Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
  • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
• • A—HUMAN NECESSITIES
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
  • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
• • A—HUMAN NECESSITIES
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
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  • A61K31/65—Tetracyclines
• • A—HUMAN NECESSITIES
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  • A61K31/69—Boron compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• • A—HUMAN NECESSITIES
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  • 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
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  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention comprises a novel penum derivative or a salt thereof that exhibits strong antibacterial activity against Gram-negative bacteria, particularly Pseudomonas aeruginosa, and one or more compounds selected from ⁇ -lactamase inhibitory compounds and antibacterial compounds or salts thereof.
• the present invention relates to a pharmaceutical composition characterized by containing.
• the present invention is one or more selected from a novel penum derivative or a salt thereof which exhibits strong antibacterial activity against Gram-negative bacteria, particularly Pseudomonas aeruginosa, and a ⁇ -lactamase inhibitory compound and an antibacterial compound or a salt thereof.
• the present invention relates to a kit characterized by containing a compound.
• Non-Patent Document 1 Non-Patent Document 1
• ⁇ -lactamase As a resistance mechanism of ⁇ -lactams, ⁇ -lactamase, which decomposes ⁇ -lactams, is known. ⁇ -lactamase is classified as Class A (TEM type, SHV type, CTX-M type, KPC type, GES type, etc.), Class B (IMP type, VIM type, NDM type, etc.), Class C (, etc.) according to Ambra's molecular classification method. It is roughly classified into Class D (OXA type, etc.) and Class D (OXA type), and each of them decomposes ⁇ -lactams with different substrate specificities (Non-Patent Document 2).
• Class A TEM type, SHV type, CTX-M type, KPC type, GES type, etc.
• Class B IMP type, VIM type, NDM type, etc.
• Class C Class C
• Non-Patent Document 2 Non-Patent Document 2
• class B ⁇ -lactamases KPC, GES and OXA ⁇ -lactamases are called carbapenemases, and most of the bacteria having them are found in almost all ⁇ -lactams including carbapenems. Shows high resistance. Furthermore, in recent years, strains of Pseudomonas aeruginosa that are highly resistant to the newly developed cephalosporin-based combination drugs ceftrozan / tazobactam and ceftazidime / avibactam have been isolated (Non-Patent Document 3).
• Infectious diseases caused by multidrug-resistant Pseudomonas aeruginosa are a major problem worldwide as intractable diseases because there are few effective therapeutic agents. It is desired to provide a pharmaceutical composition showing strong antibacterial activity against Gram-negative bacteria and drug-resistant Gram-negative bacteria. In particular, it is desired to provide a pharmaceutical composition and a kit showing strong antibacterial activity against carbapenemase-producing enterobacteria or Pseudomonas aeruginosa.
• compositions and kits comprising one or more compounds include gram-negative bacteria such as Pseudomonas aeruginosa and / or drug-resistant gram-negative bacteria such as multidrug-resistant Pseudomonas aeruginosa, eg, carbapenemase-producing intestines.
• gram-negative bacteria such as Pseudomonas aeruginosa and / or drug-resistant gram-negative bacteria
• multidrug-resistant Pseudomonas aeruginosa eg, carbapenemase-producing intestines.
• the present invention provides: ⁇ 1> General formula [1] "During the ceremony, R 1 has a hydrogen atom or a carboxyl protecting group; R 2 is an aryl group that may be substituted or a heterocyclic group that may be substituted; R 3 has a hydrogen atom or a carboxyl protecting group; X 1 may be substituted C 1-6 alkylene group, optionally substituted C 2-6 alkenylene group, optionally substituted C 2-6 alkynylene group, optionally substituted two.
• a valent cyclic hydrocarbon group or a optionally substituted divalent monocyclic saturated heterocyclic group is a heterocyclic group that may be substituted;
• Q is a divalent cyclic amino group that may be substituted or a divalent heterocyclic group that may be substituted;
• Y 2 is a optionally substituted C 1-6 alkylene group, optionally substituted C 2-6 alkenylene group or optionally substituted C 2-6 alkynylene group or bonder;
• X 3 is the formula -NR 9 - "wherein, R 9 is a hydrogen atom, a hydroxyl group which may be also a C 1-6 alkyl group or a protected substituted.” Represented by Group or bonder;
• R 10 is a C 1-6 alkyl group which may be substituted, C which may be substituted.
• 1-6 alkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di (C 1-6 alkyl) amino group, optionally substituted cyclic amino group, substituted Indicates an amino group which may be protected, an amino group which may be protected, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a carboxyl group or a ureido group which may be protected.
• R 11 represents a hydrogen atom, a optionally substituted carbamoyl group or a optionally protected carboxyl group.
• a pharmaceutical composition comprising one or more compounds selected from the compound represented by "" or a salt thereof and a ⁇ -lactamase inhibitory compound and an antibacterial compound or a salt thereof.
• R 2 is a pharmaceutical composition according to is also an aryl group substituted ⁇ 1>.
• ⁇ 4> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 3>, wherein X 1 is a C 1-6 alkylene group which may be substituted or a divalent cyclic hydrocarbon group which may be substituted.
• Stuff. ⁇ 5> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 4>, wherein Q is a divalent heterocyclic group which may be substituted.
• X 2 is a group represented by the general formula-NR 4a- "in the formula, R 4a represents a hydrogen atom or a carbamoyl group", the general formula-N + R 5a R 6a- "in the formula, R 5a and R 6a represents a C 2-6 alkylene group which may be substituted together.
• X 3 is a group or a bond represented by the general formula-NR 9a- "in the formula, R 9a represents a hydrogen atom.”
• R 10a represents a optionally substituted C 1-6 alkoxy group, a optionally protected hydroxyl group, or a ureido group.”
• CR 11a Any of ⁇ 1> to ⁇ 9>, which is a group represented by "In the formula, R 11a represents a optionally substituted carbamoyl group or a optionally protected carboxyl group.”
• the pharmaceutical composition according to paragraph 1. ⁇ 11> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 10>, wherein R 3 is a hydrogen atom.
• R 1 is a hydrogen atom.
• the pharmaceutical composition according to the section. ⁇ 14> The compound represented by the general formula [1] is (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-((1-carboxycyclobutoxy) imino).
• ⁇ 15> The medicament according to any one of ⁇ 1> to ⁇ 14>, wherein the ⁇ -lactamase inhibitory compound and the antibacterial compound or one or more compounds selected from the salts thereof are ⁇ -lactamase inhibitory compounds or salts thereof.
• ⁇ 17> ⁇ -lactamase inhibitor compounds are avivactam, nacuvactam, relevactum, didebactam, babolbactam, (3R) -3-(2- [trans-4-[(2-aminoethyl) amino] cyclohexyl] acetamide) -2-hydroxy-3.
• ⁇ 18> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 14>, wherein the ⁇ -lactamase inhibitory compound and the antibacterial compound or one or more compounds selected from the salts thereof are antibacterial compounds or salts thereof.
• Antibacterial compounds are ⁇ -lactam, macrolide, lincomycin, streptogramin, quinolone, aminoglycoside, rifamycin, tetracycline, amphenicole, sulfonamide and trimethoprim, oxazolidinone, polymyxin.
• the medicament according to any one of ⁇ 1> to ⁇ 14> and ⁇ 18> which is one or more compounds selected from compounds such as system, pleuromutilin system, glycopeptide system, imidazole system and nitrofuran system.
• the antibacterial compound is any one of ⁇ 1> to ⁇ 14> and ⁇ 18>, which is one or more compounds selected from piperacillin, ceftazidime, imipenem, mesirinum, levofloxacin, amikacin, polymyxin B, tetracycline, trimethoprim and rifampicin.
• the pharmaceutical composition according to the section is one or more compounds selected from compounds such as system, pleuromutilin system, glycopeptide system, imidazole system and nitrofuran system.
• the antibacterial compound is any one of ⁇ 1> to ⁇ 14> and ⁇ 18>, which is one or more compounds selected from piperacillin,
• ⁇ 21> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 20> for use in the treatment of infectious diseases caused by Gram-negative bacteria.
• An agent for treating an infectious disease caused by a gram-negative bacterium which comprises the pharmaceutical composition according to any one of ⁇ 1> to ⁇ 20>.
• a method for treating an infection caused by a gram-negative bacterium which comprises administering the pharmaceutical composition according to any one of ⁇ 1> to ⁇ 20> to a subject.
• R 1 has a hydrogen atom or a carboxyl protecting group
• R 2 is an aryl group that may be substituted or a heterocyclic group that may be substituted
• R 3 has a hydrogen atom or a carboxyl protecting group
• X 1 may be substituted C 1-6 alkylene group, optionally substituted C 2-6 alkenylene group, optionally substituted C 2-6 alkynylene group, optionally substituted two.
• a valent cyclic hydrocarbon group or a optionally substituted divalent monocyclic saturated heterocyclic group is a heterocyclic group that may be substituted;
• Q is a divalent cyclic amino group that may be substituted or a divalent heterocyclic group that may be substituted;
• Y 2 is a optionally substituted C 1-6 alkylene group, optionally substituted C 2-6 alkenylene group or optionally substituted C 2-6 alkynylene group or bonder;
• X 3 is the formula -NR 9 - "wherein, R 9 is a hydrogen atom, a hydroxyl group which may be also a C 1-6 alkyl group or a protected substituted.” Represented by Group or bonder;
• R 10 is a C 1-6 alkyl group which may be substituted, C which may be substituted.
• 1-6 alkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di (C 1-6 alkyl) amino group, optionally substituted cyclic amino group, substituted Indicates an amino group which may be protected, an amino group which may be protected, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a carboxyl group or a ureido group which may be protected.
• R 11 represents a hydrogen atom, a optionally substituted carbamoyl group or a optionally protected carboxyl group.
• a kit used for treating an infectious disease which comprises one or more compounds selected from the compound represented by "" or a salt thereof and a ⁇ -lactamase inhibitory compound and an antibacterial compound or a salt thereof.
• R 2 is an optionally substituted aryl group.
• A is a monocyclic heterocyclic group which may be substituted.
• X 1 is a C 1-6 alkylene group which may be substituted or a divalent cyclic hydrocarbon group which may be substituted.
• Q is a divalent heterocyclic group which may be substituted.
• X 2 is a group represented by the general formula-NR 4a- "in the formula, R 4a represents a hydrogen atom or a carbamoyl group", the general formula-N + R 5a R 6a- "in the formula, R 5a and R 6a represents a C 2-6 alkylene group which may be substituted together.
• X 3 is a group or a bond represented by the general formula-NR 9a- "in the formula, R 9a represents a hydrogen atom.” .. ⁇ 33>
• R 10a represents a optionally substituted C 1-6 alkoxy group, a optionally protected hydroxyl group, or a ureido group.”
• R 11a represents a optionally substituted carbamoyl group or a optionally protected carboxyl group.”
• the kit described in item 1. ⁇ 34> The kit according to any one of ⁇ 24> to ⁇ 33>, wherein R 3 is a hydrogen atom. ⁇ 35> The kit according to any one of ⁇ 24> to ⁇ 34>, wherein R 1 is a hydrogen atom.
• the kit described in the section. ⁇ 37> The compound represented by the general formula [1] is (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-((1-carboxycyclobutoxy) imino).
• ⁇ 38> The kit according to any one of ⁇ 24> to ⁇ 37>, wherein the ⁇ -lactamase inhibitory compound and the antibacterial compound or one or more compounds selected from the salts thereof are ⁇ -lactamase inhibitory compounds or salts thereof. .. ⁇ 39> Any one of ⁇ 24> to ⁇ 38>, wherein the ⁇ -lactamase inhibitory compound is one or more compounds selected from diazabicyclo [3.2.1] octane type inhibitory compound, boronic acid type inhibitory compound and clavam type inhibitory compound.
• ⁇ -lactamase inhibitor compounds are avivactam, nacuvactam, relevactum, didebactam, babolbactam, (3R) -3-(2- [trans-4-[(2-aminoethyl) amino] cyclohexyl] acetamide) -2-hydroxy-3.
• ⁇ 41> The kit according to any one of ⁇ 24> to ⁇ 37>, wherein the ⁇ -lactamase inhibitory compound and the antibacterial compound or one or more compounds selected from the salts thereof are the antibacterial compound or a salt thereof.
• Antibacterial compounds are ⁇ -lactam, macrolide, lincomycin, streptogramin, quinolone, aminoglycoside, rifamycin, tetracycline, amphenicole, sulfonamide and trimethoprim, oxazolidinone, polymyxin.
• the kit according to any one of ⁇ 24> to ⁇ 37> and ⁇ 41> which is one or more compounds selected from compounds such as system, pleuromutilin system, glycopeptide system, imidazole system and nitrofuran system. .. ⁇ 43>
• the antibacterial compound is any one of ⁇ 24> to ⁇ 37> and ⁇ 41>, which is one or more compounds selected from piperacillin, ceftazidime, imipenem, mesirinum, levofloxacin, amikacin, polymyxin B, tetracycline, trimethoprim and rifampicin.
• the kit described in the section is one or more compounds selected from compounds such as system, pleuromutilin system, glycopeptide system, imidazole system and nitrofuran system. .. ⁇ 43>
• the antibacterial compound is any one of ⁇ 24> to ⁇ 37> and ⁇ 41>, which is one or more compounds selected from piperacillin, ceft
• the pharmaceutical composition and kit of the present invention show strong antibacterial activity against gram-negative bacteria and / or drug-resistant gram-negative bacteria, for example, carbapenemase-producing enterobacteria or Pseudomonas aeruginosa, and are useful as pharmaceuticals.
• the pharmaceutical compositions and kits of the present invention are useful in the treatment of Gram-negative and / or drug-resistant Gram-negative bacteria infections.
• the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• the C 1-6 alkyl group is a linear or branched C 1 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. It means a -6 alkyl group.
• the C 1-3 alkyl group means a methyl, ethyl, propyl or isopropyl group.
• C 2-6 Alkenyl groups for example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and linear or branched C 2-6 alkenyl such as hexenyl Means a group.
• the C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.
• the C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
• the aryl group means a C6-18 aryl group such as a phenyl or naphthyl group.
• the aryl C 1-6 alkyl group for example, refers to a benzyl, diphenylmethyl, trityl, aryl C 1-6 alkyl groups such as phenethyl and naphthylmethyl groups.
• the C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
• the C 1-3 alkylene group means a methylene, ethylene or propylene group.
• the C 2-6 alkylene group means a linear or branched C 2-6 alkylene group such as ethylene, propylene, butylene and hexylene groups.
• the C 2-6 alkenylene group means a linear or branched C 2-6 alkenylene group such as vinylene, propenylene, butenylene and pentenylene group.
• the C 2-6 alkynylene group means a linear or branched C 2-6 alkynylene group such as ethynylene, propynylene, butynylene and pentynylene groups.
• the C 1-6 alkoxy group is a linear or branched C such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
• 1-6 means an alkyloxy group.
• the C 1-6 alkoxy C 1-6 alkyl group refers to, for example, a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
• the C 2-12 alkanoyl group for example, means acetyl, propionyl, valeryl, a linear or branched C 2-12 alkanoyl group such as isovaleryl and pivaloyl groups.
• the aloyl group means, for example, a benzoyl or naphthoyl group.
• the acyl group means, for example, a formyl group, a succinyl group, a glutalyl group, a maleoil group, a phthaloyl group, a C 2-12 alkanoyl group or an aroyl group.
• the C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl group. It means an alkyloxycarbonyl group.
• the aryl C 1-6 alkoxycarbonyl group means an al-C 1-6 alkyloxycarbonyl group such as, for example, benzyloxycarbonyl and phenethyloxycarbonyl groups.
• the aryloxycarbonyl group means, for example, a phenyloxycarbonyl or naphthyloxycarbonyl group.
• the C 1-6 alkylamino group is a linear or branched chain such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups. It means a C 1-6 alkylamino group in the form.
• the di (C 1-6 alkyl) amino groups are dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino and It means a linear or branched di (C 1-6 alkyl) amino group such as a (methyl) (propyl) amino group.
• the C 1-6 alkylthio group means a C 1-6 alkylthio group such as a methylthio, ethylthio and propylthio group.
• the C 1-6 alkylsulfonyl group refers to, for example, a C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl group.
• the arylsulfonyl group means, for example, a benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
• the C 1-6 alkyl sulfonyloxy group means a C 1-6 alkyl sulfonyl oxy group such as methyl sulfonyloxy and ethyl sulfonyl oxy group.
• the arylsulfonyloxy group means a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or the like.
• the silyl group means, for example, a trimethylsilyl, triethylsilyl or tributylsilyl group.
• Cyclic amino groups include, for example, aziridinyl, azetidinyl, pyrrolyl, dihydropyrrolill, pyrrolidinyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazolyl, pyrazolinyl, pyrazolydinyl, imidazolyl, imidazolinyl, imidazolidinyl, thiazolinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl.
• a monocyclic nitrogen-containing heterocyclic group means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a ring-forming heteroatom, for example, an azetidinyl group; pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl. , Imidazolinyl, imidazolyl, pyrazoridinyl, pyrazolinyl, pyrazolyl, triazolyl or tetrazolyl groups, etc.
• a monocyclic oxygenated heterocyclic group means a monocyclic oxygenated heterocyclic group containing only an oxygen atom as a heterocyclic group forming a ring, and is a 5-membered ring such as a tetrahydrofuranyl or a furanyl group.
• oxygenated heterocyclic groups examples include oxygenated heterocyclic groups; or 6-membered ring oxygenated heterocyclic groups such as tetrahydropyranyl or pyranyl groups.
• the monocyclic sulfur-containing heterocyclic group means a thienyl group or the like.
• the monocyclic nitrogen-containing / oxygen heterocyclic group means a monocyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming a ring, and for example, oxazolyl and oxazolidinyl. , 5-membered ring nitrogen-containing / oxygen heterocyclic groups such as isooxazolyl or oxadiazolyl groups; or 6-membered ring nitrogen-containing / oxygen heterocyclic groups such as morpholinyl groups.
• the monocyclic nitrogen-containing / sulfur heterocyclic group means a monocyclic nitrogen-containing / sulfur heterocyclic group containing only a nitrogen atom and a sulfur atom as different term atoms forming a ring, and for example, thiazolyl and isothiazolyl.
• a 5-membered ring nitrogen-containing / sulfur heterocyclic group such as a thiadiazolyl group; or a 6-membered ring nitrogen-containing / sulfur heterocyclic group such as thiomorpholinyl, 1-oxide thiomorpholinyl or 1,1-dioxide thiomorpholinyl group. The group is mentioned.
• Monocyclic heterocyclic groups are monocyclic nitrogen-containing heterocyclic groups, monocyclic oxygen-containing heterocyclic groups, monocyclic sulfur-containing heterocyclic groups, and monocyclic nitrogen-containing / oxygen heterocyclic groups. It means a group or a monocyclic nitrogen-containing / sulfur heterocyclic group.
• a monocyclic saturated heterocyclic group means a monocyclic heterocyclic group containing no multiple bonds, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolydinyl, piperazinyl, oxazolidinyl, tetrahydropyrimidyl. , Tetrahydrofuranyl, tetrahydropyranyl and morpholinyl groups.
• Bicyclic nitrogen-containing heterocyclic groups include indolinyl, indolyl, isoindolinyl, isoindrill, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolidinyl, cinnolinyl, Bicyclic nitrogen-containing compounds containing only nitrogen atoms as ring-forming heteroatoms such as phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyldinyl, prynyl, pyropyridinyl, dihydrocyclopentapyridinyl, pteridinyl and quinuclidinyl groups Means a heterocyclic group.
• Bicyclic oxygenated heterocyclic groups are 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodi. It means a bicyclic oxygenated heterocyclic group containing only an oxygen atom as a heteroatom forming a ring such as an oxanyl and a 1,4-benzodioxanyl group.
• a bicyclic sulfur-containing heterocyclic group is a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a heteroatom forming a ring such as 2,3-dihydrobenzothienyl and benzothienyl groups.
• Bicyclic nitrogen-containing / oxygen heterocyclic groups are benzoxazolyl, benzoisooxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and dihydropyridoxa.
• bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming a ring such as a dinyl group.
• a bicyclic nitrogen-containing / sulfur heterocyclic group is a bicyclic nitrogen-containing group containing a nitrogen atom and a sulfur atom as heteroatoms forming a ring such as benzothiazolyl, benzoisothiazolyl and benzothiasiazolyl groups.
• -It means a sulfur heterocyclic group.
• Bicyclic heterocyclic groups are bicyclic nitrogen-containing heterocyclic groups, bicyclic oxygen-containing heterocyclic groups, bicyclic sulfur-containing heterocyclic groups, and bicyclic nitrogen-containing groups.
• -It means an oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.
• the heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.
• the divalent cyclic hydrocarbon groups are cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclopropane-1, 2-Diyl, cyclobutane-1,3-diyl, cyclobutene-1,3-diyl, cyclopentane-1,3-diyl, cyclopentene-1,3-diyl, cyclopentadiene-1,3-diyl, cyclohexane-1, 3-Diyl, Cyclohexane-1,4-Diyl, Cyclohexene-1,3-Diyl, Cyclohexene-1,4-Diyl, Cyclohexadiene-1,3-Diyl, Cyclohexadiene-1,4-Diyl, Cyclo
• the divalent monocyclic saturated heterocyclic group is a divalent group formed by further removing any one hydrogen atom from the monocyclic heterocyclic group not containing the above multiple bonds, for example.
• the divalent heterocyclic group is a divalent group formed by further removing an arbitrary one hydrogen atom from the above heterocyclic group, and is a divalent monocyclic heterocyclic group and divalent. Includes bicyclic heterocyclic groups.
• the divalent monocyclic heterocyclic group is a divalent group formed by further removing any one hydrogen atom from the above monocyclic heterocyclic group, and is a divalent monocyclic nitrogen-containing group.
• Heterocyclic groups, divalent monocyclic oxygen-containing heterocyclic groups, divalent monocyclic sulfur-containing heterocyclic groups, divalent monocyclic nitrogen-containing / oxygen heterocyclic groups and divalent monocycles Includes ring nitrogen-containing / sulfur heterocyclic groups.
• the divalent bicyclic heterocyclic group is a divalent group formed by further removing an arbitrary one hydrogen atom from the above bicyclic heterocyclic group, and is a divalent bicyclic group.
• Nitrogen-containing heterocyclic group, divalent bicyclic oxygen-containing heterocyclic group, divalent bicyclic sulfur-containing heterocyclic group, divalent bicyclic nitrogen-containing / oxygen heterocyclic group Includes group and divalent bicyclic nitrogen-containing / sulfur heterocyclic groups.
• the divalent cyclic amino group is a divalent group formed by further removing any one hydrogen atom from the above cyclic amino group, for example, aziridine, azetidine, pyrrol, dihydropyrrole, pyrrolidine, tetrahydropyridine, and the like.
• the price group can be mentioned.
• Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group or an arylsulfonyloxy group, and an imidazole group.
• the C 1-6 alkylsulfonyloxy group, arylsulfonyloxy group or imidazole group may have a substituent.
• Hydroxyl protecting groups include all groups that can be used as conventional hydroxyl protecting groups, such as W. W.Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, INC.) Can be mentioned.
• C 1-6 alkyl group C 2-6 alkenyl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl
• examples include a group, an aryl C 1-6 alkoxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group. These groups may be substituted with one or more groups selected from the substituent group A1.
• Amino protecting groups include all groups that can be used as ordinary protecting groups for amino groups, such as W. W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons, INC.) Can be mentioned. Specifically, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, aryl C 1-6 alkoxycarbonyl group, aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group or a silyl group. These groups may be substituted with one or more groups selected from the substituent group A1.
• the imino protecting group includes all groups that can be used as a conventional imino protecting group, for example, W. W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-868, 2007, John Wiley & Sons, INC.) Can be mentioned. Specifically, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, aryl C 1-6 alkoxycarbonyl group, aryloxycarbonyl group, Examples thereof include a C 1-6 alkylsulfonyl group, an arylsulfonyl group or a silyl group. These groups may be substituted with one or more groups selected from the substituent group A1.
• Carboxyl protecting groups include all groups that can be used as conventional protecting groups for carboxyl groups, such as W. W.Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007, John Wiley & Sons, INC.) Can be mentioned. Specific examples thereof include a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group or a silyl group. These groups may be substituted with one or more groups selected from the substituent group A1.
• Aliphatic hydrocarbons include, for example, pentane, hexane, cyclohexane, heptane or decahydronaphthalene.
• halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.
• alcohols include methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
• ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether.
• ketones examples include acetone, 2-butanone and 4-methyl-2-pentanone.
• esters examples include methyl acetate, ethyl acetate, propyl acetate and butyl acetate.
• amides examples include N, N-dimethylformamide, N, N-dimethylacetamide or 1-methyl-2-pyrrolidone.
• nitriles examples include acetonitrile or propionitrile.
• aromatic hydrocarbons examples include benzene, toluene and xylene.
• Substituent group A1 Hydrogen atom, Halogen atom, Cyanide group, Nitro group, Oxy group, A C 1-6 alkyl group which may be substituted with one or more groups selected from the substituent group B2, A C 2-6 alkenyl group which may be substituted with one or more groups selected from the substituent group B2, A C 2-6 alkynyl group which may be substituted with one or more groups selected from the substituent group B2, A C 1-6 alkoxy group which may be substituted with one or more groups selected from the substituent group B2, Aryloxy groups that may be substituted with one or more groups selected from the substituent group B1. An acyl group that may be substituted with one or more groups selected from the substituent group B1.
• a C 1-6 alkylamino group which may be substituted with one or more groups selected from the substituent group B2
• a di (C 1-6 alkyl) amino group which may be substituted with one or more groups selected from the substituent group B2
• An imino group which may be substituted with one or more groups selected from the protected or substituent group B1.
• a C 1-6 alkylthio group which may be substituted with one or more groups selected from the substituent group B2, An arylthio group which may be substituted with one or more groups selected from the substituent group B1.
• Substituent group A2 Hydrogen atom, Halogen atom, Cyanide group, Nitro group, Oxy group, A C 1-6 alkoxy group which may be substituted with one or more groups selected from the substituent group B2, Aryloxy groups that may be substituted with one or more groups selected from the substituent group B1. An acyl group that may be substituted with one or more groups selected from the substituent group B1.
• a C 1-6 alkylamino group which may be substituted with one or more groups selected from the substituent group B2, A di (C 1-6 alkyl) amino group, which may be substituted with one or more groups selected from the substituent group B2, A C 1-6 alkylthio group which may be substituted with one or more groups selected from the substituent group B2, An arylthio group which may be substituted with one or more groups selected from the substituent group B1.
• a C 1-6 alkylsulfonyl group which may be substituted with one or more groups selected from the substituent group B2, Arylsulfonyl groups that may be substituted with one or more groups selected from the substituent group B1.
• a C 3-8 cycloalkyl group which may be substituted with one or more groups selected from the substituent group B1.
• Aryl groups that may be substituted with one or more groups selected from the substituent group B1, A heterocyclic group which may be substituted with one or more groups selected from the substituent group B1.
• a carbamoyl group which may be substituted with one or more groups selected from the substituent group B1.
• a sulfamoyl group which may be substituted with one or more groups selected from the substituent group B1.
• Substituent group B1 Hydrogen atom, Halogen atom, Cyanide group, Nitro group, Oxy group, A C 1-6 alkyl group which may be substituted with one or more groups selected from the substituent group C, A C 2-6 alkenyl group which may be substituted with one or more groups selected from the substituent group C, A C 2-6 alkynyl group which may be substituted with one or more groups selected from the substituent group C, A C 1-6 alkoxy group, which may be substituted with one or more groups selected from the substituent group C, Aryloxy groups that may be substituted with one or more groups selected from the substituent group C, Acyl groups that may be substituted with one or more groups selected from the substituent group C, A C 1-6 alkylamino group which may be substituted with one or more groups selected from the substituent group C, A di (C 1-6 alkyl) amino group, which may be substituted with one or more groups selected from the substituent group C, A C 1-6 alkylthio group which may be
• Substituent group B2 Hydrogen atom, Halogen atom, Cyanide group, Nitro group, Oxy group, A C 1-6 alkoxy group, which may be substituted with one or more groups selected from the substituent group C, Aryloxy groups that may be substituted with one or more groups selected from the substituent group C, Acyl groups that may be substituted with one or more groups selected from the substituent group C, A C 1-6 alkylamino group which may be substituted with one or more groups selected from the substituent group C, A di (C 1-6 alkyl) amino group, which may be substituted with one or more groups selected from the substituent group C, A C 1-6 alkylthio group which may be substituted with one or more groups selected from the substituent group C, An arylthio group which may be substituted with one or more groups selected from the substituent group C, A C 1-6 alkylsulfonyl group which may be substituted with one or more groups selected from the substituent group C, Arylsulfonyl groups
• Substituent group C Halogen atom, Cyanide group, Carbamic group, C 1-6 alkyl group, C 1-6 Alkoxy group, Amino groups that may be protected, Imino groups that may be protected, Hydroxy groups, which may be protected, Carboxyl groups that may be protected.
• the C 1-6 alkylene group, C 2-6 alkenylene group and C 2-6 alquinylene group of X 1 , Y 1 and Y 2 may be substituted with one or more groups selected from the substituent group A2. ..
• the C 1-6 alkyl groups of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 may be substituted with one or more groups selected from the substituent group A2.
• the C 2-6 alkylene and C 2-6 alkenylene groups formed by R 5 and R 6 together may be substituted with one or more groups selected from the substituent group A1.
• the C 2-6 alkylene group formed by combining R 5a and R 6a may be substituted with one or more groups selected from the substituent group A1.
• the C 1-6 alkoxy group, C 1-6 alkylamino group, di (C 1-6 alkyl) amino group and amino group of R 10 are substituted with one or more groups selected from the substituent group A2. May be good.
• the C 1-6 alkoxy group of R 10a may be substituted with one or more groups selected from the substituent group A2.
• the cyclic amino group of R 10 may be substituted with one or more groups selected from the substituent group A1.
• the carbamoyl groups of R 10 and R 11 may be substituted with one or more groups selected from the substituent group A1.
• Aryl and heterocyclic groups of R 2 may be substituted with one or more groups selected from Substituent Group A1.
• the heterocyclic group of A may be substituted with one or more groups selected from the substituent group A1.
• the divalent cyclic hydrocarbon group of X 1 may be substituted with one or more groups selected from the substituent group A1.
• the saturated heterocyclic group of the divalent monocycle of X 1 may be substituted with one or more groups selected from the substituent group A1.
• the divalent heterocyclic groups and divalent cyclic amino groups of X 2 and Q may be substituted with one or more groups selected from the substituent group A1.
• R 1 is preferably a compound which is a hydrogen atom.
• R 2 is preferably a compound which is an aryl group which may be substituted, and more preferably a compound which is a phenyl group which may be substituted. The substituent of the aryl group or heterocyclic group of R 2, 1 or more groups selected from hydroxyl group which may be halogen atoms and protection are preferred.
• R 3 is preferably a compound which is a hydrogen atom.
• X 1 is preferably a C 1-6 alkylene group which may be substituted or a divalent cyclic hydrocarbon group which may be substituted, and a C 1-3 alkylene group which may be substituted or is substituted.
• a divalent cyclic hydrocarbon group which may be used is more preferable.
• A is preferably a compound which is a optionally substituted monocyclic heterocyclic group, and may be a optionally substituted monocyclic nitrogen-containing heterocyclic group or an optionally substituted monocyclic nitrogen-containing group.
• Sulfur-containing heterocyclic groups are more preferred, monocyclic nitrogen-containing and sulfur-containing heterocyclic groups are even more preferred, 2-amino-5-chlorothiazole-4-yl, 5-amino-1,2,4-thiadiazole.
• -3-yl or 2-aminothiazole-4-yl is even more preferred, and 2-aminothiazole-4-yl is particularly preferred.
• a divalent heterocyclic group which may be substituted is preferable, a divalent monocyclic heterocyclic group which may be substituted is preferable, and a divalent imidazolidine group which may be substituted is preferable.
• a divalent piperazine group, a divalent pyrrolidine group or a divalent oxazolidine group is more preferred, and a optionally substituted divalent imidazolidine group, a divalent piperazine group or a divalent pyrrolidine group is even more preferred. ..
• Q is preferably, for example, 2-oxoimidazolidine-1-yl group, 2,3-dioxopiperazine-1-yl group, 2-oxopyrrolidine-1-yl group or 2-oxooxazolidine-3-yl group.
• Groups or binders are even more preferred.
• X 2 is a group represented by the general formula-NR 4a- "in the formula, R 4a represents a hydrogen atom or a carbamoyl group", and the general formula-N + R 5a R 6a- "in the formula, R 5a and R 6a represents a C 2-6 alkylene group which may be substituted together.
• a divalent cyclic amino group which may be substituted, a divalent heterocyclic group which may be substituted, or a bonder is preferable.
• the group or bond represented by the general formula-NR 4b- "in the formula, R 4b represents a hydrogen atom" is more preferable.
• Y 2 is preferably a C 1-6 alkylene group or a bond which may be substituted, and more preferably a C 1-3 alkylene group or a bond.
• X 3 is preferably a group or a bond represented by the general formula-NR 9a- "in the formula, R 9a represents a hydrogen atom.”
• R 10a represents a optionally substituted C 1-6 alkoxy group, a optionally protected hydroxyl group, or a ureido group.
• CR 11a -A group represented by "in the formula, R 11a represents a optionally substituted carbamoyl group or a optionally protected carboxyl group” is preferred and is of formula-C ( O)-.
• Examples of the salt of the compound of the general formula [1], the ⁇ -lactamase inhibitory compound and the antibacterial compound include commonly known salts in a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group. ..
• Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitrate and sulfuric acid; formic acid, acetic acid, citrate, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid. , Salts with organic carboxylic acids such as tartrate, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
• mineral acids such as hydrochloric acid, hydrobromic acid, nitrate and sulfuric acid
• formic acid acetic acid, citrate, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid.
• Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidin, N-methylmorpholin, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N'-dibenzylethylenediamine. And salt etc.
• alkali metals such as sodium and potassium
• salts with alkaline earth metals such as calcium and magnesium
• ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidin, N-methylmorpholin, diethy
• preferred salts include pharmacologically acceptable salts.
• the general formula [1] When isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present in the compounds of the general formula [1], ⁇ -lactamase inhibitory compounds and antibacterial compounds or salts thereof, the general formula [1]
• the compounds represented by 1], ⁇ -lactamase inhibitory compounds and antibacterial compounds or salts thereof include isomers thereof, and include solvates, hydrates and crystals of various shapes. Is.
• compositions and kits of the present invention can be further combined with one or more pharmaceutically acceptable carriers, excipients or diluents.
• pharmaceutically acceptable carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, and the like.
• additives such as commonly used bulking agents, binders, disintegrants, pH adjusters and solubilizers are mixed with the above carriers, excipients or diluents, and a conventional formulation technique is used.
• Can be used to prepare oral or parenteral medicines such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, excipients or skin patches.
• Gram-negative bacterial infections include, for example, Pseudomonas, Stenotrophomonas, Burkholderia, Acinetobacter, Alcaligenes, and Bordetella. , Brucella, Bacteroides, Fusobacterium, Neisseria, Moraxella, Campylobacter, Helicobacter, Vibrio, Aeromonas Gram-negative, such as the group consisting of (Aeromonas), Haemophilus, Chryseobacterium, Elizabethkingia, Fusobacterium and Enterobacteriaceae. Infectious diseases caused by bacteria can be mentioned.
• the pharmaceutical composition of the present invention contains a compound represented by the general formula [1] or a salt thereof, and one or more compounds selected from ⁇ -lactamase inhibitory compounds and antibacterial compounds or salts thereof in a single preparation. It is characterized by containing.
• the route of administration of the pharmaceutical composition is not particularly limited, but can be administered by intravenous, oral, intramuscular, subcutaneous, inhalation, spraying or other routes of administration.
• the kit of the present invention contains a compound represented by the general formula [1] or a salt thereof, and one or more compounds selected from ⁇ -lactamase inhibitory compounds and antibacterial compounds or salts thereof in a single package. It is characterized by that.
• the kit may include, for example, instruments for administration, instructions, instructions, package inserts and / or product labels. When the administration route of one or more compounds selected from the compound represented by the general formula [1] or a salt thereof and the ⁇ -lactamase inhibitory compound and the antibacterial compound or a salt thereof is different, or the dose setting of each component is set.
• the kit is particularly useful if it is preferred that it be done by a doctor.
• the administration route of the kit of the present invention is not particularly limited, and administration can be performed by intravenous, oral, intramuscular, subcutaneous, inhalation, spraying or other administration routes.
• the compound represented by the general formula [1] or a salt thereof is administered separately or in a specific order at the same time as one or more compounds selected from ⁇ -lactamase inhibitory compounds and antibacterial compounds or salts thereof. You may.
• the pharmaceutical compositions and kits of the present invention are useful in the treatment of Gram-negative bacterial infections, especially drug-resistant Gram-negative bacterial infections.
• the pharmaceutical compositions and kits of the present invention are further useful in the treatment of infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and / or Stenotrophomonas maltophilia. is there.
• it is useful in the treatment of infections caused by Escherichia coli, Klebsiella pneumoniae and / or Pseudomonas aeruginosa.
• the pharmaceutical compositions and kits of the present invention further include Class A (TEM, SHV, CTX-M, KPC, GES, etc.); Class B (IMP, VIM, NDM, etc.); Class C. (AmpC and CMY types, etc.); And is effective in treating infections caused by drug-resistant bacteria that produce class D (OXA type) ⁇ -lactamase.
• Class A TEM, SHV, CTX-M, KPC, GES, etc.
• Class B IMP, VIM, NDM, etc.
• Class C. AmpC and CMY types, etc.
• the pharmaceutical compositions and kits of the present invention allow for the treatment of more serious Gram-negative bacterial infections.
• more serious Gram-negative bacterial infections can be treated by administering a combination of drugs in an amount that does not cause side effects.
• it is possible to reduce the side effects of each drug by showing a strong antibacterial action even if the amount of each drug used is reduced and administered.
• Treatment with the pharmaceutical compositions and kits of the present invention includes treatment and prevention, and treatment is preferred.
• the administration method, dose and frequency of administration of the pharmaceutical composition and kit of the present invention can be appropriately selected according to the age, body weight and symptoms of the patient.
• the compound represented by the general formula [1] of the present invention, ⁇ -lactamase inhibitory compound and antibacterial As the amount of one or more compounds selected from the sex compounds or salts thereof, 0.01 to 300 mg / kg may be administered in one to several divided doses per day, respectively.
• the pharmaceutical composition and kit of the present invention are preferably administered as an injection.
• the pharmaceutical composition and kit of the present invention are preferably produced as a liquid, a freeze-dried solution or a lyophilized preparation, and a lyophilized preparation is more preferable.
• Examples of the ⁇ -lactamase inhibitory compound used in the present invention include diazabicyclo [3.2.1] octane type inhibitory compound, boronic acid type inhibitory compound and clavam type inhibitory compound, and examples thereof include avibactam, nacuvactum and relevactum.
• Examples of the diazabicyclo [3.2.1] octane type inhibitory compound include avivactum, nacuvactum, relevactum and didebactam, with avivactum, nacuvactum and didebactam being preferred, and avivactum being more preferred.
• Examples of the boronic acid type inhibitory compound include bavolbactam and (3R) -3- (2- [trans-4-[(2-aminoethyl) amino] cyclohexyl] acetamide) -2-hydroxy-3,4-dihydro-. Examples thereof include 2H-1,2-benzoxabolinin-8-carboxylic acid (development code: VNRX-5133), and bavolvactam is preferable.
• clavam-type inhibitory compound examples include sulbactam, tazobactam, clavulanic acid, (1aR, 7bS) -5-fluoro-2-hydroxy-1,1a, 2,7b-tetrahirodocyclopropa [c] [1, 2] Benoxabolinin-4-carboxylic acid (development code: QPX7728) and (2S, 3S, 5R) -3-methyl-3-[(3-methyl-1H-1,2,3-triazole-3-] Ium-1-yl) methyl] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide (development code: AAI-101), etc. Sulbactam, tazobactam and clavulanic acid are preferable, and tazobactam is more preferable.
• Examples of the antibacterial compound described in the present invention include ⁇ -lactam type, macrolide type, lincomycin type, streptogramin type, quinolone type, aminoglycoside type, riffamycin type, tetracycline type, amphenicole type and sulfonamide.
• compounds such as trimethoprim, oxazolidinone, polymyxin, preuromtiline, glycopeptide, imidazole and nitrofuran, such as piperacillin, ceftazidime, imipenem, mesylinum, levofloxacin, amikacin, polymyxin B, tetracycline. , Trimethoprim and rifampicin.
• ⁇ -lactam compounds include penicillins such as benzylpenicillin, phenoxymethylpenicillin, cloxacillin, oxacillin, naphthylin, methicillin, amoxicillin, ampicillin, ticarcillin, carbenicillin, piperacillin, azlocillin, mezlocillin and mesylinum; , Cephalotin, cefaclor, cefuroxime, cefotiam, loracalvev, cefepim, cefosoplan, cefpirom, cefazolin, cefazolin, ceftrozan and ceftoviprol and other cephalosporin compounds; cefotetan, cefoxitin and cefmethazole and other cephamycin compounds; System compounds; carbapenem-based compounds such as ertapenem, dripenem, imipenem, meropenem, biapenem and panipenem; and monobactam-
• penicillin-based compound ampicillin, piperacillin and mecillinum are preferable, and piperacillin is more preferable.
• cephalosporin-based compound ceftazidime, cefmetazole, loracarbef, cefepime, cefozopran, cefpyrom, ceftazidime, ceftaroline, ceftrozan and ceftviprol are preferable, and ceftazidime is more preferable.
• cephamycin compound cefmetazole is preferable.
• penem-based compound faropenem is preferable.
• carbapenem-based compound ertapenem, doripenem, imipenem, meropenem and biapenem are preferable, and imipenem is more preferable.
• monobactam compound aztreonam, tigemonam and carmonam are preferable, and aztreonam is more preferable.
• macrolide compound examples include erythromycin, spiramycin, josamicin, clarithromycin, azithromycin, rokitamycin, telithromycin and solithromycin, and erythromycin, spiramycin, azithromycin and solithromycin are preferable.
• Examples of lincomycin-based compounds include clindamycin and lincomycin.
• Examples of the streptogramin-based compound include quinupristin / dalhopristin.
• quinolone compounds include ofloxacin, ciprofloxacin, enoxacin, norfloxacin, spalfloxacin, grepofloxacin, levofloxacin, moxifloxacin, gemifloxacin, gachifloxacin, purlifloxacin, pazufloxacin, and galenoxacin.
• ciprofloxacin ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin, gachifloxacin, pazufloxacin, galenoxacin, citafloxacin and tosfloxacin, levofloxacin, levofloxacin, Pazfloxacin is more preferred, and levofloxacin is even more preferred.
• aminoglycoside compound examples include streptomycin, tobramycin, gentamicin, canamycin, neomycin, amikacin, dibecacin, albecacin and apramycin, and tobramycin, gentamicin and amikacin are preferable, and amikacin is more preferable.
• rifamycin-based compound examples include rifaximin, rifabutin, and rifampicin, and rifampicin is preferable.
• tetracycline-based compound examples include doxycycline, tetracycline, minocycline, tigecycline and eravacycline, with tetracycline and minocycline being preferred, and tetracycline being more preferred.
• amphenicol compound examples include chloramphenicol and the like.
• sulfonamide and trimethoprim compounds examples include trimethoprim, icrapim and sulfamethoxazole, and trimethoprim is preferable.
• oxazolidinone-based compound examples include linezolid and tedizolid.
• polymyxin-based compound examples include colistin and polymyxin B, and polymyxin B is preferable.
• examples of the pleeuromutilin-based compound include tiamulin and the like.
• glycopeptide compound examples include vancomycin, teicoplanin, teravancin, dalvavancin, oritavancin, and vancomycin is preferable.
• Examples of the imidazole compound include metronidazole and the like.
• Examples of the nitrofuran-based compound include nitrofurantoin.
• the compound represented by the general formula [1] of the present invention is produced by combining methods known per se, and can be produced, for example, according to the following production method.
• Ra is a halogen atom
• Y 1a is a bond
• X 2a is a group represented by the formula -NH-
• R 1a and R 3a are carboxyl protecting groups
• R 2 , Q. , Y 2 , Y 3 , X 1 , X 3 and A have the same meanings as described above.
• the compound of the general formula [1a] can be produced by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [2b] in the presence of a base.
• Compounds represented by the general formula [2b] include, for example, 2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzoyl chloride and 2- (2-chloro-3, Examples thereof include acid halides such as 4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetyl chloride.
• the amount of the compound represented by the general formula [2b] to be used is not particularly limited, but may be 0.9 to 10 times mol, preferably 0.9 to 2.0 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a].
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 72 hours, preferably 0 to 40 ° C. for 1 to 4 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatics. Hydrocarbons and water are mentioned, and these solvents may be mixed and used. Preferred solvents include tetrahydrofuran, acetonitrile and water, with a more preferred mixed solvent of tetrahydrofuran and water.
• Examples of the base used in this reaction include inorganic bases and organic bases.
• Preferred bases include inorganic bases, with sodium hydrogen carbonate being preferred.
• R b is a hydroxyl group or a carboxyl group
• R 1a , R 3a , R 2 , Q, Y 1a , Y 2 , Y 3 , X 1 , X 2 , X 3 and A have the same meanings as described above.
• the compound of the general formula [1b] is prepared by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [3a] in the presence of a condensing agent or an acid halide in the presence of a base. Can be manufactured.
• the amount of the compound represented by the general formula [3a] to be used is not particularly limited, but may be 0.9 to 10 times mol, preferably 0.9 to 2.0 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a].
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 72 hours, preferably 0 to 40 ° C. for 1 to 24 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatics. Hydrocarbons and water are mentioned, and these solvents may be mixed and used. When a condensing agent is used, dimethylacetamide and DMF are preferable as the solvent. When an acid halide is used, preferred solvents include tetrahydrofuran, acetonitrile and water, with a mixed solvent of tetrahydrofuran and water more preferred.
• Examples of the base used in this reaction include an inorganic base and an organic base.
• preferred bases include organic bases, with N-methylmorpholine being more preferred.
• preferred bases include inorganic bases, preferably sodium hydrogen carbonate.
• examples of the condensing agent include N, N'-diisopropylcarbodiimide (DIC), N, N'-di- (tert-butyl) carbodiimide, N, N'-dicyclohexylcarbodiimide (DCC), and the like.
• Preferred condensing agents include carbodiimides, uroniums and triazines, with EDC, HATU and DMT-MM being more preferred.
• the amount of the condensing agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula [2a].
• the condensing agent When carbodiimides are used as the condensing agent, it is preferable to add an additive.
• the additive include 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT) and ethyl (hydroxyimino) cyanoacetylate, and HOBT and ethyl (hydroxyimino) cyanoacetylate are preferable.
• the amount of the additive used may be 0.01 to 10 times mol, preferably 0.1 to 1 times mol, of the compound represented by the general formula [2a].
• the acid halides include, for example, oxalyl chlorides; carboxylic acid halides such as acetyl chloride and trifluoroacetyl chloride; sulfonic acid halides such as methanesulfonyl chloride and tosyl chloride; Chlorogate esters such as ethyl and isobutyl chlorogitate; halide halides such as thionyl chloride and thionyl bromide; and halide halides such as phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride and phosphorus pentachloride Oxalyl chloride is preferred.
• the amount of the acid halide used may be 0.9 to 3 times mol, preferably 0.9 to 1.5 times mol, of the compound represented by the general formula [3a].
• L 1c is a leaving group
• R c is a tertiary amino group or a heterocyclic group
• X. 2 is a group represented by the general formula ⁇ N + R 5 R 6 ⁇ (in the formula, R 5 and R 6 have the same meanings as described above);
• R 1a , R 3a , R 2 , Q, Y 1a , Y 2 , Y 3 , X 1 , X 3 and A have the same meanings as described above.
• the compound of the general formula [1c] can be produced by the following method.
• the compound of the general formula [4b] can be produced by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [4a] in the presence of a base.
• the amount of the compound represented by the general formula [4a] to be used is not particularly limited, but may be 0.9 to 20 times mol, preferably 0.9 to 10 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a].
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 20 times mol, of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 48 hours, preferably 0 to 40 ° C. for 1 to 5 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatics. Hydrocarbons and water are mentioned, and these solvents may be mixed and used.
• Examples of the base used in this reaction include inorganic bases and organic bases.
• Preferred bases include organic bases, with pyridine being more preferred.
• (3-2) Alkylation As a compound represented by the general formula [4c], for example, 2-chloro-3,4-bis ((4-methoxybenzyl) oxy) -N- (2) described in the present specification. -(Pyrrolidine-1-yl) ethyl) benzamide and the like are known.
• the compound of the general formula [1c] can be produced by reacting the compound represented by the general formula [4b] with the compound represented by the general formula [4c].
• the amount of the compound represented by the general formula [4c] to be used is not particularly limited, but may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula [4b]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [4b]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 72 hours, preferably 0 to 50 ° C. for 1 to 24 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• the compound of the general formula [1d] can be produced by the following method.
• the compound of the general formula [5b] can be produced by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [5a].
• the amount of the compound represented by the general formula [5a] to be used is not particularly limited, but may be 0.9 to 20 times mol, preferably 0.9 to 10 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 48 hours, preferably 0 to 50 ° C. for 1 to 4 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• an acetal-protected product of halogenated acetaldehyde is used as the compound represented by the general formula [5a]
• an acid catalyst include p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonic acid, and 10-camphorsulfonic acid, and p-toluenesulfonic acid monohydrate is preferable.
• the amount of the acid catalyst used may be 0.01 to 10 times mol, preferably 0.1 to 1 times mol, of the compound represented by the general formula [5a].
• (4-2) Alkylation As a compound represented by the general formula [4c], for example, 2-chloro-3,4-bis ((4-methoxybenzyl) oxy) -N- (2) described in the present specification. -(Pyrrolidine-1-yl) ethyl) benzamide and the like are known.
• the compound of the general formula [1d] can be produced by reacting the compound represented by the general formula [5b] with the compound represented by the general formula [4c].
• the amount of the compound represented by the general formula [4c] to be used is not particularly limited, but may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula [5b]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [5b]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 72 hours, preferably 0 to 50 ° C. for 1 to 4 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• the compound of the general formula [6b] can be produced by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [6a].
• the amount of the compound represented by the general formula [6a] to be used is not particularly limited, but may be 1 to 50 times mol, preferably 1 to 20 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 48 hours, preferably 0 to 40 ° C. for 1 to 12 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• (5-2) Iminization As a compound represented by the general formula [6c], for example, N- (2-aminoethyl) -2-chloro-3,4-bis ((4-methoxy) described in the present specification. Examples thereof include benzyl) oxy) benzamide.
• the compound of the general formula [1e] can be produced by reacting the compound represented by the general formula [6b] with the compound represented by the general formula [6c].
• the amount of the compound represented by the general formula [6c] to be used is not particularly limited, but may be 1 to 20 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [6b]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [6b]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 72 hours, preferably 0 to 40 ° C. for 1 to 12 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• R g is an acetaldehyde group
• X 2 is a group represented by the formula -NH-
• R 1a , R 3a , R 2, Q, Y 1a, Y 2, Y 3, X 1, X 3 and a have the same meanings as defined above.
• the compound of the general formula [1f] can be produced by the following method.
• Examples of the compound represented by the general formula [7a] include 2-chloro-3,4-bis ((4-methoxybenzyl) oxy) -N- (2-oxoethyl) benzamide described in the present specification. Be done.
• the compound of the general formula [1f] can be produced by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [7a].
• the amount of the compound represented by the general formula [7a] to be used is not particularly limited, but may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 72 hours, preferably 0 to 40 ° C. for 1 to 12 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• L 1e represents a leaving group
• R f represents a primary amino group, a secondary amino group and a secondary cyclic amino group
• R 1a , R 3a , R 2 , Q, Y 1a , Y 2 , Y 3 , X 1 , X 3 and A are as described above. It has the same meaning.
• the compound of the general formula [1 g] can be produced by the following method.
• the compound represented by the general formula [8a] examples include phosgene, triphosgene, and carbonyldiimidazole.
• the compound of the general formula [8b] can be produced by reacting the compound represented by the general formula [2a] with the compound represented by the general formula [8a].
• the amount of the compound represented by the general formula [8a] to be used is not particularly limited, but may be 1 to 20 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [2a]. Just do it.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [2a]. This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 48 hours, preferably 0 to 80 ° C. for 1 to 24 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• the compound of the general formula [1 g] can be produced by reacting the compound represented by the general formula [8b] with the compound represented by the general formula [6c] in the presence of a base.
• the amount of the compound represented by the general formula [6c] to be used is not particularly limited, but may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula [8b]. Just do it.
• Examples of the base used in this reaction include an inorganic base and an organic base.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [2a].
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [8b].
• This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 48 hours, preferably 0 to 40 ° C. for 1 to 12 hours.
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatics. Hydrocarbons and water are mentioned, and these solvents may be mixed and used.
• the compound represented by the general formula [9c] is a compound represented by the general formula [9a] or a hydrochloride thereof in the presence of a condensing agent or an acid halide in the presence of a base. It can be produced by reacting with the compound represented by [9b].
• a compound represented by the general formula [9a] for example, benzhydryl (3R, 5R, 6R) -6-amino-3- (3-((E) -benzylidene) amino) -2 described in the present specification. -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylate hydrochloride can be mentioned.
• the compound represented by the general formula [9a] is, for example, JP-A-4-74182, pp. 9-14, JP-A-10-182654, pp. 6-. It can be produced according to the method described on page 12, US5185330, paragraphs 8 to 20.
• Examples of the compound represented by the general formula [9b] include (Z) -2- (2-aminothiazole-4-yl) -2-(((1- (tert-butoxy)-) described in the present specification. Examples thereof include 2-methyl-1-oxopropan-2-yl) oxy) imino) acetic acid.
• the compound of the general formula [9c] can also be produced by reacting the compound represented by the general formula [9a] with the benzothiazolyl ester of the compound represented by the general formula [9b].
• the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but for example, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides and aromatics. Hydrocarbons are mentioned, and these solvents may be mixed and used.
• Preferred solvents include halogenated hydrocarbons, ethers, esters and amides, with halogenated hydrocarbons and amides being more preferred.
• the amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound represented by the general formula [9a].
• Examples of the base used in this reaction include an inorganic base and an organic base.
• Preferred bases include organic bases, with triethylamine, N, N-diisopropylethylamine and 4-methylmorpholine being more preferred, and N, N-diisopropylethylamine and 4-methylmorpholine being even more preferred.
• the amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula [9a].
• Examples of the condensing agent used in this reaction include the condensing agent described in Production Method 3.
• Preferred condensing agents include carbodiimides, with EDC being more preferred.
• the amount of the condensing agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula [9a].
• the condensing agent When carbodiimides are used as the condensing agent, it is preferable to add an additive.
• the additive include 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT) and ethyl (hydroxyimino) cyanoacetylate, and HOBT and ethyl (hydroxyimino) cyanoacetylate are preferable.
• the amount of the additive used may be 0.01 to 10 times mol, preferably 0.1 to 1 times mol, of the compound represented by the general formula [9a].
• acid halides used in this reaction include oxalyl chlorides; carboxylic acid halides such as acetyl chloride and trifluoroacetyl chloride; sulfonic acid halides such as methanesulfonyl chloride and tosyl chloride; ethyl chloride and Examples include chlorogenic acid esters such as isobutyl chlorostate; halides sulfites such as thionyl chloride and thionyl bromide; and phosphate halides such as phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride and phosphorus pentachloride. ..
• the amount of the acid halide used may be 0.9 to 3 times mol, preferably 0.9 to 1.5 times mol, of the compound represented by the general formula [9b].
• the amount of the compound represented by the general formula [9b] to be used is not particularly limited, but may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound represented by the general formula [9a]. Just do it.
• This reaction may be carried out at -30 to 150 ° C. for 30 minutes to 48 hours, preferably 0 to 50 ° C. for 1 to 12 hours.
• silica gel column chromatography is flash column chromatography, and the carrier thereof is Fuji Silysia Chemical Ltd., B.I. W. Silica gel, BW-300.
• the carrier thereof is Fuji Silysia Chemical Ltd., B.I. W. Silica gel, BW-300.
• For medium-pressure reverse-phase silica gel column chromatography Biotage Japan Co., Ltd., Isola SV or Isolera LSV was used, and as the carrier, Biotage Japan Co., Ltd., SNAP Ultra C18 Cartridge was used.
• the mixing ratio in the eluent is the volume ratio.
• the NMR spectrum was measured using AVANCE III HD400 (Bruker Co., Ltd.). The NMR spectrum showed proton NMR, the internal reference was as follows, and the ⁇ value was shown in ppm.
• the MS spectrum was measured by an electrospray ionization method (ESI) using ACQUITY SQD LC / MS System (Waters Corp.).
• each abbreviation has the following meaning.
• Alloc allyloxycarbonyl
• BH diphenylmethyl
• Boc tert-butoxycarbonyl
• Cbz benzyloxycarbonyl
• DBU 1,8-diazabicyclo [5.4.0] -7-undecene
• DMAC N, N-dimethyl Acetamide
• DMAP 4- (dimethylamino) pyridine
• DMF N, N-dimethylformamide
• EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
• ESI electrospray ionization method
• Et Ethyl
• HOBt 1-Hydroxybenzotriazole monohydrate
• HATU O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate
• IPE Diis
• Reference example 2 (2) Methanol (5.8 mL), THF (5.8 mL) and a 2 mol / L sodium hydroxide aqueous solution (4.5 mL) were added to the compound (600 mg) obtained in Reference Example 2 (1), and the mixture was stirred overnight at room temperature. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the pH was adjusted to 1.8 with 2 mol / L hydrochloric acid. The reaction mixture was stirred at room temperature for 30 minutes and the solid was collected by filtration.
• Reference example 3 (2) Methanol (13 mL), THF (13 mL) and a 2 mol / L sodium hydroxide aqueous solution (4.7 mL) were added to the compound (1.27 g) obtained in Reference Example 3 (1), and the mixture was stirred at room temperature for 2 hours and 30 minutes. 2 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 1.9. Ethyl acetate (25 mL) and water (25 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dehydrated and dried over anhydrous sodium sulfate.
• Reference example 7 (2) Dichloromethane (20 mL) and methylhydrazine (189 ⁇ L) were added to the compound (2.30 g) obtained in Reference Example 7 (1), and the mixture was stirred at room temperature for 2 hours. The solid was then filtered and the solvent evaporated under reduced pressure to give N- (2- (aminooxy) ethyl) -2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzamide (1.97). g) was obtained as a brown solid.
• Reference example 9 (4) Dichloromethane (20 mL) and methanol (10 mL) were added to the compound (1.0 g) obtained in Reference Example 9 (3), and the mixture was stirred with ice cooling. At the same temperature, 2,4-dinitrophenylhydrazine (50% wet product, 1.28 g) and p-toluenesulfonic acid monohydrate (308 mg) were sequentially added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours and 30 minutes. Ethyl acetate (220 mL) and water (110 mL) were added to the reaction mixture. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 8.2.
• Reference example 10 (2) THF (170 mL), 1,3-dimethylbarbituric acid (2.5 g) and tetrakis (triphenylphosphine) palladium (0) (1.7 g) were added to the compound (8.5 g) obtained in Reference Example 10 (1). The mixture was added sequentially and stirred at room temperature for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and dehydrated and dried over anhydrous sodium sulfate.
• Reference example 16 (2) THF (130 mL), 1,3-dimethylbarbituric acid (1.8 g) and tetrakis (triphenylphosphine) palladium (0) (1.2 g) were added to the compound (6.3 g) obtained in Reference Example 16 (1). They were added sequentially and stirred at room temperature for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and dehydrated and dried over anhydrous sodium sulfate.
• Reference example 17 (1) N- (2-Aminoethyl) -2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzamide (1.2 g) with dichloromethane (40 mL), pyridine (310 ⁇ L) and ethyl chlorooxoacetate (1.2 g) at room temperature. 430 ⁇ L) was added sequentially. The reaction mixture was stirred between 40 ° C and 50 ° C for 2 hours. At the same temperature, pyridine (100 ⁇ L) and ethyl chlorooxoacetate (145 ⁇ L) were added sequentially to the reaction mixture. The reaction mixture was stirred at the same temperature for 3 hours.
• Reference example 17 (2) THF (20 mL), water (10 mL) and lithium hydroxide (120 mg) were sequentially added to the compound obtained in Reference Example 17 (1), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were sequentially added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dehydrated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, IPE was added to the residue, and the solid was collected by filtration.
• the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated aqueous sodium chloride solution, and dehydrated and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure, IPE (20 mL) and hexane (100 mL) were added to the residue, and the solid was collected by filtration.
• Reference example 19 (2) Benzene (10 mL) was added to the compound obtained in Reference Example 19 (1). Thionyl chloride (5.4 mL) was added to the reaction mixture at room temperature, and the mixture was stirred for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue, and the solid was collected by filtration. The solid was dried to give the desired product (10.93 g) as a pale yellow solid.
• Reference example 19 (3) Benzene (120 mL) and toluene (40 mL) were added to the compound (10.93 g) obtained in Reference Example 19 (2), and the mixture was stirred. The reaction mixture was heated and stirred under reflux for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give the desired product as a pale yellow solid.
• Reference example 19 (4) DMF (80 mL) was added to the compound obtained in Reference Example 19 (3), and the mixture was stirred with ice cooling. At the same temperature, 60% oily sodium hydride (1.76 g) was added to the reaction mixture in 3 portions. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate, water and 1 mol / L hydrochloric acid were added to the reaction mixture. The solid was filtered and the organic layer was separated from the filtrate. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and washed with a 5% aqueous sodium chloride solution.
• Reference example 22 (1) Add benzhydryl 2,2-dihydroxyacetate (8.14 g) and dichloromethane (61 mL) to (S, E) -1- (benzylideneamino) -4-methylimidazolidine-2-one (6.10 g), and stir with ice cooling. did. After adding DBU (226 ⁇ L) to the reaction mixture at the same temperature, the mixture was stirred at room temperature for 5 hours and 30 minutes. Benzhydryl 2,2-dihydroxyacetate (1.16 g) was added to the reaction mixture at room temperature, and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure to give the desired product (13.3 g) as a yellow oil.
• the organic layer was separated, and the organic layer was washed successively with water and saturated aqueous sodium chloride solution.
• the organic layer was dehydrated and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. IPE was added to the residue and the solid was collected by filtration. The solid was dried to give the desired product (20.1 g) as a pale yellow solid.
• Reference example 27 (1) Benzhydryl (3R, 5R, 6R) -3-((S) -3-(((E) -benzylidene) amino) -5-methyl-2-oxoimidazolidine-1-yl) -7-oxo-6- Add dichloromethane (6.6 mL) to (2-phenylacetamide) -4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylate (660 mg) and bring the reaction mixture below -30 ° C. Cooled. N, N-Dimethylaniline (435 ⁇ L) and phosphorus pentachloride (306 mg) were sequentially added to the reaction mixture at the same temperature, and the mixture was stirred at ⁇ 30 ° C.
• Reference example 27 (2) Dichloromethane (3.6 mL) and methanol (1.8 mL) were added to the compound (180 mg) obtained in Reference Example 27 (1), and the mixture was stirred with ice cooling. At the same temperature, 2,4-dinitrophenylhydrazine (50% wet product, 165 mg) and p-toluenesulfonic acid monohydrate (40 mg) were sequentially added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 7.7.
• Reference example 35 (2) Dichloromethane (3.2 mL) and methanol (1.6 mL) were added to the compound (159 mg) obtained in Reference Example 35 (1), and the mixture was stirred with ice cooling. At the same temperature, 2,4-dinitrophenylhydrazine (50% wet product, 59 mg) and p-toluenesulfonic acid monohydrate (28 mg) were sequentially added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 6.4.
• Reference example 48 (1) 2,5-Dichloro-3,4-bis ((4-methoxybenzyl) oxy) benzoic acid (6.0 g) with dichloromethane (48 mL), N, O-dimethylhydroxylamine hydrochloride (1.64 g) and EDC (3.23 g) ) was added in sequence. The reaction mixture was stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water (20 mL), 2% aqueous sodium chloride solution (20 mL) and 10% aqueous sodium chloride solution (20 mL). The organic layer was dehydrated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (3.7 g) as a yellow oil.
• Reference example 48 (2) THF (40 mL) was added to the compound (3.7 g) obtained in Reference Example 48 (1), and the mixture was stirred with ice cooling. A 3 mol / L methylmagnesium bromide / diethyl ether solution (5.5 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours and 30 minutes. A 3 mol / L methylmagnesium bromide / diethyl ether solution (2.7 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours.
• Reference example 48 Pyridine (16 mL) and selenium dioxide (0.98 g) were sequentially added to the compound (1.62 g) obtained in Reference Example 48 (2).
• the reaction mixture was stirred at 90-100 ° C. for 5 hours and 30 minutes.
• the reaction mixture was filtered through Celite and the residue was washed successively with water and ethyl acetate.
• the organic layer was separated, 6 mol / L hydrochloric acid was added to the aqueous layer, the pH was adjusted to ⁇ 2, and the mixture was extracted with ethyl acetate.
• the organic layers were combined, dehydrated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• Reference example 49 (1) Dichloromethane (150 mL) and triethylamine (4.48 mL) were added to tert-butyl (2-aminoethyl) carbamate (5.0 g), and the mixture was stirred with ice cooling. Methyl chloroglioxylate (2.95 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 6 hours and 30 minutes. Water (100 mL) was added to the reaction mixture, and 1 mol / L hydrochloric acid was added to adjust the pH to 2.6. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (50 mL).
• Reference example 62 (2) THF (68 mL), water (34 mL) and lithium hydroxide monohydrate (1.36 g) were sequentially added to the compound (3.42 g) obtained in Reference Example 62 (1), and the mixture was stirred at room temperature for 1 hour. Water (250 mL) and 2 mol / L hydrochloric acid were added to the reaction mixture by ice cooling to adjust the pH to 1.9. The solid was collected by filtration to give 2- (2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzoyl) hydrazienyl) -2-oxoacetic acid (1.43 g) as a white solid. ..
• Reference example 63 (2) The compound (1.35 g) obtained in Reference Example 63 (1) was mixed with 2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetic acid (4.0 g), HOBt. (1.42 g), EDC (2.01 g), DMAC (80 mL) and NMM (4.4 mL) were added in sequence. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (160 mL) and water (160 mL) were added to the reaction mixture. 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 3.5.
• the organic layer was separated, washed twice with water (100 mL), and sequentially with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated aqueous sodium chloride solution (100 mL).
• the organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
• Dichloromethane (15 mL) and hexane (15 mL) were added to the residue, and the solid was collected by filtration to give the desired product (1.60 g) as a white solid.
• Reference example 63 (3) Using the compound (1.60 g) obtained in Reference Example 63 (2), 2- (2- (2- (2-chloro-3,4-bis) ((4-4-)) was used in the same manner as in Reference Example 62 (2). Methoxybenzyl) oxy) phenyl) -2-oxoacetyl) hydrazienyl) -2-oxoacetic acid (1.43 g) was obtained as a white solid.
• Reference example 65 (1) THF (70 mL), water (70 mL) and sodium hydrogen carbonate (9.8 g) were sequentially added to O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (7.5 g), and the mixture was stirred with ice cooling. Allyl chloroformate (6.2 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture. 2 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 2.3. The organic layer was separated and washed with saturated aqueous sodium chloride solution. The organic layer was dehydrated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the desired product (12.4 g) as a colorless oil.
• Reference example 65 (2) In addition to the compound (3.0 g) obtained in Reference Example 65 (1), 2- (2-hydroxyethyl) isoindoline-1,3-dione (3.2 g), triphenylphosphine (5.35 g) and toluene (30 mL) were added. Was added, and the mixture was stirred with ice cooling. A 40% diisopropyl azodicarboxylate / toluene solution (9.1 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred overnight at room temperature. Magnesium chloride (3.54 g) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hour.
• Reference example 65 (3) Using the compound (1.5 g) obtained in Reference Example 65 (2), the target product (592 mg) was obtained as a colorless oil in the same manner as in Reference Example 10 (2).
• the organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure until the amount of the solvent reached about 50 mL.
• Triethylamine (143 ⁇ L) and methyl chloroglyoxylate (92 ⁇ L) were added on ice-cooled, and the mixture was stirred overnight at room temperature.
• Water (30 mL) was added to the reaction mixture, and the organic layer was separated.
• the aqueous layer was extracted twice with dichloromethane (10 mL).
• the organic layers were combined and washed sequentially with water and saturated aqueous sodium chloride solution.
• the organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
• Reference example 65 (6) Using the compound (280 mg) obtained in Reference Example 65 (5), 2-((2- (2-chloro-3,4-bis) ((4-methoxybenzyl)) was used in the same manner as in Reference Example 62 (2). Oxy) -N-((tetrahydro-2H-pyran-2-yl) oxy) benzamide) ethyl) amino) -2-oxoacetic acid (276 mg) was obtained as a white solid.
• Reference example 69 (3) Using the compound (500 mg) obtained in Reference Example 69 (2), 2-((2- (2-chloro-3,4-bis) ((4-methoxybenzyl)) was used in the same manner as in Reference Example 62 (2). ) Oxy) benzamide) ethyl) ((tetrahydro-2H-pyran-2-yl) oxy) amino) -2-oxoacetic acid (496 mg) was obtained as a yellow solid.
• Reference example 73 (2) Dichloromethane (24 mL) was added to the compound (7.82 g) obtained in Reference Example 73 (1), and the mixture was stirred with ice cooling. Methylhydrazine (780 ⁇ L) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred at the same temperature for 2 hours and 30 minutes. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. Methanol (47 mL) was added to the residue, and the mixture was stirred with ice cooling.
• Reference example 80 In the same manner as in Reference Example 3 (1), from (2-((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methaneamine (4.5 g) to the target product (10.8 g) as a white solid. Obtained.
• Reference example 84 (2) THF (420 mL) was added to the compound (21.0 g) obtained in Reference Example 84 (1), and the mixture was stirred with ice cooling. 2,6-Lutidine (9.1 mL) and thionyl chloride (5.4 mL) were sequentially added to the reaction mixture at the same temperature. The reaction mixture was stirred at room temperature for 2 hours and 30 minutes and the insoluble material was filtered. The solvent was distilled off under reduced pressure to obtain a mixture containing the desired product.
• Reference example 84 (3) Dichloromethane (420 mL) and N-((2R, 3R) -1- (hydroxymethyl) -2-mercapto-4-oxoazetidine-3-yl) -2-phenyl were added to the mixture obtained in Reference Example 84 (2). Acetamide (13.4 g) was added in sequence and stirred with ice cooling. Triethylamine (7.0 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred for 2 hours. Water (420 mL) and 6 mol / L hydrochloric acid were added to the reaction mixture to adjust the pH to 2.0. The organic layer was separated and washed successively with water and saturated aqueous sodium chloride solution.
• Reference example 84 (4) THF (370 mL) was added to the compound (18.5 g) obtained in Reference Example 84 (3), and the mixture was stirred with ice cooling. 2,6-Lutidine (4.1 mL) and thionyl chloride (2.48 mL) were sequentially added to the reaction mixture at the same temperature. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The insoluble material was filtered and the solvent was evaporated under reduced pressure. At room temperature, THF (370 mL) and N, O-bis (trimethylsilyl) acetamide (7.8 mL) were sequentially added to the residue, and the mixture was stirred for 30 minutes.
• Hexamethylphosphoric acid triamide (23 mL) was added to the reaction mixture at the same temperature, and the mixture was cooled to -60 ° C.
• a 1.3 mol / L lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (24 mL) was added dropwise to the reaction mixture at the same temperature.
• the reaction mixture was stirred at ⁇ 10 ° C. for 1 hour.
• the reaction mixture was added to a mixture of ethyl acetate (750 mL), water (370 mL) and 1 mol / L hydrochloric acid (52 mL) on ice-cooled, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution.
• Reference example 101 (1) 4-Nitrobenzyl (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((1- (tert-butoxy) -2-methyl-1) -Oxopropane-2-yl) oxy) imino) acetamide) -3-(4-(((tert-butoxycarbonyl) amino) methyl) -1H-1,2,3-triazole-1-yl) -7- Ethyl acetate (3 mL) and 10% palladium-carbon (300 mg) were added to oxo-4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylate (300 mg) at room temperature under a hydrogen atmosphere. Was stirred for 3 hours. The reaction mixture was filtered through Celite and the residue was washed with ethyl acetate. The solvent was evaporated under reduced pressure to give the desired product (233 mg) as a yellow solid
• Reference example 101 Dichloromethane (3.5 mL) and nitromethane (1.2 mL) were added to the compound (230 mg) obtained in Reference Example 101 (1), and the mixture was stirred at ⁇ 20 ° C. Anisole (1.4 mL) and aluminum chloride (353 mg) were added sequentially to the reaction mixture at the same temperature. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 1 hour and 30 minutes. Trifluoroacetic acid (0.13 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at ⁇ 10 ° C. or lower for 1 hour and 30 minutes.
• reaction mixture was added ice-cooled into a mixture of acetonitrile (10 mL), water (10 mL) and trisodium citrate dihydrate (1.17 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• Acetic acid 14 ⁇ L was added to the reaction mixture, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was stirred at 50 ° C. for 10 hours. The reaction mixture was cooled to room temperature, ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed twice with 5% aqueous sodium chloride solution. The organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
• Reference example 116 (2) The compound (3.40 g) obtained in Reference Example 116 (1) was added to a 1 mol / L boron tribromide / dichloromethane solution (87 mL) at 10 ° C. or lower. The reaction mixture was stirred at room temperature for 6 hours and 30 minutes. The reaction mixture was added to ice water (300 mL) and extracted with ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL). The organic layer was washed with 5% aqueous sodium chloride solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. IPE was added to the residue and the solid was collected by filtration. The solid was dried to give the desired product (2.99 g) as a gray solid.
• Reference example 116 The compound (3.18 g) obtained in Reference Example 116 (3) was added to N, N-dimethylacetamide (22 mL), p-methoxybenzyl chloride (4.97 g), potassium carbonate (4.38 g) and potassium iodide (0.24 g). ) Was added. The reaction mixture was stirred at 55 ° C. for 3 hours and 15 minutes. The reaction mixture was added to water (180 mL). Concentrated hydrochloric acid was added to the mixture to adjust the pH to 7.5. The solid was collected by filtration and washed with water. The solid was blown-dried at 40 ° C. to give the desired product (4.83 g) as a yellow solid.
• Reference example 130 (1) Benzhydryl (3R, 5R, 6R) -6-((R, Z) -5-((benzhydryloxy) carbonyl) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) -8,8,9,9-tetramethyl-4,7-dioxa-3-aza-8-siladeca-2-enamid) -3-(3-(((E) -4-methylbenzylidene) amino)- 2-Oxoimidazolidine-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] Add THF (25 mL) to heptan-3-carboxylate (2.0 g) and -10.
• Example 1 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-((1-((benzhydryloxy) carbonyl) cyclo Butoxy) imino) -2- (2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-3 -THF (4.2 mL) and water (4.2 mL) were added to carboxylate (104 mg), and the mixture was stirred with ice cooling.
• Example 1 (2) Dichloromethane (1.9 mL) was added to the compound (126 mg) obtained in Example 1 (1), and the mixture was cooled to ⁇ 20 ° C. Anisole (0.59 mL) and aluminum chloride (180 mg) were sequentially added to the reaction mixture at the same temperature, and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to the mixture of acetonitrile (5 mL), water (5 mL) and trisodium citrate dihydrate (596 mg) on ice. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-((1-carboxycyclobutoxy) imino).
• Example 19 (1) Add dichloromethane (1.0 mL) to 2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetic acid (100 mg), and then ice-cool to oxalyl chloride (23 ⁇ L). And DMF (2 ⁇ L) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour to give a dichloromethane solution of 2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetyl chloride.
• Example 19 Dichloromethane (6.2 mL) was added to the compound (312 mg) obtained in Example 19 (2), and the mixture was cooled to ⁇ 20 ° C. Anisole (1.4 mL) and aluminum chloride (438 mg) were added sequentially to the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was added ice-cooled into a mixture of acetonitrile (20 mL), water (10 mL) and trisodium citrate dihydrate (1.45 g). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.2, and the aqueous layer was separated.
• the aqueous solution containing the desired product was lyophilized and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-((1-carboxycyclobutoxy) imino).
• Example 27 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl) -1-oxopropan-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4-thia-1-azabicyclo [ 3.2.0] Heptane-3-carboxylate (200 mg) with (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzoyl) glycine (112 mg), HOBt (34 mg), EDC ( 49 mg), DMF (2 mL) and NMM (31 ⁇ L) were added sequentially.
• Example 27 (2) Dichloromethane (2.8 mL) was added to the compound (188 mg) obtained in Example 27 (1), and the mixture was stirred at ⁇ 20 ° C. Anisole (0.92 mL) and aluminum chloride (282 mg) were added sequentially to the reaction mixture at the same temperature. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added to the mixture of acetonitrile (5 mL), water (5 mL) and trisodium citrate dihydrate (933 mg) on ice. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 35 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl) -1-oxopropan-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4-thia-1-azabicyclo [ 3.2.0]
• Dichloromethane (3.9 mL) and pyridine (38 ⁇ L) were added to heptane-3-carboxylate (390 mg), and the mixture was stirred with ice cooling.
• Chloroacetyl chloride (38 ⁇ L) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) and 1 mol / L hydrochloric acid (2 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (424 mg) as a yellow oil.
• Example 35 To the compound (424 mg) obtained in Example 35 (1), DMF (4.3 mL), 2-chloro-3,4-bis ((4-methoxybenzyl) oxy) -N- (2- (pyrrolidin-1) -Il) Ethyl) benzamide (473 mg) and sodium iodide (68 mg) were sequentially added, and the mixture was stirred at 40 ° C. for 11 hours. Ethyl acetate (15 mL) and water (15 mL) were added to the reaction mixture. 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 2.5.
• Example 35 Dichloromethane (15.0 mL) was added to the compound (702 mg) obtained in Example 35 (2), and the mixture was stirred at ⁇ 20 ° C. or lower.
• Anisole (3.0 mL) and aluminum chloride (1.50 g) were sequentially added to the reaction mixture at the same temperature.
• the reaction mixture was stirred at ⁇ 20 ° C. or lower for 1 hour.
• Aluminum chloride (421 mg) was added to the reaction mixture at ⁇ 20 ° C. or lower, and the mixture was stirred at ⁇ 20 ° C. or lower for 1 hour.
• the reaction mixture was added ice-cooled into a mixture of acetonitrile (25 mL), water (15 mL) and trisodium citrate dihydrate (6.37 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 37 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl) -1-oxopropan-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4-thia-1-azabicyclo [ 3.2.0] Dichloromethane (7.0 mL) and 1,1'-carbonyldiimidazole (131 mg) were added to heptane-3-carboxylate (350 mg), and the mixture was stirred at room temperature for 4 hours.
• Example 37 Dichloromethane (6.2 mL) was added to the compound (310 mg) obtained in Example 37 (1), and the mixture was stirred at ⁇ 20 ° C. or lower. Anisole (1.49 mL) and aluminum chloride (455 mg) were added sequentially to the reaction mixture at the same temperature. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (20 mL), water (20 mL) and trisodium citrate dihydrate (1.51 g). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Dichloromethane (4.3 mL) was added to 2-chloro-N- (2-hydroxyethyl) -3,4-bis ((4-methoxybenzyl) oxy) benzamide (430 mg), and the mixture was stirred with ice cooling. Dess-Martin peryogenan (773 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours.
• Dichloromethane (10 mL), water (5 mL) and 1 mol / L sodium thiosulfate aqueous solution (5 mL) were sequentially added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and then dehydrated and dried over anhydrous sodium sulfate.
• reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes.
• the reaction mixture was added ice-cooled into a mixture of acetonitrile (15 mL), water (15 mL) and trisodium citrate dihydrate (3.83 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• heptane-3-carboxylate 500 mg was added, and the mixture was stirred at room temperature for 2 hours.
• Dichloromethane (15.6 mL) was added to the reaction mixture, and the mixture was stirred at ⁇ 20 ° C. or lower.
• Anisole (3.8 mL) and aluminum chloride (1.16 g) were sequentially added to the reaction mixture at the same temperature.
• the reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes.
• the reaction mixture was added ice-cooled into a mixture of acetonitrile (20 mL), water (20 mL) and trisodium citrate dihydrate (3.83 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 49 THF (5 mL) was added to a 40% aqueous glyoxal solution (1.3 mL), and the mixture was stirred with ice cooling.
• the reaction mixture was added to a mixture of water (15 mL), dichloromethane (15 mL) and 1 mol / L hydrochloric acid (1.5 mL) and the organic layer was separated. The organic layer was washed twice with a 5% aqueous sodium chloride solution and then dehydrated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, dichloromethane (10 mL) and 2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzohydrazine (512 mg) were added to the residue, and the mixture was stirred at room temperature for 2 hours and 40 minutes.
• reaction mixture was added ice-cooled into a mixture of acetonitrile (25 mL), water (20 mL) and trisodium citrate dihydrate (3.80 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.0, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 55 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl) -1-oxopropan-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4-thia-1-azabicyclo [ 3.2.0]
• Dichloromethane (10 mL) was added to heptane-3-carboxylate (1.00 g), and the mixture was stirred with ice cooling.
• Example 55 (2) Benz Hydrill (3R, 5R, 6R) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) imino) -2- ( 2-((tert-Butyloxycarbonyl) amino) thiazole-4-yl) acetamide) -3-(3-(((E) -2-chloroethylidene) amino) -2-oxoimidazolidine-1-yl)- DMF (7.0 mL) was added to 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylate (705 mg), and the mixture was stirred with ice cooling.
• Example 55 Dichloromethane (10 mL) was added to the compound (1.175 g) obtained in Example 55 (2), and the mixture was stirred at ⁇ 20 ° C. or lower. At the same temperature, anisole (5.0 mL) and aluminum chloride (2.0 g) were added sequentially to the reaction mixture. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 40 minutes. Aluminum chloride (1.0 g) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (20 mL), water (20 mL) and trisodium citrate dihydrate (6.72 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.7, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 59 (1) Ethanol (4 mL) was added to 2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetic acid (222 mg), and the mixture was stirred with ice cooling.
• the reaction mixture was added into a mixture of ethyl acetate (40 mL) and water (40 mL). The organic layer was separated and washed twice with water (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL), and then the organic layer was dehydrated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the desired product (500 mg) as a pale yellow solid.
• Ammonium chloride 45 mg
• HOBt 106 mg
• Example 59 Dichloromethane (10 mL) was added to the compound (499 mg) obtained in Example 59 (2), and the mixture was stirred at ⁇ 20 ° C. or lower. At the same temperature, anisole (2.5 mL) and aluminum chloride (766 mg) were added sequentially to the reaction mixture. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 40 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (40 mL), water (40 mL) and trisodium citrate dihydrate (2.53 g). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.3, and the aqueous layer was separated.
• acetonitrile 40 mL
• water 40 mL
• trisodium citrate dihydrate 2.53 g
• the aqueous solution containing the desired product was freeze-dried and (3R, 5R, 6R) -3-(3-(((Z) -2-amino-1- (2-chloro-3,4-dihydroxyphenyl) -2-).
• Example 63 (1) THF (3 mL) was added to glyoxylic acid monohydrate (160 mg), and the mixture was stirred with ice cooling. At the same temperature, benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-(((1- (tert) -Butoxy) -2-methyl-1-oxopropan-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4 -Thia-1-azabicyclo [3.2.0] heptane-3-carboxylate (300 mg) was added, and the mixture was stirred at room temperature for 3 hours.
• the reaction mixture was added into a mixture of ethyl acetate (30 mL) and water (30 mL). The organic layer was separated and dehydrated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the desired product (340 mg) as a yellow solid.
• Example 63 Dichloromethane (3.4 mL) was added to the compound (168 mg) obtained in Example 63 (2), and the mixture was stirred at ⁇ 20 ° C. or lower. At the same temperature, anisole (799 ⁇ L) and aluminum chloride (244 mg) were added sequentially to the reaction mixture. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (10 mL), water (10 mL) and trisodium citrate dihydrate (809 mg). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.2, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 64 (1) Benzhydryl (3R, 5R, 6R) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) imino) -2-( 2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -3-(3-(((E) -2-((2- (2-chloro-3,4-bis) ((4) -Methylbenzyl) oxy) benzamide) ethyl) amino) -2-oxoethylidene) amino) -2-oxoimidazolidine-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] Dichloromethane (3.4 mL) was added to heptane-3-carboxylate (168 mg), and the mixture was stirred with ice cooling.
• the organic layer was separated and the aqueous layer was extracted 3 times with ethyl acetate.
• the organic layers were combined, washed successively with water and saturated aqueous sodium chloride solution, and dehydrated and dried over anhydrous sodium sulfate.
• Example 64 Dichloromethane (2.0 mL) was added to the compound (101 mg) obtained in Example 64 (1), and the mixture was stirred at ⁇ 20 ° C. or lower. At the same temperature, anisole (480 ⁇ L) and aluminum chloride (147 mg) were added sequentially to the reaction mixture. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (6 mL), water (6 mL) and trisodium citrate dihydrate (486 mg). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 65 (1) Dichloromethane (3.6 mL) was added to 2-chloro-N- (2-hydroxyethyl) -3,4-bis ((4-methoxybenzyl) oxy) benzamide (0.36 g), and the mixture was stirred with ice cooling. Dess-Martin peryogenan (0.65 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Dichloromethane (10 mL), water (5 mL) and 1 mol / L sodium thiosulfate aqueous solution (5 mL) were sequentially added to the reaction mixture, and the organic layer was separated.
• Example 65 (2) Benzhydryl (3R, 5R, 6R) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) imino) -2-( 2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -3-(3-((2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzamide)) Ethyl) Amino) -2-oxoimidazolidine-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptan-3-carboxylate (625 mg) with dichloromethane (12.5 mL) Was added, and the mixture was stirred at ⁇ 20 ° C.
• aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• triphosgene (20 mg) and N, N-diisopropylethylamine (35 ⁇ L) were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
• ammonium chloride (13 mg) and triethylamine (46 ⁇ L) were added to the reaction mixture and the mixture was stirred for 1 hour.
• the reaction mixture was added to a mixture of ethyl acetate (10 mL), water (10 mL) and 1 mol / L hydrochloric acid (2 mL). The organic layer was separated, washed with a 5% aqueous sodium chloride solution, and dehydrated and dried over anhydrous sodium sulfate.
• Example 67 (2) Dichloromethane (2 mL) was added to the compound (100 mg) obtained in Example 67 (1), and the mixture was stirred at ⁇ 20 ° C. or lower. At the same temperature, anisole (480 ⁇ L) and aluminum chloride (147 mg) were added sequentially to the reaction mixture. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 1 hour. The reaction mixture was added ice-cooled into a mixture of acetonitrile (10 mL), water (5 mL) and trisodium citrate dihydrate (486 mg). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 68 (1) Dichloromethane (1.3 mL) was added to the compound (70 mg) obtained in Reference Example 17, and the mixture was stirred with ice cooling. At the same temperature, oxalyl dichloride (13 ⁇ L) and DMF (7 ⁇ L) were sequentially added to the reaction mixture and stirred for 1 hour. At the same temperature, oxalyl dichloride (7 ⁇ L) and DMF (3 ⁇ L) were sequentially added to the reaction mixture and stirred for 1 hour to give a dichloromethane mixture of the corresponding acid chloride.
• Example 68 (2) Dichloromethane (3.6 mL) was added to the compound (179 mg) obtained in Example 68 (1), and the mixture was stirred at ⁇ 20 ° C. or lower. At the same temperature, anisole (841 ⁇ L) and aluminum chloride (258 mg) were added sequentially to the reaction mixture. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added to the mixture of acetonitrile (11 mL), water (11 mL) and trisodium citrate dihydrate (852 mg) on ice. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.1, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 69 Dichloromethane (1.9 mL) was added to N- (2-aminoethyl) -2-chloro-3,4-bis ((4-methoxybenzyl) oxy) benzamide (90 mg), and the mixture was stirred with ice cooling. Chlorosulfonyl isocyanate (17 ⁇ L) was added to the reaction mixture at the same temperature and stirred at the same temperature for 40 minutes.
• reaction mixture was added into a mixture of acetonitrile (20 mL), water (15 mL) and trisodium citrate dihydrate (1.15 g).
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.3, and the aqueous layer was separated.
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 4.6, and the mixture was stirred at room temperature for 6 days.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 105 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-((((S) -1- (benzhydryloxy)) ) -1-Oxobutane-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetamide) -7-oxo-4-thia-1-azabicyclo [ 3.2.0] Heptane-3-carboxylate (300 mg), 2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetic acid (155 mg), HATU (129 mg), DMAC (3 mL) and NMM (75 ⁇ L) were added sequentially.
• Example 105 (2) Dichloromethane (5.6 mL) was added to the compound (374 mg) obtained in Example 105 (1), and the mixture was stirred at ⁇ 20 ° C. Anisole (1.7 mL) and aluminum chloride (529 mg) were added sequentially to the reaction mixture at the same temperature. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (15 mL), water (15 mL) and trisodium citrate dihydrate (1.75 g). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.3, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((S) -1-carboxypropoxy).
• Example 137 (1) Benzhydryl (3R, 5R, 6R) -3- (3-amino-2-oxoimidazolidine-1-yl) -6-((Z) -2-(((1- (tert-butoxy) -2-methyl) -1-oxopropan-2-yl) oxy) imino) -2-(2-((tert-butoxycarbonyl) amino) thiazole-4-yl) acetylamide) -7-oxo-4-thia-1-azabicyclo [ 3.2.0] Heptane-3-carboxylate (120 mg) to (2- (2-chloro-3,4-bis ((4-methoxybenzyl) oxy) phenyl) -2-oxoacetyl) -L- Serine (166 mg), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (137 mg) and THF (3.6 mL)
• Example 137 Dichloromethane (4 mL) was added to the compound (200 mg) obtained in Example 137 (1), and the mixture was stirred at ⁇ 20 ° C. Anisole (940 ⁇ L) and aluminum chloride (288 mg) were sequentially added to the reaction mixture at the same temperature. The reaction mixture was stirred at ⁇ 20 ° C. or lower for 30 minutes. The reaction mixture was added ice-cooled into a mixture of acetonitrile (15 mL), water (15 mL) and trisodium citrate dihydrate (952 mg). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 5.2, and the aqueous layer was separated.
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 139 NMR: 1.46 (3H, s), 1.47 (3H, s), 3.40 (3H, s), 3.42-3.47 (1H, m), 3.51-3.64 (3H, m), 3.64-3.71 (2H, m), 3.84 (2H, d, J 5.6Hz),
• the aqueous solution containing the desired product was freeze-dried, and (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole-4-yl) -2-(((2-carboxypropane-2-)).
• Example 153 (1) THF (14 mL), 1,3-dimethylbarbituric acid (187 mg) and tetrakis (triphenylphosphine) palladium (0) (159 mg) were sequentially added to the compound (926 mg) obtained in Reference Example 129, and 1 at room temperature. Stirred for hours. Ethyl acetate (14 mL), water (14 mL) and 1 mol / L hydrochloric acid were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, and dehydrated and dried over anhydrous sodium sulfate.
• Example 153 Using the compound (530 mg) obtained in Example 153 (1), (3R, 5R, 6R) -6-((Z) -2- (2-aminothiazole)) in the same manner as in Example 1 (2). -4-yl) -2-(((2-carboxypropan-2-yl) oxy) imino) acetylamide) -3- (3- (2- (2- (2-chloro-3,4-dihydroxyphenyl)) -2-oxoacetyl) hydrazine-1-carboxamide) -2-oxoimidazolidine-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylic acid ( 94.4 mg) was obtained as a yellow solid.
• Oxalyl chloride (47 ⁇ L) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred at the same temperature for 1 hour to obtain a mixture of acid chlorides.
• a mixture of THF (4.5 mL), water (4.5 mL), sodium hydrogen carbonate (171 mg) and the obtained acid chloride was added to the compound (311 mg) obtained in Reference Example 28, and the mixture was stirred at room temperature for 1 hour.
• Ethyl acetate (30 mL) and water (20 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride solution and dehydrated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a yellow solid.
• Example 156 (1) Using the compound (400 mg) obtained in Reference Example 125, the target product (138 mg) was obtained as a light brown solid in the same manner as in Reference Example 27 (1).
• Example 156 (2) Using the compound (138 mg) obtained in Example 156 (1), (3R, 5R, 6R) -6-((Z) -2- (2-amino) in the same manner as in Example 1 (2). Thiazole-4-yl) -2-(((2-carboxypropan-2-yl) oxy) imino) acetylamide) -3-((S) -3-(2- (2-chloro-3,4-dihydroxy) Phenyl) -2-oxoacetamide) -2-oxopiperidin-1-yl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-3-carboxylic acid (45 mg) as a yellow solid Obtained.
• Example 158 NMR: 1.43-1.54 (6H, m), 3.20 (1H, d, J 13.2Hz), 3.65-4.12 (4H, m), 4.13-4.46 (2H, m), 4.98-5.11 (1H, m), 5.59-5.76 (2H, m), m
• Formulation Example 1 (1) Add equimolar sodium hydrogen carbonate and water to 2 g of compound A and dissolve. The resulting solution is aseptically filtered and lyophilized to give a lyophilized powder. (2) The freeze-dried powder obtained in (1) and ceftazidime hydrate (1 g as ceftazidime) are filled in one chamber of a plastic double bag (multi-chamber container) and sealed by heat-sealing welding. The other chamber is filled with 100 mL of saline and sealed to obtain an injection kit.
• Preparation example 3 After preparation using 4 g of compound B and 0.5 g of tazobactam in the same manner as in Preparation Example 2, lyophilization is performed to obtain a preparation for injection.
• Preparation example 4 A lyophilized powder containing 2 g of compound A obtained in the same manner as in Preparation Example 1 (1) and sodium sulbactam (1 g as sulbactam) are filled in one chamber of a plastic double bag (multi-chamber container) for heat-sealing welding. And seal. The other chamber is filled with 100 mL of saline and sealed to obtain an injection kit.
• Formulation Example 5 A glass vial is filled with a lyophilized powder containing 2 g of compound A equivalent to that obtained in the same manner as in Preparation Example 1 (1) and a lyophilized powder of sodium piperacillin (2 g as piperacillin). Then, it is sealed with a rubber stopper and further wrapped with an aluminum cap to obtain an injection preparation.
• Formulation Example 6 A lyophilized powder containing 4 g of compound A obtained in the same manner as in Preparation Example 1 (1) and avivactum sodium (1 g as avivactum) were filled in one chamber of a plastic double bag (multi-chamber container) and heat-sealed. Seal with. The other chamber is filled with 100 mL of saline and sealed to obtain an injection kit formulation.
• Test Example 1 Antibacterial activity evaluation test The minimum inhibitory concentration (MIC) measurement was performed according to the CLSI (Clinical and Laboratory Standards Institute) standard method, and the following trace liquid dilution method was used.
• MIC minimum inhibitory concentration
• the -48-bearing strain (Y-1062) and the Klebsiella pneumoniae NDM-1 -bearing strain (Y-1007) were used.
• test cells cultured overnight in Mueller-Hinton agar medium were scraped off, suspended in the equivalent of McFarland 0.5, and diluted 10-fold to prepare the inoculated bacterial solution.
• 0.005 mL of the inoculated bacterial solution was inoculated into a cation-adjusted Mueller-Hinton medium containing the test compound, and cultured at 35 ° C. for 16 to 20 hours.
• the minimum drug concentration at which bacterial growth was not visually observed was defined as MIC ( ⁇ g / mL).
• the test compound the compounds obtained in Examples 2, 8, 19, 20, 21, 22, 23, 28, 29, 30, 31, 45, 47, 53 and 68 were used. The results are shown in Table 38.
• Test Example 2 Mouse systemic infection protection test using multidrug-resistant Pseudomonas aeruginosa As mice, ICR male SPF mice (4 weeks old: 10 animals per group) were used. The inoculum solution was a multidrug-resistant Pseudomonas aeruginosa clinical isolate (S-2838 strain) cultured overnight at 37 ° C on a Mueller-Hintonagar plate after culturing in a cation-adjusted Mueller-Hinton medium for 5 hours. , 20-fold diluted with 10% mutin / phosphate buffer to prepare.
• S-2838 strain multidrug-resistant Pseudomonas aeruginosa clinical isolate
• Infection inoculum 0.5mL (approximately 10 6 CFU / mouse) were inoculated into mice intraperitoneally, elicited.
• the test compound was dissolved in physiological saline, and 40 mg / kg was subcutaneously administered once 1 hour after infection.
• the control group was administered the same amount of saline used as the solvent. The number of surviving animals was recorded 3 days after infection.
• the compounds obtained in Examples 19, 20, 21, 22, 23 and 31 were used as test compounds. As a result, all the control groups to which the test compound was not administered died, but the group to which the test compounds of Examples 19, 20, 21, 22, 23 and 31 were administered had 90% or more of the mice 3 days after the inoculation of the fungus. Survival was observed, and anti-multidrug-resistant Pseudomonas aeruginosa activity was observed in vivo.
• Test Example 3 An antibacterial activity evaluation test was carried out in the same manner as in Test Example 1. Examples 26, 73, 74, 76, 78, 82, 83, 84, 85, 86, 88, 104, 105, 107, 113, 114, 115, 117, 121, 122, 126, 136, 139 as test compounds. And the compound obtained in 141 was used. The results are shown in Table 39.
• Test Example 4 A mouse systemic infection protection test using multidrug-resistant Pseudomonas aeruginosa was carried out in the same manner as in Test Example 2.
• the test compound the compounds obtained in Examples 83, 105, 114, 117, 122, 126 and 139 were used.
• all the control groups to which the test compound was not administered died but 90% or more of the groups to which the test compounds of Examples 83, 105, 114, 117, 122, 126 and 139 were administered died 3 days after the inoculation of the fungus. Mice survived, and anti-multidrug-resistant Pseudomonas aeruginosa activity was observed in vivo.
• Test Example 5 Evaluation test of the combined effect of the test compound and the antibacterial compound The combined effect of the test compound and the antibacterial compound was evaluated by using the trace liquid dilution method.
• Compounds A, B and C were used as test compounds.
• antibacterial compounds PIPC (commercially available), CAZ (commercially available), IPM (commercially available), MPC (commercially available), LVFX (Chem-Impex International, Inc.), AMK (commercially available), PL- B (commercially available), TMP (commercially available) and RFP (commercially available) were used.
• Escherichia coli ATCC25922 strain (hereinafter, Escherichia coli A), Klebsiella pneumoniae ATCC13883 strain (hereinafter, Klebsiella pneumoniae A) and Pseudomonas aeruginosa ATCC27853 strain (hereinafter, Pseudomonas aeruginosa A) were used.
• the minimum inhibitory concentration (hereinafter referred to as MIC) was measured according to the CLSI (Clinical and Laboratory Standards Institute) standard method, and the trace liquid dilution method shown below was used.
• the cells cultured overnight in Mueller-Hinton agar medium were scraped off and suspended in the equivalent of McFarland 0.5, and the obtained suspension was diluted 10-fold to prepare an inoculum solution.
• 0.005 mL of the inoculated bacterial solution was inoculated into a cation-adjusted Mueller-Hinton medium containing only the test compound, only the antibacterial compound, the test compound and the antibacterial compound, and cultured at 35 ° C. for 18 to 20 hours.
• the minimum drug concentration at which bacterial growth was not visually observed was defined as MIC ( ⁇ g / mL).
• the antibacterial activity of the test compound only, the antibacterial compound only, and the combination of the test compound and the antibacterial compound was measured by the checkerboard method, and the FIC index (Fractional inhibitory concentration index) was determined.
• FIC Index was 0.5 or less, it was judged that there was a synergistic effect by the combination of both drugs.
• the FIC Index was greater than 0.5 and less than or equal to 1, it was judged that the combination of both drugs had an additive effect. (Diagnostic Microbiology and Infectious Disease, 2004, Vol. 49, p. 197)
• the FIC indexes of the combinations of compounds A, B and C and antibacterial compounds are shown in Tables 40-42.
• Compounds A, B and C all show additive or synergistic effects in the major species of Gram-negative bacteria when used in combination with antibacterial compounds of other major strains, and the antibacterial effect is enhanced. It was.
• Test Example 6 Antibacterial activity evaluation test using the test compound and ⁇ -lactamase inhibitor in combination The effect of the combined use of the test compound and ⁇ -lactamase inhibitor was evaluated using the liquid dilution method. An antibacterial activity evaluation test was carried out in the same manner as in Test Example 5.
• Compounds A, B, C, D and E were used as test compounds.
• MEPM, CTX and CAZ were used as control compounds.
• SBT commercially available
• TAZ commercially available
• CVA commercially available
• AVI commercially available
• NAC in-house
• ZID in-house
• VAB in-house
• CTX-M-15 producing Escherichia coli TK-1747 strain (hereinafter, strain A), KPC-3 and SHV-12-producing Klebsiella pneumoniae Y-1020 strain (hereinafter, strain B) NDM-1, OXA-48 and CTX-M-15 producing Klebsiella pneumoniae Y-1133 strain (hereinafter, strain C), IMP-8 producing Escherichia coli TK-3113 strain (hereinafter, strain D), CMY-2 producing Escherichia coli TK-1765 strain (hereinafter, strain E)
• strain E The antibacterial activity when only the test compound and the test compound and the ⁇ -lactamase inhibitor were added at a concentration of 4 ⁇ g / mL was measured, and the combined effect was evaluated. All ⁇ -lactamase inhibitors used in the test did not inhibit the growth of all strains when added alone at a concentration of 4 ⁇ g / mL. The results are shown in Tables 43-47.
• Test Example 7 Antibacterial activity evaluation test using a plurality of ⁇ -lactamase inhibitors and a test compound in combination The effect of the combination of a test compound and a plurality of ⁇ -lactamase inhibitors was evaluated using a liquid dilution method. An antibacterial activity evaluation test was carried out in the same manner as in Test Example 5.
• Compounds A and B were used as test compounds.
• SBT commercially available
• AVI commercially available
• MEPM was used as a control compound.
• Carbapenem-resistant Acinetobacter A514 and A515 strains were used as the strains.
• Table 48 shows the antibacterial activity of the carbapenem-resistant Acinetobacter A514 strain in combination with Compound A, SBT and AVI.
• Table 49 shows the antibacterial activity of the carbapenem-resistant Acinetobacter A515 strain in combination with Compound B, SBT and AVI.
• Test Example 8 An antibacterial activity evaluation test was carried out in the same manner as in Test Example 1. As the test compound, the compounds obtained in Examples 143, 144, 147, 153, 154 and 156 were used. The results are shown in Table 50.
• Test Example 9 An antibacterial activity evaluation test was carried out in the same manner as in Test Example 6. Compound F and compound G were used as test compounds. As the strains, strain B, strain C, strain D, and strain Y-1069 (hereinafter referred to as strain F) producing Klebsiella pneumoniae-48 and CTX-M-15, which produce ⁇ -lactamase, were used. The results are shown in Tables 51 and 52.
• compositions and kits of the present application have strong antibacterial activity against gram-negative bacteria such as Pseudomonas aeruginosa and / or drug-resistant Gram-negative bacteria including multidrug-resistant Pseudomonas aeruginosa, and are suitable for treating infectious diseases caused by these. It is useful.

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