Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—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 C07D415/00
  • C07D417/02—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 C07D415/00 containing two hetero rings
  • C07D417/04—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 C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—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 C07D415/00
  • C07D417/02—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 C07D415/00 containing two hetero rings
  • C07D417/12—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 C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—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 C07D415/00
  • C07D417/14—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 C07D415/00 containing three or more hetero rings

Definitions

• X is -CH 2 - or -(CH 2 ) 2 -;
• R 4 is halogen; Ci_ 6 alkyl; Ci_ 6 alkyl substituted by one or more halogens; or Ci_ 6 alkoxy; preferably R 4 is halogen; Ci_ 6 alkyl substituted by one or more halogens; or Ci_ 6 alkoxy; preferably R 4 is halogen; or Ci_ 6 alkoxy;
• the compounds have a structure of formula IA, whereby G 1 is -NR 2 R 3 ; Ar is phenyl; R 2 and R 3 form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen; or lower alkyl substituted by one or more halogens; and X is -(CH 2 ) 2 .
• El 7 The use of a compound as described in any one of El - El 0 for the manufacture of medicaments for the treatment of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17).
• X is -CH 2 - or -(CH 2 ) 2 -; preferably X is -(CH 2 ) 2 ;
• Incubations are performed in 96-well deep-well plates with a final incubation volume of 600 ⁇ . Incubations contain (finally) 1-2 ⁇ test compound, 0.5mg/mL liver microsomes (typically human, rat or mouse) and NADPH regenerating system. 50 ⁇ aliquots are removed after 1, 3, 6, 9, 15, 25, 35 and 45 minutes and quenched in 150 ⁇ acetonitrile containing internal standard. Samples are then cooled and centrifuged before analysis by LC- MS/MS.
• One further embodiment of the invention are compounds of formula IA wherein X is -(CH 2 ) 2 - and G 1 is -NR 2 R 3 , R 2 is hydrogen and R 3 is lower alkyl, tetrahydropyran-4-yl, - CH 2 -cycloalkyl or cycloalkyl optionally substituted by lower alkyl substituted by one or more halogens, for example the compounds
• R 2 and R 3 form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen or lower alkyl substituted by one or more halogens, for example compounds: 1 -[3-(4,4-Difluoro-piperidin- 1 -yl)-[ 1 ,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy- phenyl)-ethyl]-piperazine; 1 -[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin- 1 -yl)- [l,2,4]thiadiazol-5-yl]-piperazine; l-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-d
• One further embodiment of the invention are compounds of formula I, wherein R 2 is lower alkyl, for example the compound: Butyl-(5- ⁇ 4-[2-(3,4-difluoro-phenyl)-ethyl]- piperazin- 1 -yl ⁇ -[1 ,2,4]thiadiazol-3-yl)-ethyl-amine.
• DIPEA N,N-diisopropylethylamine
• a TAU expression plasmid was constructed by sub-cloning the cDNA encoding for human TAU-P301L protein, wherein proline at position 301 is substituted by a leucine residue, into mammalian expression vector pcDNA3.1 resulting in the plasmid pcDNA3.1- TAUP301L. Plasmids pcDNA3.1 and pcDNA3.1-TAU P301L were transfected into human neuroblastoma cells (BE-M17; ATCC No.
• the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
• the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
• the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Neurosurgery (AREA)
• Engineering & Computer Science (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Psychiatry (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

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• 2012
  • 2012-08-17 PL PL12756402T patent/PL2744798T3/pl unknown
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• 2015
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