical form
C07C 309/04 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
C07C 309/05 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
C07C 309/30 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
C07C 303/32 - Preparation of esters or amides of sulfuric acidsPreparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
59.
3, 7-diamino-10H-phenothiazine salts and their use
Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
2 is 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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/22 - [b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Pharmaceutical and medical preparations; chemical
preparations for medical and pharmaceutical purposes;
pharmaceutical and medical preparations for use in relation
to neurological diseases and disorders, neurodegenerative
diseases and disorders, infectious diseases and malaria;
chemical preparations for medical and pharmaceutical
purposes for use in relation to neurological diseases and
disorders, neurodegenerative diseases and disorders,
infectious diseases and malaria; none of the aforesaid being
pharmaceutical preparations and substances intended for the
prevention and treatment of bone/skeletal diseases. Medical, biological, biotechnological, genetic, laboratory
and pharmaceutical research, design and development
services; research, development and design of drugs and
medicine; drug discovery services; laboratory and medical
laboratory research and development services; exploitation
of scientific research and technology; preparation of
reports; development and design of prognostic and diagnostic
tools; consultancy and information services relating to all
of the aforesaid.
Described are methods and materials for use in the treatment or prophylaxis of diseases, for example cognitive disorders, using diaminophenothiazines. In particular it relates to treatments having optimized pharmacokinetic properties, and dosage forms are intended to improve the relative cognitive or CNS benefits of the diaminophenothiazines, for instance compared to haematological effects.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61K 31/542 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
(1) Pharmaceutical and medical preparations for the treatment of diseases, illnesses and ailments in humans and animals, namely: neoplasms; neurological diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, Pick's disease, frontotemporal dementia, argyrophilic disease, progressive supranuclear palsy, fronto-temporal dementia, parkinsonism linked to chromosome 17, disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-ponto-nigral degeneration, Guam-ALS syndrome; pallido-nigro-luysian degeneration, cortico-basal degeneration, mild cognitive impairment (MCI), multiple system atrophy, drug-induced parkinsonism, and pure autonomic failure; psychiatric diseases, namely, schizophrenia, mood disorders, anxiety disorders, and cognitive disorders; neurological disorders, namely, mild cognitive impairment, tauopathies, and synucleinopathies; cancer; methemoglobinemia; viral diseases, namely herpes, hepatitis, acquired immune deficiency syndrome, and West Nile virus infection; and protozoal diseases, namely malaria, visceral leishmaniasis; African sleeping sickness, toxoplasmosis, giardiasis, and Chagas' disease; pharmaceutical and medical preparations for the treatment of diseases, illnesses and ailments in humans and animals, namely for use in oncology; and pharmaceutical and medical preparations for the treatment of diseases, illnesses and ailments in humans and animals, namely antibiotics, antivirals, and antiprotozoals; chemical preparations for medical and pharmaceutical purposes, namely for the treatment of diseases, illnesses and ailments in humans and animals, namely: neoplasms; neurological diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, Pick's disease, frontotemporal dementia, argyrophilic disease, progressive supranuclear palsy, fronto-temporal dementia, parkinsonism linked to chromosome 17, disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-ponto-nigral degeneration, Guam-ALS syndrome; pallido-nigro-luysian degeneration, cortico-basal degeneration, mild cognitive impairment (MCI), multiple system atrophy, drug-induced parkinsonism, and pure autonomic failure; psychiatric diseases, namely, schizophrenia, mood disorders, anxiety disorders, and cognitive disorders; neurological disorders, namely, mild cognitive impairment, tauopathies, and synucleinopathies; cancer; methemoglobinemia; viral diseases, namely herpes, hepatitis, acquired immune deficiency syndrome, and West Nile virus infection; and protozoal diseases, namely malaria, visceral leishmaniasis; African sleeping sickness, toxoplasmosis, giardiasis, and Chagas' disease; chemical preparations for medical and pharmaceutical purposes, namely for the treatment of diseases, illnesses and ailments in humans and animals, namely for use in oncology; and chemical preparations for medical and pharmaceutical purposes, namely for the treatment of diseases, illnesses and ailments in humans and animals, namely antibiotics, antivirals, and antiprotozoals. (1) Medical, biological, biotechnological, genetic and pharmaceutical research services; research, development and design of drugs and medicine; laboratory and medical laboratory research and development services; preparation of reports of scientific and medical research concerning medicines, pharmaceuticals, genetics, biology, biotechnology and drugs; development and design of prognostic and diagnostic tools; providing research consultation and information in the fields of medical, pharmaceutical, genetic, biological, drugs, clinical, statistical and biotechnological research.
63.
METHODS OF CHEMICAL SYNTHESIS OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)
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.
Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:
2 is 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.
A61K 31/54 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame
C07D 279/18 - [b, e]-condensed with two six-membered rings
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
Described are a compound of formula (II) or (III):
The compounds are effective in the treatment of disease, including a tauopathy condition or a disease of tau protein aggregation.
A61K 31/538 - 1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
A61K 31/352 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline
A61K 31/382 - Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
A61K 31/498 - Pyrazines or piperazines ortho- or peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
C07D 491/22 - Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups , , or in which the condensed system contains four or more hetero rings
A61K 31/4545 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/4745 - QuinolinesIsoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenanthrolines
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
6-10 arylene; and pharmaceutically acceptable salts thereof, which are useful in the treatment of, for example, Alzheimer's disease. In other aspects the invention also relates to novel formulations of 3,7-diamino-10H-phenothiazinium salts.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
C07D 309/04 - Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
C07C 309/05 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
C07C 309/30 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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.
Solid dosage forms of methylthioninium chloride (MTC) further comprise at least one diluent suitable for direct compression. The MTC exists in a substantially pure and stable polymorphic form. The solid dosage forms may preferably be prepared by direct compression methods.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
Substantially pure methylthioninium chloride pentahydrate form A is prepared from methylthioninium chloride by phase equilibration of suspensions, crystallization or solvent evaporation, whereby the water content of the solvent corresponds to a water activity of at least 0.4 at 25° C., and controlled drying of said methylthioninium chloride pentahydrate form A within its stability ranges of humidity, pressure and temperature.
Three dihydrate forms B, C and D and a monohydrate form E of methylthioninium chloride are described. Forms B, C, D and E can be prepared under controlled humidity and temperature from methylthioninium chloride with higher water content or conversion of a hydrate. The hydrates can be incorporated in pharmaceutical compositions.
C07D 279/18 - [b, e]-condensed with two six-membered rings
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
The invention relates to compounds of general formula (I): wherein: each of R1 and R9 is independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; each of R3NA and R3NB is independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; each of R7NA and R7NB is independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; and wherein: each of RA and RB is independently selected from: C1-4alkyl, halogenated C1-4alkyl, and C6-10aryl; or RA and RB are linked to form a group selected from: C1-6 alkylene and C6-10 arylene; and pharmaceutically acceptable salts thereof, which are useful in the treatment of, for example, Alzheimer's disease. In other aspects the invention also relates to novel formulations of 3,7-diamino-10H-phenothiazinium salts.
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/00 - Drugs for disorders of the nervous system
Solid dosage forms of methylthioninium chloride (MTC) further comprise at least one diluent suitable for direct compression. The MTC exists in a substantially pure and stable polymorphic form. The solid dosage forms may preferably be prepared by direct compression methods.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
73.
Methods of chemical synthesis of diaminophenothiazinium compounds involving the use of persulfate oxidants
Described are methods of synthesizing and purifying certain 3,7-diamino-phenothiazin-5-ium compounds (referred to herein as “diaminophenothiazinium compounds”) including Methylhioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: a thiosulfonic acid formation (TSAF); an oxidative coupling (OC); and a ring closure (RC). Also described are resulting compounds and compositions comprising them (e.g., tablets, capsules) for use in methods of medical treatment and diagnosis, etc., for example, for tauopathies, or Alzheimer's disease (AD).
C07D 279/18 - [b, e]-condensed with two six-membered rings
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
74.
3,6-disubstituted xanthylium salts and use thereof in treatment of tauopathies
This invention pertains generally to processes, uses, methods and materials utilizing particular xanthylium compounds, including compounds of formula (I) and (II), as further defined herein. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease.
C07D 491/00 - Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups , , or
75.
Methods of synthesis and/or purification of diaminophenothiazinium compounds
Described is a method for the synthesis and/or purification of a high purity diaminophenothiazinium compound of the following formula:
characterized by a purity of greater than 98% and less than 1% Azure B, 0.15% Azure A, 0.15% Azure C and 0.05% Methylene Violet Bernthsen (MVB), as impurities. Also described are related high purity compounds, compositions, and methods of using such compounds and compositions. The compounds and compositions are useful in the treatment of diseases caused by tau aggregation, such as Alzheimer's disease and other dementias, and infection.
C07D 279/28 - [b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
76.
Synthesis of 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline and analogues and intermediates
The present invention pertains generally to methods of preparing certain 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline compounds and their analogues, and especially to methods of preparing dimebon. The present invention also pertains to methods of preparing certain intermediate compounds which find use in the synthesis of the 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline compounds.
C07D 491/00 - Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups , , or
Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example: formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
G01N 33/50 - Chemical analysis of biological material, e.g. blood, urineTesting involving biospecific ligand binding methodsImmunological testing
C07D 277/66 - Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
This invention pertains generally to the field of phenothiazine compounds, and more particularly to certain stably reduced phenothiazine compounds, specifically, certain 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of the following formula:
2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs (for example, methylthioninium chloride, MTC).
A61K 31/54 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame
C07D 279/18 - [b, e]-condensed with two six-membered rings
Three dihydrate forms B, C and D and a monohydrate form E of methylthloninium chloride (methylene blue) are described. Forms B, C, D and E can be prepared under controlled humidity and temperature from methylthioninium chloride with higher water content or conversion of a hydrate. The hydrates can be incorporated in pharmaceutical compositions.
C07D 279/18 - [b, e]-condensed with two six-membered rings
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Substantially pure methylthioninium chloride pentahydrate form A is prepared from methylthioninium chloride by phase equilibration of suspensions, crystallization or solvent evaporation, whereby the water content of the solvent corresponds to a water activity of at least 0.4 at 25°C, and controlled drying of said methylthioninium chloride pentahydrate form A within its stability ranges of humidity, pressure and temperature.
C07D 279/18 - [b, e]-condensed with two six-membered rings
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 31/00 - Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
This invention 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 Methylhioninium 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). The present invention also pertains to the 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.
The present invention relates generally to methods and materials for use in the treatment or prophylaxis of diseases, for example cognitive disorders, using diaminophenothiazines. In particular it relates to treatments having optimised pharmacokinetic properties, and dosage forms are intended to improve the relative cognitive or CNS benefits of the diaminophenothiazines, for instance compared to haematological effects.
A61K 31/542 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
83.
METHODS OF CHEMICAL SYNTHESIS OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INVOLVING THE USE OF PERSULFATE OXIDANTS
This invention 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 Methylthioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: a thiosulfonic acid formation (TSAF) as illustrated below, wherein the reaction is carried out in the presence of a thiosulfate and an oxidizing agent that is or comprises persulfate an oxidative coupling (OC); and a ring closure (RC). The resulting compounds and compositions comprising them (e.g., tablets, capsules) are useful in methods of medical treatment and diagnosis, etc., for example, tauopathies, or Alzheimer's disease (AD).
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
84.
Phenothiazine compounds for treating mild cognitive impairment
The present invention relates generally to methods and materials based on diaminophenothiazines for use in the treatment of Mild Cognitive Impairment (MCI).
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
85.
SYNTHESIS OF 9-(ARYLALKYL)-1,2,3,4-TETRAHYDRO-Υ-CARBOLINE AND ANALOGUES AND INTERMEDIATES
The present invention pertains generally to methods of preparing certain 9-(arylalkyl)- 1,2,3,4-tetrahydro-Υ-carboline compounds and their analogues, and especially to methods of preparing dimebon. The present invention also pertains to methods of preparing certain intermediate compounds which find use in the synthesis of the 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline compounds.
C07D 213/06 - Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
C07D 413/06 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
This invention pertains generally to processes, uses, methods and materials utilising particular xanthylium compounds, including compounds of formula (I) and (II), as further defined herein. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease.
C07D 491/22 - Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups , , or in which the condensed system contains four or more hetero rings
A61K 31/4375 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring hetero atom, e.g. quinolizines, naphthyridines, berberine, vincamine
A61K 31/352 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline
A61K 31/382 - Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
A61K 31/498 - Pyrazines or piperazines ortho- or peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
A61K 31/538 - 1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example:formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
G01N 33/68 - Chemical analysis of biological material, e.g. blood, urineTesting involving biospecific ligand binding methodsImmunological testing involving proteins, peptides or amino acids
C07D 275/04 - Heterocyclic compounds containing 1, 2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
C07D 277/66 - Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
C07D 279/06 - 1,3-ThiazinesHydrogenated 1,3-thiazines not condensed with other rings
88.
Methods of synthesis and/or purification of diaminophenothiazinium compounds
A method for the synthesis of a diaminophenothiazinium compound of the following formula:
comprising (a) purifying a corresponding reduced compound which is N-acylated at the heterocyclic nitrogen; (b) deacylating the purified compound to provide the corresponding reduced compound; and (c) oxidizing the reduced compound to provide the diaminophenothiazinium compound. Optional purification may performed, for example, after deacylating and after oxidizing. The method provides high purity diaminophenothiazinium compounds which are suitable for pharmaceutical and related therapeutic uses. Such uses include inactivating pathogens, the treatment of the infectious diseases, and for the treatment of diseases of protein aggregation, such as tauopathies, including Alzheimer's disease.
C07D 279/28 - [b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
The invention relates generally to the use of diaminophenothiazine compounds to inhibit or reverse the aggregation of synuclein, and for their use in the manufacture of medicaments for this purpose (e.g. for the treatment of Parkinson's Disease). Also provided are related methods of detecting or labelling of aggregated synuclein.
A61K 31/54 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame
C07D 279/36 - [b, e]-condensed, at least one with a further condensed benzene ring
A61B 5/00 - Measuring for diagnostic purposes Identification of persons
G06F 19/00 - Digital computing or data processing equipment or methods, specially adapted for specific applications (specially adapted for specific functions G06F 17/00;data processing systems or methods specially adapted for administrative, commercial, financial, managerial, supervisory or forecasting purposes G06Q;healthcare informatics G16H)
The present invention relates generally to methods and materials for use in the treatment or prophylaxis of diseases, for example cognitive disorders, using diaminophenothiazines. In particular it relates to treatments having optimised pharmacokinetic properties, and dosage forms are intended to improve the relative cognitive or CNS benefits of the diaminophenothiazines, for instance compared to haematological effects.
A61K 31/542 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs (for example, methythioninium chloride, MTC).
C07D 279/18 - [b, e]-condensed with two six-membered rings
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
93.
PHENOTHIAZINE COMPOUNDS FOR TREATING MILD COGNITIVE IMPAIRMENT
The present invention relates generally to methods and materials based on diaminophenothiazines for use in the treatment of Mild Cognitive Impairment (MCI).
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
94.
Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
95.
METHODS OF SYNTHESIS AND/OR PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS
This invention pertains generally to the field of chemical synthesis and purification, and more specifically to 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 present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment, prophylaxis, and diagnosis, etc., for example, a tauopathy; a disease of tau protein aggregation; Alzheimer's disease (AD); Pick's disease; Progressive Supranuclear Palsy (PSP); fronto temporal dementia (FTD); parkinsonism linked to chromosome 17 (FTDP-17); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC); pallido-ponto-nigral degeneration (PPND); Guam-ALS syndrome; pallido-nigro-luysian degeneration (PNLD); cortico-basal degeneration (CBD); mild cognitive impairment (MCI); skin cancer; melanoma; methemoglobinemia; a viral infection; a bacterial infection; a protozoal infection; a parasitic infection; malaria; visceral leishmaniasis; African sleeping sickness; toxoplasmosis; giardiasis; Chagas' disease; Hepatitis C virus (HCV) infection; human immunodeficiency virus (HIV) infection; West Nile virus (WNV) infection; a synucleinopathy; Parkinson's disease (PD); dementia with Lewy bodies (DLB); multiple system atrophy (MSA); drug-induced parkinsonism; and pure autonomic failure (PAF).
The invention relates generally to the use of diaminophenothiazine compounds to inhibit or reverse the aggregation of synuclein, and for their use in the manufacture of medicaments for this purpose (e.g. for the treatment of Parkinson's Disease). Also provided are related methods of detecting or labelling of aggregated synuclein.
A61K 31/00 - Medicinal preparations containing organic active ingredients
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
This invention pertains generally to the field of phenothiazine compounds, and more particularly to certain stably reduced phenothiazine compounds, specifically, certain 3,7 diamino-10H-phenothiazine (DAPTZ) compounds of the following formula wherein: each of R1 and R9 is independently selected from: -H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R3NA and R3NB is independently selected from: -H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R7NA and R7NB is independently selected from: -H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of HX1 and HX2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs (for example, methythioninium chloride, MTC).
C07D 279/20 - [b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
This invention pertains generally to processes, uses, methods and materials utilising particular diaminophenothiazinium compounds, specifically, ETC, DEMTC, DMETC, DEETC, MTZ, ETZ, MTI, MTI.HI, ETI, ETI.HI, MTN, and ETN. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease.
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
99.
Methods of treatment of a tauopathy condition comprising the use of thioninium compounds
This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7-diaminophenothiazin-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). The present invention also pertains to the 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.
A61K 31/5415 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
