WO2021200934A1 - Antimalarial drug - Google Patents

Antimalarial drug Download PDF

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WO2021200934A1
WO2021200934A1 PCT/JP2021/013516 JP2021013516W WO2021200934A1 WO 2021200934 A1 WO2021200934 A1 WO 2021200934A1 JP 2021013516 W JP2021013516 W JP 2021013516W WO 2021200934 A1 WO2021200934 A1 WO 2021200934A1
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group
alkyl
substituted
ring
aryl
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PCT/JP2021/013516
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French (fr)
Japanese (ja)
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賢志 水田
謙二 平山
修作 水上
ファルハナ モサデック
グエン ティエン フイ
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国立大学法人 長崎大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a benzimidazole derivative having excellent antimalarial activity.
  • the life cycle of malaria is divided into two, the sexual reproduction stage (mosquito) and the asexual reproduction stage (human), and the asexual reproduction stage is further divided into the intrahepatic stage and the erythrocyte stage (endoblood stage).
  • the red blood cell-infected Plasmodium merozoite first transforms into a ring and then grows into a large form called trophozoite. Trophozoites then mature into schizont and divide several times into new merozoites. Infected red blood cells eventually rupture, and merozoite in the blood travels through the bloodstream and infects new red blood cells.
  • Plasmodium in the erythrocyte stage utilizes erythrocyte hemoglobin (Hb) as a protein source and consumes 75% or more of the total intracellular Hb.
  • Hb degradation occurs in the gastrointestinal tract with the involvement of several proteases. Hb degradation is initiated by aspartic proteases (plasmepsin and tissue aspartic protease (HAP)), which hydrolyzes the Phe ⁇ 33-34 Leu bond that produces the quaternary structure of Hb. Heme is then crystallized into non-toxic hemozoin, and globin is broken down into peptide fragments and free amino acids.
  • Plasmodium malaria that invaded human erythrocytes in this way has a detoxification pathway that promotes heme aggregation to form hemozoin in order to protect itself from heme venom.
  • chloroquine and quinine target the degradation of harmful heme by hemozoin formation, but quinine also has strong antimalarial activity against chloroquine-resistant strains. This is because chloroquine resistance is caused by selective chloroquine excretion, and hemozoin formation is still considered to be a good target for new antimalarial drugs.
  • the protozoan chloroquine resistance mechanism is excreted extracellularly when the PfCRT mutated by the drug excretion pump recognizes chloroquine. It is considered necessary to escape from this mechanism in order to cope with chloroquine resistance.
  • Non-Patent Document 1 discloses, as major malaria drugs, (i) a drug that inhibits the decomposition of heme, (ii) a drug that targets folic acid metabolism, and (iii) a drug that inhibits electron transport of mitochondria. , The compound of the present invention described later is not disclosed.
  • Non-Patent Document 2 discloses that 2- (1H-benzimidazol-2-yl) hydrazone-4-nitrobenzaldehyde has antihemozoin activity, but does not disclose antimalarial activity.
  • the compound of the present invention which will be described later, is not disclosed at all.
  • Non-Patent Document 3 Compound No. 525841: 3-[(E)-(1H-benzimidazol-2-ylhydrazono) methyl] -2-chloro-7-methoxyquinoline, which is a MAPK phosphatase inhibitor, is used as an antimalaria drug. It describes the potential for usefulness.
  • Non-Patent Document 4 The following compounds are registered in CAS Registry Number: 598792-27-3, but there is no description of antimalarial activity (Non-Patent Document 4).
  • Non-Patent Document 5 The following compounds are registered in CAS Registry Number: 850186-56-0, but there is no description of antimalarial activity (Non-Patent Document 5).
  • Non-Patent Document 6 The following compounds are registered in CAS Registry Number: 877646-47-4, but there is no description of antimalarial activity (Non-Patent Document 6).
  • Non-Patent Document 7 The following compounds are registered in CAS Registry Number: 877795-60-3, but there is no description of antimalarial activity (Non-Patent Document 7).
  • Non-Patent Document 8 describes the following compounds, but does not describe the antimalarial action. Twice
  • Non-Patent Document 9 The following compounds are registered in CAS Registry Number: 850828-00-1, but there is no description of antimalarial activity (Non-Patent Document 9).
  • Non-Patent Document 10 The following compounds are registered in CAS Registry Number: 877804-77-8, but there is no description of antimalarial activity (Non-Patent Document 10).
  • Non-Patent Document 11 The following compounds are registered in CAS Registry Number: 850729-20-3, but there is no description of antimalarial activity (Non-Patent Document 11).
  • Non-Patent Document 12 The following compounds are registered in CAS Registry Number: 907964-80-1, but there is no description of antimalarial activity (Non-Patent Document 12).
  • Patent Document 1 describes the following compounds, but does not describe the antimalarial action.
  • An object of the present invention is to provide a new drug having excellent antimalarial activity (particularly antimalarial activity against chloroquine-resistant strains).
  • R is the formula (Ia):
  • R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
  • Ra represents a substituent selected from a hydrogen atom or a group other than a halogen atom and a hydroxy group.
  • Ring A represents a pyridine ring.
  • Ring B resides on an optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle).
  • the two substituents that form a ring may form a ring with the carbon atoms that are attached to each other and to which they are attached.
  • p indicates an integer of 1 to 2
  • * indicates the position of binding to the benzimidazole ring.
  • ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted.
  • R 2 represents a nitrogen-containing heterocyclic group that may be substituted. * Indicates the binding position to the benzimidazole ring.
  • R 4 is the formula: -L 2- (NH) n- Q 2 (In the formula, L 2 represents a (C 1- C 6 ) alkylene group. n represents an integer of 0 or 1, and Q 2 represents an aryl group which may be also heterocyclic group or a substituted substituted. ) Is shown. ) Indicates a group represented by, and X indicates a hydrogen atom or a halogen atom. ] A compound represented by or a salt thereof.
  • Ra may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, and a di ((C 1- C 6).
  • Ring B is a hydroxy group, Halogen atom, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkyl group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkoxy group Di ((C 1 -C 6) alkyl) amino group, (C 6- C 10 )
  • Aryl group A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively.
  • a 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are the carbons to which they are bonded together. Along with the atom, it may form a 5- to 7-membered ring which may contain 1 to 3 oxygen atoms as ring-constituting atoms.) Shows; Ring C represents a (C 1 -C 6) alkyl group and 1-3 further optionally substituted 5-7 membered nitrogen-containing heterocycle substituent selected from oxo group; R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
  • L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.
  • R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group.
  • halogen atoms C 6 -C 10 , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Shows 5-10-membered nitrogen-containing heterocyclic groups optionally substituted with substituents;
  • R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group.
  • halogen atoms C 6 -C 10 aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3
  • a 5- to 10-membered heterocyclic group which may be substituted with a substituent, Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3
  • Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1 (In the equation, L 1 indicates a bond, m represents an integer of 0 or 1, and Q 1 is a halogen
  • R 4 is the formula: -L 2- (NH) n- Q 2 (In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
  • n represents an integer of 0 or 1
  • Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di.
  • a 5- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6).
  • Ra may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, and a di ((C 1- C 6).
  • Ring B is a hydroxy group, Halogen atom, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkyl group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkoxy group Di ((C 1 -C 6) alkyl) amino group, (C 6- C 10 ) Aryl group, A benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) and 1 to 3 substituents selected from the nitro group, respectively.
  • Ring C represents a (C 1 -C 6) alkyl group and 1-3 further optionally substituted 5-7 membered nitrogen-containing heterocycle substituent selected from oxo group;
  • R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
  • L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R.
  • R 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) In optionally substituted with one to three substituents selected from the group represented (C 1 -C 6) represents an alkyl group; R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group.
  • halogen atoms C 6 -C 10 , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Shows 5-10-membered nitrogen-containing heterocyclic groups optionally substituted with substituents;
  • R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group.
  • halogen atoms C 6 -C 10 aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3
  • a 5- to 10-membered heterocyclic group which may be substituted with a substituent, Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3
  • Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1 (In the equation, L 1 indicates a bond, m represents an integer of 0 or 1, and Q 1 is a halogen
  • R 4 is the formula: -L 2- (NH) n- Q 2 (In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
  • n represents an integer of 0 or 1
  • Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di.
  • a 5- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6).
  • R is the formula (Ia):
  • Ra indicates a hydrogen atom
  • each of the other symbols is synonymous with the above.
  • Ring B is a hydroxy group, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • alkyl group and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Shows a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
  • R is the formula (Ib):
  • R is the formula (Ic): -NH-CO-R 3 (In the formula, each symbol has the same meaning as above.)
  • R is the formula (Id): -CO-NH-R 4 (In the formula, each symbol has the same meaning as above.)
  • a method for preventing or treating malaria which comprises administering an effective amount of the compound according to any one of the above [1] to [10] or a salt thereof to a mammal in need thereof.
  • R is the following formula (Ia'), formula (Ia ′′) or formula (Ia ′′ ′′):
  • R 1 represents a hydrogen atom or an optionally substituted (C 1 -C 6) alkyl group
  • Ring A' represents a benzene ring that may be further substituted.
  • Ring A ′′ represents a 5- to 6-membered nitrogen-containing aromatic heterocycle which may be further substituted with a substituent selected from groups other than the halogen atom.
  • Ring A''' represents a 6-membered nitrogen-containing aromatic heterocycle that may be further substituted.
  • Ring B' is a optionally substituted 6-membered nitrogen-containing aromatic heterocycle (here, two substituents present on adjacent carbon atoms in the 6-membered nitrogen-containing aromatic heterocycle are bonded to each other.
  • Ring B ′′ is on a optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, on an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle).
  • the two substituents present in may form a ring with the carbon atoms to which they are attached and bonded to each other).
  • a prophylactic or therapeutic agent for malaria containing the compound represented by (1) or a salt thereof as an active ingredient.
  • Ring A' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C).
  • Ring B' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, and 1 to 3 substituents may also be 6-membered optionally substituted with a group selected from a nitro group Nitrogen-containing aromatic heterocycles (here, the two substituents present on adjacent carbon atoms in a 6-membered nitrogen-containing aromatic heterocycle are 1 to 3 with the carbon atoms bonded to each other
  • Ring B'' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ).
  • aryl group optionally substituted with one to three halogen atoms (C 6 -C 10) aryl group, and with one to three substituents selected from nitro group, be each substituted
  • a good benzene ring or 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in the benzene ring or 5- to 6-membered aromatic heterocycle are attached to each other and they are bonded.
  • R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
  • L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R.
  • Ring A' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C).
  • Ring A'' may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, 1 to 3 selected from (C 6- C 10 ) aryl amino group, and nitro group.
  • Ring A''' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10). ) It may be substituted with 1 to 3 substituents selected from an aryl group, an arylamino group (C 6- C 10 ), and a nitro group, which may be substituted with 1 to 3 halogen atoms.
  • Ring B' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, and 1 to 3 substituents may also be 6-membered optionally substituted with a group selected from a nitro group Shows a nitrogen-containing aromatic heterocycle; Ring B'' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ).
  • aryl group optionally substituted with one to three halogen atoms (C 6 -C 10) aryl group, and with one to three substituents selected from nitro group, be each substituted Shows a good benzene ring or 5- to 6-membered aromatic heterocycle;
  • R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
  • L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R.
  • R 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Indicates an alkyl group. ) The prophylactic or therapeutic agent for malaria according to the above [19]. [21] Prevention or treatment of malaria according to any one of [18] to [20] above, wherein X represents a hydrogen atom and R 1 represents a hydrogen atom or an (C 1- C 6) alkyl group. Agent. [22] R is the formula (Ia''):
  • Ring A ′′ represents an unsubstituted 5- to 6-membered nitrogen-containing aromatic heterocycle, and the other symbols are synonymous with the above.
  • the prophylactic or therapeutic agent for malaria according to the above [21], which indicates the group represented by.
  • Ring A ′′ represents a pyridine ring, and ring B ′′ is a hydroxy group. It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • a method for preventing or treating malaria which comprises administering an effective amount of a compound represented by the formula (IA) described in the above [18] or a salt thereof to a mammal in need of the medication.
  • the present invention provides a benzimidazole derivative (compound (I) / compound (IA) described later) or a salt thereof, which has excellent antimalarial activity (particularly, antimalarial activity against an antichloroquine-resistant strain).
  • FIG. 1 shows the evaluation results of antimalarial activity performed in Test Example 4 described later.
  • Cpd. 19 and Cpd. 20 means a compound 1 administration group, a compound 19 administration group and a compound 20 administration group, respectively.
  • CQ means the chloroquine administration group
  • Ctl means the control group.
  • FIG. 2 shows the evaluation results of antimalarial activity performed in Test Example 5 described later.
  • 44 and 44 hydrochloride mean the compound 44 administration group and the compound 44 hydrochloride administration group, respectively.
  • CQ means the chloroquine administration group
  • Ctl means the control group.
  • examples of the salt of the compound (I) include salts with inorganic acids such as hydrochlorides, hydrobromates, sulfates and phosphates, acetates, fumarates and oxalates.
  • Salts with acids such as salts with organic acids such as citrate, methanesulfonate, benzenesulfonate, tosylate, maleate, etc .
  • alkali metal salts such as sodium salt, potassium salt, etc.
  • Salts with bases such as alkaline earth metal salts such as calcium salts; salts with amino acids such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, asparaginates and the like can be mentioned.
  • bases such as alkaline earth metal salts such as calcium salts
  • salts with amino acids such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, asparaginates and the like can be mentioned.
  • a pharmaceutically acceptable salt is preferable.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine.
  • the "C 1-6 alkyl group” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
  • C 1-6 alkylene group (including the case where it is a "C 1-6 alkylene group” portion in the definition), for example, -CH 2 -,-(CH 2 ) 2- , -(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-(CH 2 ) 6- , -CH (CH 3 )-, -C (CH 3 ) 2 -,- CH (C 2 H 5) - , - CH (C 3 H 7) -, - CH (CH (CH 3) 2) -, - (CH (CH 3)) 2 -, - CH 2 -CH (CH 3 ) -, - CH (CH 3 ) -CH 2 -, - CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2- C (CH 3 )
  • C 1-6 alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and the like. Examples thereof include sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • di ((C 1- C 6 ) alkyl) amino group refers to the above. It is an amino group substituted with two "(C 1- C 6 ) alkyl groups" of, and examples thereof include dimethylamino, diethylamino, dipropylamino, and dibutylamino.
  • heterocycle includes, for example, an aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • examples include non-aromatic heterocycles.
  • the "aromatic heterocycle” includes, for example, 5 to 14 members (for example) containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as a ring-constituting atom.
  • Aromatic heterocycles (preferably 5 to 10 members) can be mentioned.
  • Preferable examples of the "aromatic heterocycle” are thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isooxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi.
  • 5- to 6-membered monocyclic aromatic heterocycles such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazolepyridine, thienopyridine, flopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazolepyridine, Imidazopyrimidine, thienopyrimidine, flopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriadin, naphtho [2,3-b]
  • non-aromatic heterocycle is, for example, 3 to 14 members containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • non-aromatic heterocycles preferably 4 to 10 members.
  • non-aromatic heterocycle are aziridine, oxylan, thiirane, azetidine, oxetane, thietan, tetrahydropyran, tetrahydrofuran, pyrrolin, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazolin.
  • the "5- to 6-membered aromatic heterocycle” refers to a 5- to 6-membered aromatic heterocycle among the above-mentioned “aromatic heterocycles”.
  • the "5- to 6-membered nitrogen-containing aromatic heterocycle” is a 5- to 6-membered aromatic ring containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "aromatic heterocycles”. A group heterocycle.
  • the "5- to 7-membered nitrogen-containing aromatic heterocycle” is a 5- to 7-membered aromatic ring containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "aromatic heterocycles”.
  • the "6-membered nitrogen-containing aromatic heterocycle” refers to a 6-membered aromatic heterocycle containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "aromatic heterocycles”. say.
  • the "5- to 7-membered nitrogen-containing heterocycle” refers to a 5- to 7-membered heterocycle containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned “heterocycles”.
  • the "6-membered nitrogen-containing heterocycle” refers to a 6-membered heterocycle containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocycles”.
  • heterocyclic group (including the case where it is a “heterocyclic group” portion in the definition) is selected from, for example, a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • examples thereof include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered heterobridged ring groups containing 1 to 4 heteroatoms, respectively.
  • the "aromatic heterocyclic group” includes, for example, a nitrogen atom, a sulfur atom and oxygen as ring-constituting atoms in addition to a carbon atom.
  • examples thereof include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from the atoms.
  • aromatic heterocyclic group examples include thienyl, frill, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1 , 3,4-Oxaziazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and other 5- to 6-membered monocyclic aromatic heterocyclic groups; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazolypyridinyl, thieno
  • non-aromatic heterocyclic group includes, for example, a nitrogen atom and a sulfur atom in addition to a carbon atom as a ring-constituting atom.
  • 3 to 14 member preferably 4 to 10 member
  • non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from oxygen atoms.
  • non-aromatic heterocyclic group are aziridinyl, oxylanyl, thiylanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl.
  • preferred examples of the "7 to 10-membered complex crosslinked ring group” include quinucridinyl and 7-azabicyclo [2.2.1] heptanyl.
  • the "nitrogen-containing heterocyclic group” refers to a heterocyclic group containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned “heterocyclic groups”.
  • the "5- to 7-membered nitrogen-containing heterocyclic group” is a 5- to 7-membered heterocyclic group containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocyclic groups”. To say.
  • the "5- to 10-membered nitrogen-containing heterocyclic group” is a 5- to 10-membered heterocyclic group containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocyclic groups”.
  • the "5- to 10-membered heterocyclic group” refers to a 5- to 10-membered heterocyclic group among the above-mentioned “heterocyclic groups”.
  • aryl (including those which are “aryl” moiety in the definition), monocyclic or fused (C 6 -C 14) aryl group are exemplified, for example, phenyl, 1- Examples thereof include naphthyl, 2-naphthyl, 1-anthryl, 2-antryl and 9-antryl. Preferably, it is an (C 6- C 10 ) aryl group.
  • arylamino group (including those which are “arylamino group” moiety in the definition), monocyclic or fused (C 6 -C 14) aryl amino group can be mentioned, for example, Examples thereof include phenylamino, 1-naphthylamino, 2-naphthylamino, 1-anthrylamino, 2-anthrylamino and 9-anthrylamino. Preferably, it is an (C 6- C 10 ) arylamino group.
  • a ring such as a benzene ring or a 5- to 6-membered aromatic heterocycle
  • two substituents existing on adjacent carbon atoms are rings together with a carbon atom to which they are bonded to each other.
  • the ring include a carbon ring and a heterocycle, preferably containing a 5- to 7-membered carbon ring and 1 to 3 oxygen atoms as ring-constituting atoms.
  • a 5- to 7-membered heterocycle may be used, more preferably a 5- or 6-membered carbocycle, or a 5- or 6-membered heterocycle containing two oxygen atoms as ring-constituting atoms.
  • Ring A represents a pyridine ring.
  • Ra represents a substituent selected from a hydrogen atom or a group other than a halogen atom and a hydroxy group. Preferably, it may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl. ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) arylamino group, or nitro group. More preferably, it indicates a hydrogen atom.
  • P represents an integer of 1 to 2, preferably p represents 1.
  • Ring B resides on an optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle).
  • the two substituents that form a ring may form a ring with the carbon atoms that are attached to each other and to which they are attached.
  • a hydroxy group, Halogen atom It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkyl group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkoxy group Di ((C 1 -C 6) alkyl) amino group, (C 6- C 10 )
  • Aryl group A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively.
  • a 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are the carbons to which they are bonded together.
  • a 5- to 7-membered ring (preferably a 5- or 6-membered carbocyclic ring, or 2 oxygen atoms, which may contain 1 to 3 oxygen atoms as ring-constituting atoms, may be contained as ring-constituting atoms.
  • the ring B is a hydroxy group, Halogen atom, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkyl group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkoxy group Di ((C 1 -C 6) alkyl) amino group, (C 6- C 10 ) Aryl group, A benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) and 1 to 3 substituents selected from the nitro group, respectively.
  • the hydroxy group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • alkyl group and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 )
  • a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups, respectively, or a 5 to 6 member aromatic heterocycle (eg, pyrrole, furan, thiophene, imidazole, Pyridine), showing Most preferably, a hydroxy group, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • alkyl group and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Indicates a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
  • Ring C represents a 5- to 7-membered nitrogen-containing heterocycle that may be further substituted.
  • it shows a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with 1 to 3 substituents selected from (C 1- C 6) alkyl and oxo groups.
  • R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
  • a hydrogen atom, or an oxo group, a hydroxy group and the formula: -N-L 3- N (R 5 ) (R 6 ).
  • L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.
  • (C 1- C 6 ) Shows an alkyl group and More preferably, a hydrogen atom or a (C 1 -C 6) alkyl group.
  • R 2 represents a nitrogen-containing heterocyclic group that may be substituted.
  • a halogen atom a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms.
  • R 3 may be a optionally substituted heterocyclic group, an optionally substituted aryl group, or the formula: ⁇ L 1 ⁇ (S) m ⁇ Q 1 (In the equation, L 1 indicates a bond, m is an integer of 0 or 1, and Q 1 is, represents an aryl group which may be also heterocyclic group or a substituted substituted.
  • a halogen atom Preferably, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms.
  • one to three (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted by a group (eg pyrazolyl, thiazolyl, indolyl, benzothienyl), May be substituted with 1 to 3 (C 1- C 6 ) alkyl groups (C 6- C 10 ) aryl groups (eg phenyl), or formula: -L 1- (S) m- Q 1 (In the equation, L 1 indicates a bond, m is an integer of 0 or 1, and Q 1 is one to three (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted with a group (for example pyrazolyl , Thiazo
  • R 4 has the formula: -L 2 - (NH) n -Q 2 (In the formula, L 2 represents a (C 1- C 6 ) alkylene group. n represents an integer of 0 or 1, and Q 2 represents an aryl group which may be also heterocyclic group or a substituted substituted. ) Preferably, the formula: -L 2- (NH) n- Q 2 (In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
  • n represents an integer of 0 or 1
  • Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di.
  • a 5- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6).
  • n represents an integer of 0 or 1
  • Q 2, 1-3 (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted with a group (e.g., indolyl, It indicates a (quinolyl) or (C 6- C 10 ) aryl group (eg, phenyl) which may be substituted with 1 to 3 (C 1- C 6) alkyl groups. ) Is shown.
  • X represents a hydrogen atom or a halogen atom, preferably a hydrogen atom.
  • R 1 represents a hydrogen atom or an (C 1- C 6 ) alkyl group.
  • Ra is a hydrogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, Indicates an arylamino group (C 6- C 10 ) optionally substituted with 1 to 3 halogen atoms, or a nitro group;
  • p indicates an integer of 1 to 2 and represents Ring A represents a pyridine ring.
  • Ring B is a hydroxy group, Halogen atom, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkyl group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with 1 to 3 substituents selected from (C 1- C 6) alkyl and oxo groups.
  • R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group.
  • halogen atoms C 6 -C 10 aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Indicates a 5- to 10-membered nitrogen-containing heterocyclic group that may be substituted with a substituent. * Indicates the binding position to the benzimidazole ring.
  • R 3 is a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, (C 6- C).
  • substituents
  • R 4 is the formula: -L 2- (NH) n- Q 2
  • L 2 represents a (C 1- C 6 ) alkylene group.
  • n represents an integer of 0 or 1
  • Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di.
  • a 5- to 10-membered nitrogen-containing heterocyclic group (eg, indolyl, quinolyl), which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, (C 1- C 6 ) alkyl group.
  • (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group may be substituted with 1 to 3 halogen atoms ( It may be substituted with 1 to 3 substituents selected from C 6- C 10 ) arylamino groups, nitro groups, and (C 1- C 6 ) alkylene dioxy groups (C 6- C 10 ).
  • Indicates an aryl group (eg, phenyl). ) Is shown. ) Indicates a group indicated by, and X indicates a hydrogen atom. ]
  • R 1 represents a hydrogen atom or an (C 1- C 6 ) alkyl group.
  • Ra indicates a hydrogen atom
  • Ring A represents a pyridine ring.
  • Ring B is a hydroxy group, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 )
  • p indicates 1, * Indicates the binding position to the benzimidazole ring.
  • X indicates a hydrogen atom.
  • ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with 1 to 3 substituents selected from (C 1- C 6) alkyl and oxo groups.
  • R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group.
  • halogen atoms C 6 -C 10 aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Indicates a 5- to 10-membered nitrogen-containing heterocyclic group that may be substituted with a substituent. * Indicates the binding position to the benzimidazole ring.
  • n represents an integer of 0 or 1
  • Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di.
  • a 5- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6).
  • the pharmaceutically acceptable salt of compound (I) includes either an intramolecular salt or an adduct thereof, and also includes a solvate or a hydrate thereof.
  • the raw materials and reagents used in each step in the following production method, and the obtained compound may each form a salt.
  • Examples of such a salt include those similar to the above-mentioned salt of the compound of the present invention.
  • the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se.
  • the compound obtained in each step is a salt, it can be converted into a free form or another kind of salt of interest by a method known per se.
  • the commercially available product can be used as it is.
  • Rb is the formula (Ib):
  • Method 1 The reaction conditions in Method 1 can be determined by those skilled in the art by referring to the reference examples described later, the methods described in Examples, and other methods known in the art.
  • Method 2 The reaction conditions in Method 2 can be determined by those skilled in the art by referring to the reference examples described later, the methods described in Examples, and other methods known in the art.
  • the compound (I) or a salt thereof includes either an intramolecular salt or an adduct thereof, and also includes a solvate or a hydrate thereof.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate. Tautomers are also included in compound (I).
  • Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt.
  • a co-crystal or a co-crystal salt is unique in two or more kinds at room temperature, each having different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid solid.
  • the co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
  • the compound (IA) of the present invention has the formula (IA) :.
  • R is the following formula (Ia'), formula (Ia ′′) or formula (Ia ′′ ′′):
  • each group in the compound (IA) In the present specification, for the definition of each group in the compound (IA), the same ones as described above can be referred to for the compound (I). The same is true for the salt. Further, the compound (IA) or a salt thereof can also be produced by those skilled in the art according to the production method described for the compound (I) or a salt thereof. In the case of a known compound, if there is a commercially available product, the commercially available product can also be used.
  • R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
  • a hydrogen atom, or an oxo group, a hydroxy group and the formula: -N-L 3- N (R 5 ) (R 6 ).
  • L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.
  • C 1- C 6 Shows an alkyl group and More preferably, a hydrogen atom or a (C 1 -C 6) alkyl group.
  • Ring A' represents a benzene ring that may be further substituted.
  • a halogen atom a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms.
  • a benzene ring that may be substituted with a group, More preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group.
  • a benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) arylamino group and optionally 1 to 3 substituents selected from nitro groups. Show, More preferably, shows a one to three (C 1 -C 6) alkyl benzene ring which may be substituted with a group.
  • Ring A ′′ represents a 5- to 6-membered nitrogen-containing aromatic heterocycle which may be further substituted with a substituent selected from groups other than the halogen atom.
  • a hydroxy group may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl.
  • 1-3 selected from (alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, and nitro group.
  • Ring A''' represents a 6-membered nitrogen-containing aromatic heterocycle that may be further substituted.
  • a halogen atom a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms. Shows a 6-membered nitrogen-containing aromatic heterocycle that may be substituted with a group.
  • a halogen atom a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group.
  • 6 members which may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) which may be substituted with 1 to 3 halogen atoms and a nitro group.
  • Shows a nitrogen-containing aromatic heterocycle More preferably, one to three (C 1 -C 6) alkyl 6-membered nitrogen-containing aromatic may be substituted with a group heterocyclic (e.g. pyridine) shows a.
  • Ring B' is a optionally substituted 6-membered nitrogen-containing aromatic heterocycle (here, two substituents present on adjacent carbon atoms in the 6-membered nitrogen-containing aromatic heterocycle are bonded to each other. May form a ring with the carbon atoms to which they are bonded).
  • a halogen atom a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, Contains 6-membered nitrogen, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ), an arylamino group, and 1 to 3 substituents selected from nitro groups.
  • Aromatic heterocycles where, two substituents present on adjacent carbon atoms in a 6-membered nitrogen-containing aromatic heterocycle are attached to each other and together with the carbon atoms to which they are attached, 1 to 3 oxygens.
  • a 5- to 7-membered ring may contain an atom as a ring-constituting atom. May be formed), More preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group. 6-membered nitrogen which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) arylamino group and 1 to 3 substituents selected from nitro groups. Shows the contained aromatic heterocycle.
  • Ring B ′′ is on a optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, on an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle).
  • the two substituents present in may form a ring with the carbon atoms to which they are attached and bonded to each other).
  • a hydroxy group, Halogen atom It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkyl group It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • Alkoxy group Di ((C 1 -C 6) alkyl) amino group, (C 6- C 10 )
  • Aryl group A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively.
  • a 5- to 6-membered aromatic heterocycle (here, two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are carbon atoms to which they are bonded to each other. Together with, it contains a 5- to 7-membered ring (preferably a 5- or 6-membered carbon ring, or 2 oxygen atoms, which may contain 1 to 3 oxygen atoms as ring-constituting atoms.
  • a 5- or 6-membered heterocycle may be formed). More preferably, the hydroxy group, It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • alkyl group and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 )
  • a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups, respectively, or a 5 to 6 member aromatic heterocycle (eg, pyrrole, furan, thiophene, imidazole, Pyridine) is shown.
  • X represents a hydrogen atom or a halogen atom, Preferably, it indicates a hydrogen atom.
  • R is the following formula (Ia ′′):
  • R 1 represents a hydrogen atom or a (C 1- C 6 ) alkyl group.
  • Ring A ′′ represents a pyridine ring, and ring B ′′ is a hydroxy group. It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6).
  • alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 )
  • the group represented by and X represent a hydrogen atom.
  • compound (I) / compound (IA) or a salt thereof In carrying out the present invention as an antimalarial drug (particularly, an antimalarial drug against a chloroquine-resistant strain), compound (I) / compound (IA) or a salt thereof (preferably a pharmaceutically acceptable salt) (hereinafter, these (Sometimes collectively referred to as "the compound of the present invention"), either in the form of a single compound or in the form of a pharmaceutical composition (formulation) containing the compound of the present invention as an active ingredient together with a pharmaceutically acceptable carrier. It can also be used in the form of.
  • compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), suppositories, powders, granules, capsules (soft capsules, microcapsules, etc.).
  • suppositories liquids, emulsions, suspending agents, release controlled formulations (eg, immediate release preparations, sustained release preparations, sustained release microcapsules), aerosols, film agents (eg, orally disintegrating film) , Oral mucosa sticking film), injection (eg, subcutaneous injection, intravenous injection (eg, bolus), intramuscular injection, intraperitoneal injection), drip, transdermal drug, ointment, lotion Examples thereof include agents, patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal agents, lung agents (inhalants), eye drops and the like.
  • release controlled formulations eg, immediate release preparations, sustained release preparations, sustained release microcapsules
  • aerosols eg, film agents (eg, orally disintegrating film) , Oral mucosa sticking film)
  • injection eg, subcutaneous injection, intravenous injection (eg, bolus), intra
  • the “medically acceptable carrier” various carriers commonly used in the field of pharmaceutical technology can be used.
  • the "pharmaceutically acceptable carrier” include excipients (eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silicate silicate, etc.) and sulphates in solid preparations.
  • excipients eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silicate silicate, etc.
  • sulphates in solid preparations.
  • Swamps eg magnesium stearate, talc, colloidal silica, etc.
  • binders eg crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, etc.
  • Methyl cellulose, sodium carboxymethyl cellulose, etc.) and disintegrants eg, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.
  • disintegrants eg, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.
  • solvents eg, water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.
  • solubilizers eg, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, etc.
  • Surfactants such as ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.
  • suspending agents eg, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalconium chloride, glycerin monostearate, etc.
  • Activators eg, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydrophilic polymers such as hydroxypropyl cellulose, etc.
  • isotonic agents eg, glucose, D-sorbitol, sodium chloride, glycerin, etc.
  • D-mannitol or the like e.g, a buffer, a buffer such as phosphate or citrate
  • a pain-relieving agent for example, benzyl alcohol or the like
  • preservatives eg, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.
  • antioxidants eg, sulfites, ascorbic acid, ⁇ -tocopherol, etc.
  • colorants e.g., ascorbic acid, ⁇ -tocopherol, etc.
  • the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 99% (w / w), preferably 0.1 to 85%, based on the total amount of the preparation. It can be produced by adding it in a ratio of (w / w).
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, depending on its form.
  • the pharmaceutical composition of the present invention may be formed into a sustained release preparation containing an active ingredient. (About the subject of administration)
  • the compound of the present invention is expected to have low toxicity and few side effects, and has excellent properties as a pharmaceutical product. Therefore, the compounds of the present invention can be safely administered to mammals (particularly humans).
  • the compound of the present invention may be used alone or as a pharmaceutical composition orally or parenterally (eg, intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, by eye drops, etc. It can be administered intracerebrally, in the rectum, in the vagina, intraperitoneally, and to lesions).
  • parenterally eg, intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, by eye drops, etc. It can be administered intracerebrally, in the rectum, in the vagina, intraperitoneally, and to lesions).
  • the dose of the compound of the present invention varies depending on the administration subject, the administration route, and the age and symptoms of the administration subject, but is not particularly limited.
  • the dose when orally administered to an adult patient with malaria (body weight of about 40 to 80 kg, for example, 60 kg), the dose is about the active ingredient (Compound (I) / Compound (IA)) per day as the compound of the present invention. It ranges from 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 10 mg / kg body weight to about 30 mg / kg body weight, and can be administered once to several times a day. (About use as a prodrug) Compound (I) / Compound (IA) can also be used in the form of its prodrug.
  • the prodrug of compound (I) / compound (IA) is a compound that is converted into compound (I) / compound (IA) by a reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo, that is, enzymatically oxidized and reduced.
  • compound (I) / compound (IA) As a prodrug of compound (I) / compound (IA), a compound in which the amino group of compound (I) / compound (IA) is acylated, alkylated, or phosphorylated [eg, compound (I) / compound (IA) ) Amino group is eikosanoyylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivalo Iloxymethylated, tert-butylated compounds, etc.]; Compounds (I) / compounds (IA) in which the hydroxyl groups are acylated, alkylated, phosphorylated, or oxidized (eg, compound (I) / compound).
  • Etc. can be mentioned. These compounds can be prepared from compound (I) / compound (IA) by a method known per se.
  • the prodrug of compound (I) / compound (IA) is a compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development,” Vol. 7, Molecular Design, pp. 163 to 198. ) May be changed.
  • the compound of the present invention has extremely low toxicity and can be used for the prevention or treatment of malaria in combination with other drugs, and excellent preventive and / or therapeutic effects can be expected when used in combination with other drugs.
  • combination therapy will reduce the dose of other drugs to reduce the side effects of these drugs.
  • Drugs that can be used in combination with such compounds of the present invention include quinine, amodiaquine, mefloquine, piperakin, doxycycline, concomitant use of atovaquone and proguanil, lumefantrine, chloroquine, artemisinin, etc. Examples include artemether, artesunate, dihydroartemisinin and the like.
  • the concomitant drug can be appropriately selected in consideration of the type of the patient's disease, the severity of the symptom, and the like.
  • the administration form of the concomitant drug of the present invention is not particularly limited, and the compound of the present invention and the concomitant drug can be combined at the time of administration.
  • administration of a preparation containing a combination of the compound of the present invention and a concomitant drug and (2) simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug in the same route of administration.
  • it can be used in a form such as separate administration, (3) simultaneous or separate administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes.
  • the preferred form can be appropriately selected according to the actual conditions of the medical field.
  • a preparation containing the above-mentioned compound of the present invention in combination with a concomitant drug can be appropriately produced by a person skilled in the art according to the pharmaceutical composition containing the compound of the present invention described above.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the disease or symptom to be administered, the administration route, the type of concomitant drug to be used, and the like. Usually, it can be appropriately determined according to the actual conditions of the medical field based on the general clinical dose of the concomitant drug to be used.
  • Compound list A list of compounds (hereinafter, may be referred to as "compound list") that have been produced and / or evaluated in the present invention is shown below.
  • Compounds 1 to 3 are compounds provided by the compound library of the University of Tokyo Drug Discovery Organization.
  • Compounds 4 to 20 are commercially available compounds, which can be purchased from a manufacturer and obtained by those skilled in the art.
  • Compounds 21 to 50 are produced compounds. Those skilled in the art can appropriately manufacture and obtain the product by referring to the production method specifically shown in "Examples for Production of Compounds” described later and the production method known in the art.
  • Test Example 1 Anti-hemozoin activity test An anti-hemozoin activity test was conducted according to the following method to evaluate the activity of compounds 1 to 20.
  • Test method (1) Reagent preparation a. Hemin solution (12 mM hemin stock solution and solution at the time of use): A 12 mM hemin stock solution was prepared by dissolving 7.28 mg of hemin in 1 mL of DMSO and passing through a 0.2 ⁇ m pore size filter. The adjusted solution can be stored at 4 ° C for up to 1 month.
  • 0.2M acetate buffer (pH 4.8) was prepared by dissolving 1.64 g of sodium acetate in 100 mL of ultrapure water and adjusting the pH by adding HCl. Hemin solution was prepared at the time of use by adding 12.85 ⁇ L of hemin stock solution to 1 mL of 0.2 M acetate buffer.
  • NP-40 Nonidet P-40
  • 1% NP-40 was prepared by diluting a 1 mL NP-40 solution with 100 mL of ultrapure water. When used in the anti-hemozoin test, it was used at a final concentration of 0.005%.
  • the hemozoin inhibitory activity of the test compound is expressed in the form of the hemozoin inhibition rate, and the criterion for regarding the test compound as a positive hit showing the inhibitory activity is the hemozoin inhibition rate.
  • the result of the negative control (heme + DMSO / buffer) was + 3SD (standard deviation value) or more.
  • Test Example 2 Evaluation of antimalarial activity
  • the compounds whose hemozoin inhibitory activity was confirmed in the evaluation in Test Example 1 were evaluated by an in vitro antimalarial assay. The method was based on a previous report (Johnson et al., 2007; Smilestein, Sriwijaroen, Kelly, Williamat, & Riskoe, 2004). Specifically, the following is added to the culture solution (RPMI 1640) to adjust DMSO to 0.05% and pH to 7.3 to 7.4.
  • Fluorescence intensity (Ex: 485 nm, Em: 515 nm) was measured as an index of the amount of protozoan. Subsequently, the same experiment as above was performed using compounds having different concentrations. From this result, a 50% inhibitory concentration (IC 50 ) value was calculated. Specifically, the calculation was performed using GraphPad Prism 5 (GraphPad Software, Inc.).
  • Test Example 3 Evaluation of Cytotoxicity Next, a cytotoxicity test was performed. On the day before the experiment, 100 ⁇ L of extracellular fluid adjusted to 3000 cells / mL of Adult mouse brain (AMB) cells was added to each well, and the cells were cultured in an incubator at 37 ° C. and 5% CO 2 for 24 hours. On the day of the experiment, first, a dilution sequence of the control Artesunate, Chloroquine, and the test compound was prepared on the compound preparation plate. The culture solution was aspirated from each well of the experimental plate in which the cells were seeded the day before so that only the adhered cells remained at the bottom, and 100 ⁇ L of the compound solution was added to each well from the compound preparation plate.
  • AMB adult mouse brain
  • the compound treatment was carried out at 37 ° C. under 5% CO 2 for 48 hours. Then, 10 ⁇ L of alamarBlue was added to each well, and the mixture was reacted for 2 hours to measure the fluorescence intensity (Ex: 544 nm, Em: 590 nm). Using the results, a 50% inhibition concentration (sometimes referred to as "Hz inhibition rate") (CC 50 ) of each compound was calculated.
  • Hz inhibition rate 50% inhibition concentration
  • Test results in Test Examples 2 and 3 above are shown in Table 1 below.
  • the present invention provides a benzimidazole derivative having excellent antimalarial activity (particularly, antimalarial activity against an antimalarial resistant strain) useful for the prevention or treatment of malaria.

Abstract

The present invention provides a compound indicated by formula (I) or a salt thereof that is useful for the prevention or treatment of malaria (in the formula, each of the symbols is as defined in the specification).

Description

抗マラリア薬Antimalarial drug
　本発明は、優れた抗マラリア活性を有するベンゾイミダゾール誘導体に関する。 The present invention relates to a benzimidazole derivative having excellent antimalarial activity.
　世界ではマラリア感染により、年間数十万の死亡者が出ている。これまで開発された抗マラリア治療薬のうち、キニーネ、アモジアキン、クロロキン及びメフロキンは、殺マラリア原虫（主に熱帯熱マラリア）活性を持つ優れた速効性のある抗マラリア薬である。しかし近年これらに対して耐性を持つ株が生じており、耐性予防のためのアルテミシニン併用療法が主流になりつつある。しかしながら、この併用療法の主剤であるアルテミシニンにも、既に耐性株の発生が報告されており、対応策が課題となっている。
　マラリアの生活環は、有性生殖期（蚊）と無性生殖期（ヒト）の２つに分けられ、さらに無性生殖期は、肝内期と赤血球期（血内期）に分けられる。赤血球に感染したマラリア原虫メロゾイトはまずリング状に姿を変え、次にトロフォゾイトと呼ばれる大きな形態に成長する。トロフォゾイトはその後シゾントに成熟し、数回分裂して新しいメロゾイトとなる。感染赤血球は最終的に破裂し、血中のメロゾイトは血流内を移動して新しい赤血球に感染する。赤血球期のマラリア原虫は、赤血球ヘモグロビン（Ｈｂ）をタンパク源として利用し、細胞内全Ｈｂの７５％以上を消費する。Ｈｂ分解は、いくつかプロテアーゼが関与して消化胞内で起こる。Ｈｂ分解はアスパラギン酸プロテアーゼ（プラスメプシンおよび組織アスパラギン酸プロテアーゼ（ＨＡＰ））により開始され、プラスメプシンはＨｂの四次構造を生成するＰｈｅα３３－３４Ｌｅｕ結合を加水分解する。その後、ヘムは非毒性ヘモゾインに結晶化され、グロビンはペプチド断片そして遊離アミノ酸へと分解される。このようにヒト赤血球に侵入したマラリア原虫は、自らをヘム毒から守るためにヘム凝集を促進させてヘモゾインを形成する解毒経路を持っている。 Malaria infections cause hundreds of thousands of deaths worldwide each year. Among the antimalarial drugs developed so far, quinine, amodiaquine, chloroquine and mefloquine are excellent fast-acting antimalarial drugs having malaria killing protozoa (mainly falciparum malaria) activity. However, in recent years, strains resistant to these have emerged, and artemisinin combination therapy for preventing resistance is becoming mainstream. However, the development of resistant strains has already been reported for artemisinin, which is the main drug of this combination therapy, and countermeasures have become an issue.
The life cycle of malaria is divided into two, the sexual reproduction stage (mosquito) and the asexual reproduction stage (human), and the asexual reproduction stage is further divided into the intrahepatic stage and the erythrocyte stage (endoblood stage). The red blood cell-infected Plasmodium merozoite first transforms into a ring and then grows into a large form called trophozoite. Trophozoites then mature into schizont and divide several times into new merozoites. Infected red blood cells eventually rupture, and merozoite in the blood travels through the bloodstream and infects new red blood cells. Plasmodium in the erythrocyte stage utilizes erythrocyte hemoglobin (Hb) as a protein source and consumes 75% or more of the total intracellular Hb. Hb degradation occurs in the gastrointestinal tract with the involvement of several proteases. Hb degradation is initiated by aspartic proteases (plasmepsin and tissue aspartic protease (HAP)), which hydrolyzes the Pheα33-34 Leu bond that produces the quaternary structure of Hb. Heme is then crystallized into non-toxic hemozoin, and globin is broken down into peptide fragments and free amino acids. Plasmodium malaria that invaded human erythrocytes in this way has a detoxification pathway that promotes heme aggregation to form hemozoin in order to protect itself from heme venom.
　クロロキンとキニーネは両者ともにヘモゾイン形成による有害なヘムの分解を標的とするが、キニーネはクロロキン耐性株に対しても強い抗マラリア活性を有している。これはクロロキン耐性が、選択的なクロロキン排出によって起こっているためであり、ヘモゾイン形成は未だ新規抗マラリア薬の良い標的であると考えられる。
　一方、原虫のクロロキン耐性機構は、薬剤排出ポンプが変異したＰｆＣＲＴがクロロキンを認識することで、細胞外へと排出される。クロロキン耐性への対応のためには、この機構から逃れることが必要と考えられる。 Both chloroquine and quinine target the degradation of harmful heme by hemozoin formation, but quinine also has strong antimalarial activity against chloroquine-resistant strains. This is because chloroquine resistance is caused by selective chloroquine excretion, and hemozoin formation is still considered to be a good target for new antimalarial drugs.
On the other hand, the protozoan chloroquine resistance mechanism is excreted extracellularly when the PfCRT mutated by the drug excretion pump recognizes chloroquine. It is considered necessary to escape from this mechanism in order to cope with chloroquine resistance.
　非特許文献１は、主要なマラリア薬として、（ｉ）ヘムの分解を妨げる薬剤、（ｉｉ）葉酸代謝を標的とする薬剤、（ｉｉｉ）ミトコンドリアの電子輸送阻害を行う薬剤を開示しているが、後述する本発明の化合物は開示していない。 Non-Patent Document 1 discloses, as major malaria drugs, (i) a drug that inhibits the decomposition of heme, (ii) a drug that targets folic acid metabolism, and (iii) a drug that inhibits electron transport of mitochondria. , The compound of the present invention described later is not disclosed.
　他方、非特許文献２は、２－（１Ｈ－ベンゾイミダゾール－２－イル）ヒドラゾン－４－ニトロベンズアルデヒドが抗ヘモゾイン活性を有することについて開示するが、抗マラリア活性に関しては開示していない。後述する本発明の化合物についても全く開示していない。 On the other hand, Non-Patent Document 2 discloses that 2- (1H-benzimidazol-2-yl) hydrazone-4-nitrobenzaldehyde has antihemozoin activity, but does not disclose antimalarial activity. The compound of the present invention, which will be described later, is not disclosed at all.
　非特許文献３は、ＭＡＰＫホスファターゼ阻害剤である化合物番号５２５８４１：３－［（Ｅ）－（１Ｈ－ベンゾイミダゾール－２－イルヒドラゾノ）メチル］－２－クロロ－７－メトキシキノリンが、抗マラリア薬として有用である可能性について記載している。 In Non-Patent Document 3, Compound No. 525841: 3-[(E)-(1H-benzimidazol-2-ylhydrazono) methyl] -2-chloro-7-methoxyquinoline, which is a MAPK phosphatase inhibitor, is used as an antimalaria drug. It describes the potential for usefulness.
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：９５８７９２－２７－３に登録されているが、抗マラリア作用については記載がない（非特許文献４）。 The following compounds are registered in CAS Registry Number: 598792-27-3, but there is no description of antimalarial activity (Non-Patent Document 4).
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：８５０１８６－５６－０に登録されているが、抗マラリア作用については記載がない（非特許文献５）。 The following compounds are registered in CAS Registry Number: 850186-56-0, but there is no description of antimalarial activity (Non-Patent Document 5).
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：８７７６４６－４７－４に登録されているが、抗マラリア作用については記載がない（非特許文献６）。 The following compounds are registered in CAS Registry Number: 877646-47-4, but there is no description of antimalarial activity (Non-Patent Document 6).
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：８７７７９５－６０－３に登録されているが、抗マラリア作用については記載がない（非特許文献７）。 The following compounds are registered in CAS Registry Number: 877795-60-3, but there is no description of antimalarial activity (Non-Patent Document 7).
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　非特許文献８は、下記化合物を記載しているが、抗マラリア作用については記載がない。　 Non-Patent Document 8 describes the following compounds, but does not describe the antimalarial action. Twice
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：８５０８２８－００－１に登録されているが、抗マラリア作用については記載がない（非特許文献９）。 The following compounds are registered in CAS Registry Number: 850828-00-1, but there is no description of antimalarial activity (Non-Patent Document 9).
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：８７７８０４－７７－８に登録されているが、抗マラリア作用については記載がない（非特許文献１０）。 The following compounds are registered in CAS Registry Number: 877804-77-8, but there is no description of antimalarial activity (Non-Patent Document 10).
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：８５０７２９－２０－３に登録されているが、抗マラリア作用については記載がない（非特許文献１１）。 The following compounds are registered in CAS Registry Number: 850729-20-3, but there is no description of antimalarial activity (Non-Patent Document 11).
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　下記化合物は、ＣＡＳ　Ｒｅｇｉｓｔｒｙ　Ｎｕｍｂｅｒ：９０７９６４－８０－１に登録されているが、抗マラリア作用については記載がない（非特許文献１２）。 The following compounds are registered in CAS Registry Number: 907964-80-1, but there is no description of antimalarial activity (Non-Patent Document 12).
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　特許文献１は、下記化合物を記載しているが、抗マラリア作用については記載がない。 Patent Document 1 describes the following compounds, but does not describe the antimalarial action.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
国際公開第２０２０／０４７６６８号International Publication No. 2020/047666
　本発明は、優れた抗マラリア活性（特にクロロキン耐性株に対する抗マラリア活性）を有する新たな薬剤を提供することを課題とする。 An object of the present invention is to provide a new drug having excellent antimalarial activity (particularly antimalarial activity against chloroquine-resistant strains).
　本発明者らは、上記課題を解決するために鋭意研究した結果、下記式（Ｉ）で表される新規な化合物（化合物（Ｉ））またはその塩が、上記の優れた抗マラリア活性を有することを見出した。さらに、本発明者らは、化合物（Ｉ）に類縁のベンゾイミダゾール誘導体（公知化合物を含む）（以下、化合物（ＩＡ）とも表記する）にも抗マラリア活性が期待できることをも併せて見出した。即ち、本発明は、以下の通りである。 As a result of diligent research to solve the above problems, the present inventors have found that a novel compound represented by the following formula (I) (Compound (I)) or a salt thereof has the above-mentioned excellent antimalaria activity. I found that. Furthermore, the present inventors have also found that benzimidazole derivatives (including known compounds) related to compound (I) (hereinafter, also referred to as compound (IA)) can be expected to have antimalaria activity. That is, the present invention is as follows.
［１］式（Ｉ）： [1] Equation (I):
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
［式中、Ｒは、式（Ｉａ）： [In the formula, R is the formula (Ia):
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
（式中、Ｒ1は、水素原子、または
置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
Ｒａは、水素原子、または
ハロゲン原子およびヒドロキシ基以外の基から選択される置換基を示し、
環Ａは、ピリジン環を示し、
環Ｂは、置換されていてもよいベンゼン環または置換されていてもよい５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい。）を示し、
ｐは、１～２の整数を示し、および
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基；
式（Ｉｂ）： (In the formula, R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
Ra represents a substituent selected from a hydrogen atom or a group other than a halogen atom and a hydroxy group.
Ring A represents a pyridine ring.
Ring B resides on an optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle). The two substituents that form a ring may form a ring with the carbon atoms that are attached to each other and to which they are attached.)
p indicates an integer of 1 to 2, and * indicates the position of binding to the benzimidazole ring. )
Group indicated by;
Equation (Ib):
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
（式中、環Ｃは、さらに置換されていてもよい５～７員窒素含有複素環を示し、
Ｒ２は、置換されていてもよい窒素含有複素環基を示し、
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基；
式（Ｉｃ）：－ＮＨ－ＣＯ－Ｒ３
（式中、Ｒ３は、置換されていてもよい複素環基、置換されていてもよいアリール基または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、置換されていてもよい複素環基または置換されていてもよいアリール基を示す。）
を示す。）
で示される基；または
式（Ｉｄ）：－ＣＯ－ＮＨ－Ｒ４
（式中、Ｒ４は、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、置換されていてもよい複素環基または置換されていてもよいアリール基を示す。）
を示す。）
で示される基を示し、および
Ｘは、水素原子またはハロゲン原子を示す。］
で表される化合物またはその塩。
［２］Ｒａが、水素原子、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、またはニトロ基を示し；
環Ｂが、ヒドロキシ基、
ハロゲン原子、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
（Ｃ６－Ｃ１０）アリール基、
１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
ニトロ基
から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環
（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環を形成していてもよい）
を示し；
環Ｃが、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し；
Ｒ１が、水素原子、または
オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
（式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）
で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し；
Ｒ２が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し；
Ｒ３が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基、または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
を示し；
Ｒ４が、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、またはハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
を示す、上記［１］に記載の化合物またはその塩。
［３］Ｒａが、水素原子、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、またはニトロ基を示し；
環Ｂが、ヒドロキシ基、
ハロゲン原子、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
（Ｃ６－Ｃ１０）アリール基、
１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
ニトロ基
から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環
を示し；
環Ｃが、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し；
Ｒ１が、水素原子、または
オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
（式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）
で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し；
Ｒ２が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し；
Ｒ３が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基、または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
を示し；
Ｒ４が、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、またはハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
を示す、上記［１］または［２］のいずれかに記載の化合物またはその塩。
［４］Ｘが、水素原子を示し、および
Ｒ１が、水素原子または（Ｃ１－Ｃ６）アルキル基を示す、上記［１］～［３］のいずれかに記載の化合物またはその塩。 (In the formula, ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted.
R 2 represents a nitrogen-containing heterocyclic group that may be substituted.
* Indicates the binding position to the benzimidazole ring. )
Group indicated by;
Formula (Ic): -NH-CO-R 3
(In the formula, R 3 is a optionally substituted heterocyclic group, an optionally substituted aryl group or the formula: −L 1 − (S) m −Q 1
(In the equation, L 1 indicates a bond,
m is an integer of 0 or 1, and Q 1 is, represents an aryl group which may be also heterocyclic group or a substituted substituted. )
Is shown. )
Group represented by; or formula (Id): -CO-NH-R 4
(In the formula, R 4 is the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 represents an aryl group which may be also heterocyclic group or a substituted substituted. )
Is shown. )
Indicates a group represented by, and X indicates a hydrogen atom or a halogen atom. ]
A compound represented by or a salt thereof.
[2] Ra may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, and a di ((C 1- C 6). 6 ) Alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ), showing arylamino group, or nitro group;
Ring B is a hydroxy group,
Halogen atom,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
Di ((C 1 -C 6) alkyl) amino group,
(C 6- C 10 ) Aryl group,
A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively. , Or a 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are the carbons to which they are bonded together. Along with the atom, it may form a 5- to 7-membered ring which may contain 1 to 3 oxygen atoms as ring-constituting atoms.)
Shows;
Ring C represents a (C 1 -C 6) alkyl group and 1-3 further optionally substituted 5-7 membered nitrogen-containing heterocycle substituent selected from oxo group;
R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
(In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.)
In optionally substituted with one to three substituents selected from the group represented (C 1 -C 6) represents an alkyl group;
R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Shows 5-10-membered nitrogen-containing heterocyclic groups optionally substituted with substituents;
R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 A 5- to 10-membered heterocyclic group which may be substituted with a substituent,
Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1
(In the equation, L 1 indicates a bond,
m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) An alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ). Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an arylamino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
Shows;
R 4 is the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6). ) Alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
The compound according to the above [1] or a salt thereof.
[3] Ra may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, and a di ((C 1- C 6). 6 ) Alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ), showing arylamino group, or nitro group;
Ring B is a hydroxy group,
Halogen atom,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
Di ((C 1 -C 6) alkyl) amino group,
(C 6- C 10 ) Aryl group,
A benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) and 1 to 3 substituents selected from the nitro group, respectively. , Or a 5- to 6-membered aromatic heterocycle;
Ring C represents a (C 1 -C 6) alkyl group and 1-3 further optionally substituted 5-7 membered nitrogen-containing heterocycle substituent selected from oxo group;
R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
(In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.)
In optionally substituted with one to three substituents selected from the group represented (C 1 -C 6) represents an alkyl group;
R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Shows 5-10-membered nitrogen-containing heterocyclic groups optionally substituted with substituents;
R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 A 5- to 10-membered heterocyclic group which may be substituted with a substituent,
Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1
(In the equation, L 1 indicates a bond,
m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) An alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ). Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an arylamino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
Shows;
R 4 is the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6). ) Alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
The compound according to any one of the above [1] or [2] or a salt thereof.
[4] The compound according to any one of [1] to [3] above, or a salt thereof, wherein X represents a hydrogen atom and R 1 represents a hydrogen atom or an (C 1- C 6) alkyl group.
［５］Ｒが、式（Ｉａ）： [5] R is the formula (Ia):
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
（式中、各記号は前記と同義であるか；
好ましくは、
　Ｒａは水素原子を示し、およびその他の各記号は前記と同義である。）
で示される基を示す、上記［１］～［４］のいずれかに記載の化合物またはその塩。
［６］Ｒａが、水素原子を示し、
環Ｂが、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し、
ｐが、１を示す、上記［１］～［５］のいずれかに記載の化合物またはその塩。
［７］３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）キノリン（化合物３２）、
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７－メチルキノリン（化合物３４）、
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－7－メトキシキノリン（化合物３７）、
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６，７－ジメチルキノリン（化合物４４）、
またはそれらの塩である、上記［６］に記載の化合物またはその塩。 (In the formula, are each symbol synonymous with the above;
Preferably,
Ra indicates a hydrogen atom, and each of the other symbols is synonymous with the above. )
The compound according to any one of the above [1] to [4] or a salt thereof, which indicates the group represented by.
[6] Ra indicates a hydrogen atom,
Ring B is a hydroxy group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Shows a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
The compound according to any one of the above [1] to [5] or a salt thereof, wherein p indicates 1.
[7] 3-(2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) quinoline (Compound 32),
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methylquinoline (Compound 34),
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methoxyquinoline (Compound 37),
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -6,7-dimethylquinoline (Compound 44),
Or the compound according to the above [6] or a salt thereof, which is a salt thereof.
［８］Ｒが、式（Ｉｂ）： [8] R is the formula (Ib):
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（式中、各記号は前記と同義である。）
で示される基を示す、上記［１］～［４］のいずれかに記載の化合物またはその塩。
［９］Ｒが、式（Ｉｃ）：－ＮＨ－ＣＯ－Ｒ３
（式中、各記号は前記と同義である。）
で示される基を示す、上記［１］～［４］のいずれかに記載の化合物またはその塩。
［１０］Ｒが、式（Ｉｄ）：－ＣＯ－ＮＨ－Ｒ４
（式中、各記号は前記と同義である。）
で示される基を示す、上記［１］～［４］のいずれかに記載の化合物またはその塩。 (In the formula, each symbol has the same meaning as above.)
The compound according to any one of the above [1] to [4] or a salt thereof, which indicates the group represented by.
[9] R is the formula (Ic): -NH-CO-R 3
(In the formula, each symbol has the same meaning as above.)
The compound according to any one of the above [1] to [4] or a salt thereof, which indicates the group represented by.
[10] R is the formula (Id): -CO-NH-R 4
(In the formula, each symbol has the same meaning as above.)
The compound according to any one of the above [1] to [4] or a salt thereof, which indicates the group represented by.
［１１］上記［１］～［１０］のいずれかに記載の化合物またはその塩を有効性成分として含有する医薬。
［１２］マラリアの予防または治療のための、上記［１１］に記載の医薬。
［１３］上記［１］～［１０］のいずれかに記載の化合物またはその塩の有効量を、その投薬を必要とする哺乳動物に投与することを含む、マラリアの予防または治療方法。
［１４］医薬として使用するための、上記［１］～［１０］のいずれかに記載の化合物またはその塩。
［１５］マラリアの予防または治療に使用するための、上記［１］～［１０］のいずれかに記載の化合物またはその塩。
［１６］上記［１］～［１０］のいずれかに記載の化合物またはその塩の、医薬を製造するための使用。
［１７］上記［１］～［１０］のいずれかに記載の化合物またはその塩の、マラリアの予防または治療薬を製造するための使用。 [11] A drug containing the compound according to any one of the above [1] to [10] or a salt thereof as an active ingredient.
[12] The medicament according to the above [11] for the prevention or treatment of malaria.
[13] A method for preventing or treating malaria, which comprises administering an effective amount of the compound according to any one of the above [1] to [10] or a salt thereof to a mammal in need thereof.
[14] The compound according to any one of the above [1] to [10] or a salt thereof for use as a medicine.
[15] The compound according to any one of the above [1] to [10] or a salt thereof for use in the prevention or treatment of malaria.
[16] Use of the compound according to any one of the above [1] to [10] or a salt thereof for producing a drug.
[17] Use of the compound according to any one of the above [1] to [10] or a salt thereof for producing a prophylactic or therapeutic agent for malaria.
［１８］式（ＩＡ）： [18] Equation (IA):
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
［式中、Ｒは、下記の式（Ｉａ’）、式（Ｉａ’’）または式（Ｉａ’’’）： [In the formula, R is the following formula (Ia'), formula (Ia ″) or formula (Ia ″ ″):
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（上記式中、Ｒ1は、水素原子または置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
環Ａ’は、さらに置換されていてもよいベンゼン環を示し、
環Ａ’’は、ハロゲン原子以外の基から選択される置換基でさらに置換されていてもよい５～６員窒素含有芳香族複素環を示し、
環Ａ’’’は、さらに置換されていてもよい６員窒素含有芳香族複素環を示し、
環Ｂ’は、置換されていてもよい６員窒素含有芳香族複素環（ここにおいて、６員窒素含有芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい）を示し、
環Ｂ’’は、置換されていてもよいベンゼン環または置換されていてもよい５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい）を示し、
＊は、ベンゾイミダゾール環への結合位置を示し、および
部分構造式（Ｉａａ）： (In the formula, R 1 represents a hydrogen atom or an optionally substituted (C 1 -C 6) alkyl group,
Ring A'represents a benzene ring that may be further substituted.
Ring A ″ represents a 5- to 6-membered nitrogen-containing aromatic heterocycle which may be further substituted with a substituent selected from groups other than the halogen atom.
Ring A'''represents a 6-membered nitrogen-containing aromatic heterocycle that may be further substituted.
Ring B'is a optionally substituted 6-membered nitrogen-containing aromatic heterocycle (here, two substituents present on adjacent carbon atoms in the 6-membered nitrogen-containing aromatic heterocycle are bonded to each other. May form a ring with the carbon atoms to which they are bonded).
Ring B ″ is on a optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, on an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle). The two substituents present in may form a ring with the carbon atoms to which they are attached and bonded to each other).
* Indicates the binding position to the benzimidazole ring, and the partial structural formula (Iaa) :.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
で示される基は、＊＊で示される位置で環Ａ’、環Ａ’’または環Ａ’’’に結合している。）
で示される基を示し、および
Ｘは、水素原子またはハロゲン原子を示す。］
で表される化合物またはその塩を有効成分として含有する、マラリアの予防または治療剤。
［１９］環Ａ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し；
環Ａ’’が、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～６員窒素含有芳香族複素環を示し；
環Ａ’’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示し；
環Ｂ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環（ここにおいて、６員窒素含有芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環を形成していてもよい）
を示し；
環Ｂ’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環または５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環を形成していてもよい）
を示し；
Ｒ１が、水素原子、または
オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
（式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示す。）
を示す、上記［１８］に記載のマラリアの予防または治療剤。
［２０］環Ａ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し；
環Ａ’’が、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい５～６員窒素含有芳香族複素環を示し；
環Ａ’’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基、から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示し；
環Ｂ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環
を示し；
環Ｂ’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環または５～６員芳香族複素環を示し；
Ｒ１が、水素原子、または
オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
（式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示す。）
を示す、上記［１９］に記載のマラリアの予防または治療剤。
［２１］Ｘが、水素原子を示し、および
Ｒ１が、水素原子または（Ｃ１－Ｃ６）アルキル基を示す、上記［１８］～［２０］のいずれかに記載のマラリアの予防または治療剤。
［２２］Ｒが、式（Ｉａ’’）： The group indicated by is attached to ring A', ring A'' or ring A''' at the position indicated by **. )
Indicates a group represented by, and X indicates a hydrogen atom or a halogen atom. ]
A prophylactic or therapeutic agent for malaria containing the compound represented by (1) or a salt thereof as an active ingredient.
[19] Ring A'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C). 10 ) An aryl group selected from a (C 6- C 10 ) aryl amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group which may be substituted with 1 to 3 halogen atoms 1 Shows a benzene ring optionally substituted with ~ 3 substituents;
Ring A'' may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) Shows a 5- to 6-membered nitrogen-containing aromatic heterocycle optionally substituted with 1 to 3 substituents selected from alkylenedioxy groups;
Ring A'''is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10). ) Aryl group 1 to selected from (C 6- C 10 ) aryl amino group, nitro group, and (C 1 to C 6 ) alkylene dioxy group which may be substituted with 1 to 3 halogen atoms. Shows a 6-membered nitrogen-containing aromatic heterocycle optionally substituted with 3 substituents;
Ring B'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, and 1 to 3 substituents may also be 6-membered optionally substituted with a group selected from a nitro group Nitrogen-containing aromatic heterocycles (here, the two substituents present on adjacent carbon atoms in a 6-membered nitrogen-containing aromatic heterocycle are 1 to 3 with the carbon atoms bonded to each other and to which they are bonded. It may form a 5- to 7-membered ring which may contain the oxygen atom of the above as a ring-constituting atom.)
Shows;
Ring B'' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ). aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl group, and with one to three substituents selected from nitro group, be each substituted A good benzene ring or 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in the benzene ring or 5- to 6-membered aromatic heterocycle are attached to each other and they are bonded. It may form a 5- to 7-membered ring which may contain 1 to 3 oxygen atoms as a ring-constituting atom together with the carbon atom.)
Shows;
R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
(In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Indicates an alkyl group. )
The prophylactic or therapeutic agent for malaria according to the above [18].
[20] Ring A'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C). 10) aryl group, optionally substituted with one to three optionally substituted with a halogen atom (C 6 -C 10) aryl amino group, and 1 to 3 substituents selected from a nitro group Shows a good benzene ring;
Ring A'' may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, 1 to 3 selected from (C 6- C 10 ) aryl amino group, and nitro group. Shows a 5- to 6-membered nitrogen-containing aromatic heterocycle optionally substituted with a substituent of;
Ring A'''is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10). ) It may be substituted with 1 to 3 substituents selected from an aryl group, an arylamino group (C 6- C 10 ), and a nitro group, which may be substituted with 1 to 3 halogen atoms. Shows a good 6-membered nitrogen-containing aromatic heterocycle;
Ring B'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, and 1 to 3 substituents may also be 6-membered optionally substituted with a group selected from a nitro group Shows a nitrogen-containing aromatic heterocycle;
Ring B'' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ). aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl group, and with one to three substituents selected from nitro group, be each substituted Shows a good benzene ring or 5- to 6-membered aromatic heterocycle;
R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
(In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Indicates an alkyl group. )
The prophylactic or therapeutic agent for malaria according to the above [19].
[21] Prevention or treatment of malaria according to any one of [18] to [20] above, wherein X represents a hydrogen atom and R 1 represents a hydrogen atom or an (C 1- C 6) alkyl group. Agent.
[22] R is the formula (Ia''):
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（式中、環Ａ’’は、無置換の５～６員窒素含有芳香族複素環を示し、および
その他の各記号は前記と同義である。）
で示される基を示す、上記［２１］に記載のマラリアの予防または治療剤。
［２３］環Ａ’’が、ピリジン環を示し、および
環Ｂ’’が、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基で置換されていてもよいベンゼン環を示す、上記［２２］に記載のマラリアの予防または治療剤。
［２４］上記［１８］に記載の式（ＩＡ）で表される化合物またはその塩の有効量を、その投薬を必要とする哺乳動物に投与することを含む、マラリアの予防または治療方法。
［２５］マラリアの予防または治療に使用するための、上記［１８］に記載の式（ＩＡ）で表される化合物またはその塩。
［２６］上記［１８］に記載の式（ＩＡ）で表される化合物またはその塩の、マラリアの予防または治療薬を製造するための使用。 (In the formula, ring A ″ represents an unsubstituted 5- to 6-membered nitrogen-containing aromatic heterocycle, and the other symbols are synonymous with the above.)
The prophylactic or therapeutic agent for malaria according to the above [21], which indicates the group represented by.
[23] Ring A ″ represents a pyridine ring, and ring B ″ is a hydroxy group.
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) The prophylactic or therapeutic agent for malaria according to the above [22], which exhibits a benzene ring which may be substituted with 1 to 3 substituents selected from the alkoxy groups.
[24] A method for preventing or treating malaria, which comprises administering an effective amount of a compound represented by the formula (IA) described in the above [18] or a salt thereof to a mammal in need of the medication.
[25] A compound represented by the formula (IA) according to the above [18] or a salt thereof for use in the prevention or treatment of malaria.
[26] Use of the compound represented by the formula (IA) described in the above [18] or a salt thereof for producing a prophylactic or therapeutic agent for malaria.
　本発明により、優れた抗マラリア活性（特に、抗クロロキン耐性株に対する抗マラリア活性）を有するベンゾイミダゾール誘導体（後記の化合物（Ｉ）／化合物（ＩＡ））またはその塩）が提供される。 INDUSTRIAL APPLICABILITY The present invention provides a benzimidazole derivative (compound (I) / compound (IA) described later) or a salt thereof, which has excellent antimalarial activity (particularly, antimalarial activity against an antichloroquine-resistant strain).
図１は、後記の試験例４で行われた抗マラリア活性の評価結果を示す。図中、Ｃｐｄ．１、Ｃｐｄ．１９およびＣｐｄ．２０は、それぞれ化合物１投与群、化合物１９投与群および化合物２０投与群を意味する。ＣＱはクロロキン投与群、Ｃｔｌはコントロール群を意味する。FIG. 1 shows the evaluation results of antimalarial activity performed in Test Example 4 described later. In the figure, Cpd. 1. Cpd. 19 and Cpd. 20 means a compound 1 administration group, a compound 19 administration group and a compound 20 administration group, respectively. CQ means the chloroquine administration group, and Ctl means the control group. 図２は、後記の試験例５で行われた抗マラリア活性の評価結果を示す。図中、４４、４４塩酸塩は、それぞれ化合物４４投与群および化合物４４塩酸塩投与群を意味する。ＣＱはクロロキン投与群、Ｃtｌはコントロール群を意味する。FIG. 2 shows the evaluation results of antimalarial activity performed in Test Example 5 described later. In the figure, 44 and 44 hydrochloride mean the compound 44 administration group and the compound 44 hydrochloride administration group, respectively. CQ means the chloroquine administration group, and Ctl means the control group.
［本発明の化合物（Ｉ）またはその塩について］
　以下に、化合物（Ｉ）またはその塩を詳細に説明する。 [About compound (I) of the present invention or a salt thereof]
The compound (I) or a salt thereof will be described in detail below.
（本明細書中で用いられる各基の定義）
　以下、本明細書中で用いられる各基の定義について詳述する。特記しない限り各基は以下の定義を有する。 (Definition of each group used in the present specification)
Hereinafter, the definition of each group used in the present specification will be described in detail. Unless otherwise specified, each group has the following definitions.
　本明細書中、化合物（Ｉ）の塩としては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、等の無機酸との塩、酢酸塩、フマル酸塩、シュウ酸塩、クエン酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トシル酸塩、マレイン酸塩、等の有機酸との塩等の酸との塩；およびナトリウム塩、カリウム塩、等のアルカリ金属塩、カルシウム塩、等のアルカリ土類金属塩等の塩基との塩；グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩等のアミノ酸との塩等が挙げられる。本発明を抗マラリア薬として用いる場合には、医薬として許容される塩が、好ましい。 In the present specification, examples of the salt of the compound (I) include salts with inorganic acids such as hydrochlorides, hydrobromates, sulfates and phosphates, acetates, fumarates and oxalates. , Salts with acids such as salts with organic acids such as citrate, methanesulfonate, benzenesulfonate, tosylate, maleate, etc .; and alkali metal salts such as sodium salt, potassium salt, etc. Salts with bases such as alkaline earth metal salts such as calcium salts; salts with amino acids such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, asparaginates and the like can be mentioned. When the present invention is used as an antimalarial drug, a pharmaceutically acceptable salt is preferable.
　本明細書中、「ハロゲン原子」としては、例えば、フッ素、塩素、臭素、ヨウ素が挙げられる。 In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.
　本明細書中、「Ｃ１－６アルキル基」（定義中の「Ｃ１－６アルキル基」部分である場合を含む）としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、２－エチルブチルが挙げられる。 In the present specification, the "C 1-6 alkyl group" ( including the case where it is the "C 1-6 alkyl group" portion in the definition) includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
　本明細書中、「Ｃ１－６アルキレン基」（定義中の「Ｃ１－６アルキレン基」部分である場合を含む）としては、例えば、－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－（ＣＨ２）４－、－（ＣＨ２）５－、－（ＣＨ２）６－、－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－、－ＣＨ（Ｃ２Ｈ５）－、－ＣＨ（Ｃ３Ｈ７）－、－ＣＨ（ＣＨ（ＣＨ３）２）－、－（ＣＨ（ＣＨ３））２－、－ＣＨ２－ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ３）－ＣＨ２－、－ＣＨ２－ＣＨ２－Ｃ（ＣＨ３）２－、－Ｃ（ＣＨ３）２－ＣＨ２－ＣＨ２－、－ＣＨ２－ＣＨ２－ＣＨ２－Ｃ（ＣＨ３）２－、－Ｃ（ＣＨ３）２－ＣＨ２－ＣＨ２－ＣＨ２－が挙げられる。 In the present specification, as "C 1-6 alkylene group" (including the case where it is a "C 1-6 alkylene group" portion in the definition), for example, -CH 2 -,-(CH 2 ) 2- , -(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-(CH 2 ) 6- , -CH (CH 3 )-, -C (CH 3 ) 2 -,- CH (C 2 H 5) - , - CH (C 3 H 7) -, - CH (CH (CH 3) 2) -, - (CH (CH 3)) 2 -, - CH 2 -CH (CH 3 ) -, - CH (CH 3 ) -CH 2 -, - CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2- C (CH 3 ) 2- , -C (CH 3 ) 2- CH 2- CH 2- CH 2- .
　本明細書中、「Ｃ１－６アルコキシ基」（定義中の「Ｃ１－６アルコキシ基」部分である場合を含む）としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、ヘキシルオキシが挙げられる。 In the present specification, the "C 1-6 alkoxy group" ( including the case where it is the "C 1-6 alkoxy group" portion in the definition) includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and the like. Examples thereof include sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
　本明細書中、「ジ（（Ｃ１－Ｃ６）アルキル）アミノ基」（定義中の「ジ（（Ｃ１－Ｃ６）アルキル）アミノ基」部分である場合を含む）とは、前記の「（Ｃ１－Ｃ６）アルキル基」２つにより置換されたアミノ基であり、例えば、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジブチルアミノが挙げられる。 In the present specification, the term "di ((C 1- C 6 ) alkyl) amino group" ( including the case where it is a "di ((C 1- C 6 ) alkyl) amino group" portion in the definition) refers to the above. It is an amino group substituted with two "(C 1- C 6 ) alkyl groups" of, and examples thereof include dimethylamino, diethylamino, dipropylamino, and dibutylamino.
　本明細書中、「（Ｃ１－Ｃ６）アルキレンジオキシ基」（定義中の「（Ｃ１－Ｃ６）アルキレンジオキシ基」部分である場合を含む）としては、例えば、メチレンジオキシ、エチレンジオキシ、プロピレンジオキシが挙げられる。 In the present specification, (including in the definition if it is "(C 1 -C 6) alkylenedioxy group" moiety) "(C 1 -C 6) alkylenedioxy group", for example, methylenedioxy , Ethylenedioxy, propylenedioxy.
　本明細書中、「複素環」としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子をそれぞれ含有する、芳香族複素環および非芳香族複素環が挙げられる。 In the present specification, the "heterocycle" includes, for example, an aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples include non-aromatic heterocycles.
　本明細書中、「芳香族複素環」としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する５ないし１４員（好ましくは５ないし１０員）の芳香族複素環が挙げられる。該「芳香族複素環」の好適な例としては、チオフェン、フラン、ピロール、イミダゾール、ピラゾール、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール、１，２，４－チアジアゾール、１，３，４－チアジアゾール、トリアゾール、テトラゾール、トリアジンなどの５ないし６員単環式芳香族複素環；
ベンゾチオフェン、ベンゾフラン、ベンゾイミダゾール、ベンゾオキサゾール、ベンゾイソオキサゾール、ベンゾチアゾール、ベンゾイソチアゾール、ベンゾトリアゾール、イミダゾピリジン、チエノピリジン、フロピリジン、ピロロピリジン、ピラゾロピリジン、オキサゾロピリジン、チアゾロピリジン、イミダゾピラジン、イミダゾピリミジン、チエノピリミジン、フロピリミジン、ピロロピリミジン、ピラゾロピリミジン、オキサゾロピリミジン、チアゾロピリミジン、ピラゾロピリミジン、ピラゾロトリアジン、ナフト［２，３－ｂ］チオフェン、フェノキサチイン、インド－ル、イソインドール、１Ｈ－インダゾール、プリン、イソキノリン、キノリン、フタラジン、ナフチリジン、キノキサリン、キナゾリン、シンノリン、カルバゾール、β－カルボリン、フェナントリジン、アクリジン、フェナジン、フェノチアジン、フェノキサジンなどの８ないし１４員縮合多環式（好ましくは２または３環式）芳香族複素環が挙げられる。 In the present specification, the "aromatic heterocycle" includes, for example, 5 to 14 members (for example) containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as a ring-constituting atom. Aromatic heterocycles (preferably 5 to 10 members) can be mentioned. Preferable examples of the "aromatic heterocycle" are thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isooxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi. 5- to 6-membered monocyclic aromatic heterocycles such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine;
Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazolepyridine, thienopyridine, flopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazolepyridine, Imidazopyrimidine, thienopyrimidine, flopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriadin, naphtho [2,3-b] thiophene, phenoxatiin, indol, 8- to 14-membered fused polycycles of isoindole, 1H-imidazole, purine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxalin, quinazoline, cinnoline, carbazole, β-carboline, phenanthridin, aclysine, phenazine, phenothiazine, phenoxazine, etc. Formula (preferably 2- or 3-cyclic) aromatic heterocycles can be mentioned.
　本明細書中、「非芳香族複素環」としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する３ないし１４員（好ましくは４ないし１０員）の非芳香族複素環が挙げられる。該「非芳香族複素環」の好適な例としては、アジリジン、オキシラン、チイラン、アゼチジン、オキセタン、チエタン、テトラヒドロチオフェン、テトラヒドロフラン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、オキサゾリン、オキサゾリジン、ピラゾリン、ピラゾリジン、チアゾリン、チアゾリジン、テトラヒドロイソチアゾール、テトラヒドロオキサゾール、テトラヒドロイソオキサゾール、ピペリジン、ピペラジン、テトラヒドロピリジン、ジヒドロピリジン、ジヒドロチオピラン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロピラン、テトラヒドロピラン、テトラヒドロチオピラン、モルホリン、チオモルホリン、アゼパニン、ジアゼパン、アゼピン、アゾカン、ジアゾカン、オキセパンなどの３ないし８員単環式非芳香族複素環；
ジヒドロベンゾフラン、ジヒドロベンゾイミダゾール、ジヒドロベンゾオキサゾール、ジヒドロベンゾチアゾール、ジヒドロベンゾイソチアゾール、ジヒドロナフト［２，３－ｂ］チオフェン、テトラヒドロイソキノリン、テトラヒドロキノリン、４Ｈ－キノリジン、インドリン、イソインドリン、テトラヒドロチエノ［２，３－ｃ］ピリジン、テトラヒドロベンゾアゼピン、テトラヒドロキノキサリン、テトラヒドロフェナントリジン、ヘキサヒドロフェノチアジン、ヘキサヒドロフェノキサジン、テトラヒドロフタラジン、テトラヒドロナフチリジン、テトラヒドロキナゾリン、テトラヒドロシンノリン、テトラヒドロカルバゾール、テトラヒドロ－β－カルボリン、テトラヒドロアクリジン、テトラヒドロフェナジン、テトラヒドロチオキサンテン、オクタヒドロイソキノリンなどの９ないし１４員縮合多環式（好ましくは２または３環式）非芳香族複素環が挙げられる。 In the present specification, the "non-aromatic heterocycle" is, for example, 3 to 14 members containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include non-aromatic heterocycles (preferably 4 to 10 members). Preferable examples of the "non-aromatic heterocycle" are aziridine, oxylan, thiirane, azetidine, oxetane, thietan, tetrahydropyran, tetrahydrofuran, pyrrolin, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazolin. , Thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazin, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyranidin, tetrahydropyrandazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholin, azepanine, 3- to 8-membered monocyclic non-aromatic heterocycles such as diazepan, azepine, azocan, diazocan, oxepan;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtholine [2,3-b] thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinoline, indolin, isoindoline, tetrahydrothieno [2] , 3-c] Pyridine, tetrahydrobenzoazepine, tetrahydroquinoline, tetrahydrophenanthridine, hexahydrophenanthridine, hexahydrophenanthridine, tetrahydrophthalazine, tetrahydronaphthiridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carbolin , Tetrahydroacridine, tetrahydrophenanthridine, tetrahydrothioxanthene, octahydroisoquinoline and the like, 9 to 14-membered fused polycyclic (preferably 2 or 3 ring) non-aromatic heterocycles.
　本明細書中、「５～６員芳香族複素環」とは、上記の「芳香族複素環」の内、５～６員の芳香族複素環をいう。
　本明細書中、「５～６員窒素含有芳香族複素環」とは、上記の「芳香族複素環」の内、環構成原子として窒素原子を少なくとも一つ含有する、５～６員の芳香族複素環をいう。
　本明細書中、「５～７員窒素含有芳香族複素環」とは、上記の「芳香族複素環」の内、環構成原子として窒素原子を少なくとも一つ含有する、５～７員の芳香族複素環をいう。
　本明細書中、「６員窒素含有芳香族複素環」とは、上記の「芳香族複素環」の内、環構成原子として窒素原子を少なくとも一つ含有する、６員の芳香族複素環をいう。
　本明細書中、「５～７員窒素含有複素環」とは、上記の「複素環」の内、環構成原子として窒素原子を少なくとも一つ含有する、５～７員の複素環をいう。
　本明細書中、「６員窒素含有複素環」とは、上記の「複素環」の内、環構成原子として窒素原子を少なくとも一つ含有する、６員の複素環をいう。 In the present specification, the "5- to 6-membered aromatic heterocycle" refers to a 5- to 6-membered aromatic heterocycle among the above-mentioned "aromatic heterocycles".
In the present specification, the "5- to 6-membered nitrogen-containing aromatic heterocycle" is a 5- to 6-membered aromatic ring containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "aromatic heterocycles". A group heterocycle.
In the present specification, the "5- to 7-membered nitrogen-containing aromatic heterocycle" is a 5- to 7-membered aromatic ring containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "aromatic heterocycles". A group heterocycle.
In the present specification, the "6-membered nitrogen-containing aromatic heterocycle" refers to a 6-membered aromatic heterocycle containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "aromatic heterocycles". say.
In the present specification, the "5- to 7-membered nitrogen-containing heterocycle" refers to a 5- to 7-membered heterocycle containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocycles".
In the present specification, the "6-membered nitrogen-containing heterocycle" refers to a 6-membered heterocycle containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocycles".
　本明細書中、「複素環基」（定義中の「複素環基」部分である場合を含む）としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子をそれぞれ含有する、(i)芳香族複素環基、(ii)非芳香族複素環基および(iii)７ないし１０員複素架橋環基が挙げられる。 In the present specification, the "heterocyclic group" (including the case where it is a "heterocyclic group" portion in the definition) is selected from, for example, a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered heterobridged ring groups containing 1 to 4 heteroatoms, respectively.
　本明細書中、「芳香族複素環基」（定義中の「芳香族複素環基」部分である場合を含む）としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する５ないし１４員（好ましくは５ないし１０員）の芳香族複素環基が挙げられる。
　該「芳香族複素環基」の好適な例としては、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル、１，２，４－チアジアゾリル、１，３，４－チアジアゾリル、トリアゾリル、テトラゾリル、トリアジニルなどの５ないし６員単環式芳香族複素環基；
ベンゾチオフェニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、ベンゾトリアゾリル、イミダゾピリジニル、チエノピリジニル、フロピリジニル、ピロロピリジニル、ピラゾロピリジニル、オキサゾロピリジニル、チアゾロピリジニル、イミダゾピラジニル、イミダゾピリミジニル、チエノピリミジニル、フロピリミジニル、ピロロピリミジニル、ピラゾロピリミジニル、オキサゾロピリミジニル、チアゾロピリミジニル、ピラゾロトリアジニル、ナフト［２，３－ｂ］チエニル、フェノキサチイニル、インドリル、イソインドリル、１Ｈ－インダゾリル、プリニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、カルバゾリル、β－カルボリニル、フェナントリジニル、アクリジニル、フェナジニル、フェノチアジニル、フェノキサジニルなどの８ないし１４員縮合多環式（好ましくは２または３環式）芳香族複素環基が挙げられる。 In the present specification, the "aromatic heterocyclic group" (including the case where it is the "aromatic heterocyclic group" portion in the definition) includes, for example, a nitrogen atom, a sulfur atom and oxygen as ring-constituting atoms in addition to a carbon atom. Examples thereof include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from the atoms.
Preferable examples of the "aromatic heterocyclic group" include thienyl, frill, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1 , 3,4-Oxaziazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and other 5- to 6-membered monocyclic aromatic heterocyclic groups;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazolypyridinyl, thienopyridinyl, flopyridinyl, pyrrolopyrizinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolopyridinyl, imidazolopyridinyl, imidazolipyrimidinyl, thienopyrimidinyl, flopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazorotriadinyl, naphtho [2,3 -B] Thienyl, phenoxatinyl, indolyl, isoindyl, 1H-indazolyl, prynyl, isoquinolyl, quinolyl, phthalazinyl, naphthyldinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, pheno. Examples thereof include 8- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) aromatic heterocyclic groups such as thiazinyl and phenoxadinyl.
　本明細書中、「非芳香族複素環基」（定義中の「非芳香族複素環基」部分である場合を含む）としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する３ないし１４員（好ましくは４ないし１０員）の非芳香族複素環基が挙げられる。
　該「非芳香族複素環基」の好適な例としては、アジリジニル、オキシラニル、チイラニル、アゼチジニル、オキセタニル、チエタニル、テトラヒドロチエニル、テトラヒドロフラニル、ピロリニル、ピロリジニル、イミダゾリニル、イミダゾリジニル、オキサゾリニル、オキサゾリジニル、ピラゾリニル、ピラゾリジニル、チアゾリニル、チアゾリジニル、テトラヒドロイソチアゾリル、テトラヒドロオキサゾリル、テトラヒドロイソオキサゾリル、ピペリジニル、ピペラジニル、テトラヒドロピリジニル、ジヒドロピリジニル、ジヒドロチオピラニル、テトラヒドロピリミジニル、テトラヒドロピリダジニル、ジヒドロピラニル、テトラヒドロピラニル、テトラヒドロチオピラニル、モルホリニル、チオモルホリニル、アゼパニル、ジアゼパニル、アゼピニル、オキセパニル、アゾカニル、ジアゾカニルなどの３ないし８員単環式非芳香族複素環基；
ジヒドロベンゾフラニル、ジヒドロベンゾイミダゾリル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾチアゾリル、ジヒドロベンゾイソチアゾリル、ジヒドロナフト［２，３－ｂ］チエニル、テトラヒドロイソキノリル、テトラヒドロキノリル、４Ｈ－キノリジニル、インドリニル、イソインドリニル、テトラヒドロチエノ［２，３－ｃ］ピリジニル、テトラヒドロベンゾアゼピニル、テトラヒドロキノキサリニル、テトラヒドロフェナントリジニル、ヘキサヒドロフェノチアジニル、ヘキサヒドロフェノキサジニル、テトラヒドロフタラジニル、テトラヒドロナフチリジニル、テトラヒドロキナゾリニル、テトラヒドロシンノリニル、テトラヒドロカルバゾリル、テトラヒドロ－β－カルボリニル、テトラヒドロアクリジニル、テトラヒドロフェナジニル、テトラヒドロチオキサンテニル、オクタヒドロイソキノリルなどの９ないし１４員縮合多環式（好ましくは２または３環式）非芳香族複素環基が挙げられる。 In the present specification, the "non-aromatic heterocyclic group" (including the case where it is a "non-aromatic heterocyclic group" portion in the definition) includes, for example, a nitrogen atom and a sulfur atom in addition to a carbon atom as a ring-constituting atom. And 3 to 14 member (preferably 4 to 10 member) non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from oxygen atoms.
Preferable examples of the "non-aromatic heterocyclic group" are aziridinyl, oxylanyl, thiylanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl. Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyrani 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as le, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl;
Dihydrobenzofuranyl, dihydrobenzoimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, Indolinyl, isoindolinyl, tetrahydrothieno [2,3-c] pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazine, hexahydrophenoxadinyl, tetrahydrophthalazinyl, tetrahydro 9-14 such as naphthyldinyl, tetrahydroquinazolinyl, tetrahydrosinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroaclicinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl, etc. Included are member-condensed polycyclic (preferably 2- or tricyclic) non-aromatic heterocyclic groups.
　本明細書中、「７ないし１０員複素架橋環基」の好適な例としては、キヌクリジニル、７－アザビシクロ［２．２．１］ヘプタニルが挙げられる。 In the present specification, preferred examples of the "7 to 10-membered complex crosslinked ring group" include quinucridinyl and 7-azabicyclo [2.2.1] heptanyl.
　本明細書中、「窒素含有複素環基」とは、上記の「複素環基」の内、環構成原子として窒素原子を少なくとも一つ含有する複素環基をいう。
　本明細書中、「５～７員窒素含有複素環基」とは、上記の「複素環基」の内、環構成原子として窒素原子を少なくとも一つ含有する、５～７員の複素環基をいう。
　本明細書中、「５～１０員窒素含有複素環基」とは、上記の「複素環基」の内、環構成原子として窒素原子を少なくとも一つ含有する、５～１０員の複素環基をいう。
　本明細書中、「５～１０員複素環基」とは、上記の「複素環基」の内、５～１０員の複素環基をいう。 In the present specification, the "nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocyclic groups".
In the present specification, the "5- to 7-membered nitrogen-containing heterocyclic group" is a 5- to 7-membered heterocyclic group containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocyclic groups". To say.
In the present specification, the "5- to 10-membered nitrogen-containing heterocyclic group" is a 5- to 10-membered heterocyclic group containing at least one nitrogen atom as a ring-constituting atom among the above-mentioned "heterocyclic groups". To say.
In the present specification, the "5- to 10-membered heterocyclic group" refers to a 5- to 10-membered heterocyclic group among the above-mentioned "heterocyclic groups".
　本明細書中、「アリール基」（定義中の「アリール」部分である場合を含む）としては、単環又は縮合の（Ｃ６－Ｃ１４）アリール基が挙げられ、例えば、フェニル、１－ナフチル、２－ナフチル、１－アントリル、２－アントリル、９－アントリルが挙げられる。好ましくは、（Ｃ６－Ｃ１０）アリール基である。 In the present specification, "aryl" (including those which are "aryl" moiety in the definition), monocyclic or fused (C 6 -C 14) aryl group are exemplified, for example, phenyl, 1- Examples thereof include naphthyl, 2-naphthyl, 1-anthryl, 2-antryl and 9-antryl. Preferably, it is an (C 6- C 10 ) aryl group.
　本明細書中、「アリールアミノ基」（定義中の「アリールアミノ基」部分である場合を含む）としては、単環又は縮合の（Ｃ６－Ｃ１４）アリールアミノ基が挙げられ、例えば、フェニルアミノ、１－ナフチルアミノ、２－ナフチルアミノ、１－アントリルアミノ、２－アントリルアミノ、９－アントリルアミノが挙げられる。好ましくは、（Ｃ６－Ｃ１０）アリールアミノ基である。 In the present specification, the "arylamino group" (including those which are "arylamino group" moiety in the definition), monocyclic or fused (C 6 -C 14) aryl amino group can be mentioned, for example, Examples thereof include phenylamino, 1-naphthylamino, 2-naphthylamino, 1-anthrylamino, 2-anthrylamino and 9-anthrylamino. Preferably, it is an (C 6- C 10 ) arylamino group.
　本明細書中、ベンゼン環、５～６員芳香族複素環等の環において、「隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい。」場合の環としては、炭素環および複素環が挙げられ、好ましくは、５～７員の炭素環および１～３個の酸素原子を環構成原子として含有していてもよい５～７員の複素環が挙げられ、より好ましくは、５または６員炭素環、または２個の酸素原子を環構成原子として含有する５または６員複素環が挙げられる。 In the present specification, in a ring such as a benzene ring or a 5- to 6-membered aromatic heterocycle, "two substituents existing on adjacent carbon atoms are rings together with a carbon atom to which they are bonded to each other. Examples of the ring include a carbon ring and a heterocycle, preferably containing a 5- to 7-membered carbon ring and 1 to 3 oxygen atoms as ring-constituting atoms. A 5- to 7-membered heterocycle may be used, more preferably a 5- or 6-membered carbocycle, or a 5- or 6-membered heterocycle containing two oxygen atoms as ring-constituting atoms.
　本明細書中、「置換されていてもよい（Ｃ１－Ｃ６）アルキル基」、「さらに置換されていてもよい５～７員窒素含有複素環」、その他の化合物（Ｉ）に関する定義規定中の「置換されていてもよい基や環」における「置換基」としては、例えば、下記の［置換基群］から選択される置換基が挙げられる。
　該「置換基」は、置換可能な位置に１～５個（好ましくは１～３個）存在し得、置換基数が２個以上の場合、各置換基は同一であっても異なっていてもよい。
　なお、各基または環等において、その「置換基」について特段の説明がなされている場合は、その説明に従うものとする。 Herein defined provisions on "optionally substituted (C 1 -C 6) alkyl group", "further optionally substituted 5-7 membered nitrogen-containing heterocycle", other compounds (I) Examples of the "substituent" in the "optionally substituted group or ring" include a substituent selected from the following [substituent group].
The "substituents" may be present at 1 to 5 (preferably 1 to 3) substitutable positions, and when the number of substituents is 2 or more, each substituent may be the same or different. good.
If a special explanation is given for each group or ring, etc., the explanation shall be followed.
［置換基群］
（１）ハロゲン原子、
（２）ニトロ基、
（３）シアノ基、
（４）オキソ基、
（５）ヒドロキシ基、
（６）ハロゲン化されていてもよいＣ１－Ｃ６アルコキシ基（例、メトキシ、クロロメトキシ、トリフルオロエトキシ）、
（７）Ｃ６－Ｃ１４アリールオキシ基（例、フェノキシ、ナフトキシ）、
（８）Ｃ７－Ｃ１６アラルキルオキシ基（例、ベンジルオキシ）、
（９）Ｃ１－Ｃ６アルキル－カルボニルオキシ基（例、アセトキシ、プロパノイルオキシ）、
（１０）Ｃ６－Ｃ１４アリール－カルボニルオキシ基（例、ベンゾイルオキシ、１－ナフトイルオキシ、２－ナフトイルオキシ）、　
（１１）Ｃ１－Ｃ６アルコキシ－カルボニルオキシ基（例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ）、
（１２）５～１４員芳香族複素環基、　
（１３）３～１４員非芳香族複素環基、　
（１４）ホルミル基、　
（１５）カルボキシ基、　
（１６）ハロゲン化されていてもよいＣ１－Ｃ６アルキル－カルボニル基（例、アセチル、クロロアセチル、トリフルオロアセチル）、
（１７）Ｃ６－Ｃ１４アリール－カルボニル基（例、ベンゾイル、１－ナフトイル、２－ナフトイル）、
（１８）Ｃ１－Ｃ６アルコキシ－カルボニル基（例、メトキシカルボニル、エトキシカルボニル）、
（１９）カルバモイル基、
（２０）アミノ基、
（２１）モノ－またはジ－Ｃ１－Ｃ６アルキルアミノ基（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ブチルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジブチルアミノ、Ｎ－エチル－Ｎ－メチルアミノ）、　
（２２）モノ－またはジ－Ｃ６－Ｃ１４アリールアミノ基（例、フェニルアミノ）、　
（２３）ホルミルアミノ基、　
（２４）Ｃ１－Ｃ６アルキル－カルボニルアミノ基（例、アセチルアミノ、プロパノイルアミノ、ブタノイルアミノ）、　
（２５）Ｃ１－Ｃ６アルコキシ－カルボニルアミノ基（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ、ｔｅｒｔ－ブトキシカルボニルアミノ）、　
（２６）ハロゲン化されていてもよいＣ１－Ｃ６アルキル基（例、メチル、クロロメチル、ジフルオロメチル、トリフルオロメチル、エチル、２－ブロモエチル、２，２，２－トリフルオロエチル）、
（２７）Ｃ２－Ｃ６アルケニル基（例、エテニル、１－プロペニル、２－プロペニル、２－メチル－１－プロペニル、１－ブテニル）、
（２８）Ｃ２－Ｃ６アルキニル基（例、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、３－ブチニル）、
（２９）Ｃ３－Ｃ１０シクロアルキル基（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロ［２．２．１］ヘプチル、ビシクロ［２．２．２］オクチル、ビシクロ［３．２．１］オクチル、アダマンチル）、
（３０）Ｃ３－Ｃ１０シクロアルケニル基（例、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロオクテニル）、および
（３１）Ｃ６－Ｃ１４アリール基（例、フェニル、ナフチル）。
　ここで、上記［置換基群］から選択される置換基は、上記「置換基群」から選択される１～３個の置換基でさらに一度置換されていてもよい。 [Substituents]
(1) Halogen atom,
(2) Nitro group,
(3) Cyano group,
(4) Oxo group,
(5) Hydroxy group,
(6) an optionally halogenated C 1 -C be the 6 alkoxy group (e.g., methoxy, chloromethoxy, trifluoroethoxy),
(7) C 6 -C 14 aryloxy group (e.g., phenoxy, naphthoxy),
(8) C 7- C 16 aralkyloxy group (eg, benzyloxy),
(9) C 1 -C 6 alkyl - carbonyl group (e.g., acetoxy, propanoyloxy),
(10) C 6 -C 14 aryl - carbonyl group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(11) C 1 -C 6 alkoxy - carbonyl group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
(12) 5- to 14-membered aromatic heterocyclic group,
(13) 3- to 14-membered non-aromatic heterocyclic group,
(14) Holmil group,
(15) Carboxy group,
(16) an optionally halogenated C 1 -C 6 alkyl - carbonyl group (e.g., acetyl, chloroacetyl, trifluoroacetyl),
(17) C 6 -C 14 aryl - carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl),
(18) C 1 -C 6 alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl),
(19) Carbamoyl group,
(20) Amino group,
(21) Mono- or di-C 1- C 6 alkylamino groups (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl- N-methylamino),
(22) Mono- or di-C 6- C 14 arylamino groups (eg, phenylamino),
(23) Formylamino group,
(24) C 1 -C 6 alkyl - carbonyl amino group (e.g., acetylamino, propanoylamino, butanoylamino)
(25) C 1 -C 6 alkoxy - carbonyl amino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino),
(26) optionally halogenated and C 1 -C 6 alkyl group (e.g., methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl)
(27) C 2 -C 6 alkenyl group (e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl),
(28) C 2 -C 6 alkynyl group (eg, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl),
(29) C 3- C 10 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] Octyl, Adamantine),
(30) C 3 -C 10 cycloalkenyl group (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), and (31) C 6 -C 14 aryl group (e.g., phenyl, naphthyl).
Here, the substituent selected from the above [substituent group] may be further substituted once with 1 to 3 substituents selected from the above-mentioned "substituent group".
（化合物（Ｉ）の各記号について）　
　以下、前記式（Ｉ）の各記号について詳述する。 (About each symbol of compound (I))
Hereinafter, each symbol of the formula (I) will be described in detail.
　環Ａは、ピリジン環を示す。 Ring A represents a pyridine ring.
　Ｒａは、水素原子、または
ハロゲン原子およびヒドロキシ基以外の基から選択される置換基を示し、
　好ましくは、水素原子、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、またはニトロ基を示し、
　より好ましくは、水素原子を示す。 Ra represents a substituent selected from a hydrogen atom or a group other than a halogen atom and a hydroxy group.
Preferably, it may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl. ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) arylamino group, or nitro group.
More preferably, it indicates a hydrogen atom.
　ｐは、１～２の整数を示し、好ましくは、ｐは１を示す。 P represents an integer of 1 to 2, preferably p represents 1.
　環Ｂは、置換されていてもよいベンゼン環または置換されていてもよい５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい。）を示し、
　好ましくは、ヒドロキシ基、
ハロゲン原子、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
（Ｃ６－Ｃ１０）アリール基、
１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
ニトロ基
から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環
（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環（好ましくは、５または６員炭素環、または２個の酸素原子を環構成原子として含有する５または６員複素環）を形成していてもよい）を示し、
　より好ましくは、環Ｂが、ヒドロキシ基、
ハロゲン原子、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
（Ｃ６－Ｃ１０）アリール基、
１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
ニトロ基
から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環を示し、
　さらに好ましくは、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基でそれぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環（例：ピロール、フラン、チオフェン、イミダゾール、ピリジン）を示し、
　最も好ましくは、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基で置換されていてもよいベンゼン環を示す。 Ring B resides on an optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle). The two substituents that form a ring may form a ring with the carbon atoms that are attached to each other and to which they are attached.)
Preferably, a hydroxy group,
Halogen atom,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
Di ((C 1 -C 6) alkyl) amino group,
(C 6- C 10 ) Aryl group,
A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively. , Or a 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are the carbons to which they are bonded together. Along with the atom, a 5- to 7-membered ring (preferably a 5- or 6-membered carbocyclic ring, or 2 oxygen atoms, which may contain 1 to 3 oxygen atoms as ring-constituting atoms, may be contained as ring-constituting atoms. May form a 5- or 6-membered heterocycle)
More preferably, the ring B is a hydroxy group,
Halogen atom,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
Di ((C 1 -C 6) alkyl) amino group,
(C 6- C 10 ) Aryl group,
A benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) and 1 to 3 substituents selected from the nitro group, respectively. , Or a 5- to 6-membered aromatic heterocycle,
More preferably, the hydroxy group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) A benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups, respectively, or a 5 to 6 member aromatic heterocycle (eg, pyrrole, furan, thiophene, imidazole, Pyridine), showing
Most preferably, a hydroxy group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Indicates a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
　環Ｃは、さらに置換されていてもよい５～７員窒素含有複素環を示し、
　好ましくは、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し、
　より好ましくは、オキソ基でさらに置換されていてもよい５～７員窒素含有複素環（例：ジヒドロピラゾール）を示す。 Ring C represents a 5- to 7-membered nitrogen-containing heterocycle that may be further substituted.
Preferably, it shows a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with 1 to 3 substituents selected from (C 1- C 6) alkyl and oxo groups.
More preferably, it shows a 5- to 7-membered nitrogen-containing heterocycle (eg, dihydropyrazole) that may be further substituted with an oxo group.
　Ｒ1は、水素原子または置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
　好ましくは、水素原子、または
オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
（式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
　より好ましくは、水素原子または（Ｃ１－Ｃ６）アルキル基を示す。 R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
Preferably, a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
(In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Shows an alkyl group and
More preferably, a hydrogen atom or a (C 1 -C 6) alkyl group.
　Ｒ２は、置換されていてもよい窒素含有複素環基を示し、
　好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し、
　より好ましくは、１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい５～１０員窒素含有複素環基（例：ピリジル、キノリル）を示す。 R 2 represents a nitrogen-containing heterocyclic group that may be substituted.
Preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms. Indicates a 5- to 10-membered nitrogen-containing heterocyclic group optionally substituted with a group.
More preferably, one to three (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted with a group: shown (e.g. pyridyl, quinolyl) a.
　Ｒ３は、置換されていてもよい複素環基、置換されていてもよいアリール基、または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、置換されていてもよい複素環基または置換されていてもよいアリール基を示す。）を示し、
　好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基（例：フェニル）、
または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキルアミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）を示し、
　より好ましくは、１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい５～１０員窒素含有複素環基（例：ピラゾリル、チアゾリル、インドリル、ベンゾチエニル）、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基（例：フェニル）、または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい５～１０員窒素含有複素環基（例：ピラゾリル、チアゾリル、インドリル、ベンゾチエニル）、または１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基（例：フェニル）を示す。）を示す。 R 3 may be a optionally substituted heterocyclic group, an optionally substituted aryl group, or the formula: −L 1 − (S) m −Q 1
(In the equation, L 1 indicates a bond,
m is an integer of 0 or 1, and Q 1 is, represents an aryl group which may be also heterocyclic group or a substituted substituted. )
Preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms. A 5- to 10-membered heterocyclic group which may be substituted with a group,
Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl groups (eg phenyl),
Or formula: -L 1- (S) m- Q 1
(In the equation, L 1 indicates a bond,
m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) alkoxy group, di ((C 1- C 6 ) alkyl amino group, (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl. It may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group (indicating a (C 6- C 10 ) aryl group). Show,
More preferably, one to three (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted by a group (eg pyrazolyl, thiazolyl, indolyl, benzothienyl),
May be substituted with 1 to 3 (C 1- C 6 ) alkyl groups (C 6- C 10 ) aryl groups (eg phenyl), or formula: -L 1- (S) m- Q 1
(In the equation, L 1 indicates a bond,
m is an integer of 0 or 1, and Q 1 is one to three (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted with a group (for example pyrazolyl , Thiazolyl, indolyl, benzothienyl), or (C 6- C 10 ) aryl groups (eg, phenyl) that may be substituted with 1 to 3 (C 1- C 6) alkyl groups. ) Is shown.
　Ｒ４は、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、置換されていてもよい複素環基または置換されていてもよいアリール基を示す。）を示し、
好ましくは、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、またはハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）を示し、
より好ましくは、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい５～１０員窒素含有複素環基（例：インドリル、キノリル）、または１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基（例：フェニル）を示す。）を示す。 R 4 has the formula: -L 2 - (NH) n -Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 represents an aryl group which may be also heterocyclic group or a substituted substituted. )
Preferably, the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6). ) Alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
More preferably, the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2, 1-3 (C 1 -C 6) alkyl is optionally 5- to 10-membered nitrogen-containing Hajime Tamaki substituted with a group (e.g., indolyl, It indicates a (quinolyl) or (C 6- C 10 ) aryl group (eg, phenyl) which may be substituted with 1 to 3 (C 1- C 6) alkyl groups. ) Is shown.
　Ｘは、水素原子またはハロゲン原子を示し、好ましくは、水素原子を示す。 X represents a hydrogen atom or a halogen atom, preferably a hydrogen atom.
（化合物（Ｉ）の好ましい実施態様について）
　化合物（Ｉ）においては、Ｒａが水素原子である化合物が好ましい実施態様の一つとして挙げられる。
　化合物（Ｉ）の別の好ましい実施態様としては、以下のものが挙げられる。 (Preferable Embodiment of Compound (I))
In compound (I), a compound in which Ra is a hydrogen atom is mentioned as one of the preferred embodiments.
Another preferred embodiment of compound (I) includes:
［化合物Ａ］
式（Ｉ）： [Compound A]
Equation (I):
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
［式中、Ｒは、
（１）式（Ｉａ）： [In the formula, R is
Equation (1): (Ia):
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式中、Ｒ1は、水素原子または（Ｃ１－Ｃ６）アルキル基を示し、
Ｒａは、水素原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、またはニトロ基を示し；
ｐは、１～２の整数を示し、
環Ａは、ピリジン環を示し、
環Ｂは、ヒドロキシ基、
ハロゲン原子、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
（Ｃ６－Ｃ１０）アリール基、
１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
ニトロ基
から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環（例：ピリジン）を示し、
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基；
（２）式（Ｉｂ）： (In the formula, R 1 represents a hydrogen atom or an (C 1- C 6 ) alkyl group.
Ra is a hydrogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, Indicates an arylamino group (C 6- C 10 ) optionally substituted with 1 to 3 halogen atoms, or a nitro group;
p indicates an integer of 1 to 2 and represents
Ring A represents a pyridine ring.
Ring B is a hydroxy group,
Halogen atom,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
Di ((C 1 -C 6) alkyl) amino group,
(C 6- C 10 ) Aryl group,
A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively. , Or a 5- to 6-membered aromatic heterocycle (eg, pyridine),
* Indicates the binding position to the benzimidazole ring. )
Group indicated by;
Equation (Ib):
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、環Ｃは、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し、
Ｒ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し、
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基；
（３）式（Ｉｃ）：－ＮＨ－ＣＯ－Ｒ３
（式中、Ｒ３は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基、または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキルアミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）を示し、
　より好ましくは、Ｒ３は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基（例：ピラゾリル、チアゾリル、インドリル、ベンゾチエニル）、
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基（例：フェニル）を示す。）
で示される基；または
（４）式（Ｉｄ）：－ＣＯ－ＮＨ－Ｒ４
（式中、Ｒ４は、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基（例：インドリル、キノリル）、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基（例：フェニル）を示す。）
を示す。）
で示される基を示し、および
Ｘは、水素原子を示す。］
で表される化合物またはその塩。 (In the formula, ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with 1 to 3 substituents selected from (C 1- C 6) alkyl and oxo groups.
R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Indicates a 5- to 10-membered nitrogen-containing heterocyclic group that may be substituted with a substituent.
* Indicates the binding position to the benzimidazole ring. )
Group indicated by;
Equation (3): -NH-CO-R 3
(In the formula, R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C). 10 ) An aryl group selected from a (C 6- C 10 ) aryl amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group which may be substituted with 1 to 3 halogen atoms 1 A 5- to 10-membered heterocyclic group which may be substituted with up to 3 substituents,
Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1
(In the equation, L 1 indicates a bond,
m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) alkoxy group, di ((C 1- C 6 ) alkyl amino group, (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl. It may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group (indicating a (C 6- C 10 ) aryl group). Show,
More preferably, R 3 is a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, (C 6- C). 10 ) An aryl group selected from a (C 6- C 10 ) aryl amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group which may be substituted with 1 to 3 halogen atoms 1 5- to 10-membered heterocyclic groups optionally substituted with up to 3 substituents (eg, pyrazolyl, thiazolyl, indolyl, benzothienyl),
Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom (C 6- C 10 ) aryl groups (eg, phenyl) may be indicated. )
Group represented by; or equation (4) (Id): -CO-NH-R 4
(In the formula, R 4 is the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group (eg, indolyl, quinolyl), which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, (C 1- C 6 ) alkyl group. , (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms ( It may be substituted with 1 to 3 substituents selected from C 6- C 10 ) arylamino groups, nitro groups, and (C 1- C 6 ) alkylene dioxy groups (C 6- C 10 ). Indicates an aryl group (eg, phenyl). )
Is shown. )
Indicates a group indicated by, and X indicates a hydrogen atom. ]
A compound represented by or a salt thereof.
［化合物Ａ－１］
式（Ｉ）： [Compound A-1]
Equation (I):
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
［式中、Ｒは、
（１）式（Ｉａ）： [In the formula, R is
Equation (1): (Ia):
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（式中、Ｒ1は、水素原子または（Ｃ１－Ｃ６）アルキル基を示し、
Ｒａは、水素原子を示し、
環Ａは、ピリジン環を示し、
環Ｂは、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し、
ｐは、１を示し、
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基を示し、および
Ｘは、水素原子を示す。］
で表される化合物またはその塩。 (In the formula, R 1 represents a hydrogen atom or an (C 1- C 6 ) alkyl group.
Ra indicates a hydrogen atom,
Ring A represents a pyridine ring.
Ring B is a hydroxy group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Shows a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
p indicates 1,
* Indicates the binding position to the benzimidazole ring. )
Indicates a group indicated by, and X indicates a hydrogen atom. ]
A compound represented by or a salt thereof.
［化合物Ａ－１－１］
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）キノリン（化合物３２）またはその塩、
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７－メチルキノリン（化合物３４）またはその塩、
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－7－メトキシキノリン（化合物３７）またはその塩、または
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６，７－ジメチルキノリン（化合物４４）またはその塩。 [Compound A-1-1]
3-(2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) quinoline (Compound 32) or a salt thereof,
3-(2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methylquinoline (Compound 34) or a salt thereof,
3-(2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methoxyquinoline (Compound 37) or a salt thereof, or 3-((2- (1H-benzo [d]] Imidazole-2-yl) hydrazono) methyl) -6,7-dimethylquinoline (Compound 44) or a salt thereof.
［化合物Ａ－２］
式（Ｉ）： [Compound A-2]
Equation (I):
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
［式中、Ｒは、
（２）式（Ｉｂ）：  [In the formula, R is
Equation (Ib):
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
（式中、環Ｃは、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し、
Ｒ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し、
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基；
（３）式（Ｉｃ）：－ＮＨ－ＣＯ－Ｒ３
（式中、Ｒ３は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基、または
式：－Ｌ１－（Ｓ）ｍ－Ｑ１
（式中、Ｌ１は、結合を示し、
ｍは、０または１の整数を示し、および
Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキルアミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）を示し；または
（４）式（Ｉｄ）：－ＣＯ－ＮＨ－Ｒ４
（式中、Ｒ４は、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
（式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
ｎは０または１の整数を示し、および
Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
を示す。）
で示される基を示し、および
Ｘは、水素原子を示す。］
で表される化合物またはその塩。 (In the formula, ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted with 1 to 3 substituents selected from (C 1- C 6) alkyl and oxo groups.
R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Indicates a 5- to 10-membered nitrogen-containing heterocyclic group that may be substituted with a substituent.
* Indicates the binding position to the benzimidazole ring. )
Group indicated by;
Equation (3): -NH-CO-R 3
(In the formula, R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C). 10 ) An aryl group selected from a (C 6- C 10 ) aryl amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group which may be substituted with 1 to 3 halogen atoms 1 A 5- to 10-membered heterocyclic group which may be substituted with up to 3 substituents,
Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1
(In the equation, L 1 indicates a bond,
m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) alkoxy group, di ((C 1- C 6 ) alkyl amino group, (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl. It may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6 ) alkylene dioxy group (indicating a (C 6- C 10 ) aryl group). Shown; or equation (4) (Id): -CO-NH-R 4
(In the formula, R 4 is the formula: -L 2- (NH) n- Q 2
(In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6). ) Alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
Is shown. )
Indicates a group indicated by, and X indicates a hydrogen atom. ]
A compound represented by or a salt thereof.
　化合物（Ｉ）の医薬として許容される塩には、分子内塩またはその付加物のいずれもが包含され、またその溶媒和物または水和物も包含される。 The pharmaceutically acceptable salt of compound (I) includes either an intramolecular salt or an adduct thereof, and also includes a solvate or a hydrate thereof.
［化合物（Ｉ）またはその塩の製造方法について］
　本発明化合物の製造法について以下に説明する。 [About the method for producing compound (I) or a salt thereof]
The method for producing the compound of the present invention will be described below.
　以下の製造方法における各工程で用いられた原料や試薬、ならびに得られた化合物は、それぞれ塩を形成していてもよい。このような塩としては、例えば、前述の本発明化合物の塩と同様のもの等が挙げられる。 The raw materials and reagents used in each step in the following production method, and the obtained compound may each form a salt. Examples of such a salt include those similar to the above-mentioned salt of the compound of the present invention.
　各工程で得られた化合物が遊離化合物である場合には、自体公知の方法により、目的とする塩に変換することができる。逆に各工程で得られた化合物が塩である場合には、自体公知の方法により、遊離体または目的とする他の種類の塩に変換することができる。 When the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se. On the contrary, when the compound obtained in each step is a salt, it can be converted into a free form or another kind of salt of interest by a method known per se.
　各工程の原料や試薬の化合物が市販されている場合には、市販品をそのまま用いることができる。 If the raw material or reagent compound for each process is commercially available, the commercially available product can be used as it is.
方法１
　化合物（Ｉ）の一部である化合物（Ｉ－１）またはその塩は、以下の合成スキームにより製造することができる。 Method 1
Compound (I-1), which is a part of compound (I), or a salt thereof can be produced by the following synthetic scheme.
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（式中、Ｒｂは、式（Ｉｂ）： (In the formula, Rb is the formula (Ib):
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中、Ｒａ、ｐ、環Ａおよび環Ｂは、前記と同義であり、
＊は、式（ＩＩＩ）中のアルデヒド基への結合位置を示す。） (In the formula, Ra, p, ring A and ring B have the same meanings as described above.
* Indicates the bond position to the aldehyde group in the formula (III). )
　方法１における反応条件は、後記の参考例、実施例に記載された方法、その他当技術分野で既知の方法を参照して当業者であれば決定することができる。 The reaction conditions in Method 1 can be determined by those skilled in the art by referring to the reference examples described later, the methods described in Examples, and other methods known in the art.
方法２
　化合物（Ｉ）の一部である化合物（Ｉ－２）またはその塩は、以下の合成スキームにより製造することができる。 Method 2
Compound (I-2), which is a part of compound (I), or a salt thereof can be produced by the following synthetic scheme.
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（式中、Ｒ２は前記と同義である。） (In the formula, R 2 is synonymous with the above.)
　方法２における反応条件は、後記の参考例、実施例に記載された方法、その他当技術分野で既知の方法を参照して当業者であれば決定することができる。 The reaction conditions in Method 2 can be determined by those skilled in the art by referring to the reference examples described later, the methods described in Examples, and other methods known in the art.
　化合物（Ｉ）の内、上記化合物（Ｉ－１）または（Ｉ－２）以外の化合物についても、当技術分野で既知の方法を参照して当業者であれば適宜製造することができる。 Among the compounds (I), compounds other than the above compounds (I-1) or (I-2) can be appropriately produced by those skilled in the art by referring to methods known in the art.
　化合物（Ｉ）またはその塩には、分子内塩またはその付加物のいずれもが包含され、またその溶媒和物または水和物も包含される。
　化合物（Ｉ）は、水和物、非水和物、溶媒和物、無溶媒和物のいずれであってもよい。
　また、互変異性体も、化合物（Ｉ）に包含される。
　化合物（Ｉ）は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。 The compound (I) or a salt thereof includes either an intramolecular salt or an adduct thereof, and also includes a solvate or a hydrate thereof.
Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
Tautomers are also included in compound (I).
Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is unique in two or more kinds at room temperature, each having different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
［本発明の化合物（ＩＡ）またはその塩について］　
　本発明の化合物（ＩＡ）は、式（ＩＡ）： [About the compound (IA) of the present invention or a salt thereof]
The compound (IA) of the present invention has the formula (IA) :.
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
［式中、Ｒは、下記の式（Ｉａ’）、式（Ｉａ’’）または式（Ｉａ’’’）： [In the formula, R is the following formula (Ia'), formula (Ia ″) or formula (Ia ″ ″):
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
で表される化合物である。 It is a compound represented by.
（本明細書中で用いられる各基の定義）
　本明細書中、化合物（ＩＡ）における各基の定義については、化合物（Ｉ）について前記したものと同じものを参照することができる。その塩についても同様である。
　また、化合物（ＩＡ）またはその塩についても、化合物（Ｉ）またはその塩について説明された製造方法に準じて当業者であれば製造することができる。公知化合物の場合は、市販品がある場合には、当該市販品を用いることもできる。 (Definition of each group used in the present specification)
In the present specification, for the definition of each group in the compound (IA), the same ones as described above can be referred to for the compound (I). The same is true for the salt.
Further, the compound (IA) or a salt thereof can also be produced by those skilled in the art according to the production method described for the compound (I) or a salt thereof. In the case of a known compound, if there is a commercially available product, the commercially available product can also be used.
（化合物（ＩＡ）の各記号について）
　Ｒ1は、水素原子または置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
　好ましくは、水素原子、または
オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
（式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
　より好ましくは、水素原子または（Ｃ１－Ｃ６）アルキル基を示す。 (For each symbol of compound (IA))
R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
Preferably, a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
(In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Shows an alkyl group and
More preferably, a hydrogen atom or a (C 1 -C 6) alkyl group.
　環Ａ’は、さらに置換されていてもよいベンゼン環を示し、
　好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し、
　より好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し、
　さらに好ましくは、１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいベンゼン環を示す。 Ring A'represents a benzene ring that may be further substituted.
Preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms. Indicates a benzene ring that may be substituted with a group,
More preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group. A benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) arylamino group and optionally 1 to 3 substituents selected from nitro groups. Show,
More preferably, shows a one to three (C 1 -C 6) alkyl benzene ring which may be substituted with a group.
　環Ａ’’は、ハロゲン原子以外の基から選択される置換基でさらに置換されていてもよい５～６員窒素含有芳香族複素環を示し、
　好ましくは、ヒドロキシ基、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～６員窒素含有芳香族複素環を示し、
　より好ましくは、ヒドロキシ基、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい５～６員窒素含有芳香族複素環を示し、
　さらに好ましくは、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基で置換されていてもよい５～６員窒素含有芳香族複素環（例：イミダゾール、ピリジン）を示す。 Ring A ″ represents a 5- to 6-membered nitrogen-containing aromatic heterocycle which may be further substituted with a substituent selected from groups other than the halogen atom.
Preferably, a hydroxy group may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl. ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) Shows a 5- to 6-membered nitrogen-containing aromatic heterocycle optionally substituted with 1 to 3 substituents selected from alkylenedioxy groups.
More preferably, a hydroxy group, an (C 1- C 6 ) alkyl group optionally substituted with 1 to 3 halogen atoms, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 )). 1-3 selected from (alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, and nitro group. Shows a 5- to 6-membered nitrogen-containing aromatic heterocycle optionally substituted with 11 substituents.
More preferably, one to three optionally substituted with a halogen atom (C 1 -C 6) alkyl which may be substituted 5 to have 6-membered nitrogen-containing aromatic heterocycle group (e.g., imidazole, pyridine ) Is shown.
　環Ａ’’’は、さらに置換されていてもよい６員窒素含有芳香族複素環を示し、
　好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示し、
　より好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基、から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示し、
　さらに好ましくは、１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよい６員窒素含有芳香族複素環（例：ピリジン）を示す。 Ring A'''represents a 6-membered nitrogen-containing aromatic heterocycle that may be further substituted.
Preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, 1-3 substitutions selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group which may be substituted with 1 to 3 halogen atoms. Shows a 6-membered nitrogen-containing aromatic heterocycle that may be substituted with a group.
More preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group. 6 members which may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) which may be substituted with 1 to 3 halogen atoms and a nitro group. Shows a nitrogen-containing aromatic heterocycle,
More preferably, one to three (C 1 -C 6) alkyl 6-membered nitrogen-containing aromatic may be substituted with a group heterocyclic (e.g. pyridine) shows a.
　環Ｂ’は、置換されていてもよい６員窒素含有芳香族複素環（ここにおいて、６員窒素含有芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい）を示し、
　好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環（ここにおいて、６員窒素含有芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環（好ましくは、５または６員炭素環、または２個の酸素原子を環構成原子として含有する５または６員複素環）を形成していてもよい）を示し、
　より好ましくは、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示す。 Ring B'is a optionally substituted 6-membered nitrogen-containing aromatic heterocycle (here, two substituents present on adjacent carbon atoms in the 6-membered nitrogen-containing aromatic heterocycle are bonded to each other. May form a ring with the carbon atoms to which they are bonded).
Preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, Contains 6-membered nitrogen, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ), an arylamino group, and 1 to 3 substituents selected from nitro groups. Aromatic heterocycles (where, two substituents present on adjacent carbon atoms in a 6-membered nitrogen-containing aromatic heterocycle are attached to each other and together with the carbon atoms to which they are attached, 1 to 3 oxygens. A 5- to 7-membered ring (preferably a 5- or 6-membered carbon ring, or a 5- or 6-membered heterocycle containing two oxygen atoms as ring-constituting atoms) may contain an atom as a ring-constituting atom. May be formed),
More preferably, a halogen atom, a (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group. 6-membered nitrogen which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) arylamino group and 1 to 3 substituents selected from nitro groups. Shows the contained aromatic heterocycle.
　環Ｂ’’は、置換されていてもよいベンゼン環または置換されていてもよい５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい）を示し、
　好ましくは、ヒドロキシ基、
ハロゲン原子、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
（Ｃ６－Ｃ１０）アリール基、
１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
ニトロ基
から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環または５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環（好ましくは、５または６員炭素環、または２個の酸素原子を環構成原子として含有する５または６員複素環）を形成していてもよい）を示し、
　より好ましくは、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基でそれぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環（例：ピロール、フラン、チオフェン、イミダゾール、ピリジン）を示す。 Ring B ″ is on a optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, on an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle). The two substituents present in may form a ring with the carbon atoms to which they are attached and bonded to each other).
Preferably, a hydroxy group,
Halogen atom,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
Di ((C 1 -C 6) alkyl) amino group,
(C 6- C 10 ) Aryl group,
A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively. Or a 5- to 6-membered aromatic heterocycle (here, two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are carbon atoms to which they are bonded to each other. Together with, it contains a 5- to 7-membered ring (preferably a 5- or 6-membered carbon ring, or 2 oxygen atoms, which may contain 1 to 3 oxygen atoms as ring-constituting atoms. A 5- or 6-membered heterocycle) may be formed).
More preferably, the hydroxy group,
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) A benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups, respectively, or a 5 to 6 member aromatic heterocycle (eg, pyrrole, furan, thiophene, imidazole, Pyridine) is shown.
　Ｘは、水素原子またはハロゲン原子を示し、
　好ましくは、水素原子を示す。 X represents a hydrogen atom or a halogen atom,
Preferably, it indicates a hydrogen atom.
（化合物（ＩＡ）の好ましい実施態様について）
　化合物（ＩＡ）においては、環Ａ’、環Ａ’’および環Ａ’’’が無置換の環である化合物が、好ましい実施態様の一つとして挙げられる。
　化合物（ＩＡ）の別の好ましい実施態様としては、以下のものが挙げられる。
［化合物Ｂ］
式（ＩＡ）： (About preferred embodiments of compound (IA))
In the compound (IA), a compound in which the ring A', the ring A'' and the ring A''' are unsubstituted rings is mentioned as one of the preferred embodiments.
Another preferred embodiment of compound (IA) includes:
[Compound B]
Formula (IA):
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
［式中、Ｒは、下記の式（Ｉａ’’）： [In the formula, R is the following formula (Ia ″):
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
（上記式中、Ｒ１が、水素原子または（Ｃ１－Ｃ６）アルキル基を示し、
環Ａ’’が、ピリジン環を示し、および
環Ｂ’’が、ヒドロキシ基、
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
１～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し、
＊は、ベンゾイミダゾール環への結合位置を示す。）
で示される基、および
Ｘが、水素原子を示す。）
で表される化合物。 (In the above formula, R 1 represents a hydrogen atom or a (C 1- C 6 ) alkyl group.
Ring A ″ represents a pyridine ring, and ring B ″ is a hydroxy group.
It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Shows a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
* Indicates the binding position to the benzimidazole ring. )
The group represented by and X represent a hydrogen atom. )
The compound represented by.
［化合物（Ｉ）／化合物（ＩＡ）またはその塩の使用について］
　本発明を抗マラリア薬（特に、クロロキン耐性株に対する抗マラリア薬）として実施するにあたっては、化合物（Ｉ）／化合物（ＩＡ）またはその塩（好ましくは、医薬として許容される塩）（以下、これらを総称して「本発明化合物」と称する場合がある）は、単独の形態で、または本発明化合物を有効成分として、医薬として許容される担体ともに含む医薬組成物（製剤）の形態でのいずれの形態でも使用することができる。 [About the use of compound (I) / compound (IA) or a salt thereof]
In carrying out the present invention as an antimalarial drug (particularly, an antimalarial drug against a chloroquine-resistant strain), compound (I) / compound (IA) or a salt thereof (preferably a pharmaceutically acceptable salt) (hereinafter, these (Sometimes collectively referred to as "the compound of the present invention"), either in the form of a single compound or in the form of a pharmaceutical composition (formulation) containing the compound of the present invention as an active ingredient together with a pharmaceutically acceptable carrier. It can also be used in the form of.
　かかる医薬組成物としては、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤（例、ボーラス）、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等が挙げられる。 Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), suppositories, powders, granules, capsules (soft capsules, microcapsules, etc.). Includes), suppositories, liquids, emulsions, suspending agents, release controlled formulations (eg, immediate release preparations, sustained release preparations, sustained release microcapsules), aerosols, film agents (eg, orally disintegrating film) , Oral mucosa sticking film), injection (eg, subcutaneous injection, intravenous injection (eg, bolus), intramuscular injection, intraperitoneal injection), drip, transdermal drug, ointment, lotion Examples thereof include agents, patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal agents, lung agents (inhalants), eye drops and the like.
　本明細書において、「医薬として許容される担体」としては、製剤技術の分野で慣用されている各種の担体を用いることができる。 In the present specification, as the "medically acceptable carrier", various carriers commonly used in the field of pharmaceutical technology can be used.
　「医薬として許容される担体」の具体例としては、例えば、固形製剤においては、賦形剤（例えば、乳糖、白糖、Ｄ－マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等）、滑沢剤（例えば、ステアリン酸マグネシウム、タルク、コロイドシリカ等）、結合剤（例えば、結晶セルロース、白糖、Ｄ－マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等）および崩壊剤（例えば、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、Ｌ－ヒドロキシプロピルセルロース等）、等を用いることができる。 Specific examples of the "pharmaceutically acceptable carrier" include excipients (eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silicate silicate, etc.) and sulphates in solid preparations. Swamps (eg magnesium stearate, talc, colloidal silica, etc.), binders (eg crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, etc. Methyl cellulose, sodium carboxymethyl cellulose, etc.) and disintegrants (eg, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.), and the like can be used.
　液状製剤においては、溶剤（例えば、注射用水、等張食塩水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、等）、溶解補助剤（例えば、ポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、安息香酸ベンジル、エタノール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等）、懸濁化剤（例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、モノステアリン酸グリセリン等の界面活性剤；例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等）、等張化剤（例えば、ブドウ糖、Ｄ－ソルビトール、塩化ナトリウム、グリセリン、Ｄ－マンニトール等）、緩衝剤（例えば、リン酸塩、クエン酸塩等の緩衝液等）、および無痛化剤（例えば、ベンジルアルコール等）、等を用いることができる。 In liquid preparations, solvents (eg, water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizers (eg, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, etc.) Surfactants such as ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalconium chloride, glycerin monostearate, etc. Activators; eg, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydrophilic polymers such as hydroxypropyl cellulose, etc.), isotonic agents (eg, glucose, D-sorbitol, sodium chloride, glycerin, etc.) D-mannitol or the like), a buffer (for example, a buffer such as phosphate or citrate), and a pain-relieving agent (for example, benzyl alcohol or the like) can be used.
　必要により、防腐剤（例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、ソルビン酸等）、抗酸化剤（例えば、亜硫酸塩、アスコルビン酸、α－トコフェロール等）、着色剤、甘味剤等の製剤添加物をさらに添加してもよい。 If necessary, preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (eg, sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. Further formulation additives may be added.
　本発明の医薬組成物は、剤型、投与方法、担体などにより異なるが、本発明化合物を製剤全量に対して通常０．０１～９９％（ｗ／ｗ）、好ましくは０．１～８５％（ｗ／ｗ）の割合で添加することにより、製造し得る。当該医薬組成物は、その形態に応じて、製剤技術の分野で慣用の方法により製造できる。本発明の医薬組成物は、有効成分を含む徐放性製剤に成形してもよい。
（投与対象について）
　本発明化合物は、毒性が低く、かつ副作用も少ないことが期待でき、医薬品として優れた性質も有している。従って、本発明化合物は、哺乳動物（特に、ヒト）に対して、安全に投与し得る。
（投与経路について）
　本発明を実施するに当たっては、本発明化合物は、単独で、または医薬組成物として、経口的又は非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内投与、および病巣への投与）に投与し得る。
（投与量について）
　本発明化合物の投与量は、投与対象、投与経路および投与対象者の年齢や症状によって異なるが、特に限定されない。例えば、マラリアの成人患者（体重約４０～８０ｋｇ、例えば、６０ｋｇ）に経口投与する場合、その投与量は、本発明化合物として１日当たり、有効成分（化合物（Ｉ）／化合物（ＩＡ））として約０．０１ｍｇ／ｋｇ体重～約５００ｍｇ／ｋｇ体重、好ましくは約１０ｍｇ／ｋｇ体重～約３０ｍｇ／ｋｇ体重であり、１日１回～数回に分けて投与し得る。
（プロドラッグとしての使用について）
　化合物（Ｉ）／化合物（ＩＡ）はそのプロドラッグの形態で使用することもできる。化合物（Ｉ）／化合物（ＩＡ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）／化合物（ＩＡ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）／化合物（ＩＡ）に変化する化合物、胃酸等により加水分解等を起こして化合物（Ｉ）／化合物（ＩＡ）に変化する化合物をいう。化合物（Ｉ）／化合物（ＩＡ）のプロドラッグとしては、化合物（Ｉ）／化合物（ＩＡ）のアミノ基がアシル化、アルキル化、りん酸化された化合物[例、化合物（Ｉ）／化合物（ＩＡ）のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物等]；化合物（Ｉ）／化合物（ＩＡ）の水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例、化合物（Ｉ）／化合物（ＩＡ）の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等）；化合物（Ｉ）／化合物（ＩＡ）のカルボキシル基がエステル化、アミド化された化合物［例、化合物（Ｉ）／化合物（ＩＡ）のカルボキシル基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等]等が挙げられる。これらの化合物は自体公知の方法によって化合物（Ｉ）／化合物（ＩＡ）から製造することができる。
　また、化合物（Ｉ）／化合物（ＩＡ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような、生理的条件で化合物（Ｉ）に変化するものであってもよい。 The pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 99% (w / w), preferably 0.1 to 85%, based on the total amount of the preparation. It can be produced by adding it in a ratio of (w / w). The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, depending on its form. The pharmaceutical composition of the present invention may be formed into a sustained release preparation containing an active ingredient.
(About the subject of administration)
The compound of the present invention is expected to have low toxicity and few side effects, and has excellent properties as a pharmaceutical product. Therefore, the compounds of the present invention can be safely administered to mammals (particularly humans).
(Route of administration)
In carrying out the present invention, the compound of the present invention may be used alone or as a pharmaceutical composition orally or parenterally (eg, intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, by eye drops, etc. It can be administered intracerebrally, in the rectum, in the vagina, intraperitoneally, and to lesions).
(About dosage)
The dose of the compound of the present invention varies depending on the administration subject, the administration route, and the age and symptoms of the administration subject, but is not particularly limited. For example, when orally administered to an adult patient with malaria (body weight of about 40 to 80 kg, for example, 60 kg), the dose is about the active ingredient (Compound (I) / Compound (IA)) per day as the compound of the present invention. It ranges from 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 10 mg / kg body weight to about 30 mg / kg body weight, and can be administered once to several times a day.
(About use as a prodrug)
Compound (I) / Compound (IA) can also be used in the form of its prodrug. The prodrug of compound (I) / compound (IA) is a compound that is converted into compound (I) / compound (IA) by a reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo, that is, enzymatically oxidized and reduced. A compound that changes to compound (I) / compound (IA) by causing hydrolysis or the like, or a compound that changes to compound (I) / compound (IA) by causing hydrolysis or the like due to gastric acid or the like. As a prodrug of compound (I) / compound (IA), a compound in which the amino group of compound (I) / compound (IA) is acylated, alkylated, or phosphorylated [eg, compound (I) / compound (IA) ) Amino group is eikosanoyylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivalo Iloxymethylated, tert-butylated compounds, etc.]; Compounds (I) / compounds (IA) in which the hydroxyl groups are acylated, alkylated, phosphorylated, or oxidized (eg, compound (I) / compound). Compounds in which the hydroxyl groups of (IA) are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); Compounds that have been esterified and amidated [eg, compound (I) / compound (IA) in which the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl ester , Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamided compounds, etc. ] Etc. can be mentioned. These compounds can be prepared from compound (I) / compound (IA) by a method known per se.
In addition, the prodrug of compound (I) / compound (IA) is a compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198. ) May be changed.
（他剤との併用について） (About combined use with other drugs)
　本発明化合物は、上記の通り毒性が極めて低く、他の薬剤と組み合わせて、マラリアの予防または治療に用いることができ、他の薬剤との併用による優れた予防および／または治療効果が期待できる。また、かかる併用療法により他の薬剤の用量を下げて、これらが有する副作用を低減することも期待できる。
　このような本発明化合物と組み合わせて用いられ得る薬剤（以下、併用薬剤と略記する）としては、キニーネ、アモジアキン、メフロキン、ピペラキン、ドキシサイクリン、アトバコンとプログアニルの併用、ルメファントリン、クロロキン、アルテミシニン、アルテメテル、アーテスネート、ジヒドロアーテミシニン等が挙げられる。
　実際の併用療法においては、患者の疾患の種類、その症状の重篤度等に鑑みて、適宜併用薬剤を選択することができる。 As described above, the compound of the present invention has extremely low toxicity and can be used for the prevention or treatment of malaria in combination with other drugs, and excellent preventive and / or therapeutic effects can be expected when used in combination with other drugs. In addition, it can be expected that such combination therapy will reduce the dose of other drugs to reduce the side effects of these drugs.
Drugs that can be used in combination with such compounds of the present invention (hereinafter abbreviated as concomitant drugs) include quinine, amodiaquine, mefloquine, piperakin, doxycycline, concomitant use of atovaquone and proguanil, lumefantrine, chloroquine, artemisinin, etc. Examples include artemether, artesunate, dihydroartemisinin and the like.
In the actual combination therapy, the concomitant drug can be appropriately selected in consideration of the type of the patient's disease, the severity of the symptom, and the like.
　本発明の併用剤の投与形態は、特に限定されず、投与時に、本発明の化合物と併用薬物とが組み合わされ得る。例えば、（１）本発明化合物と併用薬剤とを組み合わせて含有する製剤の投与、（２）本発明化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の同一投与経路での同時または別々の投与、（３）本発明化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時または別々の投与、等の形態で用いることができる。好ましい形態は、医療現場の実態に応じて、適宜選択することができる。 The administration form of the concomitant drug of the present invention is not particularly limited, and the compound of the present invention and the concomitant drug can be combined at the time of administration. For example, (1) administration of a preparation containing a combination of the compound of the present invention and a concomitant drug, and (2) simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug in the same route of administration. Alternatively, it can be used in a form such as separate administration, (3) simultaneous or separate administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes. The preferred form can be appropriately selected according to the actual conditions of the medical field.
　上記の本発明化合物と併用薬剤とを組み合わせて含有する製剤は、先に説明された本発明化合物を含有する医薬組成物に準じて、当業者であれば適宜製造することができる。 A preparation containing the above-mentioned compound of the present invention in combination with a concomitant drug can be appropriately produced by a person skilled in the art according to the pharmaceutical composition containing the compound of the present invention described above.
　併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択し得る。また、本発明化合物と併用薬剤との配合比は、投与対象の疾患や症状、投与経路、用いる併用薬剤の種類、等により適宜選択し得る。通常は、用いる併用薬剤の一般的な臨床用量を基準にして医療現場の実態に応じて適宜決定し得る。 The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the disease or symptom to be administered, the administration route, the type of concomitant drug to be used, and the like. Usually, it can be appropriately determined according to the actual conditions of the medical field based on the general clinical dose of the concomitant drug to be used.
　本発明は、更に以下の参考例、実施例、試験例によって詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention will be further described in detail with reference to the following reference examples, examples, and test examples, but these are not limited to the present invention and may be changed without departing from the scope of the present invention.
　本発明において、製造および／または評価の対象とされた化合物のリスト（以下、「化合物リスト」と称する場合がある。）を以下に示す。
　化合物１～３は、東京大学創薬機構の化合物ライブラリーより提供を受けた化合物である。
　化合物４～２０は、市販されている化合物であり、製造業者から購入して当業者であれば入手することができる。
　化合物２１～５０は、製造された化合物である。後記の「化合物の製造に関する実施例」で具体的に示された製造方法、並びに当技術分野で既知の製造方法を参照することにより当業者であれば適宜製造して入手することができる。 A list of compounds (hereinafter, may be referred to as "compound list") that have been produced and / or evaluated in the present invention is shown below.
Compounds 1 to 3 are compounds provided by the compound library of the University of Tokyo Drug Discovery Organization.
Compounds 4 to 20 are commercially available compounds, which can be purchased from a manufacturer and obtained by those skilled in the art.
Compounds 21 to 50 are produced compounds. Those skilled in the art can appropriately manufacture and obtain the product by referring to the production method specifically shown in "Examples for Production of Compounds" described later and the production method known in the art.
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
［化合物の製造に関する実施例］ [Examples relating to the production of compounds]
　以下の参考例、実施例、比較例における「化合物２１」等の化合物番号は、上記の「化合物リスト」中の化合物番号に附合している。 The compound numbers such as "Compound 21" in the following reference examples, examples, and comparative examples are attached to the compound numbers in the above "compound list".
参考例１
２－（２－（（２－メチル－１Ｈ－インドール－３－イル）メチレン）ヒドラジニル）－１Ｈ－ベンゾ[ｄ]イミダゾール（化合物２１） Reference example 1
2- (2-((2-Methyl-1H-indole-3-yl) methylene) hydrazinyl) -1H-benzo [d] imidazole (Compound 21)
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
１Ｈ－ベンズイミダゾール－２－イルヒドラジン１２３ｍｇを酢酸（２ｍＬ）に溶解し、酢酸ナトリウム８２ｍｇ、２－メチル－１Ｈ－インドール－３－カルバルデヒド１５９ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄した。更なる精製操作を行わないで、白色固体の生成物１６０ｇ（収率６７％）を得た。 123 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (2 mL), 82 mg of sodium acetate and 159 mg of 2-methyl-1H-indole-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane. No further purification operation was performed to give 160 g (67% yield) of white solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ２．５０（ｓ，３Ｈ），６．９２－６．９４（ｍ，２Ｈ），７．１０－７．１４（ｍ，２Ｈ），７．２４－７．２５（ｍ，２Ｈ），７．３１－７．３３（ｍ，１Ｈ），８．３４（ｓ，１Ｈ），８．３７－８．３９（ｍ，１Ｈ），１１．５（ｂｒ．ｓ，ＮＨ），１１．５（ｂｒ．ｓ，ＮＨ） 1 1 HNMR (500MHz, d-DMSO) δ2.50 (s, 3H), 6.92-6.94 (m, 2H), 7.10-7.14 (m, 2H), 7.24-7. 25 (m, 2H), 7.31-7.33 (m, 1H), 8.34 (s, 1H), 8.37-8.39 (m, 1H), 11.5 (br.s, NH), 11.5 (br.s, NH)
実施例１
Ｎ－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）－２－（（３，４－ジクロロフェニル）アミノ）チアゾール－４－カルボキサミド（化合物２２） Example 1
N- (1H-benzo [d] imidazol-2-yl) -2-((3,4-dichlorophenyl) amino) thiazole-4-carboxamide (Compound 22)
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
２－アミノベンゾイミダゾール６６ｍｇをＮ，Ｎ’－ジメチルホルムアミド（４ｍＬ）に溶解し、２－（（３，４－ジクロロフェニル）アミノ）チアゾール－４－カルボン酸１４５ｍｇ、ＨＡＴＵ１９３ｍｇとジイソプロピルエチルアミン８７μＭを加えて、室温にて２４時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステル）で精製し、黄色固体の生成物３２ｍｇ（収率１６％）を得た。 66 mg of 2-aminobenzimidazole was dissolved in N, N'-dimethylformamide (4 mL), and 145 mg of 2-((3,4-dichlorophenyl) amino) thiazole-4-carboxylic acid, 193 mg of HATU and 87 μM of diisopropylethylamine were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester) to obtain 32 mg (yield 16%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ７．１２－７．１５（ｍ，２Ｈ），７．４７－７．４９（ｍ，２Ｈ），７．５６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．７４（ｄｄ，Ｊ＝２．５，８．８Ｈｚ，１Ｈ），７．９８（ｂｒ．ｓ，ＮＨ），８．０９（ｄ，Ｊ＝２．２Ｈｚ、１Ｈ），１０．７（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ7.12-7.15 (m, 2H), 7.47-7.49 (m, 2H), 7.56 (d, J = 8.8Hz, 1H), 7.74 (dd, J = 2.5, 8.8Hz, 1H), 7.98 (br.s, NH), 8.09 (d, J = 2.2Hz, 1H), 10.7 (br) .S, NH).
実施例２
Ｎ－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ベンゾ[ｂ]チオフェン－３－カルボキサミド（化合物２３） Example 2
N- (1H-benzo [d] imidazol-2-yl) benzo [b] thiophene-3-carboxamide (Compound 23)
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
２－アミノベンゾイミダゾール６６ｍｇをＮ，Ｎ’－ジメチルホルムアミド（４ｍＬ）に溶解し、ベンゾ[ｂ]チオフェン－３－カルボン酸８９ｍｇ、ＨＡＴＵ１９３ｍｇとジイソプロピルエチルアミン８７μＭを加えて、室温にて２４時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステルとヘキサン＝１：１）で精製し、白色固体の生成物５５ｍｇ（収率３７％）を得た。 66 mg of 2-aminobenzimidazole was dissolved in N, N'-dimethylformamide (4 mL), 89 mg of benzo [b] thiophene-3-carboxylic acid, 193 mg of HATU and 87 μM of diisopropylethylamine were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester and hexane = 1: 1) to obtain 55 mg (yield 37%) of a white solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ７．１３－７．１５（ｍ，２Ｈ），７．７．４５－７．５４（ｍ，４Ｈ），８．０９（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ)，８．７２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），８．８０（ｓ，１Ｈ），１２．３（ｂｒ．ｓ，ＮＨ）．  1 1 HNMR (500MHz, d-DMSO) δ7.13-7.15 (m, 2H), 7.7.45-7.54 (m, 4H), 8.09 (d, J = 8.1Hz, 1H) ), 8.72 (d, J = 7.8Hz, 1H), 8.80 (s, 1H), 12.3 (br.s, NH).
実施例３
Ｎ－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）－１－メチルー５－フェニル－１Ｈ－ピラゾール－３－カルボキサミド（化合物２４） Example 3
N- (1H-benzo [d] imidazol-2-yl) -1-methyl-5-phenyl-1H-pyrazole-3-carboxamide (Compound 24)
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
２－アミノベンゾイミダゾール６６ｍｇをＮ，Ｎ’－ジメチルホルムアミド（４ｍＬ）に溶解し、１－メチルー５－フェニル－１Ｈ－ピラゾール－３－カルボン酸１００ｍｇ、ＨＡＴＵ１９３ｍｇとジイソプロピルエチルアミン８７μＭを加えて、室温にて２４時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステルとヘキサン＝１：１）で精製し、白色固体の生成物２５ｍｇ（収率１６％）を得た。 66 mg of 2-aminobenzimidazole is dissolved in N, N'-dimethylformamide (4 mL), 100 mg of 1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid, 193 mg of HATU and 87 μM of diisopropylethylamine are added, and the mixture is added at room temperature. The mixture was stirred for 24 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester and hexane = 1: 1) to obtain 25 mg (yield 16%) of a white solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ３．９０（ｓ，３Ｈ），７．０４（ｓ，１Ｈ），７．１４－７．１６（ｍ，２Ｈ），７．４８－７．５８（ｍ，７Ｈ），７．９５（ｂｒ．ｓ，ＮＨ），１２．３（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ3.90 (s, 3H), 7.04 (s, 1H), 7.14-7.16 (m, 2H), 7.48-7.58 (m, 7H), 7.95 (br.s, NH), 12.3 (br.s, NH).
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　上記の合成スキームにより、後記の実施例４、７、および８に示される化合物を合成した。 The compounds shown in Examples 4, 7, and 8 described later were synthesized by the above synthesis scheme.
実施例４
Ｎ－（２－（１Ｈ－インドール－３－イル）エチル）－１Ｈ－ベンゾ[ｄ]イミダゾール－２－カルボキサミド（化合物２５） Example 4
N- (2- (1H-indole-3-yl) ethyl) -1H-benzo [d] imidazol-2-carboxamide (Compound 25)
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
１Ｈ－ベンゾ[ｄ]イミダゾール－２－カルボン酸３２４ｍｇを塩化チオニル（３ｍＬ）に溶解し、加熱還流下１時間撹拌した。反応液を減圧留去し、得られる酸クロリド９０ｍｇをジクロロメタン４ｍＬに溶解し、トリプタミン８０ｍｇとトリエチルアミン８３μＭを加えて、室温にて１２時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステルとヘキサン＝１：１）で精製し、白色固体の生成物４１ｍｇ（収率２７％）を得た。 324 mg of 1H-benzo [d] imidazol-2-carboxylic acid was dissolved in thionyl chloride (3 mL), and the mixture was stirred under heating under reflux for 1 hour. The reaction mixture was evaporated under reduced pressure, 90 mg of the obtained acid chloride was dissolved in 4 mL of dichloromethane, 80 mg of tryptamine and 83 μM of triethylamine were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester and hexane = 1: 1) to obtain 41 mg (yield 27%) of a white solid product.
１ＨＮＭＲ　（５００ＭＨｚ，ＣＤＣｌ３）δ３．１５（ｔ，Ｊ＝７．１Ｈｚ，２Ｈ），３．８６（ｑ，Ｊ＝７．１Ｈ，２Ｈ），７．１３－７．１６（ｍ，Ｈ），７．２３（ｔ，Ｊ＝７．３Ｈｚ，１Ｈ），７．３２－７．４１（ｍ，３Ｈ），７．５４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ），７．６４（ｂｒ．ｓ，ＮＨ），７．６６（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），７．７７（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），８．０４（ｂｒ．ｓ，ＮＨ），１０．３（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, CDCl 3 ) δ3.15 (t, J = 7.1Hz, 2H), 3.86 (q, J = 7.1H, 2H), 7.13-7.16 (m, H) , 7.23 (t, J = 7.3Hz, 1H), 7.32-7.41 (m, 3H), 7.54 (d, J = 7.6Hz, 1H), 7.64 (br. s, NH), 7.66 (d, J = 8.3Hz, 1H), 7.77 (d, J = 8.3Hz, 1H), 8.04 (br.s, NH), 10.3 ( br.s, NH).
実施例５
Ｎ－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）－２－（フェニルアミノ）チアゾール－４－カルボキサミド（化合物２６） Example 5
N- (1H-benzo [d] imidazol-2-yl) -2- (phenylamino) thiazole-4-carboxamide (Compound 26)
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
２－アミノベンゾイミダゾール３６ｍｇをＮ，Ｎ’－ジメチルホルムアミド（２ｍＬ）に溶解し、２－（フェニルアミノ）チアゾール－４－カルボン酸６０ｍｇ、ＨＡＴＵ１０４ｍｇとジイソプロピルエチルアミン４７μＭを加えて、室温にて２４時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：　酢酸エチルエステル）で精製し、黄色固体の生成物１８ｍｇ（収率２０％）を得た。 Dissolve 36 mg of 2-aminobenzimidazole in N, N'-dimethylformamide (2 mL), add 60 mg of 2- (phenylamino) thiazole-4-carboxylic acid, 104 mg of HATU and 47 μM of diisopropylethylamine, and stir at room temperature for 24 hours. bottom. The reaction mixture was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester) to obtain 18 mg (yield 20%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ７．０１（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），７．１３－７．１５（ｍ，２Ｈ），７．３７（ｔ，Ｊ＝８．３Ｈｚ，２Ｈ），７．４８－７．４９（ｍ，２Ｈ），７．７４（ｄｄ，Ｊ＝１．０，８．６Ｈｚ，２Ｈ），７．８８（ｓ，１Ｈ），１０．５（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ7.01 (d, J = 7.4Hz, 1H), 7.13-7.15 (m, 2H), 7.37 (t, J = 8.3Hz, 2H) ), 7.48-7.49 (m, 2H), 7.74 (dd, J = 1.0, 8.6Hz, 2H), 7.88 (s, 1H), 10.5 (br.s) , NH).
参考例２
Ｎ－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）－３－（１Ｈ－インドール－３－イル）プロパンアミド（化合物２７） Reference example 2
N- (1H-benzo [d] imidazol-2-yl) -3- (1H-indole-3-yl) propanamide (Compound 27)
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
２－アミノベンゾイミダゾール７４ｍｇをＮ，Ｎ’－ジメチルホルムアミド（４ｍＬ）に溶解し、３－インドールプロピオン酸９４ｍｇ、ＨＡＴＵ１９３ｍｇとジイソプロピルエチルアミン６３μＭを加えて、室温にて２４時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステル）で精製し、白色固体の生成物２７ｍｇ（収率３５％）を得た。 74 mg of 2-aminobenzimidazole was dissolved in N, N'-dimethylformamide (4 mL), 94 mg of 3-indolepropionic acid, 193 mg of HATU and 63 μM of diisopropylethylamine were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester) to obtain 27 mg (yield 35%) of a white solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ２．８２（ｔ，Ｊ＝７．１Ｈｚ，２Ｈ），３．０７（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），６．９８（ｔ，Ｊ＝７．１Ｈｚ，１Ｈ），７．０５－７．０７（ｍ，３Ｈ），７．１４（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），７．３２（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），７．３７－７．４８（ｍ，２Ｈ），７．５９（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），１０．８（ｂｒ．ｓ，ＮＨ），１１．５（ｂｒ．ｓ，ＮＨ），１２．０（ｂｒ．ｓ，ＮＨ）． 1 HNMR (500MHz, d-DMSO) δ2.82 (t, J = 7.1Hz, 2H), 3.07 (t, J = 7.6Hz, 2H), 6.98 (t, J = 7.1Hz) , 1H), 7.05-7.07 (m, 3H), 7.14 (d, J = 2.2Hz, 1H), 7.32 (d, J = 8.1Hz, 1H), 7.37 -7.48 (m, 2H), 7.59 (d, J = 8.1Hz, 1H), 10.8 (br.s, NH), 11.5 (br.s, NH), 12.0 (Br.s, NH).
実施例６
Ｎ－（ベンゾ［ｄ］［１，３］ジオキソール－５－イルメチル）－１Ｈ－ベンゾ[ｄ]イミダゾール－２－カルボキサミド（化合物２８） Example 6
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -1H-benzo [d] imidazole-2-carboxamide (Compound 28)
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
１Ｈ－ベンゾ[ｄ]イミダゾール－２－カルボン酸３２４ｍｇを塩化チオニル（３ｍＬ）に溶解し、加熱還流下１時間撹拌した。反応液を減圧留去し、得られる酸クロリド９０ｍｇをジクロロメタン４ｍＬに溶解し、ベンゾ［ｄ］［１，３］ジオキソール－５－イルメチルアミン７６ｍｇとトリエチルアミン８３μＭを加えて、室温にて１２時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステル）で精製し、白色固体の生成物１４６ｍｇ（収率９９％）を得た。 324 mg of 1H-benzo [d] imidazol-2-carboxylic acid was dissolved in thionyl chloride (3 mL), and the mixture was stirred under heating under reflux for 1 hour. The reaction mixture was distilled off under reduced pressure, 90 mg of the obtained acid chloride was dissolved in 4 mL of dichloromethane, 76 mg of benzo [d] [1,3] dioxol-5-ylmethylamine and 83 μM of triethylamine were added, and the mixture was stirred at room temperature for 12 hours. bottom. The reaction mixture was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester) to obtain 146 mg (yield 99%) of a white solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ４．３９（ｄ，Ｊ＝６．４Ｈｚ，２Ｈ），５．９７（ｓ，２Ｈ），６．８２－６．８２（ｍ，２Ｈ），６．９３（ｄ，Ｊ＝１．２Ｈｚ，１Ｈ），７．２８（ｂｒ．ｓ，２Ｈ），７．５３（ｂｒ．ｓ，１Ｈ），７．７１（ｂｒ．ｓ，１Ｈ），９．４４（ｔ，Ｊ＝６．４Ｈｚ，ＮＨ），１２．２（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ4.39 (d, J = 6.4Hz, 2H), 5.97 (s, 2H), 6.82-6.82 (m, 2H), 6.93 ( d, J = 1.2Hz, 1H), 7.28 (br.s, 2H), 7.53 (br.s, 1H), 7.71 (br.s, 1H), 9.44 (t, J = 6.4 Hz, NH), 12.2 (br.s, NH).
実施例７
Ｎ－（３－（（７－クロロキノリン－４－イル）アミノ）プロピル）－１Ｈ－ベンゾ[ｄ]イミダゾール－２－カルボキサミド（化合物２９） Example 7
N- (3-((7-Chloroquinoline-4-yl) amino) propyl) -1H-benzo [d] imidazol-2-carboxamide (Compound 29)
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
１Ｈ－ベンゾ[ｄ]イミダゾール－２－カルボン酸３２４ｍｇを塩化チオニル（３ｍＬ）に溶解し、加熱還流下１時間撹拌した。反応液を減圧留去し、得られる酸クロリド６３ｍｇをジクロロエタン４ｍＬに溶解し、Ｎ１－（７－クロロキノリン－４－イル）プロパン－１,３－ジアミン８３ｍｇとトリエチルアミン６３μＭを加えて、７０℃にて１２時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステル：メタノール＝９５：５）で精製し、白色固体の生成物９１ｍｇ（収率６８％）を得た。 324 mg of 1H-benzo [d] imidazol-2-carboxylic acid was dissolved in thionyl chloride (3 mL), and the mixture was stirred under heating under reflux for 1 hour. The reaction mixture was distilled off under reduced pressure and the resulting acid chloride 63mg was dissolved in dichloroethane 4mL, N 1 - (-4- 7- chloro-yl) was added propane-1,3-diamine 83mg of triethylamine 63μM, 70 ℃ Was stirred for 12 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester: methanol = 95: 5) to obtain 91 mg (yield 68%) of a white solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ１．６６－１．７４（ｍ，２Ｈ），３．２９－２．２９（ｍ，４Ｈ），６．４８（ｄ，Ｊ＝５．７Ｈｚ，ＮＨ），７．２５－７．３２（ｍ，３Ｈ），７．４２（ｄｄ，Ｊ＝２．２，９．１Ｈｚ，１Ｈ），７．５２（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），７．７６（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），８．２６（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），８．３６（ｄ，Ｊ＝５．４Ｈｚ，１Ｈ），９．００（ｔ，Ｊ＝５．９Ｈｚ，ＮＨ），１３．２（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ1.66-1.74 (m, 2H), 3.29-2.29 (m, 4H), 6.48 (d, J = 5.7Hz, NH), 7.25-7.32 (m, 3H), 7.42 (dd, J = 2.2,9.1Hz, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.71 (D, J = 8.1Hz, 1H), 7.76 (d, J = 2.2Hz, 1H), 8.26 (d, J = 9.1Hz, 1H), 8.36 (d, J = 5.4Hz, 1H), 9.00 (t, J = 5.9Hz, NH), 13.2 (br.s, NH).
実施例８
Ｎ－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）－４－ニトロベンズアミド（化合物３０） Example 8
N- (1H-benzo [d] imidazol-2-yl) -4-nitrobenzamide (Compound 30)
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
２－アミノベンゾイミダゾール７４ｍｇをジクロロメタン（４ｍＬ）に溶解し、４－ニトロベンゾイルクロリド９３ｍｇとトリエチルアミン１００μＭを加えて、室温にて１２時間撹拌した。反応液を減圧留去し、残渣をカラムクロマトグラフィー（展開溶媒：酢酸エチルエステル）で精製し、黄色固体の生成物４３ｍｇ（収率３１％）を得た。 74 mg of 2-aminobenzimidazole was dissolved in dichloromethane (4 mL), 93 mg of 4-nitrobenzoyl chloride and 100 μM of triethylamine were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester) to obtain 43 mg (yield 31%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ４．０５（ｂｒ．ｓ，ＮＨ），７．１９－７．２１（ｍ，２Ｈ），７．４４－７．４５（ｍ，２Ｈ），８．３３－８．３８（ｍ，４Ｈ），１２．６（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ4.05 (br.s, NH), 7.19-7.21 (m, 2H), 7.44-7.45 (m, 2H), 8.33- 8.38 (m, 4H), 12.6 (br.s, NH).
参考例３
２－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）キノリン（化合物３１） Reference example 3
2-(2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) quinoline (Compound 31)
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１２３ｍｇを酢酸（２ｍＬ）に溶解し、酢酸ナトリウム８２ｍｇ、キノリン－２－カルバルデヒド１５７ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物２０８ｍｇ（収率９０％）を得た。 123 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (2 mL), 82 mg of sodium acetate and 157 mg of quinoline-2-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 208 mg (yield 90%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ６．９９－７．０５（ｍ，２Ｈ），７．２６－７．３２（ｍ，２Ｈ），７．５９（ｔ，Ｊ＝８．１Ｈｚ，１Ｈ），７．７６（ｔ，Ｊ＝８．３Ｈｚ，１Ｈ），７．９７－８．００（ｍ，２Ｈ），８．２０（ｄ，Ｊ＝２．５Ｈｚ，１Ｈ），８．４９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．４４（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），１１．８（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ6.99-7.05 (m, 2H), 7.26-7.32 (m, 2H), 7.59 (t, J = 8.1Hz, 1H), 7.76 (t, J = 8.3Hz, 1H), 7.97-8.00 (m, 2H), 8.20 (d, J = 2.5Hz, 1H), 8.49 (d, J) = 8.8Hz, 1H), 8.44 (d, J = 8.6Hz, 1H), 11.8 (br.s, NH).
実施例９
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）キノリン（化合物３２） Example 9
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) quinoline (Compound 32)
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１２３ｍｇを酢酸（２ｍＬ）に溶解し、酢酸ナトリウム８２ｍｇ、キノリン－３－カルバルデヒド１５７ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物２２７ｍｇ（収率９５％）を得た。 123 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (2 mL), 82 mg of sodium acetate and 157 mg of quinoline-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 227 mg (yield 95%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ６．９９－７．０５（ｍ，２Ｈ），７．２６－７．３２（ｍ，２Ｈ），７．５９（ｔ，Ｊ＝７．４Ｈｚ，１Ｈ），７．７５（ｔ，Ｊ＝８．３Ｈｚ，１Ｈ），７．９８（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），８．０４（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），８．２２（ｓ，１Ｈ），８．４９（ｓ，１Ｈ），９．５８（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），１１．７（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ6.99-7.05 (m, 2H), 7.26-7.32 (m, 2H), 7.59 (t, J = 7.4Hz, 1H), 7.75 (t, J = 8.3Hz, 1H), 7.98 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.3Hz, 1H), 8.22 (s) , 1H), 8.49 (s, 1H), 9.58 (d, J = 2.0Hz, 1H), 11.7 (br.s, NH).
参考例４
４－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）キノリン（化合物３３） Reference example 4
4-(2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) quinoline (Compound 33)
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１２３ｍｇを酢酸（２ｍＬ）に溶解し、酢酸ナトリウム８２ｍｇ、キノリン－４－カルバルデヒド１５７ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物１９２ｍｇ（収率８１％）を得た。 123 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (2 mL), 82 mg of sodium acetate and 157 mg of quinoline-4-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 192 mg (yield 81%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ６．９９－７．０６（ｍ，２Ｈ），７．２４－７．３１（ｍ，２Ｈ），７．５９（ｔ，Ｊ＝７．１Ｈｚ，１Ｈ），７．８１（ｔ，Ｊ＝７．４Ｈｚ，１Ｈ），８．０７（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），８．１５（ｄ，Ｊ＝４．７Ｈｚ，１Ｈ），８．４８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），８．８１（ｓ，１Ｈ），８．９４（ｄ，Ｊ＝４．７Ｈｚ，１Ｈ），１１．７（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ6.99-7.06 (m, 2H), 7.24-7.31 (m, 2H), 7.59 (t, J = 7.1Hz, 1H), 7.81 (t, J = 7.4Hz, 1H), 8.07 (d, J = 8.3Hz, 1H), 8.15 (d, J = 4.7Hz, 1H), 8.48 (d) , J = 8.6Hz, 1H), 8.81 (s, 1H), 8.94 (d, J = 4.7Hz, 1H), 11.7 (br.s, NH).
実施例１０
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７－メチルキノリン（化合物３４） Example 10
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methylquinoline (Compound 34)
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１０７ｍｇを酢酸（２ｍＬ）に溶解し、酢酸ナトリウム８２ｍｇ、７－メチルキノリン－３－カルバルデヒド１２３ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物１９７ｍｇ（収率９１％）を得た。 107 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (2 mL), 82 mg of sodium acetate and 123 mg of 7-methylquinoline-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 197 mg (yield 91%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ２．７２（ｓ，３Ｈ），６．９４－７．０２（ｍ，２Ｈ），７．２１－７．２９（ｍ，２Ｈ），７．４８（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），７．８４（ｓ，１Ｈ），７．４８（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），８．２０（ｓ，１Ｈ），８．４４（ｓ，１Ｈ），９．５１（ｓ，１Ｈ），１１．７（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ2.72 (s, 3H), 6.94-7.02 (m, 2H), 7.21-7.29 (m, 2H), 7.48 (d, J = 8.3Hz, 1H), 7.84 (s, 1H), 7.48 (d, J = 8.3Hz, 1H), 8.20 (s, 1H), 8.44 (s, 1H) , 9.51 (s, 1H), 11.7 (br.s, NH).
参考例５
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６－プロピルキノリン－２（１Ｈ）－オン（化合物３５） Reference example 5
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -6-propylquinoline-2 (1H) -one (Compound 35)
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１５ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４０ｍｇ、２－オキソ－６－プロピル－１，２－ジヒドロキノリン－３－カルバルデヒド３０ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物３９ｍｇ（収率８１％）を得た。 Dissolve 15 mg of 1H-benzimidazol-2-ylhydrazine in acetic acid (1 mL), add 40 mg of sodium acetate and 30 mg of 2-oxo-6-propyl-1,2-dihydroquinoline-3-carbaldehyde to 100 ° C. Stirred for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 39 mg (yield 81%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ０．９１（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．６３（ｓｅｘｔ, J＝７．３Ｈｚ，２Ｈ），２．６３（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），６．９３－７．０３（ｍ，２Ｈ），７．２３－７．３０（ｍ，３Ｈ），７．３７（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．４７（ｓ，１Ｈ），８．２５（ｓ，１Ｈ），８．５７（ｓ，１Ｈ），１１．６（ｂｒ．ｓ，ＮＨ），１１．９（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ0.91 (t, J = 7.4Hz, 3H), 1.63 (sext, J = 7.3Hz, 2H), 2.63 (t, J = 7.6Hz) , 2H), 6.93-7.03 (m, 2H), 7.23-7.30 (m, 3H), 7.37 (d, J = 8.6Hz, 1H), 7.47 (s) , 1H), 8.25 (s, 1H), 8.57 (s, 1H), 11.6 (br.s, NH), 11.9 (br.s, NH).
参考例６
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６－イソプロピルキノリン－２（１Ｈ）－オン（化合物３６） Reference example 6
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -6-isopropylquinoline-2 (1H) -one (Compound 36)
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１５ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４０ｍｇ、２－オキソ－６－イソプロピル－１，２－ジヒドロキノリン－３－カルバルデヒド３０ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物４６ｍｇ（収率９２％）を得た。 Dissolve 15 mg of 1H-benzimidazol-2-ylhydrazine in acetic acid (1 mL), add 40 mg of sodium acetate and 30 mg of 2-oxo-6-isopropyl-1,2-dihydroquinoline-3-carbaldehyde to 100 ° C. Stirred for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 46 mg (yield 92%) of a yellow solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ１．２６（ｄ，Ｊ＝６．６Ｈｚ，６Ｈ），２．９７（ｈｅｐｔ，Ｊ＝６．６Ｈｚ，１Ｈ），６．９１－７．０４（ｍ，２Ｈ），７．２６－７．３４（ｍ，３Ｈ），７．４３（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），７．５１（ｓ，１Ｈ），８．２５（ｓ，１Ｈ），８．５９（ｓ，１Ｈ），１１．６（ｂｒ．ｓ，ＮＨ），１１．９（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ1.26 (d, J = 6.6Hz, 6H), 2.97 (hept, J = 6.6Hz, 1H), 6.91-7.04 (m, 2H) ), 7.26-7.34 (m, 3H), 7.43 (d, J = 8.1Hz, 1H), 7.51 (s, 1H), 8.25 (s, 1H), 8. 59 (s, 1H), 11.6 (br.s, NH), 11.9 (br.s, NH).
実施例１１　
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－7－メトキシキノリン（化合物３７） Example 11
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methoxyquinoline (Compound 37)
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン２６ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、７－メトキシキノリン－３－カルバルデヒド３３ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄土色固体の生成物４２ｍｇ（収率７３％）を得た。 26 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (1 mL), 41 mg of sodium acetate and 33 mg of 7-methoxyquinoline-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 42 mg (yield 73%) of an ocher solid product.
１ＨＮＭＲ　（５００ＭＨｚ，d-DMSO）δ３．９４（ｓ，３Ｈ），６．９８－６．９９（ｍ，２Ｈ），７．２４－７．３０（ｍ，３Ｈ），７．４４（ｄ，Ｊ＝２．５Ｈｚ，１Ｈ），７．８９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１８（ｓ，１Ｈ），８．４２（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），９．４８（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），１１．６（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ3.94 (s, 3H), 6.98-6.99 (m, 2H), 7.24-7.30 (m, 3H), 7.44 (d, J = 2.5Hz, 1H), 7.89 (d, J = 8.8Hz, 1H), 8.18 (s, 1H), 8.42 (d, J = 2.0Hz, 1H), 9. 48 (d, J = 2.2 Hz, 1H), 11.6 (br. S, NH).
実施例１２
３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）エチル）－２－メチルキノリン（化合物３８） Example 12
3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) ethyl) -2-methylquinoline (Compound 38)
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇをエタノール（１ｍＬ）に溶解し、１－（２－メチルキノリン－3－イル）エタン－１－オン６４ｍｇを加えて、８０℃にて４時間撹拌した。析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、赤紫色固体の生成物７６ｍｇ（収率７８％）を得た。 52 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in ethanol (1 mL), 64 mg of 1- (2-methylquinoline-3-yl) ethane-1-one was added, and the mixture was stirred at 80 ° C. for 4 hours. The precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 76 mg (78% yield) of a reddish purple solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ２．７１（ｓ，３Ｈ），２．７７（ｓ，３Ｈ），６．８５－６．９６（ｍ，２Ｈ），７．１１－７．１２（ｍ，２Ｈ），７．６４（ｔ，J＝７．１Ｈｚ，１Ｈ），７．８４（ｄｔ，J＝１．５，７．１Ｈｚ），７．９６（ｔ，Ｊ＝８．６Ｈｚ，１Ｈ），８．０７（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），８．９２（ｓ，１Ｈ），１０．２　（ｓ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ2.71 (s, 3H), 2.77 (s, 3H), 6.85-6.96 (m, 2H), 7.11-7.12 (m, 3H) 2H), 7.64 (t, J = 7.1Hz, 1H), 7.84 (dt, J = 1.5, 7.1Hz), 7.96 (t, J = 8.6Hz, 1H), 8.07 (d, J = 8.1Hz, 1H), 8.92 (s, 1H), 10.2 (s, 1H).
実施例１３
３－（１－（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）エチル）－２－メチル－１，８－ナフチリジン（化合物３９） Example 13
3- (1- (2- (1H-benzo [d] imidazol-2-yl) hydrazono) ethyl) -2-methyl-1,8-naphthalene (Compound 39)
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇをエタノール（１ｍＬ）に溶解し、１－（２－メチル－１，８－ナフチリジリン－3－イル）エタン－１－オン６５ｍｇを加えて、８０℃にて４時間撹拌した。析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、赤紫色固体の生成物７４ｍｇ（収率６７％）を得た。 Dissolve 52 mg of 1H-benzimidazol-2-ylhydrazine in ethanol (1 mL), add 65 mg of 1- (2-methyl-1,8-naphthylidilin-3-yl) ethane-1-one, and at 80 ° C. The mixture was stirred for 4 hours. The precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 74 mg (yield 67%) of a reddish purple solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ２．７１（ｓ，３Ｈ），２．８１（ｓ，３Ｈ），６．８７－６．９７（ｍ，２Ｈ），７．１１－７．１８（ｍ，２Ｈ），７．６７（ｄｄ，J＝２．０，８．１Ｈｚ，１Ｈ），９．００（ｓ，１Ｈ），９．１２（ｄｄ，J＝２．０，８．１Ｈｚ，１Ｈ），１０．２　（ｓ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ2.71 (s, 3H), 2.81 (s, 3H), 6.87-6.97 (m, 2H), 7.11-7.18 (m, 3H) 2H), 7.67 (dd, J = 2.0, 8.1Hz, 1H), 9.00 (s, 1H), 9.12 (dd, J = 2.0, 8.1Hz, 1H), 10.2 (s, 1H).
実施例１４
３－（１－（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）エチル）－２－（トリフルオロメチル）－１，８－ナフチリジン（化合物４０） Example 14
3- (1- (2- (1H-benzo [d] imidazol-2-yl) hydrazono) ethyl) -2- (trifluoromethyl) -1,8-naphthylidine (Compound 40)
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン４４ｍｇをエタノール（１ｍＬ）に溶解し、１－（２－トリフルオロメチル－１，８－ナフチリジリン－3－イル）エタン－１－オン７２ｍｇを加えて、８０℃にて４時間撹拌した。析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、赤紫色固体の生成物７９ｍｇ（収率７１％）を得た。 Dissolve 44 mg of 1H-benzimidazol-2-ylhydrazine in ethanol (1 mL), add 72 mg of 1- (2-trifluoromethyl-1,8-naphthylidilin-3-yl) ethane-1-one, and add 72 mg to 80 ° C. Was stirred for 4 hours. The precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 79 mg (yield 71%) of a reddish purple solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ２．７４（ｓ，３Ｈ），６．８０－６．９２（ｍ，２Ｈ），７．０８－７．２３（ｍ，２Ｈ），７．８９（ｄｄ，J＝４．２，８．１Ｈｚ，１Ｈ），８．６５（ｄｄ，J＝２．０，８．３Ｈｚ，１Ｈ），９．１７（ｓ，１Ｈ），９．３１（ｄｄ，J＝２．０，４．２Ｈｚ，１Ｈ），１０．２　（ｓ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ2.74 (s, 3H), 6.80-6.92 (m, 2H), 7.08-7.23 (m, 2H), 7.89 (dd, dd, J = 4.2,8.1Hz, 1H), 8.65 (dd, J = 2.0, 8.3Hz, 1H), 9.17 (s, 1H), 9.31 (dd, J = 2) .0, 4.2Hz, 1H), 10.2 (s, 1H).
参考例７
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－１Ｈ－インダゾール（化合物４１） Reference example 7
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -1H-indazole (Compound 41)
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン１０４ｍｇを酢酸（２ｍＬ）に溶解し、酢酸ナトリウム８２ｍｇ、１Ｈ－インダゾール－３－カルバルデヒド５１ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、白色固体の生成物１５９ｍｇ（収率８８％）を得た。 104 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (2 mL), 82 mg of sodium acetate and 51 mg of 1H-indazole-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 159 mg (yield 88%) of a white solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ６．９５－７．０１（ｍ，２Ｈ），７．２５－７．３４（ｍ，２Ｈ），７．４５（ｄｄ，J＝１．０，６．９Ｈｚ，１Ｈ），７．５６（ｄ，J＝８．３Ｈｚ，１Ｈ），８．４１（ｓ，１Ｈ），８．６３（ｄ，J＝８．１Ｈｚ，１Ｈ），１１．４（ｂｒ．ｓ，ＮＨ），１３．３（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ6.95-7.01 (m, 2H), 7.25-7.34 (m, 2H), 7.45 (dd, J = 1.0, 6.9Hz) , 1H), 7.56 (d, J = 8.3Hz, 1H), 8.41 (s, 1H), 8.63 (d, J = 8.1Hz, 1H), 11.4 (br.s) , NH), 13.3 (br.s, NH).
参考例８
２－（２－（イミダゾール[１，５－a]ピリジン－３－イルメチレン）ヒドラジニル）－１Ｈ－ベンゾ[ｄ]イミダゾール（化合物４２） Reference example 8
2- (2- (Imidazole [1,5-a] Pyridine-3-ylmethylene) hydrazinyl) -1H-benzo [d] imidazole (Compound 42)
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、イミダゾール[１，５－a]ピリジン－３－カルボアルデヒド５１ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、緑色固体の生成物３６ｍｇ（収率３８％）を得た。 52 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (1 mL), 41 mg of sodium acetate and 51 mg of imidazole [1,5-a] pyridine-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. .. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 36 mg (yield 38%) of a green solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ６．９９－７．０１（ｍ，２Ｈ），７．０６（ｔ，J＝８．８Ｈｚ，１Ｈ），７．２２－７．３２（ｍ，２Ｈ），７．６１（ｓ，１Ｈ），７．４５（ｄ，J＝８．８Ｈｚ，１Ｈ），８．４１（ｓ，１Ｈ），９．４８（ｄ，J＝７．１Ｈｚ，１Ｈ），１１．６（ｓ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ6.99-7.01 (m, 2H), 7.06 (t, J = 8.8Hz, 1H), 7.22-7.32 (m, 2H), 7.61 (s, 1H), 7.45 (d, J = 8.8Hz, 1H), 8.41 (s, 1H), 9.48 (d, J = 7.1Hz, 1H), 11. 6 (s, 1H).
参考例９
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７－メチルキノリン－２（１Ｈ）－オン（化合物４３） Reference example 9
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methylquinoline-2 (1H) -one (Compound 43)
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、２－オキソ－７－メチル－１，２－ジヒドロキノリン－３－カルバルデヒド６６ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、茶色固体の生成物９９ｍｇ（収率８９％）を得た。 Dissolve 52 mg of 1H-benzimidazol-2-ylhydrazine in acetic acid (1 mL), add 41 mg of sodium acetate and 66 mg of 2-oxo-7-methyl-1,2-dihydroquinoline-3-carbaldehyde to 100 ° C. Stirred for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 99 mg (yield 89%) of a brown solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ２．３９（ｓ，３Ｈ），６．９６－６．９８（ｍ，２Ｈ），７．０７（ｄ，J＝８．３Ｈｚ，１Ｈ），７．１３（ｓ，１Ｈ），７．２４－７．２６（ｍ，２Ｈ），７．５９（ｄ，J＝８．１Ｈｚ，１Ｈ），８．２５（ｓ，１Ｈ），８．５３（ｓ，１Ｈ），１１．７（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ2.39 (s, 3H), 6.96-6.98 (m, 2H), 7.07 (d, J = 8.3Hz, 1H), 7.13 ( s, 1H), 7.24-7.26 (m, 2H), 7.59 (d, J = 8.1Hz, 1H), 8.25 (s, 1H), 8.53 (s, 1H) , 11.7 (br.s, NH).
実施例１５
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６，７－ジメチルキノリン（化合物４４） Example 15
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -6,7-dimethylquinoline (Compound 44)
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、６，７－ジメチルキノリン－３－カルバルデヒド６５ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物１０１ｍｇ（収率９２％）を得た。 52 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (1 mL), 41 mg of sodium acetate and 65 mg of 6,7-dimethylquinoline-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 101 mg (yield 92%) of a yellow solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ２．４２（ｓ，３Ｈ），２．４４（ｓ，３Ｈ），６．９６－７．０２（ｍ，２Ｈ），７．２４－７．２８（ｍ，２Ｈ），７．７０（ｓ，１Ｈ），７．８２（ｓ，１Ｈ），８．１８（ｓ，１Ｈ），８．３４（ｓ，１Ｈ），９．４５（ｓ，１Ｈ），１１．７（ｓ，１Ｈ）． 1 1 HNMR (500 MHz, d-DMSO) δ2.42 (s, 3H), 2.44 (s, 3H), 6.96-7.02 (m, 2H), 7.24-7.28 (m, 2H), 7.70 (s, 1H), 7.82 (s, 1H), 8.18 (s, 1H), 8.34 (s, 1H), 9.45 (s, 1H), 11. 7 (s, 1H).
実施例１６
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６，７－ジメトキシキノリン（化合物４５） Example 16
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -6,7-dimethoxyquinoline (Compound 45)
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、６，７－ジメトキシキノリン－３－カルバルデヒド７６ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物１１３ｍｇ（収率９２％）を得た。 52 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (1 mL), 41 mg of sodium acetate and 76 mg of 6,7-dimethoxyquinoline-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 113 mg (yield 92%) of a yellow solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ３．９３（ｓ，３Ｈ），３．９５（ｓ，３Ｈ），６．９６－７．０２（ｍ，２Ｈ），７．２４－７．２８（ｍ，２Ｈ），７．３２（ｓ，１Ｈ），７．４１（ｓ，１Ｈ），８．１７（ｓ，１Ｈ），８．３４（ｄ，J＝２．０Ｈｚ，１Ｈ），９．２９（ｄ，J＝２．０Ｈｚ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ3.93 (s, 3H), 3.95 (s, 3H), 6.96-7.02 (m, 2H), 7.24-7.28 (m, 2H), 7.32 (s, 1H), 7.41 (s, 1H), 8.17 (s, 1H), 8.34 (d, J = 2.0Hz, 1H), 9.29 (d) , J = 2.0Hz, 1H).
実施例１７
７－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－［１，３]ジオキソール[４，５－ｇ]キノリン（化合物４６） Example 17
7-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl)-[1,3] dioxol [4,5-g] quinoline (Compound 46)
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、１，３]ジオキソール[４，５－ｇ]キノリン－７－カルバルデヒド７０ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄緑色固体の生成物１１５ｍｇ（収率９９％）を得た。 Dissolve 52 mg of 1H-benzimidazol-2-ylhydrazine in acetic acid (1 mL), add 41 mg of sodium acetate, 1,3] dioxol [4,5 g] quinoline-7-carbaldehyde, and at 100 ° C. The mixture was stirred for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 115 mg (yield 99%) of a yellow-green solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ６．２２（ｓ，２Ｈ），６．９５－７．０２（ｍ，２Ｈ），７．２２－７．２９（ｍ，２Ｈ），７．３３（ｓ，１Ｈ），７．２８（ｓ，１Ｈ），８．１５（ｓ，１Ｈ），８．３３（ｓ，１Ｈ），９．２５（ｓ，１Ｈ），１１．７（ｓ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ6.22 (s, 2H), 6.95-7.02 (m, 2H), 7.22-7.29 (m, 2H), 7.33 (s, 1H), 7.28 (s, 1H), 8.15 (s, 1H), 8.33 (s, 1H), 9.25 (s, 1H), 11.7 (s, 1H).
実施例１８
８－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－２，３－ジヒドロ－[１，４]ジオキシノ[２，３－ｇ]キノリン（化合物４７） Example 18
8-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -2,3-dihydro- [1,4] dioxyno [2,3-g] quinoline (Compound 47)
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、２，３－ジヒドロ－[１，４]ジオキシノ[２，３－ｇ]キノリン－８－カルバルデヒド７５ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄緑色固体の生成物１１２ｍｇ（収率９３％）を得た。 Dissolve 52 mg of 1H-benzimidazol-2-ylhydrazine in acetic acid (1 mL) and add 41 mg of sodium acetate, 2,3-dihydro- [1,4] dioxyno [2,3-g] quinoline-8-carbaldehyde 75 mg. In addition, the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 112 mg (yield 93%) of a yellow-green solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ４．３９（ｓ，４Ｈ），６．９７－６．９９（ｍ，２Ｈ），７．２４－７．２６（ｍ，２Ｈ），７．３８（ｄ，J＝２．２Ｈｚ，１Ｈ），７．４１（ｄ，J＝２．０Ｈｚ，１Ｈ），８．１５（ｓ，１Ｈ），８．２８（ｓ，１Ｈ），９．３０（ｔ，J＝２．０Ｈｚ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ4.39 (s, 4H), 6.97-6.99 (m, 2H), 7.24-7.26 (m, 2H), 7.38 (d, J = 2.2Hz, 1H), 7.41 (d, J = 2.0Hz, 1H), 8.15 (s, 1H), 8.28 (s, 1H), 9.30 (t, J = 2.0Hz, 1H).
実施例１９
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７－クロロキノリン（化合物４８） Example 19
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-chloroquinoline (Compound 48)
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、７－クロロキノリン－３－カルバルデヒド６８ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物１０６ｍｇ（収率９４％）を得た。 52 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in acetic acid (1 mL), 41 mg of sodium acetate and 68 mg of 7-chloroquinoline-3-carbaldehyde were added, and the mixture was stirred at 100 ° C. for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 106 mg (yield 94%) of a yellow solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ６．９９－７．００（ｍ，２Ｈ），７．２５－７．２７（ｍ，２Ｈ），７．６７（ｄｄ，J＝２．２，８．８Ｈｚ，１Ｈ），８．０３（ｄ，J＝８．８Ｈｚ，１Ｈ），８．１０（ｄ，J＝１．７Ｈｚ，１Ｈ），８．２１（ｓ，１Ｈ），８．５３（ｓ，１Ｈ），９．６１（ｄ，J＝２．０Ｈｚ，１Ｈ）． 1 1 HNMR (500MHz, d-DMSO) δ6.99-7.00 (m, 2H), 7.25-7.27 (m, 2H), 7.67 (dd, J = 2.2,8.8Hz) , 1H), 8.03 (d, J = 8.8Hz, 1H), 8.10 (d, J = 1.7Hz, 1H), 8.21 (s, 1H), 8.53 (s, 1H) ), 9.61 (d, J = 2.0Hz, 1H).
比較例１（非特許文献３に記載の化合物：化合物番号５２５８４１）
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－２－クロロ－７－メトキシキノリン（化合物４９） Comparative Example 1 (Compound described in Non-Patent Document 3: Compound No. 525841)
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -2-chloro-7-methoxyquinoline (Compound 49)
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇをメタノール（１ｍＬ）に溶解し、２－クロロ－７－メトキシキノリン－３－カルバルデヒド７６ｍｇを加えて、６０℃にて４時間撹拌した。析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物１０１ｍｇ（収率８２％）を得た。 52 mg of 1H-benzimidazol-2-ylhydrazine was dissolved in methanol (1 mL), 76 mg of 2-chloro-7-methoxyquinoline-3-carbaldehyde was added, and the mixture was stirred at 60 ° C. for 4 hours. The precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 101 mg (yield 82%) of a yellow solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ３．８４（ｓ，３Ｈ），６．８４（ｄ，J＝２．０Ｈｚ，１Ｈ），６．８７（ｄ，J＝８．８Ｈｚ，１Ｈ），６．９４－７．０１（ｍ，２Ｈ），７．２３－７．２９（ｍ，２Ｈ），７．６０（ｄ，J＝８．６Ｈｚ，１Ｈ），８．２３（ｓ，１Ｈ），８．５２（ｓ，１Ｈ），１１．６（ｂｒ．ｓ，ＮＨ），１１．９（ｂｒ．ｓ，ＮＨ）． 1 1 HNMR (500MHz, d-DMSO) δ3.84 (s, 3H), 6.84 (d, J = 2.0Hz, 1H), 6.87 (d, J = 8.8Hz, 1H), 6. 94-7.01 (m, 2H), 7.23-7.29 (m, 2H), 7.60 (d, J = 8.6Hz, 1H), 8.23 (s, 1H), 8. 52 (s, 1H), 11.6 (br.s, NH), 11.9 (br.s, NH).
実施例２０
３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７，８－ジヒドロ－６Ｈ－シクロペンタ[ｇ]キノリン（化合物５０） Example 20
3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7,8-dihydro-6H-cyclopentane [g] quinoline (Compound 50)
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
１Ｈ－ベンゾイミダゾール－２－イルヒドラジン５２ｍｇを酢酸（１ｍＬ）に溶解し、酢酸ナトリウム４１ｍｇ、７，８－ジヒドロ－６Ｈ－シクロペンタ[ｇ]キノリン－３－カルバルデヒド６９ｍｇを加えて、１００℃にて４時間撹拌した。反応液に氷、炭酸カリウム水溶液を加えて出てきた析出物をろ過、酢酸エチルエステルとヘキサンの混合溶液で洗浄し、黄色固体の生成物９６ｍｇ（収率８４％）を得た。 Dissolve 52 mg of 1H-benzimidazol-2-ylhydrazine in acetic acid (1 mL), add 41 mg of sodium acetate and 69 mg of 7,8-dihydro-6H-cyclopentane [g] quinoline-3-carbaldehyde, and at 100 ° C. The mixture was stirred for 4 hours. Ice and an aqueous potassium carbonate solution were added to the reaction solution, and the resulting precipitate was filtered and washed with a mixed solution of ethyl acetate ester and hexane to obtain 96 mg (yield 84%) of a yellow solid product.
１ＨＮＭＲ（５００ＭＨｚ，d-DMSO）δ１．５９－１．６３（ｍ，２Ｈ），２．１０－２．１３（ｍ，２Ｈ），３．０３－３．０８（ｍ，２Ｈ），６．９７－６．９９（ｍ，２Ｈ），７．２４－７．２６（ｍ，２Ｈ），７．７７（ｓ，１Ｈ），７．８４（ｓ，１Ｈ），８．２１（ｓ，１Ｈ），８．３８（ｄ，J＝２．０Ｈｚ，１Ｈ），９．４１（ｓ，１Ｈ）． 1 1 HNMR (500 MHz, d-DMSO) δ1.59-1.63 (m, 2H), 2.10-2.13 (m, 2H), 3.03-3.08 (m, 2H), 6. 97-6.99 (m, 2H), 7.24-7.26 (m, 2H), 7.77 (s, 1H), 7.84 (s, 1H), 8.21 (s, 1H) , 8.38 (d, J = 2.0Hz, 1H), 9.41 (s, 1H).
［抗マラリア活性に関する試験例］
試験例１：抗ヘモゾイン活性試験
　以下の方法に従って、抗へモゾイン活性試験を行い、化合物１～２０の活性評価を行った。
（試験方法）
（１）試薬調整
ａ．ヘミン溶液（１２ｍＭヘミンストック溶液及び使用時の溶液）：
　１２ｍＭヘミンストック溶液を、７．２８ｍｇのヘミンを１ｍＬのＤＭＳＯに溶解し、０．２μｍ孔径のフィルターを通して準備した。調整後の溶液は４°Ｃで最長１か月保存可能である。０．２Ｍ酢酸バッファー（ｐＨ４．８）は、１．６４ｇのｓｏｄｉｕｍ　ａｃｅｔａｔｅを１００ｍＬの超純水に溶解し、ＨＣｌの添加によりｐＨを調整して準備した。ヘミン溶液は、用時調製で、１２．８５μＬのヘミンストック溶液を１ｍＬの０．２Ｍ酢酸バッファーに添加することにより調整した。
ｂ．１％Ｎｏｎｉｄｅｔ　Ｐ－４０（ＮＰ－４０）：
　１％ＮＰ－４０は、１ｍＬＮＰ－４０溶液を１００ｍＬの超純水で希釈することにより準備した。抗へモゾイン試験に使用時には最終濃度０．００５％で使用した。
ｃ．５０％ピリジン（２０ｍＭＨＥＰＥＳバッファーに溶解）：
　４．７６６ｍｇのＨＥＰＥＳを１ｍＬの超純水に溶解し、２０ｍＭＨＥＰＥＳバッファーを用意した。５０％ピリジンは、ピリジンを等量の２０ｍＭＨＥＰＥＳと合わせることにより作成した。
（２）抗へモゾイン試験実施方法
　先ず、１０μＬの０．００５％ＮＰ－４０を３８４ウェルプレートに準備した。ここに５μＬのＤＭＳＯに溶解された試験化合物（最終濃度４５４μＭ）、２０μＬのヘミン溶液（最終濃度１５４μＭ）、２０μＬの超純水（純水装置を用いて準備したもの）を添加し、３７℃でオーバーナイト（約１６時間）静置した。
　その後、ここに１０μＬの５０％ピリジン（２０ｍＭＨＥＰＥＳバッファーに希釈）を添加した。慎重にシェーカーを用いて１５分間振とうした。各ウェルに７μＬの１００％アセトンを添加し、４０５ｎｍの吸光度を測定した。Ｃｈｌｏｒｏｑｕｉｎｅ（クロロキニン）（ＣＱ）とヘミンのみ（ＮＰ－４０を含まない）ウェルを陽性コントロール、ＤＭＳＯとＮＰ－４０のみ（ヘミンを含まない）ウェルを陰性コントロールとして準備された。各試験化合物が添加されたウェル（ヘミン、ＮＰ－４０の両者を含む）の吸光度が、上記コントロールの吸光度と比較され、へモゾイン阻害率が計算された。
（３）抗へモゾイン活性試験の原理
　通常、ｉｎ　ｖｉｔｒｏにおいてヘミンは、へモゾインへと変化しないが、ＮＰ－４０の存在下では、ゆっくりと時間をかけながらこの変化が生じる。抗へモゾイン活性を持つ化合物は、この反応を阻害することが出来るため、本試験を用いて各化合物の抗へモゾイン活性を測定することが可能である。試験化合物添加後のオーバーナイトのインキュベーション後に、ピリジンを添加し、遊離ヘミン濃度を測定することにより抗へモゾイン活性を測定する。その際、へモゾイン合成阻害が生じている場合には、ＯＤ値は１．８－２．２を示すが、生じていない場合には０．５－０．６程度となる。
（４）抗へモゾイン活性試験結果の評価
　試験化合物によるへモゾイン阻害活性は、へモゾイン阻害率という形で表され、試験化合物を阻害活性を示す陽性ヒットとみなす基準は、へモゾイン阻害率が、陰性コントロール（ｈｅｍｅ＋ＤＭＳＯ／ｂｕｆｆｅｒ）の結果＋３ＳＤ（標準偏差値）以上とした。 [Test example on antimalarial activity]
Test Example 1: Anti-hemozoin activity test An anti-hemozoin activity test was conducted according to the following method to evaluate the activity of compounds 1 to 20.
(Test method)
(1) Reagent preparation a. Hemin solution (12 mM hemin stock solution and solution at the time of use):
A 12 mM hemin stock solution was prepared by dissolving 7.28 mg of hemin in 1 mL of DMSO and passing through a 0.2 μm pore size filter. The adjusted solution can be stored at 4 ° C for up to 1 month. 0.2M acetate buffer (pH 4.8) was prepared by dissolving 1.64 g of sodium acetate in 100 mL of ultrapure water and adjusting the pH by adding HCl. Hemin solution was prepared at the time of use by adding 12.85 μL of hemin stock solution to 1 mL of 0.2 M acetate buffer.
b. 1% Nonidet P-40 (NP-40):
1% NP-40 was prepared by diluting a 1 mL NP-40 solution with 100 mL of ultrapure water. When used in the anti-hemozoin test, it was used at a final concentration of 0.005%.
c. 50% Pyridine (dissolved in 20 mM HEPES buffer):
4.766 mg of HEPES was dissolved in 1 mL of ultrapure water to prepare a 20 mM HEPES buffer. 50% pyridine was made by combining pyridine with an equal amount of 20 mM HEEPS.
(2) Method for conducting anti-hemozoine test First, 10 μL of 0.005% NP-40 was prepared in a 384-well plate. To this, a test compound dissolved in 5 μL DMSO (final concentration 454 μM), 20 μL hemin solution (final concentration 154 μM), and 20 μL ultrapure water (prepared using a pure water device) were added, and the temperature was 37 ° C. It was allowed to stand overnight (about 16 hours).
Then, 10 μL of 50% pyridine (diluted in 20 mM HEEPES buffer) was added thereto. Carefully shake with a shaker for 15 minutes. 7 μL of 100% acetone was added to each well, and the absorbance at 405 nm was measured. Chloroquine (CQ) and hemin-only (NP-40-free) wells were prepared as positive controls, and DMSO and NP-40-only (hemin-free) wells were prepared as negative controls. The absorbance of the well (including both hemin and NP-40) to which each test compound was added was compared with the absorbance of the above control, and the hemozoin inhibition rate was calculated.
(3) Principle of anti-hemozoin activity test Normally, hemin does not change to hemozoin in vitro, but in the presence of NP-40, this change occurs slowly over time. Since a compound having anti-hemozoin activity can inhibit this reaction, it is possible to measure the anti-hemozoin activity of each compound using this test. After overnight incubation after addition of the test compound, pyridine is added and the antihemozoin activity is measured by measuring the free hemin concentration. At that time, when hemozoin synthesis inhibition occurs, the OD value shows 1.8-2.2, but when it does not occur, it is about 0.5-0.6.
(4) Evaluation of anti-hemozoin activity test results The hemozoin inhibitory activity of the test compound is expressed in the form of the hemozoin inhibition rate, and the criterion for regarding the test compound as a positive hit showing the inhibitory activity is the hemozoin inhibition rate. The result of the negative control (heme + DMSO / buffer) was + 3SD (standard deviation value) or more.
　本試験は、主として多数の化合物の一次スクリーニングの目的で行われた。
　ここでの評価結果をもとに、前記の化合物リスト中の化合物１～２０について、以下に従って抗マラリア活性（試験例２）および細胞毒性（試験例３）を評価した。 This study was conducted primarily for the purpose of primary screening of a large number of compounds.
Based on the evaluation results here, the antimalarial activity (Test Example 2) and cytotoxicity (Test Example 3) of the compounds 1 to 20 in the above compound list were evaluated according to the following.
試験例２：抗マラリア活性の評価
　次に、試験例１での評価においてへモゾイン阻害活性が確認された化合物をｉｎ　ｖｉｔｒｏ抗マラリアアッセイで評価した。方法は以前の報告（Ｊｏｈｎｓｏｎ　ｅｔ　ａｌ．，　２００７；　Ｓｍｉｌｋｓｔｅｉｎ，　Ｓｒｉｗｉｌａｉｊａｒｏｅｎ，　Ｋｅｌｌｙ，　Ｗｉｌａｉｒａｔ，　＆　Ｒｉｓｃｏｅ，　２００４）に準じた。
　具体的には、培養液（ＲＰＭＩ　１６４０）に以下を添加し、ＤＭＳＯを０．０５％、ｐＨを７．３～７．４に調整する。
・０．０２５ｍｇ／ｍｌゲンタマイシン（ｇｅｎｔａｍｉｃｉｎ）
・０．０１ｍＭヒポキサンチン（ｈｙｐｏｘａｎｔｈｉｎｅ）
・２３．８ｍＭＮａＨＣＯ３・１１ｍＭグルコース（ｇｌｕｃｏｓｅ）
　０．５％ａｌｂｕｍａｘ　ＩＩに評価する化合物を１０μＭになるよう溶解し、９６穴クリアボトムプレートの３ウェルに５０μＬずつ準備した（陽性コントロールとしてＡｒｔｅｓｕｎａｔｅとＣｈｌｏｒｏｑｕｉｎｅを、陰性コントロールとしては化合物を含まずＤＭＳＯ濃度が同じ溶液を準備した。）。
　続いて、各ウェルにクロロキン感受性熱帯熱マラリア株（３Ｄ７Ａ）、あるいはクロロキン耐性熱帯熱マラリア株（Ｄｄ２）を感染させた感染赤血球（０．７５％寄生虫血症；２％ヘマトクリット）溶液５０μＬを添加した。プレートを、混合ガス（５％ＣＯ２、５％Ｏ２、および９０％Ｎ２）存在下３７℃で、４８時間インキュベートした。ここに、ＳＹＢＲ　ＧｒｅｅｎＩを含む１００μＬの溶液を添加し、１時間振とうし、赤血球破砕と原虫ＤＮＡの染色を行った。蛍光強度（Ｅｘ：４８５ｎｍ、Ｅｍ：５１５ｎｍ）を原虫量の指標として測定した。
　続いて、上記と同様の実験を異なる濃度の化合物を用いて行った。この結果から５０％阻害濃度（ＩＣ５０）値を計算した。具体的には、ＧｒａｐｈＰａｄ　Ｐｒｉｓｍ　５（ＧｒａｐｈＰａｄ　Ｓｏｆｔｗａｒｅ、Ｉｎｃ．）を使用して計算を行った。 Test Example 2: Evaluation of antimalarial activity Next, the compounds whose hemozoin inhibitory activity was confirmed in the evaluation in Test Example 1 were evaluated by an in vitro antimalarial assay. The method was based on a previous report (Johnson et al., 2007; Smilestein, Sriwijaroen, Kelly, Williamat, & Riskoe, 2004).
Specifically, the following is added to the culture solution (RPMI 1640) to adjust DMSO to 0.05% and pH to 7.3 to 7.4.
0.025 mg / ml gentamicin
-0.01 mM hypoxanthine (hypoxanthine)
· 23.8mMNaHCO 3 · 11mM glucose (glucose)
The compound to be evaluated to 0.5% albumax II was dissolved to 10 μM, and 50 μL was prepared in 3 wells of a 96-well clear bottom plate (Artesunate and Chloroquine as positive controls, compound-free DMSO concentration as negative controls). Prepared the same solution.)
Subsequently, 50 μL of an infected erythrocyte (0.75% parasitemia; 2% hematocrit) solution infected with a chloroquine-sensitive falciparum malaria strain (3D7A) or a chloroquine-resistant falciparum malaria strain (Dd2) was added to each well. bottom. The plates were incubated for 48 hours at 37 ° C. in the presence of a mixed gas (5% CO 2 , 5% O 2 and 90% N 2). A 100 μL solution containing SYBR Green I was added thereto, and the mixture was shaken for 1 hour to disrupt erythrocytes and stain protozoan DNA. Fluorescence intensity (Ex: 485 nm, Em: 515 nm) was measured as an index of the amount of protozoan.
Subsequently, the same experiment as above was performed using compounds having different concentrations. From this result, a 50% inhibitory concentration (IC 50 ) value was calculated. Specifically, the calculation was performed using GraphPad Prism 5 (GraphPad Software, Inc.).
試験例３：細胞毒性の評価
　次いで、細胞毒性試験を行った。
　実験前日にＡｄｕｌｔ　ｍｏｕｓｅ　ｂｒａｉｎ　（ＡＭＢ）細胞を各ウェルに３０００個／ｍＬになるように調整した細胞液を、各ウェルに１００μＬ加えて２４時間、３７℃、５％ＣＯ２のインキュベーターで培養した。
　実験当日、まず化合物調整用プレートにコントロールとなるアーテスネート（Ａｒｔｅｓｕｎａｔｅ）とクロロキン（Ｃｈｌｏｒｏｑｕｉｎｅ）及び試験化合物の希釈列を作成した。前日に細胞を播種した実験用プレートの各ウェルから接着した細胞のみが底に残るように培養液を吸引し、化合物調整用プレートから化合物溶液を各ウェルへ１００μＬ加えた。３７℃、５％ＣＯ２下で４８時間化合物処理をした。その後、ａｌａｍａｒＢｌｕｅを各ウェルに１０μＬ加え、２時間反応させ蛍光強度（Ｅｘ：５４４ｎｍ、Ｅｍ：５９０ｎｍ）を測定した。その結果を用いて各化合物の５０％阻害濃度（「Ｈｚ阻害率」と称する場合がある）（ＣＣ５０）を算出した。 Test Example 3: Evaluation of Cytotoxicity Next, a cytotoxicity test was performed.
On the day before the experiment, 100 μL of extracellular fluid adjusted to 3000 cells / mL of Adult mouse brain (AMB) cells was added to each well, and the cells were cultured in an incubator at 37 ° C. and 5% CO 2 for 24 hours.
On the day of the experiment, first, a dilution sequence of the control Artesunate, Chloroquine, and the test compound was prepared on the compound preparation plate. The culture solution was aspirated from each well of the experimental plate in which the cells were seeded the day before so that only the adhered cells remained at the bottom, and 100 μL of the compound solution was added to each well from the compound preparation plate. The compound treatment was carried out at 37 ° C. under 5% CO 2 for 48 hours. Then, 10 μL of alamarBlue was added to each well, and the mixture was reacted for 2 hours to measure the fluorescence intensity (Ex: 544 nm, Em: 590 nm). Using the results, a 50% inhibition concentration (sometimes referred to as "Hz inhibition rate") (CC 50 ) of each compound was calculated.
　以上の試験例２および３での試験結果を以下の表１に示す。 The test results in Test Examples 2 and 3 above are shown in Table 1 below.
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
　以上の化合物１～２０についての評価結果に基づいて、化合物２１～５０を新たに合成し（上記の参考例１～９、実施例１～２０、比較例１）、それらの抗マラリア活性を評価した。試験結果を以下の表２に示す。 Based on the above evaluation results for compounds 1 to 20, compounds 21 to 50 were newly synthesized (Reference Examples 1 to 9, Examples 1 to 20, Comparative Example 1 above), and their antimalarial activities were evaluated. bottom. The test results are shown in Table 2 below.
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
試験例４：マウスマラリアモデルを用いた抗マラリア活性の測定
　マウスマラリアモデルを用いた抗マラリア薬効評価試験を行った。Ｃ５７ＢＬ／６マウスにマウスマラリアＰｌａｓｍｏｄｉｕｍ　ｙｏｅｌｉｉ　１ｘ１０４個を感染させた。同日から試験対象群（化合物１、１９、２０）を１日２回の（３０ｍｇ／ｋｇ／ｄａｙ）（ＥｔＯＨ：ポリソルベート８０：クエン酸＝１００：８９６：４）溶液を腹腔内投与した（ｎ＝５）。感染後、３日、４日、５日後の血液中の赤血球のＰｌａｓｍｏｄｉｕｍ　ｙｏｅｌｉｉ感染率を評価した。陽性対照群として、１０ｍｇ／ｋｇ／ｄａｙのクロロキン（ＣＱ）の１日２回の経口投与を実施した。コントロール群には、ＣＱ投与に用いたのと同量の超純水（ＭＱ）投与を行った。
　試験結果を図１に示す。本試験結果より、化合物１、１９および２０が優れた抗マラリア活性を有することが明らかである。 Test Example 4: Measurement of antimalarial activity using a mouse malaria model An antimalarial drug efficacy evaluation test was conducted using a mouse malaria model. C57BL / 6 mice were infected with 4 mouse malaria Plasmodium yoelii 1x10. From the same day, the test subject group (Compounds 1, 19, 20) was intraperitoneally administered with a (30 mg / kg / day) (EtOH: polysorbate 80: citric acid = 100: 896: 4) solution twice daily. 5). The Plasmodium yoelii infection rate of erythrocytes in blood 3 days, 4 days, and 5 days after infection was evaluated. As a positive control group, 10 mg / kg / day of chloroquine (CQ) was orally administered twice daily. The control group was administered the same amount of ultrapure water (MQ) as that used for CQ administration.
The test results are shown in FIG. From the results of this test, it is clear that compounds 1, 19 and 20 have excellent antimalarial activity.
試験例５：マウスマラリアモデルを用いた抗マラリア活性の測定
　マウスマラリアモデルを用いた抗マラリア薬効評価試験を行った。Ｃ５７ＢＬ／６マウスにマウスマラリアＰｌａｓｍｏｄｉｕｍ　ｙｏｅｌｉｉ　１ｘ１０４個を感染させた。同日から試験対象群（化合物４４、化合物４４塩酸塩）を１日２回の（３０ｍｇ／ｋｇ／ｄａｙ）（ＥｔＯＨ：ポリソルベート８０：クエン酸＝１００：８９６：４）溶液を腹腔内投与した（ｎ＝５）。感染後、３日、４日、５日、６日後の血液中の赤血球のＰｌａｓｍｏｄｉｕｍ　ｙｏｅｌｉｉ感染率を評価した。陽性対照群として、１０ｍｇ／ｋｇ／ｄａｙのクロロキン（ＣＱ）の１日２回の経口投与を実施した。コントロール群には、ＣＱ投与に用いたのと同量の超純水（ＭＱ）投与を行った。
　試験結果を図２に示す。本試験結果より、化合物４４、その塩酸塩が優れた抗マラリア活性を有することが明らかである。 Test Example 5: Measurement of antimalarial activity using a mouse malaria model An antimalarial drug efficacy evaluation test was conducted using a mouse malaria model. C57BL / 6 mice were infected with 4 mouse malaria Plasmodium yoelii 1x10. From the same day, the test subject group (Compound 44, Compound 44 hydrochloride) was intraperitoneally administered with a (30 mg / kg / day) (EtOH: polysorbate 80: citric acid = 100: 896: 4) solution twice daily. = 5). The Plasmodium yoelii infection rate of erythrocytes in blood 3 days, 4 days, 5 days, and 6 days after infection was evaluated. As a positive control group, 10 mg / kg / day of chloroquine (CQ) was orally administered twice daily. The control group was administered the same amount of ultrapure water (MQ) as that used for CQ administration.
The test results are shown in FIG. From the results of this test, it is clear that Compound 44 and its hydrochloride salt have excellent antimalarial activity.
　本発明により、マラリアの予防または治療に有用な、優れた抗マラリア活性（特に、抗クロロキン耐性株に対する抗マラリア活性）を有するベンゾイミダゾール誘導体が提供される。 INDUSTRIAL APPLICABILITY The present invention provides a benzimidazole derivative having excellent antimalarial activity (particularly, antimalarial activity against an antimalarial resistant strain) useful for the prevention or treatment of malaria.
　本出願は、日本で出願された特願２０２０－６０５１５（出願日：２０２０年３月３０日）を基礎としており、その内容は本明細書に全て包含されるものである。 This application is based on Japanese Patent Application No. 2020-60515 (application date: March 30, 2020), the contents of which are all included in the present specification.

Claims (27)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ｒは、式（Ｉａ）：
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒ1は、水素原子、または
    置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
    Ｒａは、水素原子、または
    ハロゲン原子およびヒドロキシ基以外の基から選択される置換基を示し、
    環Ａは、ピリジン環を示し、
    環Ｂは、置換されていてもよいベンゼン環または置換されていてもよい５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい。）を示し、
    ｐは、１～２の整数を示し、および
    ＊は、ベンゾイミダゾール環への結合位置を示す。）
    で示される基；
    式（Ｉｂ）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、環Ｃは、さらに置換されていてもよい５～７員窒素含有複素環を示し、
    Ｒ２は、置換されていてもよい窒素含有複素環基を示し、
    ＊は、ベンゾイミダゾール環への結合位置を示す。）
    で示される基；
    式（Ｉｃ）：－ＮＨ－ＣＯ－Ｒ３
    （式中、Ｒ３は、置換されていてもよい複素環基、置換されていてもよいアリール基または
    式：－Ｌ１－（Ｓ）ｍ－Ｑ１
    （式中、Ｌ１は、結合を示し、
    ｍは、０または１の整数を示し、および
    Ｑ１は、置換されていてもよい複素環基または置換されていてもよいアリール基を示す。）
    を示す。）
    で示される基；または
    式（Ｉｄ）：－ＣＯ－ＮＨ－Ｒ４
    （式中、Ｒ４は、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
    （式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
    ｎは０または１の整数を示し、および
    Ｑ２は、置換されていてもよい複素環基または置換されていてもよいアリール基を示す。）
    を示す。）
    で示される基を示し、および
    Ｘは、水素原子またはハロゲン原子を示す。］
    で表される化合物またはその塩。     Equation (I):
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, R is the formula (Ia):
    Figure JPOXMLDOC01-appb-C000002
     (In the formula, R 1 represents a hydrogen atom or an optionally substituted (C 1- C 6 ) alkyl group.
    Ra represents a substituent selected from a hydrogen atom or a group other than a halogen atom and a hydroxy group.
    Ring A represents a pyridine ring.
    Ring B resides on an optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle). The two substituents that form a ring may form a ring with the carbon atoms that are attached to each other and to which they are attached.)
    p indicates an integer of 1 to 2, and * indicates the position of binding to the benzimidazole ring. )
    Group indicated by;
    Equation (Ib):
    Figure JPOXMLDOC01-appb-C000003
     (In the formula, ring C represents a 5- to 7-membered nitrogen-containing heterocycle which may be further substituted.
    R 2 represents a nitrogen-containing heterocyclic group that may be substituted.
    * Indicates the binding position to the benzimidazole ring. )
    Group indicated by;
    Formula (Ic): -NH-CO-R 3
    (In the formula, R 3 is a optionally substituted heterocyclic group, an optionally substituted aryl group or the formula: −L 1 − (S) m −Q 1
    (In the equation, L 1 indicates a bond,
    m is an integer of 0 or 1, and Q 1 is, represents an aryl group which may be also heterocyclic group or a substituted substituted. )
    Is shown. )
    Group represented by; or formula (Id): -CO-NH-R 4
    (In the formula, R 4 is the formula: -L 2- (NH) n- Q 2
    (In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
    n represents an integer of 0 or 1, and Q 2 represents an aryl group which may be also heterocyclic group or a substituted substituted. )
    Is shown. )
    Indicates a group represented by, and X indicates a hydrogen atom or a halogen atom. ]
    A compound represented by or a salt thereof.
  2. 　Ｒａが、水素原子、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、またはニトロ基を示し；
    環Ｂが、ヒドロキシ基、
    ハロゲン原子、
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
    ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
    （Ｃ６－Ｃ１０）アリール基、
    １～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
    ニトロ基
    から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環
    （ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環を形成していてもよい）
    を示し；
    環Ｃが、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し；
    Ｒ１が、水素原子、または
    オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
    （式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
    Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）
    で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し；
    Ｒ２が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し；
    Ｒ３が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
    ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基、または
    式：－Ｌ１－（Ｓ）ｍ－Ｑ１
    （式中、Ｌ１は、結合を示し、
    ｍは、０または１の整数を示し、および
    Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
    ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
    を示し；
    Ｒ４が、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
    （式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
    ｎは０または１の整数を示し、および
    Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、またはハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
    を示す、請求項１に記載の化合物またはその塩。     Ra may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl. ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, or nitro group;
    Ring B is a hydroxy group,
    Halogen atom,
    It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
    It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
    Di ((C 1 -C 6) alkyl) amino group,
    (C 6- C 10 ) Aryl group,
    A benzene ring that may be substituted with 1 to 3 substituents selected from an arylamino group (C 6- C 10 ) and a nitro group, which may be substituted with 1 to 3 halogen atoms, respectively. , Or a 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in a benzene ring or a 5- to 6-membered aromatic heterocycle are the carbons to which they are bonded together. Along with the atom, it may form a 5- to 7-membered ring which may contain 1 to 3 oxygen atoms as ring-constituting atoms.)
    Shows;
    Ring C represents a (C 1 -C 6) alkyl group and 1-3 further optionally substituted 5-7 membered nitrogen-containing heterocycle substituent selected from oxo group;
    R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
    (In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.)
    In optionally substituted with one to three substituents selected from the group represented (C 1 -C 6) represents an alkyl group;
    R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Shows 5-10-membered nitrogen-containing heterocyclic groups optionally substituted with substituents;
    R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 A 5- to 10-membered heterocyclic group which may be substituted with a substituent,
    Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1
    (In the equation, L 1 indicates a bond,
    m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) An alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ). Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an arylamino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
    Shows;
    R 4 is the formula: -L 2- (NH) n- Q 2
    (In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
    n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6). ) Alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
    The compound according to claim 1 or a salt thereof.
  3. 　Ｒａが、水素原子、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、またはニトロ基を示し；
    環Ｂが、ヒドロキシ基、
    ハロゲン原子、
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基、
    ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、
    （Ｃ６－Ｃ１０）アリール基、
    １～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、および
    ニトロ基
    から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環、または５～６員芳香族複素環
    を示し；
    環Ｃが、（Ｃ１－Ｃ６）アルキル基およびオキソ基から選択される１～３個の置換基でさらに置換されていてもよい５～７員窒素含有複素環を示し；
    Ｒ１が、水素原子、または
    オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
    （式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
    Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）
    で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し；
    Ｒ２が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基を示し；
    Ｒ３が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員複素環基、
    ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基、または
    式：－Ｌ１－（Ｓ）ｍ－Ｑ１
    （式中、Ｌ１は、結合を示し、
    ｍは、０または１の整数を示し、および
    Ｑ１は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、または
    ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
    を示し；
    Ｒ４が、式：―Ｌ２－（ＮＨ）ｎ－Ｑ２
    （式中、Ｌ２は、（Ｃ１－Ｃ６）アルキレン基を示し、
    ｎは０または１の整数を示し、および
    Ｑ２は、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～１０員窒素含有複素環基、またはハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ６－Ｃ１０）アリール基を示す。）
    を示す、請求項１または２に記載の化合物またはその塩。     Ra may be substituted with a hydrogen atom, 1 to 3 halogen atoms, an (C 1- C 6 ) alkyl group, a (C 1- C 6 ) alkoxy group, a di ((C 1- C 6 ) alkyl. ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, or nitro group;
    Ring B is a hydroxy group,
    Halogen atom,
    It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkyl group,
    It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) Alkoxy group,
    Di ((C 1 -C 6) alkyl) amino group,
    (C 6- C 10 ) Aryl group,
    A benzene ring optionally substituted with 1 to 3 substituents (C 6- C 10 ) and 1 to 3 substituents selected from the nitro group, respectively. , Or a 5- to 6-membered aromatic heterocycle;
    Ring C represents a (C 1 -C 6) alkyl group and 1-3 further optionally substituted 5-7 membered nitrogen-containing heterocycle substituent selected from oxo group;
    R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
    (In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.)
    In optionally substituted with one to three substituents selected from the group represented (C 1 -C 6) represents an alkyl group;
    R 2 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 Shows 5-10-membered nitrogen-containing heterocyclic groups optionally substituted with substituents;
    R 3 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group. , optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, a nitro group, and (C 1 -C 6) is selected from alkylenedioxy group 1-3 A 5- to 10-membered heterocyclic group which may be substituted with a substituent,
    Halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, 1-3 Substituent with 1-3 substituents selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group optionally substituted with 1 halogen atom May be (C 6- C 10 ) aryl group, or formula: -L 1- (S) m- Q 1
    (In the equation, L 1 indicates a bond,
    m represents an integer of 0 or 1, and Q 1 is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl). Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) archi A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the rangeoxy groups, or halogen atoms, (C 1- C 6 ) alkyl groups, (C 1- C). 6 ) An alkoxy group, a di ((C 1- C 6 ) alkyl) amino group, a (C 6- C 10 ) aryl group, which may be substituted with 1 to 3 halogen atoms (C 6- C 10 ). Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an arylamino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
    Shows;
    R 4 is the formula: -L 2- (NH) n- Q 2
    (In the formula, L 2 represents a (C 1- C 6 ) alkylene group.
    n represents an integer of 0 or 1, and Q 2 is a halogen atom, (C 1 -C 6) alkyl group, (C 1 -C 6) alkoxy groups, di ((C 1 -C 6) alkyl) amino Group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) alkylene di. A 5- to 10-membered nitrogen-containing heterocyclic group, which may be substituted with 1 to 3 substituents selected from the oxy group, or a halogen atom, an (C 1- C 6 ) alkyl group, (C 1- C 6). ) Alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, may be substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl Indicates a (C 6- C 10 ) aryl group that may be substituted with 1 to 3 substituents selected from an amino group, a nitro group, and a (C 1- C 6) alkylene dioxy group. )
    The compound according to claim 1 or 2, or a salt thereof.
  4. 　Ｘが、水素原子を示し、および
    Ｒ１が、水素原子または（Ｃ１－Ｃ６）アルキル基を示す、請求項１～３のいずれか一項に記載の化合物またはその塩。     X is a hydrogen atom, and R 1 is a hydrogen atom or a (C 1 -C 6) alkyl group, the compound or salt thereof according to any one of claims 1-3.
  5. 　Ｒが、式（Ｉａ）：
    Figure JPOXMLDOC01-appb-C000004
     （式中、各記号は前記と同義である。）
    で示される基を示す、請求項１～４のいずれか一項に記載の化合物またはその塩。     R is the formula (Ia):
    Figure JPOXMLDOC01-appb-C000004
     (In the formula, each symbol has the same meaning as above.)
    The compound according to any one of claims 1 to 4, or a salt thereof, which represents a group represented by.
  6. 　Ｒａが、水素原子である、請求項５に記載の化合物またはその塩。 The compound according to claim 5, or a salt thereof, wherein Ra is a hydrogen atom.
  7. 　環Ｂが、ヒドロキシ基、
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
    から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し、
    ｐが、１を示す、請求項６に記載の化合物またはその塩。     Ring B is a hydroxy group,
    It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) Shows a benzene ring that may be substituted with 1 to 3 substituents selected from the alkoxy groups.
    The compound according to claim 6, wherein p is 1, or a salt thereof.
  8. 　３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）キノリン、
    ３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－７－メチルキノリン、
    ３－（２－（（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－7－メトキシキノリン、
    ３－（（２－（１Ｈ－ベンゾ[ｄ]イミダゾール－２－イル）ヒドラゾノ）メチル）－６，７－ジメチルキノリン、
    またはそれらの塩である、請求項７に記載の化合物またはその塩。     3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) quinoline,
    3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methylquinoline,
    3- (2-((1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -7-methoxyquinoline,
    3-((2- (1H-benzo [d] imidazol-2-yl) hydrazono) methyl) -6,7-dimethylquinoline,
    Or the compound according to claim 7, which is a salt thereof, or a salt thereof.
  9. 　Ｒが、式（Ｉｂ）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、各記号は前記と同義である。）
    で示される基を示す、請求項１～４のいずれか一項に記載の化合物またはその塩。     R is the equation (Ib):
    Figure JPOXMLDOC01-appb-C000005
     (In the formula, each symbol has the same meaning as above.)
    The compound according to any one of claims 1 to 4, or a salt thereof, which represents a group represented by.
  10. 　Ｒが、式（Ｉｃ）：－ＮＨ－ＣＯ－Ｒ３
    （式中、各記号は前記と同義である。）
    で示される基を示す、請求項１～４のいずれか一項に記載の化合物またはその塩。     R is the formula (Ic): -NH-CO-R 3
    (In the formula, each symbol has the same meaning as above.)
    The compound according to any one of claims 1 to 4, or a salt thereof, which represents a group represented by.
  11. 　Ｒが、式（Ｉｄ）：－ＣＯ－ＮＨ－Ｒ４
    （式中、各記号は前記と同義である。）
    で示される基を示す、請求項１～４のいずれか一項に記載の化合物またはその塩。     R is the formula (Id): -CO-NH-R 4
    (In the formula, each symbol has the same meaning as above.)
    The compound according to any one of claims 1 to 4, or a salt thereof, which represents a group represented by.
  12. 　請求項１に記載の化合物またはその塩を有効性成分として含有する医薬。 A drug containing the compound according to claim 1 or a salt thereof as an effective ingredient.
  13. 　マラリアの予防または治療のための、請求項１０に記載の医薬。 The medicament according to claim 10, for the prevention or treatment of malaria.
  14. 　請求項１に記載の化合物またはその塩の有効量を、その投薬を必要とする哺乳動物に投与することを含む、マラリアの予防または治療方法。 A method for preventing or treating malaria, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to a mammal in need of the medication.
  15. 　医薬として使用するための、請求項１に記載の化合物またはその塩。 The compound according to claim 1 or a salt thereof for use as a medicine.
  16. 　マラリアの予防または治療に使用するための、請求項１に記載の化合物またはその塩。 The compound according to claim 1 or a salt thereof for use in the prevention or treatment of malaria.
  17. 　請求項１に記載の化合物またはその塩の、医薬を製造するための使用。 Use of the compound according to claim 1 or a salt thereof for producing a pharmaceutical product.
  18. 　請求項１に記載の化合物またはその塩の、マラリアの予防または治療薬を製造するための使用。 Use of the compound according to claim 1 or a salt thereof for producing a prophylactic or therapeutic agent for malaria.
  19. 　式（ＩＡ）：
    Figure JPOXMLDOC01-appb-C000006
     ［式中、Ｒは、下記の式（Ｉａ’）、式（Ｉａ’’）または式（Ｉａ’’’）：
    Figure JPOXMLDOC01-appb-C000007
     （上記式中、Ｒ1は、水素原子または置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示し、
    環Ａ’は、さらに置換されていてもよいベンゼン環を示し、
    環Ａ’’は、ハロゲン原子以外の基から選択される置換基でさらに置換されていてもよい５～６員窒素含有芳香族複素環を示し、
    環Ａ’’’は、さらに置換されていてもよい６員窒素含有芳香族複素環を示し、
    環Ｂ’は、置換されていてもよい６員窒素含有芳香族複素環（ここにおいて、６員窒素含有芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい）を示し、
    環Ｂ’’は、置換されていてもよいベンゼン環または置換されていてもよい５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、環を形成していてもよい）を示し、
    ＊は、ベンゾイミダゾール環への結合位置を示し、および
    部分構造式（Ｉａａ）：
    Figure JPOXMLDOC01-appb-C000008
     で示される基は、＊＊で示される位置で環Ａ’、環Ａ’’または環Ａ’’’に結合している。）
    で示される基を示し、および
    Ｘは、水素原子またはハロゲン原子を示す。］
    で表される化合物またはその塩を有効成分として含有する、マラリアの予防または治療剤。     Formula (IA):
    Figure JPOXMLDOC01-appb-C000006
     [In the formula, R is the following formula (Ia'), formula (Ia'') or formula (Ia'''):
    Figure JPOXMLDOC01-appb-C000007
     (In the formula, R 1 represents a hydrogen atom or an optionally substituted (C 1 -C 6) alkyl group,
    Ring A'represents a benzene ring that may be further substituted.
    Ring A ″ represents a 5- to 6-membered nitrogen-containing aromatic heterocycle which may be further substituted with a substituent selected from groups other than the halogen atom.
    Ring A'''represents a 6-membered nitrogen-containing aromatic heterocycle that may be further substituted.
    Ring B'is a optionally substituted 6-membered nitrogen-containing aromatic heterocycle (here, two substituents present on adjacent carbon atoms in the 6-membered nitrogen-containing aromatic heterocycle are bonded to each other. May form a ring with the carbon atoms to which they are bonded).
    Ring B ″ is on a optionally substituted benzene ring or an optionally substituted 5- to 6-membered aromatic heterocycle (here, on an adjacent carbon atom in the benzene ring or 5- to 6-membered aromatic heterocycle). The two substituents present in may form a ring with the carbon atoms to which they are attached and bonded to each other).
    * Indicates the binding position to the benzimidazole ring, and the partial structural formula (Iaa) :.
    Figure JPOXMLDOC01-appb-C000008
     The group indicated by is attached to ring A', ring A'' or ring A''' at the position indicated by **. )
    Indicates a group represented by, and X indicates a hydrogen atom or a halogen atom. ]
    A prophylactic or therapeutic agent for malaria containing the compound represented by (1) or a salt thereof as an active ingredient.
  20. 　環Ａ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し；
    環Ａ’’が、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい５～６員窒素含有芳香族複素環を示し；
    環Ａ’’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、ニトロ基、および（Ｃ１－Ｃ６）アルキレンジオキシ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示し；
    環Ｂ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環（ここにおいて、６員窒素含有芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環を形成していてもよい）
    を示し；
    環Ｂ’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環または５～６員芳香族複素環（ここにおいて、ベンゼン環または５～６員芳香族複素環における隣接する炭素原子上に存在する２個の置換基は、互いに結合してそれらが結合する炭素原子と共に、１～３個の酸素原子を環構成原子として含有していてもよい５～７員の環を形成していてもよい）
    を示し；
    Ｒ１が、水素原子、または
    オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
    （式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
    Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示す。）
    を示す、請求項１９に記載のマラリアの予防または治療剤。     Ring A'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl Group 1 to 3 selected from (C 6- C 10 ) arylamino group, nitro group, and (C 1- C 6 ) alkylenedioxy group, which may be substituted with 1 to 3 halogen atoms. Shows a benzene ring that may be substituted with a substituent of;
    Ring A'' may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms (C 6- C 10 ) aryl amino group, nitro group, and (C 1- C 6 ) Shows a 5- to 6-membered nitrogen-containing aromatic heterocycle optionally substituted with 1 to 3 substituents selected from alkylenedioxy groups;
    Ring A'''is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10). ) Aryl group 1 to selected from (C 6- C 10 ) aryl amino group, nitro group, and (C 1 to C 6 ) alkylene dioxy group which may be substituted with 1 to 3 halogen atoms. Shows a 6-membered nitrogen-containing aromatic heterocycle optionally substituted with 3 substituents;
    Ring B'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, and 1 to 3 substituents may also be 6-membered optionally substituted with a group selected from a nitro group Nitrogen-containing aromatic heterocycles (here, the two substituents present on adjacent carbon atoms in a 6-membered nitrogen-containing aromatic heterocycle are 1 to 3 with the carbon atoms bonded to each other and to which they are bonded. It may form a 5- to 7-membered ring which may contain the oxygen atom of the above as a ring-constituting atom.)
    Shows;
    Ring B'' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ). aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl group, and with one to three substituents selected from nitro group, be each substituted A good benzene ring or 5- to 6-membered aromatic heterocycle (where the two substituents present on adjacent carbon atoms in the benzene ring or 5- to 6-membered aromatic heterocycle are attached to each other and they are bonded. It may form a 5- to 7-membered ring which may contain 1 to 3 oxygen atoms as a ring-constituting atom together with the carbon atom.)
    Shows;
    R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
    (In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Indicates an alkyl group. )
    The prophylactic or therapeutic agent for malaria according to claim 19.
  21. 　環Ａ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよいベンゼン環を示し；
    環Ａ’’が、１～３個のハロゲン原子で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい５～６員窒素含有芳香族複素環を示し；
    環Ａ’’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基、から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環を示し；
    環Ｂ’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で置換されていてもよい６員窒素含有芳香族複素環
    を示し；
    環Ｂ’’が、ハロゲン原子、（Ｃ１－Ｃ６）アルキル基、（Ｃ１－Ｃ６）アルコキシ基、ジ（（Ｃ１－Ｃ６）アルキル）アミノ基、（Ｃ６－Ｃ１０）アリール基、１～３個のハロゲン原子で置換されていてもよい（Ｃ６－Ｃ１０）アリールアミノ基、およびニトロ基から選択される１～３個の置換基で、それぞれ置換されていてもよいベンゼン環または５～６員芳香族複素環を示し；
    Ｒ１が、水素原子、または
    オキソ基、ヒドロキシ基、および式：－Ｎ－Ｌ３－Ｎ（Ｒ５）（Ｒ６）
    （式中：Ｌ３は、（Ｃ１－Ｃ６）アルキレン基、および
    Ｒ５およびＲ６は、互いに独立して、（Ｃ１－Ｃ６）アルキル基を示すか、または、Ｒ５およびＲ６は、互いに結合して、隣接する窒素原子とともに６員窒素含有複素環を形成していてもよい。）で示される基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基を示す。）
    を示す、請求項１９または２０に記載のマラリアの予防または治療剤。     Ring A'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, one to three optionally substituted with a halogen atom (C 6 -C 10) aryl amino group, and 1-3 benzene ring which may be substituted with a substituent selected from a nitro group Shows;
    Ring A'' may be substituted with 1 to 3 halogen atoms (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl ) Amino group, (C 6- C 10 ) aryl group, optionally substituted with 1 to 3 halogen atoms, 1 to 3 selected from (C 6- C 10 ) aryl amino group, and nitro group. Shows a 5- to 6-membered nitrogen-containing aromatic heterocycle optionally substituted with a substituent of;
    Ring A'''is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10). ) It may be substituted with 1 to 3 substituents selected from an aryl group, an arylamino group (C 6- C 10 ), and a nitro group, which may be substituted with 1 to 3 halogen atoms. Shows a good 6-membered nitrogen-containing aromatic heterocycle;
    Ring B'is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ) aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl amino group, and 1 to 3 substituents may also be 6-membered optionally substituted with a group selected from a nitro group Shows a nitrogen-containing aromatic heterocycle;
    Ring B'' is a halogen atom, (C 1- C 6 ) alkyl group, (C 1- C 6 ) alkoxy group, di ((C 1- C 6 ) alkyl) amino group, (C 6- C 10 ). aryl group, optionally substituted with one to three halogen atoms (C 6 -C 10) aryl group, and with one to three substituents selected from nitro group, be each substituted Shows a good benzene ring or 5- to 6-membered aromatic heterocycle;
    R 1 is a hydrogen atom, or an oxo group, a hydroxy group, and the formula: -N-L 3- N (R 5 ) (R 6 ).
    (In the formula: L 3 is a (C 1- C 6 ) alkylene group, and R 5 and R 6 are independent of each other and represent a (C 1- C 6 ) alkyl group, or R 5 and R. 6 may be bonded to each other to form a 6-membered nitrogen-containing heterocycle with adjacent nitrogen atoms.) May be substituted with 1 to 3 substituents selected from the groups represented by. (C 1- C 6 ) Indicates an alkyl group. )
    The prophylactic or therapeutic agent for malaria according to claim 19 or 20.
  22. 　Ｘが、水素原子を示し、および
    Ｒ１が、水素原子または（Ｃ１－Ｃ６）アルキル基を示す、請求項１９～２１のいずれか一項に記載のマラリアの予防または治療剤。     The prophylactic or therapeutic agent for malaria according to any one of claims 19 to 21, wherein X represents a hydrogen atom and R 1 represents a hydrogen atom or an (C 1- C 6) alkyl group.
  23. 　Ｒが、式（Ｉａ’’）：
    Figure JPOXMLDOC01-appb-C000009
     （式中、環Ａ’’は、無置換の５～６員窒素含有芳香族複素環を示し、および
    その他の各記号は前記と同義である。）
    で示される基を示す、請求項２２に記載のマラリアの予防または治療剤。     R is the formula (Ia''):
    Figure JPOXMLDOC01-appb-C000009
     (In the formula, ring A ″ represents an unsubstituted 5- to 6-membered nitrogen-containing aromatic heterocycle, and the other symbols are synonymous with the above.)
    The prophylactic or therapeutic agent for malaria according to claim 22, which comprises the group indicated by.
  24. 　環Ａ’’が、ピリジン環を示し、および
    環Ｂ’’が、ヒドロキシ基、
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルキル基、および
    １～３個の（Ｃ１－Ｃ６）アルキル基で置換されていてもよいアミノ基およびカルボキシ基から選択される１～３個の置換基で置換されていてもよい（Ｃ１－Ｃ６）アルコキシ基
    から選択される１～３個の置換基で置換されていてもよいベンゼン環を示す、請求項２３に記載のマラリアの予防または治療剤。     Ring A ″ represents a pyridine ring, and ring B ″ is a hydroxy group.
    It may be substituted with 1 to 3 (C 1- C 6 ) alkyl groups and may be substituted with 1 to 3 substituents selected from amino and carboxy groups (C 1- C 6). ) alkyl group, and one to three (C 1 -C 6) optionally substituted with 1 to 3 substituents are also selected from an amino group and a carboxyl group substituted with an alkyl group ( C 1- C 6 ) The prophylactic or therapeutic agent for malaria according to claim 23, which exhibits a benzene ring which may be substituted with 1 to 3 substituents selected from the alkoxy groups.
  25. 　請求項１９に記載の式（ＩＡ）で表される化合物またはその塩の有効量を、その投薬を必要とする哺乳動物に投与することを含む、マラリアの予防または治療方法。 A method for preventing or treating malaria, which comprises administering an effective amount of a compound represented by the formula (IA) according to claim 19 or a salt thereof to a mammal in need thereof.
  26. 　マラリアの予防または治療に使用するための、請求項１９に記載の式（ＩＡ）で表される化合物またはその塩。 A compound represented by the formula (IA) according to claim 19 or a salt thereof for use in the prevention or treatment of malaria.
  27. 　請求項１９に記載の式（ＩＡ）で表される化合物またはその塩の、マラリアの予防または治療薬を製造するための使用。 Use of the compound represented by the formula (IA) according to claim 19 or a salt thereof for producing a prophylactic or therapeutic agent for malaria.
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