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• • 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
  • A61K31/435—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
  • A61K31/4353—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
  • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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

Definitions

• PDE inhibitors that have thus far been put to practical application are those inhibiting PDE3 (treatment for heart failure), PDE4 (treatment for asthma and COPD) and PDE5 (treatment for male erectile dysfunction).
• ibudilast effects include enhancement of the relaxation effect of prostacyclin (PGI2) on cerebral vascular smooth muscle, enhancement of the inhibitory effect of prostacyclin (PG12) on platelet aggregation, suppression of airway contraction, suppression of leukotriene release and inhibition of PDE, as well as improvement of memory disorder (Patent Article 5) and amelioration of multiple sclerosis (Non-patent Article 3).
• the aim of the present invention is to provide a PDE10A inhibitor, which is a potential prophylactic or therapeutic agent against Parkinson's disease, Huntington's disease, Alzheimer's disease or, schizophrenia.
• Pyrazolo[1,5-a]pyridine derivatives as represented by the general formula (1) above are known compounds. Of these derivatives, 3-isobutyryl-2-isopropyl pyrazolo[1,5-a]pyridine, commonly known as ibudilast, is widely used as a cerebral circulation improver or a treatment for bronchial asthma and allergic conjunctivitis.
• the lower alkyl group having 1 to 4 carbons may be methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl and is preferably isopropyl.
• the lower alkoxyl group having 1 to 3 carbons may be methoxy, ethoxy, propoxy, or isopropoxy.
• Alzheimer's disease is a cerebral degenerative disease that leads to severe dementia and is characterized by deposition of beta-amyloids in nerve cells, degeneration of neurofibrils, loss of nerve cells and abnormal decrease of acetylcholine and other neurotransmitters.
• cGMP is known to facilitate the release of certain neurotransmitters, such as glutamic acid and acerylcholine, facilitate the growth of dendrites, increase the viability of nerve cells, and suppress apoptosis of nerve cells induced by beta-amyloids.
• a PDE10A inhibitor which may cause an increase in the brain cGMP level, is expected to have a potential as a novel treatment for Alzheimer's disease.
• a major cause of schizophrenia is believed to be an imbalance of signaling mediated by neurotransmitters, glutamic acid, serotonin, and dopamine.
• the most plausible hypothesis for the cause of schizophrenia seems to be excessive release of dopamine in neostriatum.
• cGMP is known as a second messenger that facilitates the release of glutamic acid in neostriatum, so that an elevated cGMP level may modulate the balance of signaling mediated by neurotransmitters in neostriatum. Therefore, a PDE10A inhibitor, which may cause an increase in the cGMP level in neostriatum, is expected to have a potential as a novel treatment for schizophrenia.
• the pyrazolo[1,5-a]pyridine derivatives represented by the general formula (1) which have proven to be effective PDE10A inhibitors, are thought to be effective in the prevention and treatment of Parkinson's disease, Huntington's disease, Alzheimer's disease, and schizophrenia.
• cDNA of full length PDEs specifically, PDE1A3, PDE2A3, PDE3A, PDE3B, PDE4A4, PDE4B2, PDE4C2, PDE4D3, PDE5A1, PDE5A2, PDE5A3, PDE7A2, PDE8A1, PDE9A2, PDE10A1, and PDE11A1, were isolated by RT-PCR from human RNA.
• the isolated cDNA fragments were introduced into Sf9 insect cells using Gateway system (Invitrogen) and Bac-to-Bac® Baculovirus Expression system (Invitrogen) to express PDE proteins.
• the recombinant proteins of PDE1A3, PDE2A3, PDE3A, PDE4A4, PDE4B2, PDE4C2, PDE4D3, PDE5A1, PDE5A2, PDE5A3, PDE7A2, PDE8A1, PDE9A2, PDE10A1, and PDE11A1 were purified by ion exchange chromatography from the supernatants or cell extracts of the Sf9 cells.
• the Sf9 cells expressing PDE3B protein at a high level were suspended in a RIPA buffer [150 mM NaCl, 10 mM Tris-HCl (pH8.3), 0.1% protease inhibitor cocktail (Product No.: P8849, Sigma)], and the whole suspension was used in the experiment described below.
• a RIPA buffer 150 mM NaCl, 10 mM Tris-HCl (pH8.3), 0.1% protease inhibitor cocktail (Product No.: P8849, Sigma)
• pyrazolo[1,5-a]pyridine derivatives represented by the general formula (1) have proven to be strong inhibitors of PDE10A and have thus proven to be useful in the prevention and treatment of Parkinson's disease, Huntington's disease, Alzheimer's disease, and schizophrenia.

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• Health & Medical Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Medicinal Chemistry (AREA)
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• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biomedical Technology (AREA)
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• Neurology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Psychology (AREA)
• Psychiatry (AREA)
• Epidemiology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2003
  • 2003-12-01 WO PCT/JP2003/015315 patent/WO2004050091A1/ja active Application Filing
  • 2003-12-01 AU AU2003302588A patent/AU2003302588A1/en not_active Abandoned
  • 2003-12-01 CA CA2508194A patent/CA2508194C/en not_active Expired - Fee Related
  • 2003-12-01 US US10/537,313 patent/US20060106054A1/en not_active Abandoned
  • 2003-12-01 EP EP03812356A patent/EP1570847B1/de not_active Expired - Fee Related
  • 2003-12-01 JP JP2004556869A patent/JP4589122B2/ja not_active Expired - Fee Related
• 2007
  • 2007-10-31 US US11/980,526 patent/US7846942B2/en not_active Expired - Fee Related
• 2010
  • 2010-06-25 JP JP2010144691A patent/JP5192517B2/ja not_active Expired - Fee Related
  • 2010-10-27 US US12/913,094 patent/US8404710B2/en not_active Expired - Fee Related

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