WO2008069242A1 - Nouveau composé hétérocyclique bicyclique - Google Patents

Nouveau composé hétérocyclique bicyclique Download PDF

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WO2008069242A1
WO2008069242A1 PCT/JP2007/073506 JP2007073506W WO2008069242A1 WO 2008069242 A1 WO2008069242 A1 WO 2008069242A1 JP 2007073506 W JP2007073506 W JP 2007073506W WO 2008069242 A1 WO2008069242 A1 WO 2008069242A1
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mmol
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Katsunori Tsuboi
Yusuke Yamai
Hironori Kinoshita
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Dainippon Sumitomo Pharma Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a pathological condition involving SNS (sensory neuron specific sodium channel) containing a novel compound having a 2-quinolone skeleton as a bicyclic heterocycle or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to therapeutic or preventive drugs for the whole. Specifically, the present invention relates to a therapeutic or prophylactic agent for diseases such as neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis.
  • V ⁇ 0 sensorv neuron specific sodium channel that is, SNS is a force
  • SNS is a force
  • one of the Na channel ⁇ subunits, localized in small diameter cells (C fibers) of dorsal root ganglia involved in nerve perception Tetrodotoxin (ii) is a resistant Na channel, also called SCN10A, PN3, or NaVl.8 (Non-patent Documents 1 and 2).
  • SNS knockout mice become numb in response to mechanical stimulation !, and in the model of neuropathic pain or inflammatory pain, administration of antisense to SNS causes hypersensitivity and abnormalities. Reported to be attenuated! /
  • SNS inhibitors can be drugs that have analgesic effects on diseases such as neuropathic pain and nociceptive pain accompanied by pain, numbness, burning, dull pain, etc. involving C fiber. It was. Furthermore, since SNS is not expressed in non-neural tissues and the central nervous system, It was thought that drugs that selectively inhibit can be drugs that have no side effects derived from non-neural tissues or central nervous system.
  • SNS inhibitors are expected to be the first therapeutic or preventive agent for the induction of symptoms such as ataxia due to abnormal firing of the cerebellar nerve associated with SNS expression in multiple sclerosis.
  • Neuropathic pain means that there is no trauma, or there is no inflammatory involvement of the tissue due to complete cure, and spontaneous pain or chronic pain develops due to nerve damage or nerve stimulation! It refers to pain.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • opioids such as morphine have problems with drug resistance and psychiatric symptoms.
  • mexiletine The only drug currently marketed for the treatment of neuropathic pain is mexiletine, which is indicated for diabetic neurosis. Although mexiletine has an analgesic effect, it has been reported that side effects are concerned due to lack of selectivity for Na channel, and it cannot be taken at high doses. Several other drugs have been indicated as supplementary indications in the clinic.
  • antidepressants sulpiride, trazodone, fluvoxatin, milnacipran
  • adrenergic agonists clozidine, dexamedetomidine
  • NMDA receptor antagonists keta hydrochloride
  • anxiolytics diazepam, lorazepam, etizolam, hydroxidine hydrochloride
  • anticonvulsants carbamazepine, phenytoin, sodium valproate, zonisamide
  • calcium antagonists diphdidipine, verabamil hydrochloride, hydrochloric acid
  • Lomeridin are all used as auxiliary. Based on the above, there is no definitive therapeutic agent that has no side effects derived from non-neural tissues and central nerves and that has an analgesic effect specifically for pain.
  • Nociceptive pain refers to pain caused by activation of nociceptors ( ⁇ , C fibers) due to mechanical, thermal or chemical noxious stimuli due to tissue injury or the like.
  • Nociceptors are sensitized by endogenous chemical stimuli (pain substances) such as serotonin, substance ⁇ , bradykinin, prostaglandin, or histamine.
  • Nociceptive pain includes low back pain, abdominal pain, rheumatoid arthritis, and pain due to osteoarthritis.
  • ⁇ SAIDS acetyl salicylic acid, acetoaminophen, diclofenac sodium, indometha
  • Urine dysfunction is mainly caused by frequent urination, urinary leakage, residual urine sensation, and micturition pain.
  • pharmacotherapy for overactive bladder is mainly muscarinic receptor inhibitors that suppress the bladder parasympathetic nerve pathway, but the limitations are clear.
  • Capsaicin and resiniferatoxin, which are vanilloid receptor stimulants, have been reported to act specifically on C fibers and suppress their functions S, C Has not been found.
  • Multiple sclerosis is a type of demyelinating disease in which demyelinating foci are scattered in the white matter of the central nervous system, and the foci are also old and new. Lesions occur frequently in the white matter around the lateral ventricle, optic nerve, brain stem, and spinal cord. Histologically, the myelin sheath is destroyed and axons and nerve cells are not affected. Clinical symptoms are Symptoms such as optic neuritis, diplopia, nystagmus such as nystagmus, spastic paralysis, painful ankylosing seizures, Lermit's syndrome, ataxia, speech disorder, bladder rectal disorder, etc. . Although the cause is unknown, theories of autoimmune disease and infection have been advocated. Currently, there are no effective prophylactic and therapeutic agents for multiple sclerosis.
  • pyrazole derivatives such as pyrazole amide compounds and pyrazole sulfonate amide compounds, piperidine derivatives, and pyrazo oral pyrimidine derivatives have been disclosed so far as agents exhibiting SNS inhibitory activity (Patent Document 1). , twenty three).
  • Patent Document 1 International Publication No. 03/037274 Pamphlet
  • Patent Document 2 International Publication No. 03/037890 Pamphlet
  • Patent Document 3 International Publication No. 03/037900 Pamphlet
  • Patent Document 4 International Publication No. 94/020471 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 91/007401
  • Patent Document 6 Pamphlet of International Publication No. 00/040562
  • Non Patent Literature 1 Nature 379: 257, 1996
  • Non-Patent Document 2 Pain 78: 107, 1998
  • Non Patent Literature 3 Urology 57: 116,2001
  • Non-Patent Document 4 Brain Research 959: 235,2003
  • An object of the present invention is to provide a therapeutic or prophylactic agent for all pathological conditions related to SNS, specifically neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis. There is to serve.
  • the present inventors have identified compounds having a 2-quinolone skeleton or their pharmaceutically acceptable drugs. Was found to inhibit TTX-resistant Na channel in human SNS gene-expressing cells, that is, to have SNS inhibitory activity.
  • R 1 is a halogen atom, cyano group, nitro group, carboxyl group, carbon number;! To 4 alkynole group, 1 to 4 haloalkyl group, 1 to 4 carbon atom alkoxy group, carbon Haloalkoxy group having 4 to 4 carbon atoms; alkylthio group having 2 to 4 carbon atoms; alkoxy group having 2 to 4 carbon atoms; ruponyl group; alkylcarbonyl group having 2 to 4 carbon atoms; one or two identical or different An amino group optionally substituted with an alkyl group, or a formula: —I ⁇ —R " 3 [wherein L 1 is a single bond, —O—, —OCH—, or a formula: —N (R U ) (Wherein R 11 is a hydrogen atom, or
  • R 1 represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted aromatic group.
  • R 2 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, carbon number;! To 4 alkyl group, 1 to 4 carbon haloalkyl group, 1 to 4 carbon atom alkoxy group, 1 carbon atom ⁇ 4 haloalkoxy group, carbon number;!
  • R 12 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, substituted or unsubstituted Alternatively, it represents an unsubstituted phenyl group or a substituted or unsubstituted aromatic heterocyclic group. Or a group represented by
  • R 1 and R 2 may combine to form a 5 7-membered ring! /.
  • n an integer of 0-5.
  • R 7 represents a hydrogen atom or an alkyl group having 16 carbon atoms.
  • R 3 and R 4 are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, substituted Or an unsubstituted cycloalkenyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, Or R 3 and R 4 together with the nitrogen atom to which they are attached may form a substituted or unsubstituted, 4- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle.
  • the nitrogen-containing aliphatic heterocycle contains 0 2 oxygen atoms, 0 2 sulfur atoms, and
  • R 8 and R 9 independently represent a hydrogen atom, a fluorine atom, or a force representing an alkyl group having 16 carbon atoms, R 8 and R 9 are bonded to each other, and together with the carbon atom to which they are bonded, 3 7 A membered cycloalkane may be formed.
  • n an integer of 16
  • the plurality of R 8 and the plurality of R 9 may be the same or different independently.
  • A is the following (a) to (c):
  • R 14 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, substituted or unsubstituted It represents an unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, or R 14 and one bond to form a 47-membered saturated or unsaturated oxygen-containing aliphatic heterocyclic ring. Also good. ];
  • R 5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a haloalkyl group
  • R 6 represents a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted group
  • R 5 And R 6 combine to form a substituted or unsubstituted 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic complex ring with N—L 3 , or R 5 and one R 8 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycles, or R 6 and one R 8 to form 5- to
  • [2] IT is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, one or the same Alternatively, an amino group which may be substituted with two different alkyl groups, or the formula: L 1 R 1Q [wherein, R 1 () has the same meaning as [1].
  • R 2 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a carbon number;!
  • R 1 is a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: L 1 — R 1 () [wherein iA R " 3 is Wherein R 2 is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a alkoxy group having 1 to 4 carbon atoms, or a formula: L 2 — R 12 (wherein L 2 and R 12 have the same meanings as [1]), a compound represented by [1] or [2], or a pharmaceutically acceptable salt thereof Acceptable salts; [4] The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein m represents an integer of 0 to 2 and R 7 represents a hydrogen atom;
  • n represents an integer of 2 to 3
  • a plurality of R 8 and a plurality of R 9 independently represent a hydrogen atom, a fluorine atom or a carbon number;!
  • A is a formula: -OR 14 [wherein R 14 has the same meaning as [1].
  • R 14 has the same meaning as [1].
  • A is represented by the formula: —N (R 5 ) -L 3 -R 6 [wherein R 5 , L 3 and R 6 have the same meanings as [1].
  • p represents an integer of 1 to 4,
  • R 4a represents a hydrogen atom or an alkyl group
  • R 15 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino group, or a substituted or unsubstituted power rubamoyl group,
  • R 16 represents a hydrogen atom or an alkyl group.
  • a pharmaceutical comprising as an active ingredient the compound according to [1] to [9] or any one of the above or a pharmaceutically acceptable salt thereof;
  • An SNS inhibitor comprising, as an active ingredient, the compound according to [1] to [9] or any one of the above or a pharmaceutically acceptable salt thereof;
  • an SNS inhibitor comprising a compound having a 2 quinolone skeleton or a pharmaceutically acceptable salt thereof.
  • the SNS inhibitor of the present invention is useful as a therapeutic or prophylactic agent for all pathological conditions involving SNS, specifically, patients with neuropathic pain, nociceptive pain, dysuria, multiple sclerosis, etc. It is applicable to.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group (1-propyl group), an isopropyl group (2-propyl group). Group), butyl group (1-butyl group), sec butyl group (2-butyl group), isobutyl group (2-methyl-1-propyl group), t-butyl group (2-methyl-2-propyl group), pentyl group ( 1 pentyl group) or hexyl group (1 hexyl group). Among them, preferred is an alkyl group having 1 to 4 carbon atoms.
  • haloalkyl group examples include a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 identical or different halogen atoms, specifically, a trifluoromethyl group, Examples include 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, and the like. Preferably a C1-C4 haloalkyl group is mentioned.
  • Alkenyl group refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, a bur group, a 1 propenyl group, a 2-propenyl group, a 1 methyl bur group, 1 -Butenyl group, 1-ethylbutyl group, 1-methyl-2-propenyl group, 2 butyr group, 3-buteni group Examples include a nore group, a 2-methyl-1-propenyl group, a 2-methyl-2-propenyl group, a 1-pentenyl group, and a hexenyl group. Among them, mention is preferably made of an alkynino group having 2 to 4 carbon atoms.
  • Alkynyl group refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes an ethuryl group, a 1-propynyl group, a 2-propynyl group, a 1-buturyl group, Mention may be made of methyl-2-propynyl group, 3-buturyl group, 1-penturyl group, 1-hexyl group and the like. Among them, preferred is an alkynyl group having 2 to 4 carbon atoms.
  • Alkoxy group refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, and specifically includes a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, a butoxy group, and a 1-methyl group.
  • a propoxy group, a 2-methylpropoxy group, a 1,1-dimethylethoxy group, a pentyloxy group or a hexyloxy group can be exemplified.
  • haloalkoxy group examples include linear or branched alkoxy groups having 1 to 6 carbon atoms substituted with 1 to 5 identical or different halogen atoms. Listed include: l-methoxy group, 2,2-diphnoleic roethoxy group, 2,2,2-trifnole-throethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoropropoxy group, etc. That power S.
  • a C1-C4 haloalkoxy group is mentioned.
  • Alkylthio group refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, specifically a methylthio group, an ethylthio group, a propylthio group, a 1-methylethylthio group, a butylthio group, a 1 methyl group. Examples thereof include a propylthio group, a 2-methylpropylthio group, a 1,1 dimethylolethylthio group, a pentylthio group, and a hexylthio group. Among them, preferred is an alkylthio group having 1 to 4 carbon atoms.
  • alkyl in the "alkylcarbonyl group” examples include the same alkyl groups as those described above.
  • Preferred examples of the alkylcarbonyl group include a acetyl group, a propionyl group, and a petityl group.
  • alkylcarbonyloxy group represents a group in which an oxygen atom is bonded to the “alkylcarbonyl group”.
  • alkyl in the “alkylsulfonyl group” is the same as the above “alkyl group” Power S is mentioned.
  • Preferred examples of the alkylsulfonyl group include a methylsulfonyl group, an ethyl sulfonyl group, and a propylsulfonyl group.
  • alkoxy in the "alkoxycarbonyl group” examples include the same as the above “alkoxy group”.
  • Preferred examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like.
  • alkyl group in the "amino group optionally substituted with one, or the same or different two alkyl groups” include the same as the above-mentioned "alkyl group", and preferably a methyleno amino group, an ethylamino. Group, propylamino group, dimethylolamino group, jetylamino group, methylethylamino group and the like.
  • Cycloalkyl group refers to a 3- to 8-membered cycloalkyl group, and specific examples include a cyclopropinole group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • Power S can be. Among them, a force of 4 to 6-membered cycloalkyl group is preferred.
  • Cycloalkenyl group represents a 4- to 8-membered cycloalkenyl group, and specific examples include a cyclobutyl group, a cyclopentyl group, a cyclohexenyl group, a cycloheptyl group, and a cyclooctyl group.
  • the bonding position is not particularly limited. Of these, a 5- or 6-membered cycloalkenyl group is preferable.
  • the "saturated aliphatic heterocyclic group” includes 1 to 3 heteroatoms selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms.
  • a 4- to 8-membered saturated aliphatic heterocyclic group is shown, and the bonding position is not particularly limited as long as it is chemically stable.
  • azetiduyl group pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, azepanyl group, azocanyl group, tetrahydrofuryl group, tetrahydrochenyl group, tetrahydrobiranyl group, mono-refinolinole group, mono-repholino group, thiomorpholinyl group 1,4 dioxanyl group, 1,2,5-thiadiazinyl group, 1,4-oxazepanyl group, 1,4 diazepanyl group, etc.
  • Unsaturated aliphatic heterocyclic group includes 1 to 3 heteroatoms selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms. Including 1 to 3 double bonds A 5- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group is shown, and the bonding position is not particularly limited as long as it is chemically stable. Specific examples include 2-pyrrolinyl group, 2-imidazolinyl group, tetrahydroisoquinoline group and the like.
  • Aryl group refers to a 6- to 10-membered aryl group, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • aryloxy group In the “aryloxy group”, “arylcarbonyl group”, or “arylsulfonyl group”, the aryl group has the same meaning as described above.
  • the "aromatic heterocyclic group” includes 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms. 5 to; a 10-membered monocyclic or bicyclic aromatic heterocyclic group, and the bonding position is not particularly limited as long as it is chemically stable.
  • aromatic heterocyclic group has the same meaning as described above.
  • R 1 L 1 — R 10 [wherein L 1 is a single bond, O 2 OCH—, or N 1 (R
  • U represents one (wherein R 11 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), and R 10 represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, It represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted aromatic heterocyclic group.
  • R 11 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • R 10 represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, It represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted aromatic heterocyclic group.
  • R 1Q is bound to the side.
  • the saturated or unsaturated aliphatic heterocyclic group for R 1Q include the same as the saturated aliphatic heterocyclic group or the unsaturated aliphatic heterocyclic group.
  • the aromatic heterocyclic group in R 1 () include the same aromatic heterocyclic groups as described above, and preferably include a pyridyl group, a furyl group, a chenyl group, a pyrimidinyl group, a pyradyl group, etc. it can.
  • R 1Q when a saturated or unsaturated aliphatic heterocyclic group, phenyl group, or aromatic heterocyclic group is substituted, examples thereof include an atom, an alkyl group optionally substituted with an alkoxy group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkylthio group, and a dimethylamino group.
  • the group represented by the formula: I ⁇ —R " 3 is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted phenyloxy group, or a substituted or unsubstituted group.
  • a benzyloxy group can be mentioned, and among these, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted phenyloxy group is particularly preferable.
  • R 2 L 2 — R 12 [wherein L 2 is a single bond, O 2 OCH—, or N 1 (R
  • R 13 represents a hydrogen atom or an alkyl group having carbon atoms;! To 4
  • R 12 represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group
  • L 2 is one OCH—
  • 2-quinolone skeletal force S is
  • R 12 is bonded to the side.
  • the saturated or unsaturated aliphatic heterocyclic group for R 12 include the same as the saturated aliphatic heterocyclic group or the unsaturated aliphatic heterocyclic group.
  • the aromatic heterocyclic group for R 12 include the same aromatic heterocyclic groups as those described above, and preferably include a pyridyl group, a furyl group, a chenyl group, a pyrimidinyl group, a pyridyl group, and the like.
  • R 12 when the saturated or unsaturated aliphatic heterocyclic group, phenyl group, or aromatic heterocyclic group is substituted, the substituent may be a halogen atom or an alkyl group that may be substituted with an alkoxy group.
  • L 2 —R 12 is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted phenyloxy group, or a substituted or unsubstituted benzyloxy group.
  • a substituted or unsubstituted pyridyl group or a substituted or unsubstituted phenyl group is particularly preferable.
  • the 5- to 7-membered ring formed by combining R 1 and R 2 is such that R 1 and R 2 are each bonded to adjacent carbon atoms, and R 1 and R 2 are combined together. It represents a 5- to 7-membered ring formed by representing a trimethylene group, a tetramethylene group, a pentamethylene group, a methylenedioxy group, an ethylenedioxy group, or a trimethylenedioxy group.
  • R 1 bonded to the 6-position carbon atom of the 2-quinolone skeleton and R 2 bonded to the 7-position carbon atom are combined to form a trimethylene group
  • a 5- to 7-membered ring formed by representing a ramethylene group, a pentamethylene group, a methylenedioxy group, an ethylenedioxy group, or a trimethylenedioxy group and specific examples of the 2-quinolone skeleton when the 5- to 7-membered ring is formed Specifically, those shown in the formulas (C1) to (C6) can be mentioned.
  • the 5- to 7-membered ring formed by combining R 1 and R 2 is more preferably R 1 bonded to the 6-position carbon atom of the 2 quinolone skeleton and R 2 bonded to the 7-position carbon atom.
  • the five-membered ring formed by representing together a trimethylene group or a methylenedioxy group, that is, the above formulas (C1) and (C4) can be mentioned.
  • R 3 and R 4 are bonded together to form a nitrogen atom to which they are bonded 4 to;
  • a 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle includes 0 to 2 oxygen atoms Atoms, 0 to 2 sulfur atoms, and;!
  • nitrogen atoms containing 5 to; 10-membered nitrogen-containing aliphatic heterocycles having 0 to 3 double bonds specifically, , Azetidine, pyrrolidine, piperidine, azepane, azocan, imidazolidine, piperazine, aged xazolidine, monoreforin, aged monoreforin, tetrahydroisoquinoline, 1,4-oxazepane group, 1,4 diazepan, etc.
  • the 4- to 7-membered saturated or unsaturated oxygen-containing aliphatic heterocycle formed by combining R 14 and R 8 specifically includes oxetane, tetrahydrofuran, tetrahydropyran, oxepan, dihydro Examples include furan and dihydropyran. Tetrahydrofuran and tetrahydropyran are preferable.
  • R 5 and R 8 are combined to form 5 to 10; a 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle has 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and! ⁇ 3 nitrogen atoms, specifically, pyrrolidine, piperidine, azepan, azocan, imidazolidine, piperazine, oxazolidine, morpholine, thiomorpholine, tetrahydroisoquinoline and the like. Pyrrolidine, piperidine, and morpholine are preferable.
  • R 1 is preferably a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkynole group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, An amino group which may be substituted with one, or the same or different two alkyl groups, or a formula: ——1 ⁇ ° [wherein, R 1 () is as defined above.
  • R 1 is preferably a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, a dimethylamino group, a pyrrolidino group, or a morpholino group.
  • a substituted pyridyl group or a substituted or unsubstituted phenyl group is particularly preferred.
  • R 2 is preferably a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, 1 Or an amino group which may be substituted with two or the same or different alkyl groups, or a formula: L 2 —R 12 wherein L 2 and R 12 are as defined above.
  • R 2 is preferably a hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, dimethylamino group, pyrrolidino group.
  • R 7 is specifically a hydrogen atom, a methyl group, or an ethyl group.
  • a hydrogen atom is particularly preferable, although a hydrogen atom or a methyl group is more preferable.
  • R 8 and R 9 are preferably a hydrogen atom, a fluorine atom, or an alkyl group having 1 to 6 carbon atoms. Specifically, R 8 and R 9 are preferably a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group, more preferably a hydrogen atom, a fluorine atom, or a methyl group, and particularly preferably a hydrogen atom. .
  • n is preferably an integer of 2 to 3.
  • the plurality of R 8 and the plurality of R 9 may be the same or different independently.
  • R 5 is preferably a hydrogen atom, a methyl group, or an ethyl group, and a hydrogen atom is particularly preferable among the hydrogen atoms or methyl groups.
  • R 3 and R 4 independently represent a hydrogen atom or a substituted or unsubstituted alkyl group, or R 3 and R 4 are bonded to form a nitrogen atom to which they are bonded. Substituted 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle.
  • R 4 is more preferably a hydrogen atom or a substituted or unsubstituted alkyl group, and a hydrogen atom is particularly preferred among the hydrogen atoms or unsubstituted alkyl groups.
  • R 4a is preferably a hydrogen atom.
  • R 3 is more preferably a substituted alkyl group.
  • the substituent is preferably a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino group, or substituted or unsubstituted Is an unsubstituted force ruberamoyl group.
  • the aryl group and the aromatic heterocyclic group include a phenyl group, a furyl group, a thiazolyl group, an imidazolyl group, a virazolyl group, a furanyl group, and an indolyl group.
  • R 14 is preferably a substituted or unsubstituted alkyl group or a haloalkyl group.
  • R 3 and R 4 are formed by combining R 3 and R 4 together with the nitrogen atom to which they are bonded, a substituted or unsubstituted 4- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle, Or, a group represented by the formula (2) is preferable.
  • p is preferably an integer of 1. Also preferred as R 15 Alternatively, a substituted or unsubstituted cananolamoyl group can be mentioned.
  • alkyl group When the “alkyl group”, “alkenyl group”, or “alkynyl group” is substituted! /,
  • the substituent is selected from the following groups (i) to (v), and is the same or different substituent: Multiple groups may be substituted:
  • Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an anolenoquinole group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, a force. Examples include a rubermoyl group. ];
  • a cycloalkyl group a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group
  • these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thixo group, one, or the same or different two
  • An amino group optionally substituted with an alkyl group, a rubamoyl group optionally substituted with one or the same or different two alkyl groups, an alkoxy group, a haloalkoxy group, optionally substituted Alkoxycarbonyl group, optionally substituted! /, May! /, Alkylcarbonyl group, optionally substituted! /, May!
  • Alkylsulfonyl group optionally substituted alkyl group, substituted
  • One or more substituents may be substituted with a substituent selected from an aryl group which may be substituted, and an aromatic heterocyclic group which may be substituted.
  • Examples of the alkoxycarbonyl group, the alkylcarbonyl group, the alkylsulfonyl group, and the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group, and a strong rubamoyl group.
  • a halogen atom As the substituent of the group and the aromatic heterocyclic group, a halogen atom, a hydroxyl group , A carboxyl group, an alkenoquinole group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a strong rubamoyl group.
  • These groups include a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, and an alkoxycarbonyl group.
  • One or more substituents may be substituted with a substituent selected from an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic complex group.
  • Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group.
  • Cycloalkyl group “cycloalkenyl group”, or “saturated or unsaturated aliphatic heterocyclic group” (“saturated or unsaturated nitrogen-containing aliphatic heterocyclic group”, “saturated or unsaturated containing” Substituents in the case where “oxyaliphatic heterocyclic group” is substituted are selected from the following groups (vi) to (X), and the same or different substituents may be substituted multiple times! / May be:
  • a halogeno group a hydroxyl group, a carboxyl group, a cyano group, an oxo group, a thixo group, an amidino group optionally substituted by one or two identical or different alkoxycarbonyl groups;
  • Examples of the substituent for the aryloxy group, the aromatic complex substituent, the aryl group, and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an anolenoquinole group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and an alkoxy group. Examples include a carbonyl group, a nitro group, a cyano group, and a strong rubamoyl group. Examples of the substituent of the amino group include an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, and an optionally substituted group.
  • alkylsulfonyl group one or the same or different two substituted! /, May! /, Or an alkyl group! /, May be a rubamoyl group.
  • substituent of the alkyl group on the alkyl group, the alkylcarbonyl group, the alkylsulfonyl group, and the rubamoyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group, and a carbamoyl group. It is done. ];
  • One or more substituents may be substituted with a substituent selected from good aromatic heterocyclic groups.
  • Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • Examples of the substituent for the aryl group and the aromatic heterocyclic group include a no atom, a logon atom, and a hydroxyl group.
  • These groups include a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group,
  • substituents may be substituted with a substituent selected from an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group.
  • Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group.
  • R 3 and R 4 are bonded to form a nitrogen atom to which they are bonded to 5 to; a substituent when a 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring is substituted, and R When 5 and R 6 are combined to form a bond—N—L 3 —, the 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle is substituted! / Are independently selected from the group (vi) to (X) above, and 1 to 5 of the same or different substituents may be substituted.
  • (xii) a substituted or unsubstituted amino group, a substituted or unsubstituted force rubamoyl group, a substituted ⁇ if unsubstituted sulfamoyl group; (xiii) Anolequinol group, haloalkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfonyl group
  • These groups include a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a substituted group that may be substituted with one or two alkyl groups that are the same or different. May be an aryl group, and may be substituted V, may be! /, Or may be substituted with one or more substituents selected from aromatic heterocyclic groups! /.
  • Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an anolenoquinole group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, a force. Examples include a rubermoyl group. ];
  • a cycloalkyl group a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group
  • these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thixo group, one, or the same or different two
  • An amino group optionally substituted with an alkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted group
  • One or more substituents may be substituted with a substituent selected from good aromatic heterocyclic groups.
  • Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • Examples of the substituent for the aryl group and the aromatic heterocyclic group include a no atom, a logon atom, and a hydroxyl group.
  • aryl group aromatic heterocyclic group, aryloxy group, aromatic heterocyclic group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group
  • These groups include a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, and an alkoxycarbonyl group.
  • One or more substituents may be substituted with a substituent selected from a substituent.
  • Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group.
  • These groups include a halogen atom, a hydroxyl group, a carboxyl group, an amino group which may be substituted with one or two alkyl groups which are the same or different, a strong rubamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group.
  • substituent for the aryl group and the aromatic heterocyclic group examples include a halogen atom, a hydroxyl group, a carboxyl group, an alkynole group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a powerful ruvamoyl group.
  • a halogen atom a hydroxyl group, a carboxyl group, an alkynole group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a powerful ruvamoyl group.
  • These groups include a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thixo group, an amino group, an alkoxy group, a haloalkoxy group, an alkoxy group that may be substituted with one or two identical or different alkyl groups.
  • substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • substituents for the aryl group and the aromatic heterocyclic group include no, log. C atom, hydroxyl group, carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, nitro group, cyano group, and rubamoyl group. ];
  • aryl group aromatic heterocyclic group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group
  • Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group.
  • Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and the like.
  • amino group may be bonded to form a 5- to 10-membered nitrogen-containing aliphatic heterocyclic ring with the adjacent nitrogen atom. Good.
  • nitrogen-containing aliphatic heterocycle examples include pyrrolidine, piperidine, azepane, azocane, piperazine, morpholine, thiomorpholine, and tetrahydroisoquinoline.
  • the nitrogen-containing aliphatic heterocyclic ring is substituted with one or more groups selected from halogen, hydroxyl group, carboxyl group, optionally substituted alkyl group, haloalkyl group, alkoxy group, haloalkoxy group. May be.
  • substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group, and a strong rubamoyl group.
  • the compound of the present invention represented by the general formula (1) can be produced, for example, by the following method with the force S.
  • the compound of the present invention represented by the formula (1A) in which R 7 is a hydrogen atom can be produced by, for example, the following method.
  • the compound represented by the formula (1A) can be produced by performing a reductive amination reaction between the compound (11) and a desired amine compound.
  • the compound (1-1) can be produced by reductive amination of the desired primary amin compound with the desired aldehyde after obtaining the compound (12).
  • S can.
  • ether solvents such as tetrahydrofuran and 1,4-dioxane
  • halogen solvents such as dichloromethane, chlorophenol, 1,2-dichloroethane, ethyl acetate, N, N dimethylformamide, acetonitrile, etc.
  • dichloromethane chlorophenol
  • 1,2-dichloroethane 1,2-dichloroethane
  • ethyl acetate N, N dimethylformamide, acetonitrile, etc.
  • the reaction temperature is from 20 ° C to the reflux temperature of the reaction solvent, particularly preferably from 0 ° C to around room temperature.
  • the compound of the formula (1A) can also be produced from the compound (1 2 ') by the method shown in the following reaction formula 2.
  • R 2 , R 3 , R 4 , R 8 , R 9 , m, n and A are as defined above, and X represents a substituent having a leaving ability such as a halogen atom, a mesyloxy group or a tosyloxy group.
  • the compound represented by the formula (1A) can also be produced by the method represented by the reaction formula 3. [0057] [Chemical 7]
  • ether solvents such as tetrahydrofuran, 1,4-dioxane, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, N , N It can be produced by reacting in a solvent such as dimethylformamide, acetonitrile, etc. from 0 ° C to the reflux temperature of the reaction solvent.
  • a base potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride,
  • the force that can use potassium t-ptoxide and the like is not particularly limited.
  • the compound of the present invention represented by the formula (1B) in which R 7 is an alkyl group having 1 to 6 carbon atoms is represented by the formula (14) as shown below, for example.
  • R 3 , R 4 , R 8 , R 9 , m, n and A are as defined above, R 2 ° is the number of carbons;!
  • the compound (15) in which m is 0 can be produced, for example, by the method shown in the following reaction scheme 5.
  • reagent for boronation examples include borane, t-hexylborane, 9-BBN, and the following oxidation reactions include, for example, swan oxidation, SO pyridine oxidation, and PCC oxidation.
  • Compound (13) can be produced by converting compound (11) to alcohol by a reduction reaction and then converting the hydroxyl group to leaving group X.
  • an ethereal solvent such as tetrahydrofuran or jetinoreethenore, a halogen solvent such as dichloromethane or 1,2-dichloroethane, or an alcohol solvent such as methanol or ethanol is used as the solvent. Is performed at 78 ° C to 0 ° C using sodium borohydride, lithium aluminum hydride, disobutylaluminum hydride and the like.
  • the leaving group X is a mesyloxy group or a tosyloxy group
  • the corresponding chloride (mesyl cation lide, tosyl lip tide) is added in the presence of a base such as triethylamine or pyridine.
  • a base such as triethylamine or pyridine.
  • a mesyl body or a tosyl body can be obtained.
  • the leaving group X is a halogen atom
  • the Complicative 'Organic' Transformation by RC Laroc, VCH Public Shears Inc. (1989)
  • 4th edition Experimental Chemistry Course Maruzen
  • New Experimental Chemistry Course The bromide can be obtained by adding, for example, triphenylphosphine and carbon tetrabromide in dichloromethane.
  • Compound (2-4) can be produced by reacting compound (1-3) with sodium cyanide or potassium cyanide, followed by nitrylation, followed by a reduction reaction.
  • nitrilation N, N dimethylformamide and the like are mentioned as the solvent, and the reaction temperature is the reflux temperature of the solvent at room temperature.
  • the reduction reaction of the nitrile group can be performed with a metal hydride such as diisobutylaluminum hydride or lithium aluminum hydride, or by catalytic hydrogenation using Pd—C or the like.
  • the compound (13) was reacted with sodium cyanide in N, N dimethylformamide at room temperature to obtain a nitrile form, and then an excess amount of diisobutylaluminum hydride in dichloromethane was added at 0 ° C. Can be added to obtain compound (2-4).
  • Compound (1-4) is a commercially available or known compound (1-1) such as R 2 ° —MgBr (alkyl magnesium bromide having 1 to 6 carbon atoms) or R 2 ° —Li (alkyl having 1 to 6 carbon atoms). Lithium) and After the reaction, it can be produced by oxidizing the secondary hydroxyl group by a general method. Specifically, the compound (11) in which m is 0 can be obtained by reacting methylmagnesium bromide in tetrahydrofuran at 0 ° C and oxidizing the resulting alcohol with manganese dioxide. Monkey.
  • Compound (16) can be produced by hydrolyzing compound (2-5), and compound (2-1) can be produced by hydrolyzing compound (2-6). .
  • the hydrolysis can be performed by heating under an acidic or basic condition.
  • As the acid acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc. are used.
  • As the solvent ether solvents such as tetrahydrofuran and 1,4-dioxane, alcohol solvents such as methanol and ethanol, acetic acid, N, N dimethyl Formamide, acetonitrile, water, or a mixed solvent thereof is used.
  • the reaction temperature is from room temperature to the solvent reflux temperature.
  • compound (2-7) or compound (2-8) is mixed with 3 to 10 equivalents of phosphorus oxychloride,! To 4 equivalents of N, N dimethylformamide and heated to heat the compound. (2-5) or compound (2-6) can be produced. To produce compound (2-5), 7 equivalents of phosphorus oxychloride and 2.5 equivalents of N, N dimethylformamide are preferred. To produce compound (2-6), 7 equivalents It is preferred to use the following phosphorus oxychloride, 1.5 equivalents of N, N dimethylformamide.
  • Compound (2-7) is a commercially available or known compound, substituted aniline, in the presence of base, using acetic anhydride or acetyl chloride, ether solvents such as tetrahydrofuran, 1,4 dioxane, dichloromethane, chloroform, etc.
  • a solvent such as halogenated solvents such as ethyl acetate, N, N dimethylformamide, and acetonitrile, from 0 ° C to room temperature. It can be manufactured by making it.
  • a force S that can use pyridine, triethylamine, dimethylaminopyridine, or the like as a base is not particularly limited.
  • Compound (2-8) is a commercially available or known compound, such as a substituted aniline, in the presence of a base, sold or converted from a known carboxylic acid using oxalyl chloride, tetrahydrofuran, jetyl ether, Produced by reacting at 0 ° C to room temperature in ether solvents such as 1,4 dioxane, halogen solvents such as dichloromethane and chloroform, solvents such as ethyl acetate, N, N dimethylenoformamide, and acetonitrile. That power S.
  • ether solvents such as 1,4 dioxane, halogen solvents such as dichloromethane and chloroform
  • solvents such as ethyl acetate, N, N dimethylenoformamide, and acetonitrile. That power S.
  • pyridine, triethylamine, dimethylaminopyridine or the like as the base is not particularly limited.
  • n represents an integer of 2 or 3
  • m represents 0, R 7 , a plurality of R 8 , and a plurality of R 9 all represent a hydrogen atom
  • A represents a formula : -N (R 5 ) -L 3 -R 6 compound of the present invention, that is, the compound of the present invention represented by the general formula (1C) can also be produced, for example, by the method shown in the following reaction scheme 14. it can.
  • R 2 , R 3 , R 4 , R 5 , R 6 and L 3 are as defined above, and q represents an integer of 1 or 2.
  • the compound represented by the formula (1C) can be produced by a condensation reaction of the compound (31) with an acid halide, an acid anhydride, a sulfonylno, a ride, an isocyanate, a chromate formate, and the like.
  • reacting compound (31) in acetic anhydride and pyridine at room temperature and reacting acetyl sulfonate in dichloromethane in the presence of triethylamine from 0 ° C to room temperature. You can get a body.
  • the compound represented by the above formula (3-1) can be produced, for example, from the compound represented by the formula (3-3) by the method represented by the following reaction formula 15.
  • Compound (3-2) can be produced from compound (3-3) by the same production method as in the conversion step to the leaving group shown in Reaction Scheme 7. Conversion to compound (3-1) can be performed by the same method as in Reaction Scheme 3.
  • R 5 is a hydrogen atom, it can be obtained, for example, by reacting potassium phthalimide and hydrolyzing with acid, base, hydrazine or the like.
  • the compound represented by the above formula (3-3) can be produced, for example, from the compound represented by the formula (16) by the method represented by the following reaction formula 16.
  • the t-butyldimethylsilyl group as a protecting group, which can be deprotected with tetraptylammonium fluoride.
  • the compound (16) can be reacted with the compound (3-6) first to obtain the compound (3-5), and then subjected to reductive amination and deprotection to obtain the compound (3-3). ) Can also be obtained.
  • m represents 0, R 7 is a hydrogen atom, and R 1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted aromatic heterocyclic group.
  • R 7 is a hydrogen atom
  • R 1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted aromatic heterocyclic group.
  • the compound of the present invention represented by the general formula (1D) can be produced, for example, by the method shown in the following reaction scheme 17.
  • R 2 , R 3 , R 4 , R 8 , R 9 , n and A are as defined above, and Y is substituted or unsubstituted.
  • Compound (1D) can be obtained from compound (4 2) in the same manner as in Reaction Scheme 1.
  • Compound (42) was prepared from room temperature in a solvent such as dimethoxyethane, 1,4 dioxane, toluene, ethanol using compound (41), the desired boranoic acid compound, palladium catalyst, ligand, and base. It can manufacture by making it react at the reflux temperature of this.
  • the radium catalyst examples include, but are not limited to, the force S including palladium acetate, tetrakistriphenylphosphine palladium, trisbenzylideneacetone dipalladium, and the like.
  • the ligand includes, but is not limited to, triphenylphosphine, tri-0-trinophosphine, tri-t-butylphosphine, and the like.
  • Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, but are not particularly limited.
  • Compound (IE) can be obtained from compound (43) in the same manner as in Reaction Scheme 1.
  • Compound (4 3) was prepared by using compound (4 1), cyanide compound, palladium catalyst, and ligand in a solvent such as N, N dimethylformamide, acetonitrile, 1-methyl-2-pyrrolidone, from room temperature to the solvent. It can manufacture by making it react at reflux temperature.
  • a solvent such as N, N dimethylformamide, acetonitrile, 1-methyl-2-pyrrolidone
  • Paradium catalysts include, but are not particularly limited to, power S including palladium acetate, tetrakistrifurphosphine palladium, trisdibenzylideneacetone dipalladium, and the like.
  • the ligand includes 1, 1'-bisdiphenylphosphinophenocene, tri-0-tolylphosphine. There are no particular limitations on the force.
  • NRR the group is substituted with one or two identical or different alkyl groups.
  • Compound (1F) can also be obtained by the same deprotection as in Reaction Scheme-5 and reductive amination as in Reaction Scheme-1 for Compound (4 6).
  • Compound (46) is compound (44), compound (4-5), palladium catalyst, ligand and base, in a solvent such as dimethoxyethane, 1,4-dioxane, toluene or ethanol at room temperature. It can be produced by reacting at the reflux temperature of the solvent.
  • the radium catalyst include, but are not limited to, palladium acetate, tetrakis triphenylphosphine palladium, and trisdibenzylideneacetone dipalladium.
  • Examples of the ligand include triphenylphosphine, tri-0-tolylphosphine, tri-t-butylphosphine, 2,2'-bisdiphenylphosphino-1,1'-binaphthyl, etc.
  • Examples of the base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide.
  • Compound (1G) can be obtained from compound (48) in the same manner as in Reaction Scheme-1.
  • Compound (4 8) uses compound (4 1), compound (4 7), copper catalyst, ligand and base, and is a solvent such as N methyl biperidone, 1, 4-dioxane, dimethyl sulfoxide, N, N dimethyl formamide It can be produced by reacting at room temperature and at the reflux temperature of the solvent.
  • the copper catalyst include, but are not limited to, copper iodide, copper bromide, and copper chloride.
  • Ligands include, but are not limited to, the force S including 2,2,6,6 tetramethylheptane-3,5 dione, N, N dimethyldaricin, and the like.
  • Examples of the base include sodium carbonate, potassium carbonate and cesium carbonate, but are not particularly limited.
  • the compound represented by the formula (5) can be produced, for example, from the compound represented by the formula (5-1) by the method represented by the reaction formula 21.
  • R 2 , R 8 , R 9 and Prot are the same as described above, and represent an alkyl group having 1 to 4 carbon atoms.
  • Compound (5) can be produced by deprotecting compound (5-2).
  • Compound (5-2) can be obtained by reducing the ester group of compound (51).
  • an ether solvent such as tetrahydrofuran or jetyl ether or a halogen solvent such as dichloromethane is used as a solvent, and diisobutylaluminum hydride is used as a reducing agent.
  • diisobutylaluminum hydride is used as a reducing agent.
  • the compound represented by the formula (6) can be produced, for example, from the compound represented by the formula (5-2) by the method represented by the reaction formula 22.
  • R 2 , R 8 , R 9 , X and Prot are the same as described above, and ° represents a substituted or unsubstituted alkyl group, a haloalkyl group, or a substituted or unsubstituted cycloalkyl group.
  • Compound (6) can be produced by deprotecting compound (5-3).
  • Compound (5-3) is obtained by mixing compound (5-2) and compound (5-4) in the presence of a base in an ether solvent such as tetrahydrofuran and 1,4 dioxane, and a solvent such as N, N dimethylformamide, It can be produced by reacting from 0 ° C at the reflux temperature of the reaction solvent.
  • a base such as tetrahydrofuran and 1,4 dioxane
  • a solvent such as N, N dimethylformamide
  • the compound represented by the general formula (1) can be converted to an alkali addition salt, which is an acid addition salt with a pharmaceutically acceptable inorganic acid or organic acid, if necessary.
  • acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, and formate, acetate, fumarate, maleate, and oxalic acid.
  • pharmacologically acceptable alkali addition salts include ammonium salts, lithium salts, sodium salts, strength lithium salts, calcium salts, magnesium salts.
  • the present invention also includes solvates such as a hydrate of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, and an ethanol solvate. Furthermore, the present invention includes all tautomers, stereoisomers such as optical isomers, and all forms of crystal forms of the compound represented by the general formula (1). These can be appropriately purified using methods such as silica gel column chromatography, HPLC, ion exchange chromatography, and recrystallization well known to those skilled in the art.
  • an optical resolution method known to those skilled in the art is used.
  • an optically active acid for example, monocarboxylic acid such as mandelic acid, N-benzyloxylanine, lactic acid, etc.
  • an optically active acid for example, monocarboxylic acid such as mandelic acid, N-benzyloxylanine, lactic acid, etc.
  • the compound of the present invention or an intermediate thereof when it has an acidic substituent, it forms a salt with an optically active amine (for example, organic amines such as ⁇ -phenethylamine, cune, quinidine, cinchonidine, cinchonine, strychnine). It can also be made.
  • an optically active amine for example, organic amines such as ⁇ -phenethylamine, cune, quinidine, cinchonidine, cinchonine, strychnine.
  • an optically active amine for example, organic amines such as ⁇ -phenethylamine, cune, quinidine, cinchonidine, cinchonine, strychnine.
  • an optically active amine for example, organic amines such as ⁇ -phenethylamine, cune, quinidine, cinchonidine, cinchonine, strychnine.
  • the temperature at which the salt is formed include a range from room
  • the compound having a 2-quinolone skeleton of the present invention or a pharmaceutically acceptable salt thereof has an SNS inhibitory activity and can be used as a therapeutic agent or a preventive agent for neuropathic pain and nociceptive pain.
  • neuropathic pain include post-lumbar neuralgia, diabetic neuropathy, postherpetic neuralgia, reflex sympathetic nerve, phantom limb pain, spinal injury, end-stage cancerousness, and prolonged postoperative pain. It is done.
  • nociceptive pain include low back pain, abdominal pain, rheumatoid arthritis, and pain caused by osteoarthritis.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can also be used as a therapeutic or prophylactic agent for dysuria.
  • dysuria include frequent urination and bladder pain due to enlarged prostate.
  • it can also be used as a therapeutic or preventive agent that suppresses abnormal nerve firing of the cerebellum in multiple sclerosis.
  • a compound having SNS selective inhibitory activity is more preferable.
  • the therapeutic agent or preventive agent for neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis of the present invention is a usual pharmaceutically acceptable carrier, binder, stabilizer, enhancer.
  • Various preparation ingredients such as a form, a diluent, a ⁇ buffer, a disintegrant, a solubilizer, a solubilizer, and an isotonic agent can be added.
  • These therapeutic agents or preventive agents can be administered orally or parenterally. That is, orally, it can be administered orally in a commonly used dosage form such as tablets, pills, powders, granules, capsules, syrups, emulsions, suspensions and the like.
  • parenteral use for example, it can be prepared in the form of intravenous injection (instillation), intramuscular injection, subcutaneous injection, coating agent, eye drop, eye ointment and the like.
  • Solid preparations such as tablets contain the active ingredients as usual pharmacologically acceptable carriers or excipients such as lactose, sucrose and corn starch, hydroxypropylcellulose, polybromide It is prepared by mixing with any binder, disintegrant such as sodium carboxymethyl cellulose or sodium starch glycolate, lubricant such as stearic acid or magnesium stearate, or preservative.
  • the active ingredient is dissolved or suspended in a physiologically acceptable carrier such as water, saline, oil, aqueous dextrose, etc., and this may be used as an emulsifier, stabilizer, osmotic pressure adjusting salt. Or you may contain a buffering agent as needed.
  • a physiologically acceptable carrier such as water, saline, oil, aqueous dextrose, etc.
  • the dose and the number of administrations vary depending on the administration method and the age, weight, medical condition, etc. of the patient, a method of local administration to the bed part is preferable. In addition, it is preferable to administer once or twice a day. If it is administered more than once, it should be repeated every day, and should be repeated at appropriate intervals.
  • Dosage can be several tens of g to 2 g, preferably 1 to several hundred mg, more preferably tens of mg or less as the amount of active ingredient per adult patient, and can be used once or several times a day. It can be administered separately. For parenteral administration, a dose of 0.;! To lOOmg / day, more preferably 0.3 to 50mg / day per adult patient can be mentioned, and it is possible to administer once or several times a day. it can. Sustained-release preparations can be used to reduce the number of administrations.
  • the therapeutic agent or preventive agent for neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis of the present invention can be used as an animal drug.
  • Example 8 Using the compound obtained in Reference Example 8 as a raw material, the target product was obtained in the same manner as in Example 1.
  • Example 8 Using the compound obtained in Reference Example 8 as a raw material, the target product was obtained in the same manner as in Example 1.
  • Tetrahydrofuran (26 ml) and tetrabutylammonium fluoride (3.0 ml, 1M tetrahydrofuran solution, 3.0 mmol) were added to the resulting residue.
  • water was added and extracted with ethyl acetate.
  • the extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • the aqueous layer was made alkaline by adding 1N sodium hydroxide aqueous solution, and extracted with black mouth form. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired product (9.8 mg, 29%).
  • the obtained alcohol was dissolved in toluene (30 ml), manganese dioxide (5.0 g, 56 mmol) was added, and the mixture was stirred at 80 ° C. After 2 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the desired product (1.3 g, 79%).
  • the target product was obtained in the same manner as in Reference Example 4.
  • the target product was obtained in the same manner as in Example 59.
  • the target product was obtained in the same manner as in Example 59.
  • the target product was obtained in the same manner as in Example 59.
  • Triethylamine (5.02 ml, 36 mml) was added to an anhydrous ether solution (18 ml) of 3-phenoxyaniline (5.9 g, 32 mmol) under a nitrogen atmosphere and ice cooling.
  • An anhydrous ether solution of the acyl chloride (4.27 g, 36 mmol) synthesized above was slowly added to the reaction solution and stirred at room temperature for 16 hours.
  • the reaction mixture was washed with 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • dimethylsulfoxide (216 1, 3.04 mmol) is added to anhydrous dichloromethane solution (5 ml) of oxalinole dichloride (123 1, 1.41 mmol) so that the internal temperature becomes 60 ° C or lower.
  • the mixture was added at a speed and stirred at 70 ° C for 30 minutes.
  • An anhydrous dichloromethane solution (1.5 ml) of the compound obtained in Reference Example 24 (430 mg, 1.17 mmol) was added at such a rate that the internal temperature became 60 ° C or lower, and the mixture was stirred at 70 ° C for 1 hour.
  • the compound of interest was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 25 as a raw material.
  • the compound of interest was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 25 as a raw material.
  • Human SNS gene-expressing cells are obtained by incorporating the human SNS gene into a Chinese hamster ovary cell (CHO-K1) and stably expressing it.
  • CHO-K1 cells originally have TTX-resistant Na channel components. Therefore, it was considered that the TTX-resistant Na channel component in human SNS gene-expressing cells is SNS, and therefore the compound of the present invention is an SNS inhibitor.
  • the entire length of the human SNS a subunit gene is incorporated into an expression plasmid (pcDNA3.1Zeo (+)) containing the Zeocin resistance gene, and the entire length of the Annexin II light chain gene is incorporated into the Neomycin resistance gene-containing expression plasmid (PCDNA3.1 (+) ).
  • These two genes are simultaneously introduced into CHO-K1 cells using 1 ipofectamine 2000 and cultured in F-12 medium containing Neomycin and Zeocin to select both drug-resistant cells, that is, cells incorporating both genes. did. Both these drug-resistant strains were subjected to limiting dilution twice to clone the SNS gene-incorporated cells.
  • the introduction of SNS was confirmed by RT-PCR, and a membrane potential-sensing fluorescent indicator was used to detect TTX resistance components that respond to Na channel stimulation, confirming the functional expression of SNS.
  • the SNS inhibitory action of the compound of the present invention was evaluated. That is, the test compound was added to human SNS-expressing cells in advance, and about 30 minutes later, Na channel stimulating agent belatridine (50 ⁇ ) was added in the presence of TTX (1 11 ⁇ ), and TTX resistance The membrane potential was increased via the sex Na channel, and the test compound was evaluated for the suppression of membrane potential increase.
  • the SNS inhibition rate of the test compound was calculated using the following formula.
  • Example 1 (%) Example 1 1 2. 5 1 0 0 Example 2 1 2. 5 9 5 Example 3 1 2. 5 9 8 Example 4 1 2. 5 8 9 Example 5 1 2. 5 4 3 Example 6 1 2. 5 2 7 Example 7 1 2-5 44 Example 8 1 2. 5 3 7 Example 9 1 2. 5 7 0 Example 1 0 1 2. 5 5 8 Example 1 1 1 2. 5 9 0 Example 1 2 1 2. 5 0
  • Example 1 4 1 2. 5 1 6 Example 1 5 1 2. 5 1 1 Example 1 6 1 2. 5 2 2 Example 1 ⁇ 1 2. 5 2 7 Example 1 8 1 2. 5 1 3 Example 1 9 1 2. 5 1 3 Example 2 0 1 2. 5 34 Example 2 1 1 2. 5 7 7 Example 2 2 1 2. 5 3 9 Example 2 3 1 2. 5 6 6 Implementation Example 24 1 2. 5 7 9 Example 2 5 1 2. 5 7 5 Compound concentration SNS inhibition rate Compound
  • Example 2 6 1 (%) Example 2 6 1 2. 5 1 9 Example 2 7 1 2. 5 9 6 Example 28 1 2. 5 7 8 Example 2 9 1 2. 5 70 Example 3 0 1 2. 5 3 3 Example 3 1 1 2. 5 2 3 Example 3 4 1 2. 5 7 1 Example 3 5 1 2. 5 84 Example 3 6 1 2. 5 0
  • Example 4 1 1 2. 5 8 7
  • Example 4 2 1 2. 5 0
  • Example 4 3 1 2. 5 5 5 Example 44 1 2. 5 9 8 Example 4 5 1 2. 5 1 5 Example 4 6 1 2. 5 1
  • Example 54 1 2. 5 1 0 0
  • the target product was obtained from 3-Promoreniline in the same manner as in Reference Examples;
  • the target product was obtained from promore dilin by the same method as in Reference Examples 1 to 3.
  • the target product was obtained from the compound obtained in Reference Example 28 in the same manner as in the alkylation of Reference Example 6.
  • the target product was obtained from the compound obtained in Reference Example 40-1 by the same method as in Reference Example 41.
  • the target product was obtained from the compound obtained in Reference Example 40-1 by the same method as in Reference Example 45.
  • Pd_C (10%, 0.65 g, amount of catalyst) was added to a solution of the compound obtained in Reference Example 54 (6.5 g, 32 mmol) in ethanol (63 ml), and the mixture was stirred overnight in a hydrogen atmosphere, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (5.6 g, 100%).
  • the target product was obtained from the compound obtained in Reference Example 5 and methyl 2-bromobutanoate in the same manner as in Reference Example 58.
  • the target product was obtained from the compound obtained in Reference Example 61 by a method similar to that in Reference Example 59.
  • the target product was obtained from the compound obtained in Reference Example 62 by a method similar to that of Reference Example 60.
  • Example 142 In the same manner as in Example 142, the compounds of Examples 143 to 199 shown in Table 20 were obtained.
  • Solvent A: 0.035% TFA / CH CN, B: 0.05% TFA / H 2 O
  • Example 20 In the same manner as in Example 200, the compounds of Example 20;! To 229 shown in Table 21 were obtained. Each compound was identified by high performance liquid chromatography retention time and LC / MS spectrum. The analysis conditions are the same as in Example 142.
  • 1-methyl-2-pyrrolidone of the compound obtained in Reference Example 29 (40 mg, 0.12 mmol) (in a 2 mU solution, 4-chlorophenol (31 mg, 0.25 mmol), cesium carbonate (80 mg, 0.48 mmol), Add dipivaloylmethane (2.5 0.012 mmol) and copper (I) chloride (6.1 mg, 0.062 mmol) at room temperature and stir for 4 hours at 120 ° C. After confirming the completion of the reaction, add water to the reaction solution.
  • the target product was obtained from the compound obtained in Reference Example 4 and the compound obtained in Reference Example 68 by the same method as in Example 1.

Abstract

La présente invention concerne un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci, formule (1) dans laquelle R1 représente un atome d'halogène ou équivalent, et R2 représente un atome d'hydrogène ou équivalent, ou R1 et R2 peuvent former ensemble un cycle de 5 à 7 chaînons; m représente un entier de 0 à 5; R7 représente un atome d'hydrogène ou équivalent; R3 et R4 représentent indépendamment un groupe alkyle substitué ou non substitué ou équivalent; R8 et R9 représentent indépendamment un atome d'hydrogène ou équivalent; n représente un entier de 1 à 6; et A représente un atome de fluor ou équivalent. Le composé ou le sel pharmaceutiquement acceptable de celui-ci a une activité inhibitrice du SNS qui peut avoir un effet thérapeutique ou prophylactique sur une maladie associée au SNS telle que la douleur neuropathique, la douleur nociceptive, le trouble de la miction ou la sclérose en plaques.
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WO2016020836A1 (fr) * 2014-08-06 2016-02-11 Novartis Ag Dérivés de quinolone comme antibactériens
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US10294206B2 (en) 2015-04-21 2019-05-21 Forma Tm2, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
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US10532047B2 (en) 2018-05-16 2020-01-14 Forma Therapeutics, Inc. Solid forms of ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
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US10160726B2 (en) 2014-08-06 2018-12-25 Novartis Ag Quinolone derivatives as antibacterials
WO2016020836A1 (fr) * 2014-08-06 2016-02-11 Novartis Ag Dérivés de quinolone comme antibactériens
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US10889567B2 (en) 2014-09-19 2021-01-12 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10253015B2 (en) 2014-09-19 2019-04-09 Forma Tm2, Inc. Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
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US10005734B2 (en) 2014-09-19 2018-06-26 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10414752B2 (en) 2014-09-19 2019-09-17 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10550099B2 (en) 2014-09-19 2020-02-04 Forma Therapeutics, Inc. Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors
US9624216B2 (en) * 2015-04-21 2017-04-18 Forma Therapeutics, Inc. Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors
US10294206B2 (en) 2015-04-21 2019-05-21 Forma Tm2, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10577329B2 (en) 2015-04-21 2020-03-03 Forma Therapeutics, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10807976B2 (en) 2015-04-21 2020-10-20 Forma Therapeutics, Inc. Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors
US10407419B2 (en) 2015-04-21 2019-09-10 Forma Therapeutics, Inc. Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors
US11311527B2 (en) 2018-05-16 2022-04-26 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mIDH-1)
US11013733B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mlDH-1)
US11013734B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Treating patients harboring an isocitrate dehydrogenase-1 (IDH-1) mutation
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US11376246B2 (en) 2018-05-16 2022-07-05 Forma Therapeutics, Inc. Inhibiting mutant IDH-1
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