WO2015163431A1 - Agent thérapeutique de la migraine - Google Patents

Agent thérapeutique de la migraine Download PDF

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WO2015163431A1
WO2015163431A1 PCT/JP2015/062454 JP2015062454W WO2015163431A1 WO 2015163431 A1 WO2015163431 A1 WO 2015163431A1 JP 2015062454 W JP2015062454 W JP 2015062454W WO 2015163431 A1 WO2015163431 A1 WO 2015163431A1
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optionally substituted
group
alkyl
atom
alkoxy
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PCT/JP2015/062454
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Japanese (ja)
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岩下　弘樹
政人 中島
勇輝 井藤
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武田薬品工業株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present invention relates to a prophylactic / therapeutic agent for migraine containing a compound having a PDE2A selective inhibitory action.
  • Cyclic nucleotide phosphodiesterases are enzymes that regulate their intracellular concentrations by controlling the degradation of secondary messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).
  • PDEs are a superfamily of enzymes encoded by 21 genes, subdivided into 11 different families by structural and functional characteristics. The enzyme selectively catalyzes the hydrolysis of the 3′-ester bond to form an inactive 5′-monophosphate.
  • the PDE family further comprises three groups: i) cAMP-PDEs (PDE4, PDE7 and PDE8), ii) cGMP-PDEs (PDE5, PDE6 and PDE9), and iii) dual substrate PDEs (PDE1). , PDE2, PDE3, PDE10 and PDE11).
  • cAMP and cGMP are involved in virtually all physiological processes such as pro-inflammatory mediator production and action, ion channel function, muscle relaxation, learning and memory formation, differentiation, apoptosis, adipogenesis, glycogenolysis, and gluconeogenesis. ing.
  • Non-patent Document 1 Control of these processes by cAMP and cGMP regulates protein kinase A (PKA) and protein kinase G (PKG) that phosphorylate various substrates such as transcription factors, ion channels and receptors that regulate various physiological processes.
  • PKA protein kinase A
  • PKG protein kinase G
  • Intracellular cAMP and cGMP concentrations appear to be temporally, spatially and functionally differentiated by regulation of adenylate and guanylate cyclases in response to extracellular signaling and their degradation by PDEs (non- Patent Document 2).
  • PDEs are the only means of breaking down the cyclic nucleotides cAMP and cGMP in cells, and therefore PDEs play an essential role in cyclic nucleotide signaling. Therefore, PDEs can be a promising target for various therapeutic agents.
  • Phosphodiesterase 2A (PDE2A) is a dual substrate enzyme that hydrolyzes both cAMP and cGMP. The enzyme consists of four domains, N-terminal, GAF-A, GAF-B and catalytic domain, and functions as a homodimer. The catalytic activity of PDE2A is allosterically promoted by cGMP binding. The GAF-B domain binds cGMP with high affinity and high selectivity.
  • Non-Patent Documents 3 to 6 Due to the binding of cGMP, a conformational change occurs in the PDE2A homodimer, and the catalytic activity increases several times or more (Non-Patent Documents 3 to 6). In contrast, no example of cAMP promoting PDE2A catalytic activity in vivo is known so far. Furthermore, cAMP can bind to GAF-B only with a 30-100 fold lower affinity (Non-Patent Documents 6 and 7). PDE2A activity becomes functionally meaningful under conditions where cellular cGMP concentrations are elevated, and GAF domain regulation of the enzyme indicates a physiological role.
  • migraines are subdivided into “migraine without aura” and “migraine with aura” according to the presence or absence of aura. Signs often have visual symptoms such as a shining light and a jagged light (flash dark spot) that occur before the headache. Other signs include weakness of the body, sensory disturbance (numbness), and language impairment. The signs usually end within 60 minutes, and then the headache begins. In addition, vague headaches, sleepiness, and mood changes are known as precursors.
  • a migraine attack usually lasts 4 to 72 hours and is characterized by a unilateral pulsatile headache. However, there are also non-pulsatile migraine and bilateral migraine.
  • migraine migraine treatment
  • a treatment to relieve headache as soon as possible when a headache attack occurs acute treatment (abortion therapy)
  • daily medication on days when there are no headaches, making headache attacks less likely, and headache attacks
  • migraine pathologic hypotheses If the number of seizures is high or if the impact on life is strong, acute treatment and preventive therapy To be treated in combination. It usually takes a period of 1 to 2 months before the effect of prophylactic treatment appears, and it is necessary to determine the effect after continuing for at least 2 months.
  • Analgesics are widely used for acute treatment (abortion therapy), and triptan drugs (sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan, etc.) are used for the treatment of migraine.
  • triptan drugs sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan, etc.
  • migraine pathologic hypotheses Although the pathophysiology of migraine has not yet been shown to be a definitive mechanism, vascular, neural and trigeminal vascular theories have been proposed as migraine pathologic hypotheses.
  • migraine precursors are thought to be a phenomenon caused by cortical spreading depression (CSD) ("Chronic Headache Clinical Practice Guidelines 2013” (supervised by the Japanese Society of Neurology and the Japanese Headache Society, edited by the Committee on the Preparation of Clinical Guidelines for Chronic Headache)) , Medical School).
  • CSD cortical spreading depression
  • Patent Document 1 includes a formula:
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 2 and R 3 may be substituted together with adjacent carbon atoms.
  • X represents a bond or an optionally substituted C 1-6 alkylene group
  • A represents an optionally substituted cyclic group
  • Z 1 represents CR Z1 (R Z1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 1 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group or an optionally substituted cyclic group, or a group represented by: Indicates a nitrogen atom
  • Z 2 represents CR Z2 (R Z2 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group
  • An object of the present invention is to provide a prophylactic / therapeutic agent for migraine containing the compound (1) having a PDE2A selective inhibitory action.
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 2 and R 3 may be substituted together with adjacent carbon atoms.
  • X represents a bond or an optionally substituted C 1-6 alkylene group
  • A represents an optionally substituted cyclic group
  • Z 1 represents CR Z1 (R Z1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 1 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group or an optionally substituted cyclic group, or a group represented by: Indicates a nitrogen atom
  • Z 2 represents CR Z2 (R Z2 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group
  • R Z1 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2-6 alkynyl A group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group or a cyano group
  • Z 3 is CR Z3 (R Z3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group or an optionally substituted cyclic group).
  • the compound represented by the formula (1) is 7-methoxy-N-((1S) -2-methoxy-1- (4- (trifluoromethoxy) phenyl) ethyl) -2-oxo-2,
  • the compound represented by the formula (1) is N-((1S) -1- (3-fluoro-4- (trifluoromethoxy) phenyl) -2-methoxyethyl) -7-methoxy-2-
  • the compound represented by the formula (1) is 7-cyclopropyl-N-((1S) -2-hydroxy-2-methyl-1- (4- (trifluoromethoxy) phenyl) propyl) -2
  • the compound represented by the formula (1) is 7-cyclopropyl-N- (1- (3-fluoro-4- (trifluoromethoxy) phenyl) -2-hydroxy-2-methylpropyl) -2
  • the compound represented by the formula (1) is N- (1- (3-fluoro-4- (trifluoromethoxy) phenyl) -2-hydroxy-2-methylpropyl) -7-methyl-2-
  • the agent according to [1] above which is oxo-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxamide or a salt thereof.
  • a method for inhibiting PDE2A in a mammal comprising administering an effective amount of the compound represented by the formula (1) or the salt thereof according to [1] to the mammal.
  • [18] A method for preventing or treating migraine in a mammal, comprising administering an effective amount of the compound represented by the formula (1) or the salt thereof according to [1] to the mammal.
  • [19] Use of a compound represented by the formula (1) or a salt thereof according to [1] above for producing a prophylactic or therapeutic agent for migraine.
  • FIG. 1 is a diagram showing the results in Test Example 1.
  • FIG. 2 is a diagram showing the results in Test Example 2.
  • halogen atom in the present specification includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “optionally substituted hydrocarbon group” in the present specification include “optionally substituted C 1-10 alkyl”, “optionally substituted C 2”. ⁇ 10 alkenyl ”,“ optionally substituted C 2-10 alkynyl ”,“ optionally substituted C 3-8 cycloalkyl ”,“ optionally substituted C 3-8 cycloalkenyl ”,“ And optionally substituted C 6-14 aryl ”,“ optionally substituted C 7-14 aralkyl ”and the like.
  • C 1-10 alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl unless otherwise specified. , Heptyl, octyl, nonyl, decyl and the like.
  • C 1-6 alkyl in the present specification, among the above “C 1-10 alkyl” include the C 1-6.
  • C 1-5 alkyl among the above “C 1-10 alkyl” include the C 1-5.
  • C 2-10 alkenyl is, for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexene unless otherwise specified. -1-yl and the like can be mentioned.
  • C 2-6 alkenyl herein, of the “C 2-10 alkenyl” include the C 2-6.
  • C 2-10 alkynyl includes, for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like, unless otherwise specified. It is done.
  • C 2-6 alkynyl herein, of the “C 2-10 alkynyl” include the C 2-6.
  • C 3-8 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, unless otherwise specified.
  • C 3-8 cycloalkenyl includes, for example, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl) unless otherwise specified.
  • Cyclopentenyl eg, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl
  • cyclohexenyl eg, 1-cyclohexen-1-yl, 2-cyclohexene-1) -Yl, 3-cyclohexen-1-yl
  • C 6-14 aryl includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like, unless otherwise specified. Can be mentioned.
  • C 6-14 aryl may be partially saturated, and examples of the partially saturated C 6-14 aryl include tetrahydronaphthyl and the like.
  • C 7-14 aralkyl in the present specification includes, for example, benzyl, phenethyl, 1-methyl-2-phenylethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2 , 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like.
  • “optionally substituted hydroxy” is, for example, “hydroxy”, “optionally substituted C 1-6 alkoxy”, “optionally substituted” unless otherwise specified.
  • Heterocyclic-oxy “ optionally substituted C 6-14 aryloxy ”,“ optionally substituted C 7-14 aralkyloxy ”and the like.
  • “C 1-6 alkoxy” includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, unless otherwise specified.
  • C 1-6 alkoxy-C 1-6 alkoxy includes, for example, methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like, unless otherwise specified.
  • heterocycle-oxy examples include hydroxy substituted with a “heterocyclic group” described later.
  • Preferable examples of the heterocyclic-oxy include tetrahydropyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, oxazolyloxy, thienyloxy, furyloxy and the like.
  • C 6-14 aryloxy includes, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like, unless otherwise specified.
  • C 7-14 aralkyloxy includes, for example, benzyloxy, phenethyloxy and the like, unless otherwise specified.
  • examples of the “optionally substituted sulfanyl” include “sulfanyl”, “optionally substituted C 1-6 alkylsulfanyl”, and “optionally substituted”. Examples thereof include “good heterocycle-sulfanyl”, “optionally substituted C 6-14 arylsulfanyl”, “optionally substituted C 7-14 aralkylsulfanyl”, and the like.
  • C 1-6 alkylsulfanyl includes, for example, methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl and the like, unless otherwise specified. Can be mentioned.
  • heterocycle-sulfanyl includes sulfanyl substituted with a “heterocyclic group” described below.
  • heterocyclic-sulfanyl examples include tetrahydropyranylsulfanyl, thiazolylsulfanyl, pyridylsulfanyl, pyrazolylsulfanyl, oxazolylsulfanyl, thienylsulfanyl, furylsulfanyl and the like.
  • C 6-14 arylsulfanyl in the present specification includes, for example, phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl and the like, unless otherwise specified.
  • C 7-14 aralkylsulfanyl includes, for example, benzylsulfanyl, phenethylsulfanyl and the like, unless otherwise specified.
  • heterocyclic group is, for example, 1 or 2 selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom, and 1 to 4 unless otherwise specified.
  • 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group, (ii) Examples include 5- to 10-membered non-aromatic heterocyclic groups. Of these, a 5- or 6-membered aromatic heterocyclic group is preferable.
  • thienyl eg, 2-thienyl, 3-thienyl
  • furyl eg, 2-furyl, 3-furyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • Thiazolyl eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • oxazolyl eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl
  • pyrrolyl Example: 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl example: 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • Triazolyl eg 1-imid
  • the “optionally substituted cyclic group” in the present specification includes, for example, “ optionally substituted C 6-14 aryl”, “ optionally substituted C 3- 8 cycloalkyl ",” optionally substituted C 3-8 cycloalkenyl ", and the like” optionally substituted heterocyclic group ".
  • examples of the “optionally substituted ring” include an optionally substituted ring corresponding to the above “optionally substituted cyclic group”.
  • C 6-14 aromatic hydrocarbon includes a ring corresponding to the above “C 6-14 aryl”.
  • the “C 3-8 cycloalkane” in the present specification includes a ring corresponding to the above “C 3-8 cycloalkyl”.
  • rings corresponding to the “C 3-8 cycloalkenyl” are exemplified.
  • Examples of the “heterocycle” in the present specification include a ring corresponding to the above “heterocyclic group”.
  • a nitrogen-containing aromatic heterocycle containing 1 to 2 nitrogen atoms means, for example, as a ring constituent atom other than a carbon atom and 1 to 2 nitrogen atoms unless otherwise specified.
  • C 1-6 alkyl-carbonyl includes, for example, acetyl, isobutanoyl, isopentanoyl and the like, unless otherwise specified.
  • C 1-6 alkoxy-carbonyl in the present specification includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
  • C 3-8 cycloalkyl-carbonyl includes, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like, unless otherwise specified.
  • C 6-14 aryl-carbonyl includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like, unless otherwise specified.
  • examples of “C 7-14 aralkyl-carbonyl” in the present specification include phenylacetyl, 2-phenylpropanoyl and the like.
  • C 6-14 aryloxy-carbonyl in the present specification includes, for example, phenoxycarbonyl, naphthyloxycarbonyl and the like, unless otherwise specified.
  • C 7-14 aralkyloxy-carbonyl includes, for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like, unless otherwise specified.
  • nitrogen-containing heterocycle-carbonyl includes, for example, pyrrolidinylcarbonyl, piperidinocarbonyl and the like, unless otherwise specified.
  • C 1-6 alkylsulfonyl includes, for example, methylsulfonyl, ethylsulfonyl and the like, unless otherwise specified.
  • C 6-14 arylsulfonyl includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like, unless otherwise specified.
  • C 1-6 alkylsulfinyl in the present specification includes, for example, methylsulfinyl, ethylsulfinyl and the like, unless otherwise specified.
  • C 6-14 arylsulfinyl in the present specification includes, for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like, unless otherwise specified.
  • esterified carboxyl is, for example, carboxyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-14 aralkyl unless otherwise specified. And oxy-carbonyl.
  • C 1-6 alkyl which may be halogenated in the present specification, unless otherwise indicated, 1 to 5 of the above-mentioned “halogen atom” which may be substituted by the above “C 1- 6 alkyl ".
  • halogen atom for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, trifluoromethyl and the like can be mentioned.
  • optionally halogenated and C 1-6 alkoxy in the present specification, unless otherwise indicated, 1 to 5 of the above-mentioned “halogen atom” which may be substituted by the above “C 1- 6 alkoxy ". Examples include methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy and the like.
  • “mono- or di-C 1-6 alkyl-amino” includes amino mono- or di-substituted with the above “C 1-6 alkyl” unless otherwise specified. For example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like can be mentioned.
  • “mono- or di-C 6-14 aryl-amino” includes amino mono- or di-substituted with the above “C 6-14 aryl” unless otherwise specified. For example, phenylamino, diphenylamino, 1-naphthylamino, 2-naphthylamino and the like can be mentioned.
  • “mono- or di-C 7-14 aralkyl-amino” includes amino mono- or di-substituted with the above “C 7-14 aralkyl” unless otherwise specified.
  • benzylamino, phenethylamino and the like can be mentioned.
  • the “ NC 1-6 alkyl- NC 6-14 aryl-amino” in the present specification includes the above “C 1-6 alkyl” and the above “C 6-14 aryl”.
  • amino substituted with For example, N-methyl-N-phenylamino, N-ethyl-N-phenylamino and the like can be mentioned.
  • NC 1-6 alkyl-NC 7-14 aralkyl-amino in the present specification is the above “C 1-6 alkyl” and “C 7-14 aralkyl”. And amino substituted with.
  • N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the like can be mentioned.
  • C 1-6 alkyl-carbonylamino includes amino substituted with the above “C 1-6 alkyl-carbonyl” unless otherwise specified.
  • acetylamino, propionylamino and the like can be mentioned.
  • the “mono- or di-C 1-6 alkyl-carbamoyl” in the present specification includes carbamoyl mono- or di-substituted with the above “C 1-6 alkyl” unless otherwise specified.
  • methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like can be mentioned.
  • “mono- or di-C 6-14 aryl-carbamoyl” includes carbamoyl mono- or di-substituted with the above “C 6-14 aryl” unless otherwise specified.
  • phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like can be mentioned.
  • “mono- or di-C 3-8 cycloalkyl-carbamoyl” includes carbamoyl mono- or di-substituted with the above “C 3-8 cycloalkyl” unless otherwise specified. It is done. For example, cyclopropylcarbamoyl etc. are mentioned.
  • “mono- or di-C 7-14 aralkyl-carbamoyl” includes carbamoyl mono- or di-substituted with the above “C 7-14 aralkyl” unless otherwise specified.
  • benzylcarbamoyl etc. are mentioned.
  • “ NC 1-6 alkyl- NC 6-14 aryl-carbamoyl” means “C 1-6 alkyl” and “C 6-14 aryl” unless otherwise specified.
  • Substituted carbamoyl is mentioned. For example, (n-butyl) (phenyl) carbamoyl and the like can be mentioned.
  • “mono- or di-5 to 7-membered heterocyclic-carbamoyl” includes carbamoyl mono- or di-substituted with a 5- to 7-membered heterocyclic group unless otherwise specified.
  • the 5- to 7-membered heterocyclic group a heterocyclic group containing 1 or 2 kinds and 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom Is mentioned.
  • “mono- or di-5 to 7-membered heterocycle-carbamoyl” include 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like. .
  • the term “mono- or di-C 1-6 alkyl-sulfamoyl” includes, unless otherwise specified, sulfamoyl mono- or di-substituted with the above “C 1-6 alkyl”. Examples thereof include methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.
  • “mono- or di-C 6-14 aryl-sulfamoyl” includes, unless otherwise specified, sulfamoyl mono- or di-substituted with the above “C 6-14 aryl”.
  • Examples thereof include phenylsulfamoyl, diphenylsulfamoyl, 1-naphthylsulfamoyl, 2-naphthylsulfamoyl and the like.
  • “mono- or di-C 7-14 aralkyl-sulfamoyl” includes sulfamoyl mono- or di-substituted with the above “C 7-14 aralkyl” unless otherwise specified. For example, benzylsulfamoyl etc. are mentioned.
  • C 1-6 alkyl-carbonyloxy includes, for example, methylcarbonyloxy, ethylcarbonyloxy and the like, unless otherwise specified.
  • C 1-6 alkylene is, for example, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH, unless otherwise specified.
  • Examples of the “C 1-5 alkylene” in the present specification include those of C 1-5 among the above “C 1-6 alkylene”.
  • optionally substituted C 1-10 (or C 1-6 or C 1-5 ) alkyl include, for example, (1) a halogen atom; (2) hydroxy; (3) amino; (4) Nitro; (5) Cyano; (6) Halogen atom, hydroxy, oxo, amino, nitro, cyano, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkyl-amino, C 6-14 aryl, mono- Or di-C 6-14 aryl-amino, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6
  • optionally substituted C 3-8 cycloalkyl “optionally substituted C 3-8 cycloalkenyl”, “ optionally substituted C 6-14 aryl”, “ “Optionally substituted C 7-14 aralkyl”, “optionally substituted heterocyclic group”, “optionally substituted heterocyclic-oxy”, “optionally substituted C 6-14 aryl” Oxy ”,“ optionally substituted C 7-14 aralkyloxy ”,“ optionally substituted heterocycle-sulfanyl ”,“ optionally substituted C 6-14 arylsulfanyl ”and“ substituted
  • optionally C 7-14 aralkylsulfanyl include (1) a halogen atom; (2) hydroxy; (3) amino; (4) Nitro; (5) Cyano; (6) optionally substituted C 1-6 alkyl; (7) C 2-6 alkenyl which may be substituted; (8) C 2-6 alkynyl which may be substituted; (9) Halogen atom, hydroxy, amino
  • optionally substituted amino in the present specification is as follows. (1) optionally substituted C 1-6 alkyl; (2) optionally substituted C 2-6 alkenyl; (3) optionally substituted C 2-6 alkynyl; (4) optionally substituted C 3-8 cycloalkyl; (5) optionally substituted C 6-14 aryl; (6) optionally substituted C 1-6 alkoxy; (7) an optionally substituted acyl; (8) an optionally substituted heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl); (9) Sulfamoyl; (10) mono- or di-C 1-6 alkyl-sulfamoyl; (11) mono- or di-C 6-14 aryl-sulfamoyl; And amino optionally substituted with 1 or 2 substituents selected from the above.
  • nitrogen-containing heterocyclic ring may be formed together with the atom.
  • the “nitrogen-containing heterocycle” includes, for example, at least one nitrogen atom in addition to a carbon atom as a ring-constituting atom, and further contains 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom And a 5- to 7-membered nitrogen-containing heterocycle which may be used.
  • nitrogen-containing heterocycle examples include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like.
  • the “optionally substituted acyl” in the present specification has the formula: —COR 18 , —CO—OR 18 , —SO 2 R 18 , —SOR 18 , —PO (OR 18). ) (OR 19 ), —CO—NR 18a R 19a and —CS—NR 18a R 19a [wherein R 18 and R 19 are the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group or Represents an optionally substituted heterocyclic group, and R 18a and R 19a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 18a and R 19a may form an optionally substituted nitrogen-containing heterocycle together with the adjacent nitrogen atom. ] Etc. which are represented by these.
  • the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R 18a and R 19a together with the adjacent nitrogen atom includes, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom.
  • examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like.
  • the nitrogen-containing heterocycle may have 1 to 2 substituents at substitutable positions.
  • substituents include hydroxy, optionally halogenated C 1-6 alkyl, C 6-14 aryl, C 7-14 aralkyl, and the like. When two substituents are present, these substituents may be the same or different.
  • acyl As a suitable example of “optionally substituted acyl”, Formyl; Carboxyl; Carbamoyl; C 1-6 alkyl-carbonyl; C 1-6 alkoxy-carbonyl; C 3-8 cycloalkyl-carbonyl; C 6-14 aryl-carbonyl; C 7-14 aralkyl-carbonyl; C 6-14 aryloxy-carbonyl; C 7-14 aralkyloxy-carbonyl; Mono- or di-C 1-6 alkyl-carbamoyl; Mono- or di-C 6-14 aryl-carbamoyl; Mono- or di-C 3-8 cycloalkyl-carbamoyl; Mono- or di-C 7-14 aralkyl-carbamoyl; C 1-6 alkylsulfonyl; C 6-14 arylsulfonyl optionally substituted with nitro; Nitrogen-containing heterocycle-carbonyl; C 1-6 alkylsulf
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • R 1 is preferably a hydrogen atom or a C 1-6 alkyl group.
  • R 1 is more preferably a hydrogen atom or a C 1-3 alkyl group (preferably methyl).
  • R 1 is particularly preferably a hydrogen atom.
  • R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 2 and R 3 may be substituted together with adjacent carbon atoms.
  • a ring may be formed.
  • R 2 and R 3 are preferably each independently a hydrogen atom or a C 1-6 alkyl group (eg, methyl).
  • R 2 and R 3 are more preferably both hydrogen atoms.
  • R 20 represents an optionally substituted C 1-6 alkyl group.
  • the ring etc. which are represented by these are mentioned.
  • the substituent of the “ring” of the “optionally substituted ring” formed by R 2 and R 3 together with the adjacent carbon atom the “heterocyclic group” of the above “optionally substituted heterocyclic group” The same thing as the substituent which has is mentioned.
  • X represents a bond or an optionally substituted C 1-6 alkylene group.
  • the “C 1-6 alkylene group” of the “ optionally substituted C 1-6 alkylene group” represented by X is preferably a C 1-5 alkylene group, —CH 2 —, —CH (CH 3 ) —, —CH (CH 2 CH 3 ) —, —CH (CH 2 CH 2 CH 3 ) — or —CH (CH (CH 3 ) 2 ) — is more preferable.
  • the “C 1-6 alkylene group” of the “ optionally substituted C 1-6 alkylene group” represented by X includes —CH 2 —, —CH (CH 3 ) —, —CH (CH 2 CH 3 ) —, —CH (CH 2 CH 2 CH 3 ) —, —CH (CH (CH 3 ) 2 ) —, —CH (C (CH 3 ) 3 ) —, —CH (CH 2 CH 2 CH 2 CH 3 ) —, —CH (CH (CH 2 CH 3 ) 2 ) — or —CH 2 CH 2 — is more preferred.
  • the “C 1-6 alkylene group” of the “ optionally substituted C 1-6 alkylene group” represented by X is —CH 2 —, —CH (CH 3 ) —, — CH (CH 2 CH 3 ) —, —CH (CH 2 CH 2 CH 3 ) —, —CH (CH (CH 3 ) 2 ) —, —CH (C (CH 3 ) 3 ) —, —CH (CH 2 CH 2 CH 2 CH 3 ) — or —CH (CH (CH 2 CH 3 ) 2 ) — is more preferred.
  • X is preferably an optionally substituted C 1-6 alkylene group (preferably an optionally substituted C 1-5 alkylene group).
  • X is more preferably (1) hydroxy, (2) cyano, (3) Carbamoyl, (4) C 1-6 alkoxy (eg, methoxy), (5) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (6) C 1-6 alkylsulfonyl (eg, methylsulfonyl), (7) mono- or di-C 1-6 alkyl-amino (eg, dimethylamino), (8) C 3-8 cycloalkyl (eg, cyclopropyl), (9) may be halogenated (preferably 1 to 3 selected from C 1-6 alkoxy (eg methoxy) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom)) C 6-14 aryl optionally substituted with 3 substituents (eg, phenyl), and (10) A heterocyclic group optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (preferably a 5- or 6-membere
  • X is more preferably (1) halogen atoms (eg, fluorine atoms), (2) hydroxy, (3) amino, (4) cyano, (5) Carbamoyl, (6) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (7) (i) a halogen atom (eg, fluorine atom), and (ii) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (8) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (9) C 1-6 alkylsulfinyl (eg, methylsulfinyl), (10) C 1-6 alkylsulfonyl (eg, methylsulfonyl), (11) mono- or di
  • X is more preferably (1) halogen atoms (eg, fluorine atoms), (2) hydroxy, (3) amino, (4) cyano, (5) Carbamoyl, (6) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (7) (i) a halogen atom (eg, fluorine atom), and (ii) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (8) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (9) C 1-6 alkylsulfinyl (eg, methylsulfinyl), (10) C 1-6 alkylsulfonyl (eg, methylsulfonyl), (11) mono- or
  • X is more preferably (1) hydroxy, and (2) C 1-6 alkoxy (eg, methoxy) A C 1-6 alkylene group (preferably a C 1-5 alkylene group, more preferably —CH (CH 3 ) — or —CH (CH) optionally substituted with 1 to 3 substituents selected from (CH 3 ) 2 ) —.
  • C 1-6 alkoxy eg, methoxy
  • A represents a cyclic group which may be substituted.
  • the “optionally substituted cyclic group” represented by A includes “ optionally substituted C 6-14 aryl”, “ optionally substituted C 3-8 cycloalkyl”, “substituted C 3-8 cycloalkenyl ”, or“ optionally substituted heterocyclic group ”.
  • the “cyclic group” may be condensed, and may be condensed with, for example, a C 6-14 aromatic hydrocarbon, a C 3-8 cycloalkane, a C 3-8 cycloalkene, a heterocyclic ring, or the like.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by A is preferably a C 6-14 aryl group or a 5- or 6-membered aromatic heterocyclic group, more preferably C 6.
  • A is preferably a C 6-10 aryl group or a 5- or 6-membered nitrogen-containing aromatic heterocyclic group, each of which may be substituted, and more preferably a phenyl group which may be substituted. .
  • A is more preferably (1) halogen atoms (eg, fluorine atoms), (2) hydroxy, (3) C 1-6 alkyl (eg, methyl, isopropyl) which may be halogenated (preferably optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom)), (4) C 2-6 alkenyl (eg, prop-1-en-2-yl), (5) (i) a halogen atom (eg, fluorine atom), and (ii) C 3-8 cycloalkyl (eg, cyclopropyl) 1 selected from to 3 substituents optionally substituted by C 1-6 alkoxy (e.g., methoxy), (6) C 6-14 aryl (eg, phenyl), and (7) A heterocyclic group (preferably a 5- or 6-membered heterocyclic group) optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (eg, pyrazolyl, dihydropyr
  • A is more preferably (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) hydroxy, (3) C 1-6 alkyl (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably may be substituted with 1 to 3 halogen atoms (eg, fluorine atom)), (4) C 2-6 alkenyl (eg, prop-1-en-2-yl), (5) (i) a halogen atom (eg, fluorine atom), and (ii) C 3-8 cycloalkyl (eg, cyclopropyl) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (6) optionally substituted (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) substituted with C 1-6 alkoxy (eg, methoxy) C 6-14
  • A is more preferably (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) hydroxy, (3) C 1-6 alkyl (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably may be substituted with 1 to 3 halogen atoms (eg, fluorine atom)), (4) C 2-6 alkenyl (eg, prop-1-en-2-yl), (5) (i) a halogen atom (eg, fluorine atom), and (ii) C 3-8 cycloalkyl (eg, cyclopropyl) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (6) C 6-14 aryl (eg, phenyl), (7) a heterocyclic group optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (preferably a 4-
  • A is more preferably (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) hydroxy, (3) C 1-6 alkyl (eg, methyl, isopropyl) which may be halogenated (preferably optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom)), (4) C 2-6 alkenyl (eg, prop-1-en-2-yl), (5) (i) a halogen atom (eg, fluorine atom), and (ii) C 3-8 cycloalkyl (eg, cyclopropyl) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (6) C 6-14 aryl (eg, phenyl), (7) a heterocyclic group optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (preferably a 4- to 6-membered hetero
  • R 21 represents a hydrogen atom, an optionally substituted C 1-5 alkyl group, a C 3-8 cycloalkyl group, a carbamoyl group or a cyano group
  • R 22 represents a hydrogen atom or a substituent. It is group represented by these.
  • R 21 represents a hydrogen atom, an optionally substituted C 1-5 alkyl group, a C 3-8 cycloalkyl group, a carbamoyl group, a cyano group, or an optionally substituted heterocyclic group
  • R 22 represents a hydrogen atom or a substituent
  • p represents an integer of 1 to 5.
  • R 22 corresponds to the “substituent” of the “optionally substituted cyclic group” represented by A.
  • R 21 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a C 3-8 cycloalkyl group, an optionally substituted carbamoyl group, a cyano group, an optionally substituted heterocyclic group, A C 1-6 alkyl-carbonyl group, a C 3-8 cycloalkyl-carbonyl group, an optionally substituted C 6-14 aryl group, R 22 represents a hydrogen atom or a substituent, p represents an integer of 1 to 5. ] It is group represented by these.
  • the “substituent” represented by R 22 corresponds to the “substituent” of the “optionally substituted cyclic group” represented by A.
  • R 21 is (1) Cyano (2) Carbamoyl (3) (i) hydroxy, (ii) C 1-6 alkoxy (eg, methoxy), (iii) mono- or di-C 1-6 alkyl-amino (eg dimethylamino), (iv) C 1-6 alkylsulfanyl (eg, methylsulfanyl), and (v) C 1-6 alkylsulfonyl (eg, methylsulfonyl) C 1-5 alkyl (eg, methyl, ethyl, isopropyl, propyl) optionally substituted with 1 to 3 substituents selected from: (4) C 3-8 cycloalkyl (eg, cyclopropyl), or (5) a heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group) optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (eg, pyridyl, isoxazolyl
  • R 21 is (1) cyano, (2) Carbamoyl, (3) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (4) (i) a halogen atom (eg, fluorine atom), (ii) hydroxy, (iii) amino, (iv) cyano, (v) C 3-8 cycloalkyl (eg, cyclopropyl), (vi) (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (vii) C 3-8 cycloalkyloxy (eg, cyclopentyloxy), (viii) mono- or di-C 1-6 alkyl-amino (eg dimethyla
  • R 21 is a C 1-5 alkyl group (eg, methyl, isopropyl) optionally substituted with hydroxy or C 1-6 alkoxy (eg, methoxy);
  • R 22 is (1) a halogen atom (eg, fluorine atom), or (2) C 1-6 alkoxy (eg, methoxy) which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)), p is an integer of 1 to 2.
  • Z 1 represents CR Z1 (R Z1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 1 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group or a cyano group), or a nitrogen atom.
  • R Z1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 1 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group or a cyano group), or a nitrogen atom.
  • Z 1 represents CR Z1 (R Z1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted An optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group, or an optionally substituted cyclic group. Or a nitrogen atom.
  • R Z1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted An optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group, or an optionally substituted cyclic group. Or a nitrogen atom.
  • Z 1 is preferably CR Z1 (R Z1 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, Or a C 1-6 alkoxy group or a cyano group).
  • Z 1 is preferably CR Z1 (R Z1 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group.
  • R Z1 represents a hydrogen atom a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 1-6 alkoxy group, a cyano group, substituted Or a C 6-14 aryl group, an optionally substituted heterocyclic group, or an optionally substituted C 3-8 cycloalkyl group.
  • Z 1 is more preferably CR Z1 (R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl) A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from: (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), or (6) A cyano group. ) It is group represented by these.
  • Z 1 is more preferably CR Z1
  • R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl)
  • a C 1-6 alkyl group eg, methyl, ethyl
  • substituents selected from: (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), (6) a cyano group, (7) a C 6-14 aryl group (eg, phenyl) optionally substituted by 1 to 3 C 1-6 alkoxy (eg, methoxy), (8) a heterocyclic group (preferably a 5- or 6-membered heterocyclic group) optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (eg, pyrazolyl,
  • Z 2 represents CR Z2 (R Z2 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group, or an optionally substituted cyclic group; Or a nitrogen atom is shown.
  • R Z2 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group, or an optionally substituted cyclic group; Or a nitrogen atom is shown.
  • Z 2 is preferably CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a cyano group, or A cyclic group which may be substituted.
  • Z 2 is more preferably CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, a cyano group, an optionally substituted C 6-14 aryl group, Or a C 3-8 cycloalkyl group which may be substituted.
  • Z 2 is particularly preferably CR Z2 (R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably may be substituted with 1 to 3 halogen atoms (eg, fluorine atom)), (4) C 2-6 alkenyl group (eg, vinyl), (5) a cyano group, (6) a C 6-14 aryl group (eg, phenyl), or (7) C 3-8 cycloalkyl group (eg, cyclopropyl) It is. ) It is group represented by these.
  • R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl (eg, methyl, ethyl, isopropyl) which may be
  • Z 2 is CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, An optionally substituted C 1-6 alkoxy group, a cyano group, or an optionally substituted cyclic group.
  • Z 2 is preferably CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2-6 alkenyl group.
  • Or a nitrogen atom Or a nitrogen atom.
  • Z 2 is CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, cyano A group, an optionally substituted C 6-14 aryl group, or an optionally substituted C 3-8 cycloalkyl group.
  • Z 2 is more preferably CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2-6 alkenyl.
  • Z 2 is CR Z2 (R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl group (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) , (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), (6) a cyano group, (7) a C 6-14 aryl group (eg, phenyl), or (8) C 3-8 cycloalkyl group (eg, cyclopropyl) It is.
  • R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl group (eg, methyl, ethyl, isoprop
  • Z 2 is particularly preferably CR Z2 (R Z2 is (1) hydrogen atom, (2) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (3) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkyl group (eg, methyl, ethyl, optionally substituted with 1 to 3 substituents selected from hydroxy) Isopropyl), (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy, which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) ), (6) a cyano group, (7) C 6-14 aryl group (eg, phenyl), (8) a C 3-8 cycloalkyl group (R Z2 is (1) hydrogen atom, (2) Halogen
  • Z 2 is most preferably CR Z2 (R Z2 is (1) a C 1-6 alkoxy group (eg, methoxy), or (2) C 3-8 cycloalkyl group (eg, cyclopropyl) It is. ) It is group represented by these.
  • Z 2 is most preferably CR Z2 (R Z2 represents an optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-8 cycloalkyl group).
  • Z 2 is most preferably CR Z2 (R Z2 is (1) C 1-6 alkoxy group (eg, methoxy), (2) a C 3-8 cycloalkyl group (eg, cyclopropyl), or (3) C 1-6 alkyl group (eg, methyl) It is. ) It is group represented by these.
  • R Z2 is (1) C 1-6 alkoxy group (eg, methoxy), (2) a C 3-8 cycloalkyl group (eg, cyclopropyl), or (3) C 1-6 alkyl group (eg, methyl) It is. ) It is group represented by these.
  • Z 3 represents CR Z3 (R Z3 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3 A 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group or an optionally substituted cyclic group, or a group represented by: Indicates a nitrogen atom.
  • Z 3 represents CR Z3 (R Z3 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted An optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted amino group, a cyano group, an optionally substituted C 1-6 alkyl-carbonyl group Or a cyclic group which may be substituted.) Or a nitrogen atom.
  • Z 3 is preferably a group represented by CR Z3 (R Z3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group), or a nitrogen atom.
  • Z 3 is preferably, CR Z3 (R Z3 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group or a substituted, A C 1-6 alkyl-carbonyl group which may be substituted, or a nitrogen atom.
  • Z 3 is more preferably CR Z3 (R Z3 is a hydrogen atom or a C 1-6 alkyl group (eg, methyl)), or a nitrogen atom.
  • Z 3 is more preferably CR Z3 (R Z3 is (1) hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 hydroxy groups, (3) a C 1-6 alkoxy group (eg, methoxy), or (4) C 1-6 alkyl-carbonyl group (eg, acetyl) It is. ) Or a nitrogen atom.
  • R Z3 is more preferably a group represented by CR Z3 (R Z3 is a hydrogen atom).
  • B represents a nitrogen-containing aromatic heterocycle containing 1 to 2 nitrogen atoms.
  • B is preferably a 6-membered nitrogen-containing aromatic heterocycle containing 1 to 2 nitrogen atoms.
  • B is more preferably a pyridine ring or a pyrazine ring.
  • B is more preferably a pyridine ring, a pyrimidine ring or a pyrazine ring.
  • B is particularly preferably a pyridine ring.
  • R 1 is a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 and R 3 are a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • X is an optionally substituted C 1-6 alkylene group (preferably an optionally substituted C 1-5 alkylene group)
  • A is a C 6-10 aryl group or a 5- or 6-membered nitrogen-containing aromatic heterocyclic group, each of which may be substituted
  • Z 1 is CR Z1 (R Z1 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 1 A 1-6 alkoxy group or a cyano group);
  • Z 2 is CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 al
  • R 1 is a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 and R 3 are a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • X is an optionally substituted C 1-6 alkylene group (preferably an optionally substituted C 1-5 alkylene group)
  • A is a C 6-10 aryl group or a 5- or 6-membered nitrogen-containing aromatic heterocyclic group, each of which may be substituted
  • Z 1 is CR Z1 (R Z1 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 1 A 1-6 alkoxy group or a cyano group);
  • Z 2 is CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substitute
  • R 1 is a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 and R 3 are a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • X is an optionally substituted C 1-6 alkylene group (preferably an optionally substituted C 1-5 alkylene group)
  • A is a C 6-10 aryl group, a 4- to 10-membered heterocyclic group or a C 3-8 cycloalkyl group, each of which may be substituted
  • Z 1 is CR Z1 (R Z1 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 1 A 1-6 alkoxy group or a cyano group);
  • Z 2 is CR Z2 (R Z2 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alken
  • R 1 is a hydrogen atom
  • R 2 and R 3 are both hydrogen atoms
  • X is an optionally substituted C 1-6 alkylene group
  • A is an optionally substituted phenyl group
  • Z 1 is CH
  • Z 2 represents CR Z2 (R Z2 represents an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted C 3-8 cycloalkyl group
  • Is a group represented by Z 3 is CH, Compound (1).
  • R 1 is a hydrogen atom or a C 1-6 alkyl group; R 2 and R 3 are both hydrogen atoms;
  • X is (1) hydroxy, (2) cyano, (3) Carbamoyl, (4) C 1-6 alkoxy (eg, methoxy), (5) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (6) C 1-6 alkylsulfonyl (eg, methylsulfonyl), (7) mono- or di-C 1-6 alkyl-amino (eg, dimethylamino), (8) C 3-8 cycloalkyl (eg, cyclopropyl), (9) may be halogenated (preferably 1 to 3 selected from C 1-6 alkoxy (eg methoxy) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom)) C 6-14 aryl optionally substituted with 3 substituents (eg, phenyl), and (10) A heterogenated (
  • R 21 represents a hydrogen atom, an optionally substituted C 1-5 alkyl group, a C 3-8 cycloalkyl group, a carbamoyl group or a cyano group
  • R 22 represents a hydrogen atom or a substituent. It is group represented by these.
  • Z 1 is CR Z1 (R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) a C 6-14 aryl group (eg, phenyl) A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from: (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), or (6) A cyano group.
  • R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) a C 6-14 aryl group (eg, phenyl)
  • a C 1-6 alkyl group eg, methyl, ethyl
  • substituents selected from
  • Z 2 is CR Z2 (R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably may be substituted with 1 to 3 halogen atoms (eg, fluorine atom)), (4) C 2-6 alkenyl group (eg, vinyl), (5) a cyano group, (6) a C 6-14 aryl group (eg, phenyl), or (7) C 3-8 cycloalkyl group (eg, cyclopropyl) It is.
  • R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably may be substituted with 1 to
  • Z 3 is a group represented by CR Z3 (R Z3 is a hydrogen atom or a C 1-6 alkyl group), or a nitrogen atom; B is a pyridine ring or a pyrazine ring; Compound (1).
  • R 1 is a hydrogen atom or a C 1-6 alkyl group (preferably methyl); R 2 and R 3 are both hydrogen atoms;
  • X is (1) hydroxy, (2) cyano, (3) Carbamoyl, (4) C 1-6 alkoxy (eg, methoxy), (5) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (6) C 1-6 alkylsulfonyl (eg, methylsulfonyl), (7) mono- or di-C 1-6 alkyl-amino (eg, dimethylamino), (8) C 3-8 cycloalkyl (eg, cyclopropyl), (9) may be halogenated (preferably 1 to 3 selected from C 1-6 alkoxy (eg methoxy) optionally substituted with 1 to 3 halogen atoms (eg fluorine atom)) C 6-14 aryl optionally substituted with 3 substituents (eg, phenyl), and
  • R 21 is (1) Cyano (2) Carbamoyl (3) (i) hydroxy, (ii) C 1-6 alkoxy (eg, methoxy), (iii) mono- or di-C 1-6 alkyl-amino (eg dimethylamino), (iv) C 1-6 alkylsulfanyl (eg, methylsulfanyl), and (v) C 1-6 alkylsulfonyl (eg, methylsulfonyl) C 1-5 alkyl (eg, methyl, ethyl, isopropyl, propyl) optionally substituted with 1 to 3 substituents selected from: (4) C 3-8 cycloalkyl (eg, cyclopropyl), or (5) a heterocyclic group (preferably a 5- or 6-membered aromatic heterocyclic group) optionally substituted with 1 to 3 C 1-6 alkyl (eg, methyl) (eg, pyridyl, isoxazolyl
  • Z 1 is CR Z1 (R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl) A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from: (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), or (6) A cyano group.
  • R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl)
  • a C 1-6 alkyl group eg, methyl, ethyl
  • substituents selected from: (4) C 2-6
  • a group represented by: Z 2 is CR Z2 (R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl group (eg, methyl, ethyl, isopropyl) which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) , (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), (6) a cyano group, (7) a C 6-14 aryl group (eg, phenyl), or (8) C 3-8 cycloalkyl group (eg, cyclopropyl) It is.
  • R Z2 is (1) hydrogen atom, (2) halogen atoms (eg, bromine atoms, iodine atoms), (3) C 1-6 alkyl group (eg, methyl, ethy
  • Z 3 is CR Z3 (R Z3 is a hydrogen atom or a C 1-6 alkyl group (eg, methyl)), or a nitrogen atom; B is a pyridine ring or a pyrazine ring; Compound (1).
  • R 1 is a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
  • X is (1) halogen atoms (eg, fluorine atoms), (2) hydroxy, (3) amino, (4) cyano, (5) Carbamoyl, (6) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (7) (i) a halogen atom (eg, fluorine atom), and (ii) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (8) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (9) C 1-6 alkylsulf
  • R 21 is (1) cyano, (2) Carbamoyl, (3) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (4) (i) a halogen atom (eg, fluorine atom), (ii) hydroxy, (iii) amino, (iv) cyano, (v) C 3-8 cycloalkyl (eg, cyclopropyl), (vi) (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (vii) C 3-8 cycloalkyloxy (eg, cyclopentyloxy), (viii) mono- or di-C 1-6 alkyl-amino (eg dimethyla
  • Z 1 is CR Z1 (R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl)
  • R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl)
  • a C 1-6 alkyl group eg, methyl, ethyl
  • substituents selected from: (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), (6) a cyano group, (7) a C 6-14 aryl group (eg, phenyl) optionally substituted by 1 to 3 C 1-6 alkoxy (eg, meth
  • a group represented by: Z 2 is CR Z2 (R Z2 is (1) hydrogen atom, (2) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (3) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from hydroxy (eg, methyl, ethyl, isopropyl) ), (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy, which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) ), (6) a cyano group, (7) C 6-14 aryl group (eg, phenyl), (8) a C 3-8 cycloalkyl group (eg, cyclopropyl), or
  • Z 3 is CR Z3 (R Z3 is (1) hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 hydroxys, (3) a C 1-6 alkoxy group (eg, methoxy), or (4) C 1-6 alkyl-carbonyl group (eg, acetyl) It is. ) Or a nitrogen atom; B is a pyridine ring, pyrimidine ring or pyrazine ring; Compound (1).
  • R 1 is a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
  • X is (1) halogen atoms (eg, fluorine atoms), (2) hydroxy, (3) amino, (4) cyano, (5) Carbamoyl, (6) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (7) (i) a halogen atom (eg, fluorine atom), and (ii) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (8) C 1-6 alkylsulfanyl (eg, methylsulfanyl), (9) C 1-6 alkylsulf
  • a group represented by: Z 2 is CR Z2 (R Z2 is (1) hydrogen atom, (2) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (3) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from hydroxy (eg, methyl, ethyl, Isopropyl), (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy, which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) ), (6) a cyano group, (7) C 6-14 aryl group (eg, phenyl), (8) a C 3-8 cycloalkyl group (eg, cyclopropyl), or
  • Z 3 is CR Z3 (R Z3 is (1) hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 hydroxys, (3) a C 1-6 alkoxy group (eg, methoxy), or (4) C 1-6 alkyl-carbonyl group (eg, acetyl) It is. ) Or a nitrogen atom; B is a pyridine ring, pyrimidine ring or pyrazine ring; Compound (1).
  • R 1 is a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
  • R 21 is (1) cyano, (2) Carbamoyl, (3) mono- or di-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), (4) (i) a halogen atom (eg, fluorine atom), (ii) hydroxy, (iii) amino, (iv) cyano, (v) C 3-8 cycloalkyl (eg, cyclopropyl), (vi) (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkoxy (eg, methoxy) C 1-6 alkoxy (eg, methoxy, ethoxy, isopropoxy) optionally substituted with 1 to 3 substituents selected from (vii) C 3-8 cycloalkyloxy (eg, cyclopentyloxy), (viii) mono- or di-C 1-6 alkyl-amino (eg dimethyla
  • Z 1 is CR Z1 (R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl)
  • R Z1 is (1) hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) (i) a halogen atom (eg, fluorine atom), and (ii) C 6-14 aryl (eg, phenyl)
  • a C 1-6 alkyl group eg, methyl, ethyl
  • substituents selected from: (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy), (6) a cyano group, (7) a C 6-14 aryl group (eg, phenyl) optionally substituted by 1 to 3 C 1-6 alkoxy (eg, meth
  • a group represented by: Z 2 is CR Z2 (R Z2 is (1) hydrogen atom, (2) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (3) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkyl group (eg, methyl, ethyl, optionally substituted with 1 to 3 substituents selected from hydroxy) Isopropyl), (4) C 2-6 alkenyl group (eg, vinyl), (5) C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy, which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)) ), (6) a cyano group, (7) C 6-14 aryl group (eg, phenyl), (8) a C 3-8 cycloalkyl group (eg, cyclopropyl),
  • Z 3 is CR Z3 (R Z3 is (1) hydrogen atom, (2) a C 1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 hydroxys, (3) a C 1-6 alkoxy group (eg, methoxy), or (4) C 1-6 alkyl-carbonyl group (eg, acetyl) It is. ) Or a nitrogen atom; B is a pyridine ring, pyrimidine ring or pyrazine ring; Compound (1).
  • R 1 is a hydrogen atom; R 2 and R 3 are both hydrogen atoms;
  • X is (1) hydroxy, and (2) C 1-6 alkoxy (eg, methoxy) A C 1-6 alkylene group (preferably a C 1-5 alkylene group, more preferably —CH (CH 3 ) — or —CH (CH) optionally substituted with 1 to 3 substituents selected from (CH 3 ) 2 ) —);
  • A is (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkoxy optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) (eg, methoxy)
  • a C 6-10 aryl group eg, phenyl
  • R 21 is a C 1-5 alkyl group (eg, methyl, isopropyl) optionally substituted with hydroxy or C 1-6 alkoxy (eg, methoxy);
  • R 22 is (1) a halogen atom (eg, fluorine atom), or (2) C 1-6 alkoxy (eg, methoxy) which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)),
  • p is an integer of 1 to 2.
  • R 1 is a hydrogen atom; R 2 and R 3 are both hydrogen atoms;
  • X is (1) hydroxy, and (2) C 1-6 alkoxy (eg, methoxy) A C 1-6 alkylene group (preferably a C 1-5 alkylene group, more preferably —CH (CH 3 ) — or —CH (CH) optionally substituted with 1 to 3 substituents selected from (CH 3 ) 2 ) —);
  • A is (1) halogen atoms (eg, fluorine atoms), and (2) C 1-6 alkoxy optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) (eg, methoxy)
  • a C 6-10 aryl group eg, phenyl
  • R 21 is a C 1-5 alkyl group (eg, methyl, isopropyl) optionally substituted with hydroxy or C 1-6 alkoxy (eg, methoxy);
  • R 22 is (1) a halogen atom (eg, fluorine atom), or (2) a C 1-6 alkoxy group (eg, methoxy) which may be halogenated (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom)),
  • p is an integer of 1 to 2.
  • Specific examples of the compound (1) include the following compounds 1 to 280, for example.
  • Examples of the salt of the compound represented by the formula (1) 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. Can be mentioned.
  • Preferable examples of the 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 an organic base include 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 benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
  • salt with basic amino acid include salts with arginine, lysine, ornithine and the like
  • preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Of the above-mentioned salts, pharmaceutically acceptable salts are preferable.
  • Compound (1) can be produced according to a method known per se, for example, the production method described in International Publication WO 2013/161913 or a method analogous thereto.
  • the compound (1) may be a crystal, and the compound (1) includes a single crystal form or a crystal form mixture.
  • Compound (1) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (1) may be a solvate (eg, hydrate etc.) or non-solvate (eg, non-hydrate etc.), both of which are encompassed in compound (1).
  • the A compound labeled or substituted with an isotope eg, 3 H, 14 C, 35 S, 125 I, 2 H, 11 C, 18 F, etc.
  • a deuterium converter obtained by converting 1 H to 2 H (D) is also encompassed in compound (1).
  • a compound labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.
  • PET tracer used in Positron Emission Tomography
  • Compound (1) can be used as a prodrug or as a prophylactic or therapeutic agent for migraine.
  • the prodrug of compound (I) is a compound that is converted to compound (1) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (1) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (1) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino group of the compound (1) is acylated, alkylated or phosphorylated for example, the amino group of the compound (1) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • Compounds wherein the hydroxyl group of compound (1) is acylated, alkylated, phosphorylated, borated for example, the hydroxyl group of compound (1) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds, etc.
  • Compound (1) has an excellent PDE2A inhibitory action and is toxic (eg, phototoxicity, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc., particularly phototoxicity. ) Is low, it is excellent in stability (particularly metabolic stability) and pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), and further exhibits high solubility, it is useful as a pharmaceutical product.
  • Compound (1) has a PDE2A inhibitory effect on mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.) and prevents migraine or Safe to use as a therapeutic.
  • compound (I) is used for mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.)
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.
  • Psychiatric disorders eg, depression, major depression, bipolar depression, mood disorders, emotional disorders (seasonal emotional disorders, etc.), recurrent depression, postpartum depression, stress disorder, depressive symptoms, Mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, Tourette syndrome, autism , Autism spectrum syndrome, tuberous sclerosis, fragile X syndrome, Rett syndrome, adaptation disorder, bipolar disorder, neurosis, schizophrenia (eg, positive symptoms, negative symptoms, cognitive symptoms), associated with schizophrenia Cognitive dysfunction, chronic fatigue syndrome, anxiety, obsessive-compulsive disorder
  • a pharmaceutical composition containing the compound (1) (hereinafter referred to as “the pharmaceutical of the present invention”) is a method known per se as a method for producing a pharmaceutical preparation (eg, Japanese Pharmacopoeia) In accordance with the description method, etc.)
  • Compound (1) alone or mixed with a pharmacologically acceptable carrier for example, tablets (sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • Pills powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, solutions, emulsions, suspensions, controlled release formulations (eg, immediate release formulations, Sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, orally disintegrating film, oral mucosal film), injections (eg, subcutaneous injections, intravenous injections, intramuscular injections) , Intraperitoneal injection), point Preparations, transdermal preparations, ointments, lotions, patches, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.
  • controlled release formulations eg, immediate release formulations, Sustained-release preparations, sustained-release microcapsules
  • aerosols films (eg, orally disintegrating film, oral mucosal film), injections (eg
  • Examples of the above-mentioned “pharmacologically acceptable carrier” include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials.
  • excipients lubricants, binders and disintegrants in solid preparations, or liquid preparations
  • Solvent solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, ⁇ -starch, corn starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous
  • excipients include silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.
  • lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include ⁇ -starch, crystalline cellulose, sucrose, gum arabic, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose. And sodium carboxymethyl cellulose.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, and the like.
  • solvent examples include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like. It is done.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy
  • hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polysorbate, and polyoxyethylene hydrogenated castor oil.
  • isotonic agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • Examples of the colorant include water-soluble edible tar dyes (eg, edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos.
  • water-insoluble lake dyes eg, the above-mentioned water-soluble Edible tar pigment aluminum salts
  • natural pigments eg, ⁇ -carotene, chlorophyll, bengara
  • sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the content of the compound (1) in the medicament of the present invention varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.01 to 100% by weight of the whole medicament, preferably about 0.1 ⁇ 95% by weight.
  • the dose of compound (1) varies depending on the administration subject, administration route, symptoms and the like, but when administered orally to a migraine patient (adult, about 60 kg body weight), usually about 0.1 to about 20 mg / kg body weight, Preferably, it is about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight, and these doses are about 1 to several times a day (eg, 1 to 3 times) is preferred.
  • Compound (1) may be administered as a single active substance, or in combination with anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), analgesics and other migraine treatments Also good.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Other drugs used to treat migraine comorbidities such as hypertension, heart disease, cerebrovascular disorder, depression, bipolar disorder, anxiety disorder, epilepsy, asthma, allergic disease, autoimmune disease
  • Such other pharmaceuticals used in combination are hereinafter sometimes referred to as “concomitant drugs”.
  • Anti-inflammatory agents include NSAIDs such as aspirin, diclofenac, indomethacin, ibuprofen, ketoprofen, naproxen, piroxicam.
  • analgesics include acetaminophen.
  • Migraine treatments include triptans (eg, 5HT 1B / 1D receptor agonists such as sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan), ergotamine preparations (eg, ergotamine tartrate, mesyl Serotonin agonists such as dihydroergotamine acid), anti-serotonin drugs (eg, dimethodiazine mesylate), and Ca antagonists (eg, romeridine, verapamil, etc.).
  • triptans eg, 5HT 1B / 1D receptor agonists such as sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan
  • ergotamine preparations eg, ergotamine tartrate, mesyl Serotonin agonists such as dihydroergotamine acid
  • anti-serotonin drugs eg, dimethodi
  • Antiemetics may be used in combination when used in combination with the anti-inflammatory, analgesic or migraine treatment in the acute phase.
  • Antihypertensive drugs include ⁇ -blockers such as propranolol and metoprolol, ACE inhibitors such as lisinopril, delapril, perindopril, cilazapril, captopril, enalapril, benazepril, imidapril, and ARBs such as candesartan cilexetil, losartan, valsartan, etc. Is mentioned.
  • digitalis preparations such as digitoxin and digoxin, ⁇ 1 stimulants such as dobutamine, denopamine, dopamine, and docarpamine, adenylate cyclase (AC) activators such as colforsin dapart, aminophylline, milrinone, olprinone Phosphodiesterase inhibitors such as furosemide, hydrochlorothiazide, carperitide and the like.
  • ⁇ 1 stimulants such as dobutamine, denopamine, dopamine, and docarpamine
  • adenylate cyclase (AC) activators such as colforsin dapart, aminophylline, milrinone, olprinone Phosphodiesterase inhibitors such as furosemide, hydrochlorothiazide, carperitide and the like.
  • cerebrovascular disorder therapeutic agents include cerebral protective drugs such as edaravone, anticoagulants such as warfarin, dabigatran, rivaroxaban and edoxaban, and t-PA preparations such as alteplase, monteplase and pamiteplase.
  • cerebral protective drugs such as edaravone
  • anticoagulants such as warfarin, dabigatran, rivaroxaban and edoxaban
  • t-PA preparations such asreteplase, monteplase and pamiteplase.
  • Examples of the drug used for the treatment of depression include amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, bupropion, ecitalopram, mirtazapine, venlafaxine, duloxetine and the like.
  • bipolar disorder drug include lithium, olanzapine, aripiprazole, valproic acid and the like.
  • Examples of therapeutic agents for anxiety disorders include GABA A receptor enhancers such as alprazolam, diazepam, lorazepam, and loflazep.
  • Examples of the drug used for the treatment of epilepsy include phenytoin, phenobarbital, carbamazepine, valproic acid, ethosuximide, gabapentin, solfeton, ferbatol and the like.
  • therapeutic agents for asthma include fluticasone, beclomethasone, montelukast, cromoglycic acid, salmeterol, formoterol, tulobuterol, salbutamol, procaterol, theophylline, tiotropium, glycopyrronium and the like.
  • Anti-histamine drugs such as fexofenadine and ketotifen, chemical mediator release inhibitors such as tranilast and cromoglycic acid, anti-leukotriene drugs such as pranlukast and montelukast, and steroid drugs such as beclomethasone and fluticasone Etc.
  • therapeutic agents for autoimmune diseases include COX2 inhibitors such as Celebrex and Biox, immunosuppressants such as azathioprine, cyclosporine and methotrexate, and anti-cytokine agents such as infliximab, etanercept, and MRA.
  • the administration form of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • dosage forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different administration routes at different time intervals (eg, administration in the order of the compound of the present invention and the concomitant drug) Or
  • the concomitant drug and the compound of the present invention can be administered simultaneously.
  • the compound of this invention can be administered after administration of a concomitant agent, and a concomitant agent can be administered after administration of the compound of this invention.
  • the administration time varies depending on the active ingredient to be administered, the dosage form, and the administration method.
  • the concomitant drug or a pharmaceutical composition thereof is administered first, the compound (1) or the pharmaceutical composition thereof is administered for 1 minute to 3 days, preferably 10 minutes to 1 day after administration of the concomitant drug or the pharmaceutical composition thereof. More preferably, it can be administered within 15 minutes to 1 hour.
  • the concomitant drug or the pharmaceutical composition thereof is used for 1 minute to 1 day after administration of the compound of the present invention or the pharmaceutical composition thereof, preferably 10 minutes to It can be administered within 6 hours, more preferably within 15 minutes to 1 hour.
  • an arbitrary dose can be set.
  • the dose as a concomitant drug varies depending on the dosage form, administration subject, administration route, target disease, symptom, and the like. About 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once (eg, 1 to 3 times).
  • each dose can be reduced within a safe range in consideration of the opposite effect of each drug.
  • the concomitant drug of the present invention has low toxicity.
  • compound (1) or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, for example, a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a patch an orally disintegrating tablet, an orally disintegrating film, and the like, and can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.).
  • Examples of the “pharmacologically acceptable carrier” that may be used for the production of the combination agent of the present invention include those described above as the “pharmacologically acceptable carrier” that may be used for the production of the pharmaceutical of the present invention. Is mentioned.
  • the compounding ratio of the compound (1) and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, target disease and the like.
  • the concomitant drugs in the concomitant drug of the present invention may be used in combination of two or more as necessary.
  • the dose of the concomitant drug can be appropriately selected depending on the clinically used dose.
  • the compounding ratio of the compound (1) and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug when administered to humans, can be used in the range of about 0.01 to 100 parts by weight with respect to 1 part by weight of the compound of the present invention.
  • the content of compound (1) in the concomitant drug varies depending on the form of the preparation, but is usually about 0.01 to 99.9% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, Preferably it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug varies depending on the form of the preparation, but is usually about 0.01 to 99.9% by weight, preferably about 0.1 to 50% by weight, more preferably about 0, based on the whole preparation. .5 to 20% by weight.
  • the content of an additive such as a carrier in the concomitant agent varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. The same content may be used when compound (1) and the concomitant drug are formulated separately. As described above, since the dosage varies under various conditions, a dosage smaller than the above dosage may be sufficient, and a dosage exceeding the above range may be required.
  • Test example 1 Effect of Compound A on Rat Histamine-Induced Skin Eczema Model Experimental animals purchased male SD rats from Nippon Charles River. The animals were used for the experiments with an acclimatization period of at least 1 week after being brought into the animal experiment facility. The animal experiment facility had a 12-hour light-dark cycle, and was bred in an environment where it was possible to freely drink and drink with controlled humidity and temperature. The handling of experimental animals and the experimental procedures for this study were approved by the Experimental Animal Ethics Committee of Takeda Pharmaceutical Company Limited. Compound A was suspended in a 0.5% methylcellulose solution (solvent), and histamine (Wako Pure Chemical Industries, Ltd.) and Pontamine Sky Blue (Tokyo Chemical Industry Co., Ltd.) were dissolved in physiological saline.
  • the rat ventral side was shaved under isoflurane anesthesia (2-4%) or treated with a human hair remover.
  • Compound A or the positive control drug cetirizine (Tokyo Chemical Industry Co., Ltd.) was orally administered (2 mL / kg) and returned to the cage.
  • pentobarbital anesthesia [somnopentyl (50 mg / kg) was administered intraperitoneally, and after 5 minutes, Pontamine Sky Blue (50 mg / kg / mL) was administered into the tail vein.
  • physiological saline, 50 ⁇ g of histamine, or 100 ⁇ g (50 ⁇ L / rat) was intradermally administered.
  • Test example 2 Effect of Compound A on the Vascular Permeability of Human Umbilical Vein Endothelial Cells
  • Human umbilical vein endothelial cells (HUVEC) were treated with collagen I from the Vascular Permeability Assay Kit (CultreCoat 96 Well In Vitro Vascular Permeability Assay, Trevigen).
  • the seed was seeded at 1 ⁇ 10 5 cells / 50 ⁇ l / well in the coat top chamber, and 150 ⁇ l / well of medium was added to the bottom chamber and cultured at 37 ° C. for 3 days.
  • Endothelial cell culture medium (EGM-2 BulletKit, Lonza) was used for the culture.
  • Compound A was dissolved in a medium for endothelial cells so that the powder was dissolved in DMSO and the DMSO concentration of the final additive solution was 0.1%.
  • TNF- ⁇ was dissolved in water and diluted to a final concentration of 2.5 nM with medium for endothelial cells.
  • the solvent (0.1% DMSO-containing medium) and the additive solution (compound A solution, TNF- ⁇ solution) were each dispensed into a polypropylene 96-well plate, and heated in a 37 ° C. incubator for 30 minutes or more before being added to the cells.
  • the medium was removed, and the solvent and additive solution were added to the top chamber at 50 ⁇ l / well and the bottom chamber at 150 ⁇ l / well, respectively.
  • the solvent and additive solution were added to the top chamber at 50 ⁇ l / well and the bottom chamber at 150 ⁇ l / well, respectively.
  • add medium to the bottom chamber add FITC-labeled dextran to the top chamber, leave it at 37 ° C for 5 minutes, remove the top chamber from the plate, and remove fluorescence from the bottom chamber (excitation wavelength). 485 nm, fluorescence wavelength 520 nm).
  • the fluorescence of each group was calculated as the degree of vascular permeability when the fluorescence of the solvent group was 100%, and the average is shown in FIG. It was expressed as a graph of value + standard error. Comparison between the two groups was tested by Student's t-test (* p ⁇ 0.05, comparison between the solvent + TNF- ⁇ group and the compound A + TNF- ⁇ group).
  • the permeability of human umbilical vein endothelial cells which was increased 3.3-fold by TNF- ⁇ , decreased to 2.5-fold by the action of Compound A. From the above test results, it was suggested that Compound A suppresses the increase in vascular permeability and is effective in preventing or treating migraine.
  • Test example 3 Effect of test compound on inflammatory cytokines of rat microglia cells
  • Rat microglia cells (DIV14) were seeded in DMEM / F12 (10% FBS) at 25,000 cells / well (250 ⁇ L) in a 96-well plate (sumilon PLL coated) Incubate at 37 ° C for 1 hour. After confirming complete adhesion, the whole medium is replaced with serum-free DMEM / F12 (160 ⁇ L / well), and further cultured for 1 hour. Add 20 ⁇ L of 10 ⁇ M test substance diluted in serum-free medium, and add polyI: C 30 minutes later. After 2 hours, RNA is extracted using Fastlane PCR according to the protocol of the kit, and the amount of RNA is quantified by Taqman PCR.
  • Test example 4 Effect of test compound in brain inflammation model induced by Lipopolysaccharide (LPS) Animals can purchase male ICR mice from CLEA Japan. Use it for experiments with an acclimatization period of at least about 1 week after being brought into the animal experiment facility.
  • the animal experiment facility has a 12-hour light-dark cycle, and is kept in an environment that allows free drinking and drinking with controlled humidity and temperature.
  • the test compound is suspended in 0.5% Methyl cellulose (MC) solution and administered orally.
  • MC Methyl cellulose
  • LPS is dissolved in physiological saline and administered intraperitoneally. All drugs are administered to mice at a dose of 10 mL / kg. After drug administration, the mouse is decapitated, the brain is removed, fractionated, and stored at -80 ° C.
  • RNA is extracted according to the protocol of QIAZOL and RNeasy mini kit, and the amount of RNA is quantified by Taqman PCR.
  • Formulation Example 1 (1) Compound No. 1 10.0 g (2) Lactose 70.0g (3) Corn starch 50.0g (4) 7.0g of soluble starch (5) Magnesium stearate 3.0 g Compound 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with an aqueous solution of soluble starch (70 mL) (7.0 g as soluble starch), then dried, lactose (70.0 g) and corn starch ( (Lactose, corn starch, soluble starch, and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
  • a prophylactic / therapeutic agent for migraine comprising compound (1) having a PDE2A selective inhibitory action
  • compound (1) having a PDE2A selective inhibitory action can be provided.

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Abstract

　L'invention concerne un agent pour la prévention/le traitement de migraines, ledit agent contenant un composé (1) qui présente une action inhibitrice sélective sur. la PDE2A L'invention concerne également un composé représenté par la formule (1) (les symboles de la formule sont tels que spécifiés dans la description) ou un de ses sels.
PCT/JP2015/062454 2014-04-25 2015-04-23 Agent thérapeutique de la migraine WO2015163431A1 (fr)

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Citations (5)

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JP2004507514A (ja) * 2000-08-30 2004-03-11 リリー　アイコス　リミテッド　ライアビリティ　カンパニー 片頭痛の治療法
JP2010506561A (ja) * 2006-10-14 2010-03-04 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト Ｐｄｅ２ａの阻害
WO2012168817A1 (fr) * 2011-06-07 2012-12-13 Pfizer Inc. Composés pyrazolo[3,4-d]pyrimidine et leur utilisation comme inhibiteurs de la pde2 et/ou inhibiteurs du cyp3a4
JP2013509442A (ja) * 2009-10-29 2013-03-14 サートリス ファーマシューティカルズ， インコーポレイテッド サーチュイン調節因子としての二環式ピリジンおよび類似体
WO2013161913A1 (fr) * 2012-04-25 2013-10-31 武田薬品工業株式会社 Composé hétérocyclique azoté

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JP2004507514A (ja) * 2000-08-30 2004-03-11 リリー　アイコス　リミテッド　ライアビリティ　カンパニー 片頭痛の治療法
JP2010506561A (ja) * 2006-10-14 2010-03-04 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト Ｐｄｅ２ａの阻害
JP2013509442A (ja) * 2009-10-29 2013-03-14 サートリス ファーマシューティカルズ， インコーポレイテッド サーチュイン調節因子としての二環式ピリジンおよび類似体
WO2012168817A1 (fr) * 2011-06-07 2012-12-13 Pfizer Inc. Composés pyrazolo[3,4-d]pyrimidine et leur utilisation comme inhibiteurs de la pde2 et/ou inhibiteurs du cyp3a4
WO2013161913A1 (fr) * 2012-04-25 2013-10-31 武田薬品工業株式会社 Composé hétérocyclique azoté

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