WO2010137350A1 - Agent de traitement ou de prévention de maladies associées à l'activité de facteurs neurotrophiques - Google Patents

Agent de traitement ou de prévention de maladies associées à l'activité de facteurs neurotrophiques Download PDF

Info

Publication number
WO2010137350A1
WO2010137350A1 PCT/JP2010/003623 JP2010003623W WO2010137350A1 WO 2010137350 A1 WO2010137350 A1 WO 2010137350A1 JP 2010003623 W JP2010003623 W JP 2010003623W WO 2010137350 A1 WO2010137350 A1 WO 2010137350A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
ring
atom
membered
aromatic
Prior art date
Application number
PCT/JP2010/003623
Other languages
English (en)
Japanese (ja)
Inventor
淳一 石川
幸一 斉藤
師久 大江
健太郎 小林
Original Assignee
住友化学株式会社
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 住友化学株式会社 filed Critical 住友化学株式会社
Publication of WO2010137350A1 publication Critical patent/WO2010137350A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P1/10—Laxatives
    • 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
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/22—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
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • 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
    • C07D417/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a therapeutic or prophylactic agent for diseases involving neurotrophic factor activity.
  • Neurotrophic factors such as BDNF and NGF are proteins that play an important role in central and peripheral nervous system cell differentiation, functional maintenance, synapse formation, regeneration and repair upon injury, and neurodegenerative diseases, diabetic Effective for the treatment of neuropathy, amyotrophic lateral sclerosis, multiple sclerosis, cerebral ischemic disease, Alzheimer's disease, Parkinson's disease, Huntington's chorea, depression, peripheral neuropathy caused by cancer chemotherapy, etc. (Non-Patent Documents 2, 3, 4, and 5).
  • a neurotrophic factor is a high molecular weight protein having a molecular weight of 10,000 or more, and it is known that when such a high molecular weight protein is used as a therapeutic agent, there are restrictions on the administration method and safety problems (non-patented). From the references 6 and 7), there is an urgent need to provide a low molecular weight compound that enhances the action of a neurotrophic factor with few side effects.
  • the expression of certain transcriptional regulatory factors is controlled by neurotrophic factors (see Non-Patent Document 1), and one of the transcriptional regulatory factors whose expression is controlled by neurotrophic factors. NXF is known (see Patent Document 1).
  • NXF is important for neuroprotective action. It is known to have a role (see Patent Document 2).
  • Patent Documents 3 to 6 disclose thiadiazole compounds, respectively, but there is no suggestion that these compounds have an ability to induce NXF expression.
  • JP 2007-282502 A JP 2007-282501 A European Patent No. 1191024 Japanese Patent Laid-Open No. 56-115780 German Patent Publication No. 3702756 Until the prevention of the publication of Russian Patent No. 2281946 ", 2006, pages 649-654
  • R 1 and R 2 are each independently a hydrogen atom, Represents an optionally substituted alkyl group, or an optionally substituted cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, it may form a non-aromatic nitrogen-containing heterocycle which may be substituted, and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • a pharmaceutically acceptable salt thereof, or a solvate thereof in this specification, sometimes referred to as compound (I).
  • compound (I) has been found to enhance the activity of neurotrophic factor and protect cells against nerve cells, leading to the present invention.
  • R 1 and R 2 are each independently (1) hydrogen atom, (2) an alkyl group optionally substituted with one or more substituents selected from an alkoxy group and a non-aromatic heterocyclic group, or (3) represents an alicyclic hydrocarbon group which may be substituted with one or more substituents selected from an alkyl group, an alkoxy group, and a non-aromatic heterocyclic group (provided that R 1 is a hydrogen atom) In some cases, R 2 is not a hydrogen atom.) Or R 1 and R 2 are Together with the nitrogen atom to which they are attached, forms a non-aromatic nitrogen-containing heterocycle; Ar is formula (Where Ring A represents an aromatic 6-membered ring optionally having one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, and a carboxy group in addition to R 3 ;
  • a 5- to 6-membered aromatic heterocyclic ring which may have one or more substituents selected from an atom, a cyano group, an amino group, a sulfamoyl group, a carboxy group, an alkyl group, and an alkoxy group.
  • ring C may have one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, a carboxy group, an alkyl group, and an alkoxy group.
  • the ring D may have one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, a carboxy group, an alkyl group, and an alkoxy group. It is a 6-membered alicyclic hydrocarbon ring or a 6-membered heterocyclic ring.
  • Ring E represents an aromatic 5-membered ring optionally having one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, and a carboxy group
  • Ring F is a 5- to 6-membered alicyclic hydrocarbon ring which may have one or more substituents each selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, and a carboxy group, or 5 Represents a 6-membered heterocycle
  • R 3 is (1) an alkynyl group optionally substituted with one or more substituents selected from a halogen atom, a cyano group, a hydroxy group, an amino group, a sulfamoyl group, and a carboxyl group, (2) an alkenyl group that may be substituted with one or more substituents selected from a halogen atom, a cyano group, a hydroxy
  • —S (O) q — or —S (O) q —NR y — is represented.
  • q represents an integer of 0 to 2
  • R y represents a hydrogen atom, an alkyl group, or an alicyclic hydrocarbon group.
  • R 3a is not a non-aromatic heterocyclic group or a trifluoromethyl group.
  • X 1 represents a carbon atom or a nitrogen atom
  • X 2 represents an oxygen atom or a sulfur atom
  • X 3 represents an oxygen atom, a nitrogen atom, or a sulfur atom
  • X 4 represents a nitrogen atom.
  • R 1 and R 2 are each independently (1) hydrogen atom, (2) a C 1-6 alkyl group, or (3) a C 3-6 cycloalkyl group (provided that when R 1 is a hydrogen atom, R 2 is not a hydrogen atom), or R 1 and R 2 are The compound according to [1] above, which forms a 3- to 8-membered non-aromatic nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded.
  • Ar is formula (The symbols in the formula are as defined above.)
  • Ar is the formula (Where Ring A is an aromatic 6-membered ring having no substituent other than R 3 , R 3 is (1) a C 3-6 alkynyl group, (2) a C 3-6 alkenyl group, (3) a carbamoyl group, (4) mono-C 1-6 alkyl-carbamoyl group, (5) a di-C 1-6 alkyl-carbamoyl group, (6) a carboxy group, (7) C 1-6 alkoxy-carbonyl group, or (8)
  • q represents an integer of 0 to 2.
  • a group represented by X 1 is a carbon atom or a nitrogen atom, and X 2 is an oxygen atom or a sulfur atom.
  • Ar is (The symbols in the formula are as defined above.)
  • the compound according to [1], which is a group represented by the formula: [6] Ar is formula (Where (1) Ring C is a benzene ring and Ring D is a 5- to 6-membered aromatic heterocyclic ring, or (2) Ring C is a 6-membered heterocyclic ring, and Ring D is A benzene ring.
  • R 1 and R 2 are each independently (1) hydrogen atom, (2) a C 1-6 alkyl group, or (3) a C 3-6 cycloalkyl group (provided that when R 1 is a hydrogen atom, R 2 is not a hydrogen atom), or R 1 and R 2 are Together with the nitrogen atom to which they are attached, a 3-8 membered non-aromatic nitrogen-containing heterocycle is formed,
  • Ar is the formula (Where Ring A is an aromatic 6-membered ring having no substituent other than R 3 , R 3 is (1) a C 3-6 alkynyl group, (2) a C 3-6 alkenyl group, (3) a carbamoyl group, (4) mono-C 1-6 alkyl-carbamoyl group, (5) a di-C 1-6 alkyl-carb
  • q represents an integer of 0 to 2.
  • X 1 is a carbon atom or a nitrogen atom.
  • the compound according to [1], which is a group represented by the formula: [8] The pharmaceutical composition containing the compound as described in said [1].
  • composition which is an agent for treating or preventing a disease involving the activity of a neurotrophic factor, or an accelerator for a physical therapy effect.
  • the treatment or prevention agent for diseases involving the activity of neurotrophic factor, or the accelerator for physiotherapy effect is the treatment or prevention agent for cerebral ischemic disease or diabetic neuropathy according to [9].
  • R 1 and R 2 are each independently a hydrogen atom, Represents an optionally substituted alkyl group, or an optionally substituted cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, forms an optionally substituted non-aromatic nitrogen-containing heterocycle, and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient [12] The pharmaceutical composition according to [11] above, which is a therapeutic or preventive agent for cerebral ischemic disease or diabetic neuropathy.
  • R 1 and R 2 are each independently a hydrogen atom, Represents an optionally substituted alkyl group, or an optionally substituted cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, forms an optionally substituted non-aromatic nitrogen-containing heterocycle, and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • a method for treating or preventing a disease involving the activity of a neurotrophic factor which comprises administering an effective amount of the compound represented by the above, a pharmaceutically acceptable salt thereof or a solvate thereof to a mammal: Or a method of promoting the effect of physical therapy.
  • R 1 and R 2 are each independently a hydrogen atom, Represents an optionally substituted alkyl group, or an optionally substituted cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, forms an optionally substituted non-aromatic nitrogen-containing heterocycle, and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • a pharmaceutically acceptable salt or solvate thereof is a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides the following [1 ′] to [7 ′] and the like.
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) a C 1-6 alkyl group which may be substituted with one substituent selected from a halogen atom, a C 1-6 alkoxy group, and a 3- to 6-membered non-aromatic cyclic group, or (3 ) An optionally substituted 3- to 6-membered cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, may form an optionally substituted 3-6 membered non-aromatic nitrogen-containing heterocycle; Ar is May be condensed with an optionally substituted monocyclic or bicyclic ring, and a halogen atom, -NO 2 , -CN, and -X 3a -X 3b -R 3a A monocyclic aromatic group optionally substituted with one or more substituents selected from: X 3a is a bond or an alkylene chain; X 3b is a bond, —O—, —NR 3a —,
  • Ar is (1) A substituted phenyl group, or (2) an optionally substituted monocyclic aromatic group fused with an optionally substituted monocyclic or bicyclic ring.
  • Ar is not a phenyl group substituted with 1 to 3 halogen atoms.
  • Ar is not a phenyl group substituted with 1 to 3 hydroxy groups.
  • Ar is the formula (Wherein Alk represents a C 1-5 alkylene chain, and R x1 represents a hydrogen atom or a C 1-5 alkyl group). In addition, however, Ar is the formula (Wherein R x2 represents a C 1-4 alkyl group).
  • R 1 is An alkyl group optionally substituted with one or more substituents selected from an alkoxy group and a non-aromatic heterocyclic group, or one selected from an alkyl group, an alkoxy group, and a non-aromatic heterocyclic group Represents a non-aromatic cyclic group which may be substituted with the above substituents; and Ar is (1) Formula (Where R 3 is Nitro group, A hydroxy group, A cyano group, An optionally substituted alkenyl group, An optionally substituted alkynyl group, R b —CO—O—, R b —CO—NR b —, R b —O—, R b ′ —O—CO—L—, R b -S-, R b —SO—, R b —SO 2 —, R b ′ —NR b —L—, R b ′ —NR b —CO—L—,
  • a group represented by (2) an optionally substituted monocyclic heteroaryl group, or (3) an optionally substituted monocyclic fused to an optionally substituted monocyclic or bicyclic ring Represents an aromatic group.
  • R 1 may be substituted with (a) an alkyl group having 3 or more carbon atoms, (b) an alkyl group substituted with one non-aromatic heterocyclic group, or (c) one or more alkyl groups. If it is a good non-aromatic heterocyclic group, Ar is not (i) a pyrrolyl group substituted with two methyl groups and one further substituent, or (ii) an optionally substituted thienyl group.
  • R 1 may be substituted with (a) an alkyl group having 3 or more carbon atoms, (b) an alkyl group substituted with one non-aromatic heterocyclic group, or (c) one or more alkyl groups. If it is a good non-aromatic heterocyclic group, Ar is is not. Furthermore, Ar is a formula (Wherein R x2 represents a C 1-4 alkyl group).
  • R 1 is (1) Alkyl group substituted with one or more substituents selected from halogen atoms and cycloalkyl groups, or (2) Substitution with one or more substituents selected from halogen atoms and cycloalkyl groups Represents a non-aromatic cyclic group; and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • a pharmaceutically acceptable salt or solvate thereof is a pharmaceutically acceptable salt or solvate thereof.
  • R 1 and R 2 are each independently Represents an optionally substituted alkyl group, or an optionally substituted non-aromatic cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, they may form an optionally substituted non-aromatic nitrogen-containing heterocycle; and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • Ar is the formula (Wherein R x2 represents a C 1-4 alkyl group), or (Wherein R x3 represents a hydrogen atom, a halogen atom, —NO 2 , or —OH).
  • R 1 and R 2 are each independently an optionally substituted alkyl group, Ar is is not.
  • the graph which shows infarct volume (Test Example 2).
  • halogen (atom) examples include fluorine, chlorine, bromine, and iodine.
  • Examples of the “acyclic hydrocarbon group” include an alkyl group, an alkenyl group, an alkynyl group, and an alkenylene group.
  • Examples of the “alkyl (group)” include C 1-6 alkyl (group).
  • Examples of “C 1-6 alkyl (group)” include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, and hexyl. In this specification, methyl may be expressed as Me and ethyl may be expressed as Et in accordance with common practice.
  • Examples of the “alkenyl (group)” include C 2-6 alkenyl (group).
  • Examples of “C 2-6 alkenyl (group)” include vinyl, 2-propenyl, 3-methyl-2-butenyl, and 1,3-butadienyl.
  • Examples of “alkynyl (group)” include C 2-6 alkynyl (group).
  • Examples of “C 2-6 alkynyl (group)” include ethynyl, 2-propynyl, and 2-penten-4-ynyl.
  • Examples of the “alkenylene (group)” include C 2-6 alkenylene (group).
  • Examples of “C 2-6 alkenylene (group)” include vinylene, propenylene, and 1,3-butadienylene.
  • Examples of the “cyclic group” include an aromatic cyclic group and a non-aromatic cyclic group.
  • Examples of the “aromatic cyclic group” include aryl (group) and aromatic heterocyclic group (heteroaryl (group)).
  • Examples of the “non-aromatic cyclic group” include alicyclic hydrocarbon groups and non-aromatic heterocyclic groups.
  • aryl (group) examples include C 6-14 aryl (group) (eg, phenyl, naphthyl, anthryl).
  • heteroaryl (group) examples include a 5- to 6-membered heteroaryl (group).
  • the “5- to 6-membered heteroaryl (group)” includes, for example, 1 to 3 (preferably 1 to 2) heterocycles selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms.
  • 5- to 6-membered heteroaryl (group) having an atom examples include 1 to 3 (preferably 1 to 2) heterocycles selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms.
  • furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl) , 3-pyrrolyl
  • imidazolyl eg, 1-imidazoly
  • nitrogen-containing heteroaryl (group) for example, in addition to one nitrogen atom as a ring-constituting atom, one or two heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom are included.
  • 5- to 6-membered nitrogen-containing heteroaryl group (eg, pyrrole, imidazolyl, pyrazolyl, triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, furazanyl, thiadiazyl (eg, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl) , Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl).
  • group eg, pyrrole, imidazolyl, pyrazolyl, triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), t
  • Examples of the “alicyclic hydrocarbon group” include “cycloalkyl group”, “cycloalkenyl group”, and “cycloalkadienyl group”.
  • Examples of the “cycloalkyl (group)” include C 3-6 cycloalkyl (group).
  • Examples of “C 3-6 cycloalkyl (group)” include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • Cycloalkenyl (group)” includes C 3-6 cycloalkenyl (group).
  • Examples of “C 3-6 cycloalkenyl (group)” include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • Examples of the “cycloalkadienyl group” include a C 4-6 cycloalkadienyl group.
  • Examples of the “C 4-6 cycloalkadienyl group” include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclohexadien-1-yl. Can be mentioned.
  • Non-aromatic heterocyclic group includes 3- to 8-membered non-aromatic heterocyclic group.
  • Examples of the “3- to 8-membered non-aromatic heterocyclic group” include pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), Morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimine-1-yl), oxazolidinyl ( Examples, oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), imidazolidinyl (e
  • heterocyclic group examples include a non-aromatic heterocyclic group and a heteroaryl (group).
  • non-aromatic heterocyclic group examples include those exemplified above.
  • heteroaryl (group) examples include those exemplified above.
  • 5- to 6-membered heterocyclic group examples include those having 5 to 6 members.
  • alkoxy (group) examples include C 1-6 alkoxy (group).
  • C 1-6 alkoxy (group) examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, and n-hexyloxy groups C 1-6 alkoxy (group) such as
  • C 1-6 alkylcarbamoyl (group) examples include, for example, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, and hexyl Carbamoyl is mentioned.
  • Examples of “mono- or di-C 1-6 alkyl-ureido (group)” include mono- or di-methylureido, mono- or di-ethylureido, mono- or dipropylureido, mono- or di- -Butylureido, mono- or di-pentylureido, and mono- or di-hexylureido.
  • alkyl (group) (including those in a substituent), the “alkenyl (group)”, the “alkynyl (group)”, and the “alkoxy (group)” are each linear or branched. It may be branched.
  • Alkylene (chain) includes, for example, linear C 1-3 alkylene chains such as methylene, ethylene, and trimethylene.
  • Carbocycle examples include C 3-10 carbocycle.
  • the “carbocycle” may be an aromatic carbocycle or a non-aromatic carbocycle.
  • Examples of the “aromatic carbocycle” include benzene and naphthalene.
  • non-aromatic carbocycle for example, C 3-10 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane), C 3-10 cycloalkenes (eg, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene), and C 3-10 cycloalkadienes (eg, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptane) Diene, cyclooctadiene, cyclononadiene, cyclodecadiene).
  • C 3-10 cycloalkane eg, cycloprop
  • heterocycle is, for example, a 5- to 6-membered member having 1 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms. Heterocycles are mentioned.
  • the “heterocycle” may be an aromatic heterocycle or a non-aromatic heterocycle.
  • aromatic heterocycle for example, 5 to 6 having 1 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms.
  • aromatic heterocycles eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole (eg, 1,2,3-oxadiazole, 1,2,4- Oxadiazole, 1,3,4-oxadiazole), furazane, thiadiazole (eg, 1,2,3-thiadiazole, 1,2,4-thiadiazole.
  • monocyclic aromatic heterocycle monocyclic ones, specifically, 1 to 3 selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms
  • aromatic heterocycle having 1 to 2 heteroatoms (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole (eg, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), furazane, thiadiazole (eg, 1,2,3-thiadiazole, 1,2,4) -Thiadiazole 1.3.4-thiadiazole), triazole (eg, 1,2,3-triazole, 1,2,4-triazole), tetrazole, pyridine, pyridazine, Rimijin,
  • non-aromatic heterocycle examples include 3 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms.
  • 8-membered (preferably 4-6 membered) non-aromatic heterocycles eg oxirane, azetidine, oxetane, thietane, pyrrolidine, pyrazolidine, imidazolidine, isoxazolidine, oxazolidine, isothiazolidine, thiazolidine, tetrahydrofuran, thiolane, dioxolane (eg 1,3-dioxolane), tetrahydropyran, dihydropyran, pyran, hexahydropyridine (piperidine), tetrahydropyridine, dihydropyridine, thiane, morpholine, thiomorpholine, piperazine, hexa
  • non-aromatic nitrogen-containing heterocycle includes, for example, at least one nitrogen atom in addition to a carbon atom as a ring-constituting atom, and one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom 5- to 7-membered non-aromatic nitrogen-containing heterocycles (eg, pyrrolidine, oxopyrrolidine, dioxopyrrolidine, piperidine, morpholine, thiomorpholine, 1,1-dioxidethiomorpholine, piperazine) which may be contained It is done.
  • pyrrolidine oxopyrrolidine, dioxopyrrolidine, piperidine, morpholine, thiomorpholine, 1,1-dioxidethiomorpholine, piperazine
  • R 1 and R 2 are each independently a hydrogen atom, Represents an optionally substituted alkyl group, or an optionally substituted cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are bonded, an optionally substituted non-aromatic nitrogen-containing heterocycle may be formed.
  • alkyl group of the “optionally substituted alkyl group” represented by R 1 and R 2 examples include those exemplified above.
  • the “alkyl group” may be substituted with one or more (preferably 1 to 3) substituents.
  • substituents for example, (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a 3- to 6-membered non-aromatic cyclic group which may be substituted with one or more (preferably 1 to 3) halogen atoms, (5) R a -CO-, (6) R a —CO—O—, (7) R a —CO—NR a —, (8) R a -O-, (9) R a —O—CO—, (10) R a —O—CO—NR a —, (11) R a -S-, (12) R a -SO-, (13) R a —SO 2 —, (14) R a -NR a- , (15) R a —NR a —CO—, (16) R a —NR a —CO—NR a —, (17) R
  • Examples of the “halogen atom” include those exemplified above.
  • Examples of the “C 1-6 alkyl group” include those exemplified above.
  • Examples of the “3- to 6-membered non-aromatic cyclic group” include 3- to 6-membered “non-aromatic cyclic groups” exemplified above.
  • Examples of the “cyclic group” of the “optionally substituted cyclic group” represented by R 1 and R 2 include those exemplified above. Of these, those having 3 to 6 members are preferred.
  • the “cyclic group” may be substituted with one or more (preferably 1 to 3) substituents.
  • substituent for example, (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) halogen atoms, (5) a 3- to 6-membered non-aromatic cyclic group which may be substituted with one or more (preferably 1 to 3) halogen atoms, (6) R a -CO-, (7) R a —CO—O—, (8) R a —CO—NR a —, (9) R a -O-, (10) R a —O—CO—, (11) R a —O—CO—NR a —, (12) R a -S-, (13) R a -SO-, (14) R a —SO 2 —, (15) R a -NR a- , (16) R a —NR a —CO—, (17) R a —NR a —CO—NR
  • Examples of the “halogen atom” include those exemplified above.
  • Examples of the “C 1-6 alkyl group” include those exemplified above.
  • Examples of the “3- to 6-membered non-aromatic cyclic group” include 3- to 6-membered “non-aromatic cyclic groups” exemplified above.
  • R 1 and R 2 are Examples of the “non-aromatic nitrogen-containing heterocycle” of the “optionally substituted non-aromatic nitrogen-containing heterocycle” which may be formed together with the nitrogen atom to which they are bonded are exemplified above. Things. Of these, those having 3 to 7 members are preferred, and those having 3 to 6 members are more preferred.
  • the “non-aromatic nitrogen-containing heterocycle” may be substituted with one or more (preferably 1 to 3) substituents.
  • substituent for example, (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) halogen atoms, (5) a 3- to 6-membered non-aromatic cyclic group which may be substituted with one or more (preferably 1 to 3) halogen atoms, (6) R a -CO-, (7) R a —CO—O—, (8) R a —CO—NR a —, (9) R a -O-, (10) R a —O—CO—, (11) R a —O—CO—NR a —, (12) R a -S-, (13) R a -SO-, (14) R a —SO 2 —, (15) R a -NR a- , (16) R a —NR a —CO—, (17) R a —NR a —CO—NR
  • Examples of the “halogen atom” include those exemplified above.
  • Examples of the “C 1-6 alkyl group” include those exemplified above.
  • Examples of the “3- to 6-membered non-aromatic cyclic group” include 3- to 6-membered “non-aromatic cyclic groups” exemplified above.
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) a C 1-6 alkyl group which may be substituted with one substituent selected from a halogen atom, a C 1-6 alkoxy group, and a 3- to 6-membered non-aromatic cyclic group, or (3 ) An optionally substituted 3- to 6-membered cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, an optionally substituted 3-6 membered non-aromatic nitrogen-containing heterocycle is formed.
  • the “C 1-6 alkoxy group” is included in the R a —O—.
  • Ar represents a monocyclic aromatic group which may be substituted and may be condensed with an optionally substituted monocyclic or bicyclic ring.
  • the “aromatic group” include a phenyl group and a monocyclic heteroaryl group.
  • Examples of the “monocyclic heteroaryl group” include monocyclic groups among the “heteroaryl groups” exemplified above. Of these, 5- to 6-membered heteroaryl is preferable.
  • the “monocyclic ring” in the “monocyclic or bicyclic ring which may be substituted”, which may be condensed with the “monocyclic aromatic group”, is exemplified by “ “Carbocycle” and “heterocycle” exemplified above are mentioned.
  • the “bicyclic ring” in the “optionally substituted monocyclic or bicyclic ring” is selected from the “carbocycle” exemplified above and the “heterocycle” exemplified above. And a ring in which two rings are fused.
  • the “two rings” may be the same or different.
  • the condensation position of the “monocyclic or bicyclic ring” is preferably the c-position (or d-position) shown below.
  • Each of the “monocyclic aromatic group” and the “monocyclic or bicyclic ring” may be substituted with one or more (preferably 1 to 3) substituents.
  • the substitution position of the substituent is preferably p-position, m-position, or both p-position and m-position, and more preferably p-position.
  • substituent for example, (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and a phenyl group; (5) an optionally substituted alkenyl group (preferably (a) a phenyl group, and (b) a C 1-6 optionally substituted C 1 optionally substituted C 1 cycloalkyl group.
  • -6 alkenyl group (6) an alkynyl group which may be substituted (preferably a C 1-6 alkynyl group which may be substituted with one trimethylsilyl group), (7) a C 3-6 cycloalkyl group, (8) (a) a halogen atom, (b) a C 1-6 alkoxy group, phenyl optionally substituted with one or more (preferably 1 to 3) substituents selected from (c) a C 1-6 alkylcarbamoyl group and (d) a C 1-6 alkyl-ureido group Group, (9) (a) a halogen atom, (b) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) halogen atoms, and (c) a C 1-6 alkoxy group, A 5- to 6-membered heterocyclic group which may be substituted with one or more (preferably 1 to 3) substituents selected from: and may be condensed with a benz
  • R 3b and R 3d each independently represent an alkylene group
  • R 3c is —O—, —NR y —, —S (O) q —, —CO—O—, —O—CO—, —CO—NR y —, —NR y —CO—, —NR y. It represents —CO—NR y ′ —, —NR y —S (O) q —, or —S (O) q —NR y —.
  • R y and R y ′ each independently represent a hydrogen atom, an optionally substituted alicyclic hydrocarbon group, or an optionally substituted non-substituted group. It represents an aromatic heterocyclic group, an optionally substituted aromatic heterocyclic group, an optionally substituted phenyl group, or an optionally substituted alkyl group. ) The group represented by these is mentioned.
  • R 3a- (R 3b ) 1- (R 3c ) m- (R 3d ) n- examples include, for example, (a) R b -CO-L- (b) R b —CO—OL— (c) R b —CO—NR b —L— (d) R b —OL— (e) R b —O—CO—L— (f) R b —O—CO—NR b —L— (g) R b -SL- (h) R b -SO-L- (i) R b —SO 2 —L— (j) R b —SO 2 —NR b —L—, (k) R b —NR b —L— (l) R b —NR b —CO—L— (m) R b —NR b —CO—NR b —L— (n) R b —NR b —SL— (o) R
  • Examples of the “halogen atom” include those exemplified above.
  • Examples of the “C 1-6 alkyl group” include those exemplified above.
  • Examples of the “alkenyl group” include those exemplified above.
  • Examples of the “alkynyl group” include those exemplified above.
  • Examples of the “C 3-6 cycloalkyl group” include those exemplified above.
  • Examples of the “C 1-6 alkoxy group” include those exemplified above.
  • Examples of the “C 1-6 alkylcarbamoyl group” include those exemplified above.
  • Examples of the “C 1-6 alkyl-ureido group” include those exemplified above.
  • Examples of the “5- to 6-membered heteroaryl group” include 5- to 6-membered “heteroaryl groups” exemplified above.
  • Ar is preferably May be condensed with an optionally substituted monocyclic or bicyclic ring, and a halogen atom, -NO 2 (nitro group), -CN (cyano group), and -X 3a -X 3b -R 3a
  • a monocyclic aromatic group which may be substituted with one or more substituents selected from:
  • X 3a is a bond or an alkylene chain
  • X 3b is a bond, —O—, —NR 3a —, —S (O) q3 —, —CO —O—, —O— CO— , —CO —NR 3a —, —NR 3a —CO—, —NR 3a —S (O) q3 —, or —S (O) q3 —NR 3a —
  • R 3a is the same or different at each occurrence and is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted monocyclic heterocycl
  • Examples of the “alkylene chain” include those exemplified above.
  • Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” include “acyclic hydrocarbon group”, “alicyclic hydrocarbon group”, and “aryl (group)”. .
  • Examples of the “acyclic hydrocarbon group” include those exemplified above.
  • Examples of the “alicyclic hydrocarbon group” include those exemplified above.
  • Examples of the “aryl (group)” include those exemplified above.
  • Examples of the “monocyclic heterocyclic group” include monocyclic groups among the “heterocyclic groups” exemplified above. Of these, a 5- to 6-membered heterocyclic group is preferable.
  • Ar is more preferably, for example, (I) (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and a phenyl group; (Five) (a) a phenyl group, and (b) a C 1-6 alkenyl group optionally substituted with one substituent selected from C 3-6 cycloalkyl groups, (6) a C 1-6 alkynyl group optionally substituted by one trimethylsilyl group, (7) a C 3-6 cycloalkyl group, (8) (a) a halogen atom, (b) a C 1-6 alkoxy group, and (c) a phenyl group optionally substituted with one or more (preferably 1 to 3) substituents selected from a C 1-6 alkylcarbamoyl group, (9) (a) a halogen
  • a 5- to 6-membered heteroaryl group for example, pyridyl (eg, 2-pyridyl, etc.), which may be substituted with one or more (preferably 1 to 3, more preferably 1) substituents selected from 3-pyridyl, 4-pyridyl), pyridazinyl (eg 2-pyridazinyl), pyrrolyl (eg 2-pyrrolyl, 3-pyrrolyl), thienyl (eg 2-thienyl, 3-thienyl), furyl (eg 2- Furyl), or oxazolyl (eg, 1,3-oxazolyl)); and (III) (1) a C 1-6 alkyl group (preferably methyl) optionally substituted with one or more (preferably 1 to 3) halogen atoms, (2) an alkoxy group (preferably methoxy), (3) an oxo group, and (4) R b —SO 2 —, (Where R b represents a C 1-6 alkyl group which may be
  • Ar is more preferably, for example, (I) (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and a phenyl group; (Five) (a) a phenyl group, and (b) a C 1-6 alkenyl group optionally substituted with one substituent selected from C 3-6 cycloalkyl groups, (6) C 3-6 cycloalkyl group, (7) (a) a halogen atom, and (b) a phenyl group optionally substituted with one or more (preferably 1 to 3) substituents selected from a C 1-6 alkylcarbamoyl group, (8) (a) a halogen atom, (b) a C 1-6 alkyl group (preferably methyl) optionally substituted with one or more (preferably 1 to 3) halogen atoms, and
  • Compound (I) is more preferably one in which two or more selected from the above-mentioned preferred partial structures, more preferred partial structures, and further preferred partial structures are used in combination.
  • Compound A is a novel compound.
  • Ring C is a benzene ring optionally having one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, a carboxy group, an alkyl group, and an alkoxy group.
  • Ring D may have one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, and a carboxy group, an alkyl group, and an alkoxy group.
  • An aromatic heterocycle; and ring C is selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, a carboxy group, an alkyl group, and an alkoxy group.
  • the ring D is a halogen atom, a cyano group, an amino group, a sulfamoyl group, a carboxy group, an alkyl group, and an alkoxy group.
  • a 5- to 6-membered alicyclic hydrocarbon ring which may have one or more substituents selected from the group, or a 6-membered heterocyclic ring).
  • Ring E represents an aromatic 5-membered ring optionally having one or more substituents selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, and a carboxy group
  • Ring F is a 5- to 6-membered alicyclic hydrocarbon ring which may have one or more substituents each selected from a halogen atom, a cyano group, an amino group, a sulfamoyl group, and a carboxy group, or 5 Represents a 6-membered heterocycle
  • R 3 is (1) an alkynyl group optionally substituted with one or more substituents selected from a halogen atom, a cyano group, a hydroxy group, an amino group, a sulfamoyl group, and a carboxyl group, (2) an alkenyl group that may be substituted with one or more substituents selected from a halogen atom, a cyano group, a hydroxy
  • —S (O) q — or —S (O) q —NR y — represents; q represents an integer of 0 to 2, and R y represents a hydrogen atom, an alkyl group, or an alicyclic hydrocarbon group. However, when l and n are both 0, R 3a is not a non-aromatic heterocyclic group or a trifluoromethyl group.
  • X 1 represents a carbon atom (C) or a nitrogen atom (N)
  • X 2 represents an oxygen atom (O) or a sulfur atom (S)
  • X 3 represents an oxygen atom (O), a nitrogen atom (N), or a sulfur atom (S)
  • X 4 represents a nitrogen atom (N).
  • X 1 represents a carbon atom (C) or a nitrogen atom (N)
  • X 2 represents an oxygen atom (O) or a sulfur atom (S)
  • X 3 represents an oxygen atom (O), a nitrogen atom (N), or a sulfur atom (S)
  • X 4 represents a nitrogen atom (N).
  • R 1 and R 2 are preferably each independently (1) hydrogen atom, (2) a C 1-6 alkyl group, or (3) a C 3-6 cycloalkyl group (provided that when R 1 is a hydrogen atom, R 2 is not a hydrogen atom), or R 1 and R 2 are Together with the nitrogen atom to which they are bonded, a 3- to 8-membered non-aromatic nitrogen-containing heterocycle is formed.
  • Ar is preferably of the formula (Where Ring A is an aromatic 6-membered ring having no substituent other than R 3 , R 3 is (1) a C 3-6 alkynyl group, (2) a C 3-6 alkenyl group, (3) a carbamoyl group, (4) mono-C 1-6 alkyl-carbamoyl group, (5) a di-C 1-6 alkyl-carbamoyl group, (6) a carboxy group, (7) C 1-6 alkoxy-carbonyl group, or (8) Formula R 3a- (R 3b ) l- (R 3c ) m- (Where l and m are each independently 0 or 1, R 3a is (a) a C 3-6 cycloalkyl group, (b) a 5-6 membered non-aromatic heterocyclic group, (c) a 5- to 6-membered aromatic heterocyclic group, (d) a phenyl group substituted with a halogen atom, or (e
  • Ar is also preferably formula (Where (1) Ring C is a benzene ring and Ring D is a 5- to 6-membered aromatic heterocyclic ring, or (2) Ring C is a 6-membered heterocyclic ring, and Ring D is A benzene ring. ) Or a group represented by (Where Ring F is a benzene ring, and other symbols are as defined above. ) It is group represented by these.
  • Ar is more preferably of the formula (Where Ring C is a benzene ring, Ring D is a 5- to 6-membered aromatic heterocyclic ring) It is group represented by these.
  • R 1 and R 2 are each independently (1) hydrogen atom, (2) a C 1-6 alkyl group, or (3) a C 3-6 cycloalkyl group (provided that when R 1 is a hydrogen atom, R 2 is not a hydrogen atom), or R 1 and R 2 are Together with the nitrogen atom to which they are attached, a 3-8 membered non-aromatic nitrogen-containing heterocycle is formed,
  • Ar is the formula (Where Ring A is an aromatic 6-membered ring having no substituent other than R 3 , R 3 is (1) a C 3-6 alkynyl group, (2) a C 3-6 alkenyl group, (3) a carbamoyl group, (4) mono-C 1-6 alkyl-carbamoyl group, (5) a di-C 1-6 alkyl-carbamoyl group, (6) a carboxy group, (7) C 1-6 alkoxy-carbonyl group, or (8) Formula R 3a- (R 3b ) l- (
  • a group represented by X 1 is a carbon atom or a nitrogen atom.
  • another embodiment is preferably the following compounds (1), (2-1), (2-2) and (3). These are novel compounds. Moreover, the range of these compounds overlaps with the range of the above-mentioned compound (A).
  • Ar is (1) A substituted phenyl group, or (2) an optionally substituted monocyclic aromatic group fused with an optionally substituted monocyclic or bicyclic ring.
  • Ar is not a phenyl group substituted with 1 to 3 halogen atoms.
  • Ar is not a phenyl group substituted with 1 to 3 hydroxy groups.
  • Ar is the formula (Wherein Alk represents a C 1-5 alkylene chain, and R x1 represents a hydrogen atom or a C 1-5 alkyl group).
  • Ar is the formula (Wherein R x2 represents a C 1-4 alkyl group).
  • R 1 is An alkyl group optionally substituted with one or more substituents selected from an alkoxy group and a non-aromatic heterocyclic group, or one selected from an alkyl group, an alkoxy group, and a non-aromatic heterocyclic group Represents a non-aromatic cyclic group which may be substituted with the above substituents; and Ar is (1) Formula (Where R 3 is Nitro group, A hydroxy group, A cyano group, An optionally substituted alkenyl group, An optionally substituted alkynyl group, R b —CO—O—, R b —CO—NR b —, R b —O—, R b ′ —O—CO—L—, R b -S-, R b —SO—, R b -SO2-, R b ′ —NR b —L—, R b ′ —NR b —CO—L—, R b
  • a group represented by (2) an optionally substituted monocyclic heteroaryl group, or (3) an optionally substituted monocyclic fused to an optionally substituted monocyclic or bicyclic ring Represents an aromatic group.
  • R 1 may be substituted with (a) an alkyl group having 3 or more carbon atoms, (b) an alkyl group substituted with one non-aromatic heterocyclic group, or (c) one or more alkyl groups. If it is a good non-aromatic heterocyclic group, Ar is not (i) a pyrrolyl group substituted with two methyl groups and one further substituent, or (ii) an optionally substituted thienyl group.
  • R 1 may be substituted with (a) an alkyl group having 3 or more carbon atoms, (b) an alkyl group substituted with one non-aromatic heterocyclic group, or (c) one or more alkyl groups. If it is a good non-aromatic heterocyclic group, Ar is Furthermore, Ar is a formula (Wherein R x2 represents a C 1-4 alkyl group). ] Or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 and R 2 are each independently Represents an optionally substituted alkyl group, or an optionally substituted non-aromatic cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, they may form an optionally substituted non-aromatic nitrogen-containing heterocycle; and Ar is It represents a monocyclic aromatic group which may be substituted and may be condensed with a monocyclic or bicyclic ring.
  • Ar is the formula (Wherein R x2 represents a C 1-4 alkyl group), or (Wherein R x3 represents a hydrogen atom, a halogen atom, —NO 2 , or —OH).
  • R 1 and R 2 are each independently an optionally substituted alkyl group, Ar is is not.
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) a C 1-6 alkyl group which may be substituted with one substituent selected from a halogen atom, a C 1-6 alkoxy group, and a 3- to 6-membered non-aromatic cyclic group, or (3 )
  • An optionally substituted 3- to 6-membered cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, may form an optionally substituted 3-6 membered non-aromatic nitrogen-containing heterocycle
  • Ar is May be condensed with an optionally substituted monocyclic or bicyclic ring, and a halogen atom, -NO 2 , -CN, and -X 3a -X 3b -R 3a
  • a monocyclic aromatic group optionally substituted with one or more substituents selected from:
  • X 3a is a bond or an alkylene chain;
  • X 3b is a bond, —O—,
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) a C 1-6 alkyl group which may be substituted with one substituent selected from a halogen atom, a C 1-6 alkoxy group, and a 3- to 6-membered non-aromatic cyclic group, or (3 ) An optionally substituted 3- to 6-membered cyclic group, or R 1 and R 2 are Together with the nitrogen atom to which they are attached, forms an optionally substituted 3-6 membered non-aromatic nitrogen-containing heterocycle;
  • Ar is (I) (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and a phenyl group; (Five) (a) a phenyl group, and (b) a C 1-6 alkenyl group optionally substitute
  • a phenyl group which may be substituted with one or more (preferably 1 to 3, more preferably 1) substituents selected from: (II) (1) a halogen atom, (2) an alkoxy group (preferably methoxy) an alkoxy group (preferably methoxy), and (3) phenyl group, A 5- to 6-membered heteroaryl group (eg, pyridyl (eg, 2-yl) which may be substituted with one or more (preferably 1 to 3, more preferably 1) substituents selected from Pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 2-pyridazinyl), pyrrolyl (eg, 2-pyrrolyl, 3-pyrrolyl), thienyl (eg, 2-thienyl, 3-thienyl), furyl (eg, 2-furyl)); or (III) (1) a C 1-6 alkyl group (preferably methyl) optionally substituted with one or more (preferably 1 to 3)
  • Compound (I) may be a pharmaceutically acceptable salt.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done. Of these, pharmaceutically acceptable salts are preferred.
  • an alkali metal salt eg, lithium salt, sodium salt, potassium salt, etc.
  • an alkaline earth metal salt eg, magnesium salt, calcium salt, barium salt, etc.
  • Inorganic salts, ammonium salts, etc. and when the compound has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • salts with organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • Compound (I) has, as a tautomer, a compound represented by the formula (Ia) and a compound represented by the formula (Ib), and any one of isomers and mixtures thereof are within the scope of the present invention. is there.
  • Compound (I) is preferably an isomer having a stable structure, but the present invention is not limited to this and does not exclude other isomers.
  • compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, any one of the isomers and mixtures are within the scope of the present invention. Included in the compounds of the present invention.
  • compound (I) when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also within the scope of the present invention.
  • Compound (I) may be crystalline or amorphous and both are within the scope of the present invention.
  • Compound (I) labeled or substituted with an isotope eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.
  • Compound (I) may be a solvate (such as a hydrate) or a non-solvate.
  • each symbol of the compound in the reaction formula represents the same meaning as described above.
  • the compound in a formula also includes the case where it forms the salt, as such a salt, the thing similar to the salt of compound (I) is mentioned, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method. It can be easily purified by separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, distillation, chromatography and the like. Or when the compound in a formula is marketed, a commercial item can also be used as it is. Unless otherwise specified, room temperature herein is about 10 ° C. to about 35 ° C.
  • Compound (I) can be produced, for example, by the following method or a method analogous thereto.
  • Production method 1 is a method well known to those skilled in the art (for example, the method described in Journal of Medicinal Chemistry 2001, 44 (20), 3231-3243. Or Khimiya Geterotsiklicheskikh Soedinenii 1991, (6), 843-6. Engl. Transl. Ver .: The method described in pp 666-668).
  • the general formula (Xa represents a leaving group, Ar is as defined above)
  • a compound of formula (II) R 1 and R 2 are as described above) Is reacted with the compound (III) represented by the general formula (R 1 , R 2 and Ar are as defined above) (Ia) or (Ib) can be produced.
  • the leaving group represented by Xa for example, A halogen atom;
  • An alkylsulfonyloxy group eg, a methanesulfonyloxy group, an ethanesulfonyloxy group, and a trifluoromethanesulfonyloxy group
  • one or more eg, 1 to 3
  • an optionally substituted alkylsulfonyloxy group and an arylsulfonyloxy group optionally substituted with one or more substituents selected from a nitro group and an alkyl group (eg, 1 to 3, preferably 1)
  • a nitro group and an alkyl group eg, 1 to 3, preferably 1
  • benzenesulfonyloxy, p-toluenesulfonyloxy group, and 2-nitrobenzenesulfonyloxy group are preferable.
  • the reaction temperature is usually from room temperature to reflux temperature
  • the reaction time is usually from instantaneous to about 24 hours.
  • the amount of compound (III) to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II).
  • This production method may be carried out in the presence of an acid or a base.
  • the base used include carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate and potassium phosphate; hydroxides such as sodium hydroxide and potassium hydroxide; morpholine, piperidine, pyridine and trimethylamine.
  • Organic amines such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine.
  • Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the amount used is usually 0.001 to 4 mol per 1 mol of compound (II).
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide or Examples include aprotic solvents such as N-methylpyrrolidone; halogenated hydrocarbons such as chloroform, or mixed solvents thereof.
  • the organic amines described above may be used as a solvent.
  • halogenating agent examples include N-chlorosuccinimide (NCS); N-bromosuccinimide (NBS); pyridinium perbromide and the like; or bromine, chlorine or iodine.
  • the amount used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II ′).
  • the solvent include acetonitrile, halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and dichloromethane, aromatic hydrocarbon solvents such as monochlorobenzene and benzene, ester solvents such as ethyl acetate, or a mixed solvent thereof. Is mentioned.
  • compound (II ′′) when basic nitrogen is contained in Ar of compound (II ′), compound (II ′′) can be produced with reference to other methods known to those skilled in the art (for example, JP 2002-511889).
  • the reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.
  • Xa ′ is introduced in the presence of a halogenating agent.
  • halogenating agent examples include N-chlorosuccinimide (NCS); N-bromosuccinimide (NBS); pyridinium perbromide and the like; or bromine, chlorine Alternatively, halogen such as iodine and the like can be mentioned, and the amount used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II ′).
  • a solvent containing HXa ′ (Xa ′ is as described above) is used. Examples thereof include carboxylic acids such as hydrobromic acid-acetic acid.
  • compound (II ') used for this manufacture can be manufactured with the following method or the method according to it. Specifically, the general formula (Ar is as described above) As a starting material, compound (VI) represented by From N, O-dimethylhydroxyamine (Ar is as described above) Compound (VI ′) represented by Next, by reacting with methylmagnesium bromide, the general formula (Ar is as described above) The compound (II ') represented by these can be manufactured.
  • the first step is a production method using a condensing agent or an acid halogenating agent. When a condensing agent is used, the reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.
  • N, O-dimethylhydroxyamine may be used in the form of a salt, and the amount used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (VI).
  • the condensing agent include Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl).
  • Carbodiimide / hydrochloride DCC (N, N-dicyclohexylcarbodiimide), CDI (carbonyldiimidazole), diethyl phosphoryl cyanide, and the like.
  • the amount of the condensing agent to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol with respect to compound (VI). Further, if necessary, 1 equivalent to an excess amount of an organic base such as triethylamine may be added to the compound (VI).
  • the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, sulfoxides such as dimethyl sulfoxide, esters such as ethyl acetate, ethers such as tetrahydrofuran and 1,4-dioxane, and the like. Examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide.
  • the reaction temperature range is usually from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.
  • N, O-dimethylhydroxyamine may be used in the form of a salt, and the amount used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (VI).
  • the acid halogenating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like.
  • the amount of the acid halogenating agent to be used is generally 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of compound (VI).
  • a catalytic amount of N, N-dimethylformamide may be added to the reaction system.
  • the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; ethers such as tetrahydrofuran and 1,4-dioxane; Examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; aromatic hydrocarbons such as benzene and toluene.
  • the reaction temperature range is usually -78 degrees to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours.
  • the amount of methylmagnesium bromide to be used is about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI ′).
  • the solvent include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; saturated hydrocarbons such as cyclohexane and hexane; N, N-dimethylformamide, Amides such as N, N-dimethylacetamide and hexamethylphosphoric triamide; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; Solvents such as sulfoxides such as dimethyl sulfoxide or the like And the like.
  • This production method may be carried out in the presence of an acid or a base.
  • the base used include carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate and potassium phosphate; hydroxides such as sodium hydroxide and potassium hydroxide; morpholine, piperidine and pyridine.
  • organic amines such as trimethylamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine.
  • Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the amount to be used is usually 0.001 to 4 mol per 1 mol of compound (II ′).
  • Examples of the solvent include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; acetonitrile; aprotic solvents such as dimethylformamide; halogenated hydrocarbons such as chloroform. Or a mixed solvent thereof.
  • the organic amine described above may be used as a solvent.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instantaneous to about 24 hours.
  • This production method is carried out in the presence of a halogenating agent.
  • the halogenating agent include N-chlorosuccinimide (NCS); N-bromosuccinimide (NBS); pyridinium perbromide and the like; or bromine, chlorine or iodine.
  • the amount used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II ′).
  • the solvent examples include aprotic solvents such as acetonitrile; halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and dichloromethane; aromatic hydrocarbon solvents such as monochlorobenzene and benzene; ester solvents such as ethyl acetate; Or these mixed solvents are mentioned.
  • aprotic solvents such as acetonitrile
  • halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and dichloromethane
  • aromatic hydrocarbon solvents such as monochlorobenzene and benzene
  • ester solvents such as ethyl acetate
  • Production method 3 is a method well known to those skilled in the art (for example, translated by Kiyoshi Tomioka, “Organic synthesis strategy learned from personal reaction”, Kagaku Dojin, August 15, 2006, p258-259: Kumada cross-coupling reaction, p310- 311: Negishi cross coupling reaction, p440-441: Stilley-Kelly coupling reaction, p.448-449: Suzuki-Miyaura coupling reaction).
  • the general formula (Ar 1 represents an optionally substituted aromatic group, and R 1 , R 2 and Xa are as described above) (Ia-Xa) or (Ib-Xa) represented by the general formula Ya-Yb (Ya is an optionally substituted aromatic ring Yb is an alkaline earth metal that forms boronic acid (B (OH) 2 ) or its ester, organotin (eg SnBu 4 etc.), or other suitable organometallic compounds (For example, magnesium, zinc, etc.))
  • a compound (Yab) represented by general formula (Ia-Ya) or (Ia-Ya) represented by the formula can be produced.
  • the reaction is carried out in the presence of a transition metal catalyst, optionally in the presence of a ligand, base, additive, etc., at a temperature ranging from about 20 ° C. to the boiling point of the solvent used in a suitable inert solvent, The reaction can be carried out by reacting for 10 minutes to 48 hours.
  • the amount of compound (Yab) to be used is generally 1-3 mol, preferably 1-1.5 mol, per 1 mol of compound (Ia-Xa) or (Ib-Xa).
  • transition metal catalysts include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium chloride (II), tris (dibenzylideneacetone) dipalladium. (0), or [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II).
  • the amount of the transition metal catalyst to be used is generally 0.0001-1 mol, preferably 0.001-1 mol, per 1 mol of compound (Ia-Xa) or (Ib-Xa).
  • Examples of the ligand include triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tri-cyclohexylphosphine, triphenylarsine, 1,1′-bis (diphenylphosphine). Fino) ferrocene (dppf).
  • the amount of the ligand to be used is generally 0.0001-4 mol, preferably 0.001-4 mol, per 1 mol of compound (Ia-Xa) or (Ib-Xa).
  • Examples of the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 4 mol, per 1 mol of compound (Ia-Xa) or (Ib-Xa).
  • Examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, and copper (I) bromide.
  • Examples of the solvent include water, acetonitrile, chloroform, and dichloromethane.
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; benzene, toluene, xylene, and the like.
  • Aromatic hydrocarbon solvents ; acetonitrile; dimethylformamide; aprotic solvents such as dimethyl sulfoxide or N-methylpyrrolidone; halogenated hydrocarbons such as chloroform, or a mixed solvent thereof.
  • the reaction product is chlorinated as it is without purification, thereby giving a general formula
  • the compound (Ia) or (Ib) represented by the above formula can also be directly produced in the form of an acid salt.
  • Production method a can be carried out by methods well known to those skilled in the art.
  • the first step can be performed according to the method described in Bioorganic & Medicinal Chemistry Letters 2006, 16, 2213-2218.
  • said 2nd process can be performed according to the method as described in Journal of Heterocyclic Chemistry 2005, 42 (7), 1273-81.
  • reaction temperature is usually from room temperature to reflux temperature
  • reaction time is usually from instantaneous to about 24 hours.
  • the amount of carbon disulfide to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of hydrazine monohydrate.
  • the amount of the methylating agent represented by Me-Xa is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of hydrazine monohydrate.
  • the base include hydroxides such as sodium hydroxide, lithium hydroxide, and potassium hydroxide; inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, and potassium phosphate; for example, triethylamine, diisopropylethylamine, and the like.
  • An organic base is mentioned.
  • the amount of the base used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of hydrazine monohydrate.
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aprotic solvents such as acetonitrile, dimethylformamide and dimethyl sulfoxide, or a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instantaneous to about 24 hours.
  • the amount of compound (V) to be used is generally 1 to 10 mol, preferably 2 to 4 mol, per 1 mol of compound (III-a).
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide and Examples include aprotic solvents such as N-methylpyrrolidone; halogenated hydrocarbons such as chloroform, or mixed solvents thereof.
  • the compound (V) described above may be used as a solvent.
  • Production method b-1 can be performed according to a method well known to those skilled in the art (for example, the method described in Journal of Medicinal Chemistry 1991, 34 (5), 1594-1605).
  • 1,1′-thiocarbonyldiimidazole and the general formula (R 1 and R 2 are as described above) Is reacted with the compound (V) represented by the general formula (R 1 and R 2 are as described above) And then reacting with hydrazine monohydrate to produce the general formula III-b-1) (R 1 and R 2 are as described above)
  • the compound (III) represented by these can be manufactured.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instantaneous to about 24 hours.
  • the amount of 1,1′thiocarbonyldiimidazole to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (V).
  • the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
  • the amount thereof to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (V).
  • the solvent examples include ether solvents such as tetrahydrofuran and dioxane; acetonitrile; aprotic solvents such as dimethylformamide; dimethyl sulfoxide; and halogenated hydrocarbons such as chloroform, or a mixed solvent thereof.
  • the organic base described above may be used as a solvent.
  • An organic base may be used as a solvent.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instantaneous to about 24 hours.
  • the amount of hydrazine monohydrate to be used is generally 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of compound (III-a).
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide or An aprotic solvent such as N-methylpyrrolidone; halogenated hydrocarbons such as chloroform, or a mixed solvent thereof is used.
  • alcohol solvents such as methanol and ethanol
  • ether solvents such as tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as benzene, toluene and xylene
  • acetonitrile dimethylformamide
  • dimethyl sulfoxide or
  • An aprotic solvent such as N-methylpyrrolidone
  • halogenated hydrocarbons such as chloroform, or a mixed solvent thereof is used.
  • Production method b-2 is a method well known to those skilled in the art (for example, the method described in WO2002 / 081438) Can be done.
  • carbon disulfide, N, N-diisopropylethylamine, and general formula (R 1 and R 2 are as described above) Is reacted with the compound (V) represented by the formula, and then reacted with hydrazine monohydrate.
  • R 1 and R 2 are as described above
  • the compound (III) represented by these can be manufactured.
  • the reaction temperature is usually from room temperature to reflux temperature
  • the reaction time is usually from instantaneous to about 24 hours.
  • the amount of carbon disulfide to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (V).
  • the amount of N, N-diisopropylethylamine to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (V).
  • the amount of hydrazine monohydrate to be used is generally 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of compound (V).
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide or An aprotic solvent such as N-methylpyrrolidone; halogenated hydrocarbons such as chloroform, or a mixed solvent thereof is used.
  • alcohol solvents such as methanol and ethanol
  • ether solvents such as tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as benzene, toluene and xylene
  • acetonitrile dimethylformamide
  • dimethyl sulfoxide or
  • An aprotic solvent such as N-methylpyrrolidone
  • halogenated hydrocarbons such as chloroform, or a mixed solvent thereof is used.
  • Production method c can be carried out by methods well known to those skilled in the art (for example, the method described in Journal of Heterocyclic Chemistry 2005, 42 (7), 1273-81).
  • hydrazine monohydrate, and the general formula (R 1 is as described above) Is reacted with the compound (VI) represented by the general formula (R 1 is as described above)
  • the compound (III ') represented by these can be manufactured.
  • the reaction temperature is usually from room temperature to reflux temperature
  • the reaction time is usually from instantaneous to about 24 hours.
  • the amount of hydrazine monohydrate to be used is generally 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of compound (VI).
  • the solvent examples include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide or An aprotic solvent such as N-methylpyrrolidone; halogenated hydrocarbons such as chloroform, or a mixed solvent thereof is used.
  • alcohol solvents such as methanol and ethanol
  • ether solvents such as tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as benzene, toluene and xylene
  • acetonitrile dimethylformamide
  • dimethyl sulfoxide or
  • An aprotic solvent such as N-methylpyrrolidone
  • halogenated hydrocarbons such as chloroform, or a mixed solvent thereof is used.
  • the target compound can be obtained by converting the substituents of the compounds synthesized by the above production methods 1 to 4 by a method commonly used in the art.
  • the compounds of the present invention have tautomers. Reactions using them as starting compounds or target compounds are also included in the process for producing the compounds of the present invention, and the reactions detailed above. The same can be done.
  • the manufacturing method of compound (I) is a solution, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, and column chromatography. From the reaction mixture, it can be separated and purified by a known technique such as.
  • compound (I) when compound (I) is obtained as a free form, it can be converted to the target salt as described above by a method known per se or a method analogous thereto, and conversely, compound (I) When obtained as a salt, it can be converted into a free form or other desired salt by a method known per se or a method analogous thereto.
  • the purified compound (I) is converted into inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, By reacting with an organic acid such as p-toluenesulfonic acid, a pharmaceutically acceptable acid addition salt can be easily obtained.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid
  • the purified compound (I) is converted into, for example, lithium hydroxide, lithium methylate, sodium hydride, sodium carbonate, sodium hydroxide, sodium methylate, potassium hydroxide, potassium carbonate, potassium hydroxide, potassium-t-
  • an inorganic / organic metal salt such as butyrate
  • the compounds of the present invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts and predrug and prodrug forms of the compounds of the invention. These predrug and prodrug forms are also within the scope of the present invention.
  • the compound of the present invention has an action of enhancing the activity of neurotrophic factor, and in particular, has an action of inducing NXF gene expression that plays an important role in nerve protection. Therefore, the compound of the present invention can be used as a therapeutic or prophylactic agent for diseases involving neurotrophic factor activity. Moreover, the compound of this invention can be used as a promoter of the physical therapy effect for the recovery
  • disease is used in the meaning including a disorder and its symptoms.
  • treatment is used in the meaning including relief of symptoms.
  • diseases involving neurotrophic factor activity include the following cranial neurodegenerative diseases, spinal degenerative diseases, retinal degenerative diseases, peripheral neurodegenerative diseases, and other diseases.
  • Examples of cranial neurodegenerative diseases include: Neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, Huntington's disease, Down syndrome, etc.), cerebral ischemic diseases (stroke, cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, ischemic encephalopathy, cerebral infarction (Such as lacunar infarction, atherothrombotic cerebral infarction, cardiogenic cerebral infarction, hemorrhagic cerebral infarction, other infarction)), traumatic brain injury, leukoencephalopathy, and multiple sclerosis.
  • Neurodegenerative diseases eg, Alzheimer's disease, Parkinson's disease, Huntington's disease, Down syndrome, etc.
  • cerebral ischemic diseases stroke, cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, ischemic encephalopathy, cerebral infarction (Such as lacunar infarction, atherothrombotic cerebral infarction, cardiogenic cerebral infarction, hemor
  • spinal degenerative diseases include: Examples include amyotrophic lateral sclerosis (ALS), spinal cord injury, spinal cord injury due to various causes, spinal progressive muscular atrophy, and spinal cerebral degeneration (SCD).
  • ALS amyotrophic lateral sclerosis
  • SCD spinal cerebral degeneration
  • retinal degenerative diseases include: Examples include age-related macular degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, hypertensive retinopathy, and glaucoma.
  • AMD age-related macular degeneration
  • diabetic retinopathy examples include diabetic retinopathy, retinitis pigmentosa, hypertensive retinopathy, and glaucoma.
  • peripheral neurodegenerative diseases include Diabetic neuropathy, peripheral nerve injury, traumatic peripheral neuropathy, poisoning, peripheral neuropathy caused by other toxic substances, peripheral neuropathy caused by cancer chemotherapy, Guillain-Barre syndrome, peripheral neuropathy caused by deficiency of vitamins, Amyloid peripheral neuropathy, ischemic peripheral neuropathy, peripheral neuropathy associated with malignant tumor, uremic peripheral neuropathy, peripheral neuropathy due to physical cause, Charcot-Marie-Tooth disease, alcoholic peripheral neuropathy, autonomic neuropathy (Subconscious hypoglycemia, gastric paresis, neurogenic diarrhea and constipation, erectile dysfunction, orthostatic hypotension, arrhythmia, heart failure, painless myocardial infarction, sweating abnormalities, neurogenic bladder, etc.), bladder dysfunction (e.g., Uninhibited bladder, reflex bladder, autonomous bladder, sensory paralytic bladder, motor paralytic bladder, etc.).
  • bladder dysfunction e.g., Uninhibited bladder, reflex bladder, autonomous bladder, sensory paralytic bladder, motor paralytic bladder, etc.
  • Other diseases include, for example, Associated with depression, schizophrenia, epilepsy, autism, periodontal disease, diabetes, diabetic cardiomyopathy, diabetic foot lesions, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), dementia Problematic behavior (eg, acupuncture, aggressive behavior), anxiety, pain, hearing impairment, bone disease (eg, osteoporosis), joint disease (eg, Charcot joint, osteoarthritis, rheumatism, etc.), Hirsch Examples include Sobrung's disease.
  • the compound of the present invention is suitably applied to cerebral ischemic disease or diabetic neuropathy.
  • the compound of the present invention can be used as a composition (eg, pharmaceutical composition) formulated as it is or mixed with a pharmaceutically acceptable carrier or the like for diseases involving neurotrophic factor activity.
  • a pharmaceutically acceptable carrier or the like for diseases involving neurotrophic factor activity.
  • it can be safely administered orally or parenterally to mammals such as humans.
  • Parenterally includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and the like.
  • the composition of the present invention contains, for example, one or more compounds of the present invention and a pharmaceutically acceptable carrier, excipient, and / or additive.
  • a pharmaceutically acceptable carrier, excipient, and / or additive eg, pharmaceutical additive, food additive
  • Agent, cosmetic additive e.g., cosmetic additive
  • the pharmaceutically acceptable carrier, excipient, and / or additive used in the composition of the present invention can be appropriately selected depending on the specific use of the composition.
  • the form of the said composition can also be made into forms, such as various solid and liquid, according to a specific use, for example.
  • compositions of the present invention or the compound of the present invention when used as a pharmaceutical, specific forms such as powders, fine granules, granules, tablets, syrups, capsules, suspending agents And oral agents such as emulsions, extracts and pills, injections, transdermal solutions (external preparations for skin) such as ointments, suppositories, and parenterals for topical use. .
  • Oral preparations include, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soy lecithin, sucrose, fatty acid ester, talc, magnesium stearate, Carriers and excipients such as polyethylene glycol, magnesium silicate, and silicic anhydride, binders, disintegrants, surfactants, lubricants, fluidity promoters, diluents, preservatives, colorants, fragrances, stabilization It can be produced according to a usual method using a pharmaceutical additive such as an agent, a humectant, a preservative, and an antioxidant.
  • a pharmaceutical additive such as an agent, a humectant, a preservative, and an antioxidant.
  • the dose varies depending on the age, sex, weight, disease level, type of compound of the present invention, dosage form, etc. of the mammal to be administered.
  • the amount may be about 1 mg to about 2 g, preferably about 5 mg to about 1 g as the active ingredient amount.
  • the above-mentioned daily dose can be administered once or divided into several times.
  • injections are water-soluble solvents such as physiological saline and sterile water Ringer's solution, non-water-soluble solvents such as vegetable oil and fatty acid esters, isotonic agents such as glucose and sodium chloride, solubilizing agents, stable It can be produced according to a usual method using a pharmaceutical additive such as an agent, a preservative, a suspending agent, and an emulsifier.
  • a pharmaceutical additive such as an agent, a preservative, a suspending agent, and an emulsifier.
  • Liquid preparations for external use, percutaneous absorption agents such as gel ointments, suppositories for rectal administration and the like can also be produced according to conventional methods.
  • injection subcutaneous, intravenous, etc.
  • transdermal administration or rectal administration may be used.
  • the topical agent can be produced, for example, by incorporating the compound of the present invention into a pellet of a sustained release polymer such as an ethylene vinyl acetate polymer. This pellet may be surgically implanted into the tissue to be treated.
  • the dose varies depending on the age, sex, body weight, degree of disease, the type of the composition of the present invention or the compound of the present invention, the mode of administration, etc. And about 0.1 mg to about 500 mg may be administered as the active ingredient amount.
  • the above-mentioned daily dose can be administered once or divided into several times.
  • Reference example 1 Synthesis of 4-cyclopropylmethylthiosemicarbazide To a solution of 4.95 g of potassium hydroxide in 6 ml of water and 5 ml of isopropyl alcohol, 2.4 g of hydrazine hydrate was added at room temperature. The mixture was cooled to 10 ° C. with ice water, and 5.75 g of carbon disulfide was added dropwise over about 30 minutes. After stirring at 10 ° C. for about 2.5 hours, 10.65 g of methyl iodide was added. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration, washed with water and a small amount of ethyl acetate, and then dried in a vacuum drier.
  • Reference example 2 Synthesis of 4-cyclopropylthiosemicarbazide To 2.26 g of diisopropylethylamine and 5 ml of water, 1.0 g of cyclopropylamine was added and cooled with ice water. After dropwise addition of 1.33 g of carbon disulfide over 15 minutes, the mixture was stirred with ice cooling for 2 hours and further at room temperature for 2.5 hours. Hydrazine hydrate 0.56 g was added and reacted at 90 ° C. for 3 hours. Diisopropylethylamine was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as white crystals (1.29 g, yield 56%).
  • Example 8 Synthesis of 2-methylamino-5- ⁇ 4- (3-fluorophenyl) phenyl ⁇ -6H-1,3,4-thiadiazine hydrochloride (Compound 3- (b) -1) To 10 ml of a toluene / ethanol (1: 1) solution of 150 mg of 2-methylamino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine and 89 mg of 4-fluorophenylboric acid was added 790 ⁇ l of a 2M sodium carbonate aqueous solution. In addition, after deaeration with argon, 30 mg of tetrakistriphenylphosphine palladium was added, and the mixture was heated to reflux for 1.5 hours.
  • Example 11 Synthesis of salt (synthesis of dihydrochloride of pyridine) Synthesis of 2-methylamino-5- ⁇ 4- (3-pyridyl) phenyl ⁇ -6H-1,3,4-thiadiazine dihydrochloride (compound 4- (b) -2) To a mixed solution of 10 ml of hydrogen chloride methanol and 10 ml of isopropyl alcohol, a mixed solution of 1 g of 2-methylamino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine and 10 ml of methanol was added dropwise over 10 minutes. And then stirred at room temperature for 1 hour.
  • Example 12 Synthesis of 2-methylamino-5- (3-pyridyl) -6H-1,3,4-thiadiazine hydrochloride (Compound 5-1) 4-Methylthiosemicarbazide (115 mg, 1.1 mmol) was added to a suspension of 4 ′-(3-pyridyl) -2-bromoacetophenone (300 mg, 1.07 mmol) in methanol (5 ml), and the mixture was heated to reflux for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate.
  • the obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude crystals were purified by silica gel column chromatography.
  • the obtained crystals were dissolved in 5 ml of tetrahydrofuran, 1.5 ml of 1M hydrogen chloride diethyl ether solution was added, and the mixture was stirred for 30 minutes at room temperature.
  • the precipitated crystals were filtered, washed with tetrahydrofuran and dried to give 50 mg of the title compound as orange crystals.
  • Example 13 Synthesis of 2-methylamino-5- (2-pyridyl) -6H-1,3,4-thiadiazine hydrochloride (Compound 5-2) In the same manner as in Example 15, except that 4 '-(3-pyridyl) -2-bromoacetophenone was replaced with 4'-(2-pyridyl) -2-bromoacetophenone, 134 mg of the title compound as orange crystals was obtained.
  • Example 15 Synthesis of 2-methylamino-5- (4-aminophenyl) -6H-1,3,4-thiadiazine (Compound 5-4) 503 mg of electrolytic iron powder was added to 10 ml of a 10% aqueous acetic acid solution of 250 mg of 2-methylamino-5- (4-nitrophenyl) -6H-1,3,4-thiadiazine, and stirred with heating at 80 ° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. After completion of the reaction, potassium carbonate and ethyl acetate were added and stirred at room temperature for 30 minutes.
  • Example 17 Synthesis of 4- (azetidin-1-yl) thiosemicarbazide To a solution of 0.5 g of azetidine in 10 ml of chloroform, 1.56 g of 1,1′-thiocarbonyldiimidazole was added little by little and stirred overnight at room temperature. The reaction solution was washed with water, dried over sodium sulfate and concentrated to obtain 1.23 g (yield 84%) of an intermediate azetidin-1-yl-imidazol-1-yl-methanethione light brown oil.
  • Example 18 Synthesis of 4- (2,2,5,5-tetrafluoropyrrolidin-1-yl) thiosemicarbazide 4- (2,2,5,5-tetrafluoropyrrolidin-1-yl) thiosemicarbazide was obtained in the same manner as in Example 17 except that azetidin was replaced with 2,2,5,5-tetrafluoropyrrolidine. Obtained at 87%.
  • Example 19 Synthesis of 4- (2,2,2-trifluoroethyl) thiosemicarbazide To 4.3 g of diisopropylethylamine and 10 ml of water, 3.0 g of trifluoroethylamine was added and cooled with ice water. Carbon disulfide (2.31 g) was added dropwise over 15 minutes, and the mixture was stirred for 2 hours with ice cooling and then for 2.5 hours at room temperature. 0.97 g of hydrazine hydrate was added and reacted at 90 ° C. for 3 hours.
  • Example 20 Synthesis of 4- (2,2-difluoroethyl) thiosemicarbazide 4- (2,2-difluoroethyl) thiosemicarbazide was obtained in a yield of 10% by the same method as in Example 19 except that trifluoroethylamine was replaced with difluoroethylamine.
  • Example 21 Synthesis of 4- (cyclohexylmethyl) thiosemicarbazide Hydrazine hydrate 0.21 g was dissolved in 10 ml of methanol and heated to 70 ° C. After dropwise addition of 1.0 g of cyclohexylmethyl isothiocyanate at the same temperature, the mixture was stirred for 30 minutes while keeping warm. The solvent was distilled off, and the precipitated crystals were collected by filtration, washed with a small amount of methanol and dried to give the title compound as white crystals (270 mg, yield 22%).
  • Test example 1 (Preparation of compound evaluation cells) Forward primer: (5'-tccagtatttgagaaaaggagccaggagtctccat-3 ') (SEQ ID NO: 1), reverse primer: (5'-ggaggcttcctctttgcttcccggtcttttcg-3') ) (SEQ ID NO: 2) was prepared, and the region from about 5 kbp upstream of the NXF gene promoter partial translation region to the vicinity of the transcription start site was isolated by PCR.
  • mouse genomic DNA manufactured by Takara
  • PCR was performed by repeating a two-step reaction for 35 minutes at 95 ° C for 1 minute as denaturing conditions for PCR reaction and 8 minutes at 68 ° C as annealing and extension conditions.
  • the product was obtained.
  • the resulting NXF promoter fragment is introduced into the SmaI site of the pGL3 Basic vector (Promega) so that the luciferase gene is located downstream of the promoter, and a reporter plasmid that expresses the luciferase enzyme by the action of the NXF promoter.
  • pGL3 Basic vector Promega
  • PC12 cells purchased from ATCC were prepared using RPMI medium (GIBCO-BRL), 5% FCS (GIBCO-BRL), 15% horse serum (GIBCO-BRL), and 1 mM sodium pyruvate (GIBCO- BRL was added to the cells and cultured at 37 ° C. in the presence of 5% CO 2 .
  • the PC12 of the reporter plasmid 12 ⁇ g and 1 ⁇ g against 106 cells pRC / RSV vector were transfected sheet transfected using Lipofectamine2000 reagent (Invitrogen Corporation), 40 mg / L after 2 days transfection
  • the medium was replaced with a medium containing Geneticin sulfate (manufactured by GIBCO) and the culture was continued.
  • the culture was continued for about one month while continuing medium exchange with a culture solution containing 40 mg / L Geneticin sulfate (GIBCO) every several days, and a plurality of resulting cell colonies were picked up.
  • GIBCO Geneticin sulfate
  • a culture solution containing only a final concentration of 0.1% DMSO was used as a negative control group
  • a culture group containing a saturated concentration of NGF was used as a positive control group
  • added to 200 ng / ml NGF corresponding to a compound concentration of 0. Place an experimental plot containing 0.1% DMSO, and add 200ng / ml of NGF to the compound solution (dissolved in DMSO and prepare so that the final concentration of DMSO is 0.1%) based on the luciferase activity.
  • the relative luciferase activity of the added experimental group was calculated and used as the activity of enhancing the activity of 200 ng / ml NGF by the compound.
  • NGF activity enhancing activity is listed in Table 11 below. +: Relatively weak potentiating activity (enhancing activity only at 10 ⁇ M) ++: Shows enhancement activity ++: Shows particularly strong enhancement activity (increases NGF 200 ng / ml activity more than 2 times at 1 ⁇ M) [Table 11]
  • Test example 2 Protective effect on nerve cells in middle cerebral artery occlusion / reopening model
  • Male 8-week-old C57BL / 6J mice are normally raised for 12 days, then the left common neck and external common artery are ligated in advance, and the middle cerebral artery is occluded for 90 minutes. Then, the middle cerebral artery occlusion / reopening model was created by restarting.
  • the compound was administered into the tail vein at 30 mg / kg 3 hours after occlusion and 48 hours after 48 hours. After 3 days of occlusion / reopening, the head was decapitated, the skull was cut from the cerebellum side, and the brain was removed.
  • the excised brain was placed in a Buan solution (ph 3.5 to 4.0) and fixed. From the fixed brain, coronal sections were cut out, and after cutting, dehydration and penetration, and embedded in paraffin. Slicing was performed at 4 sites near Bregma 1.95 mm, Bregma 1.0 mm, Bregma -1.40 mm and Bregma -3.8 mm. Sections with a thickness of about 6 ⁇ m were prepared and HE-stained. Infarct volume was calculated as follows. Digital images were captured using a camera (MCD-350, Olympus Corporation) attached to an optical microscope (objective lens x 1). The imported digital image was pasted on a single mount (new layer) in Adobe Photoshop 2.0.
  • the infarct area (S, mm 2 ), the infarct side (left) area (mm 2 ), and the non-infarct side (right ) Area (MR, mm 2 ) was measured, and non-infarct area (ML, mm 2 ) on the infarct side (left) [infarct side (left) area (mm 2 ) ⁇ infarct area (mm 2 )] was calculated.
  • the infarct volume (SV, mm 3 ), the infarct side (left) non-infarct volume (MLV, mm 3 ), and the non-infarction side (right) volume (MRV, mm 3 ) were calculated by the following equations.
  • Test example 3 Examination of the neurodegeneration inhibitory effect in the rat model administered with Streptozotocin (Streptozotocin) The prophylactic effect of the compound on the latency of motor nerve transmission rate (MNCV) in the sciatic nerve in streptozotocin-induced diabetic rats was examined.
  • the group composition was a non-diabetic control group, a diabetic control group, and a compound administration group.
  • Wistar rats are normally bred for 7 or 8 days, 0.75 mmol / L citrate buffer solution at pH 4.5 is 2 ml / kg in the non-diabetic control group, and in the diabetic control group and the compound administration group.
  • Streptozotocin (chemical name: N- (Methylnitrosocarbamoyl) - ⁇ -D-glucosamine, manufacturer: SIGMA) adjusted to 20mg / ml with 0.75mmol / L citrate buffer solution is administered once in the tail vein at 2ml / kg. did. After 4 weeks, the non-diabetic control group and the diabetic control group had 5 ml / kg of water for injection, and the compound administration group had 5 ml / kg of compound solution prepared to 2 mg / ml with water for injection. Oral administration once a day for 4 weeks. MNCV was measured 3 times for each group.
  • the measurement time was the first day before administration of the streptozotocin solution or 0.75 mmol / L citrate buffer solution at pH 4.5, and the second time after 4 weeks of administration of the streptozotocin solution or pH 4.5 0.75 mmol / L citrate buffer solution, The third time was measured the day after the last day of administration of water or compound solution for 4 weeks.
  • the results (motor nerve transmission rate) of compound 4- (b) -2 are shown in FIG. 2 (in the figure, STZ represents streptozotocin). Thus, recovery of motor nerve transmission rate was recognized in the compound administration group compared to the solvent control administration group.
  • Test example 4 In the same manner as in Test Example 1, the known compounds were tested for NGF activity enhancing activity. These known compounds were obtained by purchasing commercial products. Table 12 below shows the structural formulas of known compounds subjected to the test and the test results. +: Relatively weak potentiating activity (enhancing activity only at 10 ⁇ M) ++: Shows enhancement activity ++: Shows particularly strong enhancement activity (increases NGF 200 ng / ml activity more than 2 times at 1 ⁇ M)
  • Test Example 5 In the same manner as in Test Example 1, the compounds of Examples 22 to 28 were tested for NGF activity-enhancing activity. Table 13 below shows the structural formulas of known compounds subjected to the test and the test results. +: Relatively weak potentiating activity (enhancing activity only at 10 ⁇ M) ++: Shows enhancement activity ++: Shows particularly strong enhancement activity (increases NGF 200 ng / ml activity more than 2 times at 1 ⁇ M)
  • the compound of the present invention is effective for treatment or prevention of diseases involving the activity of neurotrophic factor.
  • SEQ ID NO: 1 is a forward primer.
  • SEQ ID NO: 2 is a reverse primer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Obesity (AREA)
  • Gynecology & Obstetrics (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé renforçant l'activité de facteurs neurotrophiques et exerçant une action protectrice sur les cellules nerveuses. L'invention concerne, plus précisément, un composé de formule (Ia) ou (Ib), un sel pharmaceutiquement acceptable de celui-ci ou un solvate de celui-ci. Dans lesdites formules, R1 et R2 représentent indépendamment l'un de l'autre un atome d'hydrogène ou équivalent; et Ar représente un groupe cyclique à 5 ou 6 chaînons ou un groupe cyclique condensé.
PCT/JP2010/003623 2009-05-29 2010-05-29 Agent de traitement ou de prévention de maladies associées à l'activité de facteurs neurotrophiques WO2010137350A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-131595 2009-05-29
JP2009131595 2009-05-29

Publications (1)

Publication Number Publication Date
WO2010137350A1 true WO2010137350A1 (fr) 2010-12-02

Family

ID=43222476

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/003623 WO2010137350A1 (fr) 2009-05-29 2010-05-29 Agent de traitement ou de prévention de maladies associées à l'activité de facteurs neurotrophiques

Country Status (2)

Country Link
JP (1) JP2011006408A (fr)
WO (1) WO2010137350A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014515001A (ja) * 2011-04-20 2014-06-26 塩野義製薬株式会社 Ｔｒｐｖ４阻害活性を有する芳香族複素環誘導体
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
WO2019100062A1 (fr) * 2017-11-20 2019-05-23 Ichan School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
EP3543231A1 (fr) * 2018-03-19 2019-09-25 ETH Zurich Composés pour le traitement de maladies neurodégénératives et du système nerveux central
CN111454232A (zh) * 2020-05-30 2020-07-28 南方医科大学 一种1,3,4-噻二嗪类化合物及其应用
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11788064B2 (en) 2018-01-05 2023-10-17 Icahn School Of Medicine At Mount Sinai Method of increasing proliferation of pancreatic beta cells, treatment method, and composition
US11866427B2 (en) 2018-03-20 2024-01-09 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1191024A1 (fr) * 2000-09-22 2002-03-27 Harald Tschesche Thiadiazines et leur utilisation comme inhibiteurs de métalloproteinases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1191024A1 (fr) * 2000-09-22 2002-03-27 Harald Tschesche Thiadiazines et leur utilisation comme inhibiteurs de métalloproteinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JORG SCHRODER ET AL.: "Structure-Based Design and Synthesis of Potent Matrix Metalloproteinase Inhibitors Derived from a 6H-1,3,4-Thiadiazine Scaffold", J. MED. CHEM., vol. 44, 2001, pages 3231 - 3243, XP002416988, DOI: doi:10.1021/jm010887p *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014515001A (ja) * 2011-04-20 2014-06-26 塩野義製薬株式会社 Ｔｒｐｖ４阻害活性を有する芳香族複素環誘導体
US9340500B2 (en) 2011-04-20 2016-05-17 Shionogi & Co., Ltd. Aromatic heterocyclic derivative having TRPV4-inhibiting activity
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11547712B2 (en) 2017-11-20 2023-01-10 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
WO2019100062A1 (fr) * 2017-11-20 2019-05-23 Ichan School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
US11788064B2 (en) 2018-01-05 2023-10-17 Icahn School Of Medicine At Mount Sinai Method of increasing proliferation of pancreatic beta cells, treatment method, and composition
WO2019179890A1 (fr) * 2018-03-19 2019-09-26 Eth Zurich Composés pour le traitement de maladies du snc et de maladies neurodégénératives
EP3543231A1 (fr) * 2018-03-19 2019-09-25 ETH Zurich Composés pour le traitement de maladies neurodégénératives et du système nerveux central
US11866427B2 (en) 2018-03-20 2024-01-09 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
CN111454232A (zh) * 2020-05-30 2020-07-28 南方医科大学 一种1,3,4-噻二嗪类化合物及其应用

Also Published As

Publication number Publication date
JP2011006408A (ja) 2011-01-13

Similar Documents

Publication Publication Date Title
WO2010137350A1 (fr) Agent de traitement ou de prévention de maladies associées à l'activité de facteurs neurotrophiques
EP3300500B1 (fr) Triazoles agonistes du récepteur apj
US8461348B2 (en) Heterocyclic derivative and use thereof
US9242977B2 (en) Trk-inhibiting compound
TWI434842B (zh) Azole compounds
US11046680B1 (en) Heteroaryl-substituted triazoles as APJ receptor agonists
WO2007026761A1 (fr) Dérivé de thiazole
JP2002500619A (ja) 置換ビフェニルイソオキサゾールスルホンアミド
EA012204B1 (ru) Три(цикло)замещённые амидные соединения
AU2007261461A1 (en) Pyrazinones as cellular proliferation inhibitors
NZ587205A (en) Thiazole derivative and use thereof as vap-1 inhibitor
CN114127049A (zh) Acss2抑制剂和其使用方法
US8829035B2 (en) Agent for treatment or prevention of diseases associated with activity of neurotrophic factors
TWI582080B (zh) 礦皮質素受體拮抗劑
JP2019523237A (ja) 乳酸脱水素酵素の阻害剤としての１ｈ−ピラゾール−１−イル−チアゾールおよびそれらの使用方法
JP3591514B2 (ja) 複素環誘導体
US8835469B2 (en) Substituted benzamide derivatives as glucokinase (GK) activators
JP2017165653A (ja) アゾールカルボン酸誘導体
JP2010047517A (ja) 神経栄養因子の活性が関与する疾患の治療または予防剤、およびその製造方法
JP2004250460A (ja) 複素環誘導体
JP2017532362A (ja) ベンジルヒドロキシド誘導体、その製造及び治療上の使用

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: 10780310

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10780310

Country of ref document: EP

Kind code of ref document: A1