WO2013161929A1 - Dérivé de pyridinyl-morpholinone et composition médicamenteuse contenant celui-ci - Google Patents

Dérivé de pyridinyl-morpholinone et composition médicamenteuse contenant celui-ci Download PDF

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WO2013161929A1
WO2013161929A1 PCT/JP2013/062182 JP2013062182W WO2013161929A1 WO 2013161929 A1 WO2013161929 A1 WO 2013161929A1 JP 2013062182 W JP2013062182 W JP 2013062182W WO 2013161929 A1 WO2013161929 A1 WO 2013161929A1
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substituted
unsubstituted
group
compound
aromatic
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Japanese (ja)
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一成 服部
健二 高谷
一穂 川瀬
夏枝 青木
義人 石田
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塩野義製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to a compound useful for treating a disease or condition involving a voltage-gated sodium channel Nav1.7 (hereinafter referred to as Nav1.7), and a pharmaceutical composition containing the compound.
  • Nav1.7 voltage-gated sodium channel
  • Voltage-gated sodium channels are present in excitable cells such as the central, peripheral, cardiac, skeletal and neuroendocrine cells. Responds to depolarization of cell membrane potential and is involved in action potential generation and conduction. Voltage-gated sodium channels play an important role in signal generation and signal conduction in nerves and myocardium and are essential for maintaining the function of the nervous system, heart and muscle. Abnormalities of voltage-gated sodium channels are involved in diseases such as epilepsy (Non-patent document 1), chronic pain (Non-patent document 2), myotonia (Non-patent document 3), and arrhythmia (Non-patent document 4). Is known (Non-Patent Document 5).
  • the voltage-gated sodium channel is composed of an ⁇ subunit that forms an ion channel pore and a ⁇ subunit that is an auxiliary subunit.
  • the ⁇ subunit is a protein having a molecular weight of about 260 kDa consisting of four homologous domains each having six transmembrane regions (S1 to S6 segments) and a pore loop region existing between the S5 and S6 segments.
  • a channel that permeates sodium ions is formed at the center of the four homology domains.
  • the ⁇ subunit has 9 subtypes, Nav1.1 to Nav1.9, and the sensitivity and expression site of ion channel activity inhibition by the pufferfish tetrodotoxin (TTX) vary depending on each subtype. It has been known.
  • Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7 have ion channel activity inhibited by TTX.
  • Nav1.5, Nav1.8 and Nav1.9 are less sensitive to TTX.
  • Nav1.1, Nav1.2 and Nav1.3 are nervous systems
  • Nav1.4 is skeletal muscle
  • Nav1.5 is myocardium
  • Nav1.6 is nervous system
  • Nav1.7, Nav1.8 and Nav1.9 are mainly It is expressed in the peripheral nervous system. It is known to be related to biological functions related to each expression site (Non-patent Document 5).
  • Nav1.7 is distributed in peripheral nervous systems such as the sympathetic nervous system and sensory nervous system, and forms a TTX sensitive sodium channel. Recently, it has become clear that it is specifically involved in pain signals. In KO mice deficient in the Nav1.7 gene in sensory nerves, it has been reported that mechanical and thermal pain thresholds are increased, and increase in pain sensation is suppressed in an inflammatory pain model (Non-Patent Literature). 6). In addition, the relationship between the mutation of the gene and pain sensation has been found in humans. From the family analysis of extremity erythema showing increased flushing and pain sensation in the periphery of the limb, SCN9A encoding Nav1.7 It has been reported that a gain of function type mutation has occurred (Non-patent Document 7).
  • lidocaine and mexiletine which are subtype non-specific sodium channel inhibitors, are known to exhibit analgesic action in clinical practice and are used as pain therapeutic agents (Non-patent Document 9).
  • Nav1.7 selective inhibitor having a weak inhibitory activity against Nav1.5 exhibits a powerful analgesic action and is very useful as a therapeutic agent for various pain pathologies overcoming safety concerns. It is done.
  • Patent Documents 1 and 2 describe compounds having a Nav1.7 inhibitory action, but differ in structure from the compounds of the present invention.
  • Patent Documents 3 to 5 describe compounds having a structure similar to that of the compound of the present invention, but there is no description or suggestion regarding Nav1.7 inhibitory action.
  • An object of the present invention is to provide a novel compound having a Nav1.7 inhibitory action and a pharmaceutical composition having a Nav1.7 inhibitory action.
  • the present invention relates to the following (1) to (12) and (1 ′) to (8 ′).
  • -X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
  • Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted al
  • (4) -X- is a single bond, -O- (CH 2 ) p-, or -N (H)-(CH 2 ) r-; p and r are each independently 0 or 1, The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof.
  • R 3 is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group.
  • R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group A heterocyclic group;
  • -X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
  • Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
  • Each R 5b independently represents a hydrogen atom, substituted or unsubstituted
  • R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group
  • —X— represents a single bond, —O— (CH 2 ) p—, or —N (H) — (CH 2 ) r—
  • p and r are each independently 0 or 1 -Y- is a single bond or substituted or unsubstituted alkylene
  • R 3 represents a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Group, or substituted or unsubstituted non-aromatic heterocyclic group
  • a pharmaceutical composition comprising the compound according to any one of (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof.
  • (12) A disease associated with Nav1.7, comprising administering the compound according to any one of (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof. Treatment and / or prevention methods.
  • the compound according to the present invention has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for a disease or condition involving Nav1.7.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Yet another embodiment includes methyl, ethyl, n-propyl, isopropyl, tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position. Examples of “alkynyl” include ethynyl, propynyl, butynyl, pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included. These may further have a double bond at an arbitrary position. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.
  • “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. Examples of the “aromatic carbocyclic group” include phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a 5- to 7-membered non-aromatic heterocyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring, A non-aromatic heterocyclic group in which two or more of them are independently fused, A 5- to 7-membered non-aromatic heterocycle having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring is one or more rings in the above “aromatic carbocyclic group”, A non-aromatic heterocyclic group fused with a ring in the “non-aromatic carbocyclic group”, or a ring in the “aromatic heterocyclic group”, or A non-aromatic heterocyclic group in which the ring in the “aromatic heterocyclic group” is fused with one or more rings in the “non-aromatic carbocyclic group”; Is included.
  • non-aromatic heterocyclic group includes a group which forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzofuran, dihydrobenzodioxin and the like.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Examples of the “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom.
  • vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like can be mentioned.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the above “halogens” are bonded to the above “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Examples of the “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Examples of the “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Examples of the “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned. Examples of the “monoalkylamino” include methylamino and ethylamino.
  • Dialkylamino means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like. Examples of the “dialkylamino” include dimethylamino and diethylamino.
  • dialkylaminoalkyl means a group in which the “alkyl” is substituted with the nitrogen atom of the “dialkylamino”. Examples thereof include dimethylaminoalkyl, diethylaminoalkyl, N, N-diisopropylaminoalkyl, N-methyl-N-ethylaminoalkyl, N-isopropyl-N-ethylaminoalkyl and the like. Examples of the “dialkylaminoalkyl” include dimethylaminoalkyl and diethylaminoalkyl.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • alkylsulfonyl include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • Examples of the “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Examples of the “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like. Examples of the “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned. Examples of the “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
  • alkylcarbonyloxy include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
  • alkyloxycarbonyl include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
  • Dialkylcarbamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.
  • Dialkylsulfamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyls may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc. Examples of the “aromatic carbocyclic alkyl” include benzyl, phenethyl, and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl part is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • non-aromatic heterocyclic alkyloxy means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”.
  • non-aromatic heterocyclic alkyloxyalkyl substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • aromatic carbocyclic oxy means a group in which an “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocyclic carbonyl means a group in which an “aromatic carbocycle” is bonded to a carbonyl group.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl”
  • the “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
  • Non-aromatic carbocycle carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
  • the “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like can be mentioned.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like.
  • aromatic heterocycle moiety of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl”
  • Aromatic heterocycle oxy means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • Aromatic heterocycle carbonyl means a group in which “aromatic heterocycle” is bonded to a carbonyl group.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • “Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle for example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • the “non-aromatic heterocyclic oxycarbonyl” means a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkeny
  • An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkylcarbonyl, alkyl,
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • Preferred embodiments of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
  • R 1 is a substituted or unsubstituted monocyclic aromatic carbocyclic group, a substituted or unsubstituted monocyclic nonaromatic carbocyclic group, a substituted or unsubstituted monocyclic aromatic heterocyclic group, or a substituted group Or an unsubstituted monocyclic non-aromatic heterocyclic group is mentioned.
  • R 1 includes substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, or substituted or unsubstituted cyclohexyl. .
  • R 1 include substituted or unsubstituted phenyl.
  • —X— includes a single bond, —O— (C (R 5a ) (R 5b )) p—, or —N (R 7 ) — (C (R 8a ) (R 8b )) r—.
  • Examples of —X— include a single bond, —O— (CH 2 ) p—, or —N (H) — (CH 2 ) r—.
  • Examples of —X— include a single bond and —O— (CH 2 ) p—.
  • p, q, and r are each independently 0 or 1. Examples of p, q and r include 0.
  • R 5a is independently a hydrogen atom, or substituted or unsubstituted alkyl.
  • R 5b include independently a hydrogen atom or substituted or unsubstituted alkyl.
  • R 6a is independently a hydrogen atom, or substituted or unsubstituted alkyl.
  • Examples of R 6b include independently a hydrogen atom or substituted or unsubstituted alkyl.
  • R 7 includes a hydrogen atom, or substituted or unsubstituted alkyl.
  • R 8a includes a hydrogen atom or substituted or unsubstituted alkyl.
  • R 8b includes a hydrogen atom, or substituted or unsubstituted alkyl.
  • R 3 is a hydrogen atom, halogen, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Examples include substituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic oxy.
  • R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic group Heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic ring Oxy is mentioned.
  • R 3 includes substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted tetrahydropyranyl, substituted Or an unsubstituted phenoxy is mentioned.
  • R 3 includes substituted or unsubstituted phenyl.
  • n may be 0. As m, 0 or 1 is mentioned. m may be 0.
  • the compound represented by the formula (I), the formula (II), the formula (III), the formula (IV) or the formula (V) or a pharmaceutically acceptable salt thereof is defined as each substituent shown above. Or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof.
  • the compound in which the “—Y—R 6 ” group is hydrogen includes the following tautomers.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base.
  • a suitable catalyst such as Pd / C
  • 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fum
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph.
  • a solvate for example, a hydrate etc.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting with a condensing agent.
  • the compound represented by the above general formula (I) has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for diseases and / or conditions involving Nav1.7.
  • Nav1.7 is considered to be involved in pain (Non-Patent Documents 6 to 8 etc.), and as diseases and / or conditions in which Nav1.7 is involved, for example, acute pain, chronic pain, neuropathic pain, inflammation Pain, visceral pain, nociceptive pain, including postoperative pain, visceral, gastrointestinal tract, skull, musculoskeletal system, spine, genitourinary system, cardiovascular and central nervous system cancer pain, and back There are multiple types of pain including pain and orofacial pain.
  • a more preferred compound of the present invention is a pharmaceutical composition having a selective Nav1.7 inhibitory action.
  • lidocaine and mexiletine which are subtype non-specific sodium channel inhibitors, also show an inhibitory action against Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11).
  • Non-patent Documents 10 and 11 Have safety concerns that can affect cardiac function, which is particularly important in For this reason, it is expected to ensure Nav1.7 inhibition selectivity especially for Nav1.5 inhibition.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
  • Hal is a halogen;
  • Lg 1 is a leaving group;
  • R A and R B are each independently hydrogen or substituted or unsubstituted alkyl, or substituted together Or forms an unsubstituted non-aromatic heterocycle;
  • each R 4a independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl Substituted or unsubstituted monoalkylamino, and Is substituted or un
  • Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 molar equivalents can be used with respect to compound A1.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • reaction solvent examples include dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.
  • Process 2 Compound A4 can be obtained by adding a base to compound A3.
  • the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium hydroxide, lithium hexamethyldisilazane, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and the like. 1 to 5 molar equivalents can be used.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
  • the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • Process 3 Compound A6 can be obtained by allowing compound A4 to react with compound A5 having a leaving group and a base.
  • the leaving group include chloro, bromo, iodine, methanesulfonyl, 4-toluenesulfonyl, trifluoromethanesulfonyl and the like.
  • Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium hydroxide, lithium hexamethyldisilazane, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and the like. 1 to 5 molar equivalents can be used.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • Compound A8 can be obtained by reacting compound A6 with boronic acid or boronic ester A7 in the presence of a metal catalyst and a base.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to Compound A6.
  • Examples of the phosphine ligand include (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6- And tetramethyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, and the like.
  • 0.001 to 0.5 molar equivalent can be used.
  • [(2-biphenyl) dicyclohexylphosphine] palladium which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent based on Compound A6.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus
  • Examples thereof include tripotassium acid, potassium hydrogen phosphate and the like, and 1 to 10 molar equivalents can be used with respect to compound A6.
  • Boronic acid or boronic acid ester A7 can be used at 1 to 10 molar equivalents relative to compound A6.
  • the reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, water, ethanol, 2-propanol, tert-butanol and the like, and these can be used alone or in combination.
  • R A and R B are each independently hydrogen or substituted or unsubstituted alkyl or taken together are substituted or unsubstituted non-aromatic
  • Each R 4b independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted Monoalkylamino or substituted or unsubstituted di M2 is
  • Examples of the leaving group include chloro, bromo, iodine, methanesulfonyl, 4-toluenesulfonyl, trifluoromethanesulfonyl, and the like.
  • Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazane, lithium diisopropylamide and the like, and 1 to 5 molar equivalents can be used with respect to compound A6.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • Process 2 Compound B3 can be obtained by the method described in the fourth step of Method A using Compound B2 instead of Compound A6.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to Compound C1.
  • Examples of the phosphine ligand include (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6- And tetramethyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, and the like.
  • 0.001 to 0.5 molar equivalent can be used.
  • [(2-biphenyl) dicyclohexylphosphine] palladium which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent based on the compound C1.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus
  • Examples thereof include tripotassium acid, potassium hydrogen phosphate, lithium hexamethyldisilazane and the like, and can be used at 1 to 10 molar equivalents relative to compound C1.
  • the primary or secondary amine C2 can be used in an amount of 1 to 10 molar equivalents relative to the compound C1.
  • the reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane, and the like, and these can be used alone or in combination.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound D1.
  • the phosphine ligand includes (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2 ′, 4 ′, 6 ′.
  • [(2-biphenyl) dicyclohexylphosphine] palladium which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound D1.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus
  • Examples thereof include tripotassium acid, potassium hydrogen phosphate, lithium hexamethyldisilazane and the like, and can be used at 1 to 10 molar equivalents relative to compound D1.
  • Phenol D2 can be used at 1 to 10 molar equivalents relative to compound D1.
  • the reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane, and the like, and these can be used alone or in combination.
  • More preferred compounds of the present invention have not only a Nav1.7 inhibitory action but also usefulness as a medicament, and have any or all of the following excellent characteristics.
  • a) The inhibitory effect on CYP enzymes eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • b) Good pharmacokinetics such as high bioavailability and moderate clearance.
  • d) Does not exhibit irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • parenteral administration any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • Specific examples of the compound of the present invention include compounds having the following Rp and Rq in the following general formula (III ′).
  • Example 1 (1) Synthesis of compound 2 Compound 1 (50.00 g, 0.204 mol) and chloroacetic acid (23.09 g, 0.244 mol) were suspended in dry dichloromethane (1 L), and diisopropylethylamine (71 mL, 0.407 mol) was added under a nitrogen atmosphere. . The solid in the reaction solution was dissolved over about 10 minutes at room temperature, and the reaction solution became orange. 2-hydroxypyridine-N-oxide (27.15 g, 0.244 mol) and EDC hydrochloride (46.80 g, 0.244 mol) were sequentially added, and the mixture was stirred for 2.5 hours at room temperature under a nitrogen atmosphere. The disappearance of the raw material was confirmed by LC / MS.
  • the reaction solution was cooled in an ice-water bath, and a saturated aqueous ammonium chloride solution (250 mL) was added dropwise while maintaining the reaction solution temperature at about 10 degrees to stop the reaction.
  • the organic layer was separated and the aqueous layer was washed 3 times with ethyl acetate (250 mL).
  • the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure.
  • Isohexane about 200 mL was added to the obtained residue to solidify it.
  • the solid was collected by filtration and washed twice with isohexane (100 mL). It was dried at 40 ° C. under reduced pressure for 4 hours to obtain Compound 3 (24.02 g, yield 93%).
  • the resulting reddish brown solution is stirred at room temperature for 20 minutes.
  • the reaction is cooled with an ice-water bath and alkyl halide (75 mmol, 1.5 eq) is added over 10 minutes while maintaining the reaction temperature at 10-15 degrees. Remove the ice-water bath and stir at room temperature.
  • the reaction solution is cooled in an ice-water bath and quenched with water (50 mL).
  • the reaction solution was concentrated under reduced pressure to remove DMF. To the obtained residue are added ethyl acetate (400 mL), saturated brine (100 mL), and water (100 mL), and the mixture is separated.
  • aqueous layer is washed four times with ethyl acetate (400 mL), and the combined organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the resulting residue is solidified in diethyl ether and purified by filtration or by silica gel column chromatography (100% dichloromethane to 5% methanol-95% dichloromethane, or 80% ethyl acetate-isohexane to 100% ethyl acetate). Purification can give compound 4.
  • Example 2 Synthesis of Compound I-262 Process 1 To a solution of 2-amino-2- (5-bromopyridin-3-yl) ethanol hydrochloride (10 g, 39.4 mmol) and chloroacetic acid (4.5 g, 47.3 mmol) in dichloromethane (200 mL) was added DIEA (6. 9 mL, 39.4 mmol) was added. After stirring at room temperature for 10 minutes, 2-hydroxypyridine-1-oxide (5.3 g, 47.3 mmol) and EDC (9.1 g, 47.3 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
  • Example 5 Synthesis of Compound I-275 To a solution of compound 9 (40 mg, 0.12 mmol) obtained in the same manner as in Example 2 in DMF (0.3 mL) was added potassium tert-butoxide (20 mg, 0.17 mmol), bromomethylcyclohexane (17 mg, 0 mL). .17 mmol) was added. After stirring at room temperature overnight, ethyl acetate was added, washed with saturated brine, and the organic layer was concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound I-275 (42 mg, yield: 82%).
  • Test Example 1 Evaluation of Nav1.7 inhibitory activity The degree to which the compound of the present invention inhibits Nav1.7 function was evaluated by the following method.
  • HEK293 cells stably expressing human Nav1.7 were seeded at 8000 cells / well in a 384-well microtiter plate, cultured for 24 hours in a 37 ° C., 5% CO 2 incubator and used as an assay plate. Each well of the assay plate was washed with assay buffer (10 mmol / L HEPES, 10 mmol / L Glucose, 137 mmol / L NaCl, 4 mmol / L KCl, 1 mmol / L MgCl2, 1.8 mmol / L CaCl2, pH 7.4). .
  • the assay plate was set in a kinetic fluorescence measurement apparatus FLIPR TETRA (Molecular devices), and the fluorescence intensity derived from the fluorescent indicator in each well was measured at intervals of 1 to 10 seconds at an excitation wavelength of 488 nm and a measurement wavelength of 510 to 570 nm. .
  • FLIPR TETRA Molecular devices
  • the fluorescence intensity derived from the fluorescent indicator in each well was measured at intervals of 1 to 10 seconds at an excitation wavelength of 488 nm and a measurement wavelength of 510 to 570 nm.
  • Using a pipetter with built-in FLIPR TETRA in each well add 10 ⁇ L of the compound solution of the present invention diluted with assay buffer immediately after the start of measurement, and further open 10 ⁇ L of sodium channel diluted with assay buffer approximately 5 minutes after the start of measurement.
  • the agent Veratridine solution was added and mixed (final concentration of Veratridine: 40 ⁇ mol / L).
  • IC50 value The calculation method of Nav1.7 inhibitory activity (IC50 value) of the compound of the present invention is shown below. For each well, the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity value from immediately before the addition of Veratridine solution to 3 minutes later was calculated.
  • the inhibition rate of the compound of the present invention was calculated from the following formula using a well added with DMSO as a solvent of the compound of the present invention as a negative control and a well added with mexiletine (final concentration of mexiletine: 500 ⁇ mol / L) as a positive control.
  • Inhibition rate (1- (change amount by the compound of the present invention ⁇ change amount by positive control) / (change amount by negative control ⁇ change amount by positive object)) ⁇ 100
  • the inhibition rate was determined for the compound concentrations of the present invention of 0.156, 0.312, 0.625, 1.25, 2.50, 5.00, 10.0, 20.0 ⁇ mol / L (8 points), and the IC50 value ( ⁇ mol / L) was calculated by the logistic approximation method.
  • the test results of the compounds of the present invention are shown in the following table.
  • Test Example 2 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction.
  • NADPH a coenzyme
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
  • Intravenous administration is performed from the tail vein using a syringe with a needle.
  • Evaluation item Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
  • the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio of the group and the AUC ratio.
  • Test Example 4 Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
  • Test Example 5 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution. 7.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate:
  • the cells are suspended in 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL) To the MicroF buffer).
  • TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • HEK293 cells expressing human ether-a-go-related gene (hERG) channels are used for ventricular repolarization process.
  • I Kr delayed rectifier K + current
  • the cell was held at a membrane potential of ⁇ 80 mV by the whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, depolarization stimulation of +40 mV was applied.
  • the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
  • Test Example 7-2 hERG Test Ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Lactose 15mg Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g Are mixed well, compression molded, pulverized, sized, and sieved to obtain granules of appropriate size.
  • the compound according to the present invention has an inhibitory action against Nav1.7, and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving Nav1.7.

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Abstract

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Dans ladite formule, R1 est un groupe cyclique carboné aromatique ou analogue; -X- représente une liaison simple; -O(C(R5a)(R5b))p- ou analogue; R5a et R5b sont des atomes d'hydrogène ou analogue; p est 0 ou analogue; R2 est un halogène ou analogue; n est 0 ou analogue; -Y- représente une liaison simple, un alkylène substitué ou non substitué ou analogue; R3 est un atome d'hydrogène ou analogue; R4 est un halogène ou analogue; et m est 0 ou analogue).
PCT/JP2013/062182 2012-04-26 2013-04-25 Dérivé de pyridinyl-morpholinone et composition médicamenteuse contenant celui-ci WO2013161929A1 (fr)

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US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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