WO2008016007A1 - METALLO-β-LACTAMASE INHIBITOR - Google Patents

METALLO-β-LACTAMASE INHIBITOR 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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WIPO (PCT)
Prior art keywords
group
ring
compound
piperidine
acid
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PCT/JP2007/064895
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French (fr)
Japanese (ja)
Inventor
Yukiko Hiraiwa
Mizuyo Ida
Toshiaki Kudo
Akihiro Morinaka
Ken Chikauchi
Kenichiro Mori
Original Assignee
Meiji Seika Kaisha, Ltd.
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Application filed by Meiji Seika Kaisha, Ltd. filed Critical Meiji Seika Kaisha, Ltd.
Priority to JP2008527743A priority Critical patent/JP5301272B2/en
Publication of WO2008016007A1 publication Critical patent/WO2008016007A1/en

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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
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    • 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
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    • 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

A phthalic acid derivative represented by the general formula (1) has an inhibitory activity on metallo-β-lactamase. Therefore, when used in combination with a β-lactam antibiotic, the derivative can inhibit the deactivation of the β-lactam antibiotic against a bacterium capable of producing metallo-β-lactamase and can recover the antibacterial activity of the β-lactam antibiotic. (I) wherein R1 represents a hydroxy group, a C1-7 alkyl group, a C1-7 alkoxy group, or a saturated or unsaturated heterocyclic ring (provided that each of these groups may have a substituent); R2 represents a hydrogen atom, or a C1-7 alkyl group (provided that each of these groups may have a substituent); R3 represents a hydrogen atom, a C1-7 alkyl group, a halogen atom, an amino group, or a piperidine ring (provided that each of these groups may have a substituent); and M1 and M2 independently represent a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group capable of being hydrolyzed in vivo.

Description

明 細 書  Specification
メタロー βーラクタマーゼ阻害剤  Metallo β-lactamase inhibitor
技術分野  Technical field
[0001] 本発明は、フタル酸誘導体を有効成分とするメタロー /3—ラクタマーゼ阻害剤に関 し、より詳しくは、本発明は、動物またはヒトにおける細菌感染の治療において、 /3 - ラタタム系抗生物質と併用することにより、メタロー /3—ラクタマーゼ産生菌に対する 有効性を強化する為の医薬組成物および方法に関する。  [0001] 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.
背景技術  Background art
[0002] βーラクタマーゼは、細菌の /3—ラタタム系抗生物質に対する耐性化において非 常に重要である。特に、活性中心に亜鉛を有する、広い基質特異性を示すメタロー βーラクタマーゼは、セリン 0ーラクタマーゼに対して比較的安定であるカルバぺ ネム系抗生物質をも加水分解することから問題視されている。実際、メタロー /3—ラタ タマ一ゼを産生する菌は、臨床上重要な多くの /3—ラタタム系薬に耐性化することか ら脅威となっている。メタ口一 β—ラクタマーゼは、 Bacillus cereus、 Bacteroides fragili s、 Escherichia coli、 Aeromonas hyarophila、 Klebsiella pneumoniae^ Pseudomonas aer uginosa、 Serratia marcescens、 Stenotrophomonas maltophilia^ Shigella flexneri、 Alcal igenes xylosoxidans^ Legionella gormanii、 Chryseobacterium meningosepticum^ Chry seobacterium indologenes、 Acinetobacter baumannii^ Citrobacter freundiiおよび Ente robacter cloacae等多菌種で確認されており、特に Pseudomonas aeruginosa (緑膿菌） においては多剤耐性化も著しぐ問題も大きい。現在 /3—ラクタマーゼ阻害薬として 使用されているクラブラン酸、スルバクタム、タゾバクタムはセリンを活性中心に持つ セリン 0ーラクタマーゼには有用であるものの、メタロー 0ーラクタマーゼに対する 阻害効果はない。  [0002] β-lactamase is very important in the resistance of bacteria to / 3-ratata antibiotics. In particular, a metallo β-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. In fact, metallo-3 / 3-ratamase-producing bacteria are a threat because they become resistant to many clinically important / 3-latatams. Meta-mouth β-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.
[0003] したがって、メタロー 0ーラクタマーゼ産生による耐性菌に対して、イミぺネム等の β ラタタム系抗生物質の有効性を回復させるため、メタロー /3—ラクタマーゼ阻害 薬の必要性が高まっている。  [0003] Therefore, there is an increasing need for a metallo / 3-lactamase inhibitor in order to restore the effectiveness of β-ratam antibiotics such as imipenem against resistant bacteria caused by metallo-lactamase production.
[0004] 緑膿菌において、伝達性プラスミドにコードされたメタロー 13ーラクタマーゼが報告 されて以来、種々の化合物がメタロー 13ーラクタマーゼ阻害活性を有するものとして 報告されている。 W098/17639、 WO97/30027、 WO98/40056、 W098/39311、およ び WO97/10225には、ある種の /3—チォプロピオ二ルーアミノ酸誘導体がそのメタ口 βーラクタマーゼ類に対する阻害薬としての用途とともに記載されている。また、い くつかの文献には、メタロー 0ーラクタマーゼ阻害薬としてのチオール類およびチォ エステル類が開示されている（Biol. Pharm. Bull., 1997， 20， 1136、 FEMS Microbiolog y Letters, 1997， 157， 171、 Antimicrob. Agents Chemother. , 1997， 41， 135、 Chem. Commun., 1998， 1609、 Biochem. J., 1998， 331， 703、および WO00/076962)。さらに 、 WO01/030148、 WO01/030149には、メタロー βーラクタマーゼ阻害薬としてのコハ ク酸系化合物が記載されている。その他、各種のメタロー /3—ラクタマーゼ阻害化合 物や、メタロー /3—ラクタマーゼ産生菌に関する全般的状況について報告されてい る文献がある（Clin. Microbiol.Rev., 2005， 18， 306)。しかしながら、上記文献等には 、本発明による化合物であるフタル酸系誘導体の記載や示唆はなされて!/、な!/、。 [0004] In Pseudomonas aeruginosa, a metallo 13-lactamase encoded by a transmissible plasmid has been reported Since then, various compounds have been reported as having metallo 13-lactamase inhibitory activity. In W098 / 17639, WO97 / 30027, WO98 / 40056, W098 / 39311, and WO97 / 10225, certain / 3-thiopropiodiruo amino acid derivatives are used together with their use as inhibitors of meta-mouth β-lactamases. Are listed. In addition, several documents disclose thiols and thioesters as metallo-lactamase inhibitors (Biol. Pharm. Bull., 1997, 20, 1136, FEMS Microbiology Letters, 1997, 157). , 171, Antimicrob. Agents Chemother., 1997, 41, 135, Chem. Commun., 1998, 1609, Biochem. J., 1998, 331, 703, and WO00 / 076962). Furthermore, WO01 / 030148 and WO01 / 030149 describe succinic acid compounds as metallo β-lactamase inhibitors. In addition, there are reports on the general status of various metallo / 3-lactamase-inhibiting compounds and metallo / 3-lactamase-producing bacteria (Clin. Microbiol. Rev., 2005, 18, 306). However, in the above-mentioned documents and the like, there is a description or suggestion of a phthalic acid derivative which is a compound according to the present invention! / ,!
[0005] 医療現場において実際にメタロー /3—ラクタマーゼ産生による耐性菌に対して効 果を発揮する為には、 /3—ラタタム系抗生物質と併用することで、その有効性を回復 させること力 S必須である。し力もながら、実際の医療現場で問題となる緑膿菌等の菌 種に対して、そのような併用効果を示す報告は今までほとんどなされておらず、現在 のところヒトおよび動物の感染症に有効なメタロー /3—ラクタマーゼ阻害薬は存在し ていない。 [0005] In order to exert an effect against resistant bacteria due to the production of metallo / 3-lactamase in the medical field, the ability to restore its effectiveness by using in combination with / 3-latatam antibiotics S is essential. However, there have been few reports showing such combined effects against bacterial species such as Pseudomonas aeruginosa, which are problematic in actual medical practice, and so far they have been reported to infect human and animal infections. There is no effective metallo / 3-lactamase inhibitor.
[0006] フタル酸誘導体に関して、フタル酸 3位 (4〜6位は無置換）に酸素原子を介する化 合物として、 J. Am. Chem. So ， 1918， 40， 219が 3_ヒドロキシフタル酸を、 Pr. Chem. Soc, 1907， 22， 323が 3-メトキシフタル酸等を、また、 WO97/029079が 3_ペンチルォ キシフタル酸を開示している。しかし、環状のアルキルォキシ基、ピペリジニルォキシ 基を有するフタル酸は知られて!/、なレ、。  [0006] Regarding the phthalic acid derivative, 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. However, phthalic acid having a cyclic alkyloxy group or piperidinyloxy group is known!
また、フタル酸 3位に窒素原子を介する化合物として、特開平 10-239909が 3-ジメチ ルァミノフタル酸を開示している力 フタル酸の 3位に環状のァミン、ピぺラジン環、及 び、モルフオリン環を有する化合物は知られて!/、なレ、。  Further, 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!
さらに W097/47589がマルクーシュ構造上類似の化合物を開示している力 S、用途 が殺虫剤であること、さらに本発明によるフタル酸誘導体の開示、および示唆はないIn addition, 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.
〇 Yes
発明の開示  Disclosure of the invention
[0007] よって、本発明は、 /3—ラタタム系抗生物質の失活を抑制し、抗菌活性を回復させ る薬剤となる新規なメタロー /3—ラクタマーゼ阻害剤の提供を目的としている。  [0007] Accordingly, 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.
[0008] 本発明者らは、今般、フタル酸誘導体およびその薬理上許容される塩が、メタロー [0008] The present inventors have now disclosed that phthalic acid derivatives and pharmacologically acceptable salts thereof are metallo-
βーラクタマーゼに対し阻害作用を有することを見出した。さらにメタロー /3—ラクタ マーゼ産生菌に対して /3—ラタタム系抗生物質の活性を回復させる効果を有するこ とを見出した。本発明は力、かる知見に基づくものである。  It was found to have an inhibitory effect on β-lactamase. Furthermore, it has been found that it has an effect of recovering the activity of / 3-latatam antibiotics against metallo- / 3-lactamase producing bacteria. The present invention is based on strength and knowledge.
[0009] そして、本発明の一つの態様によれば、下記一般式 (I)で表される化合物、その塩[0009] According to one embodiment of the present invention, a compound represented by the following general formula (I), and a salt thereof
、またはそれらの水和物もしくは溶媒和物を含有してなる、メタロー /3—ラクタマーゼ 阻害剤が提供される： Or a metallo / 3-lactamase inhibitor comprising a hydrate or solvate thereof:
[化 1]  [Chemical 1]
Figure imgf000005_0001
Figure imgf000005_0001
(I) (I)
(式中、  (Where
R1は、水酸基、 C アルキル基、 C アルコキシ基、下記 Α環: R 1 is a hydroxyl group, a C alkyl group, a C alkoxy group, the following ring:
1-7 1-7  1-7 1-7
[化 2]  [Chemical 2]
Figure imgf000005_0002
—o—ピペリジン環、ピぺリジン環、フエニル基、ニトロ基、アミノ基、ァゼチジン環、ピ 口リジン環、テトラヒドロピリジン環、ピぺラジン環、モルホリン環、またはァゼパン環を 表し、これらはいずれも置換基を有していてもよぐ
Figure imgf000005_0002
--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
R2は、水素原子、または C アルキル基を表し、これらはいずれも置換基を有して R 2 represents a hydrogen atom or a C alkyl group, each of which has a substituent.
1-7  1-7
いてあよく、 Well,
R3は、水素原子、 C アルキル基、ハロゲン原子、アミノ基、またはピぺリジン環を表 R 3 represents a hydrogen atom, a C alkyl group, a halogen atom, an amino group, or a piperidine ring.
1-7  1-7
し、これらはいずれも置換基を有していてもよぐ Any of these may have a substituent.
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す。）。 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. ).
また、本発明の別の態様によれば、下記一般式 (Π)で表される新規化合物、その塩 Further, according to another aspect of the present invention, a novel compound represented by the following general formula (Π), a salt thereof
、またはそれらの水和物もしくは溶媒和物が提供される： Or a hydrate or solvate thereof:
[化 3]  [Chemical 3]
Figure imgf000006_0001
Figure imgf000006_0001
(II) (II)
(式中、  (Where
B環は、ァゼチジン環、ピロリジン環、ピぺリジン環、ピぺラジン環、モルホリン環、ま たはァゼパン環を表し、これらは!/、ずれも R4を有して!/、てもよく、 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 ! /. ,
R4は、 B環上に 0〜2個存在し、水酸基、 C アルキル基、 C アルコキシ基、ヒドロ 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
1-6 1-6  1-6 1-6
キシ C アルキル基、ォキソ（ =〇）基、ベンジル基、ベンゾィル基、フエニル基、ァミノX-C alkyl group, oxo (= 〇) group, benzyl group, benzoyl group, phenyl group, amino
1-6 1-6
基、アジド基、カルボキシル基、 C アルキルォキシカルボニル基、またはァミノカル Group, azide group, carboxyl group, C alkyloxycarbonyl group, or amino carboxyl
1-6  1-6
ボニル基を表し、これらは!/、ずれも置換基を有して!/、てもよく、 Represents a bonyl group, these may be! /, Both have substituents! /,
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す。）。 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. ).
さらに、本発明の別の態様によれば、下記一般式 (Γ )で表される新規化合物、その 塩、またはそれらの水和物もしくは溶媒和物が提供される：  Furthermore, according to another aspect of the present invention, there is provided a novel compound represented by the following general formula (Γ), a salt thereof, or a hydrate or solvate thereof:
[化 4]  [Chemical 4]
Figure imgf000007_0001
Figure imgf000007_0001
( ) ()
(式中、 (Where
R1は、ピぺリジン環、またはアミノ基を表し、これらはいずれも置換基を有していても よぐ R 1 represents a piperidine ring or an amino group, any of which may have a substituent.
R2は、水素原子を表し、 R 2 represents a hydrogen atom,
R3は、 C アルキル基、ハロゲン原子、ピぺリジン環、またはアミノ基を表し、これらR 3 represents a C alkyl group, a halogen atom, a piperidine ring, or an amino group, and these
1-6 1-6
はレ、ずれも置換基を有して!/、てもよく、 May have substituents! /,
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す。）。 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. ).
さらにまた本発明の別の態様によれば、下記一般式 (III)で表される新規化合物、 その塩、またはそれらの水和物もしくは溶媒和物が提供される：  Furthermore, 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:
[化 5] [Chemical 5]
Figure imgf000008_0001
Figure imgf000008_0001
(III) (III)
(式中、  (Where
c環における」 Lは、単結合または二重結合を表し、  in the c ring "L represents a single bond or a double bond;
R4は、 C環上に 0〜2個存在し、水酸基、 C アルキル基、 C アルコキシ基、ヒドロ 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
1-6 1-6  1-6 1-6
キシ C アルキル基、ォキソ（ =〇）基、 基、フエニル基、ァミノX-C alkyl group, oxo (= 〇) group, group, phenyl group, amino
1-6 1-6
ジド基、カルボキシル基、 C アルキルォキシカルボニル基、またはァミノカル  Zido, carboxyl, C alkyloxycarbonyl, or amino
1-6  1-6
ボニル基を表し、これらは!/、ずれも置換基を有して!/、てもよく、 Represents a bonyl group, these may be! /, Both have substituents! /,
R5は、水素原子、 C ァノレキノレ基、ベンジル基、ベンゾィル基、 C アルキルォキシ R 5 represents a hydrogen atom, a C alkenyl group, a benzyl group, a benzoyl group, a C alkyloxy group.
1-6 1-6  1-6 1-6
カルボニル基、 c アルキルカルボニル基、またはァミノカルボ二ル基を表し、これら Represents a carbonyl group, a c alkylcarbonyl group, or an aminocarbonyl group.
1-6  1-6
はレ、ずれも置換基を有して!/、ても良く、 May have a substituent! /,
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す。）。 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. ).
また本発明の別の態様によれば、下記一般式 (IV)で表される化合物、その塩、ま たはそれらの水和物もしくは溶媒和物が提供される： According to another aspect of the present invention, there is provided a compound represented by the following general formula (IV), a salt thereof, or a hydrate or solvate thereof:
Figure imgf000009_0001
Figure imgf000009_0001
(IV) (IV)
(式中、  (Where
nは 0〜6を表し、  n represents 0-6,
R6は、水酸基、環状 C アルキル基、フエニルォキシ基、フエニル基、カルボキシル 基、置換基を有してもよいピペリジル基、または上記 A環を表し、 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.
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す、 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.
但し、 nが 1のとき、 R6はフエ二ル基を表さない。）。 However, when n is 1, R 6 does not represent a phenyl group. ).
さらに本発明は以下の態様を包含するものである。  Furthermore, this invention includes the following aspects.
すなわち、本発明の一つの態様によれば、上記一般式 (I)で表される化合物と、医 薬的に許容される担体とを含んでなる医薬組成物が提供される。この医薬組成物は 、 β—ラタタム系抗生物質と同時にまたは逐次的に投与されて用いられる。また、こ の医薬組成物はデヒドロぺプチダーゼ阻害剤をさらに含んでいてもよい。  That is, according to one aspect of the present invention, there is provided 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 β-latata antibiotics. The pharmaceutical composition may further contain a dehydropeptidase inhibitor.
本発明の一つの態様によれば、さらに請求項 1に記載のメタロー /3—ラクタマーゼ 阻害剤と、 β ラタタム系抗生物質と、場合により医薬的に許容される担体とを含ん でなる、医薬組成物が提供される。この医薬組成物は、抗菌剤として用いられてもよ い。  According to one embodiment of the present invention, a pharmaceutical composition further comprising the metallo / 3-lactamase inhibitor according to claim 1, a β-ratata antibiotic, and optionally a pharmaceutically acceptable carrier. Things are provided. This pharmaceutical composition may be used as an antibacterial agent.
さらに本発明の一つの態様によれば、細菌感染の治療方法であって、 /3—ラタタム 系抗生物質と請求項 1に記載のメタロー /3—ラクタマーゼ阻害剤とを併用して投与す ることを含んでなる方法が提供される。  Furthermore, according to one embodiment of the present invention, there is provided 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.
さらにまた本発明の一つの態様によれば、細菌感染症の予防または治療剤の製造 のための、上記一般式 (I)で表される化合物の使用が提供される。 Furthermore, according to one embodiment of the present invention, production of a preventive or therapeutic agent for bacterial infections There is provided the use of a compound of general formula (I) above for
発明の具体的説明  DETAILED DESCRIPTION OF THE INVENTION
[0015] 錢 [0015] 錢
本明細書において、断りがない限り、「C 」「C 」「C 」等は、炭素数を表し、例え  In this specification, unless otherwise specified, “C”, “C”, “C” and the like represent the number of carbon atoms.
1-7 1-6 3-7  1-7 1-6 3-7
ば、「C アルキル基」は、炭素数 1 7のアルキル基を表す。また、 C は結合を表す For example, “C alkyl group” represents an alkyl group having 17 carbon atoms. C represents a bond.
1-7 01-7 0
。また、低級とは好ましくは C―を表し、環状の場合は好ましくは C を表す。 . In addition, “lower” preferably represents C—, and in the case of a ring, preferably represents C.
基または基の一部としての「アルキル基」または「アルコキシ基」は、断りがない限り、 好ましくは直鎖、分岐鎖、または環状の炭素数 1 7のアルキル基、または直鎖、分 岐鎖、または環状の炭素数 1—7のアルコキシ基を意味する。 「アルキル」の例として は、メチル、ェチル、 n—プロピル、 i—プロピル、 n ブチル、 iーブチル、 s ブチル、 tーブチノレ、 n—ペンチノレ、ネオペンチノレ、 i—ペンチノレ、 t—ペンチノレ、 n へキシノレ 、 i一へキシノレ、 n へプチノレ、 i一へプチノレ、シクロプロピノレ、シクロブチノレ、シクロぺ ンチル、シクロへキシル、シクロへプチル等が挙げられる。本明細書において、基ま たは基の一部としての「環状アルキル基」とは、好ましくは炭素数 3 7の単環のアル キル基を表し、その例としてはシクロプロピル、シクロブチル、シクロペンチル、シクロ へキシル、シクロへプチル等が挙げられる。  Unless otherwise specified, 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. Examples of “alkyl” 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. In the present specification, the “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.
[0016] 「アルコキシ」の例としては、メトキシ、エトキシ、 n—プロポキシ、 i—プロポキシ、 n- ブトキシ、 i—ブトキシ、 s—ブトキシ、 t—ブトキシ、 n—ペンチルォキシ、ネオペンチノレ ォキシ、 i ペンチノレォキシ、 t ペンチノレォキシ、 n へキシノレォキシ、 i一へキシノレ ォキシ、 n ヘプチノレオキシ、 i ヘプチノレオキシ、シクロプロボキシ、シクロブトキシ、 シクロペンチルォキシ、シクロへキシルォキシ、シクロへプチルォキシ等が挙げられる 。本明細書において、基または基の一部としての「環状アルコキシ基」とは、好ましく は炭素数 3 7の単環のアルコキシ基を表し、その例としては、シクロプロボキシ、シク ロブトキシ、シクロペンチルォキシ、シクロへキシルォキシ、シクロへプチルォキシ等 が挙げられる。 Examples of “alkoxy” 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. In the present specification, 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.
[0017] 本明細書において「いずれも置換基を有していてもよく」とは、好ましくは 1〜6個、よ り好ましくは 1〜3個の置換基を有していてもよいことを意味する。また、それらは同じ でも異なっていてもよい。本明細書において「置換基」とは、特に断りがない限り、水 酸基、ハロゲン原子、アミノ基、モノ置換アミノ基、ジ置換アミノ基、アジド基、 C アル In the present specification, “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. In the present specification, “substituent” 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 キル基、 C 環状アルキル基、置換 C 環状アルキル基、 C アルコキシ基、 C 環  1-6 Kill group, C cyclic alkyl group, substituted C cyclic alkyl group, C alkoxy group, C ring
3-7 3-7 1-6 3-7 状アルコキシ基、ヒドロキシ C アルキル基、アミド基、 N 置換アミド基、 N, N ジ置  3-7 3-7 1-6 3-7-like alkoxy group, hydroxy C alkyl group, amide group, N-substituted amide group, N, N
1-6  1-6
換アミド基、ァミノカルボニル基、置換アミノカルボニル基、カルボキシル基、 C アル Substituted amide group, aminocarbonyl group, substituted aminocarbonyl group, carboxyl group, C-al
1-6 キルォキシカルボニル基、ォキソ（ =〇）基、フエニル基、フエニルォキシ基、置換フエ ニル基、ベンジル基、置換べンジル基、ベンゾィル基、ピリジノレメチノレ基、 C アルキ  1-6 Kiloxycarbonyl group, oxo (= 〇) group, phenyl group, phenyloxy group, substituted phenyl group, benzyl group, substituted benzyl group, benzoyl group, pyridino retinoyl group, C alkyl
1-6 ルカルポニル基、置換 C アルキルカルボニル基、 A環、複素環等を意味する。  1-6 means a carbonyl group, a substituted C alkylcarbonyl group, an A ring, a heterocyclic ring, etc.
1-6  1-6
本明細書において、「複素環」とは、窒素原子、酸素原子、および硫黄原子から選 ばれた 1種または 2種、 1ないし 4個のへテロ原子を含む 5〜； 14員の単環式ないし三 環性複素環等を意味し、好ましくは、窒素原子、酸素原子、または硫黄原子を 1〜4 個含む、 5〜； 10員の単環または二環性複素環が挙げられる。さらに好ましくは、テトラ ヒドロフラン、フラン、ピロリジン、ピぺリジン、ビラゾリジン、イミダゾリジン、ピぺラジン、 モルホリン、チオモルホリン、ピロール、チォフェン、ォキサゾール、イソォキサゾール 、チアゾール、イソチアゾール、イミダゾール、ピラゾール、ピリジン、ピリダジン、ピリミ ジン、ピラジン、トリァゾール、テトラゾール、チアジアゾール、ァゼチジン、チアゾリン 、キヌタリジン、トリアジン、イソべンゾフラン、インドール、インドリジン、クロメン、キノリ ン、イソキノリン、シンノリン、キナゾリン、キノキサリン、フタラジン、プリン、プテリジン等 が挙げられる。  In the present specification, the “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. More preferably, tetrahydrofuran, furan, pyrrolidine, piperidine, virazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, Pyrimidine, pyrazine, triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinutaridin, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, pteridine, etc. .
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を表す。  "Halogen atom" represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
「カルボニルァミノ基」とは NH— CO 基を表す。  The “carbonylamino group” represents an NH—CO group.
また、本明細書において、「A環」とは下記の基を表す。  In the present specification, the “A ring” represents the following group.
[化 7] [Chemical 7]
Figure imgf000011_0001
一般式 (I)で表されろ化 物》含有してなろメタロー flーラクタマーゼ阳窖吝 II 本発明の一つの態様によれば、前記一般式 (I)で表される化合物、その塩、または それらの水和物もしくは溶媒和物を含有してなるメタロー /3—ラクタマーゼ阻害剤が 提供される。
Figure imgf000011_0001
According to one embodiment of the present invention, 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.
[0020] 一般式 (I)で表される化合物は、メタロー /3—ラクタマーゼ阻害作用を有し、当該化 合物自体をメタロー /3—ラクタマーゼ阻害剤として用いることができる。  [0020] 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.
[0021] 上述のとおり、メタロー 0ーラクタマーゼは、多くの 0 ラタタム系抗生物質を加水 分解し、その有効性を失活させてしまう。ここで、一般式 (I)で表される化合物を、 β ラタタム系抗生物質と併用すれば、その活性を回復させることが可能となる。  [0021] As described above, metallo-lactamase hydrolyzes many 0-ratam antibiotics and deactivates their effectiveness. Here, if the compound represented by the general formula (I) is used in combination with β-ratata antibiotics, the activity can be recovered.
[0022] 一般式 (I)で表される化合物は、それ自体をメタロー /3—ラクタマーゼ阻害剤として 用いることができる力、、担体と組み合わせて、さらに /3—ラタタム系抗生物質と組み合 わせて後述する医薬組成物とされて用いることが好ましレ、。  [0022] 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.
[0023] 一般式（I)において、 R1は、水酸基、 C アルキル基、 C アルコキシ基、上記 Α環、 In the general formula (I), R 1 represents a hydroxyl group, a C alkyl group, a C alkoxy group, the above-described ring,
1-7 1-7  1-7 1-7
—o—ピペリジン環、ピぺリジン環、フエニル基、ニトロ基、アミノ基、ァゼチジン環、ピ 口リジン環、テトラヒドロピリジン環、ピぺラジン環、モルホリン環、またはァゼパン環を 表し、これらはいずれも置換基を有していてもよぐ R2は、水素原子、または C アル --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
1-7 キル基を表し、これらはいずれも置換基を有していてもよぐ R3は、水素原子、 C ァ 1-7 represents a kill group, any of which may have a substituent R 3 is a hydrogen atom, C
1-7 ルキル基、ハロゲン原子、アミノ基、またはピぺリジン環を表し、これらはいずれも置 換基を有していてもよぐ M1および M2は、同一または異なっていてもよぐ水素原子 、医薬的に許容されるカチオン、または医薬的に許容される生体内で加水分解されう る基を表す。 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.
[0024] 上記一般式 (I)にお!/、て、 R1が表す「C アルキル基」は、直鎖、分岐鎖、または環 In the above general formula (I),! /, The “C alkyl group” represented by R 1 is a straight chain, branched chain, or ring
1-7  1-7
状の炭素数 1 7のアルキル基を表す。その具体例としては、メチル、ェチル、 n プ ロピノレ、 i プロピル、 n ブチル、 iーブチル、 s ブチル、 tーブチル、 n ペンチノレ、 ネオペンチノレ、 i ペンチノレ、 t ペンチノレ、 n へキシノレ、 i一へキシノレ、 n へプチ ノレ、 i一へプチル、シクロプロピル、シクロブチル、シクロペンチル、シクロへキシル、シ クロへプチル等が挙げられる。 R1は好ましくは C アルキル基であり、さらに好ましくは Represents an alkyl group having 17 carbon atoms. Specific examples include methyl, ethyl, n-propinole, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentinole, neopentino, i-pentino, t-pentino, n-hexino, i-hexino-re, n Examples include heptinole, i-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. R 1 is preferably a C alkyl group, more preferably
1-6  1-6
、メチノレ、ェチル、 n プロピル、 i プロピル、 n ブチル、 iーブチル、 s ブチル、 t ーブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロへキシルなどが挙 げられる。このアルキル基は置換基を有していてもよぐその例としては上述の置換 基が挙げられ、好ましくは、水酸基、ハロゲン原子等が挙げられる。 , Methylol, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. This alkyl group may have a substituent. Group, preferably a hydroxyl group, a halogen atom and the like.
[0025] 上記一般式 (I)において、 R1が表す「C アルコキシ基」は、直鎖または、分岐また In the above general formula (I), the “C alkoxy group” represented by R 1 is linear, branched or
1-7  1-7
は環状のいずれであってもよぐその具体例としては、メトキシ、エトキシ、 n プロボ キシ、 i—プロボキシ、 n—ブトキシ、 t—ブトキシ、 n—ペンチノレオキシ、ネ才ペンチノレ ォキシ、 i ペンチノレォキシ、 t ペンチノレォキシ、 n へキシノレォキシ、 i一へキシノレ ォキシ、シクロプロボキシ、シクロブトキシ、シクロペンチノレ才キシ、シクロへキシノレ才 キシ、シクロへプチルォキシ等が挙げられ、好ましくは C アルコキシ基であり、さらに  Specific examples of which may be cyclic 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
1-6  1-6
好ましくは、メトキシ、エトキシ、 n—プロポキシ、 i—プロポキシ、 n—ブトキシ、 t—ブト キシ、シクロプロボキシ、シクロブトキシ、シクロペンチノレ才キシ、シクロへキシノレ才キ シなどが挙げられる。このアルコキシ基は置換基を有していてもよぐその例としては 上述の置換基が挙げられ、好ましくは、水酸基、 C アルキル基、 C 環状アルキル  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.
1-6 3-7  1-6 3-7
基、カルボキシル基、フエニル基、フエニルォキシ基、上記 A環が挙げられる。  Group, carboxyl group, phenyl group, phenyloxy group and the above-mentioned A ring.
[0026] —O ピペリジン環は、いずれの位置で結合していてもよぐ好ましくは O ピぺ リジンー4ーィル基、—O ピペリジンー1ーィル基である。この—O ピペリジン環上 の水素原子は置換されていてもよぐその例としては上述の置換基が挙げられ、好ま しくはアルキルォキシカルボニル基が挙げられる。 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.
[0027] ピぺリジン環はいずれの位置で結合していてもよぐ好ましくはピペリジン 1ーィル 基、ピぺリジン 4ーィル基である。このピぺリジン環上の水素原子は置換されていて もよぐその例としては上述の置換基が挙げられ、好ましくは、水酸基、アミノ基、アジ ド基、 C アルコキシ基、ヒドロキシ C ァノレキノレ基、カルボキシル基、 C アルキルォ[0027] 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. Preferably, a hydroxyl group, an amino group, an azide group, a C alkoxy group, a hydroxy C alcoholenoquinole group, Carboxyl group, C alkylo
1-6 1-6 1-6 キシカルボニル基、ァミノカルボニル基、置換アミノカルボニル基、ォキソ（=o)基、 フエニル基、ベンジル基、 c アルキルカルボニル基、力 s挙げられる。さらに、本発明 1-6 1-6 1-6 Xyloxycarbonyl group, aminocarbonyl group, substituted aminocarbonyl group, oxo (= o) group, phenyl group, benzyl group, c alkylcarbonyl group, force s. Furthermore, the present invention
1-6  1-6
の好まし!/、態様によれば、ピぺリジン環がピぺリジン 1ーィル基である場合の置換 基としては、水酸基、アミノ基、モノ C アルキルアミノ基、ジ C アルキルアミノ基、ァ  According to the embodiment, 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,
1-6 1-6  1-6 1-6
ジド基、ヒドロキシ C ァノレキノレ基、 C アルコキシ基、カルボキシル基、 C ァノレキル  Zido group, Hydroxy C anoleno quinole group, C Alkoxy group, Carboxyl group, C anolecyl
1-6 1-6 1-6 ォキシカルボニル基、ァミノカルボニル基、置換アミノカルボニル基、ォキソ（=o)基 、フエニル基、ベンジル基が挙げられる。また、本発明の好ましい態様によれば、ピぺ リジン環がピぺリジンー4ーィル基である場合の置換基としては、 C アルキルォキシ カルボニル基、ァミノカルボニル基、置換アミノカルボニル基、ベンジル基、 C アル 1-6 1-6 1-6 Examples include an oxycarbonyl group, an aminocarbonyl group, a substituted aminocarbonyl group, an oxo (= o) group, a phenyl group, and a benzyl group. Further, according to a preferred embodiment of the present invention, when the piperidine ring is a piperidine-4-yl group, the substituent is C alkyloxy. Carbonyl group, aminocarbonyl group, substituted aminocarbonyl group, benzyl group, C-al
1-6 キルカルボニル基が挙げられる。  1-6 Killcarbonyl group is mentioned.
[0028] R1が表すフエニル基上の水素原子は置換されていてもよぐ置換基の例としては上 述の置換基が挙げられ、好ましくは水酸基、カルボキシル基、が挙げられる。 [0028] 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.
[0029] アミノ基は、置換基を有していてよぐモノ置換アミノ基またはジ置換アミノ基のいず れであってもよい。置換基の例としては上述の置換基が挙げられ、好ましくはモノ C [0029] The amino group may be either 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, preferably mono C
1-6 アルキルアミノ基、ジ C アルキルアミノ基、 C アルキルカルボニルァミノ基が挙げら  1-6 Alkylamino group, di-C alkylamino group, C alkylcarbonylamino group, etc.
1-6 1-6  1-6 1-6
れる。「モノ C アルキルアミノ基」は、直鎖、分岐鎖または環状のレ、ずれであってもよ  It is. The “mono C alkylamino group” may be linear, branched or cyclic, or shifted.
1-6  1-6
ぐ好ましくは直鎖の C アルキル基または環状の C アルキル基であり、たとえばメ  More preferably, it is a linear C alkyl group or a cyclic C alkyl group.
1-4 3-7  1-4 3-7
チノレアミノ、ェチノレアミノ、 n プロピノレアミノ、 n ブチノレアミノ、シクロプロピルァミノ、 シクロブチルァミノ、シクロペンチルァミノ、シクロへキシルァミノ、シクロへプチルァミノ 等が挙げられる。さらにこれらは、水酸基、またはピリジル基などで置換されていても よ!/、。また、「ジ C アルキルアミノ基」は、直鎖、分岐鎖または環状の!/、ずれであって  Tinoleamino, ethinoreamino, n-propinoleamino, n-butinoreamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino and the like. Furthermore, these may be substituted with a hydroxyl group or a pyridyl group! / ,. In addition, the “di-C alkylamino group” is linear, branched or cyclic! /
1-6  1-6
もよぐ好ましくは直鎖の C アルキル基であり、二つのアルキル基は同じでも異なつ  More preferably, it is a linear C alkyl group, and the two alkyl groups may be the same or different.
1-4  1-4
てもよく、たとえばジメチルァミノ、ジェチルァミノ、ジ n プロピルァミノ、ジ n ブチル ァミノ、ェチルメチルァミノ、プロピルメチルァミノ、ブチルメチルァミノ、ェチルプロピ ルァミノ、ブチルェチルァミノ、ブチルプロピルアミノ等が挙げられる。「C アルキル  Examples thereof include dimethylamino, jetylamino, di-n-propylamino, di-n-butylamino, ethylmethylamino, propylmethylamino, butylmethylamino, ethylpropylamino, butylethylamino, butylpropylamino and the like. . "C alkyl
1-6 カルボニルァミノ基」は、直鎖、分岐鎖、または環状のいずれであってもよぐ好ましく は直鎖の C ァノレキノレ基であり、メチルカルボニルァミノ、ェチルカルボニルァミノ、 n  The “1-6 carbonylamino group” may be linear, branched or cyclic, and is preferably a linear C anolenoquino group, which includes methylcarbonylamino, ethylcarbonylamino, n
1-4  1-4
-プロピルカルボニルアミ入 n-ブチルカルボニルァミノなどが挙げられ、これらは水酸 基で置換されていてもよい。  N-butylcarbonylamino and the like may be mentioned, and these may be substituted with a hydroxyl group.
[0030] ァゼチジン環は!/、ずれの位置で結合して!/、てもよく、好ましくはァゼチジン 1ーィ ル基などが挙げられる。このァゼチジン環上の水素原子は置換されていてもよぐそ の例としては上述の置換基が挙げられ、好ましくは水酸基、 C アルキル基が挙げら  [0030] 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.
1-6  1-6
れる。  It is.
[0031] ピロリジン環はいずれの位置で結合していてもよぐ好ましくはピロリジン 1ーィル 基などが挙げられる。このピロリジン環上の水素原子は置換されていてもよぐその例 としては上述の置換基が挙げられ、好ましくは水酸基、 C アルキル基が挙げられる [0032] テトラヒドロピリジン環はいずれの位置で結合していてもよぐ好ましくは、 1,2,3,6- テトラヒドロピリジン基であり、さらに好ましくは、 1，2，3，6 テトラヒドロピリジン -1-イノレ基 、 1，2，3，6 テトラヒドロピリジン -4-ィル基などが挙げられる。このテトラヒドロピリジン環 上の水素原子は置換されていてもよぐその例としては上述の置換基が挙げられ、好 ましくは C アルキルォキシカルボニル基、水酸基、 C アルキル基が挙げられる。 [0031] 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. [0032] 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.
1-6 1-6  1-6 1-6
[0033] ピぺラジン環はいずれの位置で結合していてもよぐ好ましくは、ピぺラジン 1ーィ ル基などが挙げられる。このピぺラジン環上の水素原子は置換されていてもよぐそ の例としては上述の置換基が挙げられ、好ましくは C アルキルカルボニル基、 c  [0033] 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
1-6 1-6 アルキルォキシカルボニル基、ァミノカルボニル基、置換アミノカルボニル基、ベンジ ル基、ベンゾィル基が挙げられる。  1-6 1-6 Examples include an alkyloxycarbonyl group, an aminocarbonyl group, a substituted aminocarbonyl group, a benzyl group, and a benzoyl group.
[0034] モルホリン環はいずれの位置で結合していてもよぐ好ましくは、モルホリン 4ーィ ル基などが挙げられる。このモルホリン環上の水素原子は置換されていてもよぐそ の例としては上述の置換基が挙げられ、好ましくは水酸基、 C アルキル基が挙げら  [0034] 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.
1-6  1-6
れる。  It is.
[0035] ァゼパン環はいずれの位置で結合していてもよぐ好ましくは、ァゼパン 1ーィル 基などが挙げられる。このァゼパン環上の水素原子は置換されていてもよぐその例 としては上述の置換基が挙げられ、好ましくは水酸基、 C アルキル基が挙げられる  [0035] 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.
1-6  1-6
〇  Yes
[0036] 一般式（I)にお!/、て、 R2は、水素原子または C アルキル基を表す。 R2が表す「C [0036] In the general formula (I), R 2 represents a hydrogen atom or a C alkyl group. R 2 represents “C
1-7 1-7 アルキル基」は、 R1と同義であり、好ましくは C アルキル基であり、さらに好ましくは C “1-7 1-7 alkyl group” has the same meaning as R 1 , preferably C alkyl group, more preferably C
1-6 1 ァノレキノレ基であり、たとえばメチル、ェチル、 n—プロピル、 i—プロピル、 n ブチノレ 1-6 1 is an alkenoquinol group such as methyl, ethyl, n-propyl, i-propyl, n-butynole
-4 -Four
、 iーブチル、 s ブチル、 tーブチル、シクロプロピル、シクロブチル等が挙げられる。  I-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl and the like.
[0037] 一般式（I)において、 R3は、水素原子、 C アルキル基、ハロゲン原子、アミノ基、ま [0037] In the general formula (I), R 3 represents a hydrogen atom, a C alkyl group, a halogen atom, an amino group, or
1-7  1-7
たはピぺリジン環を表し、これらはいずれも置換基を有していてもよい。 R3が表す「C Or a piperidine ring, any of which may have a substituent. R 3 represents “C
1- アルキル基」は、 R1と同義であり、好ましくは C アルキル基であり、さらに好ましくは CThe “1-alkyl group” has the same meaning as R 1 , preferably a C alkyl group, more preferably C
7 1-6 7 1-6
アルキル基であり、たとえばメチル、ェチル、 n プロピル、 i プロピル、 n ブチノレ Alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butanol
1-4 1-4
、 iーブチル、 s ブチル、 tーブチル、シクロプロピル、シクロブチル等が挙げられる。 [0038] R3が表すハロゲン原子とは前記と同義である。 R3が表すアミノ基とは、 R1と同義であ り、置換基を有していてよぐモノ置換アミノ基またはジ置換アミノ基のいずれであって もよい。置換基の例としては上述の置換基が挙げられ、その好ましい例も R1と同様の ものであってよい。 I-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl and the like. [0038] 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 .
[0039] R3が表すピぺリジン環とは、 R1と同義である。すなわち、ピぺリジン環はいずれの位 置で結合していてもよぐ好ましくはピペリジン 1ーィル基、ピぺリジン 4 ィル基 である。このピぺリジン環上の水素原子は置換されていてもよぐその例としては上述 の置換基が挙げられ、その好ましい例も R1と同様のものであってよい。さらに好ましく は水酸基またはァミノ基が挙げられる。 [0039] 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.
[0040] M1および M2は同一または異なってもよぐ「医薬的に許容されるカチオン」とは一般 式（I)の一方、または両方のカルボキシル基と塩を形成しうるカチオンであり、例えば アルカリ金属、アルカリ土類金属、アンモニゥム、有機塩基等が挙げられ、好ましくは 、リチウム、ナトリウム、カリウム、マグネシウム、カルシウム、アンモニゥム、エタノール ァミン、トリエタノールァミン、トリメチルァミン、ジイソプロピルアミン等が挙げられる。 [0040] 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.
[0041] また、一般式 (I)の化合物は、そのプロドラッグの形で用いられてもよい。プロドラッ グは生体において加水分解可能であり、胃もしくは腸の粘膜からの良好な吸収、胃 酸分解に対する耐性および他の要素から経口投与に好ましい。従って、「医薬的に 許容される生体内で加水分解されうる基」とは 一般式 (I)の一方または両方のカル ボキシル基に結合した脱離可能な基を表し、それらは生体内で代謝をうけ、加水分 解、脱離しカルボキシル基となる基を表す。  [0041] 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.
[0042] 一般式 (I)の化合物において、「医薬的に許容される生体内で加水分解されうる基」 は好ましくはエステル残基であり、その例としては、低級アルキル基、低級アルケニル 基、低級アルキルカルボニルォキシ低級アルキル基、低級シクロアルキルカルボ二 ルォキシ低級アルキル基、低級シクロアルキルメチルカルボニルォキシ低級アルキ ル基、低級アルケニルカルボニルォキシ低級アルキル基、ァリールカルボ二ルォキ シ低級アルキル基、テトラヒドロフラニルカルポニルォキシメチル基、低級アルコキシ 低級アルキル基、低級アルコキシ低級アルコキシ低級アルキル基、ァリールメチルォ キシ低級アルキル基、ァリールメチルォキシ低級アルコキシ低級アルキル基、低級ァ ルコキシカルボニルォキシ低級アルキル基、低級アルコキシカルボニルォキシ低級 アルコキシ基、低級シクロアルコキシカルボニルォキシ低級アルキル基、低級シクロ アルキルメトキシカルボニルォキシ低級アルキル基、ァリールォキシカルボ二ルォキ シ低級アルキル基、芳香環上に置換基を有してもよい 3—フタリジル基、芳香環上に 置換基を有してもよい 2—（3 フタリジリデン)ェチル基、 2 ォキソテトラヒドロフラン 5—ィル基、モノ低級アルキルアミノカルボニルォキシメチル基、ジ低級アルキルァ ミノカルボニルォキシメチル基、 2 ォキソ 5 低級アルキル 1，3 ジォキソレン 4—ィルメチル基、置換基を有してもよ!/、ピペリジニルカルボニルォキシ低級アルキル 基、低級アルキル低級シクロアルキルアミノカルボニルォキシ低級アルキル基、等の 常用のものが挙げられる。 In the compound of the general formula (I), “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 cycloalkylmethoxy A carbonyloxy lower alkyl group, an aryloxycarbonyl lower alkyl group, a 3-phthalidyl group which may have a substituent on the aromatic ring, and a substituent which may have a substituent on the aromatic ring 2- (3 phthalidylidene) ethyl group, 2-oxotetrahydrofuran 5-yl group, mono-lower alkylaminocarbonyloxymethyl group, di-lower alkylaminocarbonyloxymethyl group, 2-oxo-5 lower alkyl 1,3 dioxolene 4-ylmethyl group , May have a substituent! /, Piperidinylcarbonyl Shi lower alkyl, lower alkyl lower cycloalkyl aminocarbonyl O carboxy-lower alkyl group include those conventional equal.
「医薬的に許容される生体内で加水分解されうる基」として好ましくはメチル基、ェ チノレ基、 1- (シクロへキシルォキシカルボニルォキシ)ェチル基、ァセトキシメチル基、 1- (イソプロピルォキシカルボニルォキシ)ェチル基、 1- (エトキシカルボニルォキシ)ェ チノレ基、ビバロイルォキシメチル基、シクロへキシルォキシカルボニルォキシメチル基 、 1- (イソブチルォキシカルボニルォキシ)ェチル基、 1- (シクロへキシルォキシカルボ ニルォキシ) -2-メチルプロパン- 1-ィル基、イソブチルォキシカルボ二ルォキシメチノレ 基、イソプロピルォキシカルボニルォキシメチル基、イソブチリルォキシメチル基、（ぺ ンタン- 1-ィル)ォキシカルボニルォキシメチル基、（ブタン- 1-ィル)ォキシカルボニル ォキシメチル基、（1-ェチルプロパン- 1-ィル)ォキシカルボニルォキシメチル基、イソ ペンチルォキシカルボニルォキシメチル基、（プロパン- 1-ィル)ォキシメチル基、エト キシカルボニルォキシメチル基、ネオペンチルォキシカルボニルォキシメチル基、メト キシカノレポニノレ才キシメチノレ基、シクロペンチノレ才キシカノレポニノレ才キシメチノレ基、 t -ブトキシカルボニルォキシメチル基、フタリジル基、 1- (メトキシカルボニルォキシ)ェ チル基、 1- (シクロペンチルォキシカルボニルォキシ)ェチル基、（テトラヒドロピラン- 4- ィノレ)ォキシカルボニルォキシメチル基、 1- (ネオペンチルォキシカルボニルォキシ)ェ チル基、（ピペリジン- 1-ィル)カルボニルォキシメチル基、ァリル基、 l_(t-ブトキシカル ボニルォキシ)ェチル基、（N，N-ジ -n-プロピルァミノ)カルボニルォキシメチル基、フエ ニルォキシカルボニルォキシメチル基、（5-メチル -2-ォキソ -1,3-ジォキソレン- 4-ィ ル）メチル基、（cis-2，6-ジメチルビペリジン- 1-ィル)カルボニルォキシメチル基、 N，N- ジ- (ブタン- 1-ィル)ァミノカルボニルォキシメチル基、へキサン- 1-ィル基、 N- (へキサ ン -1-ィル) -N-メチルァミノカルボニルォキシメチル基、 N，N-ジイソブチルァミノ力ノレ ボニルォキシメチル基、 N，N-ジイソプロピルアミノカルボニルォキシメチル基、 N-シク 口へキシル -N-メチルァミノカルボニルォキシメチル基、 N-ペンタン- 1-ィルァミノカル ボニルォキシメチル基、 N-シクロへキシル -N-ェチルァミノカルボニルォキシメチル基 、 N-イソブチル -N-イソプロピルアミノカルボニルォキシメチル基、 N-t-ブチル -N-ェ チルァミノカルボニルォキシメチル基、 l-[(cis-2，6-ジメチルビペリジン- 1-ィル)カル ボニルォキシ]ェチル基、 1-(N，N-ジイソプロピルアミノカルボニルォキシ)ェチル基、 N -ェチル -N-イソアミルァミノカルボニルォキシメチル基等である。 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, Methoxycanole poninore ximethinole group, cyclopentinore xikanoleponinole ximethinole group, t-butoxycarbonyloxymethyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentylol) Xoxycarbonyloxy) ethyl group, (tetrahydropyran-4-inole) oxycarbonyloxymethyl group, 1- (neopentyloxycarbonyloxy) ethyl group, (piperidine-1-yl) carbonyloxy Methyl group, aryl group, l_ (t-butoxycarbonyloxy) ethyl group, (N, N-di-n-propylamino) carbonyl Okishimechiru group, Hue Nyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6-dimethylbiperidine-1-yl) carbonyl Oxymethyl group, N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hex-1-yl) -N -Methylaminocarbonyloxymethyl group, N, N-diisobutylaminoamino group, nonoxyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl -N-methylaminocarbonyl Oxymethyl group, N-pentane-1-ylaminocarbonyloxymethyl group, N-cyclohexyl-N-ethylaminocarbonyloxymethyl group, N-isobutyl-N-isopropylaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, l-[(cis-2,6 -Dimethylbiperidine-1-yl) carbonyloxy] ethyl group, 1- (N, N-diisopropylaminocarbonyloxy) ethyl group, N-ethyl-N-isoamylaminocarbonyloxymethyl group, etc. .
[0044] 一般式 (I)で表される化合物は、塩として提供されてもよく、好ましくは医薬的に許 容される塩として提供される。また、塩には酸付加塩も含まれる。従って、一般式 (I) の化合物は、無機酸もしくは有機酸力 誘導される塩の形態で用いることもできる。そ のような塩としては、酢酸塩、アジピン酸塩、アルギン塩、ァスパラギン酸塩、安息香 酸塩、ベンゼンスルホン酸塩、重硫酸塩、酪酸塩、クェン酸塩、樟脳酸塩、カンファ ースルホン酸塩、シクロペンタンプロピオン酸塩、ジダルコン酸塩、ドデシル硫酸塩、 エタンスルホン酸塩、フマル酸塩、ダルコヘプタン酸塩、グリセ口リン酸塩、へミ硫酸 塩、ヘプタン酸塩、へキサン酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、 2—ヒド ロキシエタンスルホン酸塩、乳酸塩、マレイン酸塩、メタンスルホン酸塩、 2—ナフタレ ンスルホン酸塩、ニコチン酸塩、シユウ酸塩、パモ酸塩、ぺクチン酸塩、過硫酸塩、 3 フエニルプロピオン酸塩、ピクリン酸塩、ビバリン酸塩、プロピオン酸塩、コハク酸塩 、酒石酸塩、チォシアン酸塩、トシル酸塩およびゥンデカン酸塩等が挙げられる。  [0044] 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. Accordingly, 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. , Cyclopentanepropionate, didarconate, dodecyl sulfate, ethane sulfonate, fumarate, darcoheptanoate, glycephosphate, hemisulfate, heptanoate, hexanoate, hydrochloride , Hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methane sulfonate, 2-naphthalene sulfonate, nicotinate, oxalate, pamo Acid, pectate, persulfate, 3-phenylpropionate, picrate, vivalate, propionate, succinate, tartrate, thiocyanate, tosylate And Undekan acid salts.
[0045] また、一般式 (I)で表される化合物は、水和物または水以外の溶媒和物として提供 されてもよい。溶媒和物の溶媒としては、メタノール、エタノール、イソプロパノール、 ブタノール、アセトン、酢酸ェチル、クロ口ホルム等が挙げられる。また、一般式（I)で 表される化合物またはその塩は、分子内に不斉炭素を有することもある。それら各々 、またはそれらの混合物の!/、ずれも本発明に包含される。 [0046] 本発明による式 (I)で表される化合物の好まし!/、化合物群としては、[0045] 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. In addition, 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! /
R1が、水酸基、 C アルキル基、 C アルコキシ基、上記 A環、—O ピぺリジン— 4 R 1 is a hydroxyl group, a C alkyl group, a C alkoxy group, the above ring A, —O piperidine—4
1-6 1-6  1-6 1-6
ーィル基、 O ピペリジン 1ーィル基、フエニル基、ピぺリジン 1ーィル基、ピぺ リジン一 4—ィル基、ニトロ基、アミノ基、モノ C ァノレキノレアミノ基、ジ C ァノレキノレアミ  -Yl group, O piperidine 1-yl group, phenyl group, piperidine 1-yl group, piperidine 1-yl group, nitro group, amino group, mono-C ano-requinolamino group, di-C ano-requinolamine
1-6 1-6  1-6 1-6
ノ基、 C アルキルカルボニルァミノ基、ァゼチジン 1ーィル基、ピロリジン 1ーィ Group, C alkylcarbonylamino group, azetidine 1-yl group, pyrrolidine 1-i
1-6 1-6
ル基、 1，2，3，6 テトラヒドロピリジン基、ピぺラジン 1ーィル基、モルホリンー4ーィル 基、またはァゼパン 1 ィル基を表し、これらはいずれも置換基を有していてもよく  Group, 1,2,3,6 tetrahydropyridine group, piperazine-1-yl group, morpholine-4-yl group, or azepanyl group, any of which may have a substituent.
R2が水素原子、または C アルキル基を表し、これらは!/、ずれも置換基を有して!/ R 2 represents a hydrogen atom or a C alkyl group, which are! /, Both of which have a substituent! /
1-6 、て もよぐ  1-6
R3が水素原子、 C アルキル基、ハロゲン原子、アミノ基、モノ C アルキルアミノ基、 R 3 is a hydrogen atom, a C alkyl group, a halogen atom, an amino group, a mono C alkylamino group,
1-6 1-6  1-6 1-6
ジ C アルキルアミノ基、ピぺリジン 1ーィル基、またはピぺリジン 4 ィル基を表 Di-C alkylamino group, piperidine 1-yl group, or piperidine 4-yl group
1-6 1-6
し、これらはいずれも置換基を有していてもよい  Any of these may have a substituent.
を表す化合物群が挙げられる。  The compound group which represents is mentioned.
[0047] また、本発明の別の態様によれば、式 (I)で表される化合物の好ましい具体的化合 物群として以下のものが挙げられる。 [0047] Further, according to another aspect of the present invention, preferred specific compound groups of the compound represented by the formula (I) include the following.
3-ヒドロキシフタル酸  3-hydroxyphthalic acid
3-ブトキシフタル酸  3-Butoxyphthalic acid
3-メトキシフタル酸  3-methoxyphthalic acid
3- (シクロへキシルォキシ)フタル酸  3- (Cyclohexyloxy) phthalic acid
3-(3_シクロへキシルプロポキシ)フタル酸  3- (3_Cyclohexylpropoxy) phthalic acid
3-(3_フエニルプロポキシ)フタル酸 3- (3_Phenylpropoxy) phthalic acid
3_(4-フエニルブトキシ)フタル酸  3_ (4-Phenylbutoxy) phthalic acid
3_(2-ヒドロキシエトキシ)フタル酸 -[l-(tert-ブトキシカルボニル)ピぺリジン- 4-ィルォキシ]フタル酸- (ピペリジン- 4-ィルォキシ)フタル酸3_ (2-hydroxyethoxy) phthalic acid -[l- (tert-Butoxycarbonyl) piperidine-4-yloxy] phthalic acid- (piperidine-4-yloxy) phthalic acid
-( β -D-グルコピラノシルォキシ)フタル酸-(β-D-Glucopyranosyloxy) phthalic acid
-[2-( β -Dグルコピラノシルォキシ)エトキシ]フタル酸-[2- (β-D-Glucopyranosyloxy) ethoxy] phthalic acid
-[3-( β -ダルコピラノシルォキシ)プロポキシ]フタル酸-[3- (β-Darcopyranosyloxy) propoxy] phthalic acid
- (ブチルァミノ)フタル酸-(Butylamino) phthalic acid
- (ピリジン- 3-ィルメチルァミノ)フタル酸-(Pyridine-3-ylmethylamino) phthalic acid
_(trans-4-ヒドロキシシクロへキシルァミノ)フタル酸_ (trans-4-hydroxycyclohexylamino) phthalic acid
-(cis_4-ヒドロキシシクロへキシルァミノ)フタル酸-(cis_4-Hydroxycyclohexylamino) phthalic acid
_(2-ヒドロキシァセトアミド)フタル酸_ (2-Hydroxyacetamido) phthalic acid
-ブチルアミドフタル酸 -Butylamidophthalic acid
(ブチル (メチル)ァミノ)フタル酸 (Butyl (methyl) amino) phthalic acid
-ジメチルアミノフタル酸-Dimethylaminophthalic acid
- (ァゼチジン- 1-ィル)フタル酸-(Azetidine-1-yl) phthalic acid
- (ピロリジン- 1-ィル)フタル酸-(Pyrrolidine-1-yl) phthalic acid
-(3_ヒドロキシピロリジン- 1-ィル)フタル酸 -(3_Hydroxypyrrolidine-1-yl) phthalic acid
(R)-3- (3-ヒドロキシピロリジン-卜イノレ)フタル酸  (R) -3- (3-Hydroxypyrrolidine- 卜 inole) phthalic acid
(S)-3_(3-ヒドロキシピロリジン- 1-ィノレ)フタル酸 (S) -3_ (3-Hydroxypyrrolidine-1-inole) phthalic acid
- (ピペリジン-卜ィル)フタル酸-(Piperidine-zyl) phthalic acid
_(4-ヒドロキシピペリジン- 1-ィル)フタル酸_ (4-Hydroxypiperidine-1-yl) phthalic acid
_(4- (ヒドロキシメチル)ピぺリジン- 1-ィル)フタル酸_ (4- (Hydroxymethyl) piperidine-1-yl) phthalic acid
_(4- (ヒドロキシェチノレ)ピペリジン-卜ィノレ)フタル酸_ (4- (Hydroxyethinole) piperidine-zinole) phthalic acid
-(3_ヒドロキシピペリジン- 1-ィル)フタル酸-(3_Hydroxypiperidine-1-yl) phthalic acid
-(3_ (ヒドロキシメチル)ピぺリジン- 1-ィル)フタル酸-(3_ (Hydroxymethyl) piperidine-1-yl) phthalic acid
_(4-メトキシピぺリジン- 1-ィル)フタル酸_ (4-Methoxypiperidine-1-yl) phthalic acid
_(4-ォキソピペリジン- 1-ィル)フタル酸_ (4-oxopiperidine-1-yl) phthalic acid
_(4-ヒドロキシ- 4-フエ二ルビペリジン-卜ィル)フタル酸_ (4-Hydroxy-4-phenylbiperidine-zyl) phthalic acid
_(4-アミノビペリジン- 1-ィル)フタル酸 _(4-アジドピペリジン- 1 -ィル)フタル酸_ (4-Aminobiperidine-1-yl) phthalic acid _ (4-Azidopiperidine-1-yl) phthalic acid
_(4-ベンジルピペリジン- 1-ィル)フタル酸_ (4-Benzylpiperidine-1-yl) phthalic acid
_(4-カルボキシピペリジン- 1-ィル)フタル酸_ (4-Carboxypiperidine-1-yl) phthalic acid
-[4- (エトキシカルボ二ノレ)ピぺリジン- 1-ィル]フタル酸-[4- (Ethoxycarboninole) piperidine-1-yl] phthalic acid
_(4-力ルバモイルビペリジン-卜ィル)フタル酸_ (4-Strength Lumamoylbiperidine-Zyl) phthalic acid
_(4- (ジメチルカルバモイル)ピぺリジン- 1-ィル)フタル酸_ (4- (Dimethylcarbamoyl) piperidine-1-yl) phthalic acid
- (ピペラジン- 1-ィル)フタル酸-(Piperazine-1-yl) phthalic acid
-(4-(tert-ブトキシカルボ二ノレ)ピぺラジン- 1-ィノレ)フタル酸-(4- (tert-Butoxycarboninole) piperazine-1-inole) phthalic acid
_(4-ベンジルピペラジン- 1-ィル)フタル酸_ (4-Benzylpiperazine-1-yl) phthalic acid
_(4-ベンゾィルビペラジン- 1-ィル)フタル酸_ (4-Benzylbiperazine-1-yl) phthalic acid
_(4-力ルバモイルピペラジン- 1-ィル)フタル酸_ (4-Strength Rubamoylpiperazine-1-yl) phthalic acid
- (モルホリン- 4-ィノレ）フタル酸-(Morpholine-4-inole) phthalic acid
- (ァゼパン- 1-ィル）フタル酸-(Azepan-1-yl) phthalic acid
-メチルフタル酸-Methylphthalic acid
-(3_ヒドロキシプロピル)フタル酸-(3_Hydroxypropyl) phthalic acid
-フエニルフタル酸-Phenylphthalic acid
_(2-ォキシド)フエニルフタル酸トリナトリウム_ (2-Oxido) phenyl sodium phthalate
-(3_ヒドロキシ)フエニルフタル酸-(3_Hydroxy) phenylphthalic acid
_(4-ヒドロキシ)フエニルフタル酸_ (4-Hydroxy) phenylphthalic acid
_(2-カルボキシ)フエニルフタル酸_ (2-Carboxy) phenylphthalic acid
-(3_カルボキシ)フエニルフタル酸-(3_Carboxy) phenylphthalic acid
_(4-カルボキシ)フエニルフタル酸_ (4-Carboxy) phenylphthalic acid
-[l_(tert-ブトキシカルボニル) -1 ,2,3,6-テトラヒドロピリジン- 4-ィル]フタル酸-[1- (tert-ブトキシカルボ二ルビペリジン) -4-ィノレ]フタル酸-[l_ (tert-Butoxycarbonyl) -1,2,3,6-tetrahydropyridine-4-yl] phthalic acid- [1- (tert-butoxycarbonylbiperidine) -4-ynole] phthalic acid
-(1_ァセチルビペリジン- 4-ィル)フタル酸-(1_acetylbiperidine-4-yl) phthalic acid
-(1_ベンジルピペリジン- 4-ィノレ)フタル酸-(1_Benzylpiperidine-4-inole) phthalic acid
- (1-力ルバモイルビペリジン- 4-ィル)フタル酸-(1-Strong rubermoyl biperidine-4-yl) phthalic acid
-フルォ口- 6-(4-ヒドロキシピペリジン- 1-ィル)フタル酸 3， 6-ビス (4-ヒドロキシピペリジン- 1 -ィル)フタル酸 -Fluoro-6- (4-hydroxypiperidine-1-yl) phthalic acid 3, 6-bis (4-hydroxypiperidine-1-yl) phthalic acid
3- (4-ヒドロキシピペリジン- 1-ィル) -6-メチルフタル酸  3- (4-Hydroxypiperidine-1-yl) -6-methylphthalic acid
3_(4-アミノビペリジン- 1-ィル) -6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸  3_ (4-aminobiperidine-1-yl) -6_ (4-hydroxypiperidine-1-yl) phthalic acid
3- (ジメチルァミノ) -6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸  3- (Dimethylamino) -6_ (4-hydroxypiperidine-1-yl) phthalic acid
3,6-ジメチルフタル酸  3,6-dimethylphthalic acid
3- (ジメチルァミノ) -6-メチルフタル酸  3- (Dimethylamino) -6-methylphthalic acid
[0048] 一般式 (11)、式 (Γ )、式 (111)、および式 (IV)で表される新規化合物 [0048] Novel compounds represented by general formula (11), formula (Γ), formula (111), and formula (IV)
一般式 (I)で表される化合物群には新規化合物が含まれる。従って、本発明の別の 態様によれば、新規なフタル酸誘導体が提供され、具体的には上記した一般式 (II) 、式 (Γ )、式 (111)、および式 (IV)で表される新規化合物が提供される。  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 (Γ), formula (111), and formula (IV) described above. New compounds are provided.
[0049] 一 式' (II)の [0049] Set of (II)
一般式 (Π)で表される化合物は、一般式 (I)において、 3位にのみ置換基を有する 化合物群であり、この 3位の置換基は窒素原子を介した環状ァミンである。  The compound represented by the general formula (Π) 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.
一般式 (Π)において、環状ァミン、すなわち B環は、ァゼチジン環、ピロリジン環、ピ ペリジン環、ピぺラジン環、モルホリン環、ァゼパン環を表し、これらはいずれも R4を 0 〜2個有していてもよい。 In the general formula (Π), 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.
R4は、水酸基、 C ァノレキノレ基、 C アルコキシ基、ヒドロキシ C ァノレキノレ基、ォキR 4 is a hydroxyl group, a C alkenoquinole group, a C alkoxy group, a hydroxy C anoleno quinole group, an oxy group,
1-6 1-6 1-6 1-6 1-6 1-6
ソ（=o)基、ベンジル基、ベンゾィル基、フエニル基、アミノ基、アジド基、カルボキシ ル基、 C アルキルォキシカルボニル基、ァミノカルボ二ル基を表し、これらはいずれ So (= o) group, benzyl group, benzoyl group, phenyl group, amino group, azide group, carboxyl group, C alkyloxycarbonyl group, and aminocarbonyl group.
1-6 1-6
も置換基を有していてもよい。  May also have a substituent.
[0050] R4が表す「C アルキル基」は、直鎖、分岐鎖、環状の!/、ずれであってもよ!/、炭素数 [0050] The "C alkyl group" represented by R 4 is linear, branched or cyclic! /, May be shifted! /, And the number of carbon atoms.
1-6  1-6
1—6のアルキル基を表す。たとえばメチル、ェチル、 n—プロピル、 i—プロピル、 n— ブチノレ、 iーブチノレ、 s ブチノレ、 tーブチノレ、 n ペンチノレ、ネオペンチノレ、 i ペンチ ノレ、 t ペンチノレ、 n へキシノレ、 i一へキシノレ、シクロプロピノレ、シクロブチノレ、シクロ ペンチル、シクロへキシル等が挙げられる。好ましくは C アルキル基であり、たとえ  Represents an 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
1-4  1-4
ばメチル、ェチル、 n プロピル、 i プロピル、 n ブチル、 iーブチル、 s ブチル、 t ブチル等が挙げられる。  Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like.
[0051] R4が表す「C アルコキシ基」は直鎖または、分岐、または環状のいずれであっても よい炭素数 1—6のアルコキシ基であり、その例としてはメトキシ、エトキシ、 n プロボ キシ、 i—プロボキシ、 n—ブトキシ、 t—ブトキシ、 n—ペンチノレオキシ、ネ才ペンチノレ ォキシ、 i ペンチノレォキシ、 t ペンチノレォキシ、 n へキシノレォキシ、 i一へキシノレ ォキシ、シクロプロボキシ、シクロブトキシ、シクロペンチノレ才キシ、シクロへキシノレ才 キシ等が挙げられる。 R4は、好ましくは C アルコキシ基であり、さらに好ましくは C ァ [0051] The "C alkoxy group" represented by R 4 may be linear, branched, or cyclic. Examples of 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
1-6 1-4 ノレコキシ基であり、その例としてはメトキシ、エトキシ、 n プロポキシ、 i プロポキシ、 n ブトキシ、 t ブトキシ、シクロプロボキシ、シクロブトキシ等が挙げられる。  1-6 1-4 Norecoxy group, examples of which include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, cyclopropoxy, cyclobutoxy and the like.
[0052] R4が表す「ヒドロキシ C アルキル基」中のアルキルの定義は、 R4が表す「C アルキ [0052] The definition of alkyl in the “hydroxy C alkyl group” represented by R 4 is “C alkyl group represented by R 4 ”.
1-6 1-6 ル基」と同義であり、好ましくはヒドロキシ C アルキル基であり、たとえばヒドロキシメ  1-6 1-6 group ”, preferably a hydroxy C alkyl group, such as hydroxy
1-4  1-4
チル、ヒドロキシェチル、ヒドロキシプロピル、ヒドロキシブチル等が挙げられる。  Examples include til, hydroxyethyl, hydroxypropyl, and hydroxybutyl.
R4が表す「C アルキルォキシカルボニル基」中のアルキルの定義は、 R4が表す「C Defining alkyl R 4 represents in "C alkyl O alkoxycarbonyl group", R 4 represents "C
1-6 1 アルキル基」と同義であり、好ましくはじ アルキルォキシカルボニル基であり、たと 1-6 1 alkyl group ”, preferably an alkyloxycarbonyl group,
- 6 1-4 -6 1-4
えばメトキシカノレポ二ノレ、エトキシカノレポニノレ、 n プロポキシカノレポニノレ、 i プロポ キシカルボニル、 n ブトキシカルボニル、 t ブトキシカルボニル等が挙げられる。  For example, methoxy canole poninore, ethoxy canole pononole, n propoxy kanole pononole, i propoxy carbonyl, n butoxy carbonyl, t butoxy carbonyl and the like.
[0053] R4が表すアミノ基は置換基を有して!/、てもよくァミノ基、モノ置換アミノ基、ジ置換ァ ミノ基が挙げられ、前記「置換基」で 1または 2個置換されており、好ましくは、この「置 換基」は C アルキル基であり、前記と同義である。 「モノ置換アミノ基」は好ましくは [0053] 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" Preferably, the “substituent” is a C alkyl group as defined above. “Mono-substituted amino group” is preferably
1-6  1-6
モノ C アルキルアミノ基であり、さらに好ましくは C アルキル基であり、たとえばメチ A mono C alkylamino group, more preferably a C alkyl group such as methyl
1-6 1-4 1-6 1-4
ルァミノ、ェチルァミノ、 n プロピルァミノ、 n—ブチルァミノ等が挙げられる。 「ジ置換 アミノ基」は好ましくはジ C アルキルアミノ基であり、さらに好ましくは直鎖の C アル And luamino, ethylamino, n- propylamino, n -butylamino and the like. The “disubstituted amino group” is preferably a di-C alkylamino group, more preferably a linear C alkyl group.
1-6 1-4 キル基であり、二つのアルキル基は同じでも異なってもよぐたとえばジメチルァミノ、 ジェチルァミノ、ジ n プロピルァミノ、ジ n ブチルァミノ、ェチルメチルァミノ、プロピ ノレメチノレアミノ、ブチルメチルァミノ、ェチルプロピルァミノ、ブチルェチルァミノ、プチ ルプロピルアミノ等が挙げられる。  1-6 1-4 Kill groups, and 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.
M1および M2は前記一般式 (I)と同義である。 M 1 and M 2 have the same meaning as in the general formula (I).
[0054] 本発明の好ましい態様によれば、好ましい式 (Π)で表される化合物群として、 [0054] According to a preferred embodiment of the present invention, as the compound group represented by the preferred formula (Π),
B環が、ァゼチジン環、ピロリジン環、ピぺリジン環、ピぺラジン環、モルホリン環、ァ ゼパン環を表し、 B環上、 R4を 1〜2個有していてもよぐ R4が、水酸基、ヒドロキシ C アルキル基、 C アルコキシ基、ォキソ（ = 0)基、フエ 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. R 4 is hydroxyl, hydroxyalkyl C alkyl group, C alkoxy group, Okiso (= 0) group, Hue
1-6 1-6  1-6 1-6
二ノレ基、ベンジル基、アジド基、アミノ基、カルボキシル基、 C アルキルォキシカル  Ninole group, benzyl group, azide group, amino group, carboxyl group, C alkyloxy
1-6  1-6
ボニル基、ァミノカルボニル基、モノ C ァノレキノレアミノ基、ジ C アルキルアミノ基を  Bonyl group, aminocarbonyl group, mono-C anolenoquinamino group, di-C alkylamino group
1-6 1-6  1-6 1-6
表し、  Represent,
M1および M2は前記一般式 (I)と同義である化合物群が挙げられる。 Examples of M 1 and M 2 include a compound group having the same meaning as in the general formula (I).
[0055] 一般式 (Γ )の化合物  [0055] Compounds of general formula (Γ)
一般式 (Γ )で表される化合物は、一般式 (I)において、 3位と 6位に置換基を有する 化合物群である。一般式 (Γ )において、 R1はピペリジン環またはアミノ基を表し、これ らはいずれも置換基を有していてもよぐ R2は水素原子を表し、 R3は C アルキル基 The compound represented by the general formula (Γ) is a group of compounds having substituents at the 3-position and the 6-position in the general formula (I). In the general formula (Γ), R 1 represents a piperidine ring or an amino group, which may have any substituent, R 2 represents a hydrogen atom, and R 3 represents a C alkyl group.
1-6  1-6
、ハロゲン原子、ピぺリジン環、またはアミノ基を表し、これらはいずれも置換基を有し ていてもよい。  , A halogen atom, a piperidine ring, or an amino group, all of which may have a substituent.
[0056] R1が表すピぺリジン環は、一般式 (I)の場合と同義であり、好ましくはピペリジン— 1 ーィル基である。また、このピぺリジン環上の水素原子は置換されていてもよぐ置換 基としては一般式 (I)の場合と同様のものが挙げられ、好ましくは水酸基およびアミノ でめる。 [0056] 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.
[0057] R1が表すアミノ基は置換されていてもよぐモノ置換アミノ基、ジ置換アミノ基いずれ であってもよい。置換基としては前記「置換基」を表し、好ましくは C アルキル基であ [0057] 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.
1-6  1-6
る。「モノ置換アミノ基」は好ましくはモノ c アルキルアミノ基であり、さらに好ましくは  The The “mono-substituted amino group” is preferably a mono-c alkylamino group, more preferably
1-6  1-6
C アルキル基であり、たとえばメチルアミ入ェチノレアミノ、 n プロピノレアミノ、 n ブ C alkyl groups, such as methylamino ethynoleamino, npropynoleamino, n
1-4 1-4
チルァミノ等が挙げられる。「ジ置換アミノ基」は好ましくはジ C アルキルアミノ基で  Examples include tyramino. The “disubstituted amino group” is preferably a di C alkylamino group.
1-6  1-6
あり、さらに好ましくは直鎖の C アルキル基であり、二つのアルキル基は同じでも異  More preferably a linear C alkyl group, and the two alkyl groups may be the same or different.
1-4  1-4
なってもよく、たとえばジメチルァミノ、ジェチルァミノ、ジ n プロピルァミノ、ジ n ブ チルァミノ、ェチルメチルァミノ、プロピルメチルァミノ、ブチルメチルァミノ、ェチルプ 口ピルァミノ、ブチルェチルァミノ、ブチルプロピルアミノ等が挙げられる。  For example, dimethylamino, jetylamino, di-n-propylamino, di-n-butylamino, ethylmethylamino, propylmethylamino, butylmethylamino, ethyl-pylamino, butylethylamino, butylpropylamino, etc. Can be mentioned.
[0058] R3が表す「C アルキル基」は、前記と同義であり、好ましくは、直鎖の C アルキル [0058] The "C alkyl group" represented by R 3 is as defined above, and preferably a linear C alkyl group
1-6 1-4 基であり、たとえばメチル、ェチル、 n プロピル、 i プロピル、 n ブチル等が挙げら れる。  1-6 1-4 groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl and the like.
[0059] R3が表す R1が表すアミノ基は置換されていてもよぐモノ置換アミノ基、ジ置換アミノ 基いずれであってもよい。置換基としては前記「置換基」を表し、好ましくは C アル [0059] 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
1-6 キル基である。 「モノ置換アミノ基」は好ましくはモノ C アルキルアミノ基であり、さら  1-6 Kill group. The “mono-substituted amino group” is preferably a mono C alkylamino group, and
1-6  1-6
に好ましくは C アルキル基であり、たとえばメチルァミノ、ェチルァミノ、 n プロピノレ  C is preferably a C alkyl group such as methylamino, ethylamino, n-propinole.
1-4  1-4
アミ入 n プチルァミノ等が挙げられる。 「ジ置換アミノ基」は好ましくはジ C アルキ  Ami n-ptylamino etc. are mentioned. The `` disubstituted amino group '' is preferably diC alkyl.
1-6 ルァミノ基であり、さらに好ましくは直鎖の C アルキル基であり、二つのアルキル基  1-6 ruamino group, more preferably a linear C alkyl group, and two alkyl groups
1-4  1-4
は同じでも異なってもよぐたとえばジメチルァミノ、ジェチルァミノ、ジ n プロピルアミ ノ、ジ n ブチルァミノ、ェチルメチルァミノ、プロピルメチルァミノ、ブチルメチルァミノ 、ェチルプロピルァミノ、ブチルェチルァミノ、ブチルプロピルアミノ等が挙げられる。 May be the same or different, for example dimethylamino, jetylamino, di- n- propylamino, di- n- butylamino, ethylmethylamino, propylmethylamino, butylmethylamino, ethylpropylamino, butylethylamino, And butylpropylamino.
[0060] 本発明の好ましい態様によれば、好ましい式 (Γ )で表される化合物群として、 [0060] According to a preferred embodiment of the present invention, as the compound group represented by the preferred formula (Γ),
R1が、置換基を有してレ、てもよ!/、ピペリジン 1 ィル基またはジ置換アミノ基を表 し、 R 1 may have a substituent, may be! /, A piperidine 1yl group or a disubstituted amino group,
R3が、 C アルキル基、アミノ基、置換基を有して!/、てもよ!/、ピペリジン 1 ィル基R 3 has a C alkyl group, an amino group, a substituent! /, May! /, A piperidine 1yl group
1-6 1-6
、またはハロゲン原子などを表し、  Or a halogen atom,
M1および M2は (I)と同義である化合物群が挙げられる。 M 1 and M 2 are a group of compounds having the same meaning as (I).
[0061] 一 式' (III)の [0061] Set of (III)
一般式 (III)で表される化合物は、一般式 (I)において、 3位にのみ炭素原子を介し てピペリジン環、または 1，2，3，6 テトラヒドロピリジン環を有する化合物群である。  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).
[0062] C環におけるニニが単結合または二重結合を表す結果、 C環は、ピぺリジン環また は 1，2，3，6 テトラヒドロピリジン環を表す。 C環上の炭素原子上には R4を 0〜2個存在 する。ここで、 R4は、水酸基、 C アルキル基、 C アルコキシ基、ヒドロキシ C アルキ [0062] As a result of Nini in the C ring representing a single bond or a double bond, the C ring represents a piperidine ring or a 1,2,3,6 tetrahydropyridine ring. There are 0-2 R 4 on the carbon atom on the C ring. Here, R 4 is a hydroxyl group, a C alkyl group, a C alkoxy group, a hydroxy C alkyl group.
1-6 1-6 1-6 ル基、ォキソ（=o)基、ベンジル基、ベンゾィル基、フエニル基、アミノ基、アジド基、 カルボキシル基、 C アルキルォキシカルボニル基、またはァミノカルボ二ル基を表し  1-6 1-6 1-6 group, oxo (= o) group, benzyl group, benzoyl group, phenyl group, amino group, azide group, carboxyl group, C alkyloxycarbonyl group, or aminocarbonyl group Representation
1-6  1-6
、これらはいずれも置換基を有していてもよぐ R5は、水素原子、 C アルキル基、ベ Any of these may have a substituent.R 5 is a hydrogen atom, a C alkyl group, a base.
1-6  1-6
ンジル基、ベンゾィル基、 C アルキルォキシカルボニル基、 C アルキルカルボニル  Benzyl group, benzoyl group, C alkyloxycarbonyl group, C alkylcarbonyl
1-6 1-6  1-6 1-6
基、またはァミノカルボ二ル基を表し、これらはいずれも置換基を有していても良ぐ M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または、医薬的に許容される生体内で加水分解されうる基を表す。 Each of which may have a substituent, 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.
[0063] R4が表す「C アルキル基」は一般式 (I)と同義であり、好ましくは C アルキル基で [0063] The "C alkyl group" represented by R 4 is as defined in general formula (I), preferably a C alkyl group.
1-6 1-4 あり、その例としてはメチノレ、ェチル、 n—プロピル、 i—プロピル、 n ブチル、 iーブチ ル、 s ブチル、 t ブチル等が挙げられる。 1-6 1-4 Examples thereof include methylol, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like.
R4が表す「C アルコキシ基」は一般式 (I)と同義であり、好ましくは C アルコキシ The “C alkoxy group” represented by R 4 is as defined in general formula (I), preferably C alkoxy
1-6 1-4  1-6 1-4
基であり、その例としてはメトキシ、エトキシ、 n プロポキシ、 i プロポキシ、 n ブト キシ、 t ブトキシ、シクロプロボキシ、シクロブトキシ等が挙げられる。 Examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, cyclopropoxy, cyclobutoxy and the like.
R4が表す「ヒドロキシ C アルキル基」中のアルキルの定義は、ここで R4が表す「C Defining alkyl in R 4 represents "hydroxy C alkyl group" is used herein represented by R 4 "C
1-6 1-6 アルキル基」と同義であり、好としてはヒドロキシ C アルキル基であり、その例として  It is synonymous with “1-6 1-6 alkyl group”, preferably hydroxy C alkyl group.
1-4  1-4
はヒドロキシメチル、ヒドロキシェチル、ヒドロキシプロピル、ヒドロキシブチル等が挙げ られる。 Examples thereof include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like.
R4が表す「C アルキルォキシカルボニル基」中のアルキルの定義は、ここで R4が表 Defining alkyl in "C alkyl O alkoxycarbonyl group", wherein R 4 is a table that R 4 represents
1-6  1-6
ましくは C アルキルォキシカルボニル基であり
Figure imgf000026_0001
エトキシカノレポニノレ、 n プロポキシカノレポニノレPreferably a C alkyloxycarbonyl group
Figure imgf000026_0001
Ethoxycanoleponinore, n propoxycanoleponinore
、 i プロポキシカルボニル、 n ブトキシカルボニル、 t ブトキシカルボニル等が挙 げられる。 , I-propoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl and the like.
R5が表す「C アルキル基」は、ここで R4が表すものと同義である。 The “C alkyl group” represented by R 5 has the same meaning as that represented by R 4 herein.
1-6  1-6
R5が表す「C アルキルォキシカルボニル基」は、ここで R4が表すものと同義である。 The “C alkyloxycarbonyl group” represented by R 5 has the same meaning as that represented by R 4 here.
1-6  1-6
R5が表す「C アルキルカルボニル基」中の「C アルキル」は前記と同義であり、好 The “C alkyl” in the “C alkylcarbonyl group” represented by R 5 has the same meaning as described above.
1-6 1-6  1-6 1-6
ましくは、直鎖または分岐鎖の C アルキルカルボニル基であり、その例としてはメチ Preferably, it is a linear or branched C alkylcarbonyl group.
1-6  1-6
ノレカノレポニノレ、ェチノレカノレポニノレ、 n プロピノレカノレポニノレ、 i プロピノレカノレポニノレ 、 n ブチルカルボニル等が挙げられる。好ましくは C アルキルカルボニル基であり Norecanoreponinore, ethinorecanoreponinore, n-propinorecanoreponinore, i-propinorecanoreponinore, n-butylcarbonyl and the like. Preferably a C alkylcarbonyl group.
1-4  1-4
、たとえばメチルカルボニル、ェチルカルボニル、 n プロピルカルボニル、 i プロピ ルカルポニル等が挙げられる。 M1および M2は一般式（I)と同義である。 Examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl and the like. M 1 and M 2 have the same meaning as in general formula (I).
本発明の好ましい態様によれば、好ましい式 (III)で表される化合物群として、 C環がピぺリジン環または 1，2，3，6 テトラヒドロピリジン環を表し、  According to a preferred embodiment of the present invention, as a preferred group of compounds represented by the formula (III), the C ring represents a piperidine ring or a 1,2,3,6 tetrahydropyridine ring,
R4が水酸基、 C アルキル基またはォキソ（ = O)基を表し、 R 4 represents a hydroxyl group, a C alkyl group or an oxo (= O) group,
1-6  1-6
R5が、水素原子、 C アルキル基、 C アルキルォキシカルボニル基、 C アルキル R 5 is a hydrogen atom, C alkyl group, C alkyloxycarbonyl group, C alkyl
1-6 1-6 1-6 カルボニル基、ベンジル基、またはァミノカルボ二ル基を表し、  1-6 1-6 1-6 represents a carbonyl group, a benzyl group, or an aminoamino group,
M1および M2は前記一般式 (I)と同義である化合物群が挙げられる。 [0065] 一般式（IV)の化合物 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)
一般式 (IV)で表される化合物は、一般式 (I)において、 3位にのみ酸素原子を介し て置換基を有する化合物群である。  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).
[0066] 一般式（IV)にお!/、て、 nは 0〜6を表し、 R6は水酸基、環状 C アルキル基、フエ二 [0066] In formula (IV),! /, N represents 0 to 6 , R 6 represents a hydroxyl group, a cyclic C alkyl group, phenyl
3-7  3-7
ルォキシ基、フエニル基、カルボキシル基、置換基を有してもよいピペリジル基、また は上記 A環を表し、 M1および M2は、同一または異なっていてもよぐ水素原子、医薬 的に許容されるカチオン、または医薬的に許容される生体内で加水分解されうる基を 表す、但し、 nが 1のとき R6はフエ二ル基を表さない。 Represents a ruoxy group, a phenyl group, a carboxyl group, an optionally substituted piperidyl group, or the above A ring, and 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.
[0067] R6が表す「環状 C アルキル基」は、その例としてはシクロプロピル、シクロブチル、 [0067] The "cyclic C alkyl group" represented by R 6 includes, for example, cyclopropyl, cyclobutyl,
3-7  3-7
シクロペンチル、シクロへキシル、シクロへプチルなどが挙げられ、好ましくは、環状 C アルキル基などであり、たとえばシクロブチル、シクロペンチル、シクロへキシル等 And cyclopentyl, cyclohexyl, cycloheptyl, etc., and preferably a cyclic C alkyl group, such as cyclobutyl, cyclopentyl, cyclohexyl, etc.
4-6 4-6
が挙げられる。  Is mentioned.
R6が表す「置換基を有してもよいピペリジノレ基」は、好ましくはピペリジン一 4—ィル 基、ピぺリジン一 1—ィル基であり、「置換基」は前記と同義であるが、好ましくは、水 素原子、 C アルキル基、 C アルキルォキシカルボニル基、 C アルキルカルボ二 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. Are preferably a hydrogen atom, a C alkyl group, a C alkyloxycarbonyl group, a C alkyl carbonyl group.
1-6 1-6 1-6 ル基などが挙げられる。 M1および M2は一般式 (I)の場合と同義である。 1-6 1-6 1-6 group. M 1 and M 2 have the same meaning as in the general formula (I).
[0068] 本発明の好ましい態様によれば、好ましい一般式 (IV)で表される化合物群として、 [0068] According to a preferred embodiment of the present invention, as a preferred group of compounds represented by the general formula (IV):
nが 0〜4を表し、  n represents 0-4,
R6が水酸基、環状 C アルキル基、フエニル基、フエニルォキシ基、カルボキシル基 R 6 is a hydroxyl group, cyclic C alkyl group, phenyl group, phenyloxy group, carboxyl group
3-6  3-6
、置換基を有していてもよいピぺリジン— 4—ィル基、または前記 A環を表し、  , Represents an optionally substituted piperidine-4-yl group, or the A ring,
M1および M2が前記一般式 (I)と同義である化合物群が挙げられる。 A group of compounds in which M 1 and M 2 have the same meaning as in the general formula (I) can be mentioned.
[0069] 医薬用涂および医薬組成物 [0069] Pharmaceutical vaginal and pharmaceutical composition
一般式 (I)の化合物は、上述のとおり、メタロー /3—ラクタマーゼ阻害作用を有する ことから、メタ口一 β—ラクタマーゼを阻害するために用いられる。その一つの具体的 な利用態様としては、メタ口一 /3—ラクタマーゼにより失活してしまう抗生物質とりわけ β ラタタム系抗生物質と併用されて、このような抗生物質の活性を回復させ、感染 症の治療の用途に用いることができる。  Since the compound of the general formula (I) has a metallo / 3-lactamase inhibitory action as described above, it is used to inhibit meta-mouth β-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 β-ratam antibiotics, to restore the activity of such antibiotics and to infect infections. It can be used for therapeutic purposes.
[0070] 従って、本発明の一つの態様によれば、 13—ラタタム系抗生物質と併用される、一 般式 (I)の化合物を有効成分として含んでなるメタロー ( ーラクタマーゼ阻害剤およ び医薬組成物が提供される。すなわち、本発明によるメタロー /3—ラクタマーゼ阻害 剤および医薬組成物は、 ( ラタタム系抗生物質と同時にまたは逐次的に投与され て用いられる。 [0070] Therefore, according to one embodiment of the present invention, 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.
[0071] β ラタタム系抗生物質としては、力ルバぺネム系抗生物質、ペニシリン系抗生物 質、セフエム系抗生物質またはそれらのプロドラッグが挙げられる。  [0071] Examples of β-ratata antibiotics include strong rubapenem antibiotics, penicillin antibiotics, cephem antibiotics, or prodrugs thereof.
[0072] 力ルバぺネム類の具体例としては、イミぺネム、メロぺネム、ビアぺネム、ドリぺネム、 エルタぺネム、テビぺネム（ビバロイルォキシメチル（4R, 5S, 6S) - 6 - [ (R) - l - ヒドロキシェチノレ]— 4 メチル一 7 ォキソ 3— {[1— (1 , 3 チアゾリン一 2 ィル) ァゼチジン 3 ィノレ]チォ }) 1ーァザビシクロ [3· 2. 0]ヘプトー 2 ェンー2 力 ノレボキシレート）、 CS_023 ((— )— (4R, 5S, 6S)— 3— [[ (3S, 5S)— 5— [(S)— 3— (2—グァニジノアセチルァミノ)ピロリジン 1ーィルカルボニル ] 1 メチルピロリジ ン一 3—ィル]チォ]—6— [ (R)—l—ヒドロキシェチノレ]— 4—メチル 7—ォキソ一ァ ザビシクロ [3· 2. 0]ヘプトー 2 ェンー2 力ルボン酸）および ME1036 ( (1S, 5R, 6 S) 2— [7—（1一力ルバモイルメチルピリジニゥムー 3 ィル)カルボ二ルイミダゾ [5 , 1—b]チアゾール 2—ィル]— 6— ( (1R)— 1—ヒドロキシェチノレ)一 1—メチル一 1 一力ルバペン 2 ェム 3 カルボキシレート）等が挙げられる。特に一般式（I)の 化合物との併用が好ましい力ルバぺネム類は、イミぺネム、メロぺネム、ビアぺネムお よびドリぺネムである。  [0072] Specific examples of the powerful rubapenems include imipenem, meropenem, biapenem, doripenem, ertapenem, tevipenem (bivaloyloxymethyl (4R, 5S, 6S) -6-[(R)-l-Hydroxyethinole] — 4 Methyl-7-oxo 3— {[1— (1, 3 Thiazoline-2-yl) azetidine 3-inore] thio}) 1-azabicyclo [3.2 .0] Heptou 2 -2 force norboxoxylate), CS_023 ((—) — (4R, 5S, 6S) — 3— [[(3S, 5S) — 5— [(S) — 3— (2—Guanidino Acetylamino) pyrrolidine 1-ylcarbonyl] 1-Methylpyrrolidin 1 3-yl] thio] —6— [(R) —l-hydroxyethinole] — 4-methyl 7-oxoZabicyclo [3 · 2.0 ] Heptoe 2 ene 2 strength rubonic acid) and ME1036 ((1S, 5R, 6 S) 2— [7— (1 strength rubamoylmethylpyridinumu 3 yl) carboluimidazo [5, 1—b] Thiazole 2 I le] - 6- ((1R) - 1- hydroxy-E Chino Les) Single 1-methyl one 1 Ichiriki Rubapen 2 E arm 3-carboxylate) and the like. In particular, the powerful rubapenems that are preferably used in combination with the compound of the general formula (I) are imipenem, meropenem, biapenem and doripenem.
[0073] ペニシリン類の例としてはべンジルペニシリン、フエノキシメチルペニシリン、カルべ ニシリン、アジドシリン、プロピシリン、アンピシリン、ァモキシシリン、ェピシリン、チカ ノレシリン、シクラシリン、ピノレべニシリン、ァズロシリン、メズロシリン、スノレべニシリン、ピ ぺラシリンならびに他の公知のペニシリン類等が挙げられる。これらのペニシリン類は 、それのプロドラッグの形でも、例えばアンピシリン、ベンジルペニシリンおよびァモキ  [0073] Examples of penicillins 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.
)ェチルおよびフタリジルエステル類のような生体内で加水分解されうるエステルとし て、または 6 a アミノアセトアミド側鎖を有するペニシリン類のアルデヒドもしくはケ トン付加物（例えばへタシリン、メタムピシリンおよびァモキシシリンの類似の誘導体が 挙げられる）として、さらに 6 a カルボキシァセトアミド側鎖を有するペニシリン類（ 例えばカルペニシリン、チカルシリンが挙げられる）のエステル体（例えばフエニル、ィ ンダニルエステル体等が挙げられる）としても用いることができる。特に一般式 (I)の 化合物との併用が好ましいペニシリン類は、アンピシリン、ァモキシシリン、カルべ二 シリン類は、例えばナトリウム塩のようなそれの医薬的に許容される塩の形で用いるこ とができる。別の形態として、アンピシリンまたはァモキシシリンは、注射用懸濁液もし くは注入用懸濁液用の両性イオン型（アンピシリン ·三水和物またはァモキシシリン- 三水和物）の微粒子の形で、一般式 (I)と併用すること力 sできる。 セファレキシン、セファセトリノレ、セファピリン、セフアマンドーノレ 'ナフェート、セフラジ ン、 4ーヒドロキシセファレキシン、セフオペラゾン、ラタモキセフ、セフミノクス、フロモ キセフ、セフスロジン、セフタジジム、セフロキシム、セフジトレン、セフメタゾーノレ、セ フォタキシム、セフトリアキソン、セフエピム、セフピロム、セフォゾプランならびに他の 公知のセフエム類等が挙げられ、これらはいずれもそれのプロドラッグの形でも用いる こと力 Sできる。特に一般式 (I)の化合物との併用が好ましいセフエム類は、セフォタキ シム、セフトリアキソン、セフタジジムおよびセフエピムであり、それらはナトリウム塩の ような医薬的に許容される塩の形で用いることができる。 ) As an 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 Furthermore, 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. As another form, ampicillin or amoxicillin is commonly used in the form of amphoteric ions (ampicillin trihydrate or amoxicillin-trihydrate) microparticles for injectable suspensions or infusion suspensions. Can be used in combination with formula (I). 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.
[0075] 本発明の好ましい態様によれば、一般式 (I)の化合物と力ルバぺネム系抗生物質と 組み合わせる場合、さらにデヒドロぺプチダーゼ (DHP)阻害薬を併用することも好ま しい。多くの力ルバぺネム類は DHPにより分解を受けやすいからである。好ましい D HP阻害薬としては、シラスタチンまたはその塩が挙げられる。  [0075] According to a preferred embodiment of the present invention, when a compound of general formula (I) is combined with a potent rubapenem antibiotic, it is also preferable to use a dehydropeptidase (DHP) inhibitor in combination. This is because many powerful rubapenems are susceptible to degradation by DHP. Preferred DHP inhibitors include cilastatin or a salt thereof.
[0076] 本発明の好ましい態様によれば、一般式 (I)の化合物に加えて、他のセリン /3— ラクタマーゼ阻害薬をさらに併用することが好ましぐ好ましい例としては、クラブラン 酸、スルバクタムまたはタゾバタタムが挙げられる。  [0076] According to a preferred embodiment of the present invention, it is preferable to further use another serine / 3-lactamase inhibitor in addition to the compound of the general formula (I) as clavulanic acid, Sulbactam or tazobatatam may be mentioned.
[0077] 抗生物質と、一般式 (I)の化合物の併用が好ましいメタロー βーラクタマーゼ産生 株としては、 列 Χ_ ίュ Bacillus cereus、 Bacteroides fragilis、 Bschenchia coli、 Aeromonas hydrophila、 Klebsiella pneumoniae^ Pseudomonas aeruginosa^ Serratia marcescens、 Stenotrophomonas maltophilia^ Shigella flexneri、 Alcaligenes xylosoxidans^ Legionell a gormanii、 Chryseobacterium meningosepticum、 Chryseobacterium indologenes、 Ac inetobacter baumannii^ Citrobacter freundiiおよひ、Enterobacter cloacae等力 S挙げら れる。 [0077] Metallo β-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.
[0078] 一般式 (I)の化合物と、抗生物質との投与量は、広い範囲で変動し得るが、例えば 、重量比 1 : 0. 5〜20程度、好ましくは；!：;!〜 8が一般的である。  [0078] The dose of the compound of the general formula (I) and the antibiotic may vary within a wide range. For example, the weight ratio is about 1: 0.5 to 20, preferably;!:;! To 8 Is common.
[0079] 一般式 (I)の化合物および /3—ラタタム系抗生物質は別個に投与することができ、 また両方の有効成分を含む単一組成物の形で投与することもできる。 V、ずれの態様 においても、一般式 (I)の化合物および/または抗生物質は、医薬的に許容される 担体 (すなわち製剤用添加物）と組み合わせることで、医薬組成物の形態とされること が好ましい。  [0079] 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. V. Even in a mode of deviation, 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.
[0080] 本発明による医薬組成物は、経口的または非経口的に投与することができる。非経 口投与としては鼻腔内、点眼、点耳、経皮、気道内、直腸内、泌尿器内、皮下、筋肉 内、および静脈内等の投与経路を挙げることができる。経口投与に適する製剤の例 としては、例えば錠剤、顆粒剤、細粒剤、散剤、シロップ剤、溶液剤、カプセル剤、チ ユアブル剤、または懸濁剤等を挙げることができ、非経口投与に適する製剤の例とし ては、例えば注射剤、点滴剤、吸入剤、噴霧剤、坐剤、膣座剤、経皮吸収剤、経粘 膜吸収剤、点眼剤、点耳剤、点鼻剤、または貼付剤等を挙げることができる。注射剤 や点滴剤等の液体製剤を、例えば凍結乾燥形態の粉末状医薬組成物として提供し 、用時に水または他の適当な媒体 (例えば生理食塩水、ブドウ糖輸液、緩衝液等が 挙げられる。 )に溶解または懸濁させて用いてもよい。  [0080] The pharmaceutical composition according to the present invention can be administered orally or parenterally. Examples of parenteral administration include intranasal, eye drop, ear drop, transdermal, intratracheal, rectal, urinary, subcutaneous, intramuscular, and intravenous routes. Examples of formulations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, wearables, suspensions, etc. Examples of suitable formulations include, for example, injections, drops, inhalants, sprays, suppositories, vaginal suppositories, transdermal absorption agents, transmucosal absorption agents, eye drops, ear drops, nasal drops, Or a patch etc. can be mentioned. Liquid preparations such as injections and infusions are provided, 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.
[0081] 担体すなわち製剤用添加物は医薬組成物の形態に応じて適宜選択可能であり、 その種類は特に限定されないが、例えば安定化剤、界面活性剤、可塑剤、滑沢剤、 可溶化剤、緩衝剤、甘味剤、基剤、吸着剤、矯味剤、結合剤、懸濁化剤、光沢化剤 、コーティング剤、着香剤 ·香料、湿潤剤、湿潤調節剤、充填剤、消泡剤、咀嚼剤、清 涼化剤、着色剤、糖衣剤、等張化剤、 pH調節剤、軟化剤、乳化剤、粘着剤、粘着増 強剤、粘稠剤、粘稠化剤、発泡剤、賦形剤、分散剤、噴射剤、崩壊剤、崩壊補助剤 、芳香剤、防湿剤、防腐剤、保存剤、無痛化剤、溶剤、溶解剤、溶解補助剤、流動 化剤等を挙げることができ、これらを二種以上組み合わせて用いてもよい。これらの 製剤用添加物の具体例は、例えば医薬品添加物事典（日本医薬品添加剤協会編 集、薬事日報社発行）に記載されているので、当業者は医薬組成物の形態に応じて 適宜の製剤用添加物を選択し、当業界で汎用の方法に従って所望の形態の医薬組 成物を製造することができる。一般的には、前記の医薬組成物は有効成分である前 記の物質を 1.0〜100% (W/W)、好ましくは 1.0〜60% (W/W)となるように調製すること ができる。 [0081] The carrier, that is, the additive for formulation, can be appropriately selected depending on the form of the pharmaceutical composition, and the type thereof is not particularly limited. For example, the stabilizer, surfactant, plasticizer, lubricant, solubilization Agent, buffering agent, sweetener, base, adsorbent, taste-masking agent, binder, suspending agent, suspending agent, brightening agent, coating agent, flavoring agent, fragrance, wetting agent, wetting regulator, filler, defoaming agent Agent, chewing agent, refreshing agent, coloring agent, sugar-coating agent, tonicity agent, pH adjusting agent, softening agent, emulsifier, adhesive, adhesion enhancer, thickener, thickener, foaming agent, Excipients, dispersants, propellants, disintegrants, disintegration aids, fragrances, desiccants, preservatives, preservatives, soothing agents, solvents, solubilizers, solubilizers, flow An agent may be used, and two or more of these may be used in combination. Specific examples of these pharmaceutical additives are described, for example, in the Pharmaceutical Additives Encyclopedia (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo Co., Ltd.). Pharmaceutical additives can be selected and pharmaceutical compositions of the desired form can be produced according to methods commonly used in the art. In general, 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). .
[0082] 担体の好ましい具体例としては、ゼラチン、乳糖、白糖、酸化チタン、デンプン、結 ゥモロコシデンプン、マイクロクリスタルワックス、白色ワセリン、メタケイ酸アルミン酸マ グネシゥム、無水リン酸カルシウム、クェン酸、クェン酸三ナトリウム、ヒドロキシプロピ ルセルロース、ソノレビトーノレ、ソルビタン脂肪酸エステル、ポリイソべート、ショ糖脂肪 酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリビュルピロリドン、ステアリン酸マグ ネシゥム、軽質無水ケィ酸、タルク、植物油、ベンジルアルコール、アラビアゴム、プロ ピレンダリコール、ポリアルキレングリコール、シクロデキストリンまたはヒドロキシプロピ ルシクロデキストリン等の製剤用添加物を用いることができる力 S、これらに限定される ことはない。  [0082] Preferable specific examples of the carrier include gelatin, lactose, sucrose, titanium oxide, starch, sorghum starch, microcrystal wax, white petrolatum, magnesium aluminometasilicate, anhydrous calcium phosphate, citrate, and citrate trioxide. Sodium, hydroxypropyl cellulose, sonolebithonole, sorbitan fatty acid ester, polyisobate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polybutyropyrrolidone, magnesium stearate, light anhydrous key acid, talc, vegetable oil, benzyl The ability to use pharmaceutical additives such as alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropylcyclodextrin S, limited to these No.
[0083] 本発明による医薬組成物の投与量および投与回数は特に限定されないが、治療ま たは予防の目的、疾患の種類、患者の年齢、体重、症状等の種々の条件に応じて、 適宜の投与量および投与回数を決定することができる。経口投与の場合には、成人 1日あたり一般式（I)の化合物として 10〜1000 mg/kgとなるように、一日あたり一回ま たは数回投与することができ、非経口投与の場合は、 1〜100 mg/kgを一日あたり一 回または数回に分けて投与するのが好ましい。  [0083] 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. In the case of 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.
[0084] また、本発明の別の態様によれば、一般式 (I)の化合物と、 /3 ラタタム系抗生物 質と、場合によってさらに /3—ラクタマーゼ阻害剤またはデヒドロぺプチダーゼ（DH P)阻害薬とを、同時または逐次的に、ヒトを含む動物に投与することを含んでなる、 感染の治療方法が提供される。  [0084] Further, according to another aspect of the present invention, there is provided a compound of the general formula (I), a / 3 ratam antibiotic, and optionally a / 3-lactamase inhibitor or dehydropeptidase (DH P). There is provided a method of treating an infection comprising administering an inhibitor to an animal, including a human, simultaneously or sequentially.
[0085] さらに本発明の別の態様によれば、 13 ラタタム系抗生物質と、場合によってさらに βーラクタマーゼ阻害剤またはデヒドロぺプチダーゼ（DHP)阻害薬とを含んでなる 医薬組成物、とりわけ感染症の治療剤の製造のための、一般式 (I)の化合物の使用 が提供される。 [0085] Further, according to another aspect of the present invention, there is further provided 13 ratatam antibiotics, and optionally There is provided the use of a compound of general formula (I) for the manufacture of a pharmaceutical composition comprising a β-lactamase inhibitor or a dehydropeptidase (DHP) inhibitor, in particular a therapeutic agent for infectious diseases.
[0086] 化合物の製造  [0086] Production of compounds
本発明による一般式 (I)の化合物は、例えば以下に示す方法またはこれらに準ずる 方法により好ましく製造することができる。  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.
[0087] 以下において、必要に応じて置換基を「保護」してもよい。その「保護基」は、 Protec tive Groups in Organic Synthesis (T. W. reene et al.， Wiley, New ΥΟΓΚ (1999))等 を参照すること力でき、当業者においては周知である。また、脱保護についても本著 書等を参照することができる。  [0087] In the following, substituents may be "protected" as required. The “protecting group” can refer to Protective Groups in Organic Synthesis (T. W. reene et al., Wiley, New ΥΟΓΚ (1999)) and the like, and is well known to those skilled in the art. You can also refer to this book on deprotection.
[0088] 以下において好適な保護基は水酸基保護基、カルボキシル保護基である。  [0088] In the following, suitable protecting groups are a hydroxyl protecting group and a carboxyl protecting group.
水酸基保護基の例としては、ァセチル、ビバロイル、トリェチルシリル、 tーブチルジ メチノレシリノレ、 t ブチルジフエニルシリル等のシリル、ベンジノレ、トリチノレ、 0—ニトロ ベンジルォキシカルボニル、 p 二トロべンジルォキシカルボニル、ベンジルォキシカ ノレボニル、ァリルォキシカルボニル、 t ブトキシカルボニル、 2,2,2—トリクロロェチノレ ォキシカルボニル等が挙げられる。  Examples of 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.
[0089] カルボキシル保護基の例としては、メチル、ェチル、 tーブチル、ァリル、ベンズヒドリ ノレ、 2—ナフチルメチル、ベンジノレ、 tーブチルジメチルシリル等のシリル、フエナシノレ 、 p メトキシベンジル、 0—二トロベンジル、 p メトキシフエニル、 p 二トロベンジル、 4 ピリジルメチル、 1—(シクロへキシルォキシカルボニルォキシ)ェチル基、ァセトキ シメチル、 1 (イソプロピルォキシカルボニルォキシ)ェチル、 1 （エトキシカルボニル ォキシ)ェチル、ピバロィルォキシメチル、シクロへキシルォキシカルボ二ルォキシメチ ル等が挙げられる。  [0089] 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.
[0090] 本発明による一般式 (I)の化合物は、公知の方法、例えば以下に示す (A〜J)の方 法、あるいはこれらに準ずる方法により製造することができ、必要に応じて保護基の 脱着工程を介することができる。例えば所望の置換基が使用する反応条件と不適合 である場合、その置換基を最初に保護基の形で導入し、反応終了後に脱保護するこ と力 Sできる。また、特別な記載がない限り、原料化合物は市販されており入手可能か 、公知物質である。 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. For example, if 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. In addition, unless otherwise specified, are raw materials commercially available? Is a known substance.
[0091] <A法〉 [0091] <Method A>
一般式 (I)において、 R1が置換された水酸基である式 (la)の化合物（式中、 R2、 R3、 M1および M2は前述と同義であり、 Rlaは置換されてもよい C アルキル基を表す）の場 In general formula (I), a compound of formula (la) wherein R 1 is a substituted hydroxyl group (wherein R 2 , R 3 , M 1 and M 2 are as defined above, R la is substituted Represents a C alkyl group)
1-7  1-7
合は以下の方法により好ましく製造される。  Is preferably produced by the following method.
[0092] [化 8] [0092] [Chemical 8]
A法
Figure imgf000033_0001
Method A
Figure imgf000033_0001
Al A2 A3 l a  Al A2 A3 l a
[0093] < A法第一工程〉 [0093] <Method A, first step>
この工程では、式 (A1)で表される化合物の 2個のカルボキシル基に保護基を導入 し、式 (A2)で表される化合物を製造する。式 (A1)で表される化合物を、酸存在下、 アルコール： ρ^ΟΗ 及び/または P2-OH中で加熱して、式（A2) (式中、 R2、 R3は前述 と同義であり、 Rlaは置換されてもよい C アルキル基を表し、 P1および P2は炭素数 1〜 In this step, 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: ρ ^ ΟΗ 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
1-7  1-7
6アルキル基を表す）で表される化合物を得る。  6 represents an alkyl group).
反応に使用されるアルコールは好ましくはメタノール、エタノールなどであり、使用さ れる酸としては塩酸、硫酸などが挙げられ、好ましくは硫酸である。反応は 30°C〜80 °Cで行われ、反応時間は通常 1時間から 2日間である。  The alcohol used in the reaction is preferably methanol, ethanol, etc., and 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.
[0094] < A法第二工程〉 [0094] <Method A second step>
この工程では、式 (A2)で表される化合物のフエノール水酸基のアルキル化反応を 行い、式 (A3)で表される化合物を製造する。この製造は、以下の（a)または (b)の 2通 りの方法のいずれかにより行うことができる。  In this step, 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).
[0095] A法第二工程- (a) [0095] Method A, Second Step- (a)
式 (A2)で表される化合物と、 R^-X1 (ここで、 Rlaは置換されてもよ!/、C アルキル基 A compound represented by formula (A2) and R ^ -X 1 (where R la may be substituted! /, C alkyl group)
1-7 を表し、 X1は塩素、臭素、ヨウ素等のハロゲン原子、メタンスルホニル基等の炭素数 1 〜4のアルキルスルホニル基、または p-トルエンスルホニル基等の脱離基を表す）で 表される化合物とを、塩基存在下反応させることにより、式 (A3) (式中、 R2、 R3、
Figure imgf000034_0001
お よび P2は前述と同義であり、 Rlaは置換されてもよい C アルキル基を表す）で表される 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). By reacting the compound represented by the formula (A3) (wherein R 2 , R 3 ,
Figure imgf000034_0001
And P 2 is as defined above, and R la represents an optionally substituted C alkyl group)
1-7  1-7
化合物を得る。化合物： R^-X1としては、例えば、ヨウ化メチル、ヨウ化工チル、臭化べ ンジルなどが挙げられる。 A compound is obtained. Compound: Examples of R ^ -X 1 include methyl iodide, iodinated til, and benzyl bromide.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 ジクロロメタン、テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシドな どが挙げられ、好ましくは N，N-ジメチルホルムアミドである。塩基としては、トリェチル ァミン、 N-メチルモルホリン、ジメチルァミノピリジン、炭酸カリウムなどが挙げられ、好 ましくは炭酸カリウムである。反応は 0〜100°Cの範囲で行われ、反応時間は通常 10 分〜 2日間である。  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.
[0096] A法第二工程- (b)  [0096] Method A, second step-(b)
式 (A2)で表される化合物と、化合物： Rla_OH (式中、 Rlaは前述と同義である）とを、 光延反応（例えば、公知の文献法（O.Mitsunobu, Yamada, Bull. Chem. Soc. Japan. , 4 0,2380 (1967))を用いて、すなわち、トリフエニルホスフィン、トリブチルホスフィンなど の存在下、ジェチルァゾカルボン酸エステル等とともに、反応に関与しないテトラヒド 口フラン等の溶媒中において反応させることにより、式 (A3) (式中 Rla、 R2、 R3、
Figure imgf000034_0002
お よび P2は前述と同義である）で表される化合物を得る。 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. In a solvent of the formula (A3) (wherein R la , R 2 , R 3 ,
Figure imgf000034_0002
And P 2 are as defined above).
[0097] < A法第三工程〉  [0097] <Method A third process>
この工程では、式 (A3)で表される化合物のカルボン酸エステルの加水分解を行い 、式 (la)で表される化合物を製造する。式 (A3)の化合物を、溶媒の存在下または非 存在下、式 (A3)の化合物に対して必要に応じて 2当量以上の水酸化アルカリ水溶液 中加水分解を行い、減圧濃縮することにより、式 (la) (式中、 Rla、 R2、および R3は前述 と同義であり、 M1, M2は金属カチオンを表す）で表される化合物を得る。また、酸を用 いて酸性にした後、精製により塩を除くことにより、式 (la) (式中、 Rla、 R2、および R3は 前述と同義であり、
Figure imgf000034_0003
M2は水素原子を表す）で表される化合物を得る。 In this step, 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. In addition, after acidifying with an acid and removing the salt by purification, the formula (la) (wherein R la , R 2 , and R 3 are as defined above,
Figure imgf000034_0003
M 2 represents a hydrogen atom).
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 1 ,4-ジォキサン、ジェチルエーテル、ァセトニトリル、エタノール、メ タノールなどが挙げられる。使用される水酸化アルカリ水溶液としては、水酸化力リウ ム水溶液、水酸化ナトリウム水溶液、水酸化ノ リウム水溶液などが挙げられ、好ましく は水酸化ナトリウム水溶液である。反応は室温〜 100°Cの範囲で行われ、反応時間 は通常 10分〜 2日間である。加水分解後の中和に用いる酸としては塩酸、硫酸など が挙げられ、好ましくは塩酸である。 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. Examples of the 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.
[0098] < B法〉 [0098] <Method B>
一般式 (I)で表される化合物中、 R1がモノ置換アミノ基またはカルボニルァミノ基で ある、式 (lb )で表される化合物（式中、 R2、 R3、 M1および M2は前述と同義である）は、 以下の方法により好ましく製造される。 In the compound represented by the general formula (I), 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.
[0099] [化 9] [0099] [Chemical 9]
B法 Method B
Figure imgf000035_0001
Figure imgf000035_0001
l b  l b
[0100] < B法第一工程〉  [0100] <Method B first step>
この工程では、式 (B1)で表される化合物の 2個のカルボキシル基に保護基を導入 し、式 (B2)で表される化合物を製造する。式 (B1)で示される化合物を、酸存在下、 P LOH (式中、 P1は前述と同義である）で表されるアルコール中、加熱してモノエステル 体を得て、このモノエステル体と、化合物： P2-X (式中、 P2は前述と同義であり、 Xは塩 素、臭素、ヨウ素等のハロゲン原子を表す。例えば、ヨウ化メチノレ、ヨウ化工チル、臭 化べンジルなどが挙げられる）とを、塩基存在下、反応させることにより、式 (B2) (式 中、 R2、 R3、 P1および P2は前述と同義である）で表される化合物を得る。 In this step, 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. For example, 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). .
反応に使用されるアルコールとしてはメタノール、エタノールなどが挙げられ、使用 される酸としては、塩酸、硫酸などが挙げられ、好ましくは硫酸である。反応は 30°C〜 80°Cで行われ、反応時間は通常 1時間から 2日間である。化合物： P2-Xとの反応に使 用される溶媒としては、反応に関与しない溶媒であれば限定されないが、ジクロロメタ ン、テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシドなどが挙げら れ、好ましく N，N-ジメチルホルムアミドである。使用される塩基としては、トリェチルアミ ン、 N-メチルモルホリン、ジメチルァミノピリジン、炭酸カリウムなどが挙げられ、好まし くは炭酸カリウムである。反応は 0〜100°Cの範囲で行われ、好ましくは室温である。 反応時間は通常 10分〜 2日間で行われる。 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.
[0101] < B法第二工程〉 [0101] <Method B second process>
この工程では、式（B2)で表される化合物のニトロ基のアミノ基への還元反応を行!/、 、式 (B3)で表される化合物を製造する。式 (B2)の化合物を、パラジウム 炭素、パラ ジゥム一黒、水酸化パラジウム、酸化白金、ラネーニッケルを用いる接触還元、また は、スズ、亜鉛、鉄等と酢酸等の酸を用いる還元反応、または水素化ホウ素ナトリウム 、ヒドラジンによる還元反応、好ましくはパラジウム—炭素を用いる接触還元反応を用 いて、式 (B3) (式中、 R2、 R3、 P1および P2は前述と同義である）で表される化合物を得 反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 メタノール、エタノール、テトラヒドロフラン、水、またはこれらの有機溶媒と水との混合 溶媒などが挙げられ、好ましくはエタノールと水との混合溶媒である。反応は 30°C 〜40°Cで行われ、好ましくは室温である。反応時間は通常 1時間〜 2日間である。 In this step, 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. Using a reduction reaction with sodium borohydride and hydrazine, preferably a catalytic reduction reaction with palladium-carbon, in the formula (B3) (wherein R 2 , R 3 , P 1 and P 2 are as defined above) 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.
[0102] < B法第三工程〉 [0102] <Method B third process>
この工程では、式 (B3)の化合物のァミノ基への置換反応を行い、式 (B4)で表され る化合物を製造する。この製造は、以下の（a)、 （b) 2通りの方法で好ましく行うことが できる。  In this step, 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).
[0103] B法第三工程- (a)  [0103] Method B third step-(a)
この工程では、式 (B3)で表される化合物と、アルデヒドまたはケトンとの還元的アミ ノ化により、式 (B4)で表されるモノ置換アミノ化合物を製造する。式 (B3)の化合物を 、アルデヒドまたはケトン化合物との還元的ァミノ化反応（例えば公知の文献方法 (W. S.Emerson, Org.React.，4， 174 (1948)) )により、水素化アルミニウムリチウム、水素化ホ ゥ素ナトリウム、シァノトリヒドロホウ素ナトリウムなどの複合水素化合物またはジボラン などの還元剤を用いて、溶媒中、 0°C〜加熱条件で 10分〜 3日間反応を行い、式 (B4 ) (式中、 R2、 R3、 P1および P2は前述と同義であり、 Rlbはアルキル基を表す）で表される 化合物を得る。溶媒としては、反応に関与しない溶媒であれば限定されないが、メタ ノール、エタノール、テトラヒドロフラン、 1 , 2-ジクロロェタンが挙げられる。アルデヒド 及びケトンとしては、例えばホルムアルデヒド、ァセトアルデヒド、 n—ブチルアルデヒド 、 n—プロピルアルデヒド、シクロへキサノンなどが挙げられる。 In this step, 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))). Ho Using a complex hydrogen compound such as sodium sodium or 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, 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. Examples of the aldehyde and ketone include formaldehyde, acetoaldehyde, n-butyraldehyde, n-propyl aldehyde, and cyclohexanone.
[0104] B法第三工程- (b) [0104] Method B, third step-(b)
この工程では、式 (B3)で表される化合物と、塩基存在下、化合物： Rlb'-CO_Cl (式 中、 Rlb'はアルキル基を表す）との反応を行い、式（B4) (式中、 R2、 R3、 P1および P2は 前述と同義であり、 Rlbはカルボニルアルキル基を表す）で表される化合物を得る。 化合物： Rlb'-CO_Clとしては、例えば、ァセチルクロライド、ァセトキシァセチルクロ ライド、プチリルクロライドなどが挙げられる。 In this step, 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). Compound: The R lb '-CO_Cl, for example, § cetyl chloride, § Seto carboxymethyl § cetyl chloride, etc. Petit Lil chloride.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 ジクロロメタン、テトラヒドロフラン、ベンゼン、ジェチルエーテルなどをが挙げられ、好 ましくはジクロロメタンである。使用される塩基としては、トリェチルァミン、 N-メチルモ ノレホリン、ジメチルァミノピリジンなどが挙げられ、好ましくはトリエチルァミンである。反 応は 0°C〜加熱条件下で行われ、反応時間は通常 10分〜 3日間である。  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.
[0105] < B法第四工程〉 [0105] <Method B Fourth Process>
B法第四工程  Process B 4th process
この工程では、式（B4)で表される化合物のカルボン酸エステルの加水分解を行い 、式（lb )で表される化合物を製造する。カルボン酸エステルの加水分解は前述の A 法第三工程と同様の条件で行うことができる。  In this step, 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.
[0106] < C法〉 [0106] <Method C>
一般式 (I)で表される化合物中、 R1がジ置換アミノ基である式 (Ic ) (式中、 R2、 R3、 M 1および M2は前述と同義である）で表される化合物の場合は、以下の方法により好まし く製造される。 In the compound represented by the general formula (I), 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.
[0107] [化 10]
Figure imgf000038_0001
[0107] [Chemical 10]
Figure imgf000038_0001
[0108] < C法第一工程〉 [0108] <Method C first step>
この工程では、式 (C 1)で表される化合物とアルデヒドとの還元的ァミノ化により、式（ C2)で表されるジ置換アミノ化合物を製造する。式 (C 1)で表される化合物を、アルデ ヒドまたはケトン化合物との還元的ァミノ化反応、例えば公知の文献方法 (W.S.Emers on,Org.React. ,4, 174 (1948))を用いて、すなわち水素化アルミニウムリチウム、水素化 ホウ素ナトリウム、シァノトリヒドロホウ素ナトリウムなどの複合水素化合物またはジボラ ンなどの還元剤を用いて、溶媒中、 0°C〜加熱条件で、 10分〜 3日間反応を行い、式 (C2) (式中、 R2、 R3、 P1および P2は前述と同義であり、 Rlb、 Rlb'はアルキル基を表す） で表される化合物を得る。溶媒としては、反応に関与しないものであれば限定される ないが、メタノール、エタノール、テトラヒドロフラン、 1 , 2-ジクロロェタンなどが挙げら れる。用いられるアルデヒドおよびケトン化合物としては、例えば、ホルムアルデヒド、 ァセトアルデヒド、 n—プロピルアルデヒド、 n—ブチルアルデヒドなどが挙げられる。 In this step, 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. Using 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. And 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.
[0109] < C法第二工程〉  [0109] <Method C second process>
この工程では、式（C2)の化合物で表されるカルボン酸エステルの加水分解を行い 、式 (Ic )で表される化合物を製造する。カルボン酸エステルの加水分解は、前述の A法第三工程と同様の条件で行うことができる。  In this step, 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.
[0110] < D法〉  [0110] <Method D>
一般式 (I)で表される化合物中、 R1がジ置換アミノ基である式 (Id ) (式中、 R2、 R3、 M 1および M2は前述と同義である）で表される化合物の場合は、以下の方法により好まし く製造される。 In the compound represented by the general formula (I), 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.
[0111] [化 11] D法 [0111] [Chemical 11] Method D
Figure imgf000039_0001
Figure imgf000039_0001
[0112] < D法第一工程〉 [0112] <First method of Method D>
この工程では、式 (D 1)で表される化合物の 2個のカルボキシル基に保護基を導入 し、式 (D2)で表される化合物を製造する。式 (D 1)で示される化合物を、酸存在下、 化合物： Ρ^ΟΗ (式中、 P1は前述と同義である）で表されるアルコール中で、 1時間か ら 2日間加熱することによりモノエステル体を得て、このモノエステル体と、化合物： P2- X (式中、 P2は前述と同義であり、 Xは塩素、臭素、ヨウ素等のハロゲン原子を表す）と を、塩基存在下反応させることにより、式 (D2) (式中、 R2、 R3、 P1および P2は前述と同 義である）で表される化合物を得る。 In this step, 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: Ρ ^ ΟΗ (where P 1 is as defined above) for 1 to 2 days. To obtain a monoester form, and this monoester form and a compound: P 2 -X (wherein P 2 is as defined above, and X represents a halogen atom such as chlorine, bromine, iodine, etc.), By reacting in the presence of a base, a compound represented by the formula (D2) (wherein R 2 , R 3 , P 1 and P 2 are as defined above) is obtained.
反応に使用されるアルコールとしてはメタノール、エタノールなどが挙げられ、使用 される酸としては、塩酸、硫酸などが挙げられ、好ましくは硫酸である。反応は 30°C〜 80°Cで行われ、反応時間は通常 1時間から 2日間である。化合物： P2-Xとの反応に使 用される溶媒としては、反応に関与しない溶媒であれば限定されないが、ジクロロメタ ン、テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシドなどが挙げら れ、好ましく N，N-ジメチルホルムアミドである。使用される塩基としては、トリェチルアミ ン、 N-メチルモルホリン、ジメチルァミノピリジン、炭酸カリウムなどが挙げられ、好まし くは炭酸カリウムである。反応は 0〜100°Cの範囲で行われ、好ましくは室温である。 反応時間は通常 10分〜 2日間である。 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. 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.
[0113] < D法第二工程〉 [0113] <Method D second process>
この工程では、式 (D2)で表される化合物のフッ素への二級ァミンの求核置換反応 により、式 (D3)で表されるジ置換アミノ化合物を製造する。式 (D2)で示される化合物 を、溶媒の存在下または非存在下、化合物： Rlb_NH-Rlbで表される二級ァミンと反応 させ、式 (D3) (式中、 R2、 R3、 P1および P2は前述と同義であり、 Rlbおよび Rlbはアルキ ル基を表す）で表される化合物を得る。 化合物： R lb-NH-Rlbで表される二級ァミンとしては、ジメチルァミン、ジェチルァミン 、 N-メチルェチルァミンなどを用いることができる。 In this step, 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). Compound: As the secondary amine represented by R lb -NH-R lb , dimethylamine, jetylamine, N-methylethylamine and the like can be used.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシドなどが挙げられる 。反応は 30°C〜100°Cの範囲で行われ、反応時間は通常 10分〜 3日間である。  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.
[0114] < D法第三工程〉 [0114] <Method D third process>
この工程では、式（D3)で表される化合物のカルボン酸エステルの加水分解を行い 、式 (Id )で表される化合物を製造する。カルボン酸エステルの加水分解は、前述の A法第三工程と同様の条件で行うことができる。  In this step, 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.
[0115] < E法〉 [0115] <Method E>
一般式 (I)で表される化合物中、 R1が B環（ァゼチジン環、ピロリジン環、ピぺリジン 環、ピぺラジン環、モルホリン環、ァゼパン環であり、環上に置換基 R4を 0〜2個有する )である、式 (Ie) (式中、 R2、 R3、 M1および M2は前述と同義である）で表される化合物 の場合は以下の方法により好ましく製造される。 In the compound represented by the general formula (I), 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. In the case of a compound represented by the formula (Ie) (wherein R 2 , R 3 , M 1 and M 2 are as defined above), the compound is preferably prepared by the following method. The
[0116] [化 12] [0116] [Chemical 12]
Figure imgf000040_0001
Figure imgf000040_0001
[0117] < E法第一工程〉 [0117] <Method E first process>
この工程では、式 (E1)で表される化合物のフッ素への、 B環で表される環状二級ァ ミンの求核置換反応により、 0〜2個の置換基 R4を環上に有する B環を持つ式 (E2)で 表される化合物を製造する。式 (E1)で示される化合物と、 0〜2個の置換基 R4を環上 に有する B環で表される二級ァミンとを、溶媒の存在下または非存在下、反応させる ことにより、式 (E2) (式中、 R2、 R3、 および R4は前述と同義である）で表される化 合物を得る。 In this step, 0 to 2 substituents R 4 are present on the ring by nucleophilic substitution reaction of the cyclic secondary amine represented by ring B to the fluorine of the compound represented by formula (E1). A compound represented by the formula (E2) having a B ring is produced. By reacting a compound represented by the formula (E1) with a secondary amine represented by ring B having 0 to 2 substituents R 4 on the ring in the presence or absence of a solvent, A compound represented by the formula (E2) (wherein R 2 , R 3 and R 4 are as defined above) is obtained.
環状二級ァミンとしては、 R4を環上に。〜 2個有していてもよいァゼチジン、ピロリジ ン、ピぺリジン、ピぺラジン、ァゼパンなどを用いることができる。 As a cyclic secondary amine, R 4 is on the ring. ~ 2 azetidines, pyrrolidi which may have , Piperidine, piperazine, azepane, etc. can be used.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシド等の溶媒が挙げ られる。反応は 30°C〜100°Cの範囲で行われ、反応時間は通常 10分〜 3日間である。  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.
R4は必要に応じて当業者において一般的な方法により変換を行うことができる。 R 4 can be converted by a general method by those skilled in the art as necessary.
[0118] < E法第二工程〉 [0118] <Method E second process>
式（E2)で表される化合物のカルボン酸エステルの加水分解を行い、式（Ie )で表さ れる化合物を製造する。カルボン酸エステルの加水分解は、前述の A法第三工程と 同様の条件で行うことができる。  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.
[0119] < F法〉 [0119] <Method F>
一般式 (I)で表される化合物中、 R1が B環（ァゼチジン環、ピロリジン環、ピぺリジン 環、ピぺラジン環、モルホリン環、ァゼパン環であり、環上に置換基 R4を 0〜2個有する )である式 (If ) (式中、 R2、 R3、 R4、 M1および M2は前述と同義である）で表される化合 物の場合は、以下の方法によってもまた好ましく製造される。 In the compound represented by the general formula (I), 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. In the case of a compound represented by the formula (If) (wherein R 2 , R 3 , R 4 , M 1 and M 2 are as defined above), Is also preferably produced.
[0120] [化 13] [0120] [Chemical 13]
Figure imgf000041_0001
Figure imgf000041_0001
[0121] < F法第一工程〉  [0121] <First step of Method F>
式 (F1)で表される化合物の 2個のカルボキシル基に保護基を導入し、式 (F2)で表 される化合物を製造する。式 (F1)で表される化合物を、化合物: ArCH X2 (式中、 Ar は置換基を有してもよい芳香環（芳香環としては例えば、フエニル、 p—メトキシフエ二 ル、 p—ニトロフエニルなどが挙げられ、好ましくはフエニルである）を表し、 X2は塩素、 臭素、ヨウ素等のハロゲン原子を表し、好ましくはベンジルブ口ミドを表す）とを、塩基 存在下反応させることにより、式 (F2) (式中、 R2、 R3は前述と同義である。）で表される 化合物を得る。 反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 ジクロロメタン、テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシドな どが挙げられ、好ましくは N，N-ジメチルホルムアミドである。使用される塩基としては、 トリェチルァミン、 N-メチノレモノレホリン、ジメチルァミノピリジン、炭酸カリウムなどが挙 げられ、好ましくは炭酸カリウムである。反応は 0〜100°Cの範囲で行われ、反応時間 は通常 10分〜 2日間である。 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.
[0122] < F法第二工程〉 [0122] <Method F, second step>
式 (F2)で表される化合物のフッ素への、 B環で表される環状二級ァミンの求核置換 反応により、 B環を持つ式 (F3)で表される化合物を製造する。この工程は、前述の E 法第一工程と同様の条件で行うことができる。  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.
[0123] < F法第三工程〉 [0123] <Method F third process>
式（F3)で表される化合物のカルボン酸エステルの脱エステル化を行い、式（If)で 表される化合物を製造する。この工程は、以下の（a)、（b) 2通りの方法で好ましく行う こと力 Sでさる。  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).
[0124] F法第三工程- (a) [0124] Method F, third step-(a)
式（F3)で表される化合物のカルボン酸エステルの加水分解を行うことにより式（If ) (式中 R2、 R3、 R4、 M1および M2は前述と同義である）で表される化合物を製造する。力 ルボン酸エステルの加水分解は、前述の A法第三工程と同様の条件で行うことができ By carrying out hydrolysis of the carboxylic acid ester of the compound represented by the formula (F3), it is represented by the formula (If) (wherein R 2 , R 3 , R 4 , M 1 and M 2 are as defined above). To produce a compound. The hydrolysis of rubonic acid ester can be performed under the same conditions as in the third step of Method A described above.
[0125] F法第三工程- (b) [0125] Method F, third step-(b)
式 (F3)で表される化合物のカルボン酸エステルを、還元条件、脱エステル化するこ とにより、式 (If )で表される化合物を製造する。式 (F3)の化合物を、パラジウム 炭 素、ノ ラジウム一黒、水酸化パラジウム、酸化白金、ラネーニッケルを用いる接触還 元反応、好ましくはパラジウム—炭素を用いる反応、により、式 (If) (式中 R2、 R3、 R4、 M1および M2は前述と同義である）で表される化合物を得る。 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).
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 その例としては、メタノール、エタノール、テトラヒドロフラン、水、またはこれらの有機 溶媒と水との混合溶媒などが挙げられ、好ましくはエタノールと水との混合溶媒であ る。反応は 0°C〜40°Cで行われ、好ましくは室温である。反応時間は通常 1時間〜 2日 間である。 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 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.
R4は必要に応じて当業者において一般的な方法により変換を行うことができる。 R 4 can be converted by a general method by those skilled in the art as necessary.
[0126] < G法〉 [0126] <G method>
一般式 (I)で表される化合物中、 R1が B環（ァゼチジン環、ピロリジン環、ピぺリジン 環、ピぺラジン環、モルホリン環、ァゼパン環であり、環上に置換基 R4を 0〜2個有する )である式 (Ig ) (式中、 R2、 R3、 M1および M2は前述と同義である）で表される化合物の 場合は、以下の方法によっても好ましく製造される。 In the compound represented by the general formula (I), 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. In the case of a compound represented by the formula (Ig) (wherein R 2 , R 3 , M 1 and M 2 are as defined above) Is done.
[0127] [化 14] [0127] [Chemical 14]
G法  Method G
Figure imgf000043_0001
Figure imgf000043_0001
[0128] < G法第一工程〉 [0128] <Method G first process>
式（G1)で表される化合物の一方のカルボキシル基に保護基を導入し、式（G2)で 表される化合物を製造する。式 (G1)で表される化合物を、酸存在下、化合物： _0 H (式中 P1は前述と同義である）で表されるアルコール中で、 10分〜 1時間加熱するこ とにより、式（G2) (式中、 R2、 R3は前述と同義であり、 P1は炭素数 1〜6のアルキル基を 表す)で表される化合物を得る。 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). 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.
反応に使用されるアルコールとしてはメタノール、エタノールなどが挙げられ、使用 される酸としては、塩酸、硫酸などが挙げられ、好ましくは硫酸である。反応は 30°C〜 80°Cで行われ、反応時間は通常 1時間から 2日間である。  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.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 ジクロロメタン、テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシドな どが挙げられ、好ましく N，N-ジメチルホルムアミドである。使用される塩基としては、ト リエチルァミン、 N-メチルモルホリン、ジメチルァミノピリジン、炭酸カリウムなどが挙げ られ、好ましくは炭酸カリウムである。反応は 0〜100°Cの範囲で行われ、好ましくは室 温である。反応時間は通常 10分〜 2日間である。 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.
[0129] < G法第二工程〉 [0129] <Method G second process>
式（G2)で表される化合物のカルボキシル基に保護基を導入し、式（G3)で表される 化合物を製造する。式 (G2)で表される化合物と、化合物: ArCH X2 (式中、 Arは置換 基を有してもよい芳香環（前述と同義）を表し、 X2は塩素、臭素、ヨウ素等のハロゲン 原子を表し、好ましくはベンジルブ口ミドを表す）とを、塩基存在下反応させることによ り式（G3) (式中、 R2、および R3は前述と同義であり、 P1は炭素数 1〜6のアルキル基を 表し、 Arは置換基を有してもよ!/、芳香環を表す）で表される化合物を得る。 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). A compound represented by the formula (G2) and a compound: ArCH X 2 (wherein Ar represents an aromatic ring which may have a substituent (as defined above), X 2 represents chlorine, bromine, iodine, etc.) (G3) (wherein R 2 and R 3 have the same meanings as described above, and P 1 represents carbon by reacting with a halogen atom, preferably benzylbutamide) in the presence of a base. Represents an alkyl group of 1 to 6 and Ar may have a substituent! /, Represents an aromatic ring).
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 ジクロロメタン、テトラヒドロフラン、 N，N-ジメチルホルムアミドなどの溶媒が挙げられ、 好ましくは N，N-ジメチルホルムアミドである。塩基としては、トリェチルァミン、 N-メチ ルモルホリン、ジメチルァミノピリジン、炭酸カリウムなどが挙げられ、好ましくは炭酸力 リウムである。反応は 0°C〜80°Cの範囲で行われ、反応時間は通常 10分から 1日間で ある。  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.
[0130] < G法第三工程〉  [0130] <Method G third process>
式 (G3)で表される化合物のフッ素への、 B環で表される環状二級ァミンの求核置換 反応により、 B環を持つ式 (G4)で表される化合物を製造する。この工程は、前述の E 法第一工程と同様の条件で行うことができる。  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.
[0131] < G法第四工程〉  [0131] <Method G fourth process>
式（G4)で表される化合物の一方のエステル基をアルカリ加水分解によって除去す ることにより、式 (G5)で表される化合物を製造する。式 (G4)で表される化合物を、式 (G4)の化合物に対して必要に応じて 1当量以上水酸化アルカリ水溶液存在下、攪拌 することにより、式（G5) (式中、 R2、 R3、 R4、および Arは前述と同義であり、 M1は金属力 チオンを表す）で表される化合物を得る。さらに酸を用いて酸性にした後、精製により 塩を除くことにより、式（G5) (式中、 R2、 R3、および R4は前述と同義であり、 M1は水素 原子を表す)で表される化合物を得る。 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. By stirring the compound represented by the formula (G4) in the presence of an aqueous alkali hydroxide solution in an amount of 1 equivalent or more as necessary with respect to the compound of the formula (G4), 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). After acidifying with acid, purification By removing the salt, a compound represented by the formula (G5) (wherein R 2 , R 3 , and R 4 are as defined above and M 1 represents a hydrogen atom) is obtained.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 1,4-ジォキサン、ジェチルエーテル、ァセトニトリル、エタノール、メ タノールなどが挙げられる。水酸化アルカリ水溶液としては、水酸化カリウム水溶液、 水酸化ナトリウム水溶液、水酸化バリウム水溶液などが挙げられ、好ましくは水酸化 ナトリウム水溶液である。反応は 0°C〜室温の範囲で行われ、反応時間は通常 10分 〜1時間である。中和を行う酸としては塩酸、硫酸などが挙げられ、好ましくは塩酸で ある。  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. Examples of 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. Examples of the acid for neutralization include hydrochloric acid and sulfuric acid, with hydrochloric acid being preferred.
[0132] < G法第五工程〉  [0132] <5th process of Method G>
式 (G5)で表される化合物のカルボン酸エステルを還元条件により脱エステル化を 行うことにより、式 (Ig )で表される化合物を製造する。この工程は、前述の F法第三ェ 程- (b)と同様の条件で行うことができる。  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).
R4は必要に応じて当業者において一般的な方法により変換を行うことができる。 R 4 can be converted by a general method by those skilled in the art as necessary.
[0133] < H法〉 [0133] <Method H>
一般式 (I)で表される化合物中、 R1が置換基を有してもよいベンゼン環、ピぺリジン -4-ィル基である式 (Ih ) (式中、 R2、 R3、 M1および M2は前述と同義であり、 R1は置換基 を有してもよ!/、ベンゼン環またはピぺリジン- 4-ィル基を表す）で表される化合物の場 合は、以下の方法によっても好ましく製造される。 In the compound represented by the general formula (I), 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.
[0134] [化 15] [0134] [Chemical 15]
H法
Figure imgf000045_0001
Method H
Figure imgf000045_0001
H1(B3) H2 H3 I h H1 (B3) H2 H3 I h
< H法第一工程〉 <First method of Method H>
式 (HI)で表される化合物のアミノ基をサンドマイヤー反応を用いて、式 (H2)で表さ れる化合物を製造する。式 (HI)で表される化合物を、例えば公知の文献法（Sandmy er，T， Chem.Ber., 17,1633 (1884))を用いて、酸存在下、亜硝酸ナトリウムを用いてジ ァゾ化を行った後、ハロゲン化銅（I)との反応を行い、式 (H2) (式中、 R2、 R3、 P1およ び P2は前述と同義である）で表される化合物を得る。 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. And a compound represented by the formula (H2) (wherein R 2 , R 3 , P 1 and P 2 are as defined above).
反応に用いられる酸としては臭化水素酸が好ましぐハロゲン化銅としては臭化銅（ I)が好ましい。反応は 10°C〜100°Cの範囲で行われ、反応時間は通常 10分〜 1日間 である。  As the acid used for the reaction, hydrobromic acid is preferred. As the 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.
[0136] < H法第二工程〉  [0136] <Method H second process>
式 (H2)で表される化合物と、置換基を有してもよ!/、フエ二ル基を有するホウ素化合 物またはピぺリジンホウ素化合物などとの炭素一炭素結合生成反応を行い、式 (H3) で表される化合物を製造する。式 (H2)で表される化合物を、例えば公知の文献法（ Kishi, Y.J.Am.Chem.Soc, 109, 4756 (1987))を用いて、パラジウム試薬存在下反応を 行い、式 (H3) (式中、 R2、 R3、 P1および P2は前述と同義である、 R1は置換基を有しても よ!/、ベンゼン環またはピぺリジン- 4-ィル基を表す）で表される化合物を得る。 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.
フエ二ル基を有するホウ素化合物またはピぺリジンホウ素化合物としては、例えばフ ェニルボロン酸、 2-フエニル -4，4，5，5，-テトラメチル -1,3,2-ジォキサボロランなどが挙 げられる。反応に用いられる溶媒としては、反応に関与しない溶媒であれば限定され ないが、トルエン、 N，N-ジメチルホルムアミドなどが挙げられる。  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.
[0137] < H法第三工程〉  [0137] <Method H third process>
式（H3)で表される化合物のカルボン酸エステルの加水分解を行い、式（Ih )で表さ れる化合物を製造する。この工程におけるカルボン酸エステルの加水分解は前述の A法第三工程と同様の条件で行うことができる。  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.
[0138] < 1法〉  [0138] <1 method>
一般式 (I)で表される化合物中、 R1が B環（ァゼチジン環、ピロリジン環、ピぺリジン 環、ピぺラジン環、モルホリン環、ァゼパン環であり、環上に置換基 R4を 0〜2個有する )であり、 R3が B環（ァゼチジン環、ピロリジン環、ピぺリジン環、ピぺラジン環、モルホリ ン環、ァゼパン環であり、環上に置換基 R4を 0〜2個有する）である式 (Π ) (式中、 R2、 M1および M2は前述と同義である）で表される化合物の場合は、以下の方法によって 好ましく製造される。 In the compound represented by the general formula (I), 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 In the case of a compound represented by the formula (Π) (wherein R 2 , M 1 and M 2 have the same meanings as described above), the compound is preferably produced by the following method.
Figure imgf000047_0001
Figure imgf000047_0001
Ii  Ii
[0140] < I法第一工程〉 [0140] <Method I first step>
式 (II)で表される化合物の 2個のカルボキシル基に保護基を導入し、式 (12)で表さ れる化合物を製造する。この工程は、前述の B法第一工程と同様の条件で行うことが できる。  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.
[0141] < 1法第二工程〉  [0141] <Method 2 second step>
式 (12)で表される化合物のフッ素への、 B環で表される環状二級ァミンの求核置換 反応により、 B環を持つ式 (13)で表される化合物を製造する。この工程は、前述の E 法第一工程と同様の条件で行うことができる。  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.
[0142] < 1法第三工程〉 [0142] <Method 3 third process>
式 (13)で表される化合物のフッ素への、 B環で表される環状二級ァミンの求核置換 反応により、 B環を持つ式 (14)で表される化合物を製造する。この工程は、前述の E 法第一工程と同様の条件で行うことができる。  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.
[0143] < 1法第四工程〉 [0143] <Method 4 Fourth Process>
式（14)で表される化合物のカルボン酸エステルの加水分解を行い、式（Ii ) (式中、 R2、 M1および M2は前述と同義である）で表される化合物を製造する。この工程におけ るカルボン酸エステルの加水分解は、前述の A法第三工程と同様の条件で行うことが できる。 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.
R4は必要に応じて当業者において一般的な方法により変換を行うことができる。 R 4 can be converted by a general method by those skilled in the art as necessary.
[0144] <J法〉 [0144] <J Method>
一般式 (I)で表される化合物中、 R1が B環（ァゼチジン環、ピロリジン環、ピぺリジン 環、ピぺラジン環、モルホリン環、ァゼパン環であり、環上に置換基 R4を 0〜2個有する )またはジアルキルァミンであり、 R3がメチル基である式（Ij-a )または（Ij-b ) (式中、 R2 、 M1および M2は前述と同義である）で表される化合物の場合は、以下の方法によって 好ましく製造される。 In the compound represented by the general formula (I), 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, and R 3 is a methyl group (Ij-a) or (Ij-b) (wherein R 2 , M 1 and M 2 are as defined above) In the case of a compound represented by), it is preferably produced by the following method.
[0145] [化 17] [0145] [Chemical 17]
Figure imgf000048_0001
Figure imgf000048_0001
[0146] <J法第一工程〉 [0146] <Method J first process>
式 (J1)で表される化合物のベンゼン環上 6位のブロム化を行い、式 (J2)で表される 化合物を製造する。式 (J1)で表される化合物とブロム化剤との反応を行い、式 (J2) ( 式中、 R2、
Figure imgf000048_0002
P2、 M1および M2は前述と同義であり、 Aは水素原子またはアルキル基を 表す)で表される化合物を得る。 Bromination of the 6-position on the benzene ring of the compound represented by formula (J1) is carried out to produce the compound represented by formula (J2). A reaction between the compound represented by formula (J1) and a brominating agent is carried out to form formula (J2) (wherein R 2 ,
Figure imgf000048_0002
P 2 , M 1 and M 2 are as defined above, and A represents a hydrogen atom or an alkyl group.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 N，N-ジメチルホルムアミドなどが挙げられ、好ましくは N，N-ジメチ ルホルムアミドである。使用されるブロム化剤としては N-ブロモコハク酸イミドが好まし い。反応は室温〜 80°Cで行われ、反応時間は通常 1時間から 2日である。 [0147] <J法第二工程〉 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>
式 (J2)で表される化合物のベンゼン環上にメチル基を導入し、式 (J3)で表される化 合物を製造する。式 (J2)で表される化合物を、塩基、ノ ラジウム触媒の存在下、有機 ホウ素試薬を用いた炭素 炭素結合生成反応を行い、式 03) (式中、 R2、
Figure imgf000049_0001
P2、 M1 および M2は前述と同義であり、 Aは水素原子またはアルキル基を表す）で表される化 合物を得る。 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 ,
Figure imgf000049_0001
P 2 , M 1 and M 2 are as defined above, and A represents a hydrogen atom or an alkyl group.
有機ホウ素試薬としては、例えばトリメチルポロキシンなどが挙げらる。  Examples of the organic boron reagent include trimethyl poroxin.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 N，N-ジメチルホルムアミドなどが挙げられ、好ましくは N，N-ジメチ ルホルムアミドである。使用される塩基としては、トリェチルァミン、 N-メチルモルホリン 、ジメチルァミノピリジン、炭酸カリウムなどが挙げられるが好ましくは炭酸カリウムであ る。反応は室温〜 80°Cで行われ、反応時間は通常 1時間から 1日である。  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.
[0148] <J法第三工程〉 [0148] <Method J third process>
式 (J3)で表される化合物のカルボン酸エステルの加水分解を行い、式（Ij-a ) (式 中、 R2、 M1および M2は前述と同義であり、 Aは水素原子またはアルキル基を表す）で 表される化合物を製造する。この工程におけるカルボン酸エステルの加水分解は、 前述の A法第三工程と同様の条件で行うことができる。 Hydrolysis of the carboxylic acid ester of the compound represented by formula (J3) is carried out, and formula (Ij-a) (wherein R 2 , M 1 and M 2 are as defined above, and A is a hydrogen atom or alkyl A compound represented by the following formula: 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.
[0149] <J法第四工程〉 [0149] <J method fourth process>
式 (J3) (式中、 R2、 P1および P2、は前述と同義であり、 Aは水素原子を表す）で表され る化合物のァミノ基より、環状アミン骨格を構築し、式 (J4)で表される化合物を製造す る。式 (J3)で表される化合物と、式 (J5) (式中、 Xはハロゲンを表す）で表される化合 物（R4を 0〜2個有してもよい）とを反応させることにより、式 (J4) (式中、 B環、 R4、 R2、 P1 および P2は前述と同義である）で表される化合物を得る。 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).
式（J5)としては、 1,5-ジクロロペンタン- 3-オン、 1,5-ジクロロペンタン、ビス (2 クロ ロェチル)ァミンなどが挙げられる。  Examples of the formula (J5) include 1,5-dichloropentane-3-one, 1,5-dichloropentane, bis (2 chloroethyl) amine and the like.
反応に使用される溶媒としては、反応に関与しない溶媒であれば限定されないが、 テトラヒドロフラン、 N，N-ジメチルホルムアミド、ジメチルスルホキシド、エタノールなど が挙げられ、好ましくはエタノールである。反応は室温〜 80°Cで行われ、反応時間は 通常 1時間から 1日である。 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.
R4は必要に応じて当業者において一般的な方法により変換を行うことができる。 R 4 can be converted by a general method by those skilled in the art as necessary.
[0150] < J法第五工程〉  [0150] <Fifth process of Method J>
式 (J4)で表される化合物のカルボン酸エステルの加水分解を行い、式（Ij-b ) (式 中、 B環、 R4、 R2、 M1および M2は前述と同義である）で表される化合物を製造する。こ の工程においけるカルボン酸エステルの加水分解は、前述の A法第三工程と同様の 条件で行うことができる。 Hydrolysis of the carboxylic acid ester of the compound represented by the formula (J4) is carried out to obtain the formula (Ij-b) (wherein the B ring, R 4 , R 2 , M 1 and M 2 are as defined above) The compound represented by these is manufactured. 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.
[0151] 上記 A〜Jの方法において得られた（la)、 (lb) , (Ic)、（Id)、（Ie)、（If)、（Ig)、（Ih)、  [0151] (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih),
(Ii)、（Ij-a)および (Ij-b)は、必要に応じて非イオン性のマクロポーラスレジンを用い るクロマトグラフィーゃセフアデックスを用いるゲル濾過、順相および逆相クロマトダラ フィ一、結晶化等の方法を用いることにより精製することができる。  (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.
[0152] (la) , (lb) , (Ic) , (Id)、（Ie)、（If)、（Ig)、（Ih)、（Ii)、（Ij- a)および (Ij- b)へ導く際 のカルボキシル保護基の他の変換法は当業界で公知であり、それも用いることがで きる。 (列えば、、 Protective Groups in Organic Synthesis, T. W. Greene et al., Wiley, New York (1999)参照）。 [0152] (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij-a) and (Ij-b) Other transformation methods for carboxyl protecting groups in leading to are known in the art and can also be used. (For example, see Protective Groups in Organic Synthesis, T. W. Greene et al., Wiley, New York (1999)).
[0153] 上記の方法で得られたナトリウム塩、カリウム塩等のアルカリ金属塩は、テトラヒドロ フラン、ジォキサン、ジェチルエーテル、ァセトニトリル、ジメチルホルムアミド、メタノ ール、エタノール、 n-プロパノール、水等またはこれらの混合溶媒中で、 2当量以上 のァミン（例えば、アンモニア、メチルァミン、ジメチルァミン、トリメチルァミン、ェチル ァミン、ジェチルァミン、トリェチルァミン）塩酸塩を作用させ、 0°C〜90°Cにおいて 5分 から 48時間反応させた後、減圧濃縮および真空乾燥することにより、一般式 (I)のァ ンモニゥム塩を得ることができる。 [0153] 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.
[0154] このようにして得られた一般式 (I)のアンモニゥム塩もまた、必要に応じて非イオン性 のマクロポーラスレジンを用いるクロマトグラフィー等の方法を用いることにより精製す ること力 Sでさる。 [0154] The thus obtained 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.
[0155] また、 M1および M2が生体内で加水分解されうる基である場合の一般式 (I)は以下の 方法により得られる。 [0155] Further, general formula (I) when M 1 and M 2 are groups that can be hydrolyzed in vivo can be obtained by the following method.
上記の方法で得られた M1および M2が金属カチオンであるナトリウム塩、カリウム塩 等のアルカリ金属塩と、生体内で加水分解されうる基のハライド化合物（ここでは M3- X3と表す。）とを反応させることにより得られる。 M3は前述の生体内で加水分解されう る基と同義であり、 X3は塩素、臭素、ヨウ素、—OSO CF —OSO CH —OSO PhCH 、 、 Sodium salt and potassium salt obtained by the above method, wherein 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, and X 3 is chlorine, bromine, iodine, —OSO CF —OSO CH —OSO PhCH,,
等の脱離基を表す。 (la) , (lb) , (Ic)、 (Id) , (Ie)、 （If)、 （Ig)、 （Ih)、 （Ii)、 （Ij- a)およ び (Ij-b)に対して必要に応じて触媒量もしくは過剰量の塩基（有機塩基としては、ジ イソプロピルェチルァミン、 1 , 8-ジァザビシクロ [5, 4, 0] -7-ゥンデセン、 2, 6-ルチジ ン等、無機塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭 酸水素カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等)存在下、 2当量以上 のアルキルノヽライド（M3-X3 : X3はハロゲン原子または脱離基を表し、好ましくは、ヨウ 素、臭素、または、塩素であり、例えば、ヨウ化メチノレ、ヨウ化工チル、 1- (シクロへキシ ノレォキシカルボニルォキシ)ェチルョーダイド、酢酸ブロモメチル 1- (イソプロピルォキ シカノレポニノレ才キシ)ェチノレョーダイド、 1- (エトキシカノレポニノレ才キシ)ェチノレョーダイ ド、ョードメチノレピバレート、シクロへキシノレ才キシカノレポニノレ才キシメチノレョーダイド 、 1- (イソブチルォキシカルボニルォキシ)ェチルョーダイド、 1- (シクロへキシルォキシ カルボニルォキシ) -2-メチルプロパン- 1-ィルョーダイド、イソブチルォキシカルボ二 ノレォキシメチルョーダイド、イソプロピルォキシカルボニルォキシメチルョーダイド、ィ ソブチリルォキシメチルョーダイド、（ペンタン- 1-ィル)ォキシカルボニルォキシメチル ョーダイド、（ブタン- 1-ィル)ォキシカルボニルォキシメチルョーダイド、（1-ェチルプロ パン- 1-ィル)ォキシカルボニルォキシメチルョーダイド、イソペンチルォキシカルボ二 ノレォキシメチルョーダイド、（プロパン- 1-ィル)ォキシメチルョーダイド、エトキシカルボ ニルォキシメチルョーダイド、ネオペンチルォキシカルボニルォキシメチルョーダイド 、メトキシカルボニルォキシメチルョーダイド、シクロペンチルォキシカルボニルォキシ メチルョーダイド、 t-ブトキシカルボニルォキシメチルョーダイド、 3-ブロモフタライド、 1- (メトキシカノレポニノレ才キシ)ェチノレョーダイド、 1- (シクロペンチノレ才キシカノレポ二ノレ ォキシ)ェチルョーダイド、（テトラヒドロピラン- 4-ィル)ォキシカルボニルォキシメチルョ ーダイド、 1- (ネオペンチルォキシカルボニルォキシ)ェチルョーダイド、（ピペリジン- 1 -ィノレ)カルボニルォキシメチルョーダイド、ァリルョーダイド、 l_(t-ブトキシカルボニル ォキシ)ェチルョーダイド、 N，N-ジ (プロパン- 1-ィル)ァミノカルボニルォキシメチルョ ーダイド、フエニルォキシカルボニルォキシメチルョーダイド、（5-メチル -2-ォキソ -1， Represents a leaving group. (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij-a) and (Ij-b) In contrast, if necessary, 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. As an inorganic base, 2 equivalents or more of 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. For example, iodomethylol, iodyl thiol, 1- (cyclohexylenocarbonylcarbonyloxy) ethyl iodide , Bromomethyl acetate 1- (Isopropyloxy decanolepile), 1- ( Toxicanoreponino xeno), odomethino repivalate, cyclohexenore Carbonyloxy) -2-methylpropane-1-yl iodide, isobutyloxycarbonyl noroxymethyl iodide, isopropyloxycarbonyloxymethyl iodide, isobutyryloxymethyl iodide, (pentane -1-yl) oxycarbonyloxymethyl iodide, (butane-1-yl) oxycarbonyloxymethyl iodide, (1-ethylprop-1-yl) oxycarbonyloxymethyl ester -Dide, Isopentyloxycarbonyl Noroxymethyl iodide, (Propane-1-yl) oxy Cylchodide, ethoxycarbonyloxymethyl iodide, neopentyloxycarbonyloxymethyl iodide, methoxycarbonyloxymethyl iodide, cyclopentyloxycarbonyloxy methyl iodide, t-butoxycarbonyloxymethyl ester Dido, 3-Bromophthalide, 1- (Methoxycanoreponinore xyl) ethinoreotide, 1- (Cyclopentinole xycanorepoinoleoxy) ethylotide, (Tetrahydropyran-4-yl) oxycarbonyl Oxymethyl iodide, 1- (neopentyloxycarbonyloxy) ethyl iodide, (piperidine-1-inoyl) carbonyloxymethyl iodide, allylooxide, l_ (t-butoxycarbonyloxy) ethyl iodide, N, N- Di (propane-1-yl) aminoca Boni Ruo carboxymethyl ® -Dide, phenyloxycarbonyloxymethyl iodide, (5-methyl-2-oxo-1,
(cis-2，6-ジメチルビペリジン- 1-ィル)カルボニルォキシメチルクロライド、 N，N^ ^-n— ブチルカルバミン酸クロロメチル、 1ーョードへキサン、 N-n-へキシル -N-メチルカル ノ ミン酸クロロメチル、 N，N-ジイソプチルカルバミン酸クロロメチル、 N，N-ジイソプロピ ノレ力ルバミン酸クロロメチル、 N-シクロへキシル -N-メチルカルバミン酸クロロメチル、 N-ペンタン- 1-ィルカルバミン酸クロロメチル、 N-シクロへキシル -N-ェチルカルバミ ン酸クロロメチル、 N-イソブチル -N-イソプロピル力ルバミン酸クロロメチル、 N十ブチ ノレ- N-ェチルカルバミン酸クロロメチル、 N，N-ジイソプロピル力ルバミン酸- 1-クロロェ チル、 l-[(cis-2，6-ジメチルビペリジン- 1-ィル)カルボニルォキシ]ェチルクロライド、 N -ェチル イソアミルカルバミン酸クロロメチル等）を、単独または混合の不活性溶 媒（例えば、 N，N-ジメチルホルムアミド、 N，N-ジメチルァセトアミド、 N，N-ジェチルホ ルムアミド、 N，N-ジェチルァセトアミド、 N-メチルピロリジノン、 N，N-ジメチルイミダゾリ ジノン、ジメチルスルホキシド、スルホラン、ァセトニトリル、アセトン、酢酸ェチル、テト ラヒドロフラン、 1 , 4—ジォキサン、ジェチルエーテル、ァニソール、ジクロロメタン、 1 , 2—ジクロロェタン、クロロホノレム、トノレェン、ベンゼン、へキサメチノレホスホリックトリ アミド、メタノーノレ、エタノール等）中、 70°C〜50°C (好ましくは、 30°C〜30°C) において 10分から 24時間反応させることにより、 M1および M2が生体内で加水分解さ れうる基である一般式 (I)を得ることができる。またあらかじめ、フローチャート A〜Hの 工程初期の段階で、 M1および M2に対応する部分に生体内で加水分解されうる基を 導入し、各フローに準じて得ることもできる。 (cis-2,6-Dimethylbiperidine-1-yl) carbonyloxymethyl chloride, N, N ^^-n— Chloromethyl butylcarbamate, 1-hydroxyhexane, Nn-hexyl-N-methylcarboxyl Chloromethyl nomate, chloromethyl N, N-diisoptylcarbamate, chloromethyl N, N-diisopropylene rubamate, N-cyclohexyl-chloromethyl N-methylcarbamate, N-pentan-1-ylcarbamine Chloromethyl acid, N-Cyclohexyl-N-ethylcarbamate Chloromethyl acid, N-Isobutyl-N-Isopropyl chloromethyl rubamate, N-butanol-chloromethyl N-ethylcarbamate, N, N-diisopropyl 1-chloroethyl l-[(cis-2,6-dimethylbiperidine-1-yl) carbonyloxy] ethyl chloride, chloromethyl N-ethyl isoamylcarbamate A single or mixed inert solvent (for example, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-jetylformamide, N, N-jetylacetamide, N -Methylpyrrolidinone, N, N-dimethylimidazolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, jetyl ether, anisole, dichloromethane, 1,2-dichloroethane, chlorophenol, By reacting for 10 to 24 hours at 70 ° C to 50 ° C (preferably 30 ° C to 30 ° C) in toluene, benzene, hexamethinorephosphoric triamide, methanol, ethanol, etc. It is possible to obtain general formula (I) in which 1 and M 2 are groups that can be hydrolyzed in vivo. In addition, groups that can be hydrolyzed in vivo are introduced into portions corresponding to M 1 and M 2 in advance in the initial steps of the flowcharts A to H, and can be obtained according to each flow.
以上のようにして得られたエステル体 (I)は、沈殿化、またはセフアデックス等を用 いるゲル濾過、順相および逆相シリカゲルカラムクロマトグラフィー等を用いることによ り、単離、精製すること力できる。  The 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.
実施例 Example
本発明を以下の実施例によって詳細に説明する力 本発明はこれらに限定される ものではない。また、合成例された化合物の構造は実施例の最後に示されるとおりで ある。 [0157] 実施例 1 : 3- 製造工程 l-(a) Power to explain the present invention in detail by the following examples The present invention is not limited to these. In addition, the structures of the synthesized compounds are as shown at the end of the examples. [0157] Example 1: 3- Production process l- (a)
3-ヒドロキシフタル酸無水物 60.0 mgを水 2.0 mLに溶解し、 lmol/L水酸化ナトリウム 水溶液を加え室温でー晚攪拌した。反応液に lmol/L塩酸を加え pH2にした後、酢 酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、表題化合 物 14.0 mgを得た。  60.0 mg of 3-hydroxyphthalic anhydride was dissolved in 2.0 mL of water, lmol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature. To the reaction solution was added lmol / L hydrochloric acid to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 14.0 mg of the title compound.
ESIMS:m/zl81[M-Hl ;  ESIMS: m / zl81 [M-Hl;
'H-NMRCCDCl ) δ： 7.07 (2H， m)， 7.44 (1H， dd， J=7.6, 8.2Hz);  'H-NMRCCDCl) δ: 7.07 (2H, m), 7.44 (1H, dd, J = 7.6, 8.2Hz);
[0158] 実施例 2 : 3-ブトキシフタル酸  Example 2: 3-Butoxyphthalic acid
製造工程 2-(a)  Manufacturing process 2- (a)
3-ヒドロキシフタル酸無水物 650 mgをエタノール 15 mLに溶解し、濃硫酸 3.0 mLを 加え一晩加熱還流した。反応液を減圧濃縮後、残渣に水を加え酢酸ェチルで抽出 し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、 3-ヒドロキシフタル酸ジェ チルエステノレ 933mgを得た。  650 mg of 3-hydroxyphthalic anhydride was dissolved in 15 mL of ethanol, 3.0 mL of concentrated sulfuric acid was added, and the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 933 mg of 3-hydroxyphthalic acid ethyl ester.
ESIMS:m/z237[M-Hl ;  ESIMS: m / z237 [M-Hl;
製造工程 2-(b)  Manufacturing process 2- (b)
製造工程 2-(a)で得られた化合物 60.0 mgを DMF 5.0 mLに溶解し、炭酸カリウム 8 7.0 mg、ヨウ化 n-ブチル 0.034 mLを加え室温でー晚攪拌した。反応液に水を加え酢 酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた 残渣をプレパラティブ TLC (へキサン：酢酸ェチル = 2 : 1)を用いて精製し、 3-ブトキ シフタル酸ジェチルエステル 52.0 mgを得た。  60.0 mg of the compound obtained in production step 2- (a) was dissolved in 5.0 mL of DMF, 87.0 mg of potassium carbonate and 0.034 mL of n-butyl iodide were added, and the mixture was stirred at room temperature. Water was added to the reaction solution 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 preparative TLC (hexane: ethyl acetate = 2: 1). Thus, 52.0 mg of 3-butoxyphthalic acid jetyl ester was obtained.
ESIMS:m/z295[M+H]+； ESIMS: m / z295 [M + H] + ;
製造工程 2-(c)  Manufacturing process 2- (c)
製造工程 2-(b)で得られた化合物 50.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで 3時間攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、表題化合物 43.0 mgを得た。  50.0 mg of the compound obtained in production step 2- (b) 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. for 3 hours. To the reaction solution was added lmol / L hydrochloric acid to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 43.0 mg of the title compound.
EIMS:m/z238[M+]; :HH--NNMMRR ((CCDDCCll )) δδ：： 00..9955 ((33HH，， tt，， JJ==77..33 HHzz)),, 11..4488 ((22HH，， mm))，， 11..7777 ((22HH，， mm))，， 44..0044 ((22HH，， ttEIMS: m / z238 [M + ]; : HH--NNMMRR ((CCDDCCll)) δδ: 00..9955 ((33HH, tt, JJ == 77..33 HHzz)), 11..4488 ((22HH, mm)), 11..7777 ((22HH, mm)), 44..0044 ((22HH, tt
，， JJ==66..55 HHzz)),, 77..1133 ((11HH，， dd，， JJ==88..00 HHzz)),, 77..3388 ((11HH，， dddd，， JJ==88..00 HHzz)),, 77..6600 ((11HH，， dd，， JJ==88..00 HHzz)) , JJ == 66..55 HHzz)), 77..1133 ((11HH, dd, JJ == 88..00 HHzz)), 77..3388 ((11HH, dddd, JJ == 88..00 HHzz)) ,, 77..6600 ((11HH, dd, JJ == 88..00 HHzz))
[[00115599]] 実実施施例例 33 :: 33--メメトトキキシシフフタタルル酸酸 [[00115599]] Working Examples 33 :: 33--Memethoxyxifphthalic acid
製製造造工工程程 33__((aa))  Manufacturing manufacturing process 33 __ ((aa))
製製造造工工程程 22--((aa))でで得得らられれたた化化合合物物をを用用いいてて、、製製造造工工程程 22--((bb))とと同同様様のの方方法法でで、、ヨヨウウ化化 nn--ブブチチルルのの代代わわりりににヨヨウウ化化メメチチルルをを用用レレ、、てて得得らられれたた化化合合物物をを用用レレ、、てて 22--((cc))とと同同様様のの方方 法法でで表表題題化化合合物物をを得得たた。。  Using the compound obtained in the manufacturing and manufacturing process step 22-((aa)), 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)). .
' 'HH--NNMMRR ((CCDD OODD)) δδ ::33..7788 ((33ΗΗ，， ss))，， 77..2211 ((11ΗΗ，， dddd，， JJ==00..9977,, 88..33 HHzz)),, 77..5511 ((11HH，， dddd，， JJ==88 '' HH--NNMMRR ((CCDD OODD)) δδ :: 33..7788 ((33ΗΗ, ss)), 77..2211 ((11ΗΗ, dddd, JJ == 00..9977 ,, 88..33 HHzz)) ,, 77..5511 ((11HH, dddd, JJ == 88
..00，， 88..33 HHzz)),, 77..4499 ((11HH，， dddd，， JJ==00..9977,, 88..00 HHzz));; ..00 ,, 88..33 HHzz)) ,, 77..4499 ((11HH, dddd, JJ == 00..9977 ,, 88..00 HHzz)) ;;
[[00116600]] 実実施施例例 44：： 33-- ((シシククロロへへキキシシルルォォキキシシ))フフタタルル酸酸 [[00116600]] Example of practical implementation 44 :: 33-- ((Cyclochlorohexoxyloxy)) phthalic acid
製製造造工工程程 44--((aa)) Manufacturing manufacturing process 44-(( aa ))
製製造造工工程程 22--((aa))でで得得らられれたた化化合合物物 113388 mmggをを TTHHFF 33..00 mmLLにに溶溶解解しし、、シシククロロへへキキササノノーー ノノレレ 7700..00 mmgg、、トトリリブブチチルルホホススフフィィンン 558866 mmgg、、 11,,11，， --ァァゾゾビビスス（（NN，，NN__ジジメメチチルルホホルルムムアアミミドド）） 55 0000 mmggをを加加ええ室室温温ででーー晚晚攪攪拌拌ししたた。。反反応応液液にに水水をを加加ええ酢酢酸酸ェェチチルルでで抽抽出出しし、、無無水水硫硫 酸酸ママググネネシシウウムムでで乾乾燥燥後後減減圧圧濃濃縮縮しし、、得得らられれたた残残渣渣ををププレレパパララテティィブブ TTLLCC ((へへキキササンン：： 酢酢酸酸ェェチチルル == 11：： 11))をを用用いいてて精精製製しし、、 33-- ((シシククロロへへキキシシルルォォキキシシ））フフタタルル酸酸ジジェェチチルルェェ スステテルル 8844..00mmggをを得得たた。。  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. Concentrate and reduce the residue, and use the pre-repaparative TTLLCC ((Hexoxasan :: Ethylyl acetate acetate == 11 :: 11)). Purification was carried out to obtain 33-(((Cyclochlorohexoxyloxy)) diphthalic acid dijetityl ruester esterl 8844..00 mmgg. .
EESSIIMMSS::mm//zz332211[[MM++HH]]++ ;; EESSIIMMSS :: mm // zz332211 [[MM ++ HH]] ++ ;;
製製造造工工程程 44--((bb))  Manufacturing manufacturing process 44-((bb))
製製造造工工程程 44--((aa))でで得得らられれたた化化合合物物 8800..00 mmggをを用用いいてて製製造造工工程程 22--((cc))とと同同様様のの方方法法でで 表表題題化化合合物物 4466..00 mmggをを得得たた。。  Using the compound compound 8800..00 mmgg obtained in the manufacturing and manufacturing process step 44-((aa)), the manufacturing and manufacturing process step 22-(( The title compound 4466..00 mmgg was obtained by the same method as in cc)). .
FFAABBMMSS::mm//zz226655[[MM++HH]]++；； FFAABBMMSS :: mm // zz226655 [[MM ++ HH]] ++ ;
: :HH--NNMMRR ((CCDDCCll ++CCDD OODD)) δδ :: 11..3333--11..8899 ((1100ΗΗ,, mm))，， 44..3355 ((11HH，， mm))，， 77..1155 ((11HH，， dd，， JJ==88..33 :: HH - NNMMRR ((CCDDCCll ++ CCDD OODD)) δδ :: 11..3333--11..8899 ((1100ΗΗ ,, mm)) ,, 44..3355 ((11HH ,, mm)) 77..1155 ((11HH, dd, JJ == 88..33
HHzz)),, HHzz)) ,,
77..3377 ((11HH，， dddd，， JJ==77..88,, 88..33 HHzz)),, 77..5599 ((11HH，， dd，， JJ==77..88 HHzz));; 77..3377 ((11HH, dddd, JJ == 77..88 ,, 88..33 HHzz)), 77..5599 ((11HH, dd, JJ == 77..88 HHzz )) ;;
Figure imgf000054_0001
Figure imgf000054_0001
製製造造工工程程 55__((aa)) シクロへキシル -1-プロパノール 1.42 gを THF 10 mLに溶解し、氷浴下トリフエニル ホスフィン 3.14 g、四臭化炭素 3.97 gを加え、室温で一晩攪拌した。反応液に水を加 え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得 られた残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル = 1： 1)を用 V、て精製し（3-ブロモプロピル)シクロへキサン 1.40 gを得た。 Manufacturing manufacturing process 55 __ ((aa)) Cyclohexyl-1-propanol (1.42 g) was dissolved in THF (10 mL), triphenylphosphine (3.14 g) and carbon tetrabromide (3.97 g) were added in an ice bath, and the mixture was stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). To obtain 1.40 g of (3-bromopropyl) cyclohexane.
[0162] 製造工程 5_(b) [0162] Manufacturing process 5_ (b)
製造工程 2-(a)で得られた化合物 290 mgを用レ、て製造工程 2_(b)と同様の方法でョ ゥ化 n-ブチルの代わりに製造工程 5_(a)で得られた化合物を用いて 3-(3_シクロへキ シルプロポキシ)フタル酸ジェチルエステル 430 mgを得た。  Compound 290 mg obtained in production step 2- (a) was used in the same manner as in production step 2_ (b), but in the same manner as in production step 2_ (b), compound obtained in production step 5_ (a) Was used to obtain 430 mg of 3- (3_cyclohexylpropoxy) phthalic acid jetyl ester.
EIMS:m/z362[M+]; EIMS: m / z362 [M + ];
製造工程 5-(c)  Manufacturing process 5- (c)
製造工程 5_(b)で得られた化合物 430 mgを用レ、て製造工程 2-(c)と同様の方法で 表題化合物 283 mgを得た。  Using 430 mg of the compound obtained in Production Process 5_ (b), 283 mg of the title compound was obtained in the same manner as in Production Process 2- (c).
ESIMS:m/z307[M+H]+； ESIMS: m / z307 [M + H] + ;
'H-NMR (CDCl ) δ :0.90 (2H， m)， 1.09—1.37 (6Η， m)， 1.67 (5Η， m)， 1.83 (2Η， m)， 4 'H-NMR (CDCl) δ: 0.90 (2H, m), 1.09—1.37 (6Η, m), 1.67 (5Η, m), 1.83 (2Η, m), 4
.06 (2Η， t， J=6.7 Hz), 7.19 (1H， d， J=8.3 Hz), 7.46 (1H， dd， J=7.8, 8.3 Hz), 7.65 (1 H， d， J=7.8 Hz); .06 (2Η, t, J = 6.7 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.46 (1H, dd, J = 7.8, 8.3 Hz), 7.65 (1 H, d, J = 7.8 Hz) );
[0163] 実施例 6： 3- (ベンジルォキシ)フタル酸 [0163] Example 6: 3- (Benzyloxy) phthalic acid
製造工程 6_(a)  Manufacturing process 6_ (a)
製造工程 2-(a)で得られた化合物を用いて製造工程 2-(b)と同様の方法でヨウ化 n- ブチルの代わりにべンジルブロマイドを用いて 3- (ベンジルォキシ)フタル酸ジェチル エステルを得た。  Using the compound obtained in production step 2- (a), using benzyl bromide instead of n-butyl iodide in the same manner as in production step 2- (b), 3- (benzyloxy) phthalyl phthalate An ester was obtained.
製造工程 6_(b)  Manufacturing process 6_ (b)
製造工程 6_(a)で得られた化合物を用いて製造工程 2-(c)と同様の方法で表題化合 物を得た。  Using the compound obtained in Production Step 6_ (a), the title compound was obtained in the same manner as in Production Step 2- (c).
'H-NMR (CD OD) δ :5.09 (2Η， s)， 7.27 (7Η， m)， 7.51 (1Η， dd， J=0.98, 7.6 Hz);  'H-NMR (CD OD) δ: 5.09 (2Η, s), 7.27 (7Η, m), 7.51 (1Η, dd, J = 0.98, 7.6 Hz);
[0164] 実施例 7： 3-(3_フエニルプロボキシ)フタル酸  [0164] Example 7: 3- (3_phenylpropoxy) phthalic acid
製造工程 7_(a) 製造工程 2-(a)で得られた化合物 82.0 mgを用いて製造工程 2-(b)と同様の方法でョ ゥ化 n-ブチルの代わりに 3-フエニルプロピルブロマイドを用いて 3-(3_フエニルプロボ キシ)フタル酸ジェチルエステル 90.0 mgを得た。 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.
EIMS:m/z356[M+]; EIMS: m / z356 [M + ];
製造工程 7_(b)  Manufacturing process 7_ (b)
製造工程 7_(a)で得られた化合物 90.0 mgを用いて製造工程 2-(c)と同様の方法で 表題化合物 54.0 mgを得た。  The title compound 54.0 mg was obtained in the same manner as in Production Step 2- (c), using 90.0 mg of the compound obtained in Production Step 7_ (a).
ESIMS:m/z301[M+H]+ ; ESIMS: m / z301 [M + H] + ;
'H-NMR (CDCl +CD OD) δ :2.11 (2H， m)， 2.81 (2H， t， J=7.6 Hz), 4.02 (2H， t， J=6. 'H-NMR (CDCl + CD OD) δ: 2.11 (2H, m), 2.81 (2H, t, J = 7.6 Hz), 4.02 (2H, t, J = 6.
2 Hz), 7.08 (1H， d， J=8.3 Hz), 7.23 (5H， m)， 7.38 (1H， dd， J=7.8, 8.3 Hz), 7.62 (1H， d， J=7.8 Hz); 2 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.23 (5H, m), 7.38 (1H, dd, J = 7.8, 8.3 Hz), 7.62 (1H, d, J = 7.8 Hz);
[0165] 実施例 8： 3_(4-フエニルブトキシ)フタル酸 [0165] Example 8: 3_ (4-phenylbutoxy) phthalic acid
製造工程 8_(a)  Manufacturing process 8_ (a)
製造工程 2-(a)で得られた化合物 170 mgを用いて製造工程 2-(b)と同様の方法でョ ゥ化 n-ブチルの代わりに 4-フエニルブチルブロマイドを用いて 3_(4-フエニルブトキシ) フタル酸ジェチルエステル 180 mgを得た。  Using 170 mg of the compound obtained in production process 2- (a), using 4-phenylbutyl bromide instead of n-butyl oxalate in the same manner as in production process 2- (b), 3_ (4 -Phenylbutoxy) 180 mg of phthalic acid jetyl ester was obtained.
ESIMS:m/z371[M+H]+ ESIMS: m / z371 [M + H] +
製造工程 8_(b)  Manufacturing process 8_ (b)
製造工程 8_(a)で得られた化合物 160 mgを用いて製造工程 2-(c)と同様の方法で表 題化合物 124 mgを得た。  Using 160 mg of the compound obtained in production step 8_ (a), 124 mg of the title compound was obtained in the same manner as in production step 2- (c).
ESIMS:m/z313[M-Hl ;  ESIMS: m / z313 [M-Hl;
:H-NMR (CDCl +CD OD) δ : 1.82 (4H， m)， 2.67 (2H， m)， 4.04 (2H， m)， 7.10-7.27 (6 : H-NMR (CDCl + CD OD) δ: 1.82 (4H, m), 2.67 (2H, m), 4.04 (2H, m), 7.10-7.27 (6
H， m)， 7.38 (1H， dd， J=8.0, 8.0 Hz), 7.60 (1H， d， J=8.0 Hz); H, m), 7.38 (1H, dd, J = 8.0, 8.0 Hz), 7.60 (1H, d, J = 8.0 Hz);
[0166] 実施例 9： 3_(4-フエノキシブトキシ)フタル酸 Example 9: 3_ (4-Phenoxybutoxy) phthalic acid
製造工程 9_(a)  Manufacturing process 9_ (a)
製造工程 2-(a)で得られた化合物 100 mgを用いて製造工程 2-(b)と同様の方法でョ ゥ化 n-ブチルの代わりに 4-フエノキシブチルブロマイドを用いて 3_(4-フエノキシブトキ シ)フタル酸ジェチルエステル 146 mgを得た。 EIMS:m/z386[M+] Using 100 mg of the compound obtained in production step 2- (a), using 4-phenoxybutyl bromide instead of n-butyl iodide in the same manner as in production step 2- (b), 3_ ( 4-Phenoxybutoxy) 146 mg of phthalic acid ethyl ester was obtained. EIMS: m / z386 [M + ]
製造工程 9_(b)  Manufacturing process 9_ (b)
製造工程 9_(a)で得られた化合物 100 mgを用いて製造工程 2-(c)と同様の方法で表 題化合物 77.0 mgを得た。  Using 100 mg of the compound obtained in production process 9_ (a), 77.0 mg of the title compound was obtained in the same manner as in production process 2- (c).
ESIMS:m/z329[M-Hl ;  ESIMS: m / z329 [M-Hl;
:H-NMR (CDCl +CD OD) δ : 1.99 (4H， m)， 4.02 (2H， m)， 4.12 (2H， m)， 6.90 (2H， m) : H-NMR (CDCl + CD OD) δ: 1.99 (4H, m), 4.02 (2H, m), 4.12 (2H, m), 6.90 (2H, m)
， 6.93 (1H， dd， J= 8.0, 8.0 Hz), 7.15 (1H， d， J=8.0 Hz), 7.27 (2H， m)， 7.40 (1H， dd， J=8.0, 8.0 Hz), 7.62 (1H， d， J=8.0 Hz); 6.93 (1H, dd, J = 8.0, 8.0 Hz), 7.15 (1H, d, J = 8.0 Hz), 7.27 (2H, m), 7.40 (1H, dd, J = 8.0, 8.0 Hz), 7.62 ( 1H, d, J = 8.0 Hz);
[0167] 実施例 10： 3_(4-カルボキシブトキシ)フタル酸 [0167] Example 10: 3_ (4-carboxybutoxy) phthalic acid
製造工程 10-(a)  Manufacturing process 10- (a)
製造工程 2-(a)で得られた化合物 100 mgを用いて製造工程 2-(b)と同様の方法でヨウ 化 n-ブチルの代わりに 5-ブロモ吉草酸ェチルを用いて 3-(5_エトキシ -5-ォキソペン チルォキシ)フタル酸ジェチルエステル 149 mgを得た。  Using 100 mg of the compound obtained in production step 2- (a), in the same manner as in production step 2- (b), using ethyl 5-bromovalerate instead of n-butyl iodide, 3- (5 _Ethoxy-5-oxopentyloxy) phthalic acid jetyl ester 149 mg was obtained.
EIMS:m/z366[M+]; EIMS: m / z366 [M + ];
製造工程 10-(b)  Manufacturing process 10- (b)
製造工程 10_(a)で得られた化合物 140 mgを用レ、て製造工程 2_(c)と同様の方法で 表題化合物 68.0 mgを得た。  Using 140 mg of the compound obtained in production step 10_ (a), 68.0 mg of the title compound was obtained in the same manner as in production step 2_ (c).
ESIMS:m/z283[M+H]+； ESIMS: m / z283 [M + H] + ;
'H-NMR (CDCl +CD OD) δ : 1.48 (4Η， m)， 2.39 (2Η， m)， 2.51 (2Η， m)， 7.13 (1Η， d， 'H-NMR (CDCl + CD OD) δ: 1.48 (4Η, m), 2.39 (2Η, m), 2.51 (2Η, m), 7.13 (1Η, d,
J=8.0 Hz), 7.39 (1H， dd， J=8.0, 8.0 Hz), 7.62 (1H， d， J=8.0 Hz); J = 8.0 Hz), 7.39 (1H, dd, J = 8.0, 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz);
[0168] 実施例 11 : 3_(2-ヒドロキシエトキシ)フタル酸 Example 11: 3_ (2-hydroxyethoxy) phthalic acid
製造工程 l l-(a)  Manufacturing process l l- (a)
製造工程 2-(a)で得られた化合物 100 mgを用レ、て製造工程 CP3168_(b)と同様の方 法でヨウ化 n-ブチルの代わりに 2-ブロモエタノールを用いて 3_(2-ヒドロキシエトキシ） フタル酸ジェチルエステル 45 mgを得た。  Using 100 mg of the compound obtained in production process 2- (a), use the same method as in production process CP3168_ (b), but replace 2-n-butyl iodide with 3_ (2- Hydroxyethoxy) 45 mg of phthalic acid ethyl ester was obtained.
EIMS:m/z282[M+]; EIMS: m / z282 [M + ];
製造工程 l l-(b)  Manufacturing process l l- (b)
製造工程 1；! -(a)で得られた化合物 45.0 mgを 1,4-ジォキサン 0.6 mL、 5.0 mol/L水 酸化ナトリウム水溶液 3.0 mLに溶解し、 80°Cで 3時間攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 18.2 mgを得た。 Production process 1 ;! 45.0 mg of the compound obtained in-(a) was added to 0.6 mL of 1,4-dioxane, 5.0 mol / L water It was dissolved in 3.0 mL of an aqueous sodium oxide solution and stirred at 80 ° C for 3 hours. 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 18.2 mg of the title compound.
ESIMS:m/z225[M-Hl ;  ESIMS: m / z225 [M-Hl;
:H-NMR (CDC1 +CD OD) δ :3.88 (2H， t， J=4.3 Hz), 4.16 (2H， t， J=4.3 Hz), 7. 17 (1 : H-NMR (CDC1 + CD OD) δ: 3.88 (2H, t, J = 4.3 Hz), 4.16 (2H, t, J = 4.3 Hz), 7. 17 (1
H，d， J=8.5 Hz), 7.42 (1H， dd， J=7.8, 8.5 Hz), 7.64 (1H， d， J=7.8 Hz); H, d, J = 8.5 Hz), 7.42 (1H, dd, J = 7.8, 8.5 Hz), 7.64 (1H, d, J = 7.8 Hz);
[0169] 実施例 12： 3_(3-ヒドロキシプロポキシ)フタル酸 [0169] Example 12: 3_ (3-hydroxypropoxy) phthalic acid
製造工程 12-(a)  Manufacturing process 12- (a)
製造工程 2-(a)で得られた化合物 100 mgを用いて製造工程 2-(b)と同様の方法でヨウ 化 n-ブチルの代わりに 3-ブロモ -1-プロパノールを用いて 3-(3_ヒドロキシプロボキシ） フタル酸ジェチルエステル 110 mgを得た。  Using 100 mg of the compound obtained in production step 2- (a), using 3-bromo-1-propanol instead of n-butyl iodide in the same manner as in production step 2- (b), 3- ( 3_hydroxypropoxy) 110 mg of phthalic acid ethyl ester was obtained.
EIMS:m/z296[M+]; EIMS: m / z296 [M + ];
製造工程 12-(b)  Manufacturing process 12- (b)
製造工程 12-(a)で得られた化合物 110 mgを用いて製造工程 1卜 (b)と同様の方 法で表題化合物 35 mgを得た。  Using 110 mg of the compound obtained in production step 12- (a), 35 mg of the title compound was obtained in the same manner as in production step 1 (b).
EIMS:m/z240[M+]; EIMS: m / z240 [M + ];
'H-NMR (CDCl +CD OD) δ :2.02 (2H， m)， 3.80 (2H， t， J=5.7 Hz), 4.18 (2H， t， J=5. 'H-NMR (CDCl + CD OD) δ: 2.02 (2H, m), 3.80 (2H, t, J = 5.7 Hz), 4.18 (2H, t, J = 5.
7 Hz), 7.16 (1H， d， J=8.3 Hz), 7.41 (1H， dd， J=7.9, 8.3 Hz), 7.64 (1H， d， J=7.9 Hz); 7 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.41 (1H, dd, J = 7.9, 8.3 Hz), 7.64 (1H, d, J = 7.9 Hz);
[0170] 実施例 13 : 3-[l-(tert-ブトキシカルボニル)ピぺリジン- 4-ィルォキシ]フタル酸 Example 13: 3- [l- (tert-butoxycarbonyl) piperidine-4-yloxy] phthalic acid
製造工程 13_(a)  Manufacturing process 13_ (a)
1-tert-ブトキシカルボニル -4-ヒドロキシピペリジン 10.0 gをピリジン 50 mLに溶解し 、 P-トルエンスルホユルクロリド 19.1 gを加え室温でー晚攪拌した。反応液に水 50 mL を加え 30分攪拌した後、ジクロロメタンで抽出し、有機層を 1.0 mol/L塩酸、飽和炭酸 水素ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥後減圧濃縮した。 得られた残渣を酢酸ェチル 5 mL, へキサン 5 mLの混合溶媒より再結晶し l-(tert-ブ トキシカルボニル) -4- (トシルォキシ)ピぺリジン 13.8 gを得た。  10.0 g of 1-tert-butoxycarbonyl-4-hydroxypiperidine was dissolved in 50 mL of pyridine, 19.1 g of P-toluenesulfuryl chloride was added, and the mixture was stirred at room temperature. 50 mL of water was added to the reaction solution, and the mixture was stirred for 30 minutes, and then extracted with dichloromethane. The organic layer was washed with 1.0 mol / L hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of 5 mL of ethyl acetate and 5 mL of hexane to obtain 13.8 g of l- (tert-butoxycarbonyl) -4- (tosyloxy) piperidine.
製造工程 13_(b)  Manufacturing process 13_ (b)
製造工程 2-(a)で得られた化合物 200 mgを用レ、て製造工程 2_(b)と同様の方法でョ ゥ化 n-ブチルの代わりに製造工程 13_(a)で得られた化合物を用いて 3-[l-(tert_ブト キシカルボニル)ピぺリジン- 4-ィルォキシ]フタル酸ジェチルエステル 330 mgを得た。 ESIMS:m/z422[M+H]+； Use 200 mg of the compound obtained in production step 2- (a), and use the same method as in production step 2_ (b). 3- [l- (tert_butoxycarbonyl) piperidine-4-yloxy] phthalic acid jetyl ester 330 mg was obtained by using the compound obtained in production process 13_ (a) instead of n-butyl fluoride. Obtained. ESIMS: m / z422 [M + H] + ;
製造工程 13-(c)  Manufacturing process 13- (c)
製造工程 13_(b)で得られた化合物 170 mgを 5.0 mol/L水酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで一晩攪拌した。反応液を減圧濃縮後、得られた残渣を樹脂 SP- 207 (水）を用いて精製し、表題化合物 20.0 mgを得た。  170 mg of the compound obtained in production step 13_ (b) was dissolved in 5.0 mL of a 5.0 mol / L aqueous sodium hydroxide solution and stirred overnight at 80 ° C. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using resin SP-207 (water) to give the title compound (20.0 mg).
ESIMS:m/z364[M-Hl；  ESIMS: m / z364 [M-Hl;
[0171] 実施例 14： 3- (ピペリジン- 4-ィルォキシ)フタル酸 Example 14: 3- (Piperidin-4-yloxy) phthalic acid
製造工程 14-(a) Production process 14- ( a )
製造工程 13-(c)で得られた化合物 50.0 mg (樹脂精製前）を 5.0 mol/L塩酸中 3日 間室温で攪拌した。反応液を減圧濃縮後、得られた残渣を樹脂 SP_207 (水 ァセト 二トリル)を用いて精製し、表題化合物 12.0 mgを得た。  The compound 50.0 mg (before resin purification) obtained in production step 13- (c) was stirred in 5.0 mol / L hydrochloric acid for 3 days at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using Resin SP_207 (hydrochlor nitrile) to give the title compound (12.0 mg).
ESIMS:m/z266[M+H]+； ESIMS: m / z266 [M + H] + ;
'H-NMR (D O) δ : 1.95 (4Η， m)， 3.10 (2Η， m)， 3.25 (2H，m)， 7.18 (1Η， d， J=8.3 Hz), 7.28 (1H， dd， J=8.2, 8.3 Hz), 7.44 (1H， d， J=8.2 Hz);  'H-NMR (DO) δ: 1.95 (4Η, m), 3.10 (2Η, m), 3.25 (2H, m), 7.18 (1Η, d, J = 8.3 Hz), 7.28 (1H, dd, J = 8.2, 8.3 Hz), 7.44 (1H, d, J = 8.2 Hz);
[0172] 実施例 15 : 3-( β _D-ダルコピラノシルォキシ)フタル酸 Example 15: 3- (β_D-Darcopyranosyloxy) phthalic acid
製造工程 15-(a)製造工程 2-(a)で得られた 3-ヒドロキシフタル酸ジェチルエステル 116 mgを THF 3.5 mLに溶解し、アルゴン雰囲気下、 2，3，4，6_テトラ- 0-メトキシメチル ダルコビラノース 187 mgの THF溶液 0.5 mLをカロえた。さらに、トリ n_ブチルホスフィン 0 .72 mL、 Ν,Ν,Ν',Ν' -テトラメチルァゾジカルボキサミド 501 mgを順次加え、室温で 2時 間攪拌した。反応液を減圧濃縮し、得られた残渣を、シリカゲルカラムクロマトグラフィ 一（へキサン 酢酸ェチル）を用いて精製し、 3-(2，3，4，6-テトラ- 0-メトキシメチル - /3 -D-ダルコピラノシルォキシ)フタル酸ジェチルエステル 269 mgを得た。  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 Ν, Ν, Ν ', Ν'-tetramethylazodicarboxamide were sequentially added, and the mixture was stirred at room temperature for 2 hours. The 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.
製造工程 15_(b)  Manufacturing process 15_ (b)
製造工程 15_(a)で得られた化合物 188 mgを 1 M塩化水素 エタノール溶液 3.7 mL に溶解し、 37°Cにて 3時間静置した。反応液を減圧濃縮し、得られた残渣をシリカゲ ルカラムクロマトグラフィー（酢酸ェチル一エタノール）を用いて精製し、 3-( /3 -D-グ ルコピラノシルォキシ)フタル酸ジェチルエステル 107 mgを得た。 188 mg of the compound obtained in the production step 15_ (a) was dissolved in 3.7 mL of 1 M hydrogen chloride / ethanol solution and allowed to stand at 37 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (ethyl acetate-ethanol) to give 3-(/ 3-D-G 107 mg of (lucopyranosyloxy) phthalic acid ethyl ester was obtained.
製造工程 15-(c)  Manufacturing process 15- (c)
製造工程 15_(b)で得られた化合物 21.5 mgを 1,4-ジォキサン 0.5 mLおよび 5 M水酸 化ナトリウム水溶液 1.0 mLの混合溶媒に溶解し、 60°Cで 5時間攪拌した。反応液を減 圧濃縮し、残渣を Dowex (登録商標） 50W-X4を用いて精製し、表題化合物 18.5 mgを 得た。  21.5 mg of the compound obtained in the production step 15_ (b) was dissolved in a mixed solvent of 0.5 mL of 1,4-dioxane and 1.0 mL of 5 M aqueous sodium hydroxide solution and stirred at 60 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using Dowex (registered trademark) 50W-X4 to obtain 18.5 mg of the title compound.
ESIMS:m/z367[M+Na]+ 343[M_Na]—； ESIMS: m / z367 [M + Na] + 343 [M_Na] —;
'H-NMR (D O) δ :3.38 (1H， m)， 3.44-3.52 (3H， m)， 3.62 (lH,dd,J=5.6,12.5Hz), 3.7 9 (lH,dd,J=2.2,12.5Hz), 5.02 (1H， d， J=7.6 Hz), 7.31-7.37 (2H，m)， 7.57 (1H， d， J=7 .3 Hz);  'H-NMR (DO) δ: 3.38 (1H, m), 3.44-3.52 (3H, m), 3.62 (lH, dd, J = 5.6,12.5Hz), 3.7 9 (lH, dd, J = 2.2, 12.5Hz), 5.02 (1H, d, J = 7.6 Hz), 7.31-7.37 (2H, m), 7.57 (1H, d, J = 7.3 Hz);
[0173] 実施例 16 : 3-[2-( β -Dダルコピラノシルォキシ)エトキシ]フタル酸  Example 16: 3- [2- (β-Ddarcopyranosyloxy) ethoxy] phthalic acid
製造工程 16_(a):  Production process 16_ (a):
Drierite (登録商標） 622 mgをナスフラスコに入れ、ヒートガンを用いて加熱して活性 化した後、製造工程 1；! -(a)で得られた 3_(2-ヒドロキシエトキシ)フタル酸ジェチルエス テル 96.2 mgをジクロロメタン 3.0 mLに溶解しカロえ、 2，3，4，6_テトラ- 0 -ァセチル _ α - D -ダルコピラノシルブロミド 210 mgをジクロロメタン 3.0 mLに溶解し加えた後室温で 5分 間攪拌した後、ァセトニトリル-ドライアイス浴を用いて冷却、攪拌しながら、トリフルォ ロメタンスルホン酸銀 130 mgをトルエン 1.0 mLに溶解した溶液を滴下し、そのまま 1時 間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽 出し、有機層を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ト ルェン—酢酸ェチル）を用いて精製し、 3-[2-(2，3，4，6-テトラ- 0-ァセチル - /3 -D-グ ルコピラノシルォキシ)エトキシ]フタル酸ジェチルエステル 85.0 mgを得た。  Drierite (registered trademark) 622 mg was placed in an eggplant flask, heated with a heat gun to activate, and then manufactured step 1;! -_ (a) 3_ (2-hydroxyethoxy) jetyl ester 96.2 obtained in (a) Dissolve mg in 3.0 mL of dichloromethane, add 2,3,4,6_tetra-0-acetyl-α-D-darcopyranosyl bromide in 210 mL of dichloromethane and add for 5 minutes at room temperature. After stirring for a while, a solution of 130 mg of silver trifluoromethanesulfonate dissolved in 1.0 mL of toluene was added dropwise with stirring and cooling with an acetonitrile-dry ice bath, and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane, and the organic layer was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (toluene-ethyl acetate) to give 3- [2- (2,3,4,6-tetra-0-acetyl- / 3-D-glucopyr Nosyloxy) ethoxy] phthalic acid ethyl ester 85.0 mg was obtained.
製造工程 16_(b)  Manufacturing process 16_ (b)
製造工程 16_(a)で得られた化合物 80.0 mgを 1,4-ジォキサン 1.4 mLおよび 1.0 M水 酸化ナトリウム水溶液の混合溶媒に溶解し、 70°Cで 2時間攪拌した。反応液を減圧濃 縮し、残渣を Dowex50W_X4を用いて精製し、表題化合物 50.0 mgを得た。  80.0 mg of the compound obtained in production step 16_ (a) was dissolved in a mixed solvent of 1.4 mL of 1,4-dioxane and 1.0 M aqueous sodium oxide solution, and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using Dowex50W_X4 to obtain 50.0 mg of the title compound.
[0174] 実施例 17： 3-[3-( β -ダルコピラノシルォキシ)プロボキシ]フタル酸 Example 17: 3- [3- (β-Darcopyranosyloxy) propoxy] phthalic acid
製造工程 17_(a) 製造工程 17_(a)と同様の方法で、 3_(2-ヒドロキシエトキシ)フタル酸ジェチルエステ ルの代わりに、 12-(a)で得られた 3-(3_ヒドロキシプロポキシ)フタル酸ジェチルエステ ル 60.3 mgを用いて 3-[3-(2，3，4，6-テトラ- 0-ァセチル- β _D_ダルコビラノシルォキシ )プロボキシ]フタル酸ジェチルエステル 69.9 mgを得た。 Manufacturing process 17_ (a) In the same manner as in the production process 17_ (a), instead of 3-ethyl (2-hydroxyethoxy) phthalate, 3- (3_hydroxypropoxy) jetyl ester 60.3 mg obtained in 12- (a) Was used to obtain 69.9 mg of 3- [3- (2,3,4,6-tetra-0-acetyl-β_D_darcobilanosiloxy) propoxy] phthalic acid jetyl ester.
製造工程 17_(b):  Manufacturing process 17_ (b):
製造工程 16_(b)と同様の方法で 17_(a)で得られた化合物 50.0 mgを用いて表題化合 物 30.0mgを得た。 30.0 mg of the title compound was obtained using 50.0 mg of the compound obtained in 17_ (a) in the same manner as in production step 16_ (b).
ESIMS: m/z403[M+H]+ 401[M_H]—； ESIMS: m / z403 [M + H] + 401 [M_H] —;
'H-NMR (D O) δ： 1.93 (2H， m )， 3.09 (1H， dd， J=8.3, 9.0 Hz), 3.19-3.33 (3H， m)， 3.53 (1H， dd， J=5.6, 12.4Hz), 3.68 (1H， dd， J=2.2, 12.4 Hz), 3.69 (1H， dt， 5.2, 10.3 Hz), 3.90 (1H， dt， J=5.2, 10.3 Hz), 4.09 (2H， t， J=6.0 Hz), 4.29 (1H， d， J=8.0 Hz), 7.24 (1H， d， J=8.2 Hz), 7.39 (1H， dd， J=8.2, 8.2 Hz), 7.48 (1H， d， J=8.2 Hz) 実施例 18 : 3- (ブチルァミノ)フタル酸  'H-NMR (DO) δ: 1.93 (2H, m), 3.09 (1H, dd, J = 8.3, 9.0 Hz), 3.19-3.33 (3H, m), 3.53 (1H, dd, J = 5.6, 12.4 Hz), 3.68 (1H, dd, J = 2.2, 12.4 Hz), 3.69 (1H, dt, 5.2, 10.3 Hz), 3.90 (1H, dt, J = 5.2, 10.3 Hz), 4.09 (2H, t, J = 6.0 Hz), 4.29 (1H, d, J = 8.0 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.39 (1H, dd, J = 8.2, 8.2 Hz), 7.48 (1H, d, J Example 18: 3- (Butylamino) phthalic acid
製造工程 18_(a)  Manufacturing process 18_ (a)
3-ニトロフタル酸 5.00 gをエタノール 100 mLに溶解し、濃硫酸 10 mLを加え 6時間加 熱還流した。反応液に水を加え酢酸ェチルで抽出し、有機層を無水硫酸マグネシゥ ムで乾燥後減圧濃縮した。得られた残渣を DMF 200 mLに溶解し、炭酸カリウム 9.78 g、ヨウ化工チル 2.9 mLを加え室温でー晚攪拌した。反応液に水を加え酢酸ェチル で抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣を シリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3-ニト 口フタル酸ジェチルエステル 5.68 gを得た。  5.00 g of 3-nitrophthalic acid was dissolved in 100 mL of ethanol, 10 mL of concentrated sulfuric acid was added, and the mixture was heated to reflux for 6 hours. 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 obtained residue was dissolved in 200 mL of DMF, 9.78 g of potassium carbonate and 2.9 mL of iodinated chill were added, and the mixture was 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 obtained residue was purified using silica gel column chromatography (hexane acetate) to obtain 5.68 g of 3-nitrate phthalic acid jetyl ester.
ESIMS:m/z268[M+H]+； ESIMS: m / z268 [M + H] + ;
製造工程 18_(b)  Manufacturing process 18_ (b)
製造工程 18_(a)で得られた化合物 2.67 gをエタノール 40 mLに溶解し、アルゴン気 流下 10 % Pd-C 0.53 gを加えた後、水素置換を行い室温で 5時間攪拌した。反応液 をセライト濾過した後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィ 一（へキサン 酢酸ェチル）を用いて精製し、 3-ァミノフタル酸ジェチルエステル 2.3 8 gを得た。 ESIMS:m/z238[M+H]+； 2.67 g of the compound obtained in production step 18_ (a) was dissolved in 40 mL of ethanol, and 0.53 g of 10% Pd—C was added under an argon stream, followed by hydrogen substitution and stirring at room temperature for 5 hours. The reaction solution was filtered through Celite and then concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexyl acetate ethyl) to obtain 2.38 g of 3-aminophthalic acid jetyl ester. ESIMS: m / z238 [M + H] + ;
製造工程 18-(c)  Manufacturing process 18- (c)
製造工程 18_(b)で得られた化合物 237 mgを 1,2-ジクロロェタン 10 mLに溶解し、 n- ブチルアルデヒド 0.13 mL、酢酸 0.11 mL、トリァセトキシ水素化ホウ素ナトリウム 420 m gを加え室温で一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え攪拌 した後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し た。得られた残渣をプレパラティブ TLC (へキサン-酢酸ェチル)を用いて精製し、 3- (ブチルァミノ)フタル酸ジェチルエステル 190 mgを得た。  Dissolve 237 mg of the compound obtained in production step 18_ (b) in 10 mL of 1,2-dichloroethane, add 0.13 mL of n-butyraldehyde, 0.11 mL of acetic acid, and 420 mg of sodium triacetoxyborohydride, and stir at room temperature overnight. did. A 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 obtained residue was purified using preparative TLC (hexane-ethyl acetate) to obtain 190 mg of 3- (butylamino) phthalic acid jetyl ester.
ESIMS:m/z294[M+H]+； ESIMS: m / z294 [M + H] + ;
製造工程 18_(d)  Manufacturing process 18_ (d)
製造工程 18_(c)で得られた化合物 190 mgを用いて製造工程 2-(c)と同様の方法で 表題化合物を得た。  The title compound was obtained in the same manner as in Production Step 2- (c) using 190 mg of the compound obtained in Production Step 18_ (c).
ESIMS:m/z236[M-Hl ; ESIMS: m / z236 [M-Hl;
'H-NMR (CDCl +CD OD) δ :0.96 (3H， t， J=7.4 Hz), 1.45 (2H， m)， 1.64 (2H，m)， 3.1 'H-NMR (CDCl + CD OD) δ: 0.96 (3H, t, J = 7.4 Hz), 1.45 (2H, m), 1.64 (2H, m), 3.1
6 (2H， t， J=7.1 Hz), 6.78 (2H，m)， 7.30 (1H， dd， J=7.9, 7.9 Hz); 6 (2H, t, J = 7.1 Hz), 6.78 (2H, m), 7.30 (1H, dd, J = 7.9, 7.9 Hz);
実施例 19 : 3- (ピリジン- 3-ィルメチルァミノ)フタル酸 Example 19: 3- (Pyridin-3-ylmethylamino) phthalic acid
製造工程 19_(a)  Manufacturing process 19_ (a)
製造工程 18_(b)で得られた化合物 100 mgを用いて製造工程 18-(c)と同様の方法 で n-ブチルアルデヒドの代わりにニコチンアルデヒドを用いて 3- (ピリジン- 3-ィルメチ ルァミノ)フタル酸ジェチルエステル 34.0 mgを得た。  Using 100 mg of the compound obtained in production process 18_ (b), using nicotinaldehyde instead of n-butyraldehyde in the same manner as in production process 18- (c), 3- (pyridine-3-ilmethylamino) 34.0 mg of phthalic acid jetyl ester was obtained.
FABMS:m/z329[M+H]+； FABMS: m / z329 [M + H] + ;
製造工程 19_(b)  Manufacturing process 19_ (b)
製造工程 19_(a)で得られた化合物 34.0 mgを用いて製造工程 1；! -(b)と同様の方法 で表題の化合物 10.0 mgを得た。  Using the compound 34.0 mg obtained in the production step 19_ (a), the title compound 10.0 mg was obtained in the same manner as in the production step 1;!-(B).
ESIMS:m/z273[M+H]+； ESIMS: m / z273 [M + H] + ;
'H-NMR (D O) δ :4.50 (2Η， s)， 6.52 (1Η， d， J=8.0 Hz), 6.75 (lH，d， J=7.6 Hz), 7.03( 1H， dd， J=6.3, 7.6 Hz), 7.69 (lH，m)， 8.24 (1H， d， J=8.0 Hz), 8.41(1H, brs), 8.51(1H ， brs); [0177] 実施例 20： 3-(trans_4-ヒドロキシシクロへキシルァミノ)フタル酸 'H-NMR (DO) δ: 4.50 (2Η, s), 6.52 (1Η, d, J = 8.0 Hz), 6.75 (lH, d, J = 7.6 Hz), 7.03 (1H, dd, J = 6.3, 7.6 Hz), 7.69 (lH, m), 8.24 (1H, d, J = 8.0 Hz), 8.41 (1H, brs), 8.51 (1H, brs); [0177] Example 20: 3- (trans_4-hydroxycyclohexylamino) phthalic acid
製造工程 20_(a)  Manufacturing process 20_ (a)
製造工程 18_(b)で得られた化合物 230 mgを用いて製造工程 18-(c)と同様の方法 で n-ブチルアルデヒドの代わりに 1,4-シクロへキサジオンモノエチレンケタールを用 いて得られた化合物 220 mgのうち 110 mgを 1,4-ジォキサン 1 mL、 5.0 mol/L塩酸 3 m Uこ溶解し、室温で一晩攪拌した。反応液を酢酸ェチルで抽出し、有機層を無水硫 酸マグネシウムで乾燥後減圧濃縮し、 3_(4-ォキソシクロへキシルァミノ)フタル酸ジェ チノレエステル 81 mgを得た。  Using 230 mg of the compound obtained in production process 18_ (b), using 1,4-cyclohexadione monoethylene ketal instead of n-butyraldehyde in the same manner as in production process 18- (c). 110 mg of 220 mg of the compound was dissolved in 1 mL of 1,4-dioxane and 3 mU of 5.0 mol / L hydrochloric acid, and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 81 mg of 3_ (4-oxocyclohexylamino) phthalic acid ethylenoester.
FABMS:m/z334[M+H]+； FABMS: m / z334 [M + H] + ;
製造工程 20_(b)  Manufacturing process 20_ (b)
製造工程 20_(a)で得られた化合物 134 mgをエタノール 10 mLに溶解し、水素化ホ ゥ素ナトリウム 20.0 mgを加え室温で一晩攪拌した。反応液に水を加え攪拌した後、 酢酸ェチルで抽出し、無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣 をプレパラティブ TLC (へキサン—酢酸ェチル）を用いて精製し、高極性化合物であ る 3-(trans_4-ヒドロキシシクロへキシルァミノ)フタル酸ジェチルエステル 37.0 mg、低 極性化合物である 3-(cis_4-ヒドロキシシクロへキシルァミノ)フタル酸ジェチルエステ ル 27.0 mgを得た。  134 mg of the compound obtained in production step 20_ (a) was dissolved in 10 mL of ethanol, 20.0 mg of sodium borohydride was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was stirred, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified using preparative TLC (hexane-ethyl acetate), and 3- (trans_4-hydroxycyclohexylamino) phthalic acid jetyl ester 37.0 mg, which is a high polarity compound, is a low polarity compound. 27.0 mg of 3- (cis_4-hydroxycyclohexylamino) phthalyl phthalate ester was obtained.
EIMS:m/z335[M+]; EIMS: m / z335 [M + ];
製造工程 20-(c)  Manufacturing process 20- (c)
製造工程 20_(b)で得られた高極性化合物 3-(trans-4-ヒドロキシシクロへキシルアミ ノ)フタル酸ジェチルエステル 35.0 mgを用いて、製造工程 l l-(b)と同様の方法で表 題化合物 26.0 mgを得た。  Using 35.0 mg of the highly polar compound 3- (trans-4-hydroxycyclohexylamino) phthalic acid ethyl ester obtained in production step 20_ (b), in the same manner as in production step l- (b) The title compound (26.0 mg) was obtained.
FABMS:m/z280[M+H]+； FABMS: m / z280 [M + H] + ;
:H-NMR (D 0) δ : 1.80 (2H， m)， 2.03 (2H， m)， 2.51 (4H， m)， 3.97 (1H， m)， 4.17 (1H; m)， 7.96 (lH，d， J=7.8 Hz), 8.02 (1H， dd， J=7.8, 7.8 Hz), 8.12 (1H， d， J=7.8 Hz); : H-NMR (D 0) δ: 1.80 (2H, m), 2.03 (2H, m), 2.51 (4H, m), 3.97 (1H, m), 4.17 (1H ; m), 7.96 (lH, d , J = 7.8 Hz), 8.02 (1H, dd, J = 7.8, 7.8 Hz), 8.12 (1H, d, J = 7.8 Hz);
[0178] 実施例 21 : 3-(cis_4-ヒドロキシシクロへキシルァミノ)フタル酸 Example 21: 3- (cis_4-hydroxycyclohexylamino) phthalic acid
製造工程 21 -(a)  Manufacturing process 21-(a)
製造工程 20_(b)で得られた低極性化合物 3-(cis_4-ヒドロキシシクロへキシルァミノ) フタル酸ジェチルエステル 25.0 mgを用いて、製造工程 l l-(b)と同様の方法で表題 化合物 13.0 mgを得た。 Low polarity compound 3- (cis_4-hydroxycyclohexylamino) obtained in production process 20_ (b) Using 25.0 mg of phthalic acid jetyl ester, 13.0 mg of the title compound was obtained in the same manner as in production step l- (b).
FABMS:m/z280[M+H]+； FABMS: m / z280 [M + H] + ;
:H-NMR (D 0) δ : 1.51-1.65 (8H， m)， 3.42 (1H， m)， 3.80 (1H， m)， 7.26 (lH，d， J=7.8 Hz), 7.29 (1H， d， J=7.8 Hz), 7.43 (1H， dd， J=7.8, 7.8 Hz); : H-NMR (D 0) δ: 1.51-1.65 (8H, m), 3.42 (1H, m), 3.80 (1H, m), 7.26 (lH, d, J = 7.8 Hz), 7.29 (1H, d , J = 7.8 Hz), 7.43 (1H, dd, J = 7.8, 7.8 Hz);
実施例 22： 3_(2-ヒドロキシァセトアミド)フタル酸 Example 22: 3_ (2-hydroxyacetamido) phthalic acid
製造工程 22-(a)  Manufacturing process 22- (a)
3-ニトロフタル酸 4.22 gをメタノール 100 mL、濃硫酸 10 mLに溶解し 5時間加熱還流 を行った。反応液を減圧濃縮後、水を加え酢酸ェチルで抽出し、無水硫酸マグネシ ゥムで乾燥後減圧濃縮した。残渣を DMF 20 mLに溶解し、炭酸カリウム 8.30 g、ヨウ 化メチル 1.86mLを加え室温でー晚攪拌した。反応液に水を加え酢酸ェチルで抽出 し、無水硫酸マグネシウムで乾燥後減圧濃縮し 3-ニトロフタル酸ジメチルエステル 3.8 0 gを得た。  4.22 g of 3-nitrophthalic acid was dissolved in 100 mL of methanol and 10 mL of concentrated sulfuric acid and heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 20 mL of DMF, 8.30 g of potassium carbonate and 1.86 mL of methyl iodide were added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3.80 g of 3-nitrophthalic acid dimethyl ester.
EIMS:m/z239[M+]; EIMS: m / z239 [M + ];
製造工程 22-(b)  Manufacturing process 22- (b)
製造工程 22-(a)で得られた化合物 3.68 gをエタノール:水 =4 : 1の混合溶媒に溶 解し、アルゴン気流下 10%パラジウム炭素 740 mgを加えた後、水素置換を行い室温で 一晩攪拌した。反応液をセライト濾過後、減圧濃縮し、得られた残渣をシリカゲルカラ ムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精製し、 3-アミノフタル酸ジメ チルエステル 3.06 gを得た。  Dissolve 3.68 g of the compound obtained in production step 22- (a) in a mixed solvent of ethanol: water = 4: 1, add 740 mg of 10% palladium on carbon in an argon stream, and then perform hydrogen substitution at room temperature. Stir overnight. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane acetate ethyl) to obtain 3.06 g of 3-aminophthalic acid dimethyl ester.
EIMS:m/z209[M+]; EIMS: m / z209 [M + ];
製造工程 22-(c)  Manufacturing process 22- (c)
製造工程 22-(b)で得られた化合物 100 mgをジクロロメタン 5 mLに溶解し、トリェチ ルァミン 0.10 mL、ァセトキシァセチルクロリド 0.061 mLを加え室温で二日間攪拌した 。反応液に水を加えた後、酢酸ェチルで抽出し、無水硫酸マグネシウムで乾燥後減 圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェ チル）を用いて精製し、 3_(2-ァセトキシァセトアミド)フタル酸ジメチルエステル 125 m gを得た。 FABMS:m/z310[M+H]+ ; 100 mg of the compound obtained in the production step 22- (b) was dissolved in 5 mL of dichloromethane, and 0.10 mL of triethylamine and 0.061 mL of acetyloxyacetyl chloride were added and stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane acetate) to obtain 125 mg of 3_ (2-acetoxyacetamide) phthalic acid dimethyl ester. FABMS: m / z310 [M + H] + ;
製造工程 22-(d)  Manufacturing process 22- (d)
製造工程 22-(c)で得られた化合物 120 mgを用いて製造工程 2-(c)と同様の方法で 表題化合物 75.0 mgを得た。  7120 mg of the title compound was obtained in the same manner as in Production Step 2- (c), using 120 mg of the compound obtained in Production Step 22- (c).
ESIMS:m/z238[M-Hl ;  ESIMS: m / z238 [M-Hl;
:H-NMR (D Ο) δ :4.08 (2H， s)， 7.44 (1H， dd， J=8.0, 8.0 Hz), 7.64 (1H， d， J=8.0 Hz) ， 7.74 (1H， d， J=8.0 Hz); : H-NMR (D Ο) δ: 4.08 (2H, s), 7.44 (1H, dd, J = 8.0, 8.0 Hz), 7.64 (1H, d, J = 8.0 Hz), 7.74 (1H, d, J = 8.0 Hz);
[0180] 実施例 23 : 3-ブチルアミドフタル酸 Example 23: 3-Butylamidophthalic acid
製造工程 23_(a)  Manufacturing process 23_ (a)
製造工程 22-(b)で得られた化合物 255 mgを用いて製造工程 22_(c)と同様の方法 でァセトキシァセチルクロリドの代わりにブチリルクロリドを用いて 3-ブチルアミドフタ ノレ酸ジメチルエステル 290 mgを得た。  Using 255 mg of the compound obtained in production step 22- (b) and using butyryl chloride instead of acetyloxyacetyl chloride in the same manner as in production step 22_ (c), dimethyl 3-butylamidophthalate 290 mg of ester was obtained.
EIMS:m/z279[M+]; EIMS: m / z279 [M + ];
製造工程 23_(b)  Manufacturing process 23_ (b)
製造工程 23_(a)で得られた化合物 250 mgを用いて製造工程 2_(c)と同様の方法で 表題化合物 206 mgを得た。  Using 250 mg of the compound obtained in production step 23_ (a), 206 mg of the title compound was obtained in the same manner as in production step 2_ (c).
ESIMS:m/z250[M-Hl ;  ESIMS: m / z250 [M-Hl;
'H-NMR (CDCl +CD OD) δ : 1.00 (3H， t， J=7.3 Hz), 1.75 (2H， m)， 2.38 (2H， t， J=7. 'H-NMR (CDCl + CD OD) δ: 1.00 (3H, t, J = 7.3 Hz), 1.75 (2H, m), 2.38 (2H, t, J = 7.
3 Hz), 7.49 (2H， m)， 8.47 (1H， brd); 3 Hz), 7.49 (2H, m), 8.47 (1H, brd);
[0181] 実施例 24 : 3— (ブチル (メチル)ァミノ)フタル酸 [0181] Example 24: 3— (Butyl (methyl) amino) phthalic acid
製造工程 24-(a)  Manufacturing process 24- (a)
3-ニトロフタル酸 4.22 gをメタノール 100 mL、濃硫酸 10 mLに溶解し 5時間加熱還流 を行った。反応液を減圧濃縮後、水を加え酢酸ェチルで抽出し、無水硫酸マグネシ ゥムで乾燥後減圧濃縮した。残渣を DMF 20 mLに溶解し、炭酸カリウム 8.30 g、ヨウ 化メチル 1.86mLを加え室温でー晚攪拌した。反応液に水を加え酢酸ェチルで抽出 し、無水硫酸マグネシウムで乾燥後減圧濃縮し 3-ニトロフタル酸ジメチルエステル 3.8 0 gを得た。  4.22 g of 3-nitrophthalic acid was dissolved in 100 mL of methanol and 10 mL of concentrated sulfuric acid and heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 20 mL of DMF, 8.30 g of potassium carbonate and 1.86 mL of methyl iodide were added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3.80 g of 3-nitrophthalic acid dimethyl ester.
EIMS:m/z239[M+]; 製造工程 24-(b) EIMS: m / z239 [M + ]; Manufacturing process 24- (b)
製造工程 24-(a)で得られた化合物 3.68 gをエタノール:水 =4 : 1の混合溶媒に溶 解し、アルゴン気流下 10%パラジウム炭素 740 mgを加えた後、水素置換を行い室温で 一晩攪拌した。反応液をセライト濾過後、減圧濃縮し、得られた残渣をシリカゲルカラ ムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精製し、 3-アミノフタル酸ジメ チルエステル 3.06 gを得た。  Dissolve 3.68 g of the compound obtained in production step 24- (a) in a mixed solvent of ethanol: water = 4: 1, add 740 mg of 10% palladium on carbon in an argon stream, and then perform hydrogen substitution at room temperature. Stir overnight. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane acetate ethyl) to obtain 3.06 g of 3-aminophthalic acid dimethyl ester.
EIMS:m/z209[M+]; EIMS: m / z209 [M + ];
製造工程 24-(c)  Manufacturing process 24- (c)
製造工程 24-(b)で得られた化合物 110 mgを 1,2-ジクロロェタン 5.0 mLに溶解し、 n- ブチルアルデヒド 0.070 mL、酢酸 0.060 mL、トリァセトキシ水素化ホウ素ナトリウム 220 mgを加え室温で一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え攪拌 した後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し た。得られた残渣をァセトニトリル 5.0 mLに溶解し、 36%ホルムアルデヒド液 0.13 mL、 酢酸 0.060 mL、トリァセトキシ水素化ホウ素ナトリウム 220 mgを加え室温でー晚攪拌 した。反応液に飽和炭酸水素ナトリウム水溶液を加え攪拌した後、酢酸ェチルで抽 出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣をシリカ ゲルシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）、プレパラティブ TL C (へキサン—酢酸ェチル）を用いて精製し、 3— (ブチル (メチル)ァミノ)フタル酸ジメ チルエステル 26.0 mgを得た。  110 mg of the compound obtained in production step 24- (b) is dissolved in 5.0 mL of 1,2-dichloroethane, and 0.070 mL of n-butyraldehyde, 0.060 mL of acetic acid and 220 mg of sodium triacetoxyborohydride are added to it overnight at room temperature. Stir. A 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 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.
FABMS:m/z280[M+H]+； FABMS: m / z280 [M + H] + ;
製造工程 24-(d) Manufacturing process 24- (d)
製造工程 24-(c)で得られた化合物 60.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、表題化合物 28.0 mgを得た。  60.0 mg of the compound obtained in production step 24- (c) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L sodium hydroxide aqueous solution and stirred at 80 ° C. Lmol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 28.0 mg of the title compound.
FABMS:m/z252[M+H]+； FABMS: m / z252 [M + H] + ;
'H-NMR (D O) δ :0.69 (3Η， t， J=7.5 Hz), 1.16 (2H， m)， 1.34 (2H， m)， 3.14 (3H， s)，3 .46 (2H， t， J=7.8 Hz), 7.53 (1H， d， J=7.6 Hz), 7.65 (1H， dd， J=7.6, 8.3 Hz), 7.71 (1 H， d， J=8.3 Hz); 'H-NMR (DO) δ: 0.69 (3Η, t, J = 7.5 Hz), 1.16 (2H, m), 1.34 (2H, m), 3.14 (3H, s), 3.46 (2H, t, J = 7.8 Hz), 7.53 (1H, d, J = 7.6 Hz), 7.65 (1H, dd, J = 7.6, 8.3 Hz), 7.71 (1 H, d, J = 8.3 Hz);
[0182] 実施例 25 : 3-ジメチルアミノフタル酸 Example 25: 3-dimethylaminophthalic acid
製造工程 25_(a)  Manufacturing process 25_ (a)
3-フルオロフタル酸 9.35 gをエタノール 200 mL、濃硫酸 20 mLに溶解し、 6時間加 熱還流した。反応液を減圧濃縮後、残渣に水を加え酢酸ェチルで抽出し、有機層を 無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣を DMF150 mLに溶解 し、炭酸カリウム 21.0 g、ヨウ化工チル 6.1 mLを加え室温で二日間攪拌した。反応液 に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃 縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル） を用いて精製し、 3-フルオロフタル酸ジェチルエステル 9.13 gを得た。  9.35 g of 3-fluorophthalic acid was dissolved in 200 mL of ethanol and 20 mL of concentrated sulfuric acid and heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 150 mL of DMF, 21.0 g of potassium carbonate and 6.1 mL of iodinated chill were added, and the mixture was stirred at room temperature for 2 days. 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) to obtain 9.13 g of 3-fluorophthalic acid jetyl ester.
EIMS:m/z240[M  EIMS: m / z240 [M
製造工程 25_(b)  Manufacturing process 25_ (b)
製造工程 25_(a)で得られた化合物 120 mgに 2.0Mジメチルァミン THF溶液 3.0 mLを 加え、封管中 90°Cで一晩攪拌した。反応液を減圧濃縮し、得られた残渣をプレパラ ティブ TLC (へキサン—酢酸ェチル）を用いて精製し、 3-ジメチルアミノフタル酸ジェ チルエステル 140 mgを得た。  To 120 mg of the compound obtained in production step 25_ (a), 3.0 mL of a 2.0M dimethylamine THF solution was added, and the mixture was stirred overnight at 90 ° C. in a sealed tube. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using preparative TLC (hexane-ethyl acetate) to obtain 140 mg of 3-dimethylaminophthalic acid ethyl ester.
FABMS:m/z266[M+H]+； FABMS: m / z266 [M + H] + ;
製造工程 25-(c)  Manufacturing process 25- (c)
製造工程 25_(b)で得られた化合物 140 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで 3時間攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 23.0 mgを得た。  140 mg of the compound obtained in production step 25_ (b) 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. for 3 hours. The reaction solution was adjusted to pH 2 by adding lmol / L hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was purified using resin SP-207 (water-acetonitrile) to obtain 23.0 mg of the title compound.
FABMS:m/z210[M+H]+ ; FABMS: m / z210 [M + H] + ;
'H-NMR (D O) δ :3.12 (6H， s)， 7.47 (1H， dd， J=1.0, 7.6 Hz), 7.62 (1H， dd， J=7.6, 8. 3 Hz), 7.73 (1H， dd， J=1.0, 8.3 Hz);  'H-NMR (DO) δ: 3.12 (6H, s), 7.47 (1H, dd, J = 1.0, 7.6 Hz), 7.62 (1H, dd, J = 7.6, 8.3 Hz), 7.73 (1H, dd, J = 1.0, 8.3 Hz);
[0183] 実施例 26： 3- (ァゼチジン- 1-ィル)フタル酸 Example 26: 3- (azetidine-1-yl) phthalic acid
製造工程 26_(a)  Manufacturing process 26_ (a)
製造工程 25_(a)で得られた 3-フルオロフタル酸ジェチルエステル 212 mgを DMSO 5.0 mLに溶解し、炭酸カリウム 610 mg、ァゼチジン塩酸塩 330 mgを加え、封管中 80 °cで一晩攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マ グネシゥムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ 一（へキサン 酢酸ェチル）を用いて精製し、 3- (ァゼチジン- 1-ィル）フタル酸ジェ チルエステル 37.0 mgを得た。 DMSO with 212 mg of 3-fluorophthalic acid jetyl ester obtained in production process 25_ (a) It melt | dissolved in 5.0 mL, potassium carbonate 610 mg and azetidine hydrochloride 330 mg were added, and it stirred at 80 degreeC overnight in the sealed tube. 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 obtained residue was purified using silica gel column chromatography (hexyl acetate) to obtain 37.0 mg of 3- (azetidine-1-yl) phthalic acid ethyl ester.
EIMS:m/z277[M+]; EIMS: m / z277 [M + ];
製造工程 26_(b)  Manufacturing process 26_ (b)
製造工程 26_(a)で得られた化合物 37.0 mgを 1,4-ジォキサン 0.5 mL、 5.0 mol/L水 酸化ナトリウム水溶液 3.0 mLに溶解し、 80°Cで一晩攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 5.0 mgを得た。  37.0 mg of the compound obtained in production step 26_ (a) was dissolved in 0.5 mL of 1,4-dioxane and 3.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. overnight. 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 5.0 mg of the title compound.
'H-NMR (D O) δ : 1.95 (2Η， m)， 3.48 (2Η， m)， 3.84 (2Η， m)， 7.00 (1Η， d， J=7.5 Hz), 7.17 (1H， d， J=7.0 Hz), 7.61(1H, dd， J=7.0, 7.5 Hz),;  'H-NMR (DO) δ: 1.95 (2Η, m), 3.48 (2Η, m), 3.84 (2Η, m), 7.00 (1Η, d, J = 7.5 Hz), 7.17 (1H, d, J = 7.0 Hz), 7.61 (1H, dd, J = 7.0, 7.5 Hz) ,;
実施例 27： 3- (ピロリジン- 1-ィル)フタル酸 Example 27: 3- (Pyrrolidine-1-yl) phthalic acid
製造工程 27_(a)  Manufacturing process 27_ (a)
製造工程 25_(a)で得られた化合物 120 mg、ピロリジン 1 mLに溶解し、 80°Cでー晚 攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ へキサン—酢酸ェチル）を用いて精製し、 3- (ピロリジン- 1-ィル）フタル酸ジェチルェ ステル 27.0 mgを得た。  The compound obtained in production step 25_ (a) (120 mg) and pyrrolidine (1 mL) were dissolved, and the mixture was stirred at 80 ° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane-ethyl acetate) to obtain 27.0 mg of 3- (pyrrolidine-1-yl) phthalic acid jetyl ester.
FABMS:m/z292[M+H]+； FABMS: m / z292 [M + H] + ;
製造工程 27_(b) Manufacturing process 27_ (b)
製造工程 27_(a)で得られた化合物 27 mgを 1,4-ジォキサン 1.0mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用 いて精製し、表題化合物 21.0 mgを得た。  27 mg of the compound obtained in the production step 27_ (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. The reaction mixture 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 21.0 mg of the title compound.
ESIMS:m/z236[M+H]+； ESIMS: m / z236 [M + H] + ;
'H-NMR (D O) δ :2.79 (4Η， m)， 4.24 (4Η， m)， 8.03 (1Η， dd， J=2.7, 5.8 Hz), 8.20 (1 H， d， J=5.8 Hz), 8.21(1H, d， J=2.7 Hz),; [0185] 実施例 28： 3-(3_ヒドロキシピロリジン- 1-ィル)フタル酸 'H-NMR (DO) δ: 2.79 (4Η, m), 4.24 (4Η, m), 8.03 (1Η, dd, J = 2.7, 5.8 Hz), 8.20 (1 H, d, J = 5.8 Hz), 8.21 (1H, d, J = 2.7 Hz) ,; Example 28: 3- (3_Hydroxypyrrolidine-1-yl) phthalic acid
製造工程 28_(a)  Manufacturing process 28_ (a)
製造工程 25_(a)で得られた化合物 120 mgを DMSO 2.0 mLに溶解し、 DL-3-ヒドロ キシピロリジノール 87.0 mgを加え、 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェ チルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、 3-(3_ヒドロキ シピロリジン- 1-ィル)フタル酸ジェチルエステル 37.0 mgを得た。  120 mg of the compound obtained in production step 25_ (a) was dissolved in 2.0 mL of DMSO, 87.0 mg of DL-3-hydroxypyrrolidinol was added, and the mixture was stirred at 80 ° C. 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 to obtain 37.0 mg of 3- (3_hydroxypyrrolidine-1-yl) phthalic acid jetyl ester. .
ESIMS:m/z308[M+H]+； ESIMS: m / z308 [M + H] + ;
製造工程 28_(b)  Manufacturing process 28_ (b)
製造工程 28_(a)で得られた化合物 37.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 25.0 mgを得た。  37.0 mg of the compound obtained in production step 28_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was 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 25.0 mg of the title compound.
ESIMS:m/z250[M-Hl  ESIMS: m / z250 [M-Hl
'H-NMR (D O) δ :2.10 (1H， m)， 2.41 (1H， m)， 3.50 (1H， m)， 3.62 (1H， m)， 3.72 (1H， m)， 3.82 (1H， m)， 4.65 (1H， m)， 7.44 (1H， d， J=7.6 Hz), 7.62 (1H， dd， J=7.6, 8.1 Hz )， 7.68 (1H， d， J=8.1Hz),;  'H-NMR (DO) δ: 2.10 (1H, m), 2.41 (1H, m), 3.50 (1H, m), 3.62 (1H, m), 3.72 (1H, m), 3.82 (1H, m) 4.65 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 7.62 (1H, dd, J = 7.6, 8.1 Hz), 7.68 (1H, d, J = 8.1 Hz) ,;
[0186] 実施例 29： (R)-3_(3-ヒドロキシピロリジン- 1-ィル)フタル酸 Example 29: (R) -3_ (3-Hydroxypyrrolidine-1-yl) phthalic acid
製造工程 29_(a)  Manufacturing process 29_ (a)
製造工程 25_(a)で得られた化合物 280 mgを DMSO 3.0 mLに溶解し、（R)_3_ヒドロ キシピロリジノール塩酸塩 580 mg、炭酸カリウム 806 mgを加え、 80°Cでー晚攪拌した 。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥 後減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸 ェチル）を用いて精製し、（R)_3-(3-ヒドロキシピロリジン- 1-ィル)フタル酸ジェチルェ ステル 107mgを得た。  Dissolve 280 mg of the compound obtained in production process 25_ (a) in 3.0 mL of DMSO, add 580 mg of (R) _3_hydroxypyrrolidinol hydrochloride and 806 mg of potassium carbonate, and stir at 80 ° C did . 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 acetate) and (R) 107 mg of _3- (3-hydroxypyrrolidine-1-yl) phthalic acid jetyl ester was obtained.
ESIMS:m/z308[M+H]+； ESIMS: m / z308 [M + H] + ;
製造工程 29_(b)  Manufacturing process 29_ (b)
製造工程 29_(a)で得られた化合物 100 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用 いて精製し、表題化合物 80.0 mgを得た。 100 mg of the compound obtained in production step 29_ (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. After the addition to pH 2, the residue obtained by concentration under reduced pressure was purified using Resin SP-207 (water-acetonitrile) to obtain 80.0 mg of the title compound.
ESIMS:m/z252[M+H]+； ESIMS: m / z252 [M + H] + ;
:H-NMR (D 0) δ :2.11 (1H， m)， 2.41 (1H， m)， 3.50 (1H， m)， 3.61 (1H， m)， 3.73 (1H， m)， 3.82 (1H， m)， 4.67 (1H， m)， 7.43 (1H， d， J=7.6 Hz), 7.61 (1H， dd， J=7.6, 8.2 Hz )， 7.67 (1H， d， J=8.2Hz),; : H-NMR (D 0) δ: 2.11 (1H, m), 2.41 (1H, m), 3.50 (1H, m), 3.61 (1H, m), 3.73 (1H, m), 3.82 (1H, m ), 4.67 (1H, m), 7.43 (1H, d, J = 7.6 Hz), 7.61 (1H, dd, J = 7.6, 8.2 Hz), 7.67 (1H, d, J = 8.2 Hz) ,;
[0187] 実施例 30： (S)-3_(3-ヒドロキシピロリジン- 1-ィル)フタル酸 Example 30: (S) -3_ (3-hydroxypyrrolidine-1-yl) phthalic acid
製造工程 30_(a)  Manufacturing process 30_ (a)
製造工程 25_(a)で得られた化合物 280 mgを DMSO 3.0 mLに溶解し、（S)_3_ヒドロキ シピロリジノール 406 mgを加え、 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェ チルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣 をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル)を用いて精製し、（S)_3 -(3-ヒドロキシピロリジン- 1-ィル)フタル酸ジェチルエステル 282mgを得た。  280 mg of the compound obtained in production step 25_ (a) was dissolved in 3.0 mL of DMSO, 406 mg of (S) _3_hydroxypyrrolidinol was added, and the mixture was stirred at 80 ° C. 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 monoethyl acetate) ( 282 mg of S) _3- (3-hydroxypyrrolidine-1-yl) phthalic acid jetyl ester was obtained.
EIMS:m/z307[M+]； EIMS: m / z 307 [M + ];
製造工程 30_(b)  Manufacturing process 30_ (b)
製造工程 30_(a)で得られた化合物 280 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用 いて精製し、表題化合物 200 mgを得た。  280 mg of the compound obtained in production step 30_ (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 the residue obtained after concentration under reduced pressure was purified using resin SP-207 (water-acetonitrile) to obtain 200 mg of the title compound.
FABMS:m/z252[M+H]+； FABMS: m / z252 [M + H] + ;
[0188] 実施例 31 : 3- (ピペリジン- 1-ィル)フタル酸 Example 31: 3- (piperidine-1-yl) phthalic acid
製造工程 31 -(a)  Manufacturing process 31-(a)
製造工程 25_(a)で得られた化合物 200 mgにピペリジン 0.82 mLをカロえ、 80°Cで一 晚攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシ ゥムで乾燥後減圧濃縮し、得られた残渣をプレパラティブ TLC (へキサン 酢酸ェチ ル）を用いて精製し、 3- (ピペリジン- 1-ィル)フタル酸ジェチルエステル 166mgを得た。  Piperidine (0.82 mL) was added to the compound (200 mg) obtained in Production Process 25_ (a), and the mixture was stirred at 80 ° C. 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 preparative TLC (hexane acetate), There was obtained 166 mg of 3- (piperidine-1-yl) phthalic acid jetyl ester.
EIMS:m/z305[M  EIMS: m / z305 [M
製造工程 31 -(b) 製造工程 3；! -(a)で得られた化合物 160 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 HP-20 (水ーァセトニトリル)を用 いて精製し、表題化合物 70.0 mgを得た。 Manufacturing process 31-(b) Production step 3;! 160 mg of the compound obtained in-(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. After adding lmol / L hydrochloric acid to the reaction solution to adjust to pH 2, the residue obtained by concentration under reduced pressure was purified using resin HP-20 (water-acetonitrile) to obtain 70.0 mg of the title compound.
FABMS:m/z250[M+H]+； FABMS: m / z 250 [M + H] + ;
[0189] 実施例 32： 3_(4-ヒドロキシピペリジン- 1-ィル)フタル酸 [0189] Example 32: 3_ (4-Hydroxypiperidine-1-yl) phthalic acid
製造工程 32-(a)  Manufacturing process 32- (a)
製造工程 25_(a)で得られた化合物 1.0 gを DMSO 10 mLに溶解し、 4-ヒドロキシピぺ リジン 4.2 gを加え、 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェチルで抽出し 、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカゲル力 ラムクロマトグラフィー（へキサン一酢酸ェチル）を用いて精製し、 3_(4-ヒドロキシピぺ リジン- 1 -ィル)フタル酸ジェチルエステル 1.35 gを得た。  1.0 g of the compound obtained in production step 25_ (a) was dissolved in 10 mL of DMSO, 4.2 g of 4-hydroxypiperidine was added, and the mixture was stirred at 80 ° C. 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 chromatography (hexane monoethyl acetate), 3_ 1.35 g of (4-hydroxypiperidine-1-yl) phthalic acid jetyl ester was obtained.
EIMS:m/z321[M+]； EIMS: m / z321 [M + ];
製造工程 32-(b)  Manufacturing process 32- (b)
製造工程 32-(a)で得られた化合物 1.0 gを 1,4-ジォキサン 5.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 25 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用 いて精製し、表題化合物 500 mgを得た。  Production process: 1.0 g of the compound obtained in 32- (a) was dissolved in 5.0 mL of 1,4-dioxane and 25 mL of a 5.0 mol / L aqueous sodium hydroxide solution and 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 500 mg of the title compound.
FABMS:m/z266[M+H]+； FABMS: m / z266 [M + H] + ;
:H-NMR (D 0) δ : 1.88 (2H， m)， 2.16 (2H， m)， 3.44 (2H， m)， 3.58 (2H， m)， 4.05 (1H， m)， 7.46 (1H， dd， J=0.97, 7.5 Hz), 7.65 (1H， dd， J=7.5, 8.1 Hz), 7.70 (1H， dd,J=0.9 7， 8.1Hz),; : H-NMR (D 0) δ: 1.88 (2H, m), 2.16 (2H, m), 3.44 (2H, m), 3.58 (2H, m), 4.05 (1H, m), 7.46 (1H, dd , J = 0.97, 7.5 Hz), 7.65 (1H, dd, J = 7.5, 8.1 Hz), 7.70 (1H, dd, J = 0.9 7, 8.1 Hz) ,;
[0190] 実施例 33： 3_(4- (ヒドロキシメチノレ)ピぺリジン- 1-ィル)フタル酸  [0190] Example 33: 3_ (4- (Hydroxymethinole) piperidine-1-yl) phthalic acid
製造工程 33_(a)  Manufacturing process 33_ (a)
製造工程 25_(a)で得られた化合物 200 mgに 4- (ヒドロキシメチル)ピぺリジン 960 mg を加え、 80°Cでー晚攪拌した。反応液をプレパラティブ TLC (へキサン 酢酸ェチル )を用いて精製し、 3_(4- (ヒドロキシメチル)ピペリジン- 1-ィル)フタル酸ジェチルエステ ノレ 50.0 mgを得た。 EIMS:m/z335[M+]； To 200 mg of the compound obtained in production step 25_ (a), 960 mg of 4- (hydroxymethyl) piperidine was added, and the mixture was stirred at 80 ° C. The reaction solution was purified using preparative TLC (hexane acetate) to obtain 50.0 mg of 3_ (4- (hydroxymethyl) piperidine-1-yl) phthalic acid jetyl ester. EIMS: m / z335 [M + ];
製造工程 33_(b)  Manufacturing process 33_ (b)
製造工程 33_(a)で得られた化合物 50 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 HP-20 (水ーァセトニトリル)を用 いて精製し、表題化合物 30 mgを得た。  50 mg of the compound obtained in production step 33_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. After adding lmol / L hydrochloric acid to the reaction solution to adjust to pH 2, the residue obtained by concentration under reduced pressure was purified using resin HP-20 (water-acetonitrile) to obtain 30 mg of the title compound.
FABMS:m/z280[M+H]+； FABMS: m / z280 [M + H] + ;
'H-NMR (D O) δ : 1.55 (2Η， m)， 1.85 (1Η， m)， 2.06 (2Η， m)， 3.48 (6Η， m)， 7.37 (1Η， dd， J=2.5, 6.5 Hz), 7.60 (1H， d， J=6.5 Hz), 7.61 (1H， d， J=2.5 Hz),;  'H-NMR (DO) δ: 1.55 (2Η, m), 1.85 (1Η, m), 2.06 (2Η, m), 3.48 (6Η, m), 7.37 (1Η, dd, J = 2.5, 6.5 Hz) , 7.60 (1H, d, J = 6.5 Hz), 7.61 (1H, d, J = 2.5 Hz) ,;
[0191] 実施例 34： 3_(4- (ヒドロキシェチノレ)ピぺリジン- 1-ィル)フタル酸 Example 34: 3_ (4- (Hydroxyethinole) piperidine-1-yl) phthalic acid
製造工程 34-(a)  Manufacturing process 34- (a)
製造工程 25_(a)で得られた化合物 152 mgを DMSO 5.0mLに溶解し、 4- (ヒドロキシ ェチル)ピぺリジン 810 mgを加え、 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェ チルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣 をプレパラティブ TLC (へキサン—酢酸ェチル）を用いて精製し、 3_(4- (ヒドロキシェ チル)ピぺリジン- 1-ィル)フタル酸ジェチルエステル 52.0 mgを得た。  152 mg of the compound obtained in production step 25_ (a) was dissolved in 5.0 mL of DMSO, 810 mg of 4- (hydroxyethyl) piperidine was added, and the mixture was stirred at 80 ° C. 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 preparative TLC (hexane-ethyl acetate), and 3_ ( 4- (Hydroxyethyl) piperidine-1-yl) phthalic acid jetyl ester (52.0 mg) was obtained.
ESIMS:m/z350[M+H]+； ESIMS: m / z 350 [M + H] + ;
製造工程 34-(b)  Manufacturing process 34- (b)
製造工程 34-(a)で得られた化合物 50.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 HP-20 (水ーァセトニトリル） を用いて精製し、表題化合物 16.0 mgを得た。  50.0 mg of the compound obtained in production step 34- (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 HP-20 (water-acetonitrile) to obtain 16.0 mg of the title compound.
ESIMS:m/z292[M-Hl;  ESIMS: m / z292 [M-Hl;
:H-NMR (D Ο) δ : 1.55 (2H， m)， 1.85 (1H， m)， 2.06 (2H， m)， 3.48 (6H， m)， 7.37 (1H， dd， J=2.5, 6.5 Hz), 7.60 (1H， d， J=6.5 Hz), 7.61 (1H， d， J=2.5 Hz),; : H-NMR (D Ο) δ: 1.55 (2H, m), 1.85 (1H, m), 2.06 (2H, m), 3.48 (6H, m), 7.37 (1H, dd, J = 2.5, 6.5 Hz ), 7.60 (1H, d, J = 6.5 Hz), 7.61 (1H, d, J = 2.5 Hz) ,;
[0192] 実施例 35： 3_(3-ヒドロキシピペリジン- 1-ィル)フタル酸 [0192] Example 35: 3_ (3-hydroxypiperidine-1-yl) phthalic acid
製造工程 35_(a)  Manufacturing process 35_ (a)
製造工程 25_(a)で得られた化合物 375 mgを DMSO 3.0 mLに溶解し、 3_ヒドロキシ ピぺリジン 1.26 gを加え、 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェチルで 抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカ ゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）を用いて精製し、 3-(3_ヒドロキ シピペリジン- 1-ィル)フタル酸ジェチルエステル 410 mgを得た。 Dissolve 375 mg of the compound obtained in production process 25_ (a) in 3.0 mL of DMSO, and add 3_hydroxy Piperidine (1.26 g) was added, and the mixture was stirred at 80 ° C. 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 monoethyl acetate). There was obtained 410 mg of-(3_hydroxypiperidine-1-yl) phthalic acid jetyl ester.
EIMS:m/z321[M+]； EIMS: m / z321 [M + ];
製造工程 35_(b)  Manufacturing process 35_ (b)
製造工程 35_(a)で得られた化合物 400 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 HP-20 (水ーァセトニトリル)を用 いて精製し、表題化合物 150 mgを得た。  400 mg of the compound obtained in production step 35_ (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. The reaction solution was adjusted to pH 2 by adding lmol / L hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was purified using resin HP-20 (water-acetonitrile) to obtain 150 mg of the title compound.
FABMS:m/z266[M+H]"； FABMS: m / z266 [M + H] ";
'H-NMR (D O) δ : 1.80 (3Η， m)， 2.15 (1Η， m)， 3.28 (1Η， dd， J=4.2, 12.4 Hz), 3.39 ( 2H， m)， 3.66 (1H， dd， J=1.6, 12.4 Hz), 4.21 (1H， m)， 7.46 (1H， dd， J=1.0, 7.6 Hz), 7.64 (1H， dd， J=7.6, 8.1 Hz), 7.70 (1H， dd， J=8.1 Hz);  'H-NMR (DO) δ: 1.80 (3Η, m), 2.15 (1Η, m), 3.28 (1Η, dd, J = 4.2, 12.4 Hz), 3.39 (2H, m), 3.66 (1H, dd, J = 1.6, 12.4 Hz), 4.21 (1H, m), 7.46 (1H, dd, J = 1.0, 7.6 Hz), 7.64 (1H, dd, J = 7.6, 8.1 Hz), 7.70 (1H, dd, J = 8.1 Hz);
実施例 36： 3_(3- (ヒドロキシメチノレ)ピぺリジン- 1-ィル)フタル酸 Example 36: 3_ (3- (hydroxymethinole) piperidine-1-yl) phthalic acid
製造工程 36 -(a) Manufacturing process 36-(a)
製造工程 25_(a)で得られた化合物 200 mgを DMSO 3mLに溶解し、 3_ (ヒドロキシメ チル)ピぺリジン 960 mgを加え、 80°Cでー晚攪拌した。反応液をシリカゲルカラムクロ マトグラフィー（へキサン 酢酸ェチル）を用いて精製し、 3-(3_ (ヒドロキシメチル)ピぺ リジン- 1-ィル)フタル酸ジェチルエステル 220 mgを得た。  200 mg of the compound obtained in production step 25_ (a) was dissolved in 3 mL of DMSO, 960 mg of 3_ (hydroxymethyl) piperidine was added, and the mixture was stirred at 80 ° C. The reaction solution was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 220 mg of 3- (3_ (hydroxymethyl) piperidin-1-yl) phthalic acid jetyl ester.
EIMS:m/z335[M+]； EIMS: m / z335 [M + ];
製造工程 36_(b)  Manufacturing process 36_ (b)
製造工程 36_(a)で得られた化合物 220 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用 いて精製し、表題化合物 150 mgを得た。  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.
FABMS:m/z280[M+H]+； FABMS: m / z280 [M + H] + ;
'H-NMR (D O) δ : 1.36 (1Η， m)， 1.83 (2Η， m)， 2.06 (2Η， m)， 3.21-3.55 (6Η， m)， 7.4 4 'H-NMR (DO) δ: 1.36 (1Η, m), 1.83 (2Η, m), 2.06 (2Η, m), 3.21-3.55 (6Η, m), 7.4 Four
(1H， d， J=7.3 Hz), 7.62-7.69 (2H， m);  (1H, d, J = 7.3 Hz), 7.62-7.69 (2H, m);
[0194] 実施例 37： 3_(4-メトキシピぺリジン- 1-ィル)フタル酸 Example 37: 3_ (4-Methoxypiperidine-1-yl) phthalic acid
製造工程 37_(a)  Manufacturing process 37_ (a)
製造工程 32-(a)で得られた化合物 0.20 gを THF 5.0 mLに溶解し、水素化ナトリウム 75.0 mg、ヨウ化メチル 0.15 mLを加え室温でー晚攪拌した。反応液に水を加え、酢 酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた 残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3_(4-メトキシピぺリジン- 1-ィル)フタル酸ジェチルエステル 58.0 mgを得た。  Production Step 32-0 g of the compound obtained in 32- (a) was dissolved in THF 5.0 mL, sodium hydride 75.0 mg and methyl iodide 0.15 mL were added, and the mixture was 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), and 3_ ( 4-Methoxypiperidine-1-yl) phthalic acid jetyl ester 58.0 mg was obtained.
FABMS:m/z336[M+H]+； FABMS: m / z336 [M + H] + ;
製造工程 37_(b)  Manufacturing process 37_ (b)
製造工程 37_(a)で得られた化合物 58.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 40.0 mgを得た。  58.0 mg of the compound obtained in production step 37_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was 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 40.0 mg of the title compound.
ESIMS:m/z278[M-Hl；  ESIMS: m / z278 [M-Hl;
'H-NMR (D O) δ : 1.95 (2Η， m)， 2.16 (2Η， m)， 3.33 (3Η， s)， 3.40 (2Η， m)， 3.56 (2Η， m)， 3.70 (1Η， m)， 7.41 (1Η， d， J=6.6 Hz), 7.62 (2H， m);  'H-NMR (DO) δ: 1.95 (2Η, m), 2.16 (2Η, m), 3.33 (3Η, s), 3.40 (2Η, m), 3.56 (2Η, m), 3.70 (1Η, m) , 7.41 (1Η, d, J = 6.6 Hz), 7.62 (2H, m);
[0195] 実施例 38： 3_(4-ォキソピペリジン- 1-ィル)フタル酸 [0195] Example 38: 3_ (4-oxopiperidine-1-yl) phthalic acid
製造工程 38_(a)  Manufacturing process 38_ (a)
製造工程 32-(a)で得られた化合物 100 mgをジクロロメタン 3.0 mLに溶解し、ジメチ ノレスルホキシド 0.66 mL、トリエチノレアミン 0.22 mL、サルファートリオキシドピリジンコン プレックス 98.0 mgを加え室温でー晚攪拌した。反応液に水を加え、酢酸ェチルで抽 出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をプレバ ラティブ TLC (へキサン—酢酸ェチル）を用いて精製し、 3_(4-ォキソピペリジン -1-ィ ノレ)フタル酸ジェチルエステル 66.0 mgを得た。  Manufacturing process 100 mg of the compound obtained in 32- (a) was dissolved in 3.0 mL of dichloromethane, and 0.66 mL of dimethylol sulfoxide, 0.22 mL of triethinoreamine, and 98.0 mg of sulfur trioxide pyridine complex were added and stirred at room temperature. did. 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 preparative TLC (hexane-ethyl acetate), and 3_ (4 There was obtained 66.0 mg of -oxopiperidine-1-ino) phthalic acid jetyl ester.
EIMS:m/z319[M+]； EIMS: m / z319 [M + ];
製造工程 38_(b) 製造工程 38_(a)で得られた化合物 60.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 20.0 mgを得た。 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.
ESIMS:m/z262[M-Hl；  ESIMS: m / z262 [M-Hl;
'H-NMR (D O) δ :2.57 (4Η， m)， 3.48 (2Η， dd， J=6.8, 7.3 Hz), 3.65 (2H， dd， J=6.8, 7 .0 Hz), 6.51 (1H， d， J=7.3 Hz), 6.86 (1H， d， J=8.7 Hz), 7.34 (1H， dd， J=8.7 Hz);  'H-NMR (DO) δ: 2.57 (4Η, m), 3.48 (2Η, dd, J = 6.8, 7.3 Hz), 3.65 (2H, dd, J = 6.8, 7.0 Hz), 6.51 (1H, d, J = 7.3 Hz), 6.86 (1H, d, J = 8.7 Hz), 7.34 (1H, dd, J = 8.7 Hz);
[0196] 実施例 39： 3_(4-ヒドロキシ -4-フエ二ルビペリジン- 1-ィル)フタル酸 Example 39: 3_ (4-Hydroxy-4-phenylbiperidine-1-yl) phthalic acid
製造工程 39_(a)  Manufacturing process 39_ (a)
製造工程 25_(a)で得られた化合物 120 mgを DMSO 2.0 mLに溶解し、 4-ヒドロキシ- 4-フエ二ルビペリジン 440 mgを加え、 80°Cでー晚攪拌した。反応液に水を加え、酢 酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた 残渣をプレパラティブ TLC (へキサン—酢酸ェチル）を用いて精製し、 3_(4-ヒドロキシ -4-フエ二ルビペリジン- 1-ィル)フタル酸ジェチルエステル 41.0 mgを得た。  120 mg of the compound obtained in production process 25_ (a) was dissolved in 2.0 mL of DMSO, 440 mg of 4-hydroxy-4-phenylbiperidine was added, and the mixture was stirred at 80 ° C. under reduced pressure. 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 preparative TLC (hexane-ethyl acetate), and 3_ ( 41.0 mg of 4-hydroxy-4-phenylbiperidine-1-yl) phthalic acid jetyl ester was obtained.
ESIMS:m/z398[M+H]+； ESIMS: m / z398 [M + H] + ;
製造工程 39_(b)  Manufacturing process 39_ (b)
製造工程 39_(a)で得られた化合物 60.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 20.0 mgを得た。  60.0 mg of the compound obtained in production step 39_ (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.
FABMS:m/z342[M+H]+； FABMS: m / z342 [M + H] + ;
:H-NMR (CDC1 +CD OD) δ :2.05 (2H， d， J=13.4 Hz), 2.64 (2H， m)， 3.14 (2H， m)， 3 : H-NMR (CDC1 + CD OD) δ: 2.05 (2H, d, J = 13.4 Hz), 2.64 (2H, m), 3.14 (2H, m), 3
• 66(2H， m)， 7.33 (1H， d， J=7.6 Hz), 7.41 (1H， dd， J=7.3, 7.6 Hz), 7.54 (1H， d， J=7.3 Hz)， 7.66 (5H， brs); • 66 (2H, m), 7.33 (1H, d, J = 7.6 Hz), 7.41 (1H, dd, J = 7.3, 7.6 Hz), 7.54 (1H, d, J = 7.3 Hz), 7.66 (5H, brs);
[0197] 実施例 40： 3_(4-アミノビペリジン _1-ィル)フタル酸 [0197] Example 40: 3_ (4-aminobiperidine_1-yl) phthalic acid
製造工程 40_(a)  Manufacturing process 40_ (a)
製造工程 32-(a)で得られた化合物 200 mgをジクロロメタン 5.0 mLに溶解し、トリェチ ルァミン 0.17 mL、メタンスルホユルクロリド 0.057 mLを加え室温で 1時間攪拌した。 反応液に水を加え、ジクロロメタンで抽出し、有機層を無水硫酸マグネシウムで乾燥 後減圧濃縮し、得られた残渣を DMF 5.0 mLに溶解し、アジ化ナトリウム 50 mgを加え 100°Cで三時間攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水 硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカゲルカラムクロマトダラ フィー（へキサン一酢酸ェチル）を用いて精製し、 3_(4-アジドピペリジン -1-ィル)フタ ノレ酸ジェチルエステル 170 mgを得た。 200 mg of the compound obtained in production step 32- (a) was dissolved in 5.0 mL of dichloromethane, 0.17 mL of triethylamine and 0.057 mL of methanesulfuryl chloride were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The resulting residue was dissolved in 5.0 mL of DMF, 50 mg of sodium azide was added, and 100 ° C was added for 3 hours. Stir. 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 monoethyl acetate), 3_ 170 mg of (4-azidopiperidine-1-yl) phthalenoic acid ethyl ester was obtained.
EIMS:m/z346[M+]； EIMS: m / z346 [M + ];
製造工程 40-(b) Manufacturing process 40- (b)
製造工程 40_(a)で得られた化合物 80.0 mgをエタノール：水 =5 : 1の混合溶媒 6.0 m Lに溶解し、アルゴン置換した後、 10%Pd_C 16.0 mgを加え水素気流下室温でー晚攪 拌した。反応液をセライト濾過後減圧濃縮し、 3_(4-アミノビペリジン -1-ィル)フタル酸 ジェチルエステル 54.0 mgを得た。  Dissolve 80.0 mg of the compound obtained in production process 40_ (a) in 6.0 mL of ethanol: water = 5: 1, purge with argon, add 16.0 mg of 10% Pd_C at room temperature under a hydrogen stream at room temperature. Stirred. The reaction solution was filtered through celite and concentrated under reduced pressure to obtain 54.0 mg of 3_ (4-aminobiperidine-1-yl) phthalic acid jetyl ester.
ESIMS:m/z321[M+H]+ ESIMS: m / z321 [M + H] +
製造工程 40-(c)  Manufacturing process 40- (c)
製造工程 40_(b)で得られた化合物 50.0 mgを 1,4-ジォキサン 2.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 2.0 mLに溶解し、 80°Cで一晩攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、減圧濃縮し得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 20.0 mgを得た。  50.0 mg of the compound obtained in the production process 40_ (b) was dissolved in 2.0 mL of 1,4-dioxane and 2.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. overnight. 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.
ESIMS:m/z263[M-Hl； ESIMS: m / z263 [M-Hl;
:H-NMR (D 0) δ : 1.61 (2H， m)， 1.98 (2H， m)， 3.06-3.66 (5H， m)， 7.05 (1H， dd， J=2. 4， 6.5 Hz), 7.21-7.27 (2H， m); : H-NMR (D 0) δ: 1.61 (2H, m), 1.98 (2H, m), 3.06-3.66 (5H, m), 7.05 (1H, dd, J = 2.4, 6.5 Hz), 7.21 -7.27 (2H, m);
実施例 41 3_(4-アジドピペリジン- 1-ィル)フタル酸 Example 41 3_ (4-azidopiperidine-1-yl) phthalic acid
製造工程 41 -(a)  Manufacturing process 41-(a)
製造工程 40_(a)で得られた化合物 110 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後 減圧濃縮し、表題化合物 15.0 mgを得た。  110 mg of the compound obtained in production process 40_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 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, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 15.0 mg of the title compound.
ESIMS:m/z291[M+H]+ ; :H-NMR (CDCl +CD OD) δ : 1.89 (2H， m)， 2.14 (2H， m)， 2.99 (2H， m)， 3.33 (2H， m)ESIMS: m / z291 [M + H] + ; : H-NMR (CDCl + CD OD) δ: 1.89 (2H, m), 2.14 (2H, m), 2.99 (2H, m), 3.33 (2H, m)
， 3.74 (1H， m)， 7.52 (1H， d， J=8.0 Hz), 7.57 (1H， dd， J=7.6, 8.0 Hz)， 7.64 (1H， d，J =7.6 Hz); , 3.74 (1H, m), 7.52 (1H, d, J = 8.0 Hz), 7.57 (1H, dd, J = 7.6, 8.0 Hz), 7.64 (1H, d, J = 7.6 Hz);
[0199] 実施例 42： 3_(4-ベンジルピペリジン- 1-ィル)フタル酸  [0199] Example 42: 3_ (4-benzylpiperidine-1-yl) phthalic acid
製造工程 42-(a) Manufacturing process 42- ( a )
製造工程 25_(a)で得られた化合物 100 mgに 4-ベンジルピペリジン 0.74 gを加え、 8 0°Cでー晚攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を lmol/L塩 酸で洗浄後無水硫酸マグネシウムで乾燥後、減圧濃縮し、得られた残渣をプレパラ ティブ TLC (へキサン 酢酸ェチル）を用レ、て精製し、 3_(4-ベンジルピペリジン- 1 -ィ ノレ)フタル酸ジェチルエステル 110 mgを得た。  To 100 mg of the compound obtained in production step 25_ (a), 0.74 g of 4-benzylpiperidine was added, and the mixture was stirred at 80 ° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with lmol / L hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was treated with preparative TLC (hexane acetate). The product was purified to obtain 110 mg of 3_ (4-benzylpiperidine-1-ino) phthalic acid jetyl ester.
ESIMS:m/z396[M+H]+； ESIMS: m / z396 [M + H] + ;
製造工程 42-(b)  Manufacturing process 42- (b)
製造工程 42-(a)で得られた化合物 100 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後 減圧濃縮し、表題化合物 18.0 mgを得た。  100 mg of the compound obtained in production step 42- (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. Lmol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 18.0 mg of the title compound.
ESIMS:m/z338[M-Hl;  ESIMS: m / z338 [M-Hl;
'H-NMR (CDCl ) δ : 1.62 (2Η， m)， 1.84 (2Η， m)， 1.91 (2Η， m)， 2.65 (2Η， d， J=7.1 Η ζ)， 3.00 (2Η， m)， 3.22 (2Η， m)， 7.39 (8Η， m);  'H-NMR (CDCl) δ: 1.62 (2 m, m), 1.84 (2 Η, m), 1.91 (2 ，, m), 2.65 (2 =, d, J = 7.1 ζ ζ), 3.00 (2 Η, m), 3.22 (2Η, m), 7.39 (8Η, m);
[0200] 実施例 43： 3_(4-カルボキシピペリジン- 1-ィル)フタル酸 Example 43: 3_ (4-Carboxypiperidine-1-yl) phthalic acid
製造工程 43-(a) Manufacturing process 43- ( a )
製造工程 25_(a)で得られた化合物 120 mgを DMSO 2.5 mLに溶解し、イソ二ペコタ ミド、（4-ピぺリジンカルボキサミド） 320 mgを加え 80°Cでー晚攪拌した。反応液に水を 加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、 得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて 精製し、 3_(4-力ルバモイルビペリジン- 1-ィル)フタル酸ジェチルエステル 49.0 mgを 得た。  120 mg of the compound obtained in production step 25_ (a) was dissolved in 2.5 mL of DMSO, and isopipecotamide and 320 mg of (4-piperidinecarboxamide) were added, followed by stirring at 80 ° C. 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) to give 3_ (4 There was obtained 49.0 mg of -force rubermoylbiperidine-1-yl) phthalic acid ethyl ester.
EIMS:m/z348[M+]； 製造工程 43-(b) EIMS: m / z348 [M + ]; Manufacturing process 43- (b)
製造工程 43_(a)で得られた化合物 45.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩 酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用いて精製し、 表題化合物 20.0 mgを得た。  45.0 mg of the compound obtained in the production step 43_ (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 is adjusted to pH 2 by adding lmol / L hydrochloric acid, extracted with ethyl acetate, the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue is used with resin SP-207 (water-acetonitrile). To obtain 20.0 mg of the title compound.
ESIMS:m/z294[M+H]+； ESIMS: m / z294 [M + H] + ;
'H-NMR (CDC1 ) δ :2.00 (2H， m)， 2.24 (2H， m)， 2.76 (1H， m)， 3.46 (4H， m)， 7.42 (1 'H-NMR (CDC1) δ: 2.00 (2H, m), 2.24 (2H, m), 2.76 (1H, m), 3.46 (4H, m), 7.42 (1
H， d， J=6.8 Hz), 7.63 (2H， m); H, d, J = 6.8 Hz), 7.63 (2H, m);
実施例 44： 3_[4- (エトキシカルボニル)ピぺリジン- 1-ィル]フタル酸 Example 44: 3_ [4- (ethoxycarbonyl) piperidine-1-yl] phthalic acid
製造工程 44-(a)  Manufacturing process 44- (a)
3-フルオロフタル酸 920 mgを DMF 10 mLに溶解し、炭酸カリウム 2.00 g、ベンジルブ ロマイド 1.3 mLを加え室温で 3日間攪拌した。反応液に水を加え酢酸ェチルで抽出し 、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカゲル力 ラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精製し、 3-フルオロフタル酸 ジベンジルエステル 1.27 gを得た。  920 mg of 3-fluorophthalic acid was dissolved in 10 mL of DMF, 2.00 g of potassium carbonate and 1.3 mL of benzyl bromide were added, and the mixture was stirred at room temperature for 3 days. 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) to obtain 3-fluoro 1.27 g of phthalic acid dibenzyl ester was obtained.
ESIMS:m/z365[M+H]+； ESIMS: m / z365 [M + H] + ;
製造工程 44-(b)  Manufacturing process 44- (b)
製造工程 44-(a)で得られた化合物 360 mgを DMSO 5.0 mLに溶解し、イソ二ペコチ ン酸ェチルエステル 780 mgを加え 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェ チルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣 をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3_[4- (エトキシカルボニル)ピぺリジン- 1-ィル]フタル酸ジベンジルエステル 54.0 mgを得た 360 mg of the compound obtained in production process 44- (a) was dissolved in 5.0 mL of DMSO, 780 mg of isopipecotic acid ethyl ester was added, and the mixture was stirred at 80 ° C. 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), and 3_ [ 4- (Ethoxycarbonyl) piperidine-1-yl] phthalic acid dibenzyl ester 54.0 mg was obtained.
〇 Yes
FABMS:m/z502[M+H]+； FABMS: m / z502 [M + H] + ;
製造工程 44-(c) Manufacturing process 44- (c)
製造工程 44-(b)で得られた化合物 140 mgをエタノール 10 mL、水 1.0 mLの混合溶 媒に溶解し、アルゴン置換後 10%Pd_C 28.0 mgを加え、水素気流下室温でー晚攪 拌した。反応液をセライト濾過した後減圧濃縮し、表題化合物 80.0 mgを得た。 Dissolve 140 mg of the compound obtained in production step 44- (b) in a mixed solvent of ethanol (10 mL) and water (1.0 mL), add 10% Pd_C (28.0 mg) after purging with argon, and stir at room temperature under a hydrogen stream. Stir. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (80.0 mg).
FABMS:m/z322[M+H]+； FABMS: m / z322 [M + H] + ;
[0202] 実施例 45： 3_(4-力ルバモイルビペリジン- 1-ィル)フタル酸 [0202] Example 45: 3_ (4-force rubamoyl biperidine-1-yl) phthalic acid
製造工程 45-(a) Manufacturing process 45- (a)
製造工程 44-(a)で得られた化合物 180 mgを DMSO 2.5 mLに溶解し、イソ二ペコタミ ド、（4-ピぺリジンカルボキサミド） 320 mgを加え 80°Cで一晩攪拌した。反応液に水を 加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、 得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて 精製し、 3_(4-力ルバモイルビペリジン- 1-ィル)フタル酸ジベンジルエステル 30.0 mg を得た。  180 mg of the compound obtained in production step 44- (a) was dissolved in 2.5 mL of DMSO, and isopipecotamide and 320 mg of (4-piperidinecarboxamide) were added and stirred overnight at 80 ° C. 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) to give 3_ (4 There was obtained 30.0 mg of -force rubermoylbiperidine-1-yl) phthalic acid dibenzyl ester.
EIMS:m/z472[M+]； EIMS: m / z472 [M + ];
製造工程 45_(b)  Manufacturing process 45_ (b)
製造工程 45_(a)で得られた化合物 30.0 mgをエタノール 5.0 mL、水 0.5 mLの混合 溶媒  Production process 45_ (a) Compound 30.0 mg mixed with ethanol 5.0 mL and water 0.5 mL
に溶解し、アルゴン置換後 10%Pd_C 6.00 mgを加え、水素気流下室温でー晚攪拌 した。反応液をセライト濾過した後減圧濃縮し、得られた残渣を樹脂 SP_207 (水ーァ セトニトリル)を用いて精製し、表題化合物 12.0 mgを得た。  After replacing with argon, 6.00 mg of 10% Pd_C was added, and the mixture was stirred at room temperature under a hydrogen stream. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified using resin SP_207 (water-acetonitrile) to give the title compound (12.0 mg).
FABMS:m/z293[M+H]+； FABMS: m / z293 [M + H] + ;
'H-NMR (D O) δ : 1.94 (2Η， m)， 2.15 (2Η， m)， 2.68 (1Η， m)， 3.50 (4Η， m)， 7.38 (1Η， dd， J=3.0, 5.9 Hz), 7.61 (2H， m);  'H-NMR (DO) δ: 1.94 (2Η, m), 2.15 (2Η, m), 2.68 (1Η, m), 3.50 (4Η, m), 7.38 (1Η, dd, J = 3.0, 5.9 Hz) , 7.61 (2H, m);
[0203] 実施例 46： 3_(4- (ジメチルカルバモイル)ピぺリジン- 1-ィル)フタル酸 [0203] Example 46: 3_ (4- (dimethylcarbamoyl) piperidine-1-yl) phthalic acid
製造工程 46-(a) Manufacturing process 46- ( a )
3-フルオロフタル酸 5.00 gを DMF 20 mgに溶解し、炭酸カリウム 11.3 g、ヨウ化メチ ノレ 3.7 mLを加え室温でー晚攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有 機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、 3-フルオロフタル酸ジメチルェ ステル 2.24 gを得た。  5.00 g of 3-fluorophthalic acid was dissolved in 20 mg of DMF, 11.3 g of potassium carbonate and 3.7 mL of methyl iodide were added, and the mixture was 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 to obtain 2.24 g of dimethyl ester 3-fluorophthalate.
FABMS:m/z213[M+H]+ ; FABMS: m / z213 [M + H] + ;
製造工程 46-(b) 製造工程 46_(a)で得られた化合物 100 mgを DMSO 5.0 mLに溶解し、 4- (ジメチルカ ノレバモイル)ピぺリジン 100 mgを加え室温でー晚攪拌攪拌した。反応液に水を加え、 酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られ た残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し 、 3_(4- (ジメチルカルバモイル)ピぺリジン- 1-ィル)フタル酸ジメチルエステル 16.0 mg を得た。 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.
FABMS:m/z349[M+H]+； FABMS: m / z 349 [M + H] + ;
製造工程 46-(c) Manufacturing process 46- ( c )
製造工程 46_(b)で得られた化合物 35.0 mgを 1,4-ジォキサン 3.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 1.0 mLに溶解し、室温で三時間攪拌した。反応液に lmol/L 塩酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで 乾燥後減圧濃縮し、表題化合物 11.0 mgを得た。  35.0 mg of the compound obtained in production step 46_ (b) was dissolved in 3.0 mL of 1,4-dioxane and 1.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added lmol / L hydrochloric acid to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 11.0 mg of the title compound.
FABMS:m/z321[M+H]+ ; FABMS: m / z321 [M + H] + ;
実施例 47： 3- (ピペラジン- 1-ィル)フタル酸 Example 47: 3- (piperazine-1-yl) phthalic acid
製造工程 47-(a) Production process 47- ( a )
製造工程 25_(a)で得られた化合物 1.20 gを 1-Boc-ピぺラジン 2.80 gと炭酸力リウ ム 2.76 g存在下 120°Cで一晩攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有 機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラ ムクロマトグラフィー（へキサン一酢酸ェチル）を用いて精製し、 3-[4-(tert_ブトキシカ ノレボニノレ)ピぺラジン- 1-ィノレ]フタル酸ジェチルエステル 710 mgを得た。  1.20 g of the compound obtained in production step 25_ (a) was stirred overnight at 120 ° C. in the presence of 2.80 g of 1-Boc-piperazine and 2.76 g of carbonic acid. 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 monoacetate) to give 710 mg of 3- [4- (tert_butoxynoleboninole) piperazine-1-inole] phthalic acid jetyl ester. Obtained.
FABMS:m/z407[M+H]+； FABMS: m / z 407 [M + H] + ;
製造工程 47_(b) Manufacturing process 47_ (b)
製造工程 47_(a)で得られた化合物 100 mgを 1,4-ジォキサン 0.5mL、 5.0 mol/L水酸 化ナトリウム水溶液 2.5 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を 加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後 減圧濃縮し、得られた残渣を樹脂 SP_207 (水—ァセトニトリル)を用いて精製した。得 られた残渣に 5.0 mol/L塩酸 10 mLを加え室温でー晚攪拌した。反応液を減圧濃縮 し、得られた残渣を樹脂 SP_207 (水ーァセトニトリル)を用いて精製し、表題化合物 5 0.0 mgを得た。 100 mg of the compound obtained in the production step 47_ (a) was dissolved in 0.5 mL of 1,4-dioxane and 2.5 mL of 5.0 mol / L aqueous sodium hydroxide solution and stirred at 80 ° C. Lmol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified using resin SP_207 (water-acetonitrile). . To the obtained residue, 10 mL of 5.0 mol / L hydrochloric acid was added and stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using resin SP_207 (water-acetonitrile) to give the title compound 5 0.0 mg was obtained.
FABMS:m/z251[M+H]+ ; FABMS: m / z251 [M + H] + ;
:H-NMR (D O) δ :3.08 (4H， m)， 3.23 (4H， m)， 7.44 (1H， dd， J=7.5, 8.0 Hz), 7.48 (1 H， d， J=8.0 Hz), 7.71 (1H， d， J=7.5 Hz); : H-NMR (DO) δ: 3.08 (4H, m), 3.23 (4H, m), 7.44 (1H, dd, J = 7.5, 8.0 Hz), 7.48 (1 H, d, J = 8.0 Hz), 7.71 (1H, d, J = 7.5 Hz);
[0205] 実施例 48： 3-(4-(tert-ブトキシカルボニル)ピぺラジン- 1-ィル)フタル酸 Example 48: 3- (4- (tert-butoxycarbonyl) piperazine-1-yl) phthalic acid
製造工程 48-(a) Manufacturing process 48- ( a )
製造工程 47_(a)で得られた 3-[4-(tert-ブトキシカルボニル)ピぺラジン- 1-ィル]フタル 酸ジェチルエステル 200 mgを 1,4-ジォキサン 0.5 mL、 5.0 mol/L水酸化ナトリウム水 溶液 3.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に lmol/L塩酸を加え pH2にし た後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、 表題化合物 43.0 mgを得た。  3- [4- (tert-Butoxycarbonyl) piperazine-1-yl] phthalic acid ethyl ester 200 mg obtained in production process 47_ (a) was added to 1,4-dioxane 0.5 mL, 5.0 mol / L This was dissolved in 3.0 mL of an aqueous sodium hydroxide solution and stirred at 80 ° C. The reaction solution was adjusted to pH 2 with lmol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 43.0 mg of the title compound.
ESIMS:m/z351[M+H]+ ; ESIMS: m / z351 [M + H] + ;
'H-NMR (CDCl ) δ : 1.50 (9Η， s)， 3.07 (4Η， m)， 3.71 (4Η， m)， 7.52 (1Η， dd， J=1.2, 8 'H-NMR (CDCl) δ: 1.50 (9Η, s), 3.07 (4Η, m), 3.71 (4Η, m), 7.52 (1Η, dd, J = 1.2, 8
.0 Hz), 7.66 (1H， dd， J=7.8, 8.0 Hz), 7.84 (1H， dd， J=1.2, 7.8 Hz); .0 Hz), 7.66 (1H, dd, J = 7.8, 8.0 Hz), 7.84 (1H, dd, J = 1.2, 7.8 Hz);
[0206] 実施例 49： 3_(4-ベンジルピペラジン- 1-ィル)フタル酸 Example 49: 3_ (4-Benzylpiperazine-1-yl) phthalic acid
製造工程 49-(a) Manufacturing process 49- ( a )
製造工程 47_(a)で得られた化合物 730 mgをエタノール 10 mL、 5.0 mol/L塩酸 5.0 mLに溶解し、室温で一晩攪拌した。反応液に水を加え炭酸水素ナトリウム水で中和 した後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し 3- (ピペラジン- 1-ィル)フタル酸ジェチルエステル 372 mgを得た。  730 mg of the compound obtained in production step 47_ (a) was dissolved in 10 mL of ethanol and 5.0 mL of 5.0 mol / L hydrochloric acid, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, neutralized with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- (piperazine-1-yl) phthalic acid jetyl ester 372 mg was obtained.
ESIMS:m/z307[M+H]+； ESIMS: m / z307 [M + H] + ;
製造工程 49-(b)  Manufacturing process 49- (b)
製造工程 49_(a)で得られた化合物 140 mgを 1,2-ジクロロェタン 5.0 mLに溶解し、酢 酸 94 ,1 1、ベンズアルデヒド 0.10 mLを加え室温で 30分間攪拌した後、トリァセトキシ 水素化ホウ素ナトリウム 230 mgを加え室温で一晩攪拌した。反応液に水を加え、酢酸 ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた 残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3_(4-ベンジルピペラジン- 1-ィル)フタル酸ジェチルエステル 160 mgを得た。 FABMS:m/z397[M+H]+； 140 mg of the compound obtained in production step 49_ (a) was dissolved in 5.0 mL of 1,2-dichloroethane, and 94,11 of acetic acid and 0.10 mL of benzaldehyde were added and stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride 230 mg was added and stirred at room temperature overnight. 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 obtained residue was purified using silica gel column chromatography (hexane acetate) to give 160 mg of 3_ (4-benzylpiperazine-1-yl) phthalic acid jetyl ester. FABMS: m / z 397 [M + H] + ;
製造工程 49-(c)  Manufacturing process 49- (c)
製造工程 49_(b)で得られた化合物 160 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで一晩攪拌した。反応液に 1.0 mol/L 塩酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで 乾燥後減圧濃縮した。得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用いて精 製し、表題化合物 100 mgを得た。  160 mg of the compound obtained in production step 49_ (b) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. overnight. The reaction solution was adjusted to pH 2 by adding 1.0 mol / L hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using resin SP-207 (water-acetonitrile) to obtain 100 mg of the title compound.
FABMS:m/z341[M+H]+ ; FABMS: m / z341 [M + H] + ;
'H-NMR (CDCl ) δ :2.97 (2Η， m)， 3.21—3.40 (6Η， m)， 4.24 (2Η， s)， 7.27-7.34 (2Η， m)， 7.39 (5Η， m)， 7.57 (1Η， d， J=7.3 Hz);  'H-NMR (CDCl) δ: 2.97 (2Η, m), 3.21-3.40 (6Η, m), 4.24 (2Η, s), 7.27-7.34 (2Η, m), 7.39 (5Η, m), 7.57 ( 1Η, d, J = 7.3 Hz);
[0207] 実施例 50： 3-(4-ベンゾィルビペラジン- 1-ィル)フタル酸  Example 50: 3- (4-Benzylbiperazine-1-yl) phthalic acid
実施例 47で得られた化合物 40.0 mgを 1.0 mol/L水酸化ナトリウム水溶液 1.0 mL、 水 3.0 mLに溶解し、ベンゾイルク口ライド 67.0 mgを加え室温で二日間攪拌した。反 応液に 1.0 mol/L塩酸を加え pH2にした後酢酸ェチルで抽出し、有機層を無水硫酸 マグネシウムで乾燥後減圧濃縮した。得られた残渣を樹脂 SP-207 (水ーァセトニトリ ノレ)を用いて精製し、表題化合物 22.0 mgを得た。  40.0 mg of the compound obtained in Example 47 was dissolved in 1.0 mL of a 1.0 mol / L aqueous sodium hydroxide solution and 3.0 mL of water, 67.0 mg of benzoyl chloride was added, and the mixture was stirred at room temperature for 2 days. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using resin SP-207 (water-acetononitrile) to obtain 22.0 mg of the title compound.
ESIMS:m/z355[M+H]+； ESIMS: m / z355 [M + H] + ;
[0208] 実施例 51 : 3_(4-力ルバモイルビペラジン- 1-ィル)フタル酸  Example 51: 3_ (4-force rubermoyl biperazine-1-yl) phthalic acid
製造工程 51 -(a)  Manufacturing process 51-(a)
製造工程 47_(a)で得られた化合物 500 mgを 1,4-ジォキサン 1.2 mL、 5.0 mol/L水酸 化ナトリウム水溶液 6.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩 酸を加え pH4にした後、ジクロロメタンで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、 3-[4-(tert-ブトキシカルボニル)ピぺラジン- 1-ィル]フタル酸 364 m gを得た。  500 mg of the compound obtained in the production step 47_ (a) was dissolved in 1.2 mL of 1,4-dioxane and 6.0 mL of 5.0 mol / L sodium hydroxide aqueous solution, and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 4, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- [4- (tert-butoxycarbonyl) piperazine- 364 mg of 1-yl] phthalic acid was obtained.
製造工程 51 -(b)  Manufacturing process 51-(b)
製造工程 5；! -(a)で得られた化合物 790 mgを N，N_ジメチルホルムアミド 25mLに溶解 し、炭酸カリウム 1.24 g、ベンジルブロミド 0.67 mLを加え室温でー晚攪拌した。反応 液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧 濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル )を用いて精製し、 3-[4-(tert-ブトキシカルボニル)ピぺラジン- 1-ィル]フタル酸ジベン ジルエステル 863 mgを得た。 Production process 5;! 790 mg of the compound obtained in-(a) was dissolved in 25 mL of N, N_dimethylformamide, and 1.24 g of potassium carbonate and 0.67 mL of benzyl bromide were added and stirred at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then reduced in pressure. Concentrated. The obtained residue was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 863 mg of 3- [4- (tert-butoxycarbonyl) piperazine-1-yl] phthalic acid dibenzil ester. It was.
ESIMS:m/z531[M+H]+ ; ESIMS: m / z531 [M + H] + ;
製造工程 51 -(c)  Manufacturing process 51-(c)
製造工程 5；! -(b)で得られた化合物 360 mgをメタノール 3.0 mLに溶解し、 5.0 mol/L 塩酸 15 mLを加え室温で一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を 加え pH8にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後 減圧濃縮し、 3- (ピペラジン- 1-ィル)フタル酸ジベンジルエステル 280 mgを得た。 製造工程 51 -(d)  Production process 5;! 360 mg of the compound obtained in-(b) was dissolved in 3.0 mL of methanol, 15 mL of 5.0 mol / L hydrochloric acid was added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 8, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- (piperazine-1-yl) phthalic acid dibenzyl ester 280 mg was obtained. Manufacturing process 51-(d)
製造工程 5；! -(c)で得られた化合物 100 mgをジクロロメタン 5.0 mLに溶解し、ピリジン 0.18 mL、酢酸 0.13 mL、トリエチノレアミン 95.0 L、シアン酸カリウム 37.0 mgを加え室 温で一晩攪拌した。反応液に水を加え酢酸ェチルで抽出し、有機層を無水硫酸マグ ネシゥムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ 酢酸ェチルーメタノール）を用いて精製し、 3_(4-力ルバモイルビペラジン- 1-ィル)フ タル酸ジベンジルエステル 71.0 mgを得た。  Production process 5;! 100 mg of the compound obtained in-(c) was dissolved in 5.0 mL of dichloromethane, and 0.18 mL of pyridine, 0.13 mL of acetic acid, 95.0 L of triethinoleamine, and 37.0 mg of potassium cyanate were added, and the mixture was kept at room temperature. Stir overnight. 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 obtained residue was purified using silica gel column chromatography (ethyl acetate-methanol) to obtain 71.0 mg of 3_ (4-force rubamoylbiperazine-1-yl) phthalic acid dibenzyl ester.
FABMS:m/z474[M+H]+； FABMS: m / z474 [M + H] + ;
製造工程 51 -(e)  Manufacturing process 51-(e)
製造工程 5；! -(d)で得られた化合物 96.0 mgをエタノール 5.0 mL、水 1.0 mLに溶解し アルゴン置換した後、 10%Pd-C 2.90 mgを加え、水素気流下室温でー晚攪拌した。 反応液をセライト濾過した後減圧濃縮し、標題化合物 62.0 mgを得た。  Production process 5;!-96.0 mg of the compound obtained in-(d) was dissolved in 5.0 mL of ethanol and 1.0 mL of water and purged with argon. Then, 2.90 mg of 10% Pd-C was added, and stirred at room temperature under a hydrogen stream. did. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 62.0 mg of the title compound.
ESIMS:m/z294[M+H]+； ESIMS: m / z294 [M + H] + ;
:H-NMR (CDC1 +CD OD) δ :3.01 (4H， m)， 3.53 (4H， m)， 7.38 (1H， d， J=8.2 Hz), 7. : H-NMR (CDC1 + CD OD) δ: 3.01 (4H, m), 3.53 (4H, m), 7.38 (1H, d, J = 8.2 Hz), 7.
43 (1H， m)， 7.73 (1H， d， J=7.3 Hz); 43 (1H, m), 7.73 (1H, d, J = 7.3 Hz);
実施例 52： 3- (モルホリン- 4-ィル）フタル酸 Example 52: 3- (morpholine-4-yl) phthalic acid
製造工程 52-(a)  Manufacturing process 52- (a)
製造工程 25_(a)で得られた化合物 200 mgにモルホリン 0.73 mLを加え 80°Cで二日 間攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシ ゥムで乾燥後減圧濃縮した。得られた残渣をプレパラティブ TLC (へキサン—酢酸ェ チル）を用いて精製し、 3- (モルホリン- 4-ィル）フタル酸ジェチルエステル 35.0 mgを 得た。 Add 0.73 mL of morpholine to 200 mg of the compound obtained in production process 25_ (a) and add it at 80 ° C for 2 days. Stir for a while. 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 obtained residue was purified using preparative TLC (hexane-ethyl acetate) to obtain 35.0 mg of 3- (morpholin-4-yl) phthalic acid jetyl ester.
EIMS:m/z240[M+]; EIMS: m / z240 [M + ];
製造工程 52-(b)  Manufacturing process 52- (b)
製造工程 52-(a)で得られた化合物 35.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで一晩攪拌した。反応液に 1.0 mol/L 塩酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで 乾燥後減圧濃縮し、得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用いて精製 し、表題化合物 13.0 mgを得た。  35.0 mg of the compound obtained in production step 52- (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 overnight at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was washed with resin SP-207 (water-acetonitrile). Purification gave 13.0 mg of the title compound.
FABMS:m/z252[M+H]+； FABMS: m / z252 [M + H] + ;
'H-NMR (CDC1 ) δ :3.34 (4H， m)， 3.92 (4H， m)， 7.44 (1H， d， J=7.3 Hz), 7.57-7.63 ( 'H-NMR (CDC1) δ: 3.34 (4H, m), 3.92 (4H, m), 7.44 (1H, d, J = 7.3 Hz), 7.57-7.63 (
2H, m); 2H, m);
実施例 53： 3- (ァゼパン- 1-ィル）フタル酸 Example 53: 3- (azepan-1-yl) phthalic acid
製造工程 53_(a)  Manufacturing process 53_ (a)
製造工程 25_(a)で得られた化合物 200 mgにへキサメチレンィミン 0.14 mLをカロえ 80 °Cで二日間攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸 マグネシウムで乾燥後減圧濃縮した。得られた残渣をプレパラティブ TLC (へキサン 酢酸ェチル）を用いて精製し、 3- (ァゼパン- 1-ィル）フタル酸ジェチルエステル 42. 0 mgを得た。  To 200 mg of the compound obtained in production step 25_ (a), 0.14 mL of hexamethyleneimine was added and stirred at 80 ° C. for 2 days. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified using preparative TLC (hexane ethyl acetate) to obtain 42.0 mg of 3- (azepan-1-yl) phthalic acid jetyl ester.
FABMS:m/z320 [M+H]+； FABMS: m / z320 [M + H] + ;
製造工程 53_(b)  Manufacturing process 53_ (b)
製造工程 53_(a)で得られた化合物 35.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで一晩攪拌した。反応液に 1.0 mol/L 塩酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで 乾燥後減圧濃縮し、得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用いて精製 し、表題化合物 9.0 mgを得た。 ESIMS:m/z264[M+H]+； 35.0 mg of the compound obtained in production step 53_ (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. overnight. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was washed with resin SP-207 (water-acetonitrile). Purification gave 9.0 mg of the title compound. ESIMS: m / z264 [M + H] + ;
[0211] 実施例 54 : 3-メチルフタル酸 Example 54: 3-methylphthalic acid
製造工程 54  Manufacturing process 54
3-メチルフタル酸無水物 500 mgを THF 5.0 mL、水 5.0 mLに溶解し、 1.0 mol/L水 酸化ナトリウム水溶液 3.0 mLを加え室温でー晚攪拌した。反応液に 1.0 mol/L塩酸 を加え pH2にした後減圧濃縮し、得られた残渣を ODS (水—ァセトニトリル)を用いて 精製し、表題化合物 630 mgを得た。  3-methylphthalic anhydride (500 mg) was dissolved in THF (5.0 mL) and water (5.0 mL), 1.0 mol / L aqueous sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred at room temperature. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by concentration under reduced pressure. The resulting residue was purified using ODS (water-acetonitrile) to obtain 630 mg of the title compound.
ESIMS:m/zl79[M-Hl;  ESIMS: m / zl79 [M-Hl;
'H-NMR (CDCl +CD OD) δ :3.12 (3H， s)， 7.34 (1H， dd， J=7.6 Hz), 7.40 (1H， d， J=7 'H-NMR (CDCl + CD OD) δ: 3.12 (3H, s), 7.34 (1H, dd, J = 7.6 Hz), 7.40 (1H, d, J = 7
.6Hz),7.84 (1H， d， J=7.6 Hz); .6Hz), 7.84 (1H, d, J = 7.6 Hz);
[0212] 実施例 55： 3_(3-ヒドロキシプロピル)フタル酸 [0212] Example 55: 3_ (3-hydroxypropyl) phthalic acid
製造工程 55_(a)  Manufacturing process 55_ (a)
製造工程 18_(b)で得られた 3-ァミノフタル酸ジェチルエステル 2.40 gを水 40 mL、 48 %臭化水素酸 20 mLの混合溶液に溶解し、亜硝酸ナトリウム 680 mgを加え室温で 1時 間攪拌した。反応液に、臭化銅 (I) 1.40 gを臭化水素酸 8.0 mLに溶解した液を加え 7 0°Cでー晚攪拌した。反応液に 5 mol/Lの水酸化ナトリウム水溶液を加え中和した後、 酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得ら れた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精 製し、 3-ブロモフタル酸ジェチルエステル 2.23 gを得た。  Dissolve 2.40 g of 3-aminophthalic acid jetyl ester obtained in production process 18_ (b) in a mixed solution of 40 mL of water and 20 mL of 48% hydrobromic acid, add 680 mg of sodium nitrite at room temperature for 1 hour. Stir for a while. A solution prepared by dissolving 1.40 g of copper bromide (I) in 8.0 mL of hydrobromic acid was added to the reaction solution, and the mixture was stirred at 70 ° C. The reaction solution was neutralized by adding 5 mol / L sodium hydroxide aqueous solution, extracted with ethyl acetate, and 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) to obtain 2.23 g of 3-bromophthalic acid jetyl ester.
EIMS: m/z300,302[M+]； EIMS: m / z300,302 [M + ];
製造工程 55_(b)  Manufacturing process 55_ (b)
製造工程 55_(a)で得られた化合物 360 mgを 1,4-ジォキサン 2.0 mLに溶解し、ァリ ノレアルコール 0.16 mL、ビス（トリ- 1-ブチルホスフィン）パラジウム (0) 14.0 mg、 N，N -ジ シクロヒキシルメチルァミン 0.50 mLを加え室温で二日間攪拌した。反応液に水をカロ え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。 得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて 精製し、 3-(3_ォキソプロピル)フタル酸ジェチルエステル 146 mgを得た。  Dissolve 360 mg of the compound obtained in production step 55_ (a) in 2.0 mL of 1,4-dioxane, 0.16 mL of alcohol, bis (tri-1-butylphosphine) palladium (0) 14.0 mg, N, N-dicyclohexylmethylamine 0.50 mL was added, and the mixture was stirred at room temperature for 2 days. 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) to obtain 146 mg of 3- (3_oxopropyl) phthalic acid jetyl ester.
EIMS: m/z279[M+]; 製造工程 55-(c) EIMS: m / z279 [M + ]; Manufacturing process 55- (c)
製造工程 55_(b)で得られた化合物 140 mgをエタノール 5.0 mLに溶解し、水素化ホ ゥ素ナトリウム 23.0 mgを加え室温でー晚攪拌した。反応液に水を加え、酢酸ェチル で抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し 3-(3_ヒドロキシプロ ピル)フタル酸ジェチルエステルを得た。  140 mg of the compound obtained in production step 55_ (b) was dissolved in 5.0 mL of ethanol, and 23.0 mg of sodium borohydride was added, and the mixture was 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 to obtain 3- (3_hydroxypropyl) phthalic acid jetyl ester.
FABMS:m/z281[M+H]+ ; FABMS: m / z281 [M + H] + ;
製造工程 55_(d) Manufacturing process 55_ (d)
製造工程 55_(c)で得られた化合物 100 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩 酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、表題化合物 46.0 mgを得た。  100 mg of the compound obtained in production step 55_ (c) 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. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 46.0 mg of the title compound.
FABMS:m/z225[M+H]+； FABMS: m / z225 [M + H] + ;
'H-NMR (DMSO) δ : 1.69 (2H， m)， 2.64 (2Η， t， J=8.0 Hz), 3.39 (2H， t， J=6.4 Hz), 7. 42 (1H， dd， J=7.6, 7.6 Hz), 7.49 (1H， d， J=7.6 Hz)， 7.72 (1H， d， J=7.6 Hz);  'H-NMR (DMSO) δ: 1.69 (2H, m), 2.64 (2Η, t, J = 8.0 Hz), 3.39 (2H, t, J = 6.4 Hz), 7. 42 (1H, dd, J = 7.6, 7.6 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.72 (1H, d, J = 7.6 Hz);
実施例 56： 3-フエニルフタル酸 Example 56: 3-phenylphthalic acid
製造工程 56_(a) Manufacturing process 56_ (a)
製造工程 55_(c)で得られた 3-ブロモフタル酸ジェチルエステル 300 mgをトルエン 5 • OmLに溶解し、アルゴン置換した後、フエ二ルポロン酸 244 mg、炭酸カリウム 276 mg 、テトラキストリフエニルホスフィンパラジウム 120 mgを加え 80°Cでー晚攪拌した。反応 液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧 濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル )を用いて精製し、 3-フエニルフタル酸ジェチルエステル 160 mgを得た。  Dissolve 300 mg of 3-bromophthalic acid jetyl ester obtained in production process 55_ (c) in 5 • OmL of toluene and substitute with argon. Then, 244 mg of phenylpolonic acid, 276 mg of potassium carbonate, tetrakistriphenylphosphine palladium 120 mg was added and stirred at 80 ° C. 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 acetate) to obtain 160 mg of 3-phenylphthalic acid jetyl ester.
ESIMS:m/z299[M+H]+； ESIMS: m / z299 [M + H] + ;
製造工程 56_(b) Manufacturing process 56_ (b)
製造工程 56_(a)で得られた化合物 160 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩 酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、表題化合物 115 mgを得た。 FABMS:m/z243[M+H]+； 160 mg of the compound obtained in production step 56_ (a) was dissolved in 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 115 mg of the title compound. FABMS: m / z 243 [M + H] + ;
:H-NMR (CDC1 ) δ :7.40 (5H， m)， 7.54-7.61 (2H， m)， 8.05 (1H， dd， J=1.5, 7.6 Hz); : H-NMR (CDC1) δ: 7.40 (5H, m), 7.54-7.61 (2H, m), 8.05 (1H, dd, J = 1.5, 7.6 Hz);
[0214] 実施例 57： 3_(2-ォキシド)フエニルフタル酸トリナトリウム  [0214] Example 57: trisodium 3_ (2-oxide) phenylphthalate
製造工程 57_(a)  Manufacturing process 57_ (a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 100 mgをトルエン 3 • OmLに溶解し、アルゴン置換した後、 2-(2-ベンジルォキシフエニル) -4,4,5,5-テトラメ チル 1,3,2-ジォキサボロラン 230 mg、炭酸カリウム 100 mg、テトラキストリフエニルホス フィンパラジウム 84.0 mgを加え 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェチ ルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣 をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3-(2- ベンジルォキシ)フエニルフタル酸ジェチルエステル 30.0 mgを得た。  Manufacturing Process 55_ (a) 3-bromophthalic acid jetyl ester 100 mg was dissolved in toluene 3 • OmL and purged with argon, then 2- (2-benzyloxyphenyl) -4,4,5 2,5-tetramethyl 1,3,2-dioxaborolane 230 mg, potassium carbonate 100 mg, tetrakistriphenylphosphine palladium 84.0 mg was added, and the mixture was stirred at 80 ° C. 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 acetate) to obtain 30.0 mg of 3- (2-benzyloxy) phenylphthalic acid jetyl ester.
ESIMS:m/z405[M+H]+； ESIMS: m / z405 [M + H] + ;
製造工程 57_(b)  Manufacturing process 57_ (b)
製造工程 57_(a)で得られた化合物 30.0 mgをエタノール 10 mL、水 1.0 mLの混合溶 液に溶解し、アルゴン置換した後、 10%Pd_C 15.0 mgを加え水素置換後、ー晚室温 で攪拌した。反応液をセライト濾過した後、減圧濃縮した。得られた残渣に 1.0 mol/L 水酸化ナトリウム水溶液 0.23 mLを加え 80°Cで二日間攪拌した。反応液を減圧濃縮し 、表題化合物 10.1 mgを得た。  Dissolve 30.0 mg of the compound obtained in production step 57_ (a) in a mixed solution of ethanol (10 mL) and water (1.0 mL), purge with argon, add 15.0 mg of 10% Pd_C, replace with hydrogen, and stir at room temperature. did. The reaction mixture was filtered through celite and concentrated under reduced pressure. To the obtained residue, 1.03 mol / L aqueous sodium hydroxide solution (0.23 mL) was added, and the mixture was stirred at 80 ° C for 2 days. The reaction solution was concentrated under reduced pressure to obtain 10.1 mg of the title compound.
ESIMS:m/z259[M+H]+； ESIMS: m / z259 [M + H] + ;
[0215] 実施例 58： 3-(3_ヒドロキシ)フエニルフタル酸 [0215] Example 58: 3- (3_hydroxy) phenylphthalic acid
製造工程 58_(a)  Manufacturing process 58_ (a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 100 mgをトルエン 3.0 mLに溶解し、アルゴン置換した後、 2-(3_ベンジルォキシフエニル) -4,4,5,5-テトラメ チル 1,3,2-ジォキサボロラン 230 mg、炭酸カリウム 100 mg、テトラキストリフエニルホス フィンパラジウム 84.0 mgを加え 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェチ ルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣 をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3-(2- ベンジルォキシ)フエニルフタル酸ジェチルエステル 37.0 mgを得た。 ESIMS:m/z405[M+H]+； Production Process 55_ (a) 3-bromophthalic acid jetyl ester 100 mg was dissolved in toluene 3.0 mL and purged with argon, then 2- (3_benzyloxyphenyl) -4,4,5, 5-tetramethyl 1,3,2-dioxaborolane (230 mg), potassium carbonate (100 mg), and tetrakistriphenylphosphine palladium (84.0 mg) were added, and the mixture was stirred at 80 ° C. 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 acetate) to obtain 37.0 mg of 3- (2-benzyloxy) phenylphthalic acid jetyl ester. ESIMS: m / z405 [M + H] + ;
製造工程 58_(b)  Manufacturing process 58_ (b)
製造工程 58_(a)で得られた化合物 37.0 mgをエタノール 10 mL、水 1.0 mLの混合溶 液に溶解し、アルゴン置換した後、 10%Pd_C 17.0 mgを加え水素置換後、一晩室温 で攪拌した。反応液をセライト濾過した後、減圧濃縮した。得られた残渣に 1,4-ジォ キサン 1.0 mL、 5.0 mol/L水酸化ナトリウム水溶液 5.0 mLを加え 80°Cでー晚攪拌した 。反応液に 1.0 mol/L塩酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水 硫酸マグネシウムで乾燥後減圧濃縮し、表題化合物 14.0 mgを得た。  Dissolve 37.0 mg of the compound obtained in production step 58_ (a) in a mixed solution of ethanol (10 mL) and water (1.0 mL), purge with argon, add 10% Pd_C (17.0 mg), replace with hydrogen, and stir at room temperature overnight. did. The reaction mixture was filtered through celite and concentrated under reduced pressure. To the obtained residue, 1.0 mL of 1,4-dioxane and 5.0 mL of a 5.0 mol / L aqueous sodium hydroxide solution were added and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 14.0 mg of the title compound.
FABMS:m/z259[M+H]+； FABMS: m / z259 [M + H] + ;
実施例 59： 3_(4-ヒドロキシ)フエニルフタル酸 Example 59: 3_ (4-hydroxy) phenylphthalic acid
製造工程 59_(a)  Manufacturing process 59_ (a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 110 mgをトルエン 5.0 mLに溶解し、アルゴン置換した後、 2-(4-ベンジルォキシフエニル) -4,4,5,5-テトラメ チル 1,3,2-ジォキサボロラン 230 mg、炭酸カリウム 110 mg、テトラキストリフエニルホス フィンパラジウム 84.0 mgを加え 80°Cで一晩攪拌した。反応液をセライト濾過し、得ら れた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精 製し、 3_(4-ベンジルォキシ)フエニルフタル酸ジェチルエステル 75.0 mgを得た。 110 mg of 3-bromophthalic acid jetyl ester obtained in production step 55_ (a) was dissolved in 5.0 mL of toluene and purged with argon, and then 2- (4-benzyloxyphenyl) -4,4,5, 5-tetramethyl 1,3,2-dioxaborolane 230 mg, potassium carbonate 110 mg, tetrakistriphenylphosphine palladium 84.0 mg was added, and the mixture was stirred at 80 ° C. overnight. The reaction solution was filtered through Celite, and the resulting residue was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 75.0 mg of 3_ (4-benzyloxy) phenylphthalic acid jetyl ester.
ESIMS:m/z405[M+H]+； ESIMS: m / z405 [M + H] + ;
製造工程 59_(b)  Manufacturing process 59_ (b)
製造工程 59_(a)で得られた化合物 75.0 mgをエタノール 5.0 mLに溶解し、アルゴン 置換した後、 10%Pd-C 15.0 mgを加え水素置換後、一晩室温で攪拌した。反応液を セライト濾過した後、減圧濃縮した。得られた残渣に 1,4-ジォキサン 1.0 mL、 5.0 mol/ L水酸化ナトリウム水溶液 5.0 mLを加え 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩 酸を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾 燥後減圧濃縮し、表題化合物 8.0 mgを得た。  75.0 mg of the compound obtained in the production step 59_ (a) was dissolved in 5.0 mL of ethanol and purged with argon. After 15.0 mg of 10% Pd-C was added and purged with hydrogen, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite and concentrated under reduced pressure. To the resulting residue, 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L sodium hydroxide aqueous solution were added and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 8.0 mg of the title compound.
FABMS:m/z259[M+H]+； FABMS: m / z259 [M + H] + ;
'H-NMR (CDC1 ) δ :6.81 (2H， d， J=8.3 Hz), 7.17 (2H， d， J=8.3 Hz), 7.47 (2H， m)， 7. 'H-NMR (CDC1) δ: 6.81 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz), 7.47 (2H, m), 7.
87 (1H， dd， J=2.7, 6.3 Hz); [0217] 実施例 60： 3-(2-カルボキシ)フエニルフタル酸 87 (1H, dd, J = 2.7, 6.3 Hz); Example 60: 3- (2-carboxy) phenylphthalic acid
製造工程 60_(a)  Manufacturing process 60_ (a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 180 mgをトルエン 1.0 mLに溶解し、アルゴン置換した後、 2-(4，4，5，5-テトラメチル 1,3,2-ジォキサボロラン- 2 -ィル)安息香酸ェチル 330 mg、炭酸カリウム 165 mg、テトラキストリフエニルホスフィン パラジウム 140 mgを加え 80°Cでー晚攪拌した。反応液に水を加え、酢酸ェチルで抽 出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣をシリカ ゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3_(2-ェトキ シカルボ二ノレ)フエニルフタル酸ジェチルエステル 24.0 mgを得た。  After dissolving 180 mg of 3-bromophthalic acid jetyl ester obtained in production process 55_ (a) in 1.0 mL of toluene and replacing with argon, 2- (4,4,5,5-tetramethyl 1,3,2 -Dioxaborolane-2-yl) Ethyl benzoate 330 mg, potassium carbonate 165 mg, tetrakistriphenylphosphine palladium 140 mg was added and stirred at 80 ° C. 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 obtained residue was purified using silica gel column chromatography (hexane acetate) to obtain 24.0 mg of 3_ (2-ethoxycarbonyl) phenylphthalic acid jetyl ester.
FABMS:m/z371[M+H]+ ; FABMS: m / z371 [M + H] + ;
製造工程 60_(b)  Manufacturing process 60_ (b)
製造工程 60_(a)で得られた化合物 24.0 mgに 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLを加え 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸 を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥 後減圧濃縮し、表題化合物 11.0 mgを得た。  To the compound (24.0 mg) obtained in production step 60_ (a), 1.0 mL of 1,4-dioxane and 5.0 mL of a 5.0 mol / L aqueous sodium hydroxide solution were added, followed by stirring at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 11.0 mg of the title compound.
FABMS:m/z287[M+H]+； FABMS: m / z 287 [M + H] + ;
[0218] 実施例 61 : 3-(3_カルボキシ)フエニルフタル酸 Example 61: 3- (3_carboxy) phenylphthalic acid
製造工程 61 -(a)  Manufacturing process 61-(a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 180 mgをトルエン 5.0 mLに溶解し、アルゴン置換した後、 3-(4，4，5，5-テトラメチル 1,3,2-ジォキサボロラン- 2 -ィル)安息香酸メチル 310 mg、炭酸カリウム 165 mg、テトラキストリフエニルホスフィン ノ ラジウム 140 mgを加え 80°Cで一晩攪拌した。反応液をセライト濾過した後減圧濃縮 し、得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用 いて精製し、 3-(3_メトキシカルボニル)フエニルフタル酸ジェチルエステル 47.0 mgを 得た。  After dissolving 180 mg of 3-bromophthalic acid jetyl ester obtained in production process 55_ (a) in 5.0 mL of toluene and replacing with argon, 3- (4,4,5,5-tetramethyl 1,3,2 -Dioxaborolane-2-yl) methyl benzoate 310 mg, potassium carbonate 165 mg, tetrakistriphenylphosphine nordium 140 mg was added and stirred at 80 ° C. overnight. The reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 47.0 mg of 3- (3_methoxycarbonyl) phenylphthalic acid jetyl ester. .
EIMS: m/z356[M+]； EIMS: m / z356 [M + ];
製造工程 61 -(b)  Manufacturing process 61-(b)
製造工程 6 l_(a)で得られた化合物 47.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLを加え 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸 を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥 後減圧濃縮し、表題化合物 12.0 mgを得た。 Production process 6 17.0 mg of 1,4-dioxane, 5.0 mol / L water, 47.0 mg of the compound obtained in l_ (a) An aqueous sodium oxide solution (5.0 mL) was added, and the mixture was stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 12.0 mg of the title compound.
ESIMS:m/z287[M+H]+； ESIMS: m / z287 [M + H] + ;
:H-NMR (DMSO-d ) δ :7.55 (4H， m)， 7.94 (3Η， m); : H-NMR (DMSO-d) δ: 7.55 (4H, m), 7.94 (3Η, m);
6  6
[0219] 実施例 62： 3_(4-カルボキシ)フエニルフタル酸  [0219] Example 62: 3_ (4-carboxy) phenylphthalic acid
製造工程 62-(a)  Manufacturing process 62- (a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 180 mgをトルエン 5.0 mLに溶解し、アルゴン置換した後、 4-(4，4，5，5-テトラメチル 1,3,2-ジォキサボロラン- 2 -ィル)安息香酸メチル 310 mg、炭酸カリウム 165 mg、テトラキストリフエニルホスフィン ノ ラジウム 140 mgを加え 80°Cで一晩攪拌した。反応液をセライト濾過した後減圧濃縮 し、得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用 いて精製し、 3_(4-メトキシカルボニル)フエニルフタル酸ジェチルエステル 160 mgを 得た。  After dissolving 180 mg of 3-bromophthalic acid ethyl ester obtained in production process 55_ (a) in 5.0 mL of toluene and replacing with argon, 4- (4,4,5,5-tetramethyl 1,3,2 -Dioxaborolane-2-yl) methyl benzoate 310 mg, potassium carbonate 165 mg, tetrakistriphenylphosphine nordium 140 mg was added and stirred at 80 ° C. overnight. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 160 mg of 3_ (4-methoxycarbonyl) phenylphthalic acid jetyl ester.
EIMS: m/z356[M+]； EIMS: m / z356 [M + ];
製造工程 62-(b)  Manufacturing process 62- (b)
製造工程 62-(a)で得られた化合物 160 mgに 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLを加え 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸 を加え pH2にした後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥 後減圧濃縮し、表題化合物 35.0 mgを得た。  To 160 mg of the compound obtained in production step 62- (a), 1.0 mL of 1,4-dioxane and 5.0 mL of 5.0 mol / L sodium hydroxide aqueous solution were added and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 35.0 mg of the title compound.
ESIMS:m/z287[M+H]+； ESIMS: m / z287 [M + H] + ;
:H-NMR (DMSO-d ) δ :7.50 (2H， d， J=8.2 Hz), 7.59 (2H， m)， 7.92 (1H， dd， J=2.5, 6 : H-NMR (DMSO-d) δ: 7.50 (2H, d, J = 8.2 Hz), 7.59 (2H, m), 7.92 (1H, dd, J = 2.5, 6
6  6
• 6Hz)， 7.98 (2H， d， J=8.2 Hz);  • 6Hz), 7.98 (2H, d, J = 8.2 Hz);
[0220] 実施例 63： 3-[l-(tert-ブトキシカルボニル) -1，2，3，6-テトラヒドロピリジン- 4-ィル]フタ ル酸 [0220] Example 63: 3- [l- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridine-4-yl] phthalic acid
製造工程 63_(a)  Manufacturing process 63_ (a)
製造工程 22-(b)で得られた 3-ァミノフタル酸ジメチルエステル 1.0 gを水 20 mL、 48% 臭化水素酸 10 mLに溶解し、氷浴下亜硝酸ナトリウム 400 mgを水 5.0 mLに溶力、した 溶液を滴下した後室温で 1時間攪拌した。臭化銅 (I) 690 mgを 48%臭化水素酸 4.0 m Lに溶解した溶液を滴下した後 70°Cで一晩攪拌した。反応液に 5.0 mol/L水酸化ナト リウム水溶液を加え中和した後、酢酸ェチルで抽出し、有機層を無水硫酸マグネシゥ ムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（へキ サン 酢酸ェチル）を用いて精製し、 3-ブロモフタル酸ジメチルエステル 910 mgを得 た。 Dissolve 1.0 g of 3-aminophthalic acid dimethyl ester obtained in production step 22- (b) in 20 mL of water and 10 mL of 48% hydrobromic acid, and dissolve 400 mg of sodium nitrite in 5.0 mL of water in an ice bath. Power The solution was added dropwise and stirred at room temperature for 1 hour. A solution of 690 mg of copper (I) bromide dissolved in 4.0 mL of 48% hydrobromic acid was added dropwise, and the mixture was stirred overnight at 70 ° C. The reaction solution was neutralized with a 5.0 mol / L aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane acetate) to obtain 910 mg of 3-bromophthalic acid dimethyl ester.
FABMS:m/z273[M+H]+ FABMS: m / z273 [M + H] +
製造工程 63_(b)  Manufacturing process 63_ (b)
製造工程 63_(a)で得られた化合物 505 mgを DMF 10 mLに溶解し、炭酸カリウム 766 mg、 4-(4，4，5，5-テトラメチル -1,3,2-ジォキサボロラン- 2-ィル) -1-tert-ブトキシカルボ ニル -1,2,3,6-テトラヒドロピリジン 628 mgを加え [1,1， -ビス (ジフエニルホスフイノ)フエ口 セン]パラジウム (II)ジクロリド 150 mgを加え 80°Cで 2時間攪拌した。反応液に水を加え 、ジェチルエーテルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し た。得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用 いて精製し、 3-[l-(tert-ブトキシカルボニル) -1,2,3,6-テトラヒドロピリジン -4-ィル]フ タル酸ジメチルエステル 595 mgを得た。 505 mg of the compound obtained in production process 63_ (a) was dissolved in 10 mL of DMF, and 766 mg of potassium carbonate, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) -1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine 628 mg was added, and [1,1, -bis (diphenylphosphino) phenolic] palladium (II) dichloride 150 mg And stirred at 80 ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with jetyl ether. 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) to give 3- [l- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridine-4-yl] phenyl. 595 mg of dimethyl tartrate was obtained.
EIMS: m/z375 [M+]； EIMS: m / z375 [M + ];
製造工程 63-(c)  Manufacturing process 63- (c)
製造工程 63_(b)で得られた化合物 28.4 mgを 1.0 mol/L水酸化ナトリウム水溶液 2.0 m L中 70°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸を加え、 pH4.5にした後、酢酸ェ チルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、表題化合物 8. 1 mgを得た。 28.4 mg of the compound obtained in production step 63_ (b) was stirred at 70 ° C. in 2.0 mL of 1.0 mol / L aqueous sodium hydroxide solution. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 4.5, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 8.1 mg of the title compound.
ESIMS:m/z346[M-Hl; ESIMS: m / z346 [M-Hl;
実施例 64： 3-[l-(tert-ブトキシカルボ二ルビペリジン) -4-ィル]フタル酸 Example 64 3- [l- (tert-butoxycarbonylbiperidine) -4-yl] phthalic acid
製造工程 64-(a)  Manufacturing process 64- (a)
製造工程 63_(b)で得られた化合物 294 mgを酢酸ェチル 5.9 mLに溶解し、アルゴン 置換後 10%Pd_C 29.4 mgを加え水素置換し、室温で一晩攪拌した。反応液をセライト 濾過し、 3-[l-(tert-ブトキシカルボ二ルビペリジン) -4-ィル]フタル酸ジメチルエステ ル 295 mgを得た。 294 mg of the compound obtained in production step 63_ (b) was dissolved in 5.9 mL of ethyl acetate, and after replacement with argon, 29.4 mg of 10% Pd_C was added, followed by replacement with hydrogen and stirring overnight at room temperature. The reaction mixture was filtered through celite, and dimethyl ester of 3- [l- (tert-butoxycarbonylbiperidine) -4-yl] phthalate was obtained. Obtained 295 mg of le.
ESIMS:m/z400[M+Na]+ ESIMS: m / z400 [M + Na] +
製造工程 64-(b)  Manufacturing process 64- (b)
製造工程 64-(a)で得られた化合物 20.7 mgを 1.0 mol/L水酸化ナトリウム水溶液 2.0 mL中 70°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸を加え pH4.5にした後、酢酸ェ チルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、表題化合物 19 .2 mgを得た。  20.7 mg of the compound obtained in production step 64- (a) was stirred at 70 ° C. in 2.0 mL of 1.0 mol / L aqueous sodium hydroxide solution. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 4.5, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 19.2 mg of the title compound.
FABMS:m/z350[M+H]+ FABMS: m / z 350 [M + H] +
[0222] 実施例 65： 3-(1_ァセチルビペリジン- 4-ィル)フタル酸 Example 65: 3- (1_Acetylbiperidine-4-yl) phthalic acid
製造工程 65_(a)  Manufacturing process 65_ (a)
製造工程 64-(a)で得られた化合物 92.5 mgをジクロロメタン 2.0 mLに溶解し、トリフ ノレォロ酢酸 0.5mLを加え、室温で 30分攪拌した。反応液を減圧濃縮した後、残渣に ピリジン 2.0 mL、無水酢酸 0.5 mLを加え室温で 4時間攪拌した。反応液に水を加え酢 酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られ た残渣をシリカゲルカラムクロマトグラフィー（酢酸ェチルーメタノール）を用いて精製 し、 3-(1_ァセチルビペリジン- 4-ィル)フタル酸ジメチルエステル 64.3 mgを得た。 ESIMS:m/z320[M+H]+ 92.5 mg of the compound obtained in production step 64- (a) was dissolved in 2.0 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, 2.0 mL of pyridine and 0.5 mL of acetic anhydride were added to the residue, followed by stirring at room temperature for 4 hours. 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 obtained residue was purified using silica gel column chromatography (ethyl acetate-methanol) to obtain 64.3 mg of 3- (1_acetylbiperidin-4-yl) phthalic acid dimethyl ester. ESIMS: m / z320 [M + H] +
製造工程 65_(b)  Manufacturing process 65_ (b)
製造工程 65_(a)で得られた化合物 39.0 mgを水 1.0 mL、 5.0 mol/L水酸化ナトリウム 水溶液 1.0 mL中ー晚攪拌した。反応液に 1.0 mol/L塩酸を加え pH9とした後、無水酢 酸 1.0 mLを加え、室温でー晚攪拌した。反応液に 5.0 mol/Lを加え pH2.5とした後、 酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、表題化 合物 20.0 mgを得た。  In the production process 65_ (a), 39.0 mg of the compound was stirred in 1.0 mL of water and 1.0 mL of a 5.0 mol / L aqueous sodium hydroxide solution. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 9, and then 1.0 mL of acetic anhydride was added and stirred at room temperature. 5.0 mol / L was added to the reaction solution to adjust the pH to 2.5, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 20.0 mg of the title compound.
ESIMS:m/z292[M+H]+ ESIMS: m / z292 [M + H] +
:H-NMR (DMSO-d ) δ : 1.49 (1Η， m)， 1.70 (2Η， m)， 2.02 (3Η， s)， 2.84 (1Η， m)， 3.04 : H-NMR (DMSO-d) δ: 1.49 (1Η, m), 1.70 (2Η, m), 2.02 (3Η, s), 2.84 (1Η, m), 3.04
6  6
(1Η， m)， 3.32 (2Η， m)， 3.92 (1Η， m)， 4.53 (1Η， m)， 7.47 (1Η， dd， J=7.7, 7.7 Hz), 7.62 (1H， d， J=7.7 Hz), 7.76 (1H， d， J=7.7 Hz);  (1Η, m), 3.32 (2Η, m), 3.92 (1Η, m), 4.53 (1Η, m), 7.47 (1Η, dd, J = 7.7, 7.7 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 7.7 Hz);
[0223] 実施例 66： 3-(l-ベンジルピペリジン- 4-ィル)フタル酸 製造工程 66_(a) Example 66: 3- (l-Benzylpiperidine-4-yl) phthalic acid Manufacturing process 66_ (a)
製造工程 64-(a)で得られた化合物 100 mgをジクロロメタン 2.0 mLに溶解し、トリフル ォロ酢酸 0.5 mLを加え 0°Cで 20分間攪拌した。反応液に 1.0 mol/L水酸化ナトリウム 水溶液を加え PH7.0にした後、クロ口ホルムで抽出し、有機層を無水硫酸マグネシゥ ムで乾燥後減圧濃縮した。得られた残渣を THF2.0 mLに溶解し、ベンズアルデヒド 42 H L、酢酸 35 L、トリァセトキシ水素化ホウ素ナトリウム 118 mgを加え室温でー晚攪 拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸ェチルで抽出し、有機 層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られ た残渣をプレパラティブ TLC (酢酸ェチル一メタノール）を用いて精製し、 3-(1_ベンジ ルビペリジン- 4-ィル)フタル酸ジメチルエステル 75.0 mgを得た。  100 mg of the compound obtained in production step 64- (a) was dissolved in 2.0 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 20 minutes. To the reaction solution was added 1.0 mol / L aqueous sodium hydroxide solution to pH 7.0, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 2.0 mL of THF, benzaldehyde 42 H L, acetic acid 35 L, and sodium triacetoxyborohydride 118 mg were added, and the mixture was stirred at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified using preparative TLC (ethyl acetate monomethanol) to obtain 75.0 mg of 3- (1_benzylbiperidine-4-yl) phthalic acid dimethyl ester.
ESIMS:m/z367[M+H]+ ESIMS: m / z367 [M + H] +
製造工程 66_(b)  Manufacturing process 66_ (b)
製造工程 66_(a)で得られた化合物 73.0 mgを水 1.0 mL、 5.0 mol/L水酸化ナトリウム 水溶液 1.0 mL、エタノール 0.5 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol /L塩酸を加え pH2とした後、酢酸ェチルで洗浄し、水槽を減圧濃縮した。得られた残 渣をプレパラティブ TLC (水—ァセトニトリル)を用いて精製し、表題化合物 10.0 mgを 得た。 73.0 mg of the compound obtained in production step 66_ (a) was dissolved in 1.0 mL of water, 1.0 mL of 5.0 mol / L aqueous sodium hydroxide solution and 0.5 mL of ethanol, and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by washing with ethyl acetate, and the water tank was concentrated under reduced pressure. The resulting residue was purified using preparative TLC (water-acetonitrile) to obtain 10.0 mg of the title compound.
'H-NMR (D O) δ : 1.80 (2Η， m)， 1.90 (2Η， m)， 2.85 (1Η， m)， 3.02 (2Η， m)， 3.45 (2Η， m)， 4.19 (2Η， s)， 7.22 (1Η， dd， J=7.5, 7.5 Hz), 7.28 (1H， d， J=7.5 Hz), 7.39 (5H， m) ， 7.50 (1H， d， J=7.5 Hz);  'H-NMR (DO) δ: 1.80 (2Η, m), 1.90 (2Η, m), 2.85 (1Η, m), 3.02 (2Η, m), 3.45 (2Η, m), 4.19 (2Η, s) 7.22 (1 (, dd, J = 7.5, 7.5 Hz), 7.28 (1H, d, J = 7.5 Hz), 7.39 (5H, m), 7.50 (1H, d, J = 7.5 Hz);
実施例 67： 3- (1-力ルバモイルビペリジン- 4-ィル)フタル酸 Example 67: 3- (1-force rubermoyl biperidine-4-yl) phthalic acid
製造工程 67_(a)  Manufacturing process 67_ (a)
製造工程 55_(a)で得られた 3-ブロモフタル酸ジェチルエステル 1.0 gを 1,4-ジォキ サン 2.0 mL、 5.0 mol/L水酸化ナトリウム水溶液 4.0 mLを加え 80°Cでー晚攪拌した。 反応液に 1.0 mol/L塩酸を加え pH3とした後に酢酸ェチルで抽出し、無水硫酸マグネ シゥムで乾燥後減圧濃縮し、 3-プロモフタル酸 650 mgを得た。  To 1.0 g of 3-bromophthalic acid jetyl ester obtained in production step 55_ (a), 2.0 mL of 1,4-dioxane and 4.0 mL of 5.0 mol / L aqueous sodium hydroxide solution were added and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 3, followed by extraction with ethyl acetate, drying over anhydrous magnesium sulfate and concentration under reduced pressure to obtain 650 mg of 3-promophthalic acid.
ESIMS:m/z243, 245[M_H]—； ESIMS: m / z243, 245 [M_H] —;
製造工程 67_(b) 製造工程 67_(a)で得られた化合物 834 mgを DMF 16 mLに溶解し、炭酸カリウム 1.38 g、ベンジルブロマイド 0.87 mLを加え室温でー晚攪拌した。反応液に水を加え、酢酸 ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた 残渣をシリカゲルカラム（へキサン 酢酸ェチル）を用いて精製し、 3-ブロモフタル酸 ジベンジルエステル 210 mgを得た。 Manufacturing process 67_ (b) 834 mg of the compound obtained in production step 67_ (a) was dissolved in 16 mL of DMF, 1.38 g of potassium carbonate and 0.87 mL of benzyl bromide were added, and the mixture was 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 a silica gel column (hexane ethyl acetate) to obtain 210 mg of 3-bromophthalic acid dibenzyl ester.
製造工程 67-(c)  Manufacturing process 67- (c)
製造工程 63_(b)と同様の方法で 3-ブロモフタル酸ジメチルエステルの代わりに製造 工程 67_(b)で得られた化合物 230 mgを用いて 3-[l-(tert-ブトキシカルボニル) -1,2,3 ，6-テトラヒドロピリジン -4-ィル]フタル酸ジベンジルエステル 178 mgを得た。 In the same manner as in Production Process 63_ (b), instead of 3-bromophthalic acid dimethyl ester, using 230 mg of the compound obtained in Production Process 67_ (b), 3- [l- (tert-butoxycarbonyl) -1, 2,3,6-Tetrahydropyridine-4-yl] phthalic acid dibenzyl ester (178 mg) was obtained.
ESIMS:m/z528[M+H]+ ESIMS: m / z528 [M + H] +
製造工程 67_(d)  Manufacturing process 67_ (d)
製造工程 67_(c)で得られた化合物 95.9 mgをジクロロメタン 2.0 mLに溶解し、トリフ ノレォロ酢酸 0.5 mLを加え 0°Cで 20分間攪拌した。反応液に 1.0 mol/L水酸化ナトリウ ム水溶液を加え PH8.0にした後、ジクロロメタンで抽出し、有機層を無水硫酸マグネシ ゥムで乾燥後減圧濃縮した。得られた残渣をジクロロメタン 2.0 mLに溶解し、酢酸 0.1 0 mL、ピリジン 0.15 mL、トリェチルァミン 0.050 mL、シアン酸カリウム 29.5 mgを加え室 温で一晩攪拌した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マ グネシゥムで乾燥後減圧濃縮した。得られた残渣をプレパラティブ TLC (へキサン 酢酸ェチル）を用いて精製し、 3-ひ-力ルバモイル- ^2,3,6-テトラヒドロピリジン- 4-ィ ノレ)フタル酸ジベンジルエステル 66.7 mgを得た。 95.9 mg of the compound obtained in the production step 67_ (c) was dissolved in 2.0 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C. for 20 minutes. A 1.0 mol / L aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 8.0, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (2.0 mL), acetic acid (0.10 mL), pyridine (0.15 mL), triethylamine (0.050 mL), and potassium cyanate (29.5 mg) were added, and the mixture was stirred overnight 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 preparative TLC (hexane acetate Echiru to), 3 - Fei - 4 I Honoré) phthalate dibenzyl ester 66.7 mg - Power Rubamoiru - ^ 2,3,6-tetrahydropyridine Obtained.
ESIMS:m/z471[M+H]+ ESIMS: m / z471 [M + H] +
製造工程 67_(e)  Manufacturing process 67_ (e)
製造工程 67_(d)で得られた化合物 65.3 mgをメタノール 1.3 mLに溶解し、アルゴン置 換した後、 10%Pd_C 6.5 mgを加え水素気流下室温でー晚攪拌した。反応液をセラ イト濾過した後、減圧濃縮し、表題化合物 39.0 mgを得た。 After dissolving 65.3 mg of the compound obtained in production step 67_ (d) in 1.3 mL of methanol and replacing with argon, 6.5 mg of 10% Pd_C was added and stirred at room temperature under a hydrogen stream. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 39.0 mg of the title compound.
ESIMS:m/z293[M+H]+ ESIMS: m / z293 [M + H] +
実施例 68： 3-フルォ口- 6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸 Example 68: 3-Fluoromouth-6_ (4-hydroxypiperidine-1-yl) phthalic acid
製造工程 68_(a) 3,6-ジフルオロフタル酸無水物 500 mgをエタノール 20 mLに溶解し、濃硫酸 2.0 mL を加えー晚加熱還流した。反応液に水を加え、酢酸ェチルで抽出し、有機層を無水 硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣を DMF10 mLに溶解し、炭 酸カリウム 1.1 g、ヨウ化工チル 0.33 mLを加え、室温で二日間攪拌した。反応液に水 を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し 、 3,6-ジフルオロフタル酸ジェチルエステル 460 mgを得た。 Manufacturing process 68_ (a) 500 mg of 3,6-difluorophthalic anhydride was dissolved in 20 mL of ethanol, 2.0 mL of concentrated sulfuric acid was added, and the mixture was heated to reflux. 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 obtained residue was dissolved in 10 mL of DMF, and 1.1 g of potassium carbonate and 0.33 mL of iodide chilled were added, and the mixture was stirred at room temperature for 2 days. 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 to obtain 460 mg of 3,6-difluorophthalic acid jetyl ester.
ESIMS:m/z259[M+H]+； ESIMS: m / z259 [M + H] + ;
製造工程 68_(b)  Manufacturing process 68_ (b)
製造工程 68_(a)で得られた化合物 100 mgを DMSO 1.0 mLに溶解し、 4-ヒドロキシピ ペリジン 980 mgを加え 80°Cでー晚攪拌した。反応液をシリカゲルカラムクロマトグラフ ィー（へキサン 酢酸ェチル）を用いて精製し、 3-フルォ口- 6_(4-ヒドロキシピペリジン -1-ィノレ)フタル酸ジェチルエステル 86.0 mgと 3,6-ビス (4-ヒドロキシピペリジン-；!-ィル )フタル酸ジェチルエステル 33.0 mgを得た。 100 mg of the compound obtained in production step 68_ (a) was dissolved in 1.0 mL of DMSO, 980 mg of 4-hydroxypiperidine was added, and the mixture was stirred at 80 ° C. The reaction solution was purified using silica gel column chromatography (hexane ethyl acetate). 3-Fluoro-6- (4-hydroxypiperidine-1-inole) phthalic acid jetyl ester 86.0 mg and 3,6-bis (4-Hydroxypiperidine-;!-Yl) 33.0 mg of phthalic acid jetyl ester was obtained.
ESIMS:m/z340[M+H]+： 3_フルォ口- 6_(4_ヒドロキシピペリジン- 1-ィノレ)フタル酸ジェ チルエステル； ESIMS: m / z 340 [M + H] + : 3_Fluo mouth-6_ (4_Hydroxypiperidine-1-inole) phthalic acid ethyl ester;
ESIMS:m/z421[M+H]+： 3，6_ビス (4-ヒドロキシピペリジン-；! _イノレ)フタル酸ジェチルェ ステル ESIMS: m / z421 [M + H] + : 3,6_bis (4-hydroxypiperidine- ;! _inole) Jetyl ester phthalate
製造工程 68-(c) Manufacturing process 68- (c)
製造工程 68_(b)で得られた 3-フルォ口- 6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸 ジェチルエステル 56.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸化ナトリウム水溶 液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸を加え pH2にし た後、減圧濃縮し、得られた残渣を樹脂 SP_207 (水ーァセトニトリル)を用いて精製し 、表題化合物 52.0 mgを得た。  3-Fluoro-6_ (4-hydroxypiperidine-1-yl) phthalic acid jetyl ester 56.0 mg obtained in production process 68_ (b) 1.0 mL of 1,4-dioxane, 5.0 mol / L sodium hydroxide This was dissolved in 5.0 mL of an aqueous solution and stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust pH to 2, followed by concentration under reduced pressure. The resulting residue was purified using resin SP_207 (water-acetonitrile) to obtain 52.0 mg of the title compound.
ESIMS:m/z282[M-Hl; ESIMS: m / z282 [M-Hl;
:H-NMR (D Ο) δ : 1.85 (2H， m)， 2.12 (2H， m)， 3.41 (2H， m)， 3.61 (2H， m)， 4.12 (1H， m)， 7.42 (1H， dd， J=8.3, 8.7 Hz), 7.71 (1H， dd， J=4.3, 8.7 Hz); : H-NMR (D Ο) δ: 1.85 (2H, m), 2.12 (2H, m), 3.41 (2H, m), 3.61 (2H, m), 4.12 (1H, m), 7.42 (1H, dd , J = 8.3, 8.7 Hz), 7.71 (1H, dd, J = 4.3, 8.7 Hz);
実施例 69： 3,6-ビス (4-ヒドロキシピペリジン- 1-ィル)フタル酸 Example 69: 3,6-bis (4-hydroxypiperidine-1-yl) phthalic acid
製造工程 69_(a) 製造工程 68_(b)で得られた 3,6-ビス (4-ヒドロキシピペリジン-卜ィル)フタル酸ジェ チルエステル 100 mgを 1,4-ジォキサン 2.0 mL、 5.0 mol/L水酸化ナトリウム水溶液 10 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸を加え pH2にした後、 減圧濃縮し、得られた残渣を樹脂 SP_207 (水ーァセトニトリル)を用いて精製し、表題 化合物 61.0 mgを得た。 Manufacturing process 69_ (a) 1,6-dioxane 2.0 mL, 5.0 mol / L aqueous sodium hydroxide solution 10 mL, 3,6-bis (4-hydroxypiperidine-zyl) phthalic acid ethyl ester 100 mg obtained in production process 68_ (b) And stirred at 80 ° C. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust pH to 2, followed by concentration under reduced pressure. The resulting residue was purified using resin SP_207 (water-acetonitrile) to obtain 61.0 mg of the title compound.
FABMS:m/z365[M+H]+ FABMS: m / z365 [M + H] +
'H-NMR (D O) δ : 1.72 (4H， m)， 2.00 (4H， m)， 3.12 (4H， m)， 3.33 (4H， m)， 3.90 (2H， m)， 7.61 (2H， brs);  'H-NMR (DO) δ: 1.72 (4H, m), 2.00 (4H, m), 3.12 (4H, m), 3.33 (4H, m), 3.90 (2H, m), 7.61 (2H, brs) ;
実施例 70： 3- (4-ヒドロキシピペリジン- 1-ィル) -6-メチルフタル酸 Example 70: 3- (4-hydroxypiperidine-1-yl) -6-methylphthalic acid
製造工程 70_(a)  Manufacturing process 70_ (a)
製造工程 18_(b)で得られた 3-ァミノフタル酸ジェチルエステル 250 mgを DMF5.0 m Lに溶解し N-ブロモコハク酸イミド 224 mgを力□え 50°Cでー晚攪拌した。反応液に水を 加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した 。得られた残渣をプレパラティブ TLC (へキサン—酢酸ェチル)を用いて精製し、 3-ァ ミノ- 6-ブロモフタル酸ジェチルエステル 216 mgと 3-ァミノ- 4,6-ジブロモフタル酸ジェ チルエステル 85mgを得た。  250 mg of 3-aminophthalic acid jetyl ester obtained in the production step 18_ (b) was dissolved in 5.0 mL of DMF, and 224 mg of N-bromosuccinimide was added and stirred at 50 ° C. 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 preparative TLC (hexane-ethyl acetate) to give 216 mg of 3-amino-6-bromophthalic acid ethyl ester and 85 mg of 3-amino-4,6-dibromophthalic acid ethyl ester. Got.
EIMS: m/z356[M+]： 3_ァミノ- 6_ブロモフタル酸ジェチルエステル； EIMS: m / z356 [M + ]: 3_amino-6_bromophthalic acid jetyl ester;
EIMS: m/z395[M+]： 3_ァミノ- 4，6_ジブロモフタル酸ジェチルエステル； EIMS: m / z 395 [M + ]: 3_amino-4,6_dibromophthalic acid jetyl ester;
製造工程 70_(b)  Manufacturing process 70_ (b)
製造工程 70_(a)で得られた 3-ァミノ- 6-ブロモフタル酸ジェチルエステル 280 mgを D MF4.0 mLに溶解し、炭酸カリウム 360 mg、テトラキストリフエニルホスフィンパラジウム 520 mg、トリメチルポロキシン 111 mgを加え 80°Cでー晚攪拌した。反応液をセライト濾 過した後、シリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製 し、 3-ァミノ- 6-メチルフタル酸ジェチルエステル 97.0 mgを得た。 Production Process 70_ (a) 3-amino-6-bromophthalic acid jetyl ester 280 mg was dissolved in D MF4.0 mL, potassium carbonate 360 mg, tetrakistriphenylphosphine palladium 520 mg, trimethylpoloxin 111 mg was added and stirred at 80 ° C. The reaction solution was filtered through Celite, and then purified using silica gel column chromatography (hexane ethyl acetate) to obtain 97.0 mg of 3-amino-6-methylphthalic acid jetyl ester.
EIMS: m/z251 [M+]； EIMS: m / z251 [M + ];
製造工程 70-(c) Manufacturing process 70- (c)
製造工程 70_(b)で得られた化合物 470 mgをエタノール 2.0 mLに溶解し、 1，5_ジクロ 口ペンタン- 3-オン 89.0 mgを加え、 60°Cで 4時間攪拌した。反応液に水を加え、酢酸 ェチルで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄後、有機層を無水硫酸マグ ネシゥムで乾燥し、減圧濃縮した。得られた残渣を 1,4-ジォキサン 7.0 mLに溶解し、 5 .0 mol/L塩酸 5.0mLを加え室温で二日間攪拌した。反応液に水を加え、酢酸ェチル で抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣を プレパラティブ TLC (へキサン—酢酸ェチル）を用いて精製し、 3-メチル -6- (4-ォキ ソピペリジン- 1-ィル）フタル酸ジェチルエステル 37.0 mgを得た。 470 mg of the compound obtained in production step 70_ (b) was dissolved in 2.0 mL of ethanol, 1,5-dichloropentan-3-one 89.0 mg was added, and the mixture was stirred at 60 ° C for 4 hr. Add water to the reaction mixture and add acetic acid. After extraction with ethyl acetate and washing with saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 7.0 mL of 1,4-dioxane, 5.0 mL of 5.0 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 2 days. 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 obtained residue was purified using preparative TLC (hexane-ethyl acetate) to obtain 37.0 mg of 3-methyl-6- (4-oxopiperidine-1-yl) phthalic acid jetyl ester.
EIMS: m/z333 [M+]； EIMS: m / z333 [M + ];
製造工程 70_(d)  Manufacturing process 70_ (d)
製造工程 70_(c)で得られた化合物 58.0 mgをエタノール 5.0 mLに溶解し、水素化ホ ゥ素ナトリウム 8.0 mgを加え、室温で 2時間攪拌した。反応液を減圧濃縮した後、残渣 に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃 縮し、 3- (4-ヒドロキシピペリジン- 1-ィル) -6-メチルフタル酸ジェチルエステル 47.0 m gを得た。  58.0 mg of the compound obtained in production step 70_ (c) was dissolved in 5.0 mL of ethanol, 8.0 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- (4-hydroxypiperidine-1-yl) -6- 47.0 mg of methylphthalic acid jetyl ester was obtained.
FABMS:m/z336[M+H]+ FABMS: m / z336 [M + H] +
製造工程 70_(e)  Manufacturing process 70_ (e)
製造工程 70_(d)で得られた化合物 45.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水 酸化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで 3.5時間攪拌した。反応液に 1.0 mol/ L塩酸を加え pH2にした後、減圧濃縮し、得られた残渣を樹脂 SP_207 (水ーァセトニト リル)を用いて精製し、表題化合物 6.0 mgを得た。  45.0 mg of the compound obtained in production step 70_ (d) 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. for 3.5 hours. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by concentration under reduced pressure. The resulting residue was purified using resin SP_207 (water-acetononitrile) to obtain 6.0 mg of the title compound.
FABMS:m/z280[M+H]+ FABMS: m / z280 [M + H] +
実施例 71： 3_(4-アミノビペリジン- 1-ィル) -6_(4-ヒドロキシピペリジン- 1-ィル)フタル 酸 Example 71: 3_ (4-aminobiperidine-1-yl) -6_ (4-hydroxypiperidine-1-yl) phthalic acid
製造工程 71 -(a)  Manufacturing process 71-(a)
製造工程 68_(b)で得られた 3-フルォ口- 6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸 ジェチルエステル 200 mgをピリジン 5.0 mL、無水酢酸 0.28 mL中室温でー晚攪拌し た。反応液に水を加え、酢酸ェチルで抽出し、 10%硫酸水素カリウム水溶液で洗浄後 有機層を無水硫酸マグネシウムで乾燥し減圧濃縮した。得られた残渣をシリカゲル力 ラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精製し、 3_(4-ァセトキシピぺ リジン- 1-ィル) -6-フルオロフタル酸ジェチルエステル 202 mgを得た。 3-Fluoro-6-6 (4-hydroxypiperidin-1-yl) phthalic acid jetyl ester 200 mg obtained in production process 68_ (b) was stirred in 5.0 mL of pyridine and 0.28 mL of acetic anhydride at room temperature. It was. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 10% aqueous potassium hydrogen sulfate solution, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (hexane ethyl acetate) to give 3_ (4-acetoxypipe 202 mg of lysine-1-yl) -6-fluorophthalic acid jetyl ester was obtained.
ESIMS:m/z382[M+H]+ ESIMS: m / z382 [M + H] +
製造工程 71_(b)  Manufacturing process 71_ (b)
製造工程 7；! -(a)で得られた化合物 200 mgを DMSO 5.0 mLに溶解し、 4-ヒドロキシ ピぺリジン 100 mgを加え 80°Cで 3日間攪拌した。反応液に水を加え、酢酸ェチルで抽 出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカゲ ルカラムクロマトグラフィー（へキサン 酢酸ェチル）を用いて精製し、 3_(4-ァセトキシ ピぺリジン- 1-ィル) -6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸ジェチルエステル 230 mgを得た。  Production process 7;!-200 mg of the compound obtained in-(a) was dissolved in 5.0 mL of DMSO, 100 mg of 4-hydroxypiperidine was added, and the mixture was stirred at 80 ° C for 3 days. Water was added to the reaction solution, 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), and 3_ ( 4-acetoxy piperidine-1-yl) -6_ (4-hydroxypiperidine-1-yl) phthalic acid ethyl ester 230 mg was obtained.
EIMS: m/z462 [M+]； EIMS: m / z462 [M + ];
製造工程 71-(c)  Manufacturing process 71- (c)
製造工程 7；! -(b)で得られた化合物 85.0 mgをジクロロメタン 5.0 mLに溶解し、トリェチ ルァミン 0.10 mL、メタンスルホユルクロリド 0.034 mLを加え室温で 4時間攪拌した。反 応液に水を加え、酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減 圧濃縮した。得られた残渣を DMF 5.0 mLに溶解し、アジ化ナトリウム 20.0 mgを加え 8 0°Cで一晩攪拌した。反応液に水を加え酢酸ェチルで抽出し、有機層を無水硫酸マ グネシゥムで乾燥後減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ へキサン 酢酸ェチル）を用いて精製し、 3_(4-ァセトキシピペリジン- 1-ィル) -6_(4- アジドピペリジン- 1-ィル)フタル酸ジェチルエステル 61.0 mgを得た。 Production process 7;! 85.0 mg of the compound obtained in-(b) was dissolved in 5.0 mL of dichloromethane, 0.10 mL of triethylamine and 0.034 mL of methanesulfuryl chloride were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 5.0 mL of DMF, 20.0 mg of sodium azide was added, and the mixture was stirred at 80 ° C. overnight. 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). -Acetoxypiperidine-1-yl) -6_ (4-azidopiperidine-1-yl) phthalic acid jetyl ester 61.0 mg was obtained.
ESIMS:m/z488[M+H]+ ESIMS: m / z488 [M + H] +
製造工程 71 -(d) Manufacturing process 71-(d)
製造工程 71 -(c)で得られた化合物 60.0 mgをエタノール 5.0 mL、水 1.0 mLに溶解し、 アルゴン置換した後、 10%Pd_C 12.0 mgを加え水素置換後室温で一晩攪拌した。反 応液をセライト濾過した後減圧濃縮し、 3_(4-ァセトキシピペリジン- 1-ィル) -6_(4-アミ ノビペリジン- 1-ィル)フタル酸ジェチルエステル 61.0 mgを得た。 60.0 mg of the compound obtained in production step 71- (c) was dissolved in 5.0 mL of ethanol and 1.0 mL of water, purged with argon, 10% Pd_C 12.0 mg was added, and the mixture was purged with hydrogen and stirred overnight at room temperature. The reaction solution was filtered through celite and concentrated under reduced pressure to obtain 6_1.0 mg of 3_ (4-acetoxypiperidine-1-yl) -6_ (4-aminobiperidine-1-yl) phthalic acid jetyl ester.
EIMS: m/z461 [M+]； EIMS: m / z461 [M + ];
製造工程 71 -(e) Manufacturing process 71-(e)
製造工程 7；! -(d)で得られた化合物 57.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cでー晚攪拌した。反応液に 1.0 mol/L塩酸 を加え pH2にした後減圧濃縮し、得られた残渣を水に溶解し、マイクロァシライザ一を 用いて脱塩操作を行!/、表題化合物 20.3 mgを得た。 Production process 7;! 57.0 mg of the compound obtained in-(d) was replaced with 1.0 mL of 1,4-dioxane, 5.0 mol / L hydroxy acid This was dissolved in 5.0 mL of an aqueous sodium chloride solution and stirred at 80 ° C. Add 1.0 mol / L hydrochloric acid to the reaction solution to adjust the pH to 2, then concentrate under reduced pressure. Dissolve the resulting residue in water and perform desalting using a micro-assistant! / To obtain 20.3 mg of the title compound. It was.
FABMS:m/z364[M+H]+ FABMS: m / z364 [M + H] +
:H-NMR (D Ο) δ : 1.65 (2H， m)， 1.84 (2H， m)， 1.98 (2H， m)， 2.13 (2H， m)， 2.81 (2H， m)， 3.08 (2H， m)， 3.23 (1H， m)， 3.37 (2H， m)， 3.52 (2H， m)， 4.02 (1H， m)， 7.56 (1H， d， J=8.8 Hz), 7.68 (1H， d， J=8.8 Hz); : H-NMR (D Ο) δ: 1.65 (2H, m), 1.84 (2H, m), 1.98 (2H, m), 2.13 (2H, m), 2.81 (2H, m), 3.08 (2H, m ), 3.23 (1H, m), 3.37 (2H, m), 3.52 (2H, m), 4.02 (1H, m), 7.56 (1H, d, J = 8.8 Hz), 7.68 (1H, d, J = 8.8 Hz);
[0229] 実施例 72： 3- (ジメチルァミノ) -6-(4-ヒドロキシピペリジン- 1-ィル)フタル酸 Example 72: 3- (dimethylamino) -6- (4-hydroxypiperidine-1-yl) phthalic acid
製造工程 72-(a)  Manufacturing process 72- (a)
製造工程 68_(b)で得られた 3-フルォ口- 6_(4-ヒドロキシピペリジン- 1-ィル)フタル酸 ジェチルエステル 160 mgをジメチルァミン 2.0MTHF溶液に溶解し、封管中 80°Cで二 日間攪拌した。反応液を減圧濃縮し、得られた残渣をプレパラティブ TLC (へキサン 酢酸ェチル）を用いて精製し、 3- (ジメチルァミノ )-6-(4-ヒドロキシピペリジン-丄 -ィ ノレ)フタル酸ジェチルエステル 100 mgを得た。 Production process 68_ (b) 3-Fluoro-6- (4-hydroxypiperidin-1-yl) phthalic acid jetyl ester (160 mg) was dissolved in dimethylamine 2.0MTHF solution, and the tube was sealed at 80 ° C. Stir for two days. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified using (hexane acetate Echiru to) preparative TLC, 3 - (Jimechiruamino) - 6 - (4 - hydroxypiperidine -丄- I Honoré) Jechiru phthalate 100 mg of ester was obtained.
EIMS: m/z364 [M+]； EIMS: m / z364 [M + ];
製造工程 72-(b)  Manufacturing process 72- (b)
製造工程 72-(a)で得られた化合物 100 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで二日間攪拌した。反応液に 1.0 mol/L塩 酸を加え pH2にした後減圧濃縮し、得られた残渣を樹脂 SP-207 (水ーァセトニトリル） を用いて精製し、表題化合物 60.0 mgを得た。  100 mg of the compound obtained in production step 72- (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. for 2 days. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by concentration under reduced pressure. The resulting residue was purified using resin SP-207 (water-acetonitrile) to obtain 60.0 mg of the title compound.
FABMS:m/z309[M+H]+； FABMS: m / z309 [M + H] + ;
:H-NMR (D 0) δ : 1.77 (2H， m)， 2.06 (2H， m)， 3.08 (6H， s)， 3.21 (2H， m)， 3.41 (2H， m)， 3.94 (1H， m)， 7.72 (1H， d， J=9.0 Hz), 7.82 (1H， d， J=9.0 Hz); : H-NMR (D 0) δ: 1.77 (2H, m), 2.06 (2H, m), 3.08 (6H, s), 3.21 (2H, m), 3.41 (2H, m), 3.94 (1H, m ), 7.72 (1H, d, J = 9.0 Hz), 7.82 (1H, d, J = 9.0 Hz);
[0230] 実施例 73 : 3,6-ジメチルフタル酸 Example 73: 3,6-dimethylphthalic acid
4,7-ジメチル -2-ベンゾフラン- 1,3-ジオン 50.0 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol /L水酸化ナトリウム水溶液 1.0 mLに溶解し、室温で一晩攪拌した。反応液に 1.0 mol /L塩酸を加え pH2にした後酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで 乾燥後減圧濃縮し、表題化合物 37.0 mgを得た。 ESIMS:m/zl93[M-Hl; 4,7-dimethyl-2-benzofuran-1,3-dione (50.0 mg) was dissolved in 1,4-dioxane (1.0 mL) and 5.0 mol / L aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred overnight at room temperature. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 37.0 mg of the title compound. ESIMS: m / zl93 [M-Hl;
実施例 74： 3- (ジメチルァミノ) -6-メチルフタル酸 Example 74: 3- (dimethylamino) -6-methylphthalic acid
製造工程 74-(a)  Manufacturing process 74- (a)
製造工程 25_(b)で得られた 3-ジメチルァミノフタル酸ジェチルエステル 530 mgを D MF10 mLに溶解し、 N-ブロモコハク酸イミド 427 mgを加え 50°Cでー晚攪拌した。反応 液に水を加え酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後減圧 濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を 用いて精製し、 3-ブロモ -6- (ジメチルァミノ)フタル酸ジェチルエステル 404 mgを得た 530 mg of 3-dimethylaminophthalic acid jetyl ester obtained in production step 25_ (b) was dissolved in 10 mL of DMF, 427 mg of N-bromosuccinimide was added, and the mixture was stirred at 50 ° C. 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) to give 3-bromo-6 -404 mg of (dimethylamino) phthalic acid jetyl ester was obtained
〇 Yes
EIMS: m/z343 [M+]； EIMS: m / z343 [M + ];
製造工程 74-(b)  Manufacturing process 74- (b)
製造工程 74-(a)で得られた化合物 244 mgを DMF:水 = 10： 1の混合溶液 3.0 mLに溶 解し、炭酸カリウム 290 mg、テトラキストリフエニルホスフィンパラジウム 200 mg、トリメチ ノレポロキシン 100 mgを加え 80°Cでー晚攪拌した。反応液に水を加え酢酸ェチルで抽 出し、有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣をシリカ ゲルカラムクロマトグラフィー（へキサン 酢酸ェチル)を用いて精製し、 3- (ジメチル ァミノ) - 6-メチルフタル酸ジェチルエステル 100 mgを得た。 Dissolve 244 mg of the compound obtained in production process 74- (a) in 3.0 mL of a mixed solution of DMF: water = 10: 1, and add 290 mg of potassium carbonate, 200 mg of tetrakistriphenylphosphine palladium, and 100 mg of trimethinorepoloxin. The mixture was stirred at 80 ° C. 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 obtained residue was purified using silica gel column chromatography (hexane ethyl acetate) to obtain 100 mg of 3- (dimethylamino) -6-methylphthalic acid jetyl ester.
ESIMS:m/z280[M+H]+； ESIMS: m / z280 [M + H] + ;
製造工程 74-(c)  Manufacturing process 74- (c)
製造工程 74-(b)で得られた化合物 100 mgを 1,4-ジォキサン 1.0 mL、 5.0 mol/L水酸 化ナトリウム水溶液 5.0 mLに溶解し、 80°Cで 7時間攪拌した。反応液に 1.0 mol/L塩 酸を加え pH2にした後酢酸ェチルで抽出し、有機層を無水硫酸マグネシウムで乾燥 後減圧濃縮した。得られた残渣を樹脂 SP-207 (水ーァセトニトリル)を用いて精製し、 得られた残渣を樹脂 SP-207 (水 ァセトニトリル)を用レ、て精製し、表題化合物 58.0 mgを得た。 100 mg of the compound obtained in production step 74- (b) 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. for 7 hours. 1.0 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using resin SP-207 (water-acetonitrile), and the obtained residue was purified using resin SP-207 (water-acetonitrile) to give the title compound (58.0 mg).
FABMS:m/z224[M+H]+； FABMS: m / z224 [M + H] + ;
'H-NMR (D O) δ :2.23 (3Η， s)， 3.10 (6Η， s)， 7.52 (1Η， d， J=8.5 Hz), 7.63 (1H， d， J= 8.5 Hz); [0232] [化 18] 'H-NMR (DO) δ: 2.23 (3Η, s), 3.10 (6Η, s), 7.52 (1Η, d, J = 8.5 Hz), 7.63 (1H, d, J = 8.5 Hz); [0232] [Chemical 18]
Figure imgf000101_0001
Figure imgf000101_0001
[0233] [化 19]
Figure imgf000102_0001
[0233] [Chemical 19]
Figure imgf000102_0001
[0234] [化 20]
Figure imgf000103_0001
[0234] [Chemical 20]
Figure imgf000103_0001
[0235] [化 21] [0235] [Chemical 21]
Figure imgf000104_0001
Figure imgf000104_0001
[0236] [化 22] 実施例 6 8 [0236] [Chemical 22] Example 6 8
実施例 6 9  Example 6 9
実施例 7 0 実施例 7 1 Example 7 0 Example 7 1
Figure imgf000105_0001
牛. ¾ †生言式,験
Figure imgf000105_0001
Cattle. ¾ †
メタロー βーラクタマーゼである IMP- 1を保有する緑膿菌（Pseudomonas aeruginosa MSC 15369)の blaIMP- 1を铸型に、その全長を PCRにて増幅した。この PCR産物を pT rcHis2 TOPOベクター（Invitrogen)にクローユングし、 Ε· coli DH5 α (ΤΟΥΟΒΟ)に導 入し、 0.5 mM(7)Isopropyl- β -D- (-) -thiogalactopyranoside (Wako)誘導ド、 37。C、 3 時間の培養により MP- 1を発現させた。菌体を回収後、スクロースによる浸透圧ショッ クによりペリプラズム画分を抽出し、 C末端の Hisタグを用いて Ni-NTA Slurry (QIAGE N)により IMP- 1を精製した。同様に、 VIM-2産生菌（Pseudomonas putida MSC06534) の blaVIM-2遺伝子をクローユングし、 Ε· coli DH5 aで発現させ、 VIM-2を精製した。 メタ口— β—ラクタマーゼ阻害活性測定には、 50 mM HEPES (pH 7.5)緩衝液 (以 降、緩衝液)を用い、基質として最終濃度 100 μ Μの nitrocefin (Oxoid)を用いた。 96 穴プレートの各ゥエルに、緩衝液に溶解した被検薬剤を添加し、 nitrocefmを添加、 混合し、ここに最終濃度 1 nMの MP-1または 1.5 nMの VM-2を室温にて 20分間反応 させた。この時、キレート作用による阻害効果を除くために最終濃度 100 の ZnSO を添加した。 nitrocefmの加水分解活性を ARVOsx microplate reader (Wallac)を用いBlaIMP-1 of Pseudomonas aeruginosa MSC 15369, which possesses IMP-1 which is a metallo β-lactamase, was amplified in a cocoon form by PCR. This PCR product was cloned into pT rcHis2 TOPO vector (Invitrogen), introduced into Εcoli DH5 α (ΤΟΥΟΒΟ), and 0.5 mM (7) Isopropyl- β -D- (-) -thiogalactopyranoside (Wako) derivative, 37. C, MP-1 was expressed by culturing for 3 hours. After recovering the cells, the periplasmic fraction was extracted by osmotic shock with sucrose, and IMP-1 was purified by Ni-NTA Slurry (QIAGE N) using the C-terminal His tag. Similarly, the blaVIM-2 gene of a VIM-2 producing bacterium (Pseudomonas putida MSC06534) was cloned and expressed in Escherichia coli DH5a to purify VIM-2. For measurement of the inhibitory activity of meta-β-lactamase, 50 mM HEPES (pH 7.5) buffer (hereinafter buffer) was used, and nitrocefin (Oxoid) with a final concentration of 100 μΜ was used as a substrate. 96 To each well of the well plate, add test drug dissolved in buffer, add nitrocefm, mix, and react with final concentration of 1 nM MP-1 or 1.5 nM VM-2 for 20 minutes at room temperature I let you. At this time, ZnSO with a final concentration of 100 was added to eliminate the inhibitory effect due to chelation. Using the ARVOsx microplate reader (Wallac) to hydrolyze nitrocefm
4 Four
て 490匪の波長を測定することにより、酵素阻害活性を測定した。対照としてメタロー 13ーラクタマーゼを除いた反応溶液を調製し、 50%阻害を示す被検薬剤濃度を IC と  The enzyme inhibitory activity was measured by measuring the wavelength of 490 mm. As a control, prepare a reaction solution without metallo 13-lactamase, and set the concentration of the test drug showing 50% inhibition as IC.
50 した。その結果は表 1に示されるとおりであった。  50. The results are shown in Table 1.
[0238] 表 1 : IMP-1および VIM-2に対する各阻害剤の IC [0238] Table 1: IC of each inhibitor against IMP-1 and VIM-2
50  50
[0239] [表 1] 例番号 化合物 IMP-K M) VIM-2C M)  [0239] [Table 1] Example number Compound IMP-K M) VIM-2C M)
実施例 12 21 26 実施例 32 2.7 54 実施例 56 1.0 14 実施例 45 2.6 10 実施例 65
Figure imgf000106_0001
2.4 19 実施例 70 HOOC COOH 0.7 12 実施例 69
Figure imgf000106_0002
Example 12 21 26 Example 32 2.7 54 Example 56 1.0 14 Example 45 2.6 10 Example 65
Figure imgf000106_0001
2.4 19 Example 70 HOOC COOH 0.7 12 Example 69
Figure imgf000106_0002
MP-1を産生する緑膿菌株を使用し、フタル酸酸誘導体の細菌におけるメタ口一 13 —ラクタマーゼによる力ルバぺネム耐性の阻害効果を評価した。 MP-1産生緑膿菌 に対するイミぺネム又はビアぺネムの最小発育阻止濃度（MIC)は、 日本化学療法学 会標準法（Chemotherapy, 1981， 29， 76)の微量液体希釈法により測定した。すなわ ち、 Mueller-Hinton brothで一夜培養した菌株を 104 CFU/wellになるように同培地で 調整し、各濃度のビアぺネムを含む同培地に添加した。これの各 wellに本発明化合 物を最終濃度 50 g/mlになるように添加し、イミぺネム又はビアぺネムの MICにより その効果を確認した。その結果は表 2に示されるとおりであった。 Using the Pseudomonas aeruginosa strain that produces MP-1, we evaluated the inhibitory effect of phthalate derivatives on the resistance to force rubapenem by meta-mouth 13-lactamase in bacteria. The minimum inhibitory concentration (MIC) of imipenem or biapenem against MP-1-producing Pseudomonas aeruginosa was measured by the microfluid dilution method of the Japan Chemotherapy Association Standard Method (Chemotherapy, 1981, 29, 76). That is, the strain cultured overnight in Mueller-Hinton broth was adjusted to the same medium to 10 4 CFU / well and added to the same medium containing each concentration of biapenem. The compound of the present invention in each well The product was added to a final concentration of 50 g / ml, and the effect was confirmed by MIC of imipenem or biapenem. The results are shown in Table 2.
[0241] 表 2 :メタロー /3—ラクタマーゼ産生緑膿菌に対するイミぺネム (表中、 IPMと略す）と、 ビアぺネム (表中、 BIPMと略す）との併用効果 (メタ口一 β—ラクタマーゼ阻害剤を 50 β g/mL併用） [0241] Table 2: Combined effect of imipenem (abbreviated as IPM in the table) and biapenem (abbreviated as BIPM in the table) against metallo / 3--lactamase-producing Pseudomonas aeruginosa Lactamase inhibitor combined with 50 β g / mL)
[0242] [表 2] 例番号 化合物 BIPMの MIC IPMの MIG [0242] [Table 2] Example number Compound BIPM MIC IPM MIG
実施例 12 16 16 実施例 32 0.5 1.0 Example 12 16 16 Example 32 0.5 1.0
Figure imgf000107_0001
Figure imgf000107_0001
実施例 56 2.0 4.0  Example 56 2.0 4.0
HOOC COOH  HOOC COOH
ノ NH2 No NH 2
実施例 45 1.0 1.0  Example 45 1.0 1.0
HOOC COOH  HOOC COOH
実施例 65 16 NT  Example 65 16 NT
HOOC COOH  HOOC COOH
実施例 70 1.0 2.0  Example 70 1.0 2.0
HOOC COOH  HOOC COOH
実施例 69 0.5 1.0 Example 69 0.5 1.0
Figure imgf000107_0002
Figure imgf000107_0002
ーラクタム薬単独 128 256  -Lactam alone 128 256
[0243] 表中、 13—ラタタム薬単独とは、 IPM、または BIPM単独での抗菌活性である。 [0243] In the table, 13-latatam alone is the antibacterial activity of IPM or BIPM alone.

Claims

請求の範囲 The scope of the claims
下記一般式 (I)で表される化合物、その塩、またはそれらの水和物もしくは溶媒和 物を含有してなる、メタロー /3—ラクタマーゼ阻害剤：  A metallo / 3-lactamase inhibitor comprising a compound represented by the following general formula (I), a salt thereof, or a hydrate or solvate thereof:
[化 1コ [Chemical 1
Figure imgf000108_0001
Figure imgf000108_0001
(I) (I)
(式中、  (Where
R1は、水酸基、 C アルキル基、 C アルコキシ基、下記 A環： R 1 is a hydroxyl group, a C alkyl group, a C alkoxy group, the following A ring:
1-7  1-7
[化 2] [Chemical 2]
Figure imgf000108_0002
Figure imgf000108_0002
—O—ピペリジン環、ピぺリジン環、フエニル基、ニトロ基、アミノ基、ァゼチジン環、ピ 口リジン環、テトラヒドロピリジン環、ピぺラジン環、モルホリン環、またはァゼパン環を 表し、これらはいずれも置換基を有していてもよぐ —O— represents a piperidine ring, piperidine ring, phenyl group, nitro group, amino group, azetidine ring, pyridine lysine ring, tetrahydropyridine ring, piperazine ring, morpholine ring, or azepane ring. It may have a substituent
R2は、水素原子、または C アルキル基を表し、これらはいずれも置換基を有して R 2 represents a hydrogen atom or a C alkyl group, each of which has a substituent.
1-7  1-7
いてあよく、 Well,
R3は、水素原子、 C アルキル基、ハロゲン原子、アミノ基、またはピぺリジン環を表 R 3 represents a hydrogen atom, a C alkyl group, a halogen atom, an amino group, or a piperidine ring.
1-7  1-7
し、これらはいずれも置換基を有していてもよぐ Any of these may have a substituent.
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す)。 R1が、水酸基、 C アルキル基、 C アルコキシ基、上記 A環、—O ピぺリジン— 4M 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 1 is a hydroxyl group, a C alkyl group, a C alkoxy group, the above ring A, —O piperidine—4
1-6 1-6 1-6 1-6
ーィル基、 O ピペリジン 1ーィル基、フエニル基、ピぺリジン 1ーィル基、ピぺ リジン一 4—ィル基、ニトロ基、アミノ基、モノ C ァノレキノレアミノ基、ジ C ァノレキノレアミ -Yl group, O piperidine 1-yl group, phenyl group, piperidine 1-yl group, piperidine 1-yl group, nitro group, amino group, mono-C ano-requinolamino group, di-C ano-requinolamine
1-6 1-6  1-6 1-6
ノ基、カルボニルァミノ基、ァゼチジン 1ーィル基、ピロリジン 1ーィル基、 1，2，3，6 ーテトラヒドロピリジン基、ピぺラジン 1ーィル基、モルホリンー4ーィル基、またはァ ゼパン一 1 ィル基を表し、これらは!/、ずれも置換基を有して!/、てもよく、 Group, carbonylamino group, azetidine 1-yl group, pyrrolidine 1-yl group, 1,2,3,6-tetrahydropyridine group, piperazine 1-yl group, morpholine 4-yl group, or azepane 1-yl group These may be! /, The deviation may also have a substituent! /,
R2が水素原子、または C アルキル基を表し、これらは!/、ずれも置換基を有してレヽ R 2 represents a hydrogen atom or a C alkyl group, which is! /
1-6  1-6
てあよく、 Well,
R3が水素原子、 C アルキル基、ハロゲン原子、アミノ基、モノ C アルキルアミノ基 R 3 is hydrogen atom, C alkyl group, halogen atom, amino group, mono C alkylamino group
1-6 1-6  1-6 1-6
、ジ C ァノレキノレアミノ基、ピぺリジン一 1—ィル基、ピぺリジン一 4—ィル基を表し、こ Represents a di-C-anolequinolamino group, a piperidine-1-yl group, and a piperidine-1-yl group.
1-6 1-6
れらは!/ヽずれも置換基を有して!/ヽてもよぐ These are also! / ヽ have a substituent! / ヽ
M1および M2が、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す、請求項 1に 記載のメタロー /3—ラクタマーゼ阻害剤。 The 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. Metallo / 3 / 3-lactamase inhibitor.
R1が、 R 1 is
水酸基、  Hydroxyl group,
水酸基で置換されていてもよい C アルキル基、  A C alkyl group optionally substituted by a hydroxyl group,
1-6  1-6
水酸基、 C アルキル基、 C 環状アルキル基、カルボキシル基、フエニル基、フエ  Hydroxyl group, C alkyl group, C cyclic alkyl group, carboxyl group, phenyl group, phenol
1-6 3-7  1-6 3-7
ニルォキシ基、または上記 A環で置換されていてもよい C アルコキシ基、 A nyloxy group, or a C alkoxy group optionally substituted with the A ring,
1-6  1-6
アルキルォキシカルボニル基で置換されていてもよい O ピペリジン 4ーィル 基または O ピペリジン 1ーィル基、  An O piperidine 4-yl group or an O piperidine 1-yl group optionally substituted by an alkyloxycarbonyl group,
水酸基またはカルボキシノレ基で置換されて!/、てもよ!/、フエニル基、  Substituted with a hydroxyl group or a carboxynole group! /, May! /, A phenyl group,
水酸基、アミノ基、アジド基、 C アルコキシ基、ヒドロキシ C アルキル基、カルボキ  Hydroxyl group, amino group, azide group, C alkoxy group, hydroxy C alkyl group, carboxyl
1-6 1-6  1-6 1-6
シル基、 C アルキルォキシカルボニル基、ァミノカルボニル基、置換アミノカルボ二 Sil group, C alkyloxycarbonyl group, aminocarbonyl group, substituted aminocarbonyl
1-6  1-6
ル基、ォキソ（ =〇）基、フエニル基、ベンジル基、および C アルキルカルボニル基 Group, oxo (= 〇) group, phenyl group, benzyl group, and C alkylcarbonyl group
1-6  1-6
からなる群から選択される基で置換されて!/、てもよ!/、ピペリジン 1 ィル基またはピ ペリジン 4ーィル基、 Substituted with a group selected from the group consisting of! /, May! /, Piperidine 1-yl group or piperidine 4-yl group,
ニトロ基、 アミノ基、 Nitro group, An amino group,
モノ C アルキルアミノ基、  Mono C alkylamino group,
1-6  1-6
ジ C ァノレキノレアミノ基、  Di-C-anolequinolamino group,
C アルキルカルボニルァミノ基  C alkylcarbonylamino group
1-6  1-6
ァゼチジン一 1ーィル基、  Azetidine 1-yl group,
水酸基で置換されてレ、てもよ!/、ピロリジン一 1ーィル基、  Substituted with a hydroxyl group, may! /, Pyrrolidine mono-1-yl group,
C アルキルォキシカルボニル基で置換されていてもよい 1，2，3，6—テトラヒドロピリ
Figure imgf000110_0001
C 1,2,3,6-tetrahydropyridyl optionally substituted by an alkyloxycarbonyl group
Figure imgf000110_0001
C アルキルカルボニル基、 C アルキルォキシカルボニル基、ァミノカルボニル基 C alkylcarbonyl group, C alkyloxycarbonyl group, aminocarbonyl group
1-6 1-6 1-6 1-6
、置換アミノカルボニル基、ベンジル基、およびベンゾィル基からなる群から選択され る基で置換されてレ、てもよ!/、ピペラジン一 1ーィル基、  Substituted with a group selected from the group consisting of a substituted aminocarbonyl group, a benzyl group, and a benzoyl group, may be! /, A piperazine monoyl group,
モルホリン一 4ーィル基、または  Morpholine 4-yl group, or
ァゼパン一 1ーィル基である、請求項 1または 2に記載のメタロー βーラクタマーゼ 阻害剤。  The metallo β-lactamase inhibitor according to claim 1 or 2, which is a azepane 1-yl group.
が  But
水素原子、  Hydrogen atom,
C アルキル基、  C alkyl group,
1-6  1-6
ハロゲン原子、  Halogen atoms,
アミノ基、  An amino group,
モノ C ァノレキノレアミノ基、  Mono-C-anolequinolamino group,
1-6  1-6
ジ C アルキルアミノ基、  Di-C alkylamino group,
1-6  1-6
水酸基またはァミノ基で置換されてレ、てもよレ、ピペリジン一 1一ィル基またはピペリ ジンー4ーィル基である、請求項 1または 2に記載のメタロー βーラクタマーゼ阻害剤  3. The metallo β-lactamase inhibitor according to claim 1 or 2, which is substituted with a hydroxyl group or an amino group, or is a piperidine monoyl group or a piperidin-4-yl group.
[5] 下記一般式 (II)で表される化合物、その塩、またはそれらの水和物もしくは溶媒和物 [5] A compound represented by the following general formula (II), a salt thereof, or a hydrate or solvate thereof
[化 3]
Figure imgf000111_0001
[Chemical 3]
Figure imgf000111_0001
(II) (II)
(式中、  (Where
B環は、ァゼチジン環、ピロリジン環、ピぺリジン環、ピぺラジン環、モルホリン環、ま たはァゼパン環を表し、これらは!/、ずれも R4を有して!/、てもよく、 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 ! /. ,
R4は、 B環上に 0〜2個存在し、水酸基、 C アルキル基、 C アルコキシ基、ヒドロ 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
1-6 1-6  1-6 1-6
キシ C アルキル基、カルボニル基 基、フエニル基、ァミノ X-C alkyl group, carbonyl group, phenyl group, amino
1-6 1-6
ジド基、ォキソ（=〇）基、 C アルキルォキシカルボニル基、またはァミノカルボ  Zido group, oxo (= 〇) group, C alkyloxycarbonyl group, or aminocarbo
1-6  1-6
二ル基を表し、これらは!/、ずれも置換基を有して!/、てもよく、  Represents a dil group, these may be! /, Both of which have substituents! /,
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す)。 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.
[6] 下記一般式 (Γ )で表される化合物、その塩、またはそれらの水和物もしくは溶媒和 物：  [6] A compound represented by the following general formula (Γ), a salt thereof, or a hydrate or solvate thereof:
[化 4]  [Chemical 4]
Figure imgf000111_0002
Figure imgf000111_0002
(!' ) (! ')
(式中、 R1は、ピぺリジン環、またはアミノ基を表し、これらはいずれも置換基を有していても よぐ (Where R 1 represents a piperidine ring or an amino group, any of which may have a substituent.
R2は、水素原子を表し、 R 2 represents a hydrogen atom,
R3は、 C アルキル基、ハロゲン原子、ピぺリジン環、またはアミノ基を表し、これらR 3 represents a C alkyl group, a halogen atom, a piperidine ring, or an amino group, and these
1-6 1-6
はレ、ずれも置換基を有して!/、てもよく、  May have substituents! /,
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す)。 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.
[7] 下記一般式 (III)で表される化合物、その塩、またはそれらの水和物もしくは溶媒和 物：  [7] A compound represented by the following general formula (III), a salt thereof, or a hydrate or solvate thereof:
[化 5]  [Chemical 5]
Figure imgf000112_0001
Figure imgf000112_0001
(III) (III)
(式中、  (Where
C環における H は、単結合または二重結合を表し、  H in ring C represents a single bond or a double bond,
R4は、 C環上に 0〜2個存在し、水酸基、 C アルキル基、 R 4 is 0 to 2 on the C ring, a hydroxyl group, a C alkyl group,
1-6 1-6  1-6 1-6
キシ C アルキル基、ォキソ（ =〇）基、 フエニル基、ァミノ XiC alkyl group, oxo (= 〇) group, phenyl group, amino
1-6 1-6
'基、カルボキシル基、 C アルキルォキシカルボニル基、またはァミノカル  'Group, carboxyl group, C alkyloxycarbonyl group, or aminocarco
1-6  1-6
ボニル基を表し、これらは!/、ずれも置換基を有して!/、てもよく、  Represents a bonyl group, these may be! /, Both have substituents! /,
R5は、水素原子、 CR 5 is a hydrogen atom, C
Figure imgf000112_0002
Figure imgf000112_0002
カルホニル基、 C アルキルカルボニル基、またはァミノカルボ二ル基を表し、これら  Represents a carbonyl group, a C alkylcarbonyl group, or an aminocarbonyl group.
1-6 はレ、ずれも置換基を有して!/、ても良く、 1-6 May have a substituent! /,
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す)。 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.
[8] 下記一般式 (IV)で表される化合物、その塩、またはそれらの水和物もしくは溶媒和 物：  [8] A compound represented by the following general formula (IV), a salt thereof, or a hydrate or solvate thereof:
[化 6]  [Chemical 6]
Figure imgf000113_0001
Figure imgf000113_0001
(IV) (IV)
(式中、  (Where
nは 0〜6を表し、  n represents 0-6,
R6は、水酸基、環状 C アルキル基、フエニルォキシ基、フエニル基、カルボキシル 基、置換基を有してもよいピペリジル基、または上記 A環を表し、 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.
M1および M2は、同一または異なっていてもよぐ水素原子、医薬的に許容される力 チオン、または医薬的に許容される生体内で加水分解されうる基を表す、 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.
但し、 nが 1のとき、 R6はフエ二ル基を表さない）。 However, when n is 1, R 6 does not represent a phenyl group).
[9] 請求項 1において定義された式 (I)の化合物と、医薬的に許容される担体とを含ん でなる、医薬組成物。  [9] A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier.
[10] メタロー 13ーラクタマーゼ阻害剤として用いられる、請求項 5〜8のいずれか一項に 記載の医薬組成物。  [10] The pharmaceutical composition according to any one of claims 5 to 8, which is used as a metallo 13-lactamase inhibitor.
[11] β ラタタム系抗生物質と同時にまたは逐次的に投与されて用いられる、請求項 9 に記載の医薬組成物。  [11] The pharmaceutical composition according to claim 9, which is used by being administered simultaneously or sequentially with a β-ratata antibiotic.
[12] 前記 /3—ラタタム系抗生物質が力ルバぺネム系抗生物質、ペニシリン系抗生物質 、セフエム系抗生物質、またはそれらのプロドラッグである、請求項 11に記載の医薬 組成物。 [12] / 3--Ratatam antibiotics are powerful rubapenem antibiotics, penicillin antibiotics 12. The pharmaceutical composition according to claim 11, which is a cephem antibiotic or a prodrug thereof.
[13] デヒドロぺプチダーゼ阻害剤をさらに含んでなる、請求項 9〜； 12のいずれか一項に 記載の医薬組成物。  [13] The pharmaceutical composition according to any one of claims 9 to 12, further comprising a dehydropeptidase inhibitor.
[14] デヒドロぺプチダーゼ阻害剤および/または一般式 (I)の化合物以外の /3—ラクタ マーゼ阻害剤と同時または逐次的に投与されて用いられる、請求項 9に記載の医薬 組成物。  [14] The pharmaceutical composition according to claim 9, which is used by being administered simultaneously or sequentially with a / 3-lactamase inhibitor other than the dehydropeptidase inhibitor and / or the compound of general formula (I).
[15] 請求項 1に記載のメタロー /3—ラクタマーゼ阻害剤と、 β ラタタム系抗生物質と、 場合により医薬的に許容される担体とを含んでなる、医薬組成物。  [15] A pharmaceutical composition comprising the metallo / 3-lactamase inhibitor according to claim 1, a β-ratata antibiotic, and optionally a pharmaceutically acceptable carrier.
[16] 前記 13 ラタタム系抗生物質が力ルバぺネム系抗生物質、ペニシリン系抗生物質 、セフエム系抗生物質、またはそれらのプロドラッグである、請求項 15に記載の医薬 組成物。  16. The pharmaceutical composition according to claim 15, wherein the 13 ratatam antibiotic is a powerful rubapenem antibiotic, a penicillin antibiotic, a cefme antibiotic, or a prodrug thereof.
[17] 抗菌剤として用いられる、請求項 9〜； 16のいずれか一項に記載の医薬組成物。  [17] The pharmaceutical composition according to any one of [9] to [16], which is used as an antibacterial agent.
[18] 細菌感染の治療方法であって、 /3 ラタタム系抗生物質と請求項 1に記載のメタ口 βーラクタマーゼ阻害剤とを併用して投与することを含んでなる、方法。 [18] A method for treating a bacterial infection, comprising: administering a combination of a / 3 ratatam antibiotic and the meta-mouth β-lactamase inhibitor according to claim 1.
[19] 前記 13 ラタタム系抗生物質が力ルバぺネム系抗生物質、ペニシリン系抗生物質[19] The 13 ratatam antibiotics are powerful rubapenem antibiotics, penicillin antibiotics
、セフエム系抗生物質、またはそれらのプロドラッグである、請求項 18に記載の方法The method according to claim 18, wherein the method is a cefme antibiotic, or a prodrug thereof.
〇 Yes
[20] 細菌感染症の予防または治療剤の製造のための、請求項 1に記載の化合物の使 用。  [20] Use of the compound according to claim 1 for the manufacture of a preventive or therapeutic agent for bacterial infections.
PCT/JP2007/064895 2006-07-31 2007-07-30 METALLO-β-LACTAMASE INHIBITOR WO2008016007A1 (en)

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WO2016175223A1 (en) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Tricyclic compounds and uses thereof
CN110746400A (en) * 2019-11-07 2020-02-04 郑州大学 Androgen receptor targeted fluorescent probe and preparation method thereof
CN113461606A (en) * 2021-06-30 2021-10-01 郑州大学 Pyridine dicarboxylic acid amine derivative as metal beta-lactamase inhibitor and preparation method thereof
CN113461606B (en) * 2021-06-30 2022-05-31 郑州大学 Pyridine dicarboxylic acid amine derivative as metal beta-lactamase inhibitor and preparation method thereof

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