WO2007086584A1 - NOUVEL INHIBITEUR DE FabK ET DE FabI/K - Google Patents

NOUVEL INHIBITEUR DE FabK ET DE FabI/K Download PDF

Info

Publication number
WO2007086584A1
WO2007086584A1 PCT/JP2007/051523 JP2007051523W WO2007086584A1 WO 2007086584 A1 WO2007086584 A1 WO 2007086584A1 JP 2007051523 W JP2007051523 W JP 2007051523W WO 2007086584 A1 WO2007086584 A1 WO 2007086584A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
alkyl
halogen atom
chemical
Prior art date
Application number
PCT/JP2007/051523
Other languages
English (en)
Japanese (ja)
Inventor
Hideo Kitagawa
Tomohiro Ozawa
Maiko Iida
Takashi Watanabe
Sho Takahata
Mototsugu Yamada
Yasuo Yamamoto
Original Assignee
Meiji Seika Kaisha, Ltd.
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
Priority claimed from JP2006021372A external-priority patent/JP2009091251A/ja
Priority claimed from JP2006243953A external-priority patent/JP2009091252A/ja
Application filed by Meiji Seika Kaisha, Ltd. filed Critical Meiji Seika Kaisha, Ltd.
Publication of WO2007086584A1 publication Critical patent/WO2007086584A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/60—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1025—Acyltransferases (2.3)
    • C12N9/1029—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)

Definitions

  • the present invention relates to a compound that inhibits fatty acid synthase FabK or FablZK and is useful for the treatment of bacterial infection and is pharmaceutically promising.
  • Fatty acid biosynthesis in bacteria is carried out by a series of enzymes called type II fatty acid synthase (FAS) systems.
  • type II fatty acid synthase FOS
  • the biosynthesis of fatty acids is catalyzed by a single multifunctional enzyme called the Type I FAS system, which is very different from the fatty acid biosynthesis system of bacteria. Therefore, compounds that inhibit the FAS enzymes of Type II, possibly as selective and novel antimicrobial agent is suggested (Prog. L ipid Res. ( 2001), 40,467-497) o
  • a fatty acid biosynthetic system of bacteria four enzyme reactions proceed sequentially to form a cycle, and a long-chain saturated fatty acid is biosynthesized through multiple cycles.
  • the first step of the cycle is a condensation reaction with
  • j8-ketosyl-ACP synthase I or II condenses malo-roux ACP and facile ACP.
  • a reduction reaction occurs with NADPH-dependency-ketocil ACP reductase (FabG).
  • FabG NADPH-dependency-ketocil ACP reductase
  • j8-hydroxyacyl-ACP dehydrase ⁇ & 1) & 1 ⁇ to obtain dehydrated transformer, 2 enol, 1 ACP.
  • it is reduced by enol-one ACP reductase (Fabl, FabK, or FabL) to yield isacyl ACP.
  • Fabl, FabK, or FabL enol-one ACP reductase
  • Enolulu ACP reductase is the rate-limiting enzyme in the fatty acid synthesis pathway of bacteria, and is an important regulatory point of overall fatty acid biosynthesis in bacteria.
  • Fabl is a target for the broad-spectrum antibiotic triclosan.
  • the complex crystal structure of NAD and triclosan and E. coli-derived Fabl has also been studied, and it has been shown that triclosan acts as a highly specific inhibitor of Fabl by mimicking its natural substrate. .
  • Conformational data on the Fabl-NAD and triclosan complex provides important information in the design of specific inhibitors. Based on this information, it has been found that inhibitors designed in this way may be useful in the treatment of bacterial infections (Nature (1998) 394,531-532, J. Biol. Chem. (1998), 273). , 30316-3032 0, Nature (1999) 398,383-384, and J. Med. Chem. (2003), 46, 1627-1635).
  • FabK is essential for growth in Streptococcus pneumoniae and has been clarified to be a flavin protein having FMN as a coenzyme at a molar concentration ratio of 1: 1 (Bioche m. J (2003)). , 370, 1055-1062) o
  • compounds that inhibit FabK even though it is weak, but there are reports of compounds that strongly inhibit FabK and three-dimensional structures of FabK. (Special Table 2003-511448, J. Med. Chem. (2003), 46,1627-1635, and Antimicrob. Agents. Chem., 46, 3118, (2002)).
  • drugs that inhibit FabK, as well as both Fabl and FabK enzymes are ideal antibacterial agents having a broad antibacterial spectrum and are expected.
  • Streptococcus pneumoniae which is a clinically important pathogen, has only Fa bK as an enoyl ACP reductase, and Pseudomonas aeruginosa and enterococci have both Fabl and FabK.
  • Conventional targeted inhibitors cannot be broader antimicrobial active agents and need to inhibit not only Fabl but also FabK.
  • reports of compounds that inhibit FabK included improvements to be made, such as the fact that most conventional FabK inhibitors are not necessarily lipid-specific, because their inhibitory ability is low. Therefore, creation of compounds having inhibitory activity against Fabl and FabK, particularly Fab K, is desired.
  • the present inventors have now found a compound of formula (I) that inhibits FabK or both Fabl and FabK enzymes and is useful in the treatment of bacterial infections.
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and an inhibitor for FabK or both Fabl and FabK enzymes.
  • an object of the present invention is to provide a compound of formula (I) that is useful in the treatment of bacterial infections.
  • the present invention provides a compound represented by the following formula (I), a salt thereof, or a solvate thereof:
  • a ′ represents a hydrogen atom or a force representing a C 1-6 alkyl group, or together with an adjacent nitrogen atom and A, the following formula (II):
  • a ' represents a hydrogen atom or a halogen atom
  • R a is a hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group, trifluoromethyl group, trifluoromethyloxy group, carboxyl group, aryl Oxycarbol group, C1 6 alkyloxycarbol group, C1 6 alkylcarboloxy group, C1 6 alkylsulfol group, sulfamoyl group, —OC H CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, I COOCH CH NH
  • R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
  • R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbonyl group, a C16 alkyl group.
  • Xyloxycarbonyl group C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Sulfol group, C2-6 alkylsulfol group, C1 6 alkylsulfur group, C2-6 alkylsulfur group Fier group, C2-6 alkyl sulfier group, pyridyl group, pyridylthio group, lysylthio group, morpholinomethyl group, piperidino group,
  • R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1 6 alkyloxy levono vinyl group, or CONHCH CH OH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group
  • R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (one to two on the phenyl group).
  • R e is also Yogu here have a number of R e radicals is a hydrogen atom, Shiano group or - represents a represents a Toro group).
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenol group, a nitro group, or an amino group,
  • R ga is a hydrogen atom, a halogen atom , C1-6 alkyl group, C1 6 alkoxy group, hydroxy carboxymethyloxy group, C1-6 alkyl carboxymethyloxy group, rubamoylmethyloxy group, C1 6 alkyloxy carboxylethyl group, OCH CONHCH CH OH, — OCH CONHPh
  • R h represents a hydrogen atom or an amino group
  • Ri represents a hydrogen atom or a C16 alkyl group
  • R j represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a trifluoromethyl group
  • R k group is
  • the R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenol group, a trifluoromethyl group, an amino group, a nitro group, a —SO 2 H group, or a C 1-6 alkyloxycarbon group.
  • the R kb group represents a hydrogen atom or a acetyl group
  • R ke group represents a hydrogen atom or a nitro group
  • R 1 group is
  • the compound of the present invention inhibited both Fabl and FabK enzymes and showed very strong antibacterial activity against Streptococcus pneumoniae. Therefore, the present invention can be used for the treatment of bacterial infections such as S. pneumoniae, Pseudomonas aeruginosa, or enterococci.
  • C1-6 alkyl group or “C1-6 alkoxy group”, “C1-6 alkyloxycarbonyl group”, “C1 6 alkylcarboxoxy group”, “hydroxy C1 6 alkyl group”, “C1—
  • the “alkyl group” in the substituents such as “6 alkylthio group”, “C 1-6 alkyl sulfol group”, and “Cl-6 alkyl sulfiel group” represents an alkyl group having 16 carbon atoms, and is a chain. It may be any of a shape, a branch, or a ring.
  • alkyl having 14 carbon atoms Preferably, it is alkyl having 14 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n propyl group, an isopropyl group, a cyclopropyl group, an n butyl group, a t butyl group, and an isobutyl group.
  • C2-6 alkenyl group refers to a straight chain, branched or cyclic alkenyl group having 26 carbon atoms, such as a bule group or a 1-probe group.
  • 2—Probing Group isopropylene group, 2-methyl-1 propylene group, 3-methyl-1 propellyl group, 2-methyl-2 propellyl group, 3-methyl-2 propellyl group, 1-butur Group, 2 Butyl Group, 3 Butyl Group, 1 Pentyl Group, 2 Pental Group, 3 Pentul Group, 4 Pental Group, Cyclopental Group, 1 Hexane Group, 2 Hexane Group A 4-hexyl group, a 4-hexyl group, a 5-hexyl group, a cyclohexyl group, or the like.
  • bur group, 1 probe group, 2 probe group isoprop group, 2-methyl 1 prop group, 3-methyl 1 prop group, 2-methyl group 2-Propyl group, 3-Methyl- 2-Propyl group, 1-Butur group, 2--Butur group, 3-Butul group, 1-Pental group, 2-Pental group, 3-Pental group, or 4 A pentenyl group and the like.
  • C2-6 alkyl group means a straight or branched alkyl group having 2 to 6 carbon atoms, such as an ethur group, a 1 propyl group, a 2-propyl group.
  • an ethur group such as an ethur group, a 1-propyl group, a 2-propyl group, a 1-butur group, a 2-butur group, or a 3-butur group
  • C1-6 alkylthio group means a linear, branched or cyclic alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, and an n-propylthio group.
  • examples include a xylthio group or a cyclohexylthio group.
  • it is alkyl having 1 to 4 carbon atoms, such as methylthio group, ethylthio group, n propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, t-butylthio group, or isobutylthio group. More preferably, it is an alkyl group having 13 carbon atoms, and is a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, or a cyclopropyl group. Such as a ruthio group.
  • C2-6 alkenylthio group means a linear, branched, or cyclic alkarylthio group having 2 to 6 carbon atoms.
  • C2-6 alkylthio group means a linear or branched alkylthio group having 2 to 6 carbon atoms, including 1 ethylthio group, 1 propylthio group.
  • Preferable examples include 1-ethylthio group, 1-propylthio group, 2-propylthio group, 1-butylthio group, 2-butynylthio group
  • C16 alkylsulfol group means a linear, branched, or cyclic alkylsulfol group having 1 to 6 carbon atoms, such as a methanesulfol group, an ethylsulfol group, or a 1propylsulfol group.
  • a methanesulfol group an ethylsulfol group ⁇ ⁇ 1-propinolesnoreno-nore group, 2-propinolesnoreno-nore group, 2-methinoreol 1-propinosoleol group, 3-methyl 1-propylsulfol group, 2-methyl-2-propylsulfol group, 3-methyl-2-propylsulfol group, 1-butylsulfol group, 2-butylsulfol group, 3-butylsulfol group, 1 pentylsulfo group Group, 2-pentylsulfol group, 3-pentylsulfol group, or 4-pentylsulfol group.
  • C2-6 alkaryl sulfonyl group refers to a linear, branched, or cyclic arnolekenino lesnorenonole group having 2 to 6 carbon atoms.
  • 2-Methinore 1 propeninores norehoninore group 3-Methinore 1 propeninores norehoninore group
  • 2-Methinore-2 propeninores norehoninole group 3-methinore-2 propeninores norehoninore group
  • 1-butenylsulfol group 2 butenylsulfol group, 3 butenylsulfol group
  • 1 penteninoresnorenonoreno group 2 penteninoresnorenorenoreno group, 3 penteninoresnorenorenoor group, or 4 A pentylsulfol group.
  • C2-6 alkynylsulfol group represents a straight or branched alkyninolesnorehoninore group having 2 to 6 carbon atoms, 1-ethyninoresnorehoninore group, 1 propyninole group Sunolehoninole group, 2-propyninoresnorehonoreno group, 1-butyninoresnorehoninole group, 2-butyninoresnorehoninore group, 3-butylpropyl group, 3-methyl-1-propynylsulfol group, 1 1-pentyl-nolesnorehonore group, 2-penti-noresnorehonore group, 3-penti-norethnorehoninore group, 4-penti-noresnorehonore group, 1-hexinolesnorehoninole group, 2 hexinolesnor
  • C16 alkyl sulfiel group refers to a linear, branched, or cyclic alkyl sulfiel group having 1 to 6 carbon atoms, such as a methyl sulfyl group, an ethyl sulfyl group, a 1 propyl sulfiel group.
  • 2-propyl sulfier group 2-methyl-1 propyl sulfier group, 3-methyl-1-propyl sulfier group, 2-methyl-2 propyl sulfier group, 3-methyl-2-propyl sulfier group, 1-butyl Sulfiel group, 2-butyl sulfier group, 3 butyl sulfier group, 1 pentyl sulfier group, 2 pentyl sulfier group, 3 pentyl sulfier group, 4 pentyl sulfinyl group, cyclopentyl sulfyl group, 1-Hexylsulfyl group, 2-Hexylsulfuryl group, 3-Hexylsulfier group, 4-Hexylsulfuryl group To 5 alkoxy Rusurufi - group or cyclohexylene, means such as cyclohexyl sulfide El group.
  • C2-6 alkaryl sulfier group refers to a straight, branched or cyclic alkenyl sulfier group having 2 to 6 carbon atoms, including a vinyl sulfier group and a 1-propyl sulfenyl group.
  • sulfulfiel group 1-propeninoresnorefinolole group, 2-propeninoresnorefininole group, isopropenenolesnorefier group, 1-butenylsulfuryl group, 2 butenylsulfiel group, Such as 3-butersulfyl group, 1-pentylsulfuric group, 2-pentylsulfuryl group, 3-pentylsulfuryl group, or 4-pentylsulfuryl group.
  • the "C2-6 alkynylsulfier group” represents a straight-chain or branched alkyninolesnorefinol group having 2 to 6 carbon atoms, and includes a 1-ethyninoresnorephinore group, 1-propynino Resnorefinole group, 2-propynyl sulfier group, 1-butyl sulfier group, 2-pentyl sulfier group, 3-pentyl sulfier group, 3-methyl-1 propynyl sulfier group, 1-methyl —3 propynyl sulfiel group, 1—pentyl sulfyl group, 2 pentyl-norethnorephi-noreth group, 3—penty-norethnorephi-noreth group, 4-penty-norethnorephinor group, 1—hexylsulfier group 2 hex
  • the term “optionally substituted” means that a certain group may have one or more substituents, and preferably 1 to 6, More preferably, it means that it may have 1 to 3 substituents.
  • substituents include a hydroxyl group, a halogen atom, an amino group, a mono-substituted amino group, a di-substituted amino group, an azide group, a C 1-6 alkyl group, a C 3-7 cyclic alkyl group, a C 16 alkoxy group, C3-7 cyclic alkoxy group, hydroxy C1 6 alkyl group, amide group, N-substituted amide group, N, N-disubstituted amide group, amino carbonyl group, carboxyl group, C16 alkyl carboxy group, phenol Group, phenyl group, substituted phenol group, benzyl group, substituted benzyl group, benzoyl group, C16 alkyl Examples
  • halogen atom includes a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom.
  • heterocycle means one or two selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 5- to 14-membered member containing 1 to 4 heteroatoms. Examples thereof include monocyclic to tricyclic heterocycles, and preferably include 5 to 10-membered monocyclic or bicyclic heterocycles containing 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms.
  • Ph and Me represent a phenyl group and a methyl group, respectively.
  • PG represents a protecting group, and desorption of the protecting group is performed as necessary during the production process.
  • the protective si is used in accordance with the protective group described in Protective groups in organic synthesis, 2nd ecu, (John Wiley & 3 ⁇ 4 ons Inc., 1991) and the method described. Further, as necessary, a known method, an experimental chemistry course (edited by the Chemical Society of Japan, Maruzen), or the like can be applied as a method for substituting the substituents on the side chain and side chain as necessary.
  • the compound according to the present invention is a compound represented by the formula (I).
  • V represents CH or a nitrogen atom
  • Y represents hydrogen
  • Aa represents a hydrogen atom, a C16 alkyl group, a hydroxy C1-6 alkyl group, a mono (CH) Ph group,
  • R a represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group.
  • COOCH N represents, R b is a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C 1-6 al
  • R e is a hydrogen atom, a halogen atom, C1 6 alkyl, C2- 6 Aruke - Le group
  • C2-6 alkyl group hydroxycarboromethyl group, C1-6 alkyloxycarboro group, C1 6 alkyloxycarboromethyl group, C1 6 alkylcarboxyloxy group, naphthyl group, C1 6 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1 6 alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkylsulfol group, C 1 —6 alkyl sulfiel groups, C2-6 alkyl sulfyl groups, C2-6 alkyl sulfiel groups, pyridyl groups, pyridylthio groups, nitropyridylthio groups, morpholinomethyl groups, piperidino groups,
  • R ea is hydrogen atom, halogen atom, C1 6 alkyl, C1 6 alkoxy group, a force Rubamoiru group, or - represents OC (CH) COOCH CH, R eb is hydrogen, halo
  • R ⁇ is a hydrogen atom, halogen atom, C1-6 alkyl group
  • R d represents a hydrogen atom, a phenol group, a -SO phenol group
  • R e groups may be present on the phenyl group
  • R e represents a hydrogen atom, a cyan group, or a -tro group
  • B a is
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenyl group, a nitro group, or an amino group, and represents a hydrogen atom, a halogen atom, or a phenyl group
  • Hue - Le group is a hydrogen atom
  • Yogu R ga be one to three amino substituents at R ga, halogen atom, C1 6 alkyl group, C1- 6 alkoxy group, hydroxycarbonated - Rumechiruokishi group, C1 6 alkyl Oxycarboxymethyloxy group, strong rubamoyl methyloxy group, C16 alkyloxycarboruethyl group, —OCH CONHCH
  • R h represents a hydrogen atom or an amino group
  • Ri represents a hydrogen atom or a C 1-6 alkyl group
  • R j represents a hydrogen atom, a halogen atom, C1 6 alkyl or triflates Ruo Russia methyl group, . ].
  • Y represents a hydrogen atom or a methyl group
  • R a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C16 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryloxycarbo Group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OCH CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, 1 COOCH CH NHC
  • R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1 6 alkoxy group, a C1-6 alkylcarbonyl group, or COOCH CH N (SO 2 CH 3),
  • R ca represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a carbamoyl group, or —OC (CH 2) COOCH CH,
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyloxy group norboninole group, or CONHCH CH OH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group
  • R d is a hydrogen atom, a phenyl group, a —SO phenyl group (one or two on the phenyl group)
  • R g represents a hydrogen atom, a halogen atom, or a phenyl group, and the phenyl group may be substituted by 1 to 3 of R ga .
  • R ga is a hydrogen atom, halogen atom, C1 6 alkyl group, C1-6 alkoxy group, hydroxy carboxymethyloxy group, C1 6 alkyloxy carboxymethyloxy group, force
  • R 1 represents a hydrogen atom or a CI 6 alkyl group.
  • B a is
  • R g represents a phenylene group
  • the Hue alkenyl group is one to three amino substituents at R ga, at best, the R ga a hydrogen atom, a halogen atom, C1- 6 alkyl group, C1- 6 alkoxy group, hydroxy Cycarboxylmethyloxy group, C16 alkyloxycarboxylmethyl group, force Rubamoylmethyloxy group, C16 alkyloxycarboxyl group, OCH C
  • Still another preferred embodiment of the present invention is the above formula (Iaa), wherein A a is
  • Another preferred embodiment of the present invention provides a compound represented by the following formula (lab), a salt thereof, or a solvate thereof:
  • X represents a halogen atom
  • IT represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarbonmethyl group, a C1-6 alkyl group.
  • R ea is hydrogen atom, halogen atom, C1 6 alkyl, C1 6 alkoxy group, a force Rubamoiru group, or - represents OC (CH) COOCH CH
  • R eb is hydrogen, halogen
  • R ⁇ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group, and these may have a substituent.
  • X represents a halogen atom
  • R e is a C1-6 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, C 1-6 Alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkylsulfol group, C1-6 alkylsulfur group Represents a Fiel group, a C2-6 alkylsulfuryl group, or a C2-6 alkylsulfuryl group, which is provided with an optionally substituted compound, a salt thereof, or a solvent thereof.
  • Another embodiment of the present invention provides a compound represented by the following formula (lb), a salt thereof, or a solvate thereof:
  • a ′ represents a hydrogen atom, a C1-6 alkyl group, or an adjacent nitrogen atom, A b together with the following formula (II),
  • a ′ ′ represents a hydrogen atom or a halogen atom
  • a b is
  • R a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C16 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryloxycarbo Group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OCH CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, 1 COOCH CH NHC
  • R b represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a C1-6 alkyl carboxy group, or COOCH CH N (SO CH);
  • R ca represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a carbamoyl group, or —OC (CH 2) COOCH CH,
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyloxy group norboninole group, or CONHCH CH OH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group
  • R d is a hydrogen atom, a phenyl group, a —SO phenyl group (one or two on the phenyl group)
  • B b is a C 1-6 alkyloxycarboluminomethyl group, CH—S—R k group, CH—
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenyl group, a nitro group, or an amino group,
  • R h represents a hydrogen atom or an amino group
  • R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenyl group, a trifluoromethyl group, an amino group, a nitro group, a SOH group, or a C16 alkyloxycarbon group.
  • R kb group represents a hydrogen atom or a acetyl group
  • R ke group represents a hydrogen atom or -tro group
  • R 1 group is
  • a ′ represents a hydrogen atom
  • a b represents [Chemical Formula 35] 1-3
  • B b is a compound representing a —CH—S—R k group, a salt thereof, or a solvate thereof.
  • Another embodiment provides a compound represented by the following formula (Ic), a salt thereof, or a solvate thereof:
  • NA, -CO-CH O— N C (B,) one or
  • a ′ represents a hydrogen atom, a C1-6 alkyl group, or an adjacent nitrogen atom, A e together with the following formula (II):
  • a ′ ′ represents a hydrogen atom or a halogen atom
  • a e is a hydrogen atom, a C16 alkyl group
  • Ra is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an arylo group.
  • R b represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO CH);
  • R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarboromethyl group, a C16 alkyloxycarbon group, a C16 alkyl group Xyloxymethyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1-6 alkylsulfol group, C2 — 6-alkylsulfol group, C2— 6-alkynylsulfol group, C1-6 alkylsulfuryl group, C2—6-alkylsulfuryl group, C2—6-alkylsulfuryl group, pyridylthio group, morpholinomethyl Group, piperidino group,
  • R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C16 alkyloxycarbon group, or CONHCH CHOH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group
  • R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (on the phenyl group, 1 to 2 Having a number of R e groups,
  • B e is a naphthyl group
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a phenyl group, a nitro group, or an amino group,
  • R h represents a hydrogen atom or an amino group, NR,
  • Ri represents a hydrogen atom or a C16 alkyl group.
  • a ′ represents a hydrogen atom
  • Another aspect is a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound or a salt thereof as an active ingredient, preferably a FabK inhibitor comprising the above-described compound or a salt thereof as an active ingredient, or Fabl and The compound or salt thereof as described above, which inhibits FabK.
  • the compound according to the present invention can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto.
  • the compounds according to the present invention are not limited to the following production methods, and salts and reagents are exemplified for the sake of convenience, and are not limited thereto.
  • PG represents a protective group, and the protective group is desorbed as necessary during the production process.
  • Protective groups are used in accordance with the protective groups described in Protective groups in organic synthesis, 2nd ed., (John Wiley & Sons Inc., 1991) and the methods described above.
  • a known method for substituting the side chain and the substituent on the side chain as necessary a known method, an experimental chemistry course (edited by the Chemical Society of Japan, Maruzen), etc. can be applied.
  • urea-type derivatives can be produced according to Scheme I or II, or a method via isocyanate.
  • the obtained compound of the formula (2) is used as it is or after purification, and in the presence of a suitable base as necessary (as the organic base, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene,
  • a suitable base as necessary
  • examples of inorganic bases such as 2,6-lutidine include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and preferably diisopropylethyl.
  • a suitable solvent acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, (Toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof may be mentioned, preferably tetrahydrofuran, N, N-dimethylformamide, etc.). be able to.
  • the reaction temperature is preferably 0 to 150 ° C., more preferably 20 to 50 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 18 hours.
  • the reaction solvent may be inert to the halogenating agent.
  • the halogenating agent for example, dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, N , N-dimethylformamide, benzene, toluene, xylene, hexane, or octane, preferably dichloromethane.
  • the reaction temperature is 0 to: LOO ° C is preferably 0 to 30 ° C, and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 13 hours. .
  • the step of reacting the formulas (5) and (6) is carried out in the presence of a suitable base (for example, diisopropylpyrutamine, diazabicyclo [2, 2, 2] undecene, or 2,6-lutidine as the organic base
  • a suitable base for example, diisopropylpyrutamine, diazabicyclo [2, 2, 2] undecene, or 2,6-lutidine
  • the inorganic base include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and preferably diisopropyl etheramine.
  • reaction solvent is inert to the halogenating agent, for example, dichloromethane, chloroform, carbon tetrachloride, disulfide Carbonized carbon, N, N-dimethylformamide, benzene, toluene, xylene, hexane, octane, etc. are preferable, and dichloromethane is preferable.
  • the reaction temperature is 0 to: LO 0 ° C is preferred, more preferably 0 to 30 ° C, and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 6 hours.
  • the acetophenone represented by the formula (8) which is available as a commercial product or obtained by the method described in J. Macromol. Sci. Chem., (1977),, (3), 507, is converted to an appropriate halogen An agent (eg, J. Am. Chem. So, (1964), 29, 3459, J. Het. Chem “(1988), 25,337, J. Am. Chem. Soc, (1980), 102, 2838, Biorg Med. Chem. Lett., (1996), 6 (3), 253, J. Med. Chem "(1988), 31 (10), 1910, J. Am. Chem. Soc., (1999), 121,248 , J. Macro mol. Sci.
  • a suitable solvent eg acetone, acetonitrile, dichloromethane, chloroform
  • 1,2-dichloroethane 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol To Kisamechirurin triamide, etc.
  • reaction temperature is -10 ⁇ 1 00 ° C is preferable, and 0 to 30 ° C is more preferable.
  • reaction time is preferably 0.5 to 24 hours. More preferably, it is 1 to 6 hours.
  • a suitable base for example, triethylamine, diiso
  • the inorganic base examples include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably sodium methoxide.
  • the ammonium salt eg, ammonium nitrate, salty ammonium, odorous ammonia, ammonium sulfate, or ammonium acetate.
  • salt salt ammonium or bromide ammonium and converted to amidines represented by formula (10).
  • the reaction temperature is ⁇ 10 to: L00 ° C is preferable, and more preferably 0 to 30 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 4 hours.
  • the obtained amidine (10) and the formula (9) are combined with a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, or 2,6 as the organic base).
  • a suitable base for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, or 2,6 as the organic base.
  • — Lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably calcium carbonate
  • the 2-aminomethylimidazo complex can be obtained by reacting in the presence.
  • the reaction temperature is preferably 0 to: L0 0 ° C, more preferably 20 to 70 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 1-3 hours.
  • Acid salts hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. as inorganic acids, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. as organic acids
  • formula (3-2) A compound is obtained.
  • the 2-aminothiazole compound represented by the formula (13) is also available as a commercial product.
  • halogenated alkyl (F) and thiourea in a suitable solvent (aceton, acetonitrinol, dichloromethane, chlorohonolem, 1,2-dichloroethane, ethynole acetate, tetrahydrofuran, dioxane, jetyl ether , Isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, or a mixed solvent thereof, preferably in ethanol)
  • a suitable solvent aceton, acetonitrinol, dichloromethane, chlorohonolem, 1,2-dichloroethane, ethynole acetate, tetrahydrofuran, dioxane, jetyl ether , Isopropyl ether,
  • the reaction temperature is preferably -10 to 100 ° C, more preferably 50 to 80 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 1 hour.
  • Suitable bases for commercially available 2-amino-5 bromothiazole halides (D) and (E) for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene as organic bases
  • the inorganic base includes sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably hydroxide Quaternary ammonium salts (for example, tetraptyl ammonium fluoride, benzyl dimethyl phenol ammonium chloride, benzyl tributyl ammonium chloride, phenol triethyl) Ammo-um chloride, tetraptyl ammo
  • the reaction temperature is -10 ⁇ : LOO ° C is preferred More preferably, it is 25 to 50 ° C.
  • the reaction time is preferably 0.5 to 48 hours, more preferably 24 to 30 hours.
  • the 2-aminothiazole compound represented by the formula (13) is mixed in a suitable solvent (for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, Examples thereof include jetyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably tetrahydrofuran, etc.
  • a suitable solvent for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane
  • a suitable solvent for example, acetone, acetonitrile, dichloromethane, chlor
  • CDI 1, 1'-carbonyldiimidazole
  • the reaction temperature is preferably 0 to 100 ° C. More preferably, it is 10 to 40 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 1 to 12 hours. .
  • the reaction between the formulas (2-2) and (3-2) is carried out in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene as the organic base, or 2, 6-lutidine and the like, and the inorganic base includes sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. Is diisopropylethylamine, etc.
  • a suitable base for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene
  • the inorganic base includes sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. Is diisopropylethylamine, etc.
  • a suitable solvent for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, Hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, hexamethylphosphorus (Examples include triamide and the like, or a mixed solvent thereof, and preferably tetrahydrofuran, etc.)
  • a compound represented by the formula (42) was obtained.
  • the reaction temperature was 0 to: LOO ° C is more preferably 10 to 40 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 1 to 12 hours.
  • the formula (1) or (3) such as triphosgene is an isocyanate compound, and in the case of the isocyanate compound of the formula (1), the formula (3) is replaced by the formula (3).
  • the formula (4) can be obtained by reacting the formula (1).
  • the compound represented by the formula (4) obtained by Scheme I, the formula (7) obtained by Scheme II, and the formula (4 2) obtained by Scheme III may have a side chain as necessary. You can also convert The order of response can be changed as necessary.
  • the compound of the present invention corresponding to the formula (16) can be produced by Eur. J. Med. Chem., (2003), 38, 10 25, J. Med. Chem., (1999), 42, 3458. Chem. Pharm. Bull. (2001), 49.
  • the amine represented by the formula (17) is a halogenated acetyl chloride (for example, chloroacetyl chloride) and a suitable solvent (acetone, acetonitrile, dichloromethane, Form, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethyl phosphate triamide Or a mixed solvent thereof, preferably benzene, etc.
  • a suitable solvent acetone, acetonitrile, dichloromethane, Form, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane
  • a halogenated acetamide of formula (14) is obtained by reaction.
  • the reaction temperature is preferably -10 to 100 ° C, more preferably 40 to 80 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 2 hours.
  • the oxime compound represented by formula (15) can be synthesized with formula (14) in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, or 2 , 6-lutidine, and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably Is potassium carbonate) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether).
  • a suitable base for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, or 2 , 6-lutidine, and the like
  • the reaction temperature is preferably ⁇ 10 to 100 ° C., more preferably 0 to 30 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 3 hours.
  • the oxime compound represented by the formula (15) is mixed with an a-halogenoacetate ester represented by the formula (20) in the presence of an appropriate base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, 2,6-lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, Or cesium carbonate, etc., preferably sodium hydride, etc.) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, Jetyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethylsulfate (E.g., amide, toluene,
  • an appropriate base for example
  • the reaction temperature is preferably 10 to: L0 0 ° C, more preferably 0 to 30 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 3 hours.
  • Formula (22) can be manufactured by the method of Tetrahedron (2001), 57,1551 or Tetrahedron (1999), 55,13159.
  • the obtained compound represented by the formula (22) is converted into a suitable halogenating agent such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, salt oxalil, or N , ⁇ '-dicyclohexylcarbodiimide, ⁇ -hydroxyphthalimide, ⁇ -hydroxysuccinimide, or HOBT (l- Hydroxybenzotriazole hydrate) ⁇ WS (Water soluble carbodnmide nydro chloride, 1— Ethyl— «3— (3— dimethylaminopropyl ) carbodiimide hydrochloride) and other suitable solvents (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, hexane,
  • the reaction temperature is preferably 10 to 100 ° C, more preferably 10 to 50 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 1 to 6 hours.
  • the obtained compound represented by the formula (18) and the amine represented by the formula (17) are present in the presence of an appropriate base (as the organic base, triethylamine, diisopropylethylamine, diazabicyclo [2] , 2, 2] undecene, or 2,6-lutidine, and the inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, cesium carbonate.
  • an appropriate base as the organic base, triethylamine, diisopropylethylamine, diazabicyclo [2] , 2, 2] undecene, or 2,6-lutidine
  • the inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, cesium carbonate.
  • Etc. preferably diisopropylethylamine, triethylamine, etc.
  • a suitable solvent acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl
  • Ether isopropyl ether, hexane, N, N dimethylformamide, dimethylsulfoxy , Toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably benzene, etc.
  • the reaction temperature is — 10-100 ° C is preferred, more preferably 10-50 ° C.
  • the reaction time is preferably 0.5-24 hours. More preferably, it is 1 to 6 hours.
  • the compound of formula (22) can be obtained from the formula (16) obtained by reacting with the formula (17) using the condensing agent for peptide synthesis.
  • formula (24) is obtained by peptide-bonding formula (17) and formula (23) using the condensing agent for peptide synthesis usually used by those skilled in the art. .
  • the formula (23), which is commercially available, is converted into an appropriate solvent (acetone, acetonitrile, dichloromethane, chloroform, 1, 2, -dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, Examples thereof include isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric acid triamide, or a mixed solvent thereof, preferably tetrahydrofuran or N, N dimethylformamide.
  • the compound (24) is obtained by reacting with the peptide synthesis condensing agent and the compound represented by the formula (17).
  • the reaction temperature is preferably 10 to 100, more preferably 10 to 50 ° C.
  • the reaction time is preferably 0.5 to 24 hours! /. More preferably, it is 1 to 6 hours.
  • the compound represented by the formula (14) is added in the presence of a suitable base
  • the organic base is Ethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine and the like
  • inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, carbonate Examples include potassium hydrogen, sodium carbonate, potassium carbonate, cesium carbonate, and preferably sodium methoxide. ), Commercially available, or Acta Chem.
  • a compound according to the present invention in which the salt is preferably a pharmaceutically acceptable salt may be provided as the salt.
  • the salt examples include alkali metals, alkaline earth metals, ammonium, organic bases, etc., preferably lithium, sodium, potassium, magnesium, calcium, ammonium, ethanolamine, triethanolamine, trimethyl. And amine, triethylamine, diisopropylamine and the like.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, kenate, camphorate, camphorsulfone.
  • Acid salt cyclopentanepropionate, didarconate, dodecyl sulfate, ethane sulfonate, fumarate, darcoheptanoate, glycephosphate, hemisulfate, heptanoate, hexaneate, Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, Pamoate, pectate, persulfate, 3-phenolpropionate, picrate, bivalinate, propionate, succinate, tartrate, thiocyanate, Examples include tosylate and undecanoate.
  • the compounds (I) or ( ⁇ ⁇ ⁇ ) to (V) according to the present invention are hydrates or non-hydrates. Also good. These compounds or salts thereof may have asymmetric carbon and geometric isomerism in the molecule. Each of them or mixtures thereof are included in the present invention.
  • solvates may include water, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, Or black mouth form etc. are mentioned.
  • the medicament provided by the present invention comprises a compound represented by the general formula (I) and a physiologically acceptable salt thereof, and a group force that is a solvate power thereof as an active ingredient. It is characterized by containing.
  • the medicament of the present invention can be administered orally or parenterally. Examples of parenteral administration include intranasal, eye drop, ear drop, transdermal, respiratory tract, intrarectal, intraurinary, subcutaneous, intramuscular, and intravenous routes.
  • parenteral administration include intranasal, eye drop, ear drop, transdermal, respiratory tract, intrarectal, intraurinary, subcutaneous, intramuscular, and intravenous routes.
  • the above-mentioned substance as an active ingredient may be administered as it is, but generally, a pharmaceutical composition is produced using one or two or more pharmaceutical additives (carriers). It is desirable to invest.
  • preparations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, wearables, suspensions, etc.
  • suitable formulations include, for example, injections, drops, inhalants, sprays, suppositories, vaginal suppositories, transdermal absorption agents, transmucosal absorption agents, eye drops, ear drops, nasal drops, or A patch etc. can be mentioned.
  • Liquid preparations such as injections and infusions are provided as powdered pharmaceutical compositions in lyophilized form, and water or other suitable media (for example, physiological saline, glucose infusion solution, buffer solution, etc.) can be mentioned at the time of use. )) Or dissolved in suspension.
  • the additive for the formulation can be appropriately selected depending on the form of the pharmaceutical composition, and the type thereof is not particularly limited, but for example, a stabilizer, a surfactant, a plasticizer, a lubricant, a solubilizing agent.
  • Agent buffering agent, sweetener, base, adsorbent, flavoring agent, binder, suspending agent, brightening agent, coating agent, flavoring agent, fragrance, wetting agent, wetting regulator, filler, extinguishing agent foams, chews, fresheners, wearing colorant, dragees, tonicity agents, P H modifiers, softeners, emulsifiers, adhesives, adhesion enhancer, viscous agents, thickening agents, foaming agents , Excipients, dispersants, propellants, disintegrants, disintegration aids, fragrances, desiccants, preservatives, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents, etc.
  • the pharmaceutical composition of a desired form can be manufactured according to a method generally used in this field.
  • the pharmaceutical composition can be prepared so that the substance as an active ingredient is 1.0 to 100% (W / W), preferably 1.0 to 60% (W / W). wear.
  • the compounds described herein are inhibitors of FabK or Fabl / FabK and are useful for the treatment of bacterial infections.
  • these compounds include upper respiratory tract infections (eg, otitis media, bacterial tracheitis, acute pharyngitis, or thyroiditis), lower respiratory tract infections (eg, empyema or lung abscess).
  • Heart infection eg, infection endocarditis
  • gastrointestinal infection eg, secretory diarrhea, spleen abscess, or retroperitoneal abscess
  • CNS infection eg, cerebrum
  • eye infections eg, conjunctivitis, keratitis, endophthalmitis, anterior septum, blepharitis and orbital cellulitis, or lacrimal cystitis
  • kidney and ureteral infections for example, accessory testicularitis, intrarenal and perirenal abscess, or toxic shock syndrome
  • skin infections eg, impetigo, folliculitis, skin abscess, cellulitis, wound infection, or bacterial myositis As well as bone And joint infections (e.g., septic arthritis or osteomyelitis, and the like.) are effective in the treatment of bacterial infections, such as.
  • the compounds of the present invention are also useful as antifungal agents, and the compounds can be used in combination with known antibiotics.
  • the dose and frequency of administration of the medicament of the present invention are not particularly limited, but it is appropriately administered according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, or symptoms of the patient.
  • the amount and number of administrations can be determined. In the case of oral administration, it can be administered once or several times per day so that the amount of active ingredient per day for adults is 0.1 to 1000 mg / kg.In the case of parenteral administration, 0.001 to 500 mg / kg It is preferable to administer once or several times a day.
  • Example 30 The compound of Example 30 was produced in the same manner as in Example 25.
  • Example 30 The compound obtained in Example 30 22.5 mg, 28% aqueous ammonia 5 L, using the above Example 2
  • Example 41 N— (2 Hydroxyethyl) 4 (2— (3 — ((4 ferro- 1H imidazole-2 yl) methyl) ureido) thiazole-5-ylthio) benzamide
  • Example 30 Using 22.5 mg of the compound obtained in 1 above and 5 L of aminoethanol, 8.9 mg of the title compound was obtained in the same manner as in Example 26.
  • Example 56 was prepared in the same manner as in Example 302 described later, the compound of Example 57 was treated in the same manner as in Example 55, and the compounds of Examples 58 to 62 were synthesized in the same manner as in Example 29. In the same manner, the compounds of Examples 63 to 64 were produced in the same manner as in Example 302 described later.
  • Example 66 was prepared by the same method as in Example 65, the compound of Example 67 was prepared by the same method as in Example 29, and the compound of Example 68 was prepared by the same method as in Example 25.
  • Examples 69 to 70 The compounds were prepared in the same manner as in Example 29.
  • Example 72 The compound of Example 72 was produced in the same manner as in Example 29.
  • the compound of this example was produced in the same manner as in Example 29.
  • the compound of this example was produced in the same manner as in Example 29.
  • Example 80 The compound of Example 79 was produced in the same manner as in Example 302 described later. [0119] [Example 80]
  • Example 77 Using 10.6 mg of the compound obtained in Example 77, 6. lmg of the title compound was obtained in the same manner as in Example 25.
  • Example 83 The compound of Example 83 was produced in the same manner as in Example 84 described later.
  • N- (5-Methylthiothiazol-2-yl) -1H-imidazole-1 Carboxamide 12 mg (0. O50 mmol) was dissolved in 1 mL of tetrahydrofuran, and (4- (4 bromophenol) -1H-imidazole-2-yl) Methylamine hydrochloride 18 mg (0. 55 mmol), N 2, ⁇ , -diisopropylethylamine 19 L (0. 1 mmol) was added and stirred at room temperature overnight. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol 10 Zl) to obtain the title compound (21 mg, 99%) o
  • Example 90 The compound of Example 90 was produced in the same manner as in Example 29.
  • Example 98 The compound of Example 98 was produced in the same manner as in Example 29.
  • Example 101 to 102 were produced in the same manner as in Example 29, and Example 103 was produced in the same manner as in Example 302 described later.
  • Example 108 to 197 were the same as in Example 29, Example 198 was the same as Example 302 described later, and Examples 199 to 215 were the same as Example 29.
  • Example 216 was produced in the same manner as Example 302 described later, and Examples 217 to 231 were produced in the same manner as in Example 29.
  • Example 233 to 256 were the same as in Example 29, the compound of Example 257 was the same as Example 302 described later, and the compounds of Examples 258 to 276 were In the same manner as in Example 29, the compound of Example 277 was prepared in the same manner as in Example 302 described later, and the compounds of Examples 278 to 301 were prepared in the same manner as in Example 29.
  • N— (6-Methoxybenzo [d] thiazol-2-yl) -1H-imidazole 1-carboxamide 27 mg is dissolved in 1 mL of tetrahydrofuran, and 2-aminomethyl 4-phenol — 1H-imidazole hydrochloride 30 mg, N , N, -Diisopropylethylamine 41 ⁇ L was added and stirred overnight at room temperature. The reaction system was concentrated under reduced pressure, and the residue was purified by ⁇ -TLC (black mouth form ⁇ methanol 20 Zl) to obtain the title compound.
  • Example 400 was produced in the same manner as in Example 401 described later.
  • the extract was concentrated under reduced pressure, and the resulting solid was recrystallized and purified with a mixed solution of ethyl acetate and methanol. The resulting crystals were collected by filtration with a Kiriyama funnel and washed with methanol to give the title compound. (23.4 mg, 30%).
  • Example 408 to 414 are the same as in Example 401, the compounds of Examples 415 to 501 are the same as in Example 669 described later, and the compound of Example 502 is described later.
  • Example 671 the compounds of Examples 503 to 668 were prepared in the same manner as in Example 669 described later.
  • Example 735 to 737 were produced in the same manner as in Example 734, and the compounds of Examples 738 to 750 were produced in the same manner as in Example 703.
  • Tables 2 and 3 are compounds represented by the formulas (3-2) and (13) in the schemelll described above.
  • Benzyl 2 amino-2-iminoethylcarbamate hydrobromide 86 4 mg (3. Om mol) dissolved in 30 mL of a mixed solution of tetrahydrofuran / water 10/1, potassium carbonate 41 5 mg (3. Ommol), 2 Promo 1 One (4 bromophenol) Ethanone 584mg (2. lmm ol) was added and stirred at 80 ° C. for 30 minutes. Saturated brine was added to the mixed solution, extracted with methyl chloride, and dried over sodium sulfate. The solid obtained by concentration under reduced pressure was washed with black mouthform to obtain the title compound (232 mg, 20%).
  • the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • the title compound was obtained (4. Omg, 43%).
  • N- (5 thiocyanatothiazole-2-yl) acetamide lllmg (0.56 mmol) was dissolved in 8 mL of methanol, and 171 mg (l.llmmol) of dithiothreitol was added and stirred at room temperature for 2 hours.
  • the mixed solution was concentrated under reduced pressure, replaced with argon, and redissolved in 8 mL of N, N, -dimethylformamide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biotechnology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Microbiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)

Abstract

L’invention concerne un composé capable d’inhiber à la fois FabI et FabK, qui sont des synthases d’acides gras, afin de présenter un spectre antibactérien comprenant Streptococcus pneumoniae, Pseudomonas aeruginosa et Enterococcus faecalis, et pouvant donc être utilisé pour le traitement d’une infection bactérienne.
PCT/JP2007/051523 2006-01-30 2007-01-30 NOUVEL INHIBITEUR DE FabK ET DE FabI/K WO2007086584A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2006021372A JP2009091251A (ja) 2006-01-30 2006-01-30 新規ＦａｂＫおよびＦａｂＩ／Ｋ阻害剤とその製造法
JP2006-021372 2006-01-30
JP2006243953A JP2009091252A (ja) 2006-09-08 2006-09-08 新規ＦａｂＫ阻害剤およびその製造法
JP2006-243953 2006-09-08

Publications (1)

Publication Number Publication Date
WO2007086584A1 true WO2007086584A1 (fr) 2007-08-02

Family

ID=38309361

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/051523 WO2007086584A1 (fr) 2006-01-30 2007-01-30 NOUVEL INHIBITEUR DE FabK ET DE FabI/K

Country Status (1)

Country Link
WO (1) WO2007086584A1 (fr)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009159939A (ja) * 2007-12-28 2009-07-23 Korea Advanced Inst Of Sci Technol ＦａｂＫ蛋白質の３次元結晶構造、及びこれを利用したＦａｂＫ蛋白質阻害剤開発方法
KR101062770B1 (ko) 2008-12-04 2011-09-07 한국생명공학연구원 ＦａｂＫ 저해활성을 갖는 신규한 항폐렴 화합물, 이의 제조방법 및 이를 포함하는 항폐렴용 약학 조성물
WO2011132048A1 (fr) * 2010-04-19 2011-10-27 Glenmark Pharmaceutical S.A. Composés hétéroaryle en tant qu'inhibiteurs de la pde 10a
JP2013511486A (ja) * 2009-11-18 2013-04-04 ファブ ファーマ エスエーエス 新規の複素環式アクリルアミド及び医薬としてのその使用
CN104292224A (zh) * 2014-09-24 2015-01-21 贵州大学 含取代1,3,4-噻(噁)二唑硫醚苯并噻唑酰胺类衍生物及其制备方法和应用
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
WO2016105485A3 (fr) * 2014-12-23 2016-09-01 Proteostasis Therapeutics, Inc. Composés, compositions et procédés pour augmenter l'activité du cftr
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
JP2017520528A (ja) * 2014-05-21 2017-07-27 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ホルミルペプチド受容体調節物質としてのイミダゾール誘導体
US9725427B2 (en) 2012-03-16 2017-08-08 Biohaven Pharmaceutical Holding Company Limited Prodrugs of riluzole and their method of use
US9745292B2 (en) 2014-03-13 2017-08-29 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
WO2017155052A1 (fr) * 2016-03-09 2017-09-14 日本曹達株式会社 Composé pyridine et son utilisation
US9790219B2 (en) 2014-03-13 2017-10-17 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
JP2018526413A (ja) * 2015-09-09 2018-09-13 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
WO2018229197A1 (fr) * 2017-06-14 2018-12-20 European Molecular Biology Laboratory Composés d'urée ou de carbamate hétéroaromatiques bicycliques destinés à être utilisés en thérapie
US10174014B2 (en) 2014-06-19 2019-01-08 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10344023B2 (en) 2014-12-23 2019-07-09 Proteostasis Therapeutics, Inc. Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10392378B2 (en) 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylathiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
WO2020010252A1 (fr) * 2018-07-05 2020-01-09 Daiichi Sankyo Company, Limited Composé cyclique fusionné ayant une structure d'urée
US10550106B2 (en) 2015-10-06 2020-02-04 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
US10548878B2 (en) 2015-07-24 2020-02-04 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods of increasing CFTR activity
US10662207B2 (en) 2016-04-07 2020-05-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
US10738011B2 (en) 2014-12-23 2020-08-11 Proteostasis Therapeutics, Inc. Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10899751B2 (en) 2016-06-21 2021-01-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5084539A (fr) * 1973-11-29 1975-07-08
JPH05148249A (ja) * 1991-11-28 1993-06-15 Japan Tobacco Inc ベンゾオキサジノン誘導体
JPH06509331A (ja) * 1991-07-10 1994-10-20 ローン−プーラン・ロレ・ソシエテ・アノニム ピロリジンおよびチアゾリジン誘導体、それらの製造およびそれらを含んでいる薬剤
JP2003511448A (ja) * 1999-10-08 2003-03-25 スミスクライン・ビーチャム・コーポレイション Ｆａｂｉ阻害剤
JP2004501066A (ja) * 2000-01-28 2004-01-15 ブリストル−マイヤーズ　スクイブ　カンパニー 脂肪酸結合タンパク質のテトラヒドロピリミドンインヒビターおよび方法
WO2004004657A2 (fr) * 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Inhibiteurs de l'integrase du vih
WO2004032716A2 (fr) * 2002-10-08 2004-04-22 Massachusetts Institute Of Technology Composes pour la modulation du transport du cholesterol
WO2004082586A2 (fr) * 2003-03-17 2004-09-30 Affinium Pharmaceuticals, Inc. Compositions comportant plusieurs agents antibiotiques, et leurs procedes de mise en oeuvre
JP2005515206A (ja) * 2001-12-12 2005-05-26 ブリストル−マイヤーズ　スクイブ　カンパニー Ｈｉｖインテグラーゼ・インヒビター
WO2006074025A1 (fr) * 2004-12-30 2006-07-13 Janssen Pharmaceutica N.V. Urees piperazinyle et piperidinyle en tant que modulateurs de l’amide hydrolase d’acides gras
WO2007020888A1 (fr) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Agent protegeant des cellules du cerveau/neuronales et agent therapeutique pour des troubles du sommeil

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5084539A (fr) * 1973-11-29 1975-07-08
JPH06509331A (ja) * 1991-07-10 1994-10-20 ローン−プーラン・ロレ・ソシエテ・アノニム ピロリジンおよびチアゾリジン誘導体、それらの製造およびそれらを含んでいる薬剤
JPH05148249A (ja) * 1991-11-28 1993-06-15 Japan Tobacco Inc ベンゾオキサジノン誘導体
JP2003511448A (ja) * 1999-10-08 2003-03-25 スミスクライン・ビーチャム・コーポレイション Ｆａｂｉ阻害剤
JP2004501066A (ja) * 2000-01-28 2004-01-15 ブリストル−マイヤーズ　スクイブ　カンパニー 脂肪酸結合タンパク質のテトラヒドロピリミドンインヒビターおよび方法
JP2005515206A (ja) * 2001-12-12 2005-05-26 ブリストル−マイヤーズ　スクイブ　カンパニー Ｈｉｖインテグラーゼ・インヒビター
WO2004004657A2 (fr) * 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Inhibiteurs de l'integrase du vih
WO2004032716A2 (fr) * 2002-10-08 2004-04-22 Massachusetts Institute Of Technology Composes pour la modulation du transport du cholesterol
WO2004082586A2 (fr) * 2003-03-17 2004-09-30 Affinium Pharmaceuticals, Inc. Compositions comportant plusieurs agents antibiotiques, et leurs procedes de mise en oeuvre
WO2006074025A1 (fr) * 2004-12-30 2006-07-13 Janssen Pharmaceutica N.V. Urees piperazinyle et piperidinyle en tant que modulateurs de l’amide hydrolase d’acides gras
WO2007020888A1 (fr) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Agent protegeant des cellules du cerveau/neuronales et agent therapeutique pour des troubles du sommeil

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009159939A (ja) * 2007-12-28 2009-07-23 Korea Advanced Inst Of Sci Technol ＦａｂＫ蛋白質の３次元結晶構造、及びこれを利用したＦａｂＫ蛋白質阻害剤開発方法
KR101062770B1 (ko) 2008-12-04 2011-09-07 한국생명공학연구원 ＦａｂＫ 저해활성을 갖는 신규한 항폐렴 화합물, 이의 제조방법 및 이를 포함하는 항폐렴용 약학 조성물
US9051321B2 (en) 2009-11-18 2015-06-09 Fab Pharma S.A.S. Heterocyclic acrylamides and their use as pharmaceuticals
JP2013511486A (ja) * 2009-11-18 2013-04-04 ファブ ファーマ エスエーエス 新規の複素環式アクリルアミド及び医薬としてのその使用
US9321769B2 (en) 2009-11-18 2016-04-26 Fab Pharma S.A.S. Heterocyclic acrylamides and their use as pharmaceuticals
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors
WO2011132048A1 (fr) * 2010-04-19 2011-10-27 Glenmark Pharmaceutical S.A. Composés hétéroaryle en tant qu'inhibiteurs de la pde 10a
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US10844026B2 (en) 2012-03-16 2020-11-24 Biohaven Pharmaceutical Holding Company Ltd. Prodrugs of riluzole and their method of use
US9725427B2 (en) 2012-03-16 2017-08-08 Biohaven Pharmaceutical Holding Company Limited Prodrugs of riluzole and their method of use
US10562870B2 (en) 2012-03-16 2020-02-18 Biohaven Pharmaceutical Holding Company Ltd. Prodrugs of riluzole and their method of use
US11440893B2 (en) 2012-03-16 2022-09-13 Biohaven Pharmaceutical Holding Company Ltd. Prodrugs of riluzole and their method of use
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9790219B2 (en) 2014-03-13 2017-10-17 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US10017503B2 (en) 2014-03-13 2018-07-10 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US9745292B2 (en) 2014-03-13 2017-08-29 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
JP2017520528A (ja) * 2014-05-21 2017-07-27 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ホルミルペプチド受容体調節物質としてのイミダゾール誘導体
US10174014B2 (en) 2014-06-19 2019-01-08 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US10738040B2 (en) 2014-06-19 2020-08-11 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
CN104292224A (zh) * 2014-09-24 2015-01-21 贵州大学 含取代1,3,4-噻(噁)二唑硫醚苯并噻唑酰胺类衍生物及其制备方法和应用
CN107207487A (zh) * 2014-12-23 2017-09-26 蛋白质平衡治疗股份有限公司 用于提高cftr活性的化合物、组合物和方法
US11098035B2 (en) 2014-12-23 2021-08-24 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
WO2016105485A3 (fr) * 2014-12-23 2016-09-01 Proteostasis Therapeutics, Inc. Composés, compositions et procédés pour augmenter l'activité du cftr
CN107207487B (zh) * 2014-12-23 2021-12-28 蛋白质平衡治疗股份有限公司 用于提高cftr活性的化合物、组合物和方法
US10738011B2 (en) 2014-12-23 2020-08-11 Proteostasis Therapeutics, Inc. Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10344023B2 (en) 2014-12-23 2019-07-09 Proteostasis Therapeutics, Inc. Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10392372B2 (en) 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US10392378B2 (en) 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylathiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US11083709B2 (en) 2015-07-24 2021-08-10 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods of increasing CFTR activity
US10548878B2 (en) 2015-07-24 2020-02-04 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods of increasing CFTR activity
US11142507B2 (en) 2015-09-09 2021-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
JP2018526413A (ja) * 2015-09-09 2018-09-13 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
JP7028766B2 (ja) 2015-09-09 2022-03-02 ダナ－ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
US11136313B2 (en) 2015-10-06 2021-10-05 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
US10550106B2 (en) 2015-10-06 2020-02-04 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
JPWO2017155052A1 (ja) * 2016-03-09 2019-01-17 日本曹達株式会社 ピリジン化合物およびその用途
US10781177B2 (en) 2016-03-09 2020-09-22 Nippon Soda Co., Ltd. Pyridine compound and use thereof
WO2017155052A1 (fr) * 2016-03-09 2017-09-14 日本曹達株式会社 Composé pyridine et son utilisation
US10662207B2 (en) 2016-04-07 2020-05-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
US11248010B2 (en) 2016-04-07 2022-02-15 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
US10899751B2 (en) 2016-06-21 2021-01-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
WO2018229197A1 (fr) * 2017-06-14 2018-12-20 European Molecular Biology Laboratory Composés d'urée ou de carbamate hétéroaromatiques bicycliques destinés à être utilisés en thérapie
WO2020010252A1 (fr) * 2018-07-05 2020-01-09 Daiichi Sankyo Company, Limited Composé cyclique fusionné ayant une structure d'urée
JP7399122B2 (ja) 2018-07-05 2023-12-15 サンフォード バーンハム プレビス メディカル ディスカバリー インスティテュート ウレア構造を有する縮合環化合物
US11918568B2 (en) 2018-07-05 2024-03-05 Sanford Burnham Prebys Medical Discovery Institute Fused ring compound having urea structure
JP2022511209A (ja) * 2018-07-05 2022-01-31 サンフォード バーンハム プレビス メディカル ディスカバリー インスティテュート ウレア構造を有する縮合環化合物

Similar Documents

Publication Publication Date Title
WO2007086584A1 (fr) NOUVEL INHIBITEUR DE FabK ET DE FabI/K
EP3313828B1 (fr) Inhibiteurs de métallo-bêta-lactamases
KR102008032B1 (ko) 글리코시다아제 저해제로서 피라노[3,2-d][1,3]티아졸
US8293919B2 (en) Antibacterial sulfone and sulfoxide substituted heterocyclic urea compounds
EP1171428B1 (fr) Inhibiteurs de fab i
CA2371876A1 (fr) Inhibiteur de metalloprotease a base d'acide hydroxamique aromatique sulfone
BRPI0911035B1 (pt) ativadores de pirrolidinona glicoquinase
EP3390396B1 (fr) Compose d'isoindole
WO2020216773A1 (fr) Composés de 4h-pyrrolo[3,2-c]pyridin-4-one
US20210284644A1 (en) Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
WO2017024996A1 (fr) Dérivé d'hydroxyamidine, son procédé de préparation et son utilisation en médecine
EP3490984B1 (fr) Agents antibacteriaux de 2-pyrrolidine phenylhydrazide
KR101905295B1 (ko) 나프티리딘디온 유도체
US9896448B2 (en) Pyrimido[4,5-b]quinoline-4,5(3H, 10H)-dione derivatives
WO1998027061A1 (fr) Derives de guanidine n-[(heteroaryle a cinq chainons substitue) carbonyle]
US8026232B2 (en) Benzothiophene oxide derivative and salt thereof
EP4011880A1 (fr) Inhibiteur de janus kinases jak et son utilisation
AU2006212209A1 (en) [1,2,4]-dithiazoli(di)ne derivatives, inducers of gluthathione-S-transferase and NADPH quinone oxido-reductase, for prophylaxis and treatment of adverse conditions associated with cytotoxicity in general and apoptosis in particular
JP2009091251A (ja) 新規ＦａｂＫおよびＦａｂＩ／Ｋ阻害剤とその製造法
EP3693374B1 (fr) Nouveau composé de 2-carboxypéname ou sel de celui-ci, composition pharmaceutique contenant ledit composé ou ledit sel, et application associée
WO2003018135A1 (fr) Procede d'utilisation de 5-(arylsulfonyle)-,5-(arylsulfinyle), et 5-(arylsulfanyle)-thiazolidine-2,4-diones pour l'inhibition de la farnesyle-proteine transferase
WO2023196556A1 (fr) Antagonistes/agonistes inverses du récepteur cannabinoïde 1 et leurs utilisations
US20180099937A1 (en) Novel aryl-cyanoguanidine compounds
KR20150064727A (ko) 신규한 페닐아세트아미드 화합물 및 이를 함유하는 의약
JP2009091252A (ja) 新規ＦａｂＫ阻害剤およびその製造法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07707741

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP