WO2008016007A1 - INHIBITEUR DE LA MÉTALLO-β-LACTAMASE - Google Patents

INHIBITEUR DE LA MÉTALLO-β-LACTAMASE Download PDF

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Publication number
WO2008016007A1
WO2008016007A1 PCT/JP2007/064895 JP2007064895W WO2008016007A1 WO 2008016007 A1 WO2008016007 A1 WO 2008016007A1 JP 2007064895 W JP2007064895 W JP 2007064895W WO 2008016007 A1 WO2008016007 A1 WO 2008016007A1
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Prior art keywords
group
ring
compound
piperidine
acid
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PCT/JP2007/064895
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English (en)
Japanese (ja)
Inventor
Yukiko Hiraiwa
Mizuyo Ida
Toshiaki Kudo
Akihiro Morinaka
Ken Chikauchi
Kenichiro Mori
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Meiji Seika Kaisha, Ltd.
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Priority to JP2008527743A priority Critical patent/JP5301272B2/ja
Publication of WO2008016007A1 publication Critical patent/WO2008016007A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen 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
    • C07D213/24—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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/10—Oxygen atoms
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    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • the present invention relates to a metallo / 3-lactamase inhibitor comprising a phthalic acid derivative as an active ingredient. More specifically, the present invention relates to a / 3-ratata antibiotic in the treatment of bacterial infection in animals or humans. The present invention relates to a pharmaceutical composition and method for enhancing the effectiveness against metallo-3 / 3-lactamase producing bacteria by using in combination with a substance.
  • ⁇ -lactamase is very important in the resistance of bacteria to / 3-ratata antibiotics.
  • a metallo ⁇ -lactamase having zinc at the active center and showing a wide substrate specificity has been regarded as a problem because it also hydrolyzes a carbapenem antibiotic which is relatively stable with respect to serine 0-lactamase.
  • metallo-3 / 3-ratamase-producing bacteria are a threat because they become resistant to many clinically important / 3-latatams.
  • Meta-mouth ⁇ -lactamases are Bacillus cereus, Bacteroides fragilis, Escherichia coli, Aeromonas hyarophila, Klebsiella pneumoniae ⁇ Pseudomonas aer uginosa, Serratia marcescens, Stenotrophomonas maltophilia ⁇ Chigella geni Acinetobacter baumannii ⁇ Citrobacter freundii and Ente robacter cloacae have been confirmed, especially in Pseudomonas aeruginosa (Pseudomonas aeruginosa).
  • Clavulanic acid, sulbactam, and tazobactam which are currently used as / 3-lactamase inhibitors, are useful for serine 0-lactamases with serine as the active center, but have no inhibitory effect on metallo-lactamase.
  • J. Am. Chem. So, 1918, 40, 219 is 3_hydroxyphthalic acid as a compound having an oxygen atom at the 3rd position of phthalic acid (the 4th to 6th positions are unsubstituted).
  • Pr. Chem. Soc, 1907, 22, 323 discloses 3-methoxyphthalic acid and the like, and WO97 / 029079 discloses 3_pentyloxyphthalic acid.
  • phthalic acid having a cyclic alkyloxy group or piperidinyloxy group is known!
  • JP-A-10-239909 discloses 3-dimethylaminophthalic acid as a compound having a nitrogen atom at the 3-position of phthalic acid. Cyclic ammine, piperazine ring, and morpholine at the 3-position of phthalic acid. A compound with a ring is known!
  • W097 / 47589 discloses similar compounds in the Marcouch structure. Is an insecticide, and there is no disclosure or suggestion of a phthalic acid derivative according to the present invention.
  • an object of the present invention is to provide a novel metallo / 3-lactamase inhibitor that is a drug that suppresses the inactivation of a / 3-ratata antibiotic and restores the antibacterial activity.
  • the present invention is based on strength and knowledge.
  • a metallo / 3-lactamase inhibitor comprising a hydrate or solvate thereof:
  • R 1 is a hydroxyl group, a C alkyl group, a C alkoxy group, the following ring:
  • --O- represents a piperidine ring, piperidine ring, phenyl group, nitro group, amino group, azetidine ring, piper lysine ring, tetrahydropyridine ring, piperazine ring, morpholine ring, or azepane ring, all of which It may have a substituent
  • R 2 represents a hydrogen atom or a C alkyl group, each of which has a substituent.
  • R 3 represents a hydrogen atom, a C alkyl group, a halogen atom, an amino group, or a piperidine ring.
  • M 1 and M 2 represent a hydrogen atom which may be the same or different, a pharmaceutically acceptable force thione, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. ).
  • Ring B represents an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, or a azepane ring, which may be! /, Which also has R 4 ! /. ,
  • R 4 is 0 to 2 on the B ring and is a hydroxyl group, a C alkyl group, a C alkoxy group, a hydro
  • X-C alkyl group, oxo ( ⁇ ) group, benzyl group, benzoyl group, phenyl group, amino
  • M 1 and M 2 are hydrogen atoms which may be the same or different, pharmaceutically acceptable force Thion, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. ).
  • R 1 represents a piperidine ring or an amino group, any of which may have a substituent.
  • R 2 represents a hydrogen atom
  • R 3 represents a C alkyl group, a halogen atom, a piperidine ring, or an amino group, and these
  • M 1 and M 2 represent a hydrogen atom which may be the same or different, a pharmaceutically acceptable force thione, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. ).
  • Another aspect of the present invention provides a novel compound represented by the following general formula (III), a salt thereof, or a hydrate or solvate thereof:
  • L represents a single bond or a double bond
  • R 4 is 0 to 2 on the C ring, and is a hydroxyl group, a C alkyl group, a C alkoxy group, a hydro
  • R 5 represents a hydrogen atom, a C alkenyl group, a benzyl group, a benzoyl group, a C alkyloxy group.
  • M 1 and M 2 represent a hydrogen atom which may be the same or different, a pharmaceutically acceptable force thione, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. ).
  • n 0-6,
  • R 6 represents a hydroxyl group, a cyclic C alkyl group, a phenyloxy group, a phenyl group, a carboxyl group, an optionally substituted piperidyl group, or the A ring.
  • M 1 and M 2 represent a hydrogen atom which may be the same or different, a pharmaceutically acceptable force thione, or a pharmaceutically acceptable group that can be hydrolyzed in vivo.
  • R 6 does not represent a phenyl group.
  • this invention includes the following aspects.
  • a pharmaceutical composition comprising a compound represented by the above general formula (I) and a pharmaceutically acceptable carrier.
  • This pharmaceutical composition is used by being administered simultaneously or sequentially with ⁇ -latata antibiotics.
  • the pharmaceutical composition may further contain a dehydropeptidase inhibitor.
  • a pharmaceutical composition further comprising the metallo / 3-lactamase inhibitor according to claim 1, a ⁇ -ratata antibiotic, and optionally a pharmaceutically acceptable carrier. Things are provided.
  • This pharmaceutical composition may be used as an antibacterial agent.
  • a method for treating bacterial infection comprising administering a combination of a / 3-ratatam antibiotic and the metallo / 3-lactamase inhibitor according to claim 1.
  • a method comprising is provided.
  • C alkyl group represents an alkyl group having 17 carbon atoms.
  • C represents a bond.
  • lower preferably represents C—, and in the case of a ring, preferably represents C.
  • an “alkyl group” or “alkoxy group” as a group or a part of a group is preferably a linear, branched, or cyclic alkyl group having 17 carbon atoms, or a linear or branched chain. Or a cyclic alkoxy group having 1 to 7 carbon atoms.
  • alkyl examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butinole, n-pentinole, neopentinole, i-pentinole, t-pentinole, Examples thereof include i-hexynole, n-heptinole, i-heptinole, cyclopropinole, cyclobutynole, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • cyclic alkyl group as a group or a part of the group preferably represents a monocyclic alkyl group having 37 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, Examples thereof include cyclohexyl and cycloheptyl.
  • alkoxy examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, neopentinoreoxy, i pentinoreoxy, t Pentinoreoxy, n-hexenoreoxy, i-hexenoreoxy, n-heptinoreoxy, i-heptinoreoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like.
  • the “cyclic alkoxy group” as a group or a part of the group preferably represents a monocyclic alkoxy group having 37 carbon atoms, and examples thereof include cyclopropoxy, cyclobutoxy, cyclopentylthio. And xyloxy, cyclohexyloxy, cycloheptyloxy and the like.
  • any of which may have a substituent preferably means that it may have 1 to 6, more preferably 1 to 3 substituents. means. They may be the same or different.
  • substituted means water unless otherwise specified. Acid group, halogen atom, amino group, mono-substituted amino group, di-substituted amino group, azide group, C-al
  • 1-6 means a carbonyl group, a substituted C alkylcarbonyl group, an A ring, a heterocyclic ring, etc.
  • heterocycle means one or two selected from a nitrogen atom, an oxygen atom, and a sulfur atom, 5 to 14 containing 1 to 4 heteroatoms, and 14-membered monocyclic Or a tricyclic heterocycle, preferably 5 to 10-membered monocyclic or bicyclic heterocycle containing 1 to 4 nitrogen, oxygen or sulfur atoms.
  • Halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the “carbonylamino group” represents an NH—CO group.
  • a ring represents the following group.
  • the compound represented by the general formula (I), a salt thereof, or a salt thereof, or A metallo / 3-lactamase inhibitor comprising the hydrate or solvate thereof is provided.
  • the compound represented by the general formula (I) has a metallo / 3-lactamase inhibitory action, and the compound itself can be used as a metallo / 3-lactamase inhibitor.
  • the compound represented by the general formula (I) itself can be used as a metallo / 3-lactamase inhibitor, combined with a carrier, and further combined with a / 3-latatam antibiotic. It is preferable to use it as a pharmaceutical composition described later.
  • R 1 represents a hydroxyl group, a C alkyl group, a C alkoxy group, the above-described ring,
  • --O- represents a piperidine ring, piperidine ring, phenyl group, nitro group, amino group, azetidine ring, piper lysine ring, tetrahydropyridine ring, piperazine ring, morpholine ring, or azepane ring, all of which R 2 which may have a substituent is a hydrogen atom or C
  • R 3 is a hydrogen atom
  • M 1-7 represents an alkyl group, a halogen atom, an amino group, or a piperidine ring, any of which may have a substituent, M 1 and M 2 may be the same or different
  • a hydrogen atom represents a pharmaceutically acceptable cation or a pharmaceutically acceptable group that can be hydrolyzed in vivo.
  • the “C alkyl group” represented by R 1 is a straight chain, branched chain, or ring
  • R 1 is preferably a C alkyl group, more preferably
  • This alkyl group may have a substituent.
  • Group preferably a hydroxyl group, a halogen atom and the like.
  • cyclic examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentinoreoxy, ne-pentinoreoxy, i-pentinoreoxy, t-pentinoreoxy, n-hexenoreoxy, i-hexenoreoxy, cyclopropoxy, cyclobutoxy, cyclopentinoleoxy, cyclohexenoreoxy, cycloheptyloxy, etc., preferably C alkoxy group, and
  • Preferable examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, cyclopropoxy, cyclobutoxy, cyclopentinole, and cyclohexenole.
  • Examples of the alkoxy group may have a substituent.
  • Examples of the alkoxy group include the above-mentioned substituents, preferably a hydroxyl group, a C alkyl group, a C cyclic alkyl.
  • the —O piperidine ring may be bonded at any position, and is preferably an O piperidine-4-yl group or an —O piperidine-1-yl group.
  • Examples of the hydrogen atom on the —O piperidine ring may be substituted, and examples thereof include the above-mentioned substituents, and preferably an alkyloxycarbonyl group.
  • the piperidine ring may be bonded at any position, and is preferably a piperidine 1-yl group or a piperidine 4-yl group.
  • Examples of the hydrogen atom on the piperidine ring may be substituted, and examples thereof include the above-mentioned substituents.
  • the substituent when the piperidine ring is a piperidine 1-yl group, the substituent may be a hydroxyl group, an amino group, a mono-C alkylamino group, a di-C alkylamino group,
  • the substituent is C alkyloxy.
  • Examples of the substituent on which the hydrogen atom on the phenyl group represented by R 1 may be substituted include the above-mentioned substituents, preferably a hydroxyl group and a carboxyl group.
  • the amino group may be either a mono-substituted amino group or a di-substituted amino group which may have a substituent.
  • substituents include the above-mentioned substituents, preferably mono C
  • the “mono C alkylamino group” may be linear, branched or cyclic, or shifted.
  • it is a linear C alkyl group or a cyclic C alkyl group.
  • it is a linear C alkyl group, and the two alkyl groups may be the same or different.
  • Examples thereof include dimethylamino, jetylamino, di-n-propylamino, di-n-butylamino, ethylmethylamino, propylmethylamino, butylmethylamino, ethylpropylamino, butylethylamino, butylpropylamino and the like. .
  • C alkyl
  • the “1-6 carbonylamino group” may be linear, branched or cyclic, and is preferably a linear C anolenoquino group, which includes methylcarbonylamino, ethylcarbonylamino, n
  • N-butylcarbonylamino and the like may be mentioned, and these may be substituted with a hydroxyl group.
  • the azetidine ring may be! /, Bonded at a shift position! /, Preferably a azetidine 1-yl group and the like.
  • Examples of the hydrogen atom on the azetidine ring which may be substituted include the above-mentioned substituents, preferably a hydroxyl group and a C alkyl group.
  • the pyrrolidine ring may be bonded at any position, and a pyrrolidine 1-yl group is preferable.
  • Examples of the hydrogen atom on the pyrrolidine ring may be substituted, and examples thereof include the above-mentioned substituents, preferably a hydroxyl group and a C alkyl group.
  • the tetrahydropyridine ring may be bonded at any position, and is preferably a 1,2,3,6-tetrahydropyridine group, more preferably 1,2,3,6 tetrahydropyridine -1. -Inole group, 1,2,3,6 tetrahydropyridine-4-yl group and the like.
  • Examples of the hydrogen atom on the tetrahydropyridine ring may be substituted, and examples thereof include the above-mentioned substituents, and preferred examples include a C alkyloxycarbonyl group, a hydroxyl group, and a C alkyl group.
  • the piperazine ring may be bonded at any position, and preferred examples include a piperazine 1-yl group.
  • Examples of the hydrogen atom on the piperazine ring that may be substituted include the above-mentioned substituents, preferably a C alkylcarbonyl group, c
  • Examples include an alkyloxycarbonyl group, an aminocarbonyl group, a substituted aminocarbonyl group, a benzyl group, and a benzoyl group.
  • the morpholine ring may be bonded at any position, and preferably includes a morpholine 4-yl group.
  • Examples of the hydrogen atom on the morpholine ring which may be substituted include the above-mentioned substituents, preferably a hydroxyl group and a C alkyl group.
  • the azepan ring may be bonded at any position, and preferably includes an azepanyl group.
  • Examples of the hydrogen atom on the azepan ring may be substituted, and examples thereof include the above-mentioned substituents, preferably a hydroxyl group and a C alkyl group.
  • R 2 represents a hydrogen atom or a C alkyl group.
  • R 2 represents “C
  • “1-7 1-7 alkyl group” has the same meaning as R 1 , preferably C alkyl group, more preferably C
  • 1-6 1 is an alkenoquinol group such as methyl, ethyl, n-propyl, i-propyl, n-butynole
  • R 3 represents a hydrogen atom, a C alkyl group, a halogen atom, an amino group, or
  • R 3 represents “C
  • the “1-alkyl group” has the same meaning as R 1 , preferably a C alkyl group, more preferably C
  • Alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butanol
  • the halogen atom represented by R 3 has the same meaning as described above.
  • the amino group represented by R 3 has the same meaning as R 1, and may be a mono-substituted amino group or a di-substituted amino group which may have a substituent. Examples of the substituent include the above-mentioned substituents, and preferred examples thereof may be the same as those for R 1 .
  • the piperidine ring represented by R 3 has the same meaning as R 1 . That is, the piperidine ring may be bonded at any position, and is preferably a piperidine 1-yl group or a piperidine 4-yl group.
  • Examples of the hydrogen atom on the piperidine ring that may be substituted include the above-mentioned substituents, and preferred examples thereof may be the same as those for R 1 . More preferred is a hydroxyl group or an amino group.
  • M 1 and M 2 may be the same or different.
  • the “pharmaceutically acceptable cation” is a cation capable of forming a salt with one or both of the carboxyl groups of the general formula (I). Examples include alkali metals, alkaline earth metals, ammonium, organic bases, and preferably lithium, sodium, potassium, magnesium, calcium, ammonium, ethanolamine, triethanolamine, trimethylamine, diisopropylamine, and the like. It is done.
  • the compound of the general formula (I) may be used in the form of a prodrug thereof.
  • Prodrugs are hydrolyzable in the body and are preferred for oral administration due to good absorption from the stomach or intestinal mucosa, resistance to gastric acid degradation and other factors. Therefore, “a pharmaceutically acceptable group that can be hydrolyzed in vivo” refers to a detachable group bonded to one or both carboxyl groups of general formula (I), which are metabolized in vivo. Represents a group that undergoes hydrolysis, elimination, and becomes a carboxyl group.
  • a pharmaceutically acceptable group that can be hydrolyzed in vivo is preferably an ester residue, and examples thereof include a lower alkyl group, a lower alkenyl group, Lower alkyl carbonyloxy lower alkyl group, lower cycloalkyl carbonyloxy lower alkyl group, lower cycloalkylmethyl carbonyloxy lower alkyl group, lower alkenyl carbonyloxy lower alkyl group, aryl carbonyl lower alkyl group, tetrahydrofuranyl Carbonyloxymethyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, arylmethyl Xyloxy lower alkyl group, allylmethyloxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxycarbonyloxy lower alkoxy group, lower cycloalkoxycarbonyloxy lower alkyl group, lower cycloalkyl
  • the “pharmaceutically acceptable group that can be hydrolyzed in vivo” is preferably a methyl group, an ethynole group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, a acetoxymethyl group, 1- (isopropyloxy group).
  • Carbonyloxy) ethyl group 1- (ethoxycarbonyloxy) ethynole group, bivalyloxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, 1- (Cyclohexyloxycarbonyl) -2-methylpropane-1-yl group, isobutyloxycarbonyloxymethylol group, isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (pentane -1-yl) oxycarbonyloxymethyl group, (butane-1-yl) oxycarbonyloxymethyl group, (1-ethylpropane-1- Yl) oxycarbonyloxymethyl group, isopentyloxycarbonyloxymethyl group, (propane-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl group, Meth
  • the compound represented by the general formula (I) may be provided as a salt, and is preferably provided as a pharmaceutically acceptable salt.
  • the salt also includes acid addition salts.
  • the compound of the general formula (I) can also be used in the form of a salt derived from inorganic acid or organic acid power.
  • Such salts include acetate, adipate, algin, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, kenate, camphorate, camphorsulfonate.
  • the compound represented by the general formula (I) may be provided as a hydrate or a solvate other than water.
  • Solvents for the solvate include methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, and chloroform.
  • the compound represented by the general formula (I) or a salt thereof may have an asymmetric carbon in the molecule. Also included in the present invention are! /, Deviations of each of these or mixtures thereof. [0046] Preference for the compound represented by formula (I) according to the present invention! /
  • R 1 is a hydroxyl group, a C alkyl group, a C alkoxy group, the above ring A, —O piperidine—4
  • R 2 represents a hydrogen atom or a C alkyl group, which are! /, Both of which have a substituent! /
  • R 3 is a hydrogen atom, a C alkyl group, a halogen atom, an amino group, a mono C alkylamino group,
  • preferred specific compound groups of the compound represented by the formula (I) include the following.
  • the compound group represented by the general formula (I) includes a novel compound. Therefore, according to another aspect of the present invention, a novel phthalic acid derivative is provided, specifically represented by the general formula (II), formula ( ⁇ ), formula (111), and formula (IV) described above. New compounds are provided.
  • the compound represented by the general formula ( ⁇ ) is a compound group having a substituent only at the 3-position in the general formula (I), and the 3-position substituent is a cyclic amine via a nitrogen atom.
  • the cyclic amine that is, the B ring, represents a azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, or a azepane ring, each of which has 0 to 2 R 4. You may do it.
  • R 4 is a hydroxyl group, a C alkenoquinole group, a C alkoxy group, a hydroxy C anoleno quinole group, an oxy group,
  • the "C alkyl group” represented by R 4 is linear, branched or cyclic! /, May be shifted! /, And the number of carbon atoms.
  • alkyl group of 1-6 For example, methyl, ethyl, n-propyl, i-propyl, n-butinole, i-butinole, s butinole, t-butinole, n pentinore, neopentinole, i-pentinole, t-pentinore, n-hexinore, i-hexinole, cyclopropinole, cyclobutinore , Cyclopentyl, cyclohexyl and the like.
  • Preferred is a C alkyl group, for example
  • Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like.
  • the "C alkoxy group" represented by R 4 may be linear, branched, or cyclic.
  • suitable alkoxy groups having 1 to 6 carbon atoms include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentinoreoxy, ne-pentinoreoxy, i-pentinoreoxy, Examples include t-pentinoreoxy, n-hexenoreoxy, i-hexenoreoxy, cyclopropoxy, cyclobutoxy, cyclopentinole-oxygen, and cyclohexenole-oxygen.
  • R 4 is preferably a C alkoxy group, more preferably C
  • Norecoxy group examples of which include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, cyclopropoxy, cyclobutoxy and the like.
  • alkyl in the “hydroxy C alkyl group” represented by R 4 is “C alkyl group represented by R 4 ”.
  • 1-6 1-6 group preferably a hydroxy C alkyl group, such as hydroxy
  • Examples include til, hydroxyethyl, hydroxypropyl, and hydroxybutyl.
  • R 4 represents in "C alkyl O alkoxycarbonyl group", R 4 represents "C
  • 1-6 1 alkyl group preferably an alkyloxycarbonyl group
  • methoxy canole poninore methoxy canole poninore
  • ethoxy canole pononole n propoxy kanole pononole
  • i propoxy carbonyl n butoxy carbonyl, t butoxy carbonyl and the like.
  • an amino group represented by R 4 is the substituted? /, At best Amino group, mono-substituted amino group, and a disubstituted ⁇ amino group, wherein one or two substituents in the "substituent"
  • the “substituent” is a C alkyl group as defined above.
  • “Mono-substituted amino group” is preferably
  • a mono C alkylamino group more preferably a C alkyl group such as methyl
  • the “disubstituted amino group” is preferably a di-C alkylamino group, more preferably a linear C alkyl group.
  • the two alkyl groups may be the same or different, for example, dimethylamino, jetylamino, di-n-propylamino, di-n-butylamino, ethylmethylamino, propinoremethinoleamino, butylmethyl
  • Examples include amino, ethylpropylamino, butylethylamino, propylpropylamino and the like.
  • M 1 and M 2 have the same meaning as in the general formula (I).
  • B ring represents an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, or a azepan ring, and may have 1 or 2 R 4 on the B ring.
  • Bonyl group aminocarbonyl group, mono-C anolenoquinamino group, di-C alkylamino group
  • Examples of M 1 and M 2 include a compound group having the same meaning as in the general formula (I).
  • the compound represented by the general formula ( ⁇ ) is a group of compounds having substituents at the 3-position and the 6-position in the general formula (I).
  • R 1 represents a piperidine ring or an amino group, which may have any substituent
  • R 2 represents a hydrogen atom
  • R 3 represents a C alkyl group.
  • a halogen atom a piperidine ring, or an amino group, all of which may have a substituent.
  • the piperidine ring represented by R 1 has the same meaning as in general formula (I), and is preferably a piperidine-1-yl group. Further, examples of the substituent which may be substituted on the hydrogen atom on the piperidine ring include those similar to those in the general formula (I), and are preferably a hydroxyl group and an amino group.
  • the amino group represented by R 1 may be a mono-substituted amino group or a di-substituted amino group which may be substituted.
  • the substituent is the above-mentioned “substituent”, preferably a C alkyl group.
  • the “mono-substituted amino group” is preferably a mono-c alkylamino group, more preferably
  • C alkyl groups such as methylamino ethynoleamino, npropynoleamino, n
  • Examples include tyramino.
  • the “disubstituted amino group” is preferably a di C alkylamino group.
  • a linear C alkyl group More preferably a linear C alkyl group, and the two alkyl groups may be the same or different.
  • dimethylamino for example, dimethylamino, jetylamino, di-n-propylamino, di-n-butylamino, ethylmethylamino, propylmethylamino, butylmethylamino, ethyl-pylamino, butylethylamino, butylpropylamino, etc.
  • dimethylamino jetylamino, di-n-propylamino, di-n-butylamino, ethylmethylamino, propylmethylamino, butylmethylamino, ethyl-pylamino, butylethylamino, butylpropylamino, etc.
  • C alkyl group represented by R 3 is as defined above, and preferably a linear C alkyl group
  • 1-6 1-4 groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl and the like.
  • the amino group represented by R 1 represented by R 3 may be a mono-substituted amino group or a di-substituted amino group. Any group may be used.
  • the substituent is the above-mentioned “substituent”, preferably C
  • the “mono-substituted amino group” is preferably a mono C alkylamino group
  • C is preferably a C alkyl group such as methylamino, ethylamino, n-propinole.
  • the ⁇ disubstituted amino group '' is preferably diC alkyl.
  • 1-6 ruamino group more preferably a linear C alkyl group, and two alkyl groups
  • R 1 may have a substituent, may be! /, A piperidine 1yl group or a disubstituted amino group,
  • R 3 has a C alkyl group, an amino group, a substituent! /, May! /, A piperidine 1yl group
  • M 1 and M 2 are a group of compounds having the same meaning as (I).
  • the compound represented by the general formula (III) is a group of compounds having a piperidine ring or a 1,2,3,6 tetrahydropyridine ring via a carbon atom only at the 3-position in the general formula (I).
  • the C ring represents a piperidine ring or a 1,2,3,6 tetrahydropyridine ring.
  • R 4 is a hydroxyl group, a C alkyl group, a C alkoxy group, a hydroxy C alkyl group.
  • R 5 is a hydrogen atom, a C alkyl group, a base.
  • M 1 and M 2 may be the same or different, hydrogen atom, pharmaceutically acceptable force thione Or a pharmaceutically acceptable group that can be hydrolyzed in vivo.
  • C alkyl group represented by R 4 is as defined in general formula (I), preferably a C alkyl group.
  • 1-6 1-4 examples thereof include methylol, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like.
  • C alkoxy group represented by R 4 is as defined in general formula (I), preferably C alkoxy
  • Examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, cyclopropoxy, cyclobutoxy and the like.
  • alkyl in R 4 represents "hydroxy C alkyl group" is used herein represented by R 4 "C
  • 1-6 1-6 alkyl group preferably hydroxy C alkyl group.
  • Examples thereof include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like.
  • alkyl in "C alkyl O alkoxycarbonyl group", wherein R 4 is a table that R 4 represents
  • the “C alkyl group” represented by R 5 has the same meaning as that represented by R 4 herein.
  • the “C alkyloxycarbonyl group” represented by R 5 has the same meaning as that represented by R 4 here.
  • it is a linear or branched C alkylcarbonyl group.
  • a C alkylcarbonyl group Preferably a C alkylcarbonyl group.
  • M 1 and M 2 have the same meaning as in general formula (I).
  • the C ring represents a piperidine ring or a 1,2,3,6 tetrahydropyridine ring
  • R 5 is a hydrogen atom, C alkyl group, C alkyloxycarbonyl group, C alkyl
  • 1-6 1-6 1-6 represents a carbonyl group, a benzyl group, or an aminoamino group
  • Examples of M 1 and M 2 include a compound group having the same meaning as in the general formula (I). [0065] Compound of general formula (IV)
  • the compound represented by the general formula (IV) is a group of compounds having a substituent only at the 3-position through an oxygen atom in the general formula (I).
  • N represents 0 to 6
  • R 6 represents a hydroxyl group, a cyclic C alkyl group, phenyl
  • M 1 and M 2 may be the same or different hydrogen atoms, pharmaceutically acceptable Or a pharmaceutically acceptable group that can be hydrolyzed in vivo, provided that when n is 1, R 6 does not represent a phenyl group.
  • the "cyclic C alkyl group" represented by R 6 includes, for example, cyclopropyl, cyclobutyl,
  • cyclopentyl cyclohexyl, cycloheptyl, etc., and preferably a cyclic C alkyl group, such as cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the “piperidinole group optionally having substituent (s)” represented by R 6 is preferably a piperidine-1-yl group or a piperidine-1-yl group, and the “substituent” has the same meaning as described above.
  • M 1 and M 2 have the same meaning as in the general formula (I).
  • n 0-4
  • R 6 is a hydroxyl group, cyclic C alkyl group, phenyl group, phenyloxy group, carboxyl group
  • the compound of the general formula (I) has a metallo / 3-lactamase inhibitory action as described above, it is used to inhibit meta-mouth ⁇ -lactamase.
  • One specific mode of use is that it can be used in combination with antibiotics that are inactivated by meta-mouth / 3-lactamase, particularly ⁇ -ratam antibiotics, to restore the activity of such antibiotics and to infect infections. It can be used for therapeutic purposes.
  • a combination of 13-ratata antibiotics and Metallo (-lactamase inhibitors and pharmaceutical compositions comprising a compound of general formula (I) as an active ingredient are provided. That is, the metallo / 3-lactamase inhibitors and pharmaceutical compositions according to the present invention comprise (latatam Used simultaneously or sequentially with antibiotics.
  • ⁇ -ratata antibiotics include strong rubapenem antibiotics, penicillin antibiotics, cephem antibiotics, or prodrugs thereof.
  • penicillins examples include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxicillin, epicillin, ticanorecillin, cyclacillin, pinolebenicillin, azulocillin, mezurecillin, , Piperacillin and other known penicillins. These penicillins are also in their prodrug form, for example ampicillin, benzylpenicillin and amoxy.
  • ester that can be hydrolyzed in vivo such as ethyl and phthalidyl esters, or aldehyde or keton adducts of penicillins with 6a aminoacetamide side chains (eg similar to hetacillin, metampicillin and amoxicillin) Derivative
  • penicillins with 6a aminoacetamide side chains eg similar to hetacillin, metampicillin and amoxicillin
  • it can also be used as an ester of a penicillin having a 6a carboxyacetamide side chain (for example, carpenicillin, ticarcillin) (for example, phenyl, indanyl ester, etc.). it can.
  • Penicillins that are particularly preferred to be used in combination with the compound of general formula (I) are ampicillin, amoxicillin and carbecillins which can be used in the form of their pharmaceutically acceptable salts such as sodium salts. it can.
  • ampicillin or amoxicillin is commonly used in the form of amphoteric ions (ampicillin trihydrate or amoxicillin-trihydrate) microparticles for injectable suspensions or infusion suspensions.
  • Cephalexin Cefacetrinore, Cefapirin, Cefamandonore 'Nafate, Cefradine, 4-Hydroxycephalexin, Cef Operazone, Latamoxef, Cefminox, Flomoxef, Cefsulosin, Cefazidime, Cefoxime, Cefditoren, Cefmetazomone, Cefmetazomone And cefozopran as well as other known cefmes, which can all be used in the form of their prodrugs.
  • Cefems that are particularly preferred to be used in combination with the compound of general formula (I) are cefotaxime, ceftriaxone, ceftazidime and cefepime, which can be used in the form of a pharmaceutically acceptable salt such as a sodium salt. it can.
  • DHP dehydropeptidase
  • Metallo ⁇ -lactamase producing strains that are preferably used in combination with antibiotics and compounds of general formula (I) include the following: , Stenotrophomonas maltophilia ⁇ Shigella flexneri, Alcaligenes xylosoxidans ⁇ Legionell a gormanii, Chryseobacterium meningosepticum, Chryseobacterium indologenes, Ac inetobacter baumannii ⁇ Citrobacter freundii and Enterobacter cloacae.
  • the dose of the compound of the general formula (I) and the antibiotic may vary within a wide range.
  • the weight ratio is about 1: 0.5 to 20, preferably;!:;! To 8 Is common.
  • the compound of general formula (I) and the / 3-latatam antibiotic can be administered separately or can be administered in the form of a single composition comprising both active ingredients.
  • the compound of the general formula (I) and / or the antibiotic must be in the form of a pharmaceutical composition by combining with a pharmaceutically acceptable carrier (that is, a pharmaceutical additive). Is preferred.
  • the pharmaceutical composition according to the present invention can be administered orally or parenterally.
  • parenteral administration include intranasal, eye drop, ear drop, transdermal, intratracheal, rectal, urinary, subcutaneous, intramuscular, and intravenous routes.
  • formulations 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.
  • Liquid preparations such as injections and infusions are provided, for example, 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 may be used after dissolving or suspending in the solution.
  • suitable media for example, physiological saline, glucose infusion solution, buffer solution, etc.
  • the carrier that is, the additive for formulation
  • compositions of the desired form can be produced according to methods commonly used in the art.
  • the aforementioned pharmaceutical composition can be prepared so that the above-mentioned substance as an active ingredient is 1.0 to 100% (W / W), preferably 1.0 to 60% (W / W). .
  • the carrier include gelatin, lactose, sucrose, titanium oxide, starch, sorghum starch, microcrystal wax, white petrolatum, magnesium aluminometasilicate, anhydrous calcium phosphate, citrate, and citrate trioxide.
  • the dose and frequency of administration of the pharmaceutical composition according to the present invention are not particularly limited, but are appropriately determined according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, and symptoms of the patient. And the number of doses can be determined.
  • oral administration it can be administered once or several times per day so that the daily dose is 10 to 1000 mg / kg as a compound of general formula (I) for adults. In this case, it is preferable to administer 1 to 100 mg / kg once or several times a day.
  • a method of treating an infection comprising administering an inhibitor to an animal, including a human, simultaneously or sequentially.
  • a compound of general formula (I) for the manufacture of a pharmaceutical composition comprising a ⁇ -lactamase inhibitor or a dehydropeptidase (DHP) inhibitor, in particular a therapeutic agent for infectious diseases.
  • the compound of the general formula (I) according to the present invention can be preferably produced, for example, by the method shown below or a method analogous thereto.
  • substituents may be "protected” as required.
  • the “protecting group” can refer to Protective Groups in Organic Synthesis (T. W. reene et al., Wiley, New ⁇ (1999)) and the like, and is well known to those skilled in the art. You can also refer to this book on deprotection.
  • suitable protecting groups are a hydroxyl protecting group and a carboxyl protecting group.
  • hydroxyl protecting groups include: acetyl such as acetyl, bivaloyl, triethylsilyl, t-butyldimethinoresilinole, t-butyldiphenylsilyl, benzinole, tritinole, 0-nitrobenzyloxycarbonyl, p-nitrobenoxycarbonyl, benzyloxycarbonyl , Aryloxycarbonyl, t-butoxycarbonyl, 2,2,2-trichloroethinoreoxycarbonyl, and the like.
  • acetyl such as acetyl, bivaloyl, triethylsilyl, t-butyldimethinoresilinole, t-butyldiphenylsilyl, benzinole, tritinole, 0-nitrobenzyloxycarbonyl, p-nitrobenoxycarbonyl, benzyloxycarbonyl , Aryloxycarbon
  • Examples of the carboxyl protecting group include silyl such as methyl, ethyl, t-butyl, allyl, benzhydrinole, 2-naphthylmethyl, benzinole, t-butyldimethylsilyl, phenacinole, p-methoxybenzyl, 0-ditrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl, 1- (cyclohexyloxycarbonyloxy) ethyl group, acetylmethyl, 1 (isopropyloxycarbonyloxy) ethyl, 1 (ethoxycarbonyloxy) ethyl, Examples include pivaloyloxymethyl and cyclohexyloxycarbonyl.
  • the compound of the general formula (I) according to the present invention can be produced by a known method, for example, the following methods (A to J) or a method analogous thereto, and if necessary, a protecting group It is possible to go through the desorption process.
  • the desired substituent is incompatible with the reaction conditions used, the substituent can be first introduced in the form of a protecting group and deprotected after completion of the reaction.
  • the substituent can be first introduced in the form of a protecting group and deprotected after completion of the reaction.
  • a protecting group is introduced into the two carboxyl groups of the compound represented by formula (A1) to produce a compound represented by formula (A2).
  • the compound represented by the formula (A1) is heated in an alcohol: ⁇ ⁇ ⁇ and / or P 2 -OH in the presence of an acid, and the formula (A2) (wherein R 2 and R 3 are as defined above).
  • R la represents an optionally substituted C alkyl group, and P 1 and P 2 have 1 to
  • the alcohol used in the reaction is preferably methanol, ethanol, etc.
  • the acid used includes hydrochloric acid, sulfuric acid, etc., preferably sulfuric acid.
  • the reaction is carried out at 30 ° C to 80 ° C, and the reaction time is usually 1 hour to 2 days.
  • an alkylation reaction of the phenol hydroxyl group of the compound represented by the formula (A2) is carried out to produce a compound represented by the formula (A3).
  • This production can be performed by either of the following two methods (a) or (b).
  • a compound represented by formula (A2) and R ⁇ -X 1 (where R la may be substituted! /, C alkyl group)
  • X 1 represents a halogen atom such as chlorine, bromine or iodine, an alkylsulfonyl group having 1 to 4 carbon atoms such as a methanesulfonyl group, or a leaving group such as a p-toluenesulfonyl group).
  • R ⁇ -X 1 examples include methyl iodide, iodinated til, and benzyl bromide.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, and the like, preferably N, N-dimethylformamide.
  • Examples of the base include triethylamine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate and the like, and potassium carbonate is preferable.
  • the reaction is carried out in the range of 0 to 100 ° C, and the reaction time is usually 10 minutes to 2 days.
  • a compound represented by the formula (A2) the compound: (wherein, R la is as defined above) R la _OH and the Mitsunobu reaction (e.g., a known literature procedure (O.Mitsunobu, Yamada, Bull. Chem. Soc. Japan., 40,2380 (1967)), ie, tetrahydraphthalfuran that does not participate in the reaction, etc. in the presence of triphenylphosphine, tributylphosphine, etc., together with jetylazocarboxylic acid ester, etc.
  • a solvent of the formula (A3) (wherein R la , R 2 , R 3 , And P 2 are as defined above).
  • the carboxylic acid ester of the compound represented by the formula (A3) is hydrolyzed to produce the compound represented by the formula (la).
  • the compound of formula (A3) is hydrolyzed in an aqueous alkali hydroxide solution of 2 equivalents or more as necessary to the compound of formula (A3) in the presence or absence of a solvent, and concentrated under reduced pressure.
  • formula (la) (wherein, R la, R 2, and R 3 are as defined above, M 1, M 2 represents a metal cation) to obtain a compound represented by.
  • the formula (la) (wherein R la , R 2 , and R 3 are as defined above, M 2 represents a hydrogen atom).
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, jetyl ether, acetonitrile, ethanol, and methanol.
  • alkali hydroxide aqueous solution used include Aqueous solution of sodium chloride, aqueous solution of sodium hydroxide, aqueous solution of sodium hydroxide, etc., preferably aqueous solution of sodium hydroxide.
  • the reaction is carried out in the range of room temperature to 100 ° C, and the reaction time is usually 10 minutes to 2 days.
  • Examples of the acid used for neutralization after hydrolysis include hydrochloric acid and sulfuric acid, with hydrochloric acid being preferred.
  • a compound represented by the formula (lb), wherein R 1 is a mono-substituted amino group or a carbonylamino group (wherein R 2 , R 3 , M 1 and M 2 is as defined above, and is preferably produced by the following method.
  • a protecting group is introduced into the two carboxyl groups of the compound represented by formula (B1) to produce a compound represented by formula (B2).
  • the compound represented by the formula (B1) is heated in an alcohol represented by P LOH (wherein P 1 has the same meaning as described above) in the presence of an acid to obtain a monoester, and this monoester And a compound: P 2 -X (wherein P 2 has the same meaning as described above, X represents a halogen atom such as chlorine, bromine, iodine, etc.
  • methylolate iodide, acetyl iodide, benzyl iodide Is obtained in the presence of a base to obtain a compound represented by the formula (B2) (wherein R 2 , R 3 , P 1 and P 2 are as defined above).
  • Examples of the alcohol used in the reaction include methanol and ethanol, and examples of the acid used include hydrochloric acid and sulfuric acid, and sulfuric acid is preferable.
  • Reaction is 30 ° C ⁇
  • the reaction is carried out at 80 ° C and the reaction time is usually 1 hour to 2 days.
  • Compound The solvent used in the reaction with P 2 -X is not limited as long as it does not participate in the reaction, and examples thereof include dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, and the like. N, N-dimethylformamide is preferred.
  • Examples of the base used include triethylamine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate, and the like, and potassium carbonate is preferable.
  • the reaction is carried out in the range of 0 to 100 ° C., preferably at room temperature.
  • the reaction time is usually 10 minutes to 2 days.
  • the compound represented by the formula (B2) is subjected to a reduction reaction of the nitro group to the amino group to produce a compound represented by the formula (B3).
  • the compound of formula (B2) is subjected to catalytic reduction using palladium carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, or reduction reaction using tin, zinc, iron, etc. and an acid such as acetic acid, or hydrogen.
  • the solvent used in the reaction is not limited as long as it is a solvent that does not participate in the reaction, but includes methanol, ethanol, tetrahydrofuran, water, or a mixed solvent of these organic solvents and water. Preferably, it is a mixed solvent of ethanol and water.
  • the reaction is carried out at 30 ° C to 40 ° C, preferably at room temperature.
  • the reaction time is usually 1 hour to 2 days.
  • a compound represented by the formula (B4) is produced by performing a substitution reaction of the compound of the formula (B3) with an amino group.
  • This production can be preferably carried out by the following two methods (a) and (b).
  • a monosubstituted amino compound represented by the formula (B4) is produced by reductive amination of the compound represented by the formula (B3) with an aldehyde or a ketone.
  • the compound of formula (B3) is converted into lithium aluminum hydride, hydrogenated by reductive amination reaction with an aldehyde or ketone compound (for example, known literature method (WSEmerson, Org. React., 4, 174 (1948))).
  • the reaction is carried out in a solvent at 0 ° C to heating conditions for 10 minutes to 3 days, and the formula (B4) (wherein , R 2 , R 3 , P 1 and P 2 are as defined above, and R lb represents an alkyl group).
  • the solvent is not limited as long as it does not participate in the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, and 1,2-dichloroethane.
  • the aldehyde and ketone include formaldehyde, acetoaldehyde, n-butyraldehyde, n-propyl aldehyde, and cyclohexanone.
  • the compound represented by the formula (B3) is reacted with the compound: R lb '-CO_Cl (where R lb ' represents an alkyl group) in the presence of a base, and the formula (B4) ( In which R 2 , R 3 , P 1 and P 2 are as defined above, and R lb represents a carbonylalkyl group).
  • R lb '-CO_Cl for example, ⁇ cetyl chloride, ⁇ Seto carboxymethyl ⁇ cetyl chloride, etc. Petit Lil chloride.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include dichloromethane, tetrahydrofuran, benzene, and jetyl ether, with dichloromethane being preferred.
  • Examples of the base to be used include triethylamine, N-methylmonomorpholine, dimethylaminopyridine and the like, and triethylamine is preferable.
  • the reaction is carried out at 0 ° C to heating, and the reaction time is usually 10 minutes to 3 days.
  • the carboxylic acid ester of the compound represented by the formula (B4) is hydrolyzed to produce the compound represented by the formula (lb). Hydrolysis of the carboxylic acid ester can be carried out under the same conditions as in the third step of Method A described above.
  • R 1 is a disubstituted amino group (Ic) (wherein R 2 , R 3 , M 1 and M 2 are as defined above) Is preferably produced by the following method.
  • a disubstituted amino compound represented by the formula (C2) is produced by reductive amination of the compound represented by the formula (C1) and an aldehyde.
  • a reductive amination reaction of a compound represented by the formula (C 1) with an aldehyde or a ketone compound for example, a known literature method (WSEmers on, Org. React., 4, 174 (1948)), That is, using a complex hydrogen compound such as lithium aluminum hydride, sodium borohydride, sodium cyanohydrohydroboron or a reducing agent such as diborane, the reaction is carried out in a solvent at 0 ° C to heating conditions for 10 minutes to 3 days.
  • a compound represented by the formula (C2) (wherein R 2 , R 3 , P 1 and P 2 are as defined above, and R lb and R lb ′ represent an alkyl group) is obtained.
  • the solvent is not limited as long as it does not participate in the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,2-dichloroethane and the like.
  • Examples of the aldehyde and ketone compound to be used include formaldehyde, acetoaldehyde, n-propyl aldehyde, n-butyraldehyde and the like.
  • the carboxylic acid ester represented by the compound of formula (C2) is hydrolyzed to produce the compound represented by formula (Ic). Hydrolysis of the carboxylic acid ester can be carried out under the same conditions as in the third step of Method A described above.
  • R 1 is a disubstituted amino group (Id) (wherein R 2 , R 3 , M 1 and M 2 are as defined above) Is preferably produced by the following method.
  • a protecting group is introduced into the two carboxyl groups of the compound represented by the formula (D 1) to produce a compound represented by the formula (D2).
  • the compound represented by the formula (D 1) is heated in the presence of an acid in an alcohol represented by the compound: ⁇ ⁇ ⁇ (where P 1 is as defined above) for 1 to 2 days.
  • P 2 -X (wherein P 2 is as defined above, and X represents a halogen atom such as chlorine, bromine, iodine, etc.)
  • a compound represented by the formula (D2) (wherein R 2 , R 3 , P 1 and P 2 are as defined above) is obtained.
  • Examples of the alcohol used in the reaction include methanol and ethanol, and examples of the acid used include hydrochloric acid and sulfuric acid, and sulfuric acid is preferable.
  • the reaction is carried out at 30 ° C to 80 ° C, and the reaction time is usually 1 hour to 2 days.
  • the solvent used in the reaction with P 2 -X is not limited as long as it does not participate in the reaction, and examples thereof include dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, and the like. N, N-dimethylformamide is preferred.
  • Examples of the base used include triethylamine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate, and the like, and potassium carbonate is preferable.
  • the reaction is carried out in the range of 0 to 100 ° C., preferably at room temperature.
  • the reaction time is usually 10 minutes to 2 days.
  • a disubstituted amino compound represented by the formula (D3) is produced by a nucleophilic substitution reaction of a secondary amine with fluorine of the compound represented by the formula (D2).
  • the compound represented by the formula (D2) is reacted with a secondary amine represented by the compound: R lb _NH-R lb in the presence or absence of a solvent to obtain the formula (D3) (wherein R 2 , R 3 , P 1 and P 2 are as defined above, and R lb and R lb represent an alkyl group).
  • R lb -NH-R lb dimethylamine, jetylamine, N-methylethylamine and the like can be used.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like.
  • the reaction is carried out in the range of 30 ° C to 100 ° C, and the reaction time is usually 10 minutes to 3 days.
  • the carboxylic acid ester of the compound represented by the formula (D3) is hydrolyzed to produce the compound represented by the formula (Id). Hydrolysis of the carboxylic acid ester can be carried out under the same conditions as in the third step of Method A described above.
  • R 1 is a B ring (azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azepan ring, and a substituent R 4 is present on the ring.
  • R 2 , R 3 , M 1 and M 2 are as defined above
  • the compound is preferably prepared by the following method.
  • R 4 is on the ring.
  • ⁇ 2 azetidines, pyrrolidi which may have , Piperidine, piperazine, azepane, etc. can be used.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like.
  • the reaction is carried out in the range of 30 ° C to 100 ° C, and the reaction time is usually 10 minutes to 3 days.
  • R 4 can be converted by a general method by those skilled in the art as necessary.
  • Hydrolysis of the carboxylic acid ester of the compound represented by the formula (E2) is carried out to produce a compound represented by the formula (Ie). Hydrolysis of the carboxylic acid ester can be carried out under the same conditions as in the third step of Method A described above.
  • R 1 is a B ring (azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azepan ring, and a substituent R 4 is present on the ring.
  • R 4 is a substituent R 4 present on the ring.
  • Is also preferably produced.
  • a protecting group is introduced into two carboxyl groups of the compound represented by the formula (F1) to produce a compound represented by the formula (F2).
  • a compound represented by the formula (F1) is converted into a compound: ArCH X 2 (wherein Ar is an aromatic ring which may have a substituent (for example, phenyl, p-methoxyphenyl, p-nitrophenyl)
  • X 2 is a halogen atom such as chlorine, bromine, iodine, etc., preferably benzylbutamide), and is reacted in the presence of a base to give the formula ( F2) (wherein R 2 and R 3 have the same meanings as described above) are obtained.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, and the like, preferably N, N-dimethylformamide.
  • Examples of the base to be used include triethylamine, N-methinolemonoreforin, dimethylaminopyridine, potassium carbonate and the like, and potassium carbonate is preferable.
  • the reaction is carried out in the range of 0 to 100 ° C, and the reaction time is usually 10 minutes to 2 days.
  • a compound represented by the formula (F3) having a B ring is produced by a nucleophilic substitution reaction of a cyclic secondary amine represented by a B ring with fluorine of the compound represented by the formula (F2). This step can be performed under the same conditions as the first step of the E method.
  • Decarboxylation of the carboxylic acid ester of the compound represented by the formula (F3) is carried out to produce the compound represented by the formula (If).
  • This step is preferably performed by the following two methods (a) and (b).
  • the compound represented by the formula (If) is produced by deesterifying the carboxylic acid ester of the compound represented by the formula (F3) under reducing conditions.
  • the compound of formula (F3) can be converted to a compound of formula (If) (wherein the catalytic reduction reaction using palladium on carbon, noradium black, palladium hydroxide, platinum oxide, Raney nickel, preferably using palladium-carbon).
  • R 2 , R 3 , R 4 , M 1 and M 2 are as defined above).
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, but examples thereof include methanol, ethanol, tetrahydrofuran, water, or a mixed solvent of these organic solvents and water. Preferably a mixed solvent of ethanol and water.
  • the reaction is carried out at 0 ° C to 40 ° C, preferably at room temperature.
  • the reaction time is usually 1 hour to 2 days.
  • R 4 can be converted by a general method by those skilled in the art as necessary.
  • R 1 is a B ring (azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azepan ring, and a substituent R 4 is present on the ring.
  • R 2 , R 3 , M 1 and M 2 are as defined above
  • a protecting group is introduced into one carboxyl group of the compound represented by the formula (G1) to produce a compound represented by the formula (G2).
  • a compound represented by the formula (G2) By heating the compound represented by the formula (G1) in an alcohol represented by the compound: _0 H (wherein P 1 is as defined above) in the presence of an acid for 10 minutes to 1 hour, A compound represented by the formula (G2) (wherein R 2 and R 3 are as defined above, and P 1 represents an alkyl group having 1 to 6 carbon atoms) is obtained.
  • Examples of the alcohol used in the reaction include methanol and ethanol, and examples of the acid used include hydrochloric acid and sulfuric acid, and sulfuric acid is preferable.
  • the reaction is carried out at 30 ° C to 80 ° C, and the reaction time is usually 1 hour to 2 days.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, Examples include dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, and the like, with N, N-dimethylformamide being preferred.
  • Examples of the base used include triethylamine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate and the like, and potassium carbonate is preferable.
  • the reaction is carried out in the range of 0 to 100 ° C., preferably room temperature.
  • the reaction time is usually 10 minutes to 2 days.
  • a protecting group is introduced into the carboxyl group of the compound represented by the formula (G2) to produce a compound represented by the formula (G3).
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include dichloromethane, tetrahydrofuran, N, N-dimethylformamide, and the like, and preferably N, N-dimethylformamide.
  • Examples of the base include triethylamine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate, and the like, preferably potassium carbonate.
  • the reaction is carried out in the range of 0 ° C to 80 ° C, and the reaction time is usually 10 minutes to 1 day.
  • a compound represented by the formula (G4) having a B ring is produced by a nucleophilic substitution reaction of a cyclic secondary amine represented by a B ring with fluorine of the compound represented by the formula (G3). This step can be performed under the same conditions as the first step of the E method.
  • a compound represented by the formula (G5) is produced by removing one ester group of the compound represented by the formula (G4) by alkaline hydrolysis.
  • the compound of the formula (G5) (wherein R 2 , R 3 , R 4 , and Ar are as defined above, and M 1 represents a metal force thione).
  • M 1 represents a metal force thione
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, jetyl ether, acetonitrile, ethanol, and methanol.
  • the alkali hydroxide aqueous solution include a potassium hydroxide aqueous solution, a sodium hydroxide aqueous solution, and a barium hydroxide aqueous solution, and a sodium hydroxide aqueous solution is preferable.
  • the reaction is carried out in the range of 0 ° C. to room temperature, and the reaction time is usually 10 minutes to 1 hour.
  • the acid for neutralization include hydrochloric acid and sulfuric acid, with hydrochloric acid being preferred.
  • the compound represented by the formula (Ig) is produced by deesterifying the carboxylic acid ester of the compound represented by the formula (G5) under reducing conditions. This step can be performed under the same conditions as in the above-mentioned F method, third step- (b).
  • R 4 can be converted by a general method by those skilled in the art as necessary.
  • R 1 is an optionally substituted benzene ring, a piperidine-4-yl group (Ih) (wherein R 2 , R 3 , M 1 and M 2 are as defined above, and R 1 may have a substituent! /, A benzene ring or a piperidine-4-yl group) Is also preferably produced by the following method.
  • the compound represented by the formula (H2) is produced using the Sandmeyer reaction of the amino group of the compound represented by the formula (HI).
  • the compound represented by the formula (HI) is converted into, for example, a known literature method (Sandmy er, T, Chem. Ber., 17,1633 (1884)), diazotization with sodium nitrite in the presence of acid, followed by reaction with copper (I) halide.
  • a compound represented by the formula (H2) (wherein R 2 , R 3 , P 1 and P 2 are as defined above).
  • reaction As the acid used for the reaction, hydrobromic acid is preferred.
  • copper halide copper (I) bromide is preferred.
  • the reaction is carried out in the range of 10 ° C to 100 ° C, and the reaction time is usually 10 minutes to 1 day.
  • a compound represented by the formula (H2) may have a substituent! /, A boron compound having a phenyl group or a piperidine boron compound, etc.
  • a compound represented by (H3) is produced.
  • the compound represented by the formula (H2) is reacted in the presence of a palladium reagent using, for example, a known literature method (Kishi, YJAm. Chem. Soc, 109, 4756 (1987)) to obtain a formula (H3) (formula R 2 , R 3 , P 1 and P 2 are as defined above, R 1 may have a substituent! /, Represents a benzene ring or a piperidine-4-yl group) The compound represented is obtained.
  • Examples of the boron compound or piperidine boron compound having a phenyl group include phenylboronic acid, 2-phenyl-4,4,5,5, -tetramethyl-1,3,2-dioxaborolane, and the like.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include toluene and N, N-dimethylformamide.
  • Hydrolysis of the carboxylic acid ester of the compound represented by the formula (H3) is carried out to produce a compound represented by the formula (Ih).
  • the hydrolysis of the carboxylic acid ester in this step can be carried out under the same conditions as in the third step of Method A described above.
  • R 1 is a B ring (azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azepan ring, and a substituent R 4 is present on the ring.
  • R 3 is a B ring (azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, or azepane ring), and the substituent R 4 is substituted on the ring by 0 to 2
  • the compound is preferably produced by the following method.
  • a protecting group is introduced into two carboxyl groups of the compound represented by the formula (II) to produce a compound represented by the formula (12). This step can be performed under the same conditions as in the first step of Method B described above.
  • a compound represented by the formula (13) having a B ring is produced by a nucleophilic substitution reaction of a cyclic secondary amine represented by the B ring to the fluorine of the compound represented by the formula (12). This step can be performed under the same conditions as the first step of the E method.
  • a compound represented by the formula (14) having a B ring is produced by a nucleophilic substitution reaction of a cyclic secondary amine represented by a B ring with fluorine of the compound represented by the formula (13). This step can be performed under the same conditions as the first step of the E method.
  • Hydrolysis of the carboxylic acid ester of the compound represented by the formula (14) is performed to produce a compound represented by the formula (Ii) (wherein R 2 , M 1 and M 2 are as defined above).
  • Hydrolysis of the carboxylic acid ester in this step can be performed under the same conditions as in the third step of Method A described above. it can.
  • R 4 can be converted by a general method by those skilled in the art as necessary.
  • R 1 is a B ring (azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azepan ring, and a substituent R 4 is present on the ring. 0 to 2) or dialkylamine
  • R 3 is a methyl group (Ij-a) or (Ij-b) (wherein R 2 , M 1 and M 2 are as defined above)
  • it is preferably produced by the following method.
  • the solvent used for the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, and preferably N, N-dimethylformamide.
  • N-bromosuccinimide is preferred as the brominating agent used.
  • the reaction is carried out at room temperature to 80 ° C, and the reaction time is usually 1 hour to 2 days. [0147] ⁇ Method J second process>
  • a methyl group is introduced onto the benzene ring of the compound represented by formula (J2) to produce a compound represented by formula (J3).
  • the compound represented by formula (J2) is subjected to a carbon-carbon bond formation reaction using an organoboron reagent in the presence of a base and a noradium catalyst, and formula 03) (where R 2 , P 2 , M 1 and M 2 are as defined above, and A represents a hydrogen atom or an alkyl group.
  • organic boron reagent examples include trimethyl poroxin.
  • the solvent used for the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, and preferably N, N-dimethylformamide.
  • examples of the base used include triethylamine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate and the like, and potassium carbonate is preferred.
  • the reaction is carried out at room temperature to 80 ° C, and the reaction time is usually 1 hour to 1 day.
  • a cyclic amine skeleton is constructed from an amino group of a compound represented by the formula (J3) (wherein R 2 , P 1 and P 2 are as defined above, and A represents a hydrogen atom).
  • the compound represented by J4) is produced. Reacting a compound represented by the formula (J3) with a compound represented by the formula (J5) (wherein X represents halogen) (which may have 0 to 2 R 4 ). To obtain a compound represented by the formula (J4) (wherein ring B, R 4 , R 2 , P 1 and P 2 are as defined above).
  • Examples of the formula (J5) include 1,5-dichloropentane-3-one, 1,5-dichloropentane, bis (2 chloroethyl) amine and the like.
  • the solvent used in the reaction is not limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethanol, and the like, and preferably ethanol.
  • the reaction is performed at room temperature to 80 ° C, and the reaction time is Usually 1 hour to 1 day.
  • R 4 can be converted by a general method by those skilled in the art as necessary.
  • (Ii), (Ij-a), and (Ij-b) are gel filtration using a non-ionic macroporous resin, gel filtration using Sephadex, normal phase and reverse phase chromatography, if necessary. It can be purified by using a method such as crystallization.
  • Alkali metal salts such as sodium salt and potassium salt obtained by the above method are tetrahydrofuran, dioxane, jetyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n -propanol, water, etc. 2 min or more of amin (for example, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, jetylamine, triethylamine) hydrochloride is allowed to act in a mixed solvent of 5 minutes to 48 hours at 0 ° C to 90 ° C. After the reaction, the ammonium salt of the general formula (I) can be obtained by vacuum concentration and vacuum drying.
  • amin for example, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, jetylamine, triethylamine
  • ammonium salt of the general formula (I) can also be purified by a method such as chromatography using a nonionic macroporous resin, if necessary. Monkey.
  • M 1 and M 2 are metal cations It is obtained by reacting an alkali metal salt such as a halide compound of a group that can be hydrolyzed in vivo (represented here as M 3 -X 3 ).
  • M 3 is synonymous with the group that can be hydrolyzed in vivo
  • X 3 is chlorine, bromine, iodine, —OSO CF —OSO CH —OSO PhCH,
  • a catalytic amount or an excess amount of a base as an organic base, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, 2,6-lutidine, etc.
  • an alkyl halide (M 3 -X 3 :) in the presence of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • X 3 represents a halogen atom or a leaving group, and is preferably iodine, bromine, or chlorine.
  • ester (I) obtained as described above is isolated and purified by precipitation, gel filtration using Sephadex, etc., normal phase and reverse phase silica gel column chromatography, etc. I can do it.
  • Example 1 3- Production process l- (a)
  • the manufacturing and manufacturing process step 22-((bb)) In the same way as above, instead of yoiodination nn-butbutyryl, iodomethymethylyl is used as an alternative, and the resulting compound is obtained.
  • the title compound was obtained in the same manner as in the case of 22-((cc)). .
  • Example of practical implementation 44 33-- ((Cyclochlorohexoxyloxy)) phthalic acid
  • the chemical compound 113388 mmgg obtained in the manufacturing and manufacturing process step 22-((aa)) was dissolved and dissolved in TTHHFF 33..00 mmLL, and hexoxanone Nonolere 7700..00 mmgg, Totriribbutyryl rufophos phosphine 558866 mmgg, 11, 11, 11, 0000 mmgg was added, and the mixture was stirred at room temperature at room temperature. . Add water to the reaction solution, extract with ethyl acetate, extract, dry with anhydrous magnesium sulfate, dry and dry.
  • EESSIIMMSS :: mm // zz332211 [[MM ++ HH]] ++ ;;
  • FFAABBMMSS :: mm // zz226655 [[MM ++ HH]] ++ ;
  • Example 7 3- (3_phenylpropoxy) phthalic acid
  • Manufacturing process 7_ (a) Using 82.0 mg of the compound obtained in production step 2- (a), in the same manner as in production step 2- (b), using 3-phenylpropyl bromide instead of n-butyl oxalate, 3- ( 90.0 mg of 3_phenylpropoxy) phthalic acid ethyl ester was obtained.
  • Example 8 3_ (4-phenylbutoxy) phthalic acid
  • Example 10 3_ (4-carboxybutoxy) phthalic acid
  • Example 12 3_ (3-hydroxypropoxy) phthalic acid
  • Production process 15- (a) Production process 2- (a) 3-hydroxyphthalic acid cetyl ester 116 mg was dissolved in THF 3.5 mL, and 2, 3, 4, 6_tetra- 0.5 mL of THF solution of 187 mg of 0-methoxymethyl darcoviranose was calorie. Further, 0.72 mL of tri-n-butylphosphine and 501 mg of ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylazodicarboxamide were sequentially added, and the mixture was stirred at room temperature for 2 hours.
  • reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 3- (2,3,4,6-tetra-0-methoxymethyl ⁇ / 3 ⁇ . 269 mg of D-darcopyranosyloxy) phthalic acid ethyl ester was obtained.
  • the obtained residue was dissolved in 5.0 mL of acetonitrile, added with 0.13 mL of 36% formaldehyde solution, 0.060 mL of acetic acid and 220 mg of sodium triacetoxyborohydride, and stirred at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel silica gel column chromatography (hexane acetate) and preparative TLC (hexane-ethyl acetate). 3- (Butyl (methyl) amino) phthalic acid dimethyl ester 26.0 mg Got.
  • DMSO with 212 mg of 3-fluorophthalic acid jetyl ester obtained in production process 25_ (a) It melt
  • Example 32 3_ (4-Hydroxypiperidine-1-yl) phthalic acid
  • Example 33 3_ (4- (Hydroxymethinole) piperidine-1-yl) phthalic acid
  • Example 36 3_ (3- (hydroxymethinole) piperidine-1-yl) phthalic acid
  • the compound 220 mg obtained in the production step 36_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of a 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. Lmol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, and then the residue obtained by concentration under reduced pressure was purified using resin SP-207 (water-acetonitrile) to obtain 150 mg of the title compound.
  • Example 38 3_ (4-oxopiperidine-1-yl) phthalic acid
  • Manufacturing process 38_ (b) 60.0 mg of the compound obtained in production step 38_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of a 5.0 mol / L aqueous sodium hydroxide solution, and stirred at 80 ° C. The reaction solution was adjusted to pH 2 by adding lmol / L hydrochloric acid, and then concentrated under reduced pressure, and the resulting residue was purified using resin SP-207 (water-acetonitrile) to obtain 20.0 mg of the title compound.
  • resin SP-207 water-acetonitrile
  • Example 40 3_ (4-aminobiperidine_1-yl) phthalic acid
  • Example 42 3_ (4-benzylpiperidine-1-yl) phthalic acid
  • Example 45 3_ (4-force rubamoyl biperidine-1-yl) phthalic acid
  • Production process 45_ (a) Compound 30.0 mg mixed with ethanol 5.0 mL and water 0.5 mL
  • Example 46 3_ (4- (dimethylcarbamoyl) piperidine-1-yl) phthalic acid
  • Manufacturing process 46- (b) 100 mg of the compound obtained in the production step 46_ (a) was dissolved in 5.0 mL of DMSO, 100 mg of 4- (dimethylcanolamoyl) piperidine was added, and the mixture was stirred and stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane ethyl acetate). 16.0 mg of (dimethylcarbamoyl) piperidine-1-yl) phthalic acid dimethyl ester was obtained.

Abstract

La présente invention concerne un dérivé de l'acide phtalique représenté par la formule générale (1) et ayant une activité inhibitrice de la métallo-β-lactamase. Par conséquent, quand il est utilisé en combinaison avec un antibiotique au β-lactame, le dérivé peut inhiber la désactivation de l'antibiotique au β-lactame par une bactérie capable de produire une métallo-β-lactamase et il peut rétablir l'activité antibactérienne de l'antibiotique au β-lactame. (I) dans laquelle R1 représente un groupe hydroxy, un groupe alkyle en C1-7, un groupe alcoxy en C1-7 ou un noyau hétérocyclique saturé ou insaturé (à condition que chacun de ces groupes puisse avoir un substituant) ; R2 représente un atome d'hydrogène ou un groupe alkyle en C1-7 (à condition que chacun de ces groupes puisse avoir un substituant) ; R3 représente un atome d'hydrogène, un groupe alkyle en C1-7, un atome d'halogène, un groupe amino ou un noyau pipéridine (à condition que chacun de ces groupes puisse avoir un substituant) ; et M1 et M2 représentent indépendamment un atome d'hydrogène, un cation pharmaceutiquement acceptable ou un groupe pharmaceutiquement acceptable capable d'être hydrolysé in vivo.
PCT/JP2007/064895 2006-07-31 2007-07-30 INHIBITEUR DE LA MÉTALLO-β-LACTAMASE WO2008016007A1 (fr)

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WO2016175223A1 (fr) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Composés tricycliques et utilisations de ceux-ci
CN110746400A (zh) * 2019-11-07 2020-02-04 郑州大学 一种靶向雄激素受体的荧光探针及其制备方法
CN113461606A (zh) * 2021-06-30 2021-10-01 郑州大学 金属β-内酰胺酶抑制剂吡啶二羧酸胺衍生物及其制备方法

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WO2008016007A1 (fr) * 2006-07-31 2008-02-07 Meiji Seika Kaisha, Ltd. INHIBITEUR DE LA MÉTALLO-β-LACTAMASE

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016175223A1 (fr) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Composés tricycliques et utilisations de ceux-ci
CN110746400A (zh) * 2019-11-07 2020-02-04 郑州大学 一种靶向雄激素受体的荧光探针及其制备方法
CN113461606A (zh) * 2021-06-30 2021-10-01 郑州大学 金属β-内酰胺酶抑制剂吡啶二羧酸胺衍生物及其制备方法
CN113461606B (zh) * 2021-06-30 2022-05-31 郑州大学 金属β-内酰胺酶抑制剂吡啶二羧酸胺衍生物及其制备方法

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