DK2004155T3 - Inhibitorer af protein-aggregation - Google Patents

Inhibitorer af protein-aggregation Download PDF

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DK2004155T3
DK2004155T3 DK07712961.7T DK07712961T DK2004155T3 DK 2004155 T3 DK2004155 T3 DK 2004155T3 DK 07712961 T DK07712961 T DK 07712961T DK 2004155 T3 DK2004155 T3 DK 2004155T3
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synuclein
unsubstituted
compound
independently selected
substituted
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Claude Michel Wischik
Janet Elizabeth Rickard
Charles Robert Harrington
David Horsley
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Wista Lab Ltd
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
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    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
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    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/003—Thiazine dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0465—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (25)

1. Anvendelse af en diaminophenothiazin-forbindelse til fremstilling af et medikament til inhibering eller reversering af aggregation af synuclein, hvor aggregationen er forbundet med en sygdomstilstand manifesteret som neurodegeneration og/eller klinisk demens, hvilken sygdom er udvalgt blandt: Parkinsons sygdom (PD), demens med Lewy-legemer (DLB), multipel systematrofi (MSA), lægemiddelinduceret parkinsonisme; PAF (pure autonomic failure), og hvor medikamentet er til behandling af sygdomstilstanden, og hvor diami-nophenothiazin-forbindelsen i behandlingen indgives oralt som enten: (i) dosisenheder på ca. 10, 20, 30, 40, 50, 60, 80, 90, 100, 110, 120 eller 130 mg tre gange om dagen; eller (ii) dosisenheder på ca. 10, 20, 30, 40, 50, 60, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 eller 200 mg to gange om dagen; eller (iii) en dosis på mindre end eller lig med 400 mg samlet daglig dosis, hvor forbindelsen er udvalgt blandt forbindelser med følgende formler:
hvor hver enkelt af R1, R2, R4, R6, R8 og R9 uafhængigt er udvalgt blandt: -H; -F; -Cl; -Br; -I; -OH; -OR; -SH; -SR; -NO2; -C(=0)R; -C(=0)OH; -C(=0)OR; -C(=0)NH2; -C(=0)NHR; -C(=0)NR2; -C(=0)NRN1RN2; -NH2; -NHR; -NR2; -NRN1RN2; -NHC(=0)H; -NRC(=0)H; -NHC(=0)R; -NRC(=0)R; -R; hvor hvert R uafhængigt er udvalgt blandt: usubstitueret alifatisk Ci-6alkyl; substitueret alifatisk Ci ealkyl; usubstitueret alifatisk C2-6alkenyl; substitueret alifatisk C2-6alkenyl; usubstitueret C3-6Cycloalkyl; substitueret C3-6cycloalkyl; usubstitueret C6-iocarboaryl; substitueret Ce-iocarboaryl; usubstitueret Cs-ioheteroaryl; substitueret Cs-ioheteroaryl; usubstitueret C6-iocarboaryl-Ci-4alkyl; substitueret C6-iocarboaryl-Ci-4alkyl; hvor, i hver gruppe -NRN1RN2, uafhængigt, RN1 og RN2 sammen med nitrogenatomet, hvortil de er knyttet, danner en ring med fra 3 til 7 ringatomer; og hvor, i hver gruppe -nr3NAR3NA: hver enkelt af R3NA og R3NB uafhængigt er udvalgt blandt: -H; usubstitueret alifatisk Ci-6alkyl; substitueret alifatisk Ci-6alkyl; usubstitueret alifatisk C2-6alkenyl; substitueret alifatisk C2-6alkenyl; usubstitueret C3-6cycloalkyl; substitueret C3-6cycloalkyl; usubstitueret Ce-iocarboaryl; substitueret Ce-iocarboaryl; usubstitueret Cs-ioheteroaryl; substitueret Cs-ioheteroaryl; usubstitueret C6-iocarboaryl-Ci-4alkyl; substitueret C6-iocarboaryl-Ci-4alkyl; eller: R3NA og R3NB sammen med nitrogenatomet, hvortil de er knyttet, danner en ring med fra 3 til 7 ringatomer; og hvor gruppen -NR7NAR7NB er den samme som -NR3NAR3NB; og hvor X- er en eller flere anioniske modioner til opnåelse af elektrisk neutralitet; og farmaceutisk acceptable salte, blandingssalte, hydrater og solvater deraf.
2. Anvendelse ifølge krav 1, hvor hver enkelt af R1, R2, R4, R6, R8 og R9 uafhængigt er udvalgt blandt: -H; -R.
3. Anvendelse ifølge krav 1 eller krav 2, hvor hvert R uafhængigt er udvalgt blandt: usubstitueret alifatisk C-i-ealkyl; substitueret alifatisk C-i-ealkyl.
4. Anvendelse ifølge et hvilket som helst af kravene 1 til 3, hvor substituenter på R, hvis til stede, uafhængigt er udvalgt blandt: -F; -Cl; -Br; -I; -OH; -OR; -C(=0)0H; -C(=0)0R'; -R', hvor hvert R' uafhængigt er udvalgt blandt: usubstitueret alifatisk Ci-6alkyl; usubstitueret alifatisk C2-6alkenyl; usubstitueret C3-6cycloalkyl; usubstitueret Ce-iocarboaryl; usubstitueret Cs-ioheteroaryl; usubstitueret Ce-iocarboaryl-Ci^alkyl.
5. Anvendelse ifølge krav 1, hvor hver enkelt af R1, R2, R4, R6, R8 og R9 uafhængigt er udvalgt blandt: -H, -Me, -Et, -nPr og -iPr.
6. Anvendelse ifølge krav 5, hvor hvert enkelt af R1, R2, R4, R6, R8 og R9 uafhængigt er udvalgt blandt: -H, -Me og -Et.
7. Anvendelse ifølge krav 1, hvor hver enkelt af R1, R2, R4, R6, R8 og R9 uafhængigt er udvalgt blandt: -H og -Me.
8. Anvendelse ifølge krav 7, hvor hvert af R1, R2, R4, R6, R8 og R9 er -H.
9. Anvendelse ifølge et hvilket som helst af kravene 1 til 8, hvor, i hver gruppe -NR3NAR3NB, hver af R3NA og R3NB uafhængigt er udvalgt blandt: -H, -Me, -Et, -nPr og -iPr.
10. Anvendelse ifølge krav 9, hvor, i hver gruppe -NR3NAR3NB, hver af R3NA og R3NB uafhængigt er udvalgt blandt: -H og -Me.
11. Anvendelse ifølge et hvilket som helst af kravene 1 til 10, hvor X-, hvis til stede, er en eller flere anioniske modioner til opnåelse af elektrisk neutralitet, eventuelt udvalgt blandt Cl', Br eller h
12. Anvendelse ifølge krav 1, hvor forbindelsen er udvalgt blandt de følgende forbindelser og farmaceutisk acceptable salte, blandingssalte, hydrater og solvater deraf:
13. Diaminophenothiazin-forbindelse ifølge et hvilket som helst af kravene 1 til 12, til anvendelse i en fremgangsmåde til behandling eller forebyggelse af en neurodegenerativ sygdomstilstand og/eller klinisk demens forbundet med synuclein-aggregation, hvilken fremgangsmåde omfatter indgivelse til et individ af en profylaktisk eller terapeutisk virksom mængde af diaminophenothiazin-forbindelsen eller en terapeutisk sammensætning omfattende samme til hæmning af aggregation af synuclein, hvor aggregationen er forbundet med en sygdomstilstand manifesteret som neurodegeneration og/eller klinisk demens, hvilken sygdom er udvalgt blandt: Parkinsons sygdom (PD), demens med Lewy-legemer (DLB), multipel systematrofi (MSA), lægemiddelinduceret parkinsonisme; PAF (pure autonomic failure), hvor diaminophenothiazin-forbindelsen i fremgangsmåden indgives oralt som enten: (i) dosisenheder på ca. 10, 20, 30, 40, 50, 60, 80, 90, 100, 110, 120 eller 130 mg tre gange om dagen; eller (ii) dosisenheder på ca. 10, 20, 30, 40, 50, 60, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 eller 200 mg to gange om dagen; eller (iii) en dosis på mindre end eller lig med 400 mg samlet daglig dosis.
14. Anvendelse ifølge et hvilket som helst af kravene 1 til 12, hvor behandlingen omfatter indgivelse af diaminophenothizin-forbindelsen i kombination med en forbindelse, modulerer dopaminniveauer hos det pattedyr, der skal behandles.
15. Anvendelse ifølge et hvilket som helst af kravene 1 til 12 eller 14, hvor mere end eller lig med 300, 200 eller 100 mg samlet daglig dosis indgives.
16. Forbindelse ifølge krav 13, hvor behandlingen omfatter indgivelse af dia-minophenothizin-forbindelsen i kombination med en forbindelse, der modulerer dopaminniveauer hos det pattedyr, der skal behandles.
17. Forbindelse ifølge krav 13 eller 16, hvor mere end eller lig med 300, 200 eller 100 mg samlet daglig dosis indgives.
18. Anvendelse af en diaminophenothiazin-forbindelse, der kan mærke ag-gregeret synuclein, i en fremgangsmåde til fremstilling af et diagnostisk eller prognostisk reagens til anvendelse inden for diagnose eller prognose af en synucleinopati-sygdomstilstand, hvor diaminophenothiazin-forbindelsen er en forbindelse ifølge et hvilket som helst af kravene 1 til 12 og inkorporerer, er konjugeret til, er chelateret med eller på anden måde er forbundet med en eller flere isotoper, radioisotoper, positron-emitterende atomer, magnetisk resonans-mærker, farver, fluorescerende markører eller antigene grupper.
19. Anvendelse ifølge krav 18, hvor mindst et ringcarbonatom af diami-nophenothiazin-forbindelsen er 11C, og/eller mindst et af carbonatomerne af mindst en af substituenterne Ft1, Ft2, Ft4, Ft6, Ft8, Ft9, R3NA, Ft3NB, Ft7NA og Ft7NB er 11C.
20. Anvendelse ifølge krav 19, udvalgt blandt følgende forbindelser og farmaceutisk acceptable salte, blandingssalte, hydrater og solvate deraf:
21. Fremgangsmåde til mærkning af aggregeret synuclein, omfattende trinnene: at bringe det aggregerede synuclein i kontakt med en diaminopheno-thiazin-forbindelse ifølge et hvilket som helst af kravene 18 til 20.
22. Diaminophenothiazin-forbindelse ifølge et hvilket som helst af kravene 18 til 20 til anvendelse i en fremgangsmåde til diagnose eller prognose af en synucleinopati hos et individ, der formodes at lide af sygdommen, omfattende trinnene: (i) at indføre diaminophenothiazin-forbindelsen i individet, (ii) at bestemme tilstedeværelsen og/eller mængden af forbindelsen bundet til synuclein eller aggregeret synuclein i individets hjerne, (iii) at korrelere resultatet af den bestemmelse, der blev foretaget i (ii), med individets sygdomstilstand.
23. Anvendelse ifølge et hvilket som helst af kravene 1 til 12 eller 14 til 15 eller 18 til 20, hvor synuclein er a-synuclein.
24. Fremgangsmåde ifølge krav 21, hvor synuclein er a-synuclein.
25. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 13, eller 16 til 17, hvor synuclein er a-synuclein.
DK07712961.7T 2006-03-29 2007-03-28 Inhibitorer af protein-aggregation DK2004155T3 (da)

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US78670006P 2006-03-29 2006-03-29
PCT/GB2007/001105 WO2007110629A1 (en) 2006-03-29 2007-03-28 Inhibitors of protein aggregation

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US (3) US8263589B2 (da)
EP (1) EP2004155B1 (da)
JP (1) JP5654748B2 (da)
CN (2) CN103735554B (da)
AU (1) AU2007231126B2 (da)
CA (1) CA2645946C (da)
DK (1) DK2004155T3 (da)
ES (1) ES2667002T3 (da)
MY (1) MY153198A (da)
PL (1) PL2004155T3 (da)
PT (1) PT2004155T (da)
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