WO2021200934A1 - 抗マラリア薬 - Google Patents

抗マラリア薬 Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
substituted
ring
aryl
Prior art date
Application number
PCT/JP2021/013516
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
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
Original Assignee
国立大学法人 長崎大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人 長崎大学 filed Critical 国立大学法人 長崎大学
Priority to JP2022512531A priority Critical patent/JPWO2021200934A1/ja
Publication of WO2021200934A1 publication Critical patent/WO2021200934A1/ja

Links

Images

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP2021/013516 2020-03-30 2021-03-30 抗マラリア薬 WO2021200934A1 (ja)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022512531A JPWO2021200934A1 (enrdf_load_stackoverflow) 2020-03-30 2021-03-30

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020060515 2020-03-30
JP2020-060515 2020-03-30

Publications (1)

Publication Number Publication Date
WO2021200934A1 true WO2021200934A1 (ja) 2021-10-07

Family

ID=77928872

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/013516 WO2021200934A1 (ja) 2020-03-30 2021-03-30 抗マラリア薬

Country Status (2)

Country Link
JP (1) JPWO2021200934A1 (enrdf_load_stackoverflow)
WO (1) WO2021200934A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024258900A3 (en) * 2023-06-13 2025-04-17 University Of Georgia Research Foundation, Inc. Plasmodium falciparum blood stage inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011524365A (ja) * 2008-06-11 2011-09-01 アイアールエム・リミテッド・ライアビリティ・カンパニー マラリアの処置に有用な化合物および組成物
US20120329747A1 (en) * 2011-06-21 2012-12-27 Jayaram Hiremagular N Novel hydrazone derivatives having potent antitumor activity toward multi-drug resistant tumor cells
US20170042905A1 (en) * 2014-04-29 2017-02-16 Emory University Prostaglandin Receptor EP2 Antagonists, Derivatives, Compositions, and Uses Related Thereto
US20180105500A1 (en) * 2016-09-29 2018-04-19 Duke University Novel inhibitors of transforming growth factor kinase and methods of use thereof
JP2019504009A (ja) * 2015-12-17 2019-02-14 ミッション セラピューティクス リミティド 新規化合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011524365A (ja) * 2008-06-11 2011-09-01 アイアールエム・リミテッド・ライアビリティ・カンパニー マラリアの処置に有用な化合物および組成物
US20120329747A1 (en) * 2011-06-21 2012-12-27 Jayaram Hiremagular N Novel hydrazone derivatives having potent antitumor activity toward multi-drug resistant tumor cells
US20170042905A1 (en) * 2014-04-29 2017-02-16 Emory University Prostaglandin Receptor EP2 Antagonists, Derivatives, Compositions, and Uses Related Thereto
JP2019504009A (ja) * 2015-12-17 2019-02-14 ミッション セラピューティクス リミティド 新規化合物
US20180105500A1 (en) * 2016-09-29 2018-04-19 Duke University Novel inhibitors of transforming growth factor kinase and methods of use thereof

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CHAMPBELL, C. 0. ET AL.: "In silica Characterization of an Atypical MAPK Phosphatase of Plasmodium falciparum as a Suitable Target for Drug Discovery", CHEM. BIOL. DRUG. DES., vol. 84, 2014, pages 158 - 168, XP055373623, DOI: 10.1111/cbdd.12315 *
GEMMA SANDRA; GIOVANI SIMONE; BRINDISI MARGHERITA; TRIPALDI PIERANGELA; BROGI SIMONE; SAVINI LUISA; FIORINI ISABELLA; NOVELLINO ET: "Quinolylhydrazones as novel inhibitors ofPlasmodium falciparumserine protease PfSUB1", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 22, no. 16, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 5317 - 5321, XP028932824, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2012.06.023 *
ODAME FELIX, BETZ RICHARD, HOSTEN ERIC C., KRAUSE JASON, ISAACS MICHELLE, HOPPE HEINRICH C., KHANYE SETSHABA D., SAYED YASIEN, FRO: "A New Synthetic Method for Tetraazatricyclic Derivatives and Evaluation of Their Biological Properties", CHEMISTRYSELECT, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 3, no. 48, 28 December 2018 (2018-12-28), DE , pages 13613 - 13618, XP055924660, ISSN: 2365-6549, DOI: 10.1002/slct.201802930 *
SHI HAIBIN, TICE COLIN M., EMERT-SEDLAK LORI, CHEN LI, LI WING FAI, CARLSEN MARIANNE, WROBEL JAY E., REITZ ALLEN B., SMITHGALL THO: "Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation", ACS INFECTIOUS DISEASES, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 2, 14 February 2020 (2020-02-14), US , pages 302 - 312, XP055924686, ISSN: 2373-8227, DOI: 10.1021/acsinfecdis.9b00382 *
SOUVIK SARKAR, ASIM A. SIDDIQUI, SHUBHRA J. SAHA, RUDRANIL DE, SOMNATH MAZUMDER, CHINMOY BANERJEE, MOHD S. IQBAL, SHILADITYA NAG, : "ABSTRACT", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 60, no. 7, 1 July 2016 (2016-07-01), US , pages 4217 - 4228, XP055522624, ISSN: 0066-4804, DOI: 10.1128/AAC.01575-15 *
SUBRAMANIAN GOWTHAM, BABU RAJEEV C.P., MOHAN CHAKRABHAVI DHANANJAYA, SINHA AMEYA, CHU TRANG T.T., ANUSHA SEBASTIAN, XIMEI HUANG, F: "Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 26, no. 14, 1 July 2016 (2016-07-01), AMSTERDAM, NL , pages 3300 - 3306, XP055924676, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2016.05.049 *
SUJATHA KODAM, OMMI NAIDU BABU, MUDIRAJ ANWITA, BABU PHANITHI PRAKASH, VEDULA RAJESWAR RAO: "Synthesis of thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines as a class of antimalarial agents", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 352, no. 12, 1 December 2019 (2019-12-01), Weinheim , XP055924672, ISSN: 0365-6233, DOI: 10.1002/ardp.201900079 *
WICHT KATHRYN J., COMBRINCK JILL M., SMITH PETER J., HUNTER ROGER, EGAN TIMOTHY J.: "Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against Plasmodium falciparum", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 59, no. 13, 14 July 2016 (2016-07-14), US , pages 6512 - 6530, XP055924596, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00719 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024258900A3 (en) * 2023-06-13 2025-04-17 University Of Georgia Research Foundation, Inc. Plasmodium falciparum blood stage inhibitors

Also Published As

Publication number Publication date
JPWO2021200934A1 (enrdf_load_stackoverflow) 2021-10-07

Similar Documents

Publication Publication Date Title
ES2252656T3 (es) Nuevos derivados de piridina y quinolina.
CA2736097C (en) Carbazole compounds for inhibition of nf-kb activity
JP4405602B2 (ja) ヒストン脱アセチル化酵素阻害剤
WO2017114509A1 (zh) 醛基类化合物及其制法和用途
BG107285A (bg) Бета - карболинови производни като инхибитори на фосфодиестераза
JP2017519795A (ja) 抗寄生生物活性を有するアゼパニル（ａｚｅｐａｎｙｌ）誘導体およびそれを含む医薬組成物
TW202003472A (zh) 鈣蛋白酶(calpain)調節劑及其醫療用途
WO2013075596A1 (zh) 作为dhodh抑制剂的五元二氢杂环酮类衍生物及应用
JPWO2016148114A1 (ja) 酸化ストレス誘導神経細胞死抑制化合物
JP6088639B2 (ja) 抗マラリア薬
CZ20014637A3 (cs) Substituované fenoxyoctové kyseliny
US8871802B2 (en) Naphthoquinones for disease therapies
JP2022502497A (ja) Ｈｄａｃ１、２の阻害剤
JP6903266B2 (ja) １，２ナフトキノン誘導体及びその製造方法
CN115232126B (zh) 一种β-卡波林-1,2,3-三唑化合物及其制备方法与抗阿尔兹海默病的应用
WO2021200934A1 (ja) 抗マラリア薬
US20070197512A1 (en) Carboxylic Acid Compounds and Use Thereof
US9447103B2 (en) Inauhzin analogues that induce P53, inhibit cell growth, and have antitumor activity
JPWO2005021486A1 (ja) エステル誘導体及びその医薬用途
JPS60105668A (ja) ベンゾ〔ａ〕フエノチアジン類およびその水素化誘導体類
US20090029975A1 (en) 1,3-benzothiazinone derivative and use thereof
JPWO2004002484A1 (ja) ホスホジエステラーゼ阻害剤
EP0404536A1 (en) Indenoindole compounds I
EP2917204B1 (fr) Derives de 1h-indole-3-carboxamide et leurs utilisation comme antagonistes du p2y12
WO2001014384A1 (fr) Derives dihydrobenzofuran tricycliques, leur procede de preparation et agents

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21779415

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022512531

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21779415

Country of ref document: EP

Kind code of ref document: A1