WO2019054430A1 - Composé amide ayant un hétérocycle aromatique - Google Patents

Composé amide ayant un hétérocycle aromatique Download PDF

Info

Publication number
WO2019054430A1
WO2019054430A1 PCT/JP2018/033912 JP2018033912W WO2019054430A1 WO 2019054430 A1 WO2019054430 A1 WO 2019054430A1 JP 2018033912 W JP2018033912 W JP 2018033912W WO 2019054430 A1 WO2019054430 A1 WO 2019054430A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
group
mmol
triazol
disorder
Prior art date
Application number
PCT/JP2018/033912
Other languages
English (en)
Japanese (ja)
Inventor
亨 谷口
理 岩本
啓志 齋藤
勝義 中島
泰之 小川
青木　一真
伸也 栗川
田中　伸治
Original Assignee
第一三共株式会社
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 第一三共株式会社 filed Critical 第一三共株式会社
Publication of WO2019054430A1 publication Critical patent/WO2019054430A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • 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
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound having a specific chemical structure having peripheral and / or central anti-inflammatory activity or a pharmacologically acceptable salt thereof, a method for producing the same, and the like.
  • the present invention also relates to the mechanism of action of the compound or a pharmacologically acceptable salt thereof, a pharmaceutical composition, a method for producing, preventing and / or treating the pharmaceutical composition, and the like.
  • Non-Patent Documents 1 and 2 It has been reported that stress increases the production of inflammatory cytokines from microglia and that blood cytokines (TNF ⁇ etc.) levels are high in mental disease patients (depression, schizophrenia etc.), and brain inflammation in mental diseases Involvement of is suggested.
  • TNF ⁇ etc. blood cytokines
  • brain inflammation in mental diseases Involvement of is suggested.
  • proteins considered to be the cause cause inflammation in the brain by activation of microglia it has also been suggested that proteins considered to be the cause cause inflammation in the brain by activation of microglia.
  • the present invention relates to a compound having a specific chemical structure having anti-inflammatory activity, useful as an active ingredient for the prevention and / or treatment of inflammatory diseases, a pharmacologically acceptable salt thereof, or a novel preparation thereof
  • a compound having a specific chemical structure having anti-inflammatory activity useful as an active ingredient for the prevention and / or treatment of inflammatory diseases
  • a pharmacologically acceptable salt thereof or a novel preparation thereof
  • the compounds of the present invention and their pharmacologically acceptable salts are considered to be useful as novel pharmaceuticals because they have different properties from existing anti-inflammatory agents in various aspects.
  • the compound of the present invention and pharmacologically acceptable salts thereof have anti-inflammatory activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained efficacy, physical stability, It has been found that it has excellent properties in terms of drug interaction, toxicity, etc. and is useful as a medicine.
  • the present inventors have intensively studied for the purpose of developing a compound useful as an active ingredient for the prevention and / or treatment of an inflammatory disease, a pharmacologically acceptable salt thereof and the like, and as a result, the compound of the present invention We found pharmacologically acceptable salts etc. That is, the present invention is as described below.
  • X any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
  • Y may form a
  • Substituent group Y 1 Hydroxyl group, Amino group, Nitro group, Cyano group, Halogen atom, A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ; A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; 5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2
  • Substituent group Y 2 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3
  • Substituent group Y 3 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group
  • R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
  • R 3 hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
  • R 4 hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
  • R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
  • E is -O-, n 1 is 0, and n 2 is 1.
  • G is any one selected from the following.
  • n 3 is 0, [1] - a compound or a pharmacologically acceptable salt thereof according to any one of [5].
  • Y is any group (Note selected from the following, Y may be substituted with same or different 1-3 groups selected from Substituent Group Y 1.
  • Substituent group Y 1 is The compound or pharmacologically acceptable salt thereof according to any of [1]-[6], which is as defined in [1].
  • Y Either group selected from the following (Note, Y may be substituted with same or different 1-3 groups selected from substituent group Y 1 substituent group Y 1 is [ As defined in 1).)
  • R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo C1-C6 alkyl group, or a halo C1-C6 alkoxy group
  • R 3 hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
  • R 4 hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
  • R5c and R5d each independently a hydrogen atom or a C1-C6 alkyl group]
  • a pharmaceutical composition comprising the compound according to any one of [1]-[9] or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to [11] which is for the prevention and / or treatment of an inflammatory disease.
  • the pharmaceutical composition according to [12], wherein the inflammatory disease is a peripheral inflammatory disease.
  • the pharmaceutical composition according to [12], wherein the inflammatory disease is a central inflammatory disease.
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, celiac disease, ⁇ ⁇ , radiation enteritis, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, cirrhosis, peripheral neuritis , Ankylosing spondylitis, eczema (acute, subacute, chronic), contact dermatitis, sun (ultraviolet) dermatitis, radiation dermatitis, atopic dermatitis, seborrhoeic dermatitis,
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary Sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, sun (ultraviolet) dermatitis, atopic dermatitis, seborrhoeic dermatitis, psoriasis vulgaris, arthritic psoriasis Psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, rosacea, alopecia areata, pemphigus, erythema, acne
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spine
  • the pharmaceutical composition according to [13] which is any one selected from the group consisting of inflammation, wounds, intractable stomatitis, glossitis and Behcet's disease.
  • [twenty two] [11] A method for preventing and / or treating an inflammatory disease, which comprises administering an effective amount of the pharmaceutical composition according to [11].
  • the compound having a specific chemical structure having a peripheral and / or central anti-inflammatory activity or a pharmacologically acceptable salt thereof of the present invention has properties different from anti-inflammatory agents existing in various aspects from the past. It is considered to be useful as a new medicine because of In addition, the compound of the present invention and pharmacologically acceptable salts thereof have anti-inflammatory activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained efficacy, physical stability, It has excellent properties in terms of drug interaction, toxicity, etc. and is useful as a medicine.
  • One embodiment of the present invention is a compound of the general formula (1) or a pharmacologically acceptable salt thereof.
  • X any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
  • Y may form a
  • Substituent group Y 1 Hydroxyl group, Amino group, Nitro group, Cyano group, Halogen atom, A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ; A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; 5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
  • Substituent group Y 2 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3 ;
  • Substituent group Y 3 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group
  • R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
  • R 3 hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
  • R 4 hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
  • R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
  • Preferred embodiments of the present invention are the compounds described in the examples or pharmacologically acceptable salts thereof.
  • the “5-membered aromatic heterocycle optionally having sulfur atom, nitrogen atom or oxygen atom” in G is a 5-membered member, and atoms constituting the ring are nitrogen atom, oxygen atom, and An aromatic ring containing 1 to 4 atoms selected from the group consisting of sulfur atoms, such as a ring shown below (having two or more bonds).
  • it is a 5-membered aromatic heterocycle having a bond as follows.
  • the "halogen atom” in the present specification is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
  • the "C1-C6 alkyl group” in the present specification is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or an isobutyl group. It is a group.
  • the "C1-C6 alkoxy group” in the present specification is a group in which a C1-C6 alkyl group is bonded to an oxygen atom, and preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or an isobutoxy group. is there.
  • the "C3-C8 cycloalkyl group” in the present specification is a cyclic alkyl group having 3 to 8 carbon atoms, and preferably represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the group as shown below is also included.
  • C3-C8 cycloalkoxy group in the present specification is a group in which a C3-C8 cycloalkyl group is bonded to an oxygen atom, and preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or And cyclohexyloxy.
  • the "halo C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkyl group is substituted by an appropriate number of halogen atoms, and preferably a difluoromethyl group, a trifluoromethyl group or a difluoroethyl group. is there.
  • halo C1-C6 alkoxy group in the present specification is a group in which an appropriate number of halogen atoms are substituted to a C1-C6 alkoxy group, and preferably a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group. is there.
  • amino C1-C6 alkyl group in the present specification is a group in which an amino group is bonded to a C1-C6 alkyl group, and is preferably an aminomethyl group, an aminoethyl group or an aminopropyl group.
  • the “di C1-C6 alkylamino group” in the present specification is a group in which two identical or different C1-C6 alkyl groups are bonded to an amino group, and preferably a dimethylamino group or a diethylamino group.
  • the “5-6 membered aromatic heterocyclic group” in the present specification is a 5- or 6-membered, 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. It refers to a monocyclic aromatic cyclic group contained, for example, a group having one bond in the ring as shown below.
  • the "4-7 membered saturated heterocyclic group" in the present specification is a 4-7 member, and contains 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a monocyclic saturated cyclic group is, for example, a group having one bond in the ring as shown below.
  • the "C1-C6 alkyl carbonyl group” in the present specification is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and is preferably an acetyl group, an ethyl carbonyl group or a propyl carbonyl group.
  • the “C1-C6 alkoxycarbonyl group” in the present specification is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and preferably a methoxycarbonyl group, an ethoxycarbonyl group or a t-butoxycarbonyl group.
  • C3-C8 cycloalkyl carbonyl group in the present specification is a group in which a C3-C8 cycloalkyl group is bonded to a carbonyl group, and preferably a cyclopropyl carbonyl group, a cyclobutyl carbonyl group or a cyclopentyl carbonyl group. is there.
  • C3-C8 cycloalkoxycarbonyl group in the present specification is a group in which a C3-C8 cycloalkoxy group is bonded to a carbonyl group, and preferably a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group It is.
  • the "halo C1-C6 alkyl carbonyl group” in the present specification is a group in which a halo C1-C6 alkyl group is bonded to a carbonyl group, and preferably a difluoromethyl carbonyl group, a trifluoromethyl carbonyl group, a difluoroethyl carbonyl group.
  • halo C1-C6 alkoxycarbonyl group in the present specification is a group in which a halo C1-C6 alkoxy group is bonded to a carbonyl group, and preferably a difluoromethoxycarbonyl group, a trifluoromethoxycarbonyl group, a difluoroethoxycarbonyl group. It is a group.
  • the "phenyl carbonyl group” in the present specification is a group in which a phenyl group is bonded to a carbonyl group.
  • phenoxycarbonyl group in the present specification is a group in which a phenoxy group is bonded to a carbonyl group.
  • the pharmacologically acceptable salt indicates a salt that can be used as a pharmaceutical.
  • a salt thereof is shown because it can be converted to a basic salt or an acidic salt by reacting with a base or an acid.
  • the pharmacologically acceptable “basic salt” of the compound is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; Methyl morpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salts such as picoline salt or glycine salt, lysine salt, They are amino acid salts such as arginine salts, ornithine salts, glutamates and aspartates, preferably alkali metal salts.
  • alkali metal salt such as sodium salt, potassium salt or lithium salt
  • an alkaline earth metal salt such as magnesium salt or calcium salt
  • Methyl morpholine salt triethylamine salt, tributylamine salt, diisopropylethylamine
  • the pharmacologically acceptable “acid salt” of the compound is preferably a hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, nitrate, Inorganic acid salts such as chlorate, sulfate and phosphate; methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonate such as ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid Allyl sulfonates such as salts, acetates, malates, fumarates, succinates, citrates, citrates, ascorbates, tartrates, borates, borates, maleates and the like; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate, and most preferably hydrohalide (especially
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become hydrate upon standing in the air or recrystallization.
  • the present invention also encompasses compounds of such various hydrates, solvates and crystalline polymorphs.
  • the compounds of the present invention may be cis isomer, geometric isomer such as trans isomer, tautomer or d isomer, l isomer etc. While various isomers such as optical isomers of may exist, the compounds include all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratio, unless otherwise specified. It is Mixtures of these isomers can be separated by known resolution means.
  • the compounds of the present invention also include labels, that is, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2H, 3H, 13C, 14C, 35S, etc.).
  • the invention also encompasses so-called prodrugs.
  • the prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, Prog. Med., Vol. 5, pp. 2157-2161 (1985).
  • the prodrug (1)
  • an amino group is present in the compound, Compounds in which the amino group is acylated, alkylated or phosphorylated (eg, the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4- (4) And the like, and compounds such as methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the hydroxyl group is acylated, alkylated, phosphorylated, borated compound (eg, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, analylated, dimethylaminomethylcarbonylated Compounds, etc.) and the like.
  • a carboxy group is present in the compound, A compound in which the carboxy group is esterified or amidated (eg, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl ester And the like), and the like.
  • Method A is a method of producing the compound (A-IV) of the present invention.
  • Step A1 A step of deprotecting an amino group This step is to obtain a compound (A-III) by deprotecting an amino group from the compound (AI).
  • the protecting group is a tert-butoxycarbonyl group
  • compound (A-III) can be obtained by dissolving compound (AI) in a solvent and adding an acid.
  • the reaction temperature is about ⁇ 20 to 100 ° C.
  • the reaction time is about 1 to 24 hours.
  • an acid to be used trifluoroacetic acid, hydrochloric acid and the like can be mentioned.
  • the solvent to be used dichloromethane, chloroform, methanol, ethyl acetate, 1,4-dioxane etc., or a mixture thereof can be mentioned.
  • Step A2 A step of reducing a nitro group to an amino group From the compound (A-II), a step of obtaining a compound (A-III) by hydrogenation in the presence of a metal catalyst such as 10% palladium carbon is there.
  • the solvent to be used may be terhydrohydrofuran, 1,4-dioxane, methanol, ethanol or the like, or a mixture thereof, and the reaction temperature is usually about room temperature to 60 ° C., and the reaction time is 0.5 to 24. It is about time.
  • this step can also be carried out by heating under reflux in an ethanol / water solvent a reduction reaction between iron powder and ammonium chloride.
  • Step A3 A step of forming an amide by condensation (i) Activate carboxylic acid as acid chloride and then react with compound (A-III) to produce compound (A-IV), or (ii) Carboxylic acid
  • the acid and the compound (A-III) are reacted in the presence of a condensing agent to produce a compound (A-IV).
  • a condensing agent for example, oxalyl chloride and a small amount of dimethylformamide are added to a dichloromethane solution of a carboxylic acid at 0 ° C. to room temperature, and after standing for a while, the compound ( Compound (A-IV) can be obtained by adding A-III) and a base such as pyridine.
  • the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
  • a base and a condensing agent can be added to a solution of a carboxylic acid and a compound (A-III) in dimethylformamide or dichloromethane to obtain a compound (A-IV).
  • the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
  • tertiary amines such as diisopropylethylamine can be mentioned.
  • G is the following 1,2,4-triazole
  • Method E Can be produced, for example, by using the following method B to produce a compound corresponding to the compound (A-I) and the compound (A-II) used in the method A. Further, a compound corresponding to the compound (A-IV) of Method A can be produced using Method E below.
  • Method B is a method for producing (B-III) (the compound corresponding to Compound (AI) and Compound (A-II) used in Method A).
  • N 1 represents P n NH- or NO 2- .
  • Step B1 Step of Forming Triazole Ring Compound (BI) is reacted with an alkylating agent such as methyl iodide to convert it into the corresponding thioimidate, and reacted with compound (B-II) to give compound (B-III) Manufacturing process.
  • an alkylating agent such as methyl iodide
  • compound (B-II) to give compound (B-III) Manufacturing process.
  • Tetrahydrofuran, 1,4-dioxane, etc. can be mentioned as a solvent used in the reaction of compound (BI) and methyl iodide, and the reaction temperature is usually about room temperature to 80 ° C., and the reaction time is 1 to 24 hours. It is an extent.
  • examples of the solvent used in the reaction of thioimidate with the compound (B-II) include tetrahydrofuran and 1,4-dioxane, and the reaction temperature is usually from room temperature to 120 ° C., and the reaction time is from 1 to It is about 24 hours.
  • Method C is a method of producing a compound (C-III) (a compound corresponding to the compound (BI) used in the method B).
  • Step C1 A step of forming an amide by condensation This is a step of producing a compound (C-II) from a compound (CI) which can be synthesized by a commercially available method or a known method under the same conditions as in the step A3 step.
  • Step C2 Step of Thiocarbonylation This is a step of reacting compound (C-II) with a sulfurizing agent such as Lawesson's reagent in a solvent to obtain compound (C-III).
  • a sulfurizing agent such as Lawesson's reagent
  • the solvent to be used hydrochlorohydrofuran, 1,4-dioxane, etc., or a mixture thereof can be mentioned.
  • the reaction temperature is about 0 to 100 ° C.
  • the reaction time is about 0.5 to 24 hours. .
  • Method D is a method of producing a compound (D-II) (a compound corresponding to the compound (B-II) used in the method B).
  • P C represents a group that protects a carboxy group.
  • Step D1 A step of forming a hydrazide This is a step of heating a compound (DI) which can be synthesized by a commercially available method or a known method with hydrazine in a solvent to produce a compound (D-II).
  • a solvent to be used methanol, ethanol, water and the like, or a mixture thereof can be mentioned.
  • the reaction temperature is about room temperature to 100 ° C.
  • the reaction time is about 0.5 to 24 hours.
  • Method E is a method of producing the compound (E-VIII) of the present invention (the compound corresponding to the compound (A-IV) of Method A).
  • P 2 O represents a group that protects a hydroxyl group.
  • Step E1 A step of forming a hydrazide This is a step of producing a compound (E-II) from a compound (EI) which can be synthesized by a known method, under the same conditions as in the step D1.
  • Step E2 A step of forming a triazole ring Compound (E-II) and compound (E-III) (a compound corresponding to (C-III) in Method C) to compound B (Compound B) under the same conditions as in Method B1.
  • E-IV is produced.
  • Step E3 A step of reducing a nitro group to an amino group This is a step of producing a compound (EV) from compound (E-IV) under the same conditions as in Step A2.
  • Step E4 A step of forming an amide by condensation This is a step of producing a compound (E-VI) from the compound (EV) and a corresponding carboxylic acid under the same conditions as in the method A3 step.
  • Step E5 Step for Deprotection This is a step for obtaining compound (E-VII) by deprotecting a hydroxyl group from compound (E-VI).
  • the protecting group is a tetrahydropyranyl group
  • compound (E-VI) can be dissolved in a solvent and acid can be added to give compound (E-VII).
  • the reaction temperature is about 0 to 80 ° C.
  • the reaction time is about 0.5 to 24 hours.
  • Step E6 A step of etherifying by Mitsunobu reaction This is a step of obtaining compound (E-VIII) from compound (E-VII) using a corresponding alcohol in the presence of phosphine and azodicarboxylic acid ester or diazodicarboxamide.
  • phosphine to be used triphenyl phosphine, tri-n-butyl phosphine and the like can be mentioned.
  • azodicarboxylate ester or diazodicarboxamide to be used include diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipyridine and the like.
  • the solvent to be used include terehydrofuran, 1,4-dioxane, toluene and the like, or a mixture thereof.
  • the reaction temperature is about 0 to 100 ° C.
  • the reaction time is about 0.5 to 24 hours. is there.
  • G is the following pyrazole
  • Method F is a method of producing a compound (F-II) (a compound corresponding to the compound (A-II) used in the method A).
  • Step F1 Step of Etherifying by Mitsunobu Reaction This is a step of producing compound (F-II) from compound (FI) commercially available or which can be synthesized by a known method under the same conditions as in step E6 of method E.
  • G is the following 1,2,4-triazole
  • Method G is a method of producing a compound (G-III) (a compound corresponding to the compound (A-II) used in the method A).
  • Step G1 A step of reducing an ester to form an alcohol This is a step of producing a compound (G-II) from a compound (GI) which can be synthesized by a known method, under the same conditions as in the step J2 of step J2.
  • Step G2 A step of etherifying by Mitsunobu reaction This is a step of producing a compound (G-III) from the compound (G-II) under the same conditions as in the step E6.
  • G is the following imidazole
  • Method H is a method of producing a compound (H-III) (a compound corresponding to the compound (AI) used in the method A).
  • Step H1 A step of etherifying by Mitsunobu reaction A step of producing compound (H-II) from compound (HI) and a corresponding alcohol which can be synthesized by a commercially available method or a known method under the same conditions as in step E6 step It is.
  • triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), hydrogen carbonate Potassium, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, sodium phosphate and the like can be mentioned.
  • the solvent to be used methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, N, N-dimethylformamide, dimethylsulfoxide, toluene, etc., or a mixture thereof can be mentioned, and usually the reaction temperature Is about 60 to 120.degree. C., and the reaction time is about 0.5 to 24 hours.
  • G is the following isoxazole
  • Method I is a method of producing a compound (I-II) (a compound corresponding to the compound (A-II) used in the method A).
  • Step I1 A step of etherifying by Mitsunobu reaction A step of producing compound (I-II) from compound (II) which can be synthesized by a commercially available method or a known method and an alcohol corresponding thereto, under the same conditions as in Step E6. It is.
  • G is the following pyrazole
  • Method J is a method of producing a compound (J-IV) (a compound corresponding to the compound (A-II) used in the method A).
  • Step J1 The step of protecting the amino group of pyrazole This is a step of producing compound (J-II) from compound (JI) which can be synthesized by a known method, by introducing a protecting group into the amino group of pyrazole. .
  • compound (JI) is reacted with 3,4-dihydro-2H-pyran in a solvent under acidic conditions to give compound (J-II).
  • the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
  • Step J2 A step of reducing an ester to form an alcohol This is a step of producing a compound (J-III) by reacting the compound (J-II) with a reducing agent in a solvent.
  • a reducing agent to be used lithium aluminum hydride (LAH), diisobutyl aluminum hydride (DIBAL), etc.
  • Step J3 Step of Etherifying by Mitsunobu Reaction This is a step of producing compound (J-IV) from compound (J-III) and an alcohol corresponding thereto, under the same conditions as Step E6.
  • Method K when G of compound (KI) contains a protecting group P n , the protecting group is deprotected to give a compound (K-II) of the present invention (the compound used in Method A (A-IV) And the corresponding compound).
  • Step K1 Step for Deprotection This is a step for obtaining compound (K-II) by performing deprotection from compound (KI).
  • the protecting group is a tetrahydropyranyl group
  • the compound (KI) is dissolved in a solvent, and an acid is added to give a compound (K-II).
  • the reaction temperature is about room temperature to 80 ° C.
  • the reaction time is about 1 to 24 hours.
  • the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate.
  • the solvent methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water and the like or mixtures thereof can be mentioned.
  • optical isomers can be isolated and purified by known methods such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
  • optical isomers can be isolated and purified by a conventional method such as fractional recrystallization (salt resolution) or recrystallization with an appropriate salt.
  • fractional recrystallization salt resolution
  • recrystallization with an appropriate salt.
  • Administration is orally using tablets, pills, capsules, granules, powders, solutions, etc., or injections for intraarticular, intravenous, intramuscular etc., suppositories, eye drops, eye ointments, for transdermal use It may be in any form of parenteral administration by liquid solution, ointment, transdermal patch, transmucosal liquid, transmucosal patch, inhalant and the like.
  • Such solid compositions may comprise one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl piriddon And / or magnesium metasilicate magnesium aluminate and the like.
  • the solid composition contains, according to a conventional method, an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium ruboxymethylstarch, a stabilizer, and a solubilizer. It may be done.
  • the tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance, if necessary.
  • liquid composition for oral administration Pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like are used. To such liquid compositions it is possible to add generally used inert diluents such as purified water or ethanol.
  • the liquid composition may contain, in addition to an inert diluent, solubilizers, adjuvants such as wetting agents, sweetening agents, flavoring agents, fragrances, preservatives.
  • the aqueous solvent includes, for example, distilled water for injection or physiological saline.
  • Nonaqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or Polysorbate 80.
  • Such an injection composition may further contain a tonicity agent, preservative, wetting agent, emulsifying agent, dispersing agent, stabilizing agent, or solubilizing agent.
  • These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter, incorporation of a bactericide or irradiation.
  • these injection compositions can be used to prepare sterile solid compositions and to be dissolved or suspended in sterile water or sterile injectable solvent prior to use.
  • Ointments, plasters, creams, jellies, patches, sprays, lotions, eye drops, eye ointments and the like are used.
  • These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like.
  • ointment or lotion base polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauro macrogol, sorbitan sesquioleate, etc. used.
  • Transmucosal agents such as inhalants and transnasal agents are used in solid, liquid or semisolid form, and can be produced according to a conventionally known method.
  • known excipients pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate.
  • devices suitable for inhalation or insufflation can be used as the method of administration.
  • the compounds may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and dry powder or powder containing capsules may be used.
  • a suitable propellant may be used.
  • it may be in the form of a pressurized aerosol spray using a suitable gas such as chlorofluoroaluminum, hydrofluoroaluminum or carbon dioxide.
  • the daily dose is suitably about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg of body weight, once Or divided into two or more doses.
  • the appropriate daily dose is about 0.0001-10 mg / kg of body weight, which is administered once or several times daily.
  • about 0.001 to 100 mg / kg of body weight is administered in one or more divided doses a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like.
  • combination In the present invention, it can be used in combination with various therapeutic or preventive agents for diseases which are considered to show its efficacy.
  • the combination may be administered simultaneously, or separately separately, continuously, or at desired time intervals.
  • Co-administered formulations may be formulated or formulated separately.
  • Formulation Example 1 Powdered Powder A powder is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 895 g of lactose and 100 g of corn starch in a blender.
  • Formulation Example 2 Granules After 5 g of the compound of the present invention or a salt thereof, 865 g of lactose and 100 g of low substituted hydroxypropyl cellulose are mixed, 300 g of a 10% aqueous solution of hydroxypropyl cellulose is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
  • Formulation Example 3 Tablet A compound is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender and tableting with a tableting machine.
  • IL-10 increase rate 100 mg / kg of test substance suspended in 0.5% (w / v) methyl cellulose was orally administered to mice, and 1 hour later, lipopolysaccharide (LPS, Sigma-Aldrich, L2630 (trade name) 0.4 mg / kg was intraperitoneally administered to cause inflammation.
  • LPS lipopolysaccharide
  • IL-10 increase rate (% control ratio) (IL-10 amount in compound administration group) x 100 / (IL-10 amount in 0.5% (w / v) methyl cellulose administration group)
  • Example 3 4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-[[4- (trifluoromethyl) -2-pyridyl] oxymethyl] -1,2,4-triazole-3- [I] Phenyl] benzamide 4-[(dimethylamino) methyl] -N- [4- [4-methyl-5-[[4- (trifluoromethyl) -2-pyridinyl] oxymethyl] -1,2,4-triazol-3-yl] phenyl] benzamide
  • Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.2 g, 0.55 mmol) is dissolved in N, N-dimethylformamide (4 mL) and 2-chloro-4- (trifluoro) pyridine (A
  • Example 4 4-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropoxyphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide 4-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropoxyphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] benzamide
  • Example 2 (2e): 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.15 g (0.41 mmol) is suspended in 1,4-dioxane (3 mL) and cyanomethylene tributylphosphorane (0.21 mL, 0.82 mmol), 3- (propan-2-yloxy) phenol (Enamine catalog
  • Example 5 4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] benzamide (5a) tert-Butyl N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] carbamate tert-butyl N- [4- [4-methyl-5- (2-phenylethyl) -1,2,4-triazol-3-yl] carbamate The tert-butyl N- [4- (methylcarbamothiol) phenyl] carbamate (200 mg, 0.75 mmol) of Example 1 (1b) was dissolved in tetrahydrofuran (1 mL), methyl iodide (0.93 mL, 15 mmol) ) was added and stirred at room temperature for 3 hours.
  • Example 9 After distilling off the solvent under reduced pressure and azeotroping with toluene twice, the residue is dissolved in pyridine (3 mL) and dichloromethane (3 mL), and 5- [4-methyl-5- of Example 9 (9 d) is obtained. [[3- (Trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridin-2-amine (0.2 g, 0.57 mmol) was added and stirred at room temperature for 2 hours.
  • Example 10 4-[(Dimethylamino) methyl] -N- [4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] phenyl] benzamide (10a) 4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole 4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole Dissolve [1- (4-nitrophenyl) imidazol-4-yl] methanol (CAS Registry Number: 85102-89-2, Synthesis, 1983, 47-49) (790 mg, 3.6 mmol) in dichloromethane (30 mL) Then, 3-isopropylphenol (780 mg, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were added.
  • diethyl azodicarboxylate (2.2 M solution in toluene, 0.42 mL, 0.94 mmol) was slowly added dropwise and stirred at room temperature for 17 hours.
  • Example 13 4-[(Dimethylamino) methyl] -N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] Tetrahydropyran-3-yl] benzamide (13a) Methyl 2- (3-isopropylphenoxy) acetate methyl 2- (3-isopropylphenoxy) acetate Dissolve 3-isopropylphenol (10 g, 73 mmol) in N, N-dimethylformamide (100 mL) and add potassium carbonate (20 g, 147 mmol), methyl bromoacetate (Tokyo Chemical Industry Co., Ltd.
  • Example 14 1-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine-4-carboxamide 1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-4-carboxamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (32 mg, 68 mmol) of Example 1 (1 d) And 1-methylpiperidine-4-carboxylic acid (Combi-blocks catalog code: SS-5926) (0.025 g, 0.17 mmol) are dissolved in dehydrated N, N-dimethylformamide (1 mL), 4- (4,6,4 -Dimethoxy-1
  • Example 15 4-Cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] benzamide 4-cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.4 g, 1.15 mmol) of Example 1 (1d) 4-cyano-2-methyl-benzoic acid (Combi-blocks catalog code: SH-5948) (0.22 mg, 1.38 mmol) in dichloromethane (2.3 mL) solution of 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydro
  • Example 16 4-[(Dimethylamino) methyl] -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- [I] Phenyl] benzamide (16a) 4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl ] Benzamide 4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide 4-Cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl of Example 15 To
  • Example 17 4-[(1S) -1- (azetidin-1-yl) ethyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazole -3-yl] cyclohexyl] benzamide (17a) tert-Butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] carbamate tert-butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] carbamate
  • the methyl 4- (tert-butoxycarbonylamino) -N-methyl-cyclohexanecarboximidothioate (1.4 g, 4.9 mmol) of Example 7 (7b) was methyl
  • the reaction solution is quenched with aqueous sodium thiosulfate solution, extracted three times with ethyl acetate, the organic layer is dried over magnesium sulfate, filtered and concentrated, and the obtained residue is dissolved in methanol (4 mL) and hydrogenated Sodium boron (78 mg, 0.21 mmol) was added at 0 ° C. and stirred for 30 minutes. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain 91.4 mg (yield: 94%) of the title compound as a white solid.
  • Example 20 1-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] pyrazole-4-carboxamide 1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyrazole-4-carboxamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.1 g, 0.29 mmol) of Example 1 (1d) Is dissolved in dichloromethane (0.6 mL), 1-methyl-1H-pyrazole-4-carboxylic acid (Combi-blocks catalog code: HC-3334) (0.0434 g, 0.34 mmol), 1-ethyl-3- (3-) Dimethylamino
  • Example 22b 4-[(3-Fluoroazetidin-1-yl) methyl] benzoic acid 4-[(3-fluoroazetidin-1-yl) methyl] benzoic acid
  • the methyl 4-[(3-fluoroazetidin-1-yl) methyl] benzoate (0.29 g, 1.3 mmol) of Example 22 (22a) was dissolved in a mixed solvent of tetrahydrofuran (1.3 mL) and methanol (1.3 mL) A solution of sodium hydroxide (0.26 g, 6.5 mmol) in water (1.5 mL) was added, and the mixture was stirred at room temperature for 5 hours.
  • Example 23 4-[(3-hydroxyazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl] phenyl] benzamide
  • 23a 4-formyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] benzamide
  • the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the organic layer was washed with brine and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and then dried to obtain 28 mg (yield: 50%) of the title compound as a colorless solid.
  • Example 26 4-[(Dimethylamino) methyl] -N- [4- [5-[(3-fluorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide 4-[(dimethylamino) methyl] -N- [4- [5-[(3-fluorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
  • Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( Suspend 0.15 g (0.41 mmol) in acetonitrile (5 mL) and add 3-fluorophenol (Tokyo Chemical Industry Catalog No .: F0159) (0.055 g, 0.49 mmol) and cyanomethylenetributyl
  • Example 30 4-Fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine- 4-carboxamide 4-fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-4- carboxamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (50 mg, 0.14 mmol) of Example 1 (1d) And 4-fluoro-1-methyl-piperidine-4-carboxylic acid hydrochloride (ZERENEX catalog code: ZXH001982) (34 mg, 0.17 mmol) in a solution of dehydrated N, N-dimethylformamide (1
  • Example 31 4- (Azetidin-1-ylmethyl) -2-fluoro-N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3 -Pyridyl] benzamide
  • 31a tert-Butyl N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3-pyridyl] carbamate tert-butyl N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3-pyridine] carbamate
  • Example 8b tert-butyl N- [6- (methylcarbamothiol) -3-pyridyl] carbamate (1.7 g, 6.4 mmol) was dissolved in te
  • Example 13 Example 13 (13b) was added, and the mixture was stirred at 100 ° C. for 6 hours.
  • Example 32 6-[(Dimethylamino) methyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] pyridine- 3-carboxamide 6-[(dimethylamino) methyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] pyridine-3- carboxamide
  • Example 35 4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] phenyl] benzamide (35a) 3-[(3-Isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole 3-[(3-isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole Dissolve methyl 5- (4-nitrophenyl) isoxazole-3-carboxylate (CAS Registry Number: 487034-01-5, Organic Letters, 2006, 8, 713-716) (300 mg, 1.2 mmol) in ethanol, Sodium borohydride (92 mg, 2.4 mmol) was added at room temperature and stirred at 50 ° C.
  • the mixture was diluted with dichloromethane, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure is dissolved in acetonitrile, 3-isopropylphenol (0.17 mL, 1.2 mmol) and cesium carbonate (1 g, 3.1 mmol) are added, and the mixture is stirred at room temperature for 12 hours did.
  • the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure to give 530 mg (yield: quantitative) of the title compound as a yellow solid.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Communicable Diseases (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Anesthesiology (AREA)
  • Nutrition Science (AREA)

Abstract

L'objet de la présente invention est de fournir un composé ayant une action anti-inflammatoire, un sel acceptable sur le plan pharmacologique de celui-ci, etc. La solution selon l'invention porte sur un composé représenté par la formule générale (1) ou un sel acceptable sur le plan pharmacologique de celui-ci. [Les symboles dans la formule sont définis ci-dessous : A1, A2 et A3 représentent -CH=, etc. ; E représente -CH2-, etc. ; G est un hétérocycle aromatique à 5 chaînons, etc. ; X est un cycle benzène, etc. ; Y est un groupe alkyle en C1-C6, etc. ; R1 et R2 représentent un atome d'hydrogène, etc. ; R3 représente un atome d'hydrogène, etc. ; R4 représente un atome d'hydrogène, etc. ; R5a, R5b, R5c et R5d représentent un atome d'hydrogène, etc. ; n1, n2 et n3 sont 1, etc.]
PCT/JP2018/033912 2017-09-14 2018-09-13 Composé amide ayant un hétérocycle aromatique WO2019054430A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017176890 2017-09-14
JP2017-176890 2017-09-14

Publications (1)

Publication Number Publication Date
WO2019054430A1 true WO2019054430A1 (fr) 2019-03-21

Family

ID=65722793

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/033912 WO2019054430A1 (fr) 2017-09-14 2018-09-13 Composé amide ayant un hétérocycle aromatique

Country Status (1)

Country Link
WO (1) WO2019054430A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020532506A (ja) * 2017-09-01 2020-11-12 デナリ セラピューティクス インコーポレイテッドＤｅｎａｌｉ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 化合物、組成物、及び、方法
US11851440B2 (en) 2017-08-09 2023-12-26 Denali Therapeutics Inc. Modulators of eukaryotic initiation factor 2B, compositions and methods
US11958840B2 (en) 2019-02-13 2024-04-16 Denali Therapeutics Inc. Compounds, compositions and methods

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012504604A (ja) * 2008-10-01 2012-02-23 シンタ ファーマシューティカルズ コーポレーション 炎症および免疫関連使用のための化合物
WO2015002080A1 (fr) * 2013-07-02 2015-01-08 日本曹達株式会社 Dérivé aminopyridine, et fongicide agricole et horticole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012504604A (ja) * 2008-10-01 2012-02-23 シンタ ファーマシューティカルズ コーポレーション 炎症および免疫関連使用のための化合物
WO2015002080A1 (fr) * 2013-07-02 2015-01-08 日本曹達株式会社 Dérivé aminopyridine, et fongicide agricole et horticole

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISIRN 18 June 2015 (2015-06-18), Database accession no. 1783302-80-6 *
DATABASE REGISIRY 18 June 2015 (2015-06-18), Database accession no. 1783194-21-7 *
DATABASE REGISIRY 18 June 2015 (2015-06-18), Database accession no. 1783281-39-9 *
DATABASE REGISIRY 18 June 2015 (2015-06-18), Database accession no. 1783288-22-1 *
DATABASE REGISIRY 18 June 2015 (2015-06-18), Database accession no. 1783294-60-9 *
DATABASE REGISTRY 18 June 2015 (2015-06-18), Database accession no. 1783037-55-7 *
DATABASE REGISTRY 18 June 2015 (2015-06-18), Database accession no. 1783061-99-3 *
DATABASE REGISTRY 18 June 2015 (2015-06-18), Database accession no. 1783079-48-0 *
DATABASE REGISTRY 18 June 2015 (2015-06-18), Database accession no. 1783117-31-6 *
DATABASE REGISTRY 18 June 2015 (2015-06-18), Database accession no. 1783169-01-6 *
DATABASE REGISTRY 18 June 2015 (2015-06-18), Database accession no. 1783170-13- 7 *
DATABASE REGISTRY 9 August 2004 (2004-08-09), Database accession no. 724438-71-5 *
DATABASE REGISTRY 9 February 2017 (2017-02-09) *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068698-23-5 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068701-53-9 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068704-57-2 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068710-04-1 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068730-55-0 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068733-34-4 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068737-31-3 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068747-03-3 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068755-88-2 *
DATABASE REGISTRY 9 February 2017 (2017-02-09), Database accession no. 2068758-12-1 *
FRIDMAN, S. G. ET AL.: "2-Alkoxymethyl- and 2-ary loxymethy 1-5 (p-aminophenyl)-thiazoles", ZHURNAL OBSHCHEI KHIMII, vol. 25, 1955, pages 970 - 975, XP009181690 *
LOHREY, L. ET AL.: "2,4- and 2,5-Disubstituted Arylthiazoles:Rapid Synthesis by C-H Coupling and Biological Evaluation", EUR. J. ORG. CHEM., 2014, pages 3387 - 3394, XP055583490 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11851440B2 (en) 2017-08-09 2023-12-26 Denali Therapeutics Inc. Modulators of eukaryotic initiation factor 2B, compositions and methods
JP2020532506A (ja) * 2017-09-01 2020-11-12 デナリ セラピューティクス インコーポレイテッドＤｅｎａｌｉ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 化合物、組成物、及び、方法
JP7382308B2 (ja) 2017-09-01 2023-11-16 デナリ セラピューティクス インコーポレイテッド 化合物、組成物、及び、方法
US11958840B2 (en) 2019-02-13 2024-04-16 Denali Therapeutics Inc. Compounds, compositions and methods

Similar Documents

Publication Publication Date Title
JP6204975B2 (ja) Ａｂｌ１、ａｂｌ２およびｂｃｒ−ａｂｌ１の活性を阻害するためのベンズアミド誘導体
JP6078640B2 (ja) Ａｂｌ１、ａｂｌ２およびｂｃｒ−ａｂｌ１の活性を阻害するためのベンズアミド誘導体
US9604937B2 (en) Pyrimidine-2,4-diamine derivatives for treatment of cancer
JP5124471B2 (ja) 置換二環式ピリミドン誘導体
RU2642777C2 (ru) Производные 2-аминопиразина в качестве ингибиторов csf-1r киназы
JP2011525905A (ja) 神経変性疾患治療用のｇｓｋ３−ベータ阻害剤としての４−（ピリジン−４−イル）−１ｈ−（１，３，５）トリアジン−２−オン誘導体
TW201249823A (en) Tetrasubstituted cyclohexyl compounds as kinase inhibitors
TW200825060A (en) Chemical compounds
US11834427B2 (en) Griseofulvin compound
JP2014524886A (ja) カリウムチャネル遮断剤としてのアミン誘導体
WO2019054430A1 (fr) Composé amide ayant un hétérocycle aromatique
US20220340564A1 (en) Antibacterial compounds
US20230331700A1 (en) Compound having cyclic structure
US10494363B2 (en) Non-steroidal glucocorticoid receptor modulators for local drug delivery
RU2795119C2 (ru) Соединение, обладающее циклической структурой
WO2024024962A1 (fr) Dérivé à noyau hétérocyclique saturé contenant de l'azote
US20230002346A1 (en) New compounds and methods
WO2023220225A1 (fr) Inhibiteurs du virus respiratoire syncytial humain et du métapneumovirus humain
CA3196333A1 (fr) Derives d'amino-quinazoline utilises en tant qu'inhibiteurs de p2x3

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 18855634

Country of ref document: EP

Kind code of ref document: A1