[go: up one dir, main page]

WO2010087313A1 - Stimulateur d'élongation d'axone - Google Patents

Stimulateur d'élongation d'axone Download PDF

Info

Publication number
WO2010087313A1
WO2010087313A1 PCT/JP2010/050923 JP2010050923W WO2010087313A1 WO 2010087313 A1 WO2010087313 A1 WO 2010087313A1 JP 2010050923 W JP2010050923 W JP 2010050923W WO 2010087313 A1 WO2010087313 A1 WO 2010087313A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound represented
general formula
test
group
neurite
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2010/050923
Other languages
English (en)
Japanese (ja)
Inventor
人水 太田
研志 穐田
恒孝 太田
敏雄 河田
恵温 福田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hayashibara Seibutsu Kagaku Kenkyujo KK
Original Assignee
Hayashibara Seibutsu Kagaku Kenkyujo KK
Hayashibara Biochemical Laboratories Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hayashibara Seibutsu Kagaku Kenkyujo KK, Hayashibara Biochemical Laboratories Co Ltd filed Critical Hayashibara Seibutsu Kagaku Kenkyujo KK
Priority to JP2010548503A priority Critical patent/JPWO2010087313A1/ja
Publication of WO2010087313A1 publication Critical patent/WO2010087313A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—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
    • A61K31/352—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. methantheline 
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—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
    • C07D413/06—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
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a neurite outgrowth promoter comprising a compound represented by general formula 1 as an active ingredient.
  • R 1 to R 3 in General Formula 1 each independently represent a hydrogen atom or an appropriate substituent
  • Z 1 represents a heterocyclic ring
  • Z 2 represents a heterocyclic ring or an aromatic ring that is the same as or different from Z 1.
  • These heterocyclic rings and aromatic rings may have a substituent.
  • o represents an integer that is either 0, 1, or 2
  • p represents an integer that is either 0 or 1
  • p is 1 when o is 0 or 2
  • o is 1
  • P is 0.
  • X l - represents a suitable counter anion
  • q is an integer of either 1 or 2.
  • Neurodegenerative diseases are pathological conditions caused by systematic neuronal degeneration and disruption of the neural network based on loss, and many intractable diseases such as Alzheimer's disease, Parkinson's disease, Parkinson's syndrome, cerebrovascular dementia, frontal side Known as lobar dementia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's disease, spinocerebellar degeneration, and the like.
  • NGF nerve growth factor
  • systemic administration such as subcutaneously or intravascularly cannot be expected to have a therapeutic effect on neurodegenerative diseases caused by central nerve degeneration because it is difficult to cross the blood-brain barrier due to the polymer.
  • Surgical treatment is necessary to administer it into the brain with the expectation of an effect, and the patient is accompanied by a large physical and mental burden.
  • neurodegenerative diseases vary depending on the disease, but they vary from minor to severe. Typical examples include tremor, rigidity, agitation, peristalsis, and movement. Slowness, postural reflex disorder, autonomic disorder, lunging phenomenon, gait disorder, depression, memory disorder, muscle atrophy, muscle weakness, upper limb dysfunction, articulation disorder, dysphagia, respiratory disorder, numbness or paralysis, etc. Both are major obstacles in daily life.
  • Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are serious diseases that cause degeneration of nerve cells, and various compounds are used as active ingredients to improve these diseases and their associated pathological conditions and neurological dysfunction.
  • International Publication No. WO97 / 030703, JP-A-11-228417, JP-A-2006-143708, and JP-A-2006-321737 See, for example, International Publication No. WO97 / 030703, JP-A-11-228417, JP-A-2006-143708, and JP-A-2006-321737.
  • an accelerator or the like has been proposed (see, for example, JP-A-2002-234841), an effective disease treatment method has not yet been found.
  • systemic administration such as subcutaneous or intravascular, has a low physical and mental burden on the patient, acts on nerve cells of the central nervous system, activates nerve cell bodies, suppresses neurite atrophy, or Therefore, development of a novel neurite outgrowth promoter capable of promoting neurite outgrowth and ameliorating neurological degeneration or dysfunction associated with neurodegeneration is eagerly desired.
  • An object of the present invention is to provide a novel neurite extension promoter.
  • the present invention mainly comprises a neurite outgrowth promoter containing a compound represented by the following general formula 1 as an active ingredient.
  • R 1 to R 3 in General Formula 1 each independently represent a hydrogen atom or an appropriate substituent
  • Z 1 represents a heterocyclic ring
  • Z 2 represents a heterocyclic ring or an aromatic ring that is the same as or different from Z 1.
  • These heterocyclic rings and aromatic rings may have a substituent.
  • o represents an integer that is either 0, 1, or 2
  • p represents an integer that is either 0 or 1
  • p is 1 when o is 0 or 2
  • o is 1
  • P is 0.
  • X l - represents a suitable counter anion
  • q is an integer of either 1 or 2.
  • the neurite outgrowth promoting agent of the present invention promotes neurite outgrowth and activates nerve function in various administration routes of oral administration and parenteral administration, and various symptoms associated with nerve dysfunction (for example, , Tremor, stiffness, immobility, peristalsis, slow movement, postural reflex disorder, autonomic disorder, lunging phenomenon, gait disorder, depression, memory disorder, muscle atrophy, muscle weakness, upper / lower limb dysfunction, articulation disorder, swallowing Disorder, breathing problems, numbness and paralysis).
  • nerve dysfunction for example, Tremor, stiffness, immobility, peristalsis, slow movement, postural reflex disorder, autonomic disorder, lunging phenomenon, gait disorder, depression, memory disorder, muscle atrophy, muscle weakness, upper / lower limb dysfunction, articulation disorder, swallowing Disorder, breathing problems, numbness and paralysis.
  • security of the compound represented by General formula 1 which is an active ingredient is very high.
  • the neurite means an axon and dendrite extending from a neuronal cell body.
  • the neurite outgrowth promoting action refers to the action of activating nerve cells to extend axons and / or dendrites, the action of suppressing neurite atrophy and reduction, and the action of promoting synapse formation between nerve cells. And the action of suppressing the decrease in synapses.
  • the neurite extension promoter of the present invention contains a compound represented by the following general formula 1 as an active ingredient.
  • R 1 to R 3 in General Formula 1 each independently represent a hydrogen atom or an appropriate substituent
  • Z 1 represents a heterocyclic ring
  • Z 2 represents a heterocyclic ring or an aromatic ring that is the same as or different from Z 1.
  • These heterocyclic rings and aromatic rings may have a substituent.
  • o represents an integer that is either 0, 1, or 2
  • p represents an integer that is either 0 or 1
  • p is 1 when o is 0 or 2
  • o is 1
  • P is 0.
  • X l - represents a suitable counter anion
  • q is an integer of either 1 or 2.
  • X l in the general formula 1 - represents an appropriate counter anion, usually, for example, fluorine ion, chlorine ion, bromine ion, iodine ion, perchlorate ion, periodic acid ion, hexafluorophosphate ion, Rokudoruka Inorganic acid anions such as antimonate ions, hexafluorostannate ions, phosphate ions, borofluoride ions, tetrafluoroborate ions, thiocyanate ions, benzenesulfonate ions, naphthalenesulfonate ions, naphthalene disulfonate ions Organic acid anions such as p-toluenesulfonate ion, alkylsulfonate ion, benzenecarboxylate ion, alkylcarboxylate ion, trihaloalkylcarboxylate ion,
  • the compound represented by the general formula 1 include dye compounds such as a pentamethine cyanine dye represented by any one of the general formulas 2 to 4 and a dimethine styryl dye represented by the general formula 5 (hereinafter referred to as “a dye compound”). And may be simply referred to as “compound”).
  • R 4 to R 6 represent the same or different aliphatic hydrocarbon groups.
  • X 2 - represents an appropriate counter anion.
  • R 7 to R 9 represent the same or different aliphatic hydrocarbon groups.
  • X 3 - represents an appropriate counter anion.
  • R 10 to R 12 represent the same or different aliphatic hydrocarbon groups.
  • X 4 - represents an appropriate counter anion.
  • Z 3 represents a heteroaromatic ring, and the heteroaromatic ring may have a substituent.
  • Z 4 represents an aromatic ring or a heteroaromatic ring, and the heteroaromatic ring and the aromatic ring may have a substituent.
  • R 13 represents an aliphatic hydrocarbon group, and the aliphatic hydrocarbon group may have a substituent.
  • the R 14 is hydrogen atom or an appropriate substituent and, X 5 - represents a suitable counter anion.
  • the aliphatic hydrocarbon group represented by R 4 to R 13 in the general formulas 2 to 5 those having 1 to 12 carbon atoms are usually selected, those having 2 to 10 are preferable, and those having 2 to 9 are preferable. Those are more preferred.
  • the R4 to R6 aliphatic hydrocarbon group of the compound represented by the general formula 2 has 2 to 12 carbon atoms, or the R7 to R9 aliphatic hydrocarbon group of the compound represented by the general formula 3
  • a compound having 4 to 10 carbon atoms is particularly desirable because it has a strong neurite outgrowth promoting action.
  • Examples of the individual aliphatic hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a tert-pentyl group.
  • suitable counter anions represented by X 2 ⁇ to X 5 ⁇ in the general formulas 2 to 5 are usually, for example, fluorine ion, chlorine ion, bromine ion, iodine ion, perchlorate ion, periodate ion , Inorganic acid anions such as hexafluorophosphate ion, hexafluoroantimonate ion, hexafluorostannate ion, phosphate ion, borofluoride ion, tetrafluoroborate ion, thiocyanate ion, benzenesulfonate ion , Naphthalene sulfonate ion, naphthalene disulfonate ion, p-toluene sulfonate ion, alkyl sulfonate ion, benzene carboxylate ion, alkyl carboxylate ion,
  • examples of the compound represented by the general formula 2 include a compound represented by the chemical formula 1 (hereinafter sometimes referred to as “NK-9694”) and a compound represented by the chemical formula 2 (hereinafter referred to as “NK-9694”).
  • NK-4 a compound having 4 carbon atoms in the side chain alkyl group (R4 to R6) of the general formula 2 (hereinafter, sometimes referred to as “NK-26”) and the like.
  • Examples thereof include compounds in which the alkyl group (R4 to R6) in the side chain of Formula 2 has 3 carbon atoms (hereinafter sometimes referred to as “NK-234”).
  • the structure of the compound corresponding to the NK number in this specification is also described in, for example, “Photosensitive Dye Table”, published by Photosensitive Dye Research Institute (1969).
  • NK-150 a compound represented by the chemical formula 3
  • NK-150 a compound represented by the chemical formula 4
  • NK-19 may be mentioned.
  • the counter anion of the NK-19 (I -) of Cl - in the compound represented by Chemical Formula 5 for changing (. Which hereinafter may be referred to as "NK-53"), similar to the NK-19 advantageously Available.
  • R 7 to R 9 represent the same alkyl group having 7 to 9 carbon atoms, and mX 3 — represents I 2 — or Cl 2 — .
  • NK-100 a compound represented by the chemical formula 6
  • Examples of the compound represented by the general formula 5 include compounds represented by the chemical formulas 7 to 9 (hereinafter sometimes referred to as “NK-528”, “NK-557”, and “NK-1516”, respectively). can do.
  • NK-234 and NK-26 represented by any one of chemical formulas 1 to 9 are all cytotoxic factors such as starvation, radicals, and amyloid ⁇ peptide in addition to the nerve activation action and neurite outgrowth promoting action From the point of strength of its action and effect, it is more desirable as an active ingredient of the neurite outgrowth promoting agent of the present invention.
  • NK-9694 (a compound represented by Chemical Formula 1)
  • NK-150 a compound represented by Chemical Formula 3
  • NK-4, NK-234 and NK-26 is desirable and NK-4 is particularly desirable.
  • the compound represented by the general formula 1 used as an active ingredient of the neurite outgrowth promoter of the present invention is not limited in its origin or production method.
  • the neurite outgrowth promoter of the present invention is a compound represented by general formula 1, preferably a pentamethine cyanine dye represented by any one of general formulas 2 to 4 and / or a dimethine represented by general formula 5. It contains one or more styryl dyes.
  • the neurite outgrowth promoting agent of the present invention if necessary, in addition to the compound represented by the general formula 1 which is an active ingredient, is pharmaceutically acceptable in the food field, cosmetic field, pharmaceutical field, quasi-drug It is provided in the form of a preparation containing one or more components used in the product field.
  • Examples of pharmaceutically acceptable ingredients include additives, excipients, disintegrants, lubricants, stabilizers, surfactants, preservatives (antibacterial agents), fragrances, thickeners, and antioxidants.
  • blend combining suitably 1 type (s) or 2 or more types of these components, and to manufacture by a conventional method according to the target dosage form.
  • a neurite outgrowth promoting agent having an active ingredient other than the compound represented by the general formula 1 and a therapeutic agent for neurodegenerative diseases, pathological conditions and neurological dysfunctions resulting therefrom can be advantageously implemented.
  • cerebrovascular disorders eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, reperfusion injury, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, arachnoid membrane) Etc.), brain tumors (eg, astrocytoma, brain abscess, etc.), blood volume reducing shock, traumatic shock, head injury and / or cerebrospinal trauma (eg, brain contusion, penetration, shear) ⁇
  • therapeutic agents for neurological dysfunction associated with compression / laceration, labor trauma, infant whiplash, etc. neurodegenerative diseases (eg Parkinson's disease, Parkinson's syndrome, striatal nigra degeneration, Huntington's disease
  • therapeutic agents for neurodegenerative diseases used in combination with the anti-neurodegenerative disease agent of the present invention and the pathological conditions and neurological dysfunctions resulting therefrom preferably, for example, cerebrovascular disorders (for example, stroke, cerebral infarction (for example, cerebral thrombus) , Cerebral embolism, etc.), transient cerebral ischemic attack, cerebral hemorrhage (eg hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.), brain tumor treatment agent, cerebrospinal trauma (eg cerebral contusion, etc.)
  • Therapeutic agents for neurological dysfunction associated with neurodegenerative diseases eg Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, senile dementia, spinocerebellar degeneration), motor neuropathy (eg muscle atrophy)
  • Therapeutic agents for lateral sclerosis, etc. therapeutic agents for demyelinating diseases (eg, multiple sclerosis), cerebrospinal diseases associated with infections (eg, men
  • Therapeutic agents for diseases eg, Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, senile dementia, etc.
  • therapeutic agents for amyotrophic lateral sclerosis therapeutic agents for multiple sclerosis, Neurosis, psychosomatic disorders, anxiety, schizophrenia, manic depression, etc.
  • epilepsy and / or dystonia diabetes, diabetes Complication treatment and / or hyperlipidemia treatment agent, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopamine agonist, central anticholinergic agent, aromatic L-amino acid decarboxylase Inhibitor (DCI), monoamine oxidase (MAO-B) inhibitor, catechol-O-methyltransferase (COMT) inhibitor, norepinephrine (noradrenaline) supplement, acetylcholinesterase inhibitor, NMDA (N-methyl-D-asparagine) Acid) receptor antagonist, ⁇ -secretase inhibitor, ⁇
  • the neurite extension promoter of the present invention is usually provided in the form of a parenteral injection preparation or the like. Moreover, when parenteral administration is difficult, it may be used in the form of an oral preparation.
  • the compound represented by the general formula 1, which is an active ingredient, is a process from the raw material stage to the completion of the product in consideration of the composition of the target injection preparation and oral preparation and the purpose of use. What is necessary is just to mix
  • the methods include, for example, mixing, kneading, dissolving, melting, dispersing, suspending, emulsifying, reverse micellization, infiltration, crystallization, spraying, application, adhesion, spraying, coating (coating), pouring, dipping, solidifying,
  • One or more methods such as loading are appropriately selected.
  • the neurite outgrowth promoting agent of the present invention in the case of a preparation for oral administration, depending on the target disease or symptom, for example, solution, syrup, mass kit, paste, powder, solid, Any shape such as granules, tablets, etc. may be used as it is, or as necessary, mixed with a filler, excipient, binder, etc. to form granules, spheres, short bars, plates, cubes It is also optional to use it in various shapes such as tablets and capsules.
  • parenteral preparations such as injection preparations
  • parenteral preparations such as injection preparations
  • it is usually dissolved in an aqueous medium that does not contain pyrogen, depending on the target disease or symptom, and then intradermally, subcutaneously, intramuscularly, intracorporeally (intrathoracic) , Intraperitoneal, etc.), intravascular or intracerebral (including spinal cord)
  • the preparation may be a dry preparation or a liquid preparation.
  • a dry preparation it may be used by dissolving it in an aqueous medium such as purified water for injection, physiological saline, and glucose solution at the time of use.
  • a solution it may be administered as it is, or it may be added to an infusion solution or a perfusion solution.
  • solubility in a solvent or solubility in an aqueous medium when there is a problem with solubility in a solvent or solubility in an aqueous medium, or when preparing a sustained-release preparation, it is effective to use an amphiphilic solvent, an oily base material, an emulsifier, etc. Increasing the solubility of the components in the solvent is optional.
  • the aqueous medium referred to in the present invention has water as an essential element, and if necessary, for example, alcohols such as ethanol, propanol and isopropanol, ketones such as acetone, ethers such as diethyl ether, dimethyl
  • aqueous medium comprising one or more hydrophilic organic solvents including sulfur-containing compounds such as sulfoxide (hereinafter sometimes abbreviated as “DMSO”).
  • DMSO hydrophilic organic solvents including sulfur-containing compounds such as sulfoxide
  • purified water for injection, physiological saline, Ringer's solution, etc. are used alone, or purified water for injection and physiological such as ethanol, propanol, isopropanol, diethyl ether, DMSO, etc. It is desirable to use a mixed solution with a hydrophilic organic solvent which is acceptable.
  • Such a liquid agent depending on the compound represented by the general formula 1 used, it may become unstable due to dissolved oxygen or the like. In that case, for example, if the dissolved oxygen concentration of the compound solution is reduced, Good.
  • Such a liquid composition is usually prepared by a method through a step of dissolving the compound in an aqueous medium and a step of lowering the oxygen concentration in the atmospheric environment at normal temperature and pressure using the aqueous medium. be able to.
  • a predetermined amount of a compound is added to an appropriate amount of an aqueous medium, dissolved as necessary with heating and stirring, and then, if necessary, An aqueous medium may be added until the concentration reaches a predetermined level.
  • the compound solution is prepared and stored under reduced pressure, or the oxygen dissolved in the compound solution is separated from another gas. Or a method of bringing the compound solution into contact with an oxygen scavenger is preferred.
  • a relatively inert gas such as nitrogen or a rare gas such as neon, argon, krypton, or xenon is used. Just bubbling.
  • the liquid composition is prepared by, for example, adding L-ascorbic acid, L-ascorbic acid stearate, sodium sulfite, sodium hydrogen sulfite, alphathioglycerin, sodium edetate, cysteine hydrochloride Citric acid, soybean lecithin, sodium thioglycolate, sodium thiomalate, sodium pyrosulfite, butylhydroxyanisole and the like may be added in appropriate amounts. These methods may be applied to the compound solution or to an aqueous medium before the compound is dissolved. In this case, the concentration of oxygen dissolved in the aqueous medium is usually 0.4 ppm or less, preferably 0.1 ppm or less.
  • the thus obtained solution of the compound represented by the general formula 1 may be stored in a state where it is sealed in an appropriate container that can block oxygen.
  • the material of the container is not particularly limited as long as it can hold the liquid composition in principle and can substantially block oxygen, but it is light-shielded like a brown bottle or brown ampoule. Sex containers are desirable.
  • the liquid composition is usually dispensed into containers such as glass ampoules and vials, sealed, and then sterilized by high-pressure sterilization or the like.
  • the neurite outgrowth promoting agent of the present invention can be used in the form of an oral preparation, a haptic agent, a sucking and spraying agent, etc. in addition to the injection, and in the form of a sustained-release preparation embedded in the body such as subcutaneously. It can also be used. It is also optional to treat animals other than humans, including pets that have developed neurodegenerative diseases, and to use as preventives or therapeutic agents for pathological conditions and neurological dysfunction associated with neurodegenerative diseases.
  • the neurite outgrowth promoting agent of the present invention produced in this way is a safe preparation without serious side effects even when used for a long time.
  • the daily dose of the neurite outgrowth promoting agent of the present invention is not particularly limited as long as the desired action and effect can be obtained.
  • it is represented by the general formula 1.
  • 0.01 mg / kg ⁇ body weight / day or more is desirable, 0.1 to 20 mg / kg ⁇ body weight / day is more desirable, and 0.5 to 5 mg / kg ⁇ body weight / day is particularly desirable.
  • the compound represented by general formula 1, which is an active ingredient of the neurite outgrowth promoting agent of the present invention is generally administered subcutaneously in view of its low absorption rate from the digestive tract. It is necessary to set a higher dose than the case.
  • the neurite outgrowth promoting agent of the present invention in addition to the neurite outgrowth promoting action, protects the brain and nerve cells from damaging factors and suppresses degeneration, activates the nerve cells, inhibits neurite atrophy, Since neuronal survival and degeneration can be suppressed, neurodegenerative diseases, particularly diseases caused by degeneration of the central nervous system can be treated.
  • a neurodegenerative disease is a nerve cell (central nervous system (for example, cranial nerve, spinal nerve), and / or peripheral nerve (for example, autonomic nervous system (for example, sympathetic nerve, parasympathetic nerve)), motor nervous system, sensory nervous system) )
  • central nervous system for example, cranial nerve, spinal nerve
  • peripheral nerve for example, autonomic nervous system (for example, sympathetic nerve, parasympathetic nerve)), motor nervous system, sensory nervous system)
  • any disease that is generally regarded as a neurodegenerative disease may be used.
  • Parkinson's disease Parkinson's syndrome, striatal nigra degeneration, Huntington's disease, chorea-ataxia, progressive Supranuclear paralysis, diffuse Lewy body disease, basal ganglia degeneration, Alzheimer's disease, senile dementia, Pick's disease, frontotemporal lobar dementia, familial dementia, spinocerebellar degeneration (eg olive Bridge cerebellar atrophy, late cerebellar cortical atrophy, familial spinocerebellar ataxia (eg, Maccard Joseph disease, etc.), dentate nucleus erythrocytic Ryukyu atrophy, familial spastic paraplegia, Friedreich Disease), motor neuropathy (eg, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, etc.), demyelinating diseases (eg, multiple sclerosis, multiple sclerosis, acute disseminated) Encephalomyelitis, acute encephalitis, transverse myelitis,
  • neurodegenerative diseases that are preferable as the neurite extension promoter of the present invention include, for example, Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, senile dementia, spinocerebellar degeneration, amyotrophic lateral sclerosis, Demyelinating diseases (for example, multiple sclerosis), cerebrovascular disorders (for example, stroke, cerebral infarction (for example, cerebral thrombosis, cerebral embolism, etc.), transient cerebral ischemic attacks, cerebral hemorrhage (for example, hypertensive intracerebral hemorrhage) ), Brain tumors, traumatic shock, head injury and / or cerebrospinal trauma (eg, cerebral contusion), cerebrospinal disease (eg, meninges) Inflammation, influenza encephalopathy, Creutzfeldt-Jakob disease, dementia due to AIDS encephalopathy, etc.), diseases derived from neurodegeneration of the central nervous system such as epilepsy, more preferably For
  • the neurite outgrowth promoting agent of the present invention can treat nerve dysfunction by activating nerve cells, extending neurites, and promoting synapse formation.
  • the target neurological dysfunction may be any neurological dysfunction, such as cognitive dysfunction, consciousness disorder, bilateral quadriplegia, contralateral hemiplegia, alternating hemiplegia. , Sensory disorders, transient blindness (eg, transient cataract), homonymous half-blindness, dizziness, nystagmus, double vision, aphasia, tinnitus, coma and the like. Particularly preferred are those neurological dysfunctions associated with the neurodegenerative diseases.
  • the neurological dysfunction associated with the above-mentioned neurodegenerative diseases for example, neurological dysfunction associated with cerebral infarction varies depending on the site of vascular occlusion, and the symptoms vary depending on the level to be impaired. It can be seen.
  • the presence or absence of neurological dysfunction in cerebral infarction may be determined by various diagnostic tests known in the art for detecting neurological dysfunction. Specific examples of the diagnostic test include, for example, a cognitive function score (Alzheimer's Dissease Assessment-cognitive part; ADAS-cog) used for evaluation of memory and cognitive impairment due to Alzheimer's disease, clinical symptoms, and the like.
  • a cognitive function score Alzheimer's Dissease Assessment-cognitive part
  • the neurite outgrowth promoting agent of the present invention is advantageous as a nerve cell protective agent, nerve cell activator, Purkinje cell degeneration / dropout inhibitor, therapeutic agent for neurodegenerative diseases and associated pathologies, therapeutic agent for neurological dysfunction, etc.
  • Can be used for The treatment of neurodegenerative diseases and neurological dysfunctions as used in the present invention refers to the pathology and dysfunction caused by neurodegeneration in the direction of healing, in addition to so-called treatment, prevention of progression that suppresses progression and stops progression of the disease, Also includes the prevention of the onset of the disease itself.
  • NGF Neuro Growth Factor
  • PC-12HS cells NGF (Neural Growth Factor) hypersensitive strain of PC-12 cells derived from rat adrenal pheochromocytoma
  • PC-12HS cells which is a suitable model for studying human neurite outgrowth promoting action (Obtained from Human Science Research Resource Bank) was diluted with a 10 volume% FBS-added D-MEM medium to a collagen-coated 96-well microplate at 5 ⁇ 10 3 cells / well and seeded at 100 ⁇ l / well.
  • each test sample was diluted with D-MEM (10% by volume FBS) and adjusted to 400 ng / ml, 50 ⁇ l / well, and D containing 20 ng / ml NGF (available from Chemicon, mouse, final concentration 5 ng / ml).
  • -MEM medium (10% by volume FBS) 50 ⁇ l / well was added and cultured for 3 days. On the third day of culture, the cells were fixed with 10% by volume glutaraldehyde for 20 minutes at room temperature. As a control, PC12-HS cells cultured for 3 days only in 10% by volume FBS-added D-MEM medium were fixed with glutaraldehyde.
  • the fixed cells are observed under a microscope to evaluate the presence or absence of neurite outgrowth.
  • the ratio of cells with neurite outgrowth is 30% or more, it is determined that there is a strong neurite outgrowth promoting action. 1 was marked with a circle.
  • the percentage of cells in which neurite outgrowth was observed was determined by observing cells under a microscope at a magnification containing about 100 cells in one field of view, and showing neurites at least twice the major axis of the cell body. The number of cells was counted, divided by the total number of cells in the same field, and multiplied by 100.
  • NGF NGF
  • ⁇ Experiment 2 Effect of pigment compound concentration on neurite outgrowth> Among the compounds determined to have a strong neurite outgrowth promoting effect in Experiment 1, the concentrations of NK-19, NK-53, NK-100, and NK-557 are related to neurite outgrowth of PC12-HS cells. The effect was examined using the same method as in Experiment 1. That is, the culture is continued by adding any one of NK-4, NK-19, NK-53, NK-100, and NK-557 so that the final concentration of the compound in the medium becomes the concentration shown in Table 2. The cells were fixed with glutaraldehyde. Table 2 shows the results of microscopic observation at a magnification including about 100 cells in one field, and determining the percentage (%) of cells in which neurite outgrowth was observed with respect to the total number of cells.
  • NK-19 which was confirmed to have a neurite outgrowth promoting action, was tested to confirm that its analogs had the same action. That is, a compound in which the alkyl group (R) in the side chain of the compound represented by the following general formula 3 has 1 to 12 carbon atoms (synthesized by Hayashibara Biochemical Laboratories Co., Ltd.) was synthesized. The strength of the neurite outgrowth promoting action on PC-12HS cells was examined using the proportion of cells in which neurite outgrowth was observed as an index.
  • NK-19 Twelve types of analogs of NK-19 including NK-19 shown in Table 3 were synthesized and dissolved in DMSO to a concentration of 5 mg / ml. This solution was diluted with D-MEM medium supplemented with 10% by volume FBS, and the concentration of the compound was diluted to 2 ⁇ g / ml to prepare a test sample solution. Moreover, the NK-24 and NK-19 is the counter anion I - Cl from - compounds instead (NK-56 and NK-53) was also dissolved at a 5 mg / ml in DMSO. These solutions were diluted with D-MEM medium supplemented with 10% by volume FBS, and the test sample solutions were prepared by diluting the compound concentration to 2 ⁇ g / ml each.
  • PC12-HS cells were diluted with 10 volume% FBS-added D-MEM medium to a 96-well microplate previously coated with collagen at 5 ⁇ 10 3 cells / well, and seeded at 100 ⁇ l / well. did. After 24 hours, 50 ⁇ l / well of each test sample solution adjusted to a compound concentration of 2 ⁇ g / ml and 50 ⁇ l / well of NGF (final concentration 5 ng / ml) were added, and 10% by volume glutaraldehyde was added at room temperature on the third day of culture. Fixed for 20 minutes.
  • PC12-HS cells were cultured for 3 days only in 10% by volume FBS-added D-MEM medium, and the cells were fixed with glutaraldehyde. The fixed cells were observed under a microscope, and the cells were counted by the same method as in Experiment 1 to determine the percentage (%) of cells in which neurite extension was observed. The results are also shown in Table 3. In addition, the test was implemented twice with each triplet for each test sample solution, and the average was obtained. In addition, when only NGF was added to this experimental system (5 ng / ml), the proportion of cells in which neurite outgrowth was observed was about 5%.
  • R 7 to R 9 represent the same alkyl group having 7 to 9 carbon atoms, and mX 3 — represents I 2 — or Cl 2 — .
  • NK-19 analog a compound having 3 to 12 carbon atoms in the side chain alkyl group has a neurite outgrowth promoting action, and the action is strong at 3 to 10; 10 having the structure represented by the general formula 3 such as NK-19, NK-53, NK-150, etc., wherein the alkyl group in the side chain has 3 to 10 carbon atoms.
  • the compound is useful as a neurite outgrowth promoting agent, indicating that it can be used as a therapeutic agent for neurodegenerative diseases including Alzheimer's disease and cerebellar ataxia.
  • the neurite outgrowth promoting action of the NK-19 analog was not different depending on the type of counter anion.
  • NK-4 seven kinds of compounds shown in Table 4, NK-234, NK-26, NK-9815, NK-9694, NK-28 and NK-147, each in DMSO at 5 mg / ml. It dissolved so that it might become. This solution was diluted with 10% by volume FBS-added D-MEM so that the final concentrations of the compounds were as shown in Table 4 or 5, respectively, to prepare test sample solutions.
  • NK-19 analogs NK-13, NK-392, NK-19 and NK-150 are dissolved in DMSO to a concentration of 5 mg / ml, so that the compound concentration becomes the concentration shown in Table 4 or 5.
  • Table 4 shows the results of the cell growth promoting action
  • Table 5 shows the results of the neurite extension promoting action.
  • R 4 to R 6 represent the same alkyl group having 1 to 12 carbon atoms
  • X 2 represents I ⁇
  • m represents 2.
  • the NK-4 analog represented by the general formula 2 is a cell having 3 to 8 carbon atoms in the side chain alkyl group, which is the same or higher than NK-4. Growth and neurite outgrowth promoting effects were observed. When compared at a compound concentration of 80 ng / ml, the cell growth promoting action was particularly strong for compounds having 4 to 6 carbon atoms in the side chain alkyl group. As for the neurite outgrowth promoting action, a strong activity was observed in the compounds having 4 and 5 carbon atoms in the side chain alkyl group.
  • NK-19 analog compound was found to show strong cell proliferation and neurite outgrowth promoting activity.
  • NK-4 and its analogs can be used as neurite outgrowth promoters and therapeutic agents for neurodegenerative diseases, so human neurodegenerative diseases (such as spinocerebellar degeneration) Of cerebellar degenerative ataxia (hereinafter referred to as “cerebellar ataxia”) hamster (hereinafter referred to as “cerebellar ataxia hamster”) suitable as a model animal of NK-4, and its effects on the behavior and brain tissue The influence of was investigated.
  • pulmonary Purkinje cells were shed after 3 weeks of age, followed by spontaneous gene mutations known to spontaneously develop ataxia and cerebellar ataxia after 7 weeks of age ( Nna1 inhibition) 25 hamsters (see Akita K. et al., “J. Neurogenetics”, Volume 21, pages 1 to 11 (2007), reared at Hayashibara Biochemical Research Institute, Inc.) Test groups 1-5 were randomly assigned 5 animals in each group. Test group 1 hamsters were administered with 10 ml / kg / day of PBS before the onset of cerebellar ataxia (3 weeks of age).
  • the hamsters in test groups 2 to 4 were administered NK-4 at 20 ⁇ g / kg, 100 ⁇ g / kg, or 500 ⁇ g / kg / day before the onset of cerebellar ataxia (3 weeks of age).
  • the hamster of Test Group 5 is abbreviated as “IGF-1”, an insulin-like trophic factor-1 known as a neuronal trophic factor (sold by Assaypro, trade name “IGF-1, human”, human origin). ) was administered at 25 ⁇ g / kg / day. These administration components were administered intraperitoneally once daily until 10 weeks of age.
  • the degree of cerebellar ataxia and the effect of NK-4 on improving the symptoms were evaluated by using the rotarod test and slope endurance test described later once a week, with the improvement of hamster motor coordination as an index. Furthermore, at the age of 10 weeks, after measuring the number of hamster falls, the brain was removed and histologically evaluated, and the glutamic acid concentration in blood and cerebrospinal fluid (CSF) was also measured. As test group 6, 5 normal hamsters of the same age as the cerebellar ataxia hamster used in test groups 1 to 5 were treated with PBS at 10 ml / kg / day before the onset of cerebellar ataxia (3 weeks old). The same test as that of the cerebellar ataxia hamster was carried out by intraperitoneal administration once a day until 10 weeks of age.
  • ⁇ Rotarod test> The hamster walked with the rotation of the rotarod and used the duration of the exercise to stay on the rotarod as an indicator of motor coordination. Specifically, a hamster was placed on a rotarod apparatus (manufactured by Hayashibara Biochemical Laboratories Co., Ltd., rotarod diameter 60 mm) rotating at a constant speed (6 rpm), and the time until it dropped from the rotarod was measured (Fernandez et al., “Proc. Natl. Acad. Sci. USA, 95, 1253-1258 (1998)). The test is conducted 6 times for one hamster, and the first 5 times is a preliminary motion test for acclimatization to the rotational motion.
  • ⁇ Slope durability test> Determine the angle at which the hamster's head is placed on a plate whose tilt angle can be changed and can rest for 5 seconds, and the slope endurance angle (Rivlin et al., “J. Neurosurg.”, Vol. 47, Vol. 577-581 (1997)). The tilt angle started from 25 degrees and increased by 5 degrees. If the vehicle falls in less than 5 seconds, subtract the angle at 1 degree intervals from the tilt angle, determine the angle at which it can stand for 5 seconds, measure the slope endurance tilt angle, The average was calculated. The results are shown in Table 8.
  • cerebellar ataxia hamster used in this test is known to have a reduced cell density in addition to Purkinje cells, which are inhibitory neurons, and granule cells, which are excitatory neurons. Therefore, cerebellar slices cut in the sagittal direction were stained with hematoxylin and eosin by a conventional method, and microscopically measured to determine the total number of Purkinje cells in the Purkinje cell layer (lobules I to X) and the number of granule cells per unit area. In addition, the number of individuals with demyelination in the cerebellar white matter was confirmed. The results are also shown in Table 9. In addition, since the cerebral volume did not recognize a significant difference between each test group, Table 9 shows only the calculation result of the cerebellum volume.
  • test group 4 (500 ⁇ g / kg ⁇ body weight), a significant effect of reducing the drop time was observed compared to test group 1. This inhibitory effect lasted until the end of the study at 10 weeks of age (7 weeks of administration). Even in Test Group 2 (20 ⁇ g / kg / body weight), after 2 weeks (5 weeks old) after the start of NK-4 administration, the effect of reducing the drop time was observed more than in Test Group 1, but Test Group 3 and Compared with test group 4, the effect was weak. In addition, when IGF-1 which is considered to be effective in the treatment of motor neurodegenerative diseases was administered (Test Group 5), the effect of suppressing the fall time was hardly observed.
  • NK-4 can be used as a therapeutic agent for human neurodegeneration and its pathological conditions and symptoms.
  • test group 6 normal hamster
  • test group 1 using cerebellar ataxia hamsters.
  • PBS administration group it was already significantly lower at 410.6 ⁇ 0.3 degrees at the start of the test, decreased with aging, further decreased after 8 weeks of age, and 35. It was 8 ⁇ 1.0 degrees.
  • test group 5 (IGF-1 administration)
  • 44.4 ⁇ 0.2 degrees at 4 weeks of age which is a significant slope durability inclination angle compared to 40.6 ⁇ 0.3 degrees in test group 1
  • the slope durability inclination angle decreased as in Test Group 1
  • no significant decrease suppressing effect was observed after 5 weeks of age.
  • test groups 2 to 4 (NK-4 administration)
  • no decrease in endurance tilt angle was observed throughout the test period at any dose used in the test, and a high slope endurance tilt angle decrease suppression effect was observed. It was.
  • the slope endurance slopes of the test groups 2 to 4 (NK-4 administration) at 10 weeks of age are 45.8 ⁇ 0.6, 51.6 ⁇ 0.6, and 51.8 ⁇ 0.4 degrees, respectively. Both were significantly higher than those in Test Group 1 (PBS administration) and Test Group 5 (IGF-1 administration).
  • test group 1 PBS administration
  • test group 6 IGF-1 administration
  • test group 5 IGF-1 administration
  • a significant cerebellar atrophy suppression effect was observed as compared to test group 1, which was 77.6 ⁇ 6.1 (mm 3 ).
  • a dose-dependent cerebellar atrophy suppression effect was also observed in the NK-4 administration group, and 76.0 ⁇ 8.2, 77.0 ⁇ 2.8, 80 in the 20, 100, and 500 ⁇ g / kg administration groups, respectively. 5 ⁇ 10.8 mm 3 (all significant at P ⁇ 0.05).
  • NK-4 improves motor coordination of cerebellar ataxia hamsters, effectively suppresses cerebellar atrophy, and its effect is superior to IGF-1. .
  • the granule cell density in the granule cell layer of the cerebellar cortex is 480 ⁇ 6 / 20,000 ⁇ m 2 in 10-week-old normal hamsters (test group 6).
  • test group 6 When PBS was administered to a cerebellar ataxia hamster (test group 1), the number was significantly reduced to 380 ⁇ 4/20000 ⁇ m 2 .
  • the granule cell density in test group 5 (IGF-1 administration) was 371 ⁇ 11 cells / 20,000 ⁇ m 2, which was not different from test group 1.
  • test groups 2 to 4 (NK-4 administration), the doses were 408 ⁇ 8, 419 ⁇ 6, 436 ⁇ 7 / 20,000 ⁇ m 2 , respectively, and an inhibitory effect on the decrease in granule cell density depending on the dose of NK-4 was observed. It was.
  • specific data are not shown, in microscopic observation of the cerebellar parenchyma, in the test groups 1 and 5, granule cell atrophy and degeneration were significant, whereas in the test groups 2 to 4, granule cells were observed. It was confirmed that atrophy and degeneration were suppressed.
  • NK-4 cerebellar ataxia hamster
  • NK-4 administration test groups 2 to 4 (NK-4 administration)
  • NK-4 Purkinje cells Suppression of atrophy of neurites (dendrites) in the body was also confirmed.
  • NK-4 is useful as a neurite extension promoter.
  • NK-4 also shows that it is useful as an inhibitor of cerebellar white matter demyelination, that is, as an inhibitor of Purkinje cell degeneration and shedding.
  • NK-4 administered intraperitoneally acted on cerebral neurons and suppressed cerebellar ataxia by suppressing neurite outgrowth (including suppression of atrophy) and suppressing neuronal function decline.
  • NK-4 is useful as a neurite outgrowth promoter as a therapeutic agent that can be systemically administered to human neurodegeneration and various pathological conditions and clinical symptoms associated therewith.
  • the body weight of the cerebellar ataxia hamster was measured once every week until the end of the test (10 weeks of age), and the average of each group was determined.
  • PBS, NK-4, IGF-1 administration group Since no significant difference was observed, NK-4 was judged to be a highly safe compound even when administered to a living body.
  • NK-4, NK-19, NK-53, NK-100, and NK-557 have been confirmed to have therapeutic effects on neurodegeneration.
  • atropine (fuso medicine, 0.3 mg / kg / body weight) was subcutaneously administered, and urethane (Sigma, 600 mg / kg / body weight) and ⁇ -chloralose (Sigma, 60 mg / kg / body weight) were intraperitoneally injected. Anesthesia was given, and it was fixed to a fixator with natural breathing. A midline cervical incision was made and the right carotid bifurcation was reached, paying attention to the preservation of the vagus nerve.
  • the common carotid artery and the external carotid artery were peeled off from the surrounding connective tissue, centering on the right carotid artery bifurcation, and ligated with 6-0 nylon yarn (Alfresser Pharma Co., Ltd., trade name “Nesscoacher”).
  • a 6-0 nylon thread was applied to the internal carotid artery to prepare for fixation after embolization.
  • the common carotid artery was incised, and an embolus (Doccol) made of 4-0 nylon thread coated with silicon at the tip was inserted into the internal carotid artery about 16 mm and fixed to the common carotid artery with a clip.
  • the tip portion of the embolus that is silicon-coated enters the anterior cerebral artery beyond the middle cerebral artery bifurcation and closes the middle cerebral artery entrance.
  • the cerebral artery is occluded for 2 hours on a thermal pad at 37 ° C., then the inserted embolus is removed, blood flow is resumed (reperfusion), and then bleeding from the common carotid artery incision is prevented. Therefore, the internal carotid artery was ligated near the carotid bifurcation. Since the right common carotid artery is ligated in this model, the blood flow is resumed from the left inner diameter artery, the vertebral artery, and the basilar artery via the anterior / posterior traffic artery.
  • NK-4, NK-19, NK-53, NK-100 and NK-557 used in the test were each dissolved in DMSO (SIGMA, product number “D8418”) at a concentration of 5 mg / ml, and then the membrane. Filtration (sold by Millipore, trade name “Millex-LG SLLG025SS”, using DMSO resistant membrane) was performed. Each compound was dissolved in PBS to 25 ng / ml at the time of use, and any one of them was administered to 5 or 7 rats in 5 groups each 1 hour after middle cerebral artery occlusion and blood reperfusion.
  • DMSO product number “D8418”
  • test groups 1 to 5 Behavioral and histological evaluation was performed 24 hours after resumption of blood flow. Of the remaining 2 groups, 5 out of 5 animals, 1 group had 6 ml of PBS containing no compound as the control group 1 in the tail vein at 1 ml after middle cerebral artery occlusion and at the time of blood reperfusion. Administered.
  • control group 2 In addition, in the remaining 5 animals in 1 group, as control group 2, after ligation of the common neck, external carotid, and internal carotid artery, sham operation was resumed without inserting an embolus near the middle cerebral artery ( (Sham operation) was performed.
  • PBS containing no compound was also administered into the tail vein at 4 ml / kg ⁇ body weight, 1 hour after ligation of the common neck, external neck, and internal carotid artery, and at the time of blood reperfusion.
  • each rat was exsanguinated by severing the posterior vena cava while perfusing physiological saline from the left ventricle under ether anesthesia.
  • the brain is removed within 3 minutes after death, and sliced to a thickness of 2 mm in the coronal direction using a slicer (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), and then the cerebral infarction site is specifically stained.
  • 2,3,5-triphenyltetrazole chloride (TTC) was incubated in PBS containing 2% by mass / volume at 37 ° C.
  • NK-4, NK-19, NK-53, NK-100 and NK-557 are effective in treating neurodegeneration including neurite atrophy caused by ischemia and associated neurological dysfunction. It tells you that it has an effect.
  • NK-4 analog or NK-19 analog Effect of NK-4 analog or NK-19 analog on rat model of cerebral infarction>
  • the effects of NK-4, NK-26, and NK-15, which were confirmed to have cell proliferation promoting action and neurite promoting action on PC-12HS cells, on cerebral infarction were examined using human cerebral infarction model rats. That is, according to Experiment 6, SD rats (manufactured by Charles River Japan, male, 8 weeks old, body weight 280 to 330 g) were embolized in the middle cerebral artery.
  • NK-150, NK-26, and NK-4 were each dissolved in DMSO at a concentration of 5 mg / ml, filtered through a membrane filter with a pore size of 0.45 ⁇ m, and further 2.5 to 0.05 mg / ml in DMSO. What was adjusted to the concentration was stored in the dark.
  • These compound solutions were diluted 250-fold with saline at the time of use and administered to the embolized rat through the tail vein twice after 1 hour of occlusion and at the time of reopening (fluid amount: 5 ml / kg / body weight).
  • NK-4 was prepared as a 10 mg / ml solution, diluted 250 to 167 times, and administered from the tail vein (fluid volume: 5 ml / kg / body weight).
  • physiological saline was administered as a negative control
  • an existing drug edaravone manufactured by Mitsubishi Tanabe Pharma Corporation, trade name “Radicut”
  • DMSO DMSO
  • a behavioral score was obtained by the same method as in Experiment 6 to evaluate neurological symptoms.
  • the actual volume value was obtained by dividing by the swelling rate.
  • the results and group composition are shown in Table 12.
  • NK-4 analog and NK-19 analog on model mice of human Alzheimer type dementia The above experiments suggested that NK-4 can be used as a therapeutic agent for Alzheimer's dementia.
  • NK-4 analogs and NK-19 analogs were modeled on human Alzheimer's model mice. The effect was verified.
  • NK-4, NK-234, NK-26, NK-19 and NK-150 were used as test samples.
  • physiological saline 200 ⁇ l / animal
  • Donepezil hydrochloride was used as control 2.
  • Each test sample was dissolved in DMSO to a concentration of 5 mg / ml, and diluted with physiological saline for administration.
  • mice manufactured by Charles River Japan, male, 5 weeks old, body weight 25 to 30 g
  • Chloral hydrate SIGMA, 350 mg / kg, body weight, intraperitoneal administration
  • Anesthetized mice were fixed on the back, and a midline incision was made on the head.
  • the amyloid ⁇ fragment ( ⁇ -Amyloid 25-35 : Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met amino acid was determined by setting the insertion point 0.5 mm behind.
  • Peptide having sequence 9 nmol / 6 ⁇ l / animal of solution was administered into the ventricle (for the administration method, see “Brain Research”, 706, 181-193 (1996)).
  • a microsyringe equipped with a 28 gauge stainless needle (3 mm) was used for administration.
  • Evans blue solution (0.3 ⁇ g / 0.3 ⁇ l) is administered in advance for the insertion site instead of the amyloid ⁇ fragment solution, and the lateral ventricle, dorsal third ventricle, ventral third brain of the left and right forehead cross section It was confirmed that coloring was observed in the room. After the administration, the scalp was sutured, and one of the compounds was intraperitoneally administered once a day for 13 days from the next day, and behavioral evaluation was performed by the following method. The results and group composition are shown in Table 13.
  • ⁇ Evaluation method> ⁇ New object recognition test> The novel object recognition test uses the characteristics of the mouse when it likes the novelty, and unlike many other learning evaluation systems, it does not use artificial reinforcement factors.
  • the test consisted of three departments: acclimatization, training trials, and retention trials, which were performed 6-8 days after amyloid ⁇ fragment was administered into the ventricle.
  • An open field experimental device (40 cm long, 30 cm wide, 30 cm high) with wood chips on the floor was installed in a noise-free place under about 1,000 lux lighting. First, on the 6th day, the mouse was placed in the center of the experimental apparatus without the search object and allowed to search freely for 10 minutes (acclimation).
  • the object identification index is the ratio of the time allotted to the search for new objects to the total search time, and if the animal stores the object once searched, the value of the object identification index becomes large, If not stored, the value becomes smaller.
  • ⁇ Passive avoidance test> A step-through type using the property that the mouse prefers the dark room is adopted as an index of memory, which is the avoidance behavior shown to the aversive stimulation (electrical stimulation) once experienced by the animal.
  • the movement time to the dark room side when the mouse was put in the light room side of the device where the light room and dark room were connected by a door was used as an index of memory.
  • the passive avoidance test was performed 9 to 12 days after amyloid ⁇ fragment was administered into the ventricle. On the 9th day, the light room (1,000 lux, length 30 cm, width 30 cm, height 15 cm) was placed in a dark room (length 30 cm, width 30 cm, height 15 cm) for 2 minutes to acclimatize.
  • the acclimatization was similarly performed on the 10th day.
  • the mouse was first placed in the center of the light room, and at the same time the mouse moved into the dark room, the door between the light room and the dark room was closed, and electrical stimulation was applied (0.8 mA, 1 Seconds). After 24 hours (day 12), the mouse was placed in the center of the light room again as in the previous day, and the moving time (seconds) to the dark room was measured as a passive avoidance response. If the aversive stimulus by energization is memorized, the passive avoidance reaction becomes longer.
  • NK-4 is 500 ⁇ g / kg ⁇ body weight
  • NK-234 is 500 ⁇ g / kg ⁇ body weight
  • NK-26 is 50 ⁇ g / kg ⁇ body weight
  • NK-19 is 500 ⁇ g / kg ⁇ body weight
  • NK ⁇ In mice administered with 150 at 500 ⁇ g / kg ⁇ body weight, a significant improvement was observed in the novel object recognition test compared to mice administered with amyloid ⁇ fragment alone.
  • NK-4 is 50 ⁇ g / kg ⁇ body weight
  • NK-4 is 500 ⁇ g / kg ⁇ body weight
  • NK-234 is 500 ⁇ g / kg ⁇ body weight
  • NK-26 is 50 ⁇ g / kg ⁇ body weight
  • NK-26 is 500 ⁇ g / kg ⁇ body weight.
  • Significant improvement was observed in the passive avoidance test in mice administered with body weight and NK-19 at 500 ⁇ g / kg / body weight, compared with mice administered with amyloid ⁇ fragment alone.
  • NK-4, NK-234, NK-26, NK-19 and NK-150 are all against neurodegeneration including neurite atrophy caused by amyloid ⁇ peptide and neurological dysfunction associated therewith. It has a therapeutic effect.
  • mice wild type, female, 10 weeks old, body weight 15 to 23 g
  • physiological saline was intraperitoneally injected 5 times a week.
  • physiological saline 200 ⁇ l / mouse
  • APP Tg mice were administered donepezil hydrochloride 5 times a week for 12 weeks.
  • ⁇ Water maze test method> A circular pool with a diameter of 130 cm was filled with water colored with white ink to a depth of 20 cm, and the water temperature was maintained at 23 ⁇ 1 ° C. with a water tank heater.
  • the pool was divided into four parts, and an evacuation platform was installed at a position 10 cm from the side of the pool so as to be 2 cm below the surface of the water. The platform position was fixed until the end of the test. From the day after the end of the passive avoidance test, the mouse was released on the surface of the pool toward the side of the pool, and the time taken to reach the platform hidden under the surface of the water was measured.
  • the starting position was 10 cm away from the central part of one of the fractions of the pool divided into 4 centimeters, and was randomly changed for each trial.
  • the mouse After searching the platform freely for 2 minutes, if the mouse could not reach the platform within 2 minutes, it was guided to the platform, allowed to stay on the platform for 30 seconds and then transferred to a cage with paper towels.
  • the second test started 1 minute after the end of the first test. This test was conducted for 4 consecutive days, and the average value of the two trials was taken as the value of the day.
  • mice administered NK-4 markedly improved the cognitive impairment of APP Tg mice in any of the object identification index, passive avoidance reaction, and water maze test. Moreover, the improvement effect was significantly stronger than that of commercially available Alzheimer-type dementia therapeutic agent donepezil hydrochloride. During the study, no side effects believed to be caused by administration of NK-4 were observed.
  • NK-4 Effects of NK-4 on cerebrovascular dementia model mice>
  • the above-mentioned experiments confirmed that NK-4 is effective in improving dyskinesia and Alzheimer-type cognitive impairment resulting from cerebral infarction.
  • mice 50 mg / kg were intraperitoneally administered and anesthetized, and a permanent ligation operation was performed on the right common carotid artery (refer to Japanese Patent Application Laid-Open No. 2008-193941 for the operation method). After the operation, all mice were reared alone, and were bred with free eating and drinking water. Of the 21 animals subjected to ligation surgery, 10 animals were reared as they were (ligation group), and the remaining 11 animals were administered NK-4 (administration group). In addition, 10 animals that had not undergone surgery were used as controls (no surgery group).
  • NK-4 has a therapeutic effect on neurodegeneration including neurite atrophy caused by ischemia and associated neurological dysfunction.
  • the above results are similar to those of the compounds having the structure represented by general formula 3, such as NK-19, NK-53, NK-150, etc., and having a side chain alkyl group having 3 to 10 carbon atoms.
  • the compound having the structure represented by 2 and having 2 to 8 carbon atoms in the side chain alkyl group is useful as a neurite extension promoter. These compounds all improve neurite atrophy in ischemia due to cerebral infarction and vascular injury, Alzheimer's disease, cerebellar ataxia, Parkinson's disease, etc., and cognitive impairment due to neurite atrophy or decrease And that it can improve various clinical symptoms.
  • the compound represented by the general formula 2 is desirable, and NK— in which the side chain alkyl group has 2 to 4 carbon atoms. 4, NK-234 and NK-26 were desirable, and NK-4 was particularly desirable.
  • ⁇ Liquid preparation for injection> A solution prepared by dissolving 60 g of purified maltose for injection (manufactured by Hayashibara Co., Ltd.) in 370 g of purified water for injection, NK-4 (compound represented by Chemical Formula 2), NK-9694 as an active ingredient in 170 g of purified water for injection (Compound represented by chemical formula 1), NK-28 (compound in which the carbon number of the alkyl group (R) in the side chain of the compound represented by general formula 2 is 7), NK-147 (expressed by general formula 2) A compound in which the alkyl group (R) in the side chain of the compound has 8 carbon atoms), NK-19 (a compound represented by Chemical Formula 4), NK-53 (a compound represented by Chemical Formula 5), NK- 150 (compound represented by chemical formula 3), NK-393 (compound in which the side chain alkyl group (R) of the compound represented by general formula 3 has 8 carbon atoms), NK-100 (compound represented by chemical
  • All of these products are pyrogen-free and can be used as neurite outgrowth promoters.
  • this product can be used as a neurodegeneration inhibitor, a nerve cell protective agent, or a therapeutic agent for pathological conditions or neurological dysfunction associated with neurodegeneration.
  • the remaining 10 animals in a group were intraperitoneally administered with a 10% aqueous solution of sterile maltose (pyrogen-free) from 3 weeks to 10 weeks of age, once daily for 56 days, daily at 0.5 ml / mouse. (Control group).
  • the day after the end of the administration period the weight of each hamster was measured in the same manner as in Experiment 5, and the rotarod test, the slope endurance test, and the number of falls were measured.
  • Table 16 shows the types of compounds that are active ingredients of the preparations administered to each group and the measurement results.
  • the average body weight at 3 weeks of hamster was 35.4 g
  • the average body weight at 10 weeks of age was 122.9 g
  • Table 16 shows only the rotarod test, the slope endurance test, and the measurement results of the number of falls.
  • a hamster cerebellar tissue specimen was prepared in the same manner as in Experiment 4, and it was determined by microscopic observation whether or not the cerebellar Purkinje cell atrophy was suppressed compared to the control group. The results are also shown in Table 16.
  • Example 1 As is clear from Table 16, the 12 preparations prepared in Example 1 all suppressed neurite (dendrites) atrophy of cerebellar Purkinje cells in a 10-week-old cerebellar ataxia hamster, The drop time from the rod, the slope endurance slope angle and the number of falls were significantly improved. Comparing the strength of the effect when 12 types of preparations were administered, in any test, preparations containing dimethine styryl dye compounds (NK-523, NK-557, and NK-1516) were administered.
  • NK-523, NK-557, and NK-1516 dimethine styryl dye compounds
  • the pentamethine cyanine dye compounds (NK-4, NK-9694, NK-28, NK-147, NK-19, NK-53, NK-150, NK-393, K When -100, K-528, K-557, and NK-1516) were administered (Experimental groups 1 to 9), a stronger effect of improving motor coordination was observed. When the strength of the effect was improved among the pentamethine-based cyanine dye compounds, NK-4, NK-26, NK-9694, MK-150 and NK-393 were particularly effective in improving motor coordination. This result indicates that any of the prepared preparations is useful as a therapeutic agent for neurodegenerative diseases. Moreover, even if these preparations were administered for 56 days, the body weight of the hamster was not significantly different from that of the control group.
  • NK-19 A solution prepared by dissolving 60 g of purified maltose for injection (manufactured by Hayashibara Co., Ltd.) in 370 g of purified water for injection, and 2 g of lecithin and an active ingredient NK-4 (compound represented by Chemical Formula 2) in 170 g of purified water for injection, NK-234 (a compound in which the alkyl group (R) in the side chain of the compound represented by the general formula 2 has 3 carbon atoms), NK-26 (an alkyl group in the side chain of the compound represented by the general formula 2 ( R) is a compound having 4 carbon atoms), NK-9694 (a compound represented by Chemical Formula 1), NK-28 (a compound having a general formula 2 having a side chain alkyl group (R) having a carbon number of 7), NK-147 (a compound in which the alkyl group (R) in the side chain of the compound represented by Formula 2 has 8 carbon atoms), NK-19 (a
  • Each of the 14 types of neurite outgrowth promoters prepared in Example 2 was administered to 10 ddy mice (average body weight 25.6 g) in a single dose of 0.3 ml / animal, and the body weight was daily for one week after administration.
  • a 10% maltose solution containing 0.2% lecithin was administered to 10 ddy mice (average body weight 26.3 g) as a control, and the course was observed.
  • no significant change in body weight was observed, and no other change in appearance was observed.
  • the LD 50 of the compound formulated as the active ingredient of the 12 types of neurite outgrowth promoting agents prepared in Example 2 is 8.6 mg / kg ⁇ body weight or more. It shows that it is safe to administer.
  • ⁇ Powder for injection> A solution prepared by dissolving 60 g of purified maltose for injection (manufactured by Hayashibara Co., Ltd.) in 370 g of purified water for injection, 3 g of polysorbate 80 (sold by Nippon Oil & Fats Co., Ltd.) in 170 g of purified water for injection, and NK-4 ( A compound represented by Chemical Formula 2), NK-234 (a compound in which the alkyl group (R) in the side chain of the compound represented by General Formula 2 has 3 carbon atoms), NK-26 (a compound represented by General Formula 2) A compound in which the alkyl group (R) in the side chain of the compound has 4 carbon atoms), NK-9694 (a compound represented by the chemical formula 1), NK-28 (a compound represented by the general formula 2) Compounds in which the alkyl group (R) has 7 carbon atoms), NK-147 (compounds in which the alkyl group (R) in the side chain of the compound
  • This product can be used as a neurite extension promoter.
  • the product can also be used as a neurode
  • ⁇ Capsule> Capsules containing the following components per tablet were prepared.
  • the mixture of the above component A was kneaded with an 8% aqueous solution of polyvinyl pyrrolidone K-90, dried at 60 ° C., pulverized, mixed with component B, filled into capsules at 150 mg per capsule, Capsule
  • the neurite outgrowth promoting agent of the present invention is used for the prevention, treatment and / or progression inhibition of Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, dementia, or stroke caused by neurodegeneration of nerve cells, or nerve from neurodegeneration.
  • Useful for cell protection for various pathological conditions and neurological dysfunctions associated with neurodegenerative diseases (for example, tremor, rigidity, ataxia, peristalsis, slow movement, posture reflex disorder, autonomic disorder, lunging phenomenon, gait disorder, depression, memory disorder, It is also useful for improving muscle atrophy, muscle weakness, upper limb dysfunction, articulation disorder, dysphagia, respiratory disorder, numbness and paralysis.
  • the neurite outgrowth promoting agent of the present invention has no side effects even when administered for a long period of time, so it is highly safe and can be used with confidence.
  • the present invention is an invention that exhibits such remarkable effects, and is a truly significant invention that contributes greatly to the world.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nutrition Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Anesthesiology (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention porte sur un nouveau stimulateur d'élongation d'axone. Le stimulateur d'élongation d'axone comprend un composé représenté par la formule générale (1) en tant qu'ingrédient actif. Dans la formule générale (1), R1 à R3 représentent indépendamment un atome d'hydrogène ou un substituant approprié ; Z1 représente un noyau hétérocyclique, et Z2 représente un noyau hétérocyclique identique ou différent du noyau hétérocyclique représenté par Z1, ou un noyau aromatique, dans lequel chacun du noyau hétérocyclique et du noyau aromatique peuvent comprendre un substituant ; o représente un entier de valeur 0,1 ou 2, et p représente un entier de 0 ou 1, p ayant la valeur 1 lorsque o représente 0 ou 2, p ayant la valeur 0 lorsque o représente 1, R1 et R2 n'existent pas lorsque o a la valeur 0, et R3 n'existe pas et un atome de carbone auquel R2 est lié et Z2 sont liés l'un à l'autre par une liaison simple lorsque p représente 0 ; X1 - représente un contre-anion approprié ; et q représente un entier de valeur 1 ou 2.
PCT/JP2010/050923 2009-01-29 2010-01-25 Stimulateur d'élongation d'axone Ceased WO2010087313A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2010548503A JPWO2010087313A1 (ja) 2009-01-29 2010-01-25 神経突起伸展促進剤

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2009018778 2009-01-29
JP2009-018778 2009-01-29
JP2009206362 2009-09-07
JP2009-206362 2009-09-07

Publications (1)

Publication Number Publication Date
WO2010087313A1 true WO2010087313A1 (fr) 2010-08-05

Family

ID=42395574

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/050923 Ceased WO2010087313A1 (fr) 2009-01-29 2010-01-25 Stimulateur d'élongation d'axone

Country Status (2)

Country Link
JP (1) JPWO2010087313A1 (fr)
WO (1) WO2010087313A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776583A (zh) * 2019-01-25 2019-05-21 郑州大学 一种吡啶类链状共轭体系分子衍生物及其制备方法和应用
WO2020158225A1 (fr) * 2019-01-28 2020-08-06 株式会社バイオラジカル研究所 Antioxydant et utilisation de celui-ci
WO2020226165A1 (fr) * 2019-05-08 2020-11-12 国立大学法人大阪大学 COMPOSITION DESTINÉE À INHIBER L'ACCUMULATION D'α-SYNUCLÉINE ET COMPOSITION DESTINÉE À INHIBER LA PROPAGATION D'AGRÉGATS D'α-SYNUCLÉINE
WO2021125345A1 (fr) * 2019-12-18 2021-06-24 株式会社バイオラジカル研究所 Vasodilatateur et son utilisation
CN116941625A (zh) * 2023-07-28 2023-10-27 中国农业大学 硫代噻唑烷酮类化合物作为海藻糖酶抑制剂的应用

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005177A1 (fr) * 1993-08-13 1995-02-23 Seikagaku Corporation Remede contre les maladies nerveuses
JP2000355579A (ja) * 1999-05-05 2000-12-26 Adir 新規な置換ピリジン又はピペリジン化合物、その製造法、及びそれを含有する医薬組成物
WO2002007781A2 (fr) * 2000-07-25 2002-01-31 Neurochem Inc. Agents d'imagerie ciblant les substances amyloides et utilisation desdits agents
JP2002121416A (ja) * 2000-10-16 2002-04-23 Hayashibara Biochem Lab Inc 液状組成物
JP2002518380A (ja) * 1998-06-18 2002-06-25 ブリストル−マイヤーズ スクイブ カンパニー サイクリン依存キナーゼの炭素置換アミノチアゾール抑制剤
WO2002090314A1 (fr) * 2001-05-03 2002-11-14 Galileo Laboratories, Inc. Derives de pyruvates
JP2003137784A (ja) * 2001-11-02 2003-05-14 Hayashibara Biochem Lab Inc インターフェロンγ産生促進剤
JP2003534341A (ja) * 2000-05-24 2003-11-18 スージェン・インコーポレーテッド ３−（ピロール−２−イルメチリデン）−２−インドリノン誘導体のプロドラッグ
WO2003106439A1 (fr) * 2002-06-12 2003-12-24 株式会社ビーエフ研究所 Compose sonde pour le diagnostic par imagerie d'une maladie liee a l'accumulation d'amyloide, compose pour colorer des taches de vieillesse/taches de vieillesse diffuses, et agent de traitement pour maladie liee a l'accumulation d'amyloide
WO2004050088A1 (fr) * 2002-12-03 2004-06-17 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de jnk
JP2004250407A (ja) * 2003-02-21 2004-09-09 Bf Kenkyusho:Kk アミロイド蓄積性疾患の診断プローブおよび治療用化合物
JP2005505519A (ja) * 2001-07-23 2005-02-24 ガリレオ ファーマシューティカルズ， インコーポレイテッド 細胞保護化合物、薬学的処方物および美容用処方物、ならびに方法
JP2005514368A (ja) * 2001-11-21 2005-05-19 スージェン・インコーポレーテッド インドリノン誘導体を含む医薬製剤
US20060018825A1 (en) * 2003-08-13 2006-01-26 Bf Research Institute, Inc. Probe for diseases with amyloid accumulation, amyloid-staining agent, remedy and preventive for diseases with amyloid accumulation and diagnostic probe and staining agent for neurofibrillary change
WO2007041358A2 (fr) * 2005-09-30 2007-04-12 Miikana Therapeutics, Inc. Composes pyrazole substitues
WO2009003147A1 (fr) * 2007-06-26 2008-12-31 Parkinson's Institute Procédés et compositions destinés au traitement d'affections neurologiques

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005177A1 (fr) * 1993-08-13 1995-02-23 Seikagaku Corporation Remede contre les maladies nerveuses
JP2002518380A (ja) * 1998-06-18 2002-06-25 ブリストル−マイヤーズ スクイブ カンパニー サイクリン依存キナーゼの炭素置換アミノチアゾール抑制剤
JP2000355579A (ja) * 1999-05-05 2000-12-26 Adir 新規な置換ピリジン又はピペリジン化合物、その製造法、及びそれを含有する医薬組成物
JP2003534341A (ja) * 2000-05-24 2003-11-18 スージェン・インコーポレーテッド ３−（ピロール−２−イルメチリデン）−２−インドリノン誘導体のプロドラッグ
WO2002007781A2 (fr) * 2000-07-25 2002-01-31 Neurochem Inc. Agents d'imagerie ciblant les substances amyloides et utilisation desdits agents
JP2002121416A (ja) * 2000-10-16 2002-04-23 Hayashibara Biochem Lab Inc 液状組成物
WO2002090314A1 (fr) * 2001-05-03 2002-11-14 Galileo Laboratories, Inc. Derives de pyruvates
US20030013656A1 (en) * 2001-05-03 2003-01-16 Bing Wang Pyruvate derivatives
JP2005505519A (ja) * 2001-07-23 2005-02-24 ガリレオ ファーマシューティカルズ， インコーポレイテッド 細胞保護化合物、薬学的処方物および美容用処方物、ならびに方法
JP2003137784A (ja) * 2001-11-02 2003-05-14 Hayashibara Biochem Lab Inc インターフェロンγ産生促進剤
JP2005514368A (ja) * 2001-11-21 2005-05-19 スージェン・インコーポレーテッド インドリノン誘導体を含む医薬製剤
WO2003106439A1 (fr) * 2002-06-12 2003-12-24 株式会社ビーエフ研究所 Compose sonde pour le diagnostic par imagerie d'une maladie liee a l'accumulation d'amyloide, compose pour colorer des taches de vieillesse/taches de vieillesse diffuses, et agent de traitement pour maladie liee a l'accumulation d'amyloide
WO2004050088A1 (fr) * 2002-12-03 2004-06-17 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de jnk
JP2004250407A (ja) * 2003-02-21 2004-09-09 Bf Kenkyusho:Kk アミロイド蓄積性疾患の診断プローブおよび治療用化合物
US20060018825A1 (en) * 2003-08-13 2006-01-26 Bf Research Institute, Inc. Probe for diseases with amyloid accumulation, amyloid-staining agent, remedy and preventive for diseases with amyloid accumulation and diagnostic probe and staining agent for neurofibrillary change
WO2007041358A2 (fr) * 2005-09-30 2007-04-12 Miikana Therapeutics, Inc. Composes pyrazole substitues
WO2009003147A1 (fr) * 2007-06-26 2008-12-31 Parkinson's Institute Procédés et compositions destinés au traitement d'affections neurologiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOCHEMISTRY, vol. 45, no. 19, 2006, pages 6085 - 6094 *
EUROPEAN J.PHARMACOLOGY, vol. 559, no. 2-3, 2007, pages 124 - 131 *
J.BIOLOGICAL CHEMISTRY, vol. 280, no. 9, 2005, pages 7614 - 7623 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776583A (zh) * 2019-01-25 2019-05-21 郑州大学 一种吡啶类链状共轭体系分子衍生物及其制备方法和应用
WO2020158225A1 (fr) * 2019-01-28 2020-08-06 株式会社バイオラジカル研究所 Antioxydant et utilisation de celui-ci
JPWO2020158225A1 (ja) * 2019-01-28 2021-11-18 株式会社 バイオラジカル研究所 抗酸化剤およびその用途
JP7297321B2 (ja) 2019-01-28 2023-06-26 株式会社 バイオラジカル研究所 抗酸化剤およびその用途
WO2020226165A1 (fr) * 2019-05-08 2020-11-12 国立大学法人大阪大学 COMPOSITION DESTINÉE À INHIBER L'ACCUMULATION D'α-SYNUCLÉINE ET COMPOSITION DESTINÉE À INHIBER LA PROPAGATION D'AGRÉGATS D'α-SYNUCLÉINE
JPWO2020226165A1 (fr) * 2019-05-08 2020-11-12
WO2021125345A1 (fr) * 2019-12-18 2021-06-24 株式会社バイオラジカル研究所 Vasodilatateur et son utilisation
CN116941625A (zh) * 2023-07-28 2023-10-27 中国农业大学 硫代噻唑烷酮类化合物作为海藻糖酶抑制剂的应用

Also Published As

Publication number Publication date
JPWO2010087313A1 (ja) 2012-08-02

Similar Documents

Publication Publication Date Title
JP5591720B2 (ja) 抗神経変性疾患剤
JP7774170B2 (ja) 翼状片を治療するための組成物及び方法
US20220202798A1 (en) Use of pridopidine for the treatment of fragile x syndrome
CN104995176B (zh) 调节bace所介导的app加工的乙内酰脲
JP2007500219A (ja) 複素環化合物およびその使用法
KR20100024951A (ko) 세포를 자극하기 위한 방법 및 조성물
TW201841637A (zh) 使用ccr3-抑制劑治療老化相關損傷之方法及組合物
WO2010087315A1 (fr) Agent anti-maladie d'alzheimer
WO2010087313A1 (fr) Stimulateur d'élongation d'axone
US6268396B1 (en) Use of valproic acid analog for the treatment and prevention of migraine and affective illness
JP2022511266A (ja) 陰性症状および障害を処置するため、神経可塑性を増大するため、ならびに神経保護を促進するためのロルペリドンの使用
US9427439B1 (en) Methods and compositions for recovery from stroke
GB2619119A (en) Compounds for use in the treatment of diseases and conditions associated with neurodegenerative dysfunction
CN108348524A (zh) 用于从中风恢复的方法和组合物
JP2024153742A (ja) Ｃｃｒ３阻害剤を用いて、加齢性機能障害を治療するための方法および組成物
JP2005501108A (ja) 神経変性治療におけるネフィラセタムの使用
CN114712361A (zh) 用于预防或降低短暂性脑缺血发作发病率的组合物及方法
KR20150058159A (ko) 바클로펜 및 아캄프로세이트 기반 황반 변성 장애의 치료
WO2015060746A1 (fr) Combinaison pour traiter et/ou prévenir l'apparition de troubles psychiques, cognitifs, comportementaux et neurologiques lors de maladies organiques du système nerveux central de genèse diverse
JP2022529742A (ja) 神経修復方法
TWI896143B (zh) 一種有效延緩及治療近視的藥物組合物
HK40102267A (zh) 用於治疗孤独症谱系障碍(asd)的方法
AU2018372065A1 (en) Neuroprotective peptide
JPWO2004035053A1 (ja) 神経栄養因子産生促進剤
RU2799049C2 (ru) Способы лечения изменений поведения

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10735781

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2010548503

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10735781

Country of ref document: EP

Kind code of ref document: A1