WO2016175223A1 - Composés tricycliques et utilisations de ceux-ci - Google Patents

Composés tricycliques et utilisations de ceux-ci Download PDF

Info

Publication number
WO2016175223A1
WO2016175223A1 PCT/JP2016/063138 JP2016063138W WO2016175223A1 WO 2016175223 A1 WO2016175223 A1 WO 2016175223A1 JP 2016063138 W JP2016063138 W JP 2016063138W WO 2016175223 A1 WO2016175223 A1 WO 2016175223A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
hydrogen atom
group
compound
Prior art date
Application number
PCT/JP2016/063138
Other languages
English (en)
Japanese (ja)
Inventor
健二 山脇
博喜 草野
俊明 青木
Original Assignee
塩野義製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 塩野義製薬株式会社 filed Critical 塩野義製薬株式会社
Priority to JP2017515564A priority Critical patent/JPWO2016175223A1/ja
Publication of WO2016175223A1 publication Critical patent/WO2016175223A1/fr

Links

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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • 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
    • A61K31/54—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
    • 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
    • A61K31/54—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/897—Compounds with substituents other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D507/00—Heterocyclic compounds containing a condensed beta-lactam ring system, not provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D505/00; Such ring systems being further condensed
    • 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 relates to a novel tricyclic compound having an antibacterial action, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an antibacterial agent containing them. Further, a tricyclic compound having an antibacterial action, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a compound having a ⁇ -lactamase inhibitory action, a pharmaceutically acceptable salt thereof, Or it is related with the pharmaceutical characterized by combining those solvates.
  • ⁇ -lactamases are broadly classified into four classes. Class A (TEM type, SHV type, CTX-M type, KPC type, etc.), Class B (NDM type, IMP type, VIM type, L-1 type, etc.), Class C (AmpC type, ADC type, CMY type) Type, DHA type, etc.) and class D (OXA type, etc.).
  • Class A TEM type, SHV type, CTX-M type, KPC type, etc.
  • Class B NDM type, IMP type, VIM type, L-1 type, etc.
  • Class C AmpC type, ADC type, CMY type
  • Type DHA type, etc.
  • OXA type OXA type, etc.
  • Class A, C, and D types are broadly classified into serine- ⁇ -lactamases, while Class B types are broadly divided into metallo- ⁇ -lactamases, which are known to hydrolyze ⁇ -lactam drugs by different mechanisms.
  • Class B types are broadly divided into metallo- ⁇ -lactamases, which are known to hydrolyze ⁇ -lactam drugs by different mechanisms.
  • KPC Klebsiella pneumoniae Carbapeenase
  • class B metallo- ⁇ -lactamases The existence of Gram-negative bacteria highly resistant to many ⁇ -lactam drugs including carbapenem and carbapenem has become a clinical problem.
  • Enterobacteriaceae bacteria that produce KPC and metallo- ⁇ -lactamase are known to exhibit high resistance to carbapenem antibacterial agents, which are important for the treatment of Gram-negative bacterial infections.
  • Cephem compounds that exhibit moderate activity against gram-negative bacteria, including metallo- ⁇ -lactamase-producing gram-negative bacteria are known (eg, Patent Document 1), but stronger antibacterial activity, especially various ⁇ -lactamase-producing gram Development of ⁇ -lactams effective against negative bacteria is eagerly desired.
  • Patent Documents 2 to 4 report ⁇ -lactam compounds having a novel skeleton, but do not describe antibacterial activity against the above-mentioned carbapenem-resistant bacteria and the like that have been problematic in recent years. Moreover, from the described antibacterial activity, it cannot be imagined at all that the compound group having this skeleton has an antibacterial activity in carbapenem-resistant bacteria. Furthermore, these patent documents do not describe or suggest a combination of a ⁇ -lactam compound having a novel skeleton with other drugs or the combined use effect.
  • the present invention relates to a 5-oxotetrahydrofuran ring, a 6-oxotetrahydropyran ring or a 2-oxo-1,3-dioxolane exhibiting a strong antibacterial spectrum against various bacteria including Gram negative bacteria and / or Gram positive bacteria.
  • a tricyclic compound comprising a ring is provided.
  • carbapenem-resistant bacteria including tricyclic compounds containing a 5-oxotetrahydrofuran ring or a 6-oxotetrahydropyran ring, esters thereof or pharmaceutically acceptable salts thereof, or hydrates thereof.
  • a pharmaceutical composition having antibacterial activity is provided.
  • a compound showing strong antibacterial activity against ⁇ -lactamase-producing gram-negative bacteria, or a pharmaceutical composition containing the compound is provided. More preferably, a compound exhibiting strong antibacterial activity against a carbapenem-resistant bacterium, a multidrug-resistant bacterium, particularly a class B metallo- ⁇ -lactamase (MBL) -producing gram-negative bacterium, or a pharmaceutical composition containing the compound is provided. . More preferably, a compound showing effective antibacterial activity also against a substrate-specific extended ⁇ -lactamase (ESBL) -producing bacterium or a compound containing the compound is provided.
  • ESBL substrate-specific extended ⁇ -lactamase
  • the present invention provides a compound or a pharmaceutical composition having an antibacterial action against a carbapenem-resistant bacterium, which has at least the following structural characteristics to solve the above problems. 1) It has a tricyclic mother nucleus containing a 5-oxotetrahydrofuran ring, a 6-oxotetrahydropyran ring or a 2-oxo-1,3-dioxolane ring. 2) It has an amide substituent (a carbonylamino group having a substituent) on the lactam ring or cyclic carbonyl hydrazide ring in the tricyclic mother nucleus.
  • R 11 is amino or amino substituted with acyl
  • R 12 is a hydrogen atom, —OCH 3 or —NH—CH ( ⁇ O)
  • R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl
  • U is —S—, —S—CH 2 — or —CH 2 —S—).
  • (Item 3) —Z— is a single bond
  • R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted
  • the compound according to Item 2 which is carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino, or hydroxy, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof .
  • Item 4 Item 1 wherein —Z— is —CR 7A R 7B —, Y is N, —W— is —CH 2 —, and —T— is —CR 4A R 4B —. Or its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, an ester thereof, or the like Or a hydrate thereof.
  • R 1 is the following formula: (Wherein X is CH, CCl, CF, CBr or N) 6.
  • X is CH, CCl, CF, CBr or N.
  • R 1 is the following formula: (Wherein X is CCl, CF or CBr) 6.
  • X is CCl, CF or CBr 6.
  • R 2A and R 2B taken together have a methylidene having a substituent shown below: Or substituted or unsubstituted hydroxyimino:
  • R 10 is a hydrogen atom or substituted or unsubstituted alkyl, and in the formula, R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted Or an unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R 8 and R 9 taken together to form a substituted or unsubstituted methylidene, or R 8 and R 9 May be taken together with adjacent atoms to form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
  • Q is a single bond, substituted or unsubstituted carbocyclic diyl Or substituted or unsubstituted
  • R 2A and R 2B together form the following formula: (In the formula, each symbol is as defined above.) 8.
  • R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) Is; R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (In the formula, each definition has the same meaning as item 8) Is; R 3 is a hydrogen atom or —OCH 3 , R 16 is carboxy, and R 17 is a hydrogen atom, a compound thereof, an ester thereof, a pharmaceutically acceptable salt
  • R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) A group represented by: For R 2A and R 2B a) R 2A is a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or carbonyloxy having a substituent And R 2B is
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • a disease associated with bacterial infection which comprises administering the compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Treatment or prevention.
  • R 11 is the following formula: Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
  • R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
  • R 13 is a hydrogen atom;
  • R 14 and R 15 are each independently a hydrogen atom or methyl, and a carbapenem-resistant bacterium containing the compound according to item 22, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof
  • R 1 ′ is the following formula: (Where X ′ is CH or N) A group represented by R 2′A and R 2′B each independently represent a hydrogen atom, or the following formula: Or R 2′A and R 2′B together are represented by the following formula: Wherein R 10 ′ is a hydrogen atom or alkyl, and R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl. 24.
  • a carbapenem-resistant compound comprising the compound of item 22 or 23, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 12 is a hydrogen atom or methoxy: A pharmaceutical composition having an antibacterial action against bacteria.
  • R 11 is amino or amino substituted with acyl
  • R 12 is a hydrogen atom, —OCH 3 or —NH—CH ( ⁇ O)
  • R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl
  • U is —S—, —S—CH 2 — or —CH 2 —S—
  • a pharmaceutically acceptable salt thereof or a hydrate thereof, and a compound having an inhibitory action on (B-1) ⁇ -lactamase, an ester thereof or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical comprising a combination of a salt or a solvate thereof.
  • R 11 in (A-2) is the following formula: Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
  • R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
  • R 13 is a hydrogen atom; 26.
  • the medicament according to item 25, wherein R 14 and R 15 are each independently a hydrogen atom or methyl, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 ′ in (A-2) is the following formula: (Where X ′ is CH or N)
  • R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, or hydroxy Or its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, the compound according to any one of items 1A to 4A, an ester thereof, or a pharmaceutically acceptable salt thereof Salts, or hydrates thereof.
  • R 1 is the following formula: (Wherein X is CH, CCl, CF, CBr or N) The compound according to any one of items 1A to 5A, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by the formula:
  • R 2A and R 2B taken together have a methylidene having the substituents shown below: Or substituted or unsubstituted hydroxyimino: (Wherein R 10 is a hydrogen atom or substituted or unsubstituted alkyl)
  • R 10 is a hydrogen atom or substituted or unsubstituted alkyl
  • R 2A and R 2B together form the following formula: Wherein R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic A group, R 8 and R 9 together form a substituted or unsubstituted methylidene, or R 8 and R 9 together with an adjacent atom are substituted or unsubstituted non-aromatic carbocycle Or may form a substituted or unsubstituted non-aromatic heterocyclic ring; Q is a single bond, substituted or unsubstituted carbocyclic diyl or substituted or unsubstituted heterocyclic diyl; m is 0-3 Is an integer)
  • (Item 10A) -Z- is a single bond; Y is CH; -W- is -S-CH 2- ; -T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and; R 4A and R 4B are each independently a hydrogen atom or hydroxy; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) Is; R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (In the formula, each definition has the same meaning as item 8) Is; The compound according to Item 1A, wherein R 3 is a hydrogen atom or OCH 3 , an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) A group represented by: R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (In the formula, each definition has the same meaning as item 8) A group represented by: The compound according to item 1A, wherein R 3 is a hydrogen atom, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • (Item 12A) A pharmaceutical composition comprising the compound according to any one of items 1A to 11A, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 11 is the following formula: Wherein R 1 is a substituted or unsubstituted heterocyclic group;
  • R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Carbamoyl, hydroxy, or substituted carbonyloxy, or b)
  • R 2A and R 2B may be taken together to form a substituted or unsubstituted hydroxyimino)
  • R 13 is a hydrogen atom;
  • R 14 and R 15 are each independently a hydrogen atom or methyl, and the compound according to item 14A, its ester or pharmaceutically acceptable salt thereof, or a carbapenem-resistant bacterium, including hydrates thereof, A pharmaceutical composition having an antibacterial action.
  • R 1 is the following formula: (Wherein X is CH, CCl or N)
  • a group represented by R 2A and R 2B are each independently a hydrogen atom, or the following formula: Or R 2A and R 2B together are represented by the following formula: (Wherein R 10 is a hydrogen atom or alkyl, and R 8 and R 9 are each independently a hydrogen atom or alkyl) Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, including the compound of item 14A or 15A, wherein R 12 is a hydrogen atom or methoxy;
  • a pharmaceutical composition having an antibacterial action against bacteria wherein X is CH, CCl or N
  • the compound according to the present invention is useful as a pharmaceutical in that it has at least one of the following characteristics.
  • a strong antibacterial spectrum is shown against various bacteria including Gram negative bacteria and / or Gram positive bacteria.
  • CRE carbapenem-resistant Enterobacteriaceae
  • KPC Klebsiella pneumoniae Carbapenemase
  • NDM New Delhi metallo-beta-lactamase
  • H Does not show cross resistance with existing cephem and / or carbapenem drugs.
  • I Does not show side effects such as fever after in vivo administration.
  • J) The stability of the compound (for example, solution stability and light stability in various liquid properties) and / or solubility in water is high.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
  • Alkyl includes a straight or branched carbon hydrogen group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, Examples include isooctyl, n-nonyl, n-denyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included.
  • “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, still more preferably 3 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • aromatic carbocycle means a ring derived from the above “aromatic carbocyclic group”.
  • non-aromatic carbocycle means a ring derived from the above “non-aromatic carbocyclic group”.
  • Cycloalkyl means a cyclic saturated hydrocarbon group, preferably having 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 3 to 8 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like can be mentioned.
  • Preferable embodiments of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • “Cycloalkane” means a ring derived from the above “cycloalkyl”.
  • the “carbocyclic group” includes the above “aromatic carbocyclic group” and “non-aromatic carbocyclic group”.
  • Carbocycle means a ring derived from the above “carbocyclic group”.
  • Carbocyclic diyl means a divalent group derived from the above “carbocyclic group”.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • the 5-membered monocyclic aromatic heterocyclic group includes pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like, and includes a 6-membered monocyclic aromatic group.
  • group heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include, for example, indolinyl, isoindolinyl, chromanyl, isochromanyl, octahydro-7H-pyrano [2,3-c] pyridin-7-yl, hexahydro-2H-pyrano [3, 2-c] pyridin-6 (5H) -yl, 7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl and the like.
  • Aromatic heterocycle means a ring derived from the above “aromatic heterocyclic group”.
  • the “non-aromatic heterocyclic ring” means a ring derived from the above “non-aromatic heterocyclic group”.
  • heterocyclic group includes the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”.
  • Heterocycle means a ring derived from the above “heterocyclic group”.
  • Heterocyclic diyl means a divalent group derived from the above “heterocyclic group”.
  • “Acyl” means formyl and substituted carbonyl. “Substituted carbonyl” means substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic Examples thereof include carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl and the like.
  • “Acyl-substituted amino” means a group in which one or two hydrogen atoms bonded to the nitrogen atom of “amino” are replaced with the above “acyl”, that is, monoacylamino or diacylamino. . Preferably, it is monoacylamino. Two “acyl” of “diacylamino” may be the same or different. Preferred examples of the “acyl” include substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, etc., more preferably substituted or unsubstituted. Of alkylcarbonyl.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, hexyloxy and the like.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy, trichloromethoxy and the like.
  • “Acyloxy” means formyloxy and carbonyloxy having a substituent.
  • “Carbonyloxy having a substituent” means a group in which the above “carbonyl having a substituent” is bonded to an oxygen atom.
  • substituted or unsubstituted alkylcarbonyloxy substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted nonaromatic carbon Ring carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy and the like.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
  • Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxyalkyl means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” replaces the hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like. . Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfanyl” include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, hexylsulfanyl and the like.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Haloalkylsulfanyl means a group in which the above “haloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfanyl” include trifluoromethylsulfanyl, trichloromethylsulfanyl and the like.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • Carbocyclic alkyl “Aromatic carbocyclic alkyl”, “Non-aromatic carbocyclic alkyl”, “Heterocyclic alkyl”, “Aromatic heterocyclic alkyl”, “Non-aromatic heterocyclic alkyl”, “Carbocyclic alkyl” “Oxy”, “aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “heterocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, “non-aromatic heterocyclic alkyloxy", “carbon” Ring alkyloxycarbonyl ",” aromatic carbocyclic alkyloxycarbonyl ",” non-aromatic carbocyclic alkyloxycarbonyl ",” heterocyclic alkyloxycarbonyl “,” aromatic heterocyclic oxycarbonyl ",” non-aromatic heterocyclic " "Oxycarbonyl”, “carbocyclic alkyloxyalkyl”, "ar
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below: Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl, benzhydryl and the like.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below: Etc.
  • Carbocyclic alkyl includes “aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyl”.
  • Preferable embodiments of “carbocycle alkyl” include benzyl, phenethyl, benzhydryl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups shown below: Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • Non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • Heterocyclic alkyl includes “aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyl”. Preferred embodiments of “heterocyclic alkyl” include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, iso Pyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below: Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below: Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below: Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below: Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below: Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below: Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic oxy” means a group in which the above “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocycle for example, phenyloxy, naphthyloxy and the like can be mentioned.
  • Aromatic carbocyclic carbonyl means a group in which the above “aromatic carbocycle” is bonded to a carbonyl group. Examples include benzoyl and naphthylcarbonyl.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfinyl” means a group in which an “aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfinyl”, and “non-aromatic
  • the “non-aromatic carbocyclic” portion of the “aromatic carbocyclic sulfonyl” is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which the “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocyclic carbonyl means a group in which the above “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclopropenylcarbonyl, indanylcarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxycarbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. Examples thereof include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
  • non-aromatic carbocyclic oxycarbonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • non-aromatic carbocyclic sulfanyl means a group in which the “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic carbocyclic sulfinyl means a group in which the “non-aromatic carbocyclic ring” is bonded to a sulfinyl group.
  • examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclohexenylsulfinyl, tetrahydronaphthylsulfinyl, adamantylsulfinyl and the like.
  • non-aromatic carbocycle sulfonyl means a group in which the above “non-aromatic carbocycle” is bonded to a sulfonyl group.
  • cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • “Aromatic heterocycle oxy” means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom.
  • aromatic heterocycle oxy means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • “Aromatic heterocycle carbonyl” means a group in which the above “aromatic heterocycle” is bonded to a carbonyl group.
  • pyrrolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, oxazolylcarbonyl, indolylcarbonyl and the like can be mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • aromatic heterocyclic oxy means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which the above “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • aromatic heterocycle means a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfinyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group.
  • aromatic heterocycle a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group.
  • pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic sulfinyl”, and “Non-aromatic”
  • the “non-aromatic heterocyclic” part of the “aromatic heterocyclic sulfonyl” is the same as the above “non-aromatic heterocyclic group”.
  • Non-aromatic heterocyclic oxy means a group in which the above “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • dioxanyloxy, thiranyloxy, oxiranyloxy, oxetanyloxy, oxathiolanyloxy, azetidinyloxy, thianyloxy, thiazolidinyloxy, pyrrolidinyloxy, pyrrolinyloxy, imidazolidinyloxy, imidazo Examples include linyloxy, pyrazolidinyloxy, pyrazolinyloxy, piperidyloxy, piperazinyloxy, morpholinyloxy, indolinyloxy, chromanyloxy and the like.
  • non-aromatic heterocyclic carbonyl means a group in which the above “non-aromatic heterocyclic” is bonded to a carbonyl group. Examples include dioxanylcarbonyl, oxetanylcarbonyl, pyrazolinylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl, indolinylcarbonyl and the like.
  • non-aromatic heterocyclic oxycarbonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • non-aromatic heterocyclic oxycarbonyl for example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which the “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic heterocyclic sulfinyl means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfinyl group.
  • piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
  • non-aromatic heterocyclic sulfonyl means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • Carbamoyloxy means a group in which an oxygen atom is bonded to carbamoyl.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituent group A.
  • Substituent group A halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl,
  • the atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B.
  • Substituent group B oxo, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano , Cyanoalkyl, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, hydroxyalkyloxy, alky
  • Substituent group B can also be mentioned as substituents on the “carbocycle” and “heterocycle” rings of “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”.
  • the atom at any position on the ring may be bonded to one or more groups selected from the substituent group B. When two or more substituents are present, they may be the same or different.
  • the substituent group A can be exemplified as the substituent of the “alkyl” part of “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”.
  • the hydrogen atom at any position may be substituted with one or more groups selected from the substituent group A. When two or more substituents are present, they may be the same or different.
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted sulfamoyl” and “substituted or unsubstituted carbamoyloxy” include the following substituent group C: It is done. When two substituents are present, they may be the same or different.
  • Substituent group C hydroxy, amino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic Aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aro
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”.
  • oxo means a group in which two hydrogen atoms on a carbon atom are substituted with oxo as follows.
  • substituents of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino” include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, etc. are mentioned. When substituted with a plurality of substituents, the substituents may be the same or different.
  • Examples of the “leaving group” include halogen, C 1-6 alkylsulfonyloxy, halo C 1-6 alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy and the like.
  • a preferred embodiment of the ring of the “substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group” of R 1 and R 1 ′ is a 5- to 6-membered ring, and a more preferred embodiment is substituted Or an unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
  • the carbocyclic group include phenyl, hydroxyphenyl, dihydroxyphenyl, phenyl having halogen as a substituent, and phenyl having halogen and hydroxy as a substituent.
  • heterocyclic group examples include aminothiazole, aminothiazole having halogen as a substituent, aminothiadiazole, thiophene, furan, benzothiazole, pyridine, pyrimidine, pyridazine, aminopyridine and the like.
  • carbocyclic group examples include phenyl, hydroxyphenyl, dihydroxyphenyl, chlorodihydroxyphenyl and the like.
  • heterocyclic group include aminothiazole, aminothiazole having a halogen as a substituent, and aminothiadiazole.
  • heterocyclic group are aminothiazole, aminochlorothiazole, aminofluorothiazole, aminobromothiazole or aminothiadiazole.
  • carbocyclic group include the groups shown below.
  • heterocyclic group include the groups shown below.
  • Other preferred examples of the heterocyclic group include the groups shown below. More preferable examples of the heterocyclic group include the groups shown below.
  • R 2A and R 2B and R 2′A and R 2′B are each independently a hydrogen atom, substituted or unsubstituted When it is amino, sulfo, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, for example: Preferred examples of are: The substituted amino shown below: Substituted sulfamoyl, shown below: (Wherein ring C represents a substituted or unsubstituted heterocyclic group); Substituted carbamoyl shown below: (Wherein ring B represents a substituted or unsubstituted heterocyclic group); or substituted carbonyloxy as shown below: (Wherein, ring C represents a substituted or unsubstituted
  • R 2A and R 2B , or R 2′A and R 2′B together form a substituted or unsubstituted methylidene preferably the formula: (R 21 is substituted or unsubstituted alkyl.) It is group shown by these.
  • the wavy line between the carbon atom forming a double bond and R 21 means a cis bond, a trans bond, or a mixture thereof.
  • a wavy line between a carbon atom forming a double bond and a carboxy group or an alkyl group means a cis bond, a trans bond or a mixture thereof
  • R 2A and R 2B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably having the formula: (Wherein R 10 is a hydrogen atom or an alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carbamoylalkyl optionally substituted with one or more groups selected from substituent group D.
  • substituent group D is A group consisting of halogen, hydroxy, amino, carbamoyl, alkyloxycarbonylamino and phenyl), or a group represented by the formula:
  • R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic
  • Q is a single bond, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group
  • m is 0-3 Is an integer). More preferably, Wherein each definition is as defined above.
  • R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group.
  • Examples of the case include a hydrogen atom, a fluorine atom, a chlorine atom, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, carbamoylmethyl, Carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, allyloxycarbonylaminomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybe Zyl, 4-carboxybenzyl, 3,4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazoly
  • R 8 and R 9 is (hydrogen atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, hydrogen atom), (hydrogen atom, methyl), (Methyl, hydrogen atom),), (hydrogen atom, ethyl), (ethyl, hydrogen atom) (hydrogen atom, isopropyl), (isopropyl, hydrogen atom), (hydrogen atom, phenyl), (phenyl, hydrogen atom), (Hydrogen atom, carboxymethyl), (carboxymethyl, hydrogen atom), (hydrogen atom, hydroxymethyl), (hydroxymethyl, hydrogen atom), (hydrogen atom, aminomethyl), (aminomethyl, hydrogen atom), (methyl , Methyl) and the like.
  • R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably having the formula: (Wherein R 10 ′ is a hydrogen atom or alkyl), or a group represented by the formula: Wherein R 8 ′ and R 9 ′ are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted A cyclic group, R 8 ′ and R 9 ′ together form a substituted or unsubstituted methylidene, or R 8 ′ and R 9 ′ together with adjacent atoms are substituted or unsubstituted Or a substituted or unsubstituted heterocyclic group; Q ′ is a single bond, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group M
  • R 8 ′ and R 9 ′ are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group.
  • ⁇ is a hydrogen atom, fluorine atom, chlorine atom, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, carbamoyl '' Methyl, carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-carboxybenzyl, 3, 4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
  • R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl
  • examples of the case where “R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl” include a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, tert-butyl and the like.
  • R 8 ′ and R 9 ′ , (R 8 ′ , R 9 ′ ) is (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (methyl, hydrogen atom), or (methyl, methyl) ).
  • R 8 and R 9 , or R 8 ′ and R 9 ′ together form a substituted or unsubstituted methylidene include: (Wherein R 22 and R 23 are each independently a hydrogen atom or substituted or unsubstituted alkyl). Preferable examples of R 22 and R 23 are each independently a hydrogen atom, methyl, fluoromethyl, trifluoromethyl, ethyl or the like, more preferably a hydrogen atom at the same time.
  • R 8 and R 9 , or R 8 ′ and R 9 ′ together with adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle”
  • a 3- to 6-membered monocycle is preferable, and a 3- or 4-membered ring is more preferable.
  • Preferred examples include cyclopropane, cyclobutane, cycloheptane, cyclohexane, aziridine, oxirane, thiirane, azirine, thylene, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran and the like.
  • a more preferred example is cyclopropane.
  • R 3 is a hydrogen atom, OCH 3 or NH—CH ( ⁇ O), preferably a hydrogen atom.
  • R 16 is carboxy, tetrazolyl or substituted or unsubstituted carbamoyl, preferably carboxy, carbamoyl or the following formula: It is. More preferably, it is carboxy. Another preferred embodiment of R 16 is tetrazolyl.
  • R 17 is a hydrogen atom or substituted or unsubstituted alkyl, preferably a hydrogen atom or alkyl. More preferably, it is a hydrogen atom.
  • R 7A and R 7B are each independently a hydrogen atom, hydroxy, carboxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkyl, haloalkyl, alkyl Examples include oxy and haloalkyloxy. More preferably, R7A is a hydrogen atom or methyl, and R7B is a hydrogen atom, methyl, trifluoromethyl, hydroxy or methoxy.
  • a preferred embodiment of —Z— is a single bond, —CH 2 —, —C (CH 3 ) H— or — (CH 3 ) 2 —, and a more preferred embodiment is a single bond or —CH 2 —. is there.
  • -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -.
  • Preferred is —S—CH 2 —, —CH 2 —S— or —S—. More preferred is —S—CH 2 —.
  • R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, carboxy, sulfamoyl, mono Examples include alkylsulfamoyl, dialkylsulfamoyl, alkyl, haloalkyl, haloalkyloxy, alkyloxy, acyl, acyloxy, cyano, amidino, guanidino, carbamoyloxy, alkylcarbonyloxy and the like.
  • R 4A and R 4B are each independently a hydrogen atom, hydroxy, amino, carboxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, carbamoyloxy, acetyloxy, and the like, and more preferably R 4A is a hydrogen atom or methyl, and R 4B is a hydrogen atom, methyl, hydroxy, carbamoyloxy or acetyloxy. More preferably, R 4A is a hydrogen atom or methyl, and R 4B is a hydrogen atom or methyl.
  • R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, hydroxy, amino, carboxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyano.
  • R 5A and R 6A are hydrogen atoms
  • R 5B and R 6B are each independently a hydrogen atom and hydroxy. More preferably, R 5A , R 5B , R 6A and R 6B are hydrogen atoms.
  • -T- is -CR 4A R 4B -, more preferably an, -CH 2 -, - C ( CH 3) H -, - C (CH 3) 2 - or -C (OH) H- It is.
  • -Z- when is a single bond, Y is CH, -W- is -S-CH 2 - and is, and -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B — or —O—.
  • -Z- -CR 7A R 7B is - when, Y is N, -W- is -CH 2 - and is, and -T- is -CR 4A R 4B - is.
  • —U— is —S—, —S—CH 2 — or —CH 2 —S—.
  • Preferred is —S—CH 2 —.
  • R 11 is amino or amino substituted with acyl. Preferred is substituted or unsubstituted alkylcarbonylamino. In a preferred embodiment of R 11 , the following formula: Wherein R 1 ′ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; For R 2′A and R 2′B , a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino) It is group shown by these.
  • R 1 ′ is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • R 10 ′ is a hydrogen atom or alkyl
  • R 8 ′ and R Each 9 ′ is independently a hydrogen atom or alkyl
  • R 12 is a hydrogen atom, OCH 3 or NH—CH ( ⁇ O), preferably a hydrogen atom.
  • R 13 is preferably a hydrogen atom.
  • R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl. Preferably, they are each independently a hydrogen atom or methyl. More preferably, they are simultaneously hydrogen atoms or simultaneously methyl.
  • R 1 is the following formula: (Wherein each definition has the same meaning as above) A group represented by: For R 2A and R 2B a) R 2A each independently has a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituent.
  • R 2B is a hydrogen atom, b-1)
  • R 2A and R 2B taken together have a methylidene having the following substituents: Or b-2)
  • Embodiment 2-1 Formula (I) is: (Wherein, -Z- is -CR 7A R 7B - is; Y is N; -W- is -CH 2- ; -T- is -CR 4A R 4B - a and; R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino; R 1 is the following formula: (Wherein each definition has the same meaning as above) A group represented by: For R 2A and R 2B a) R 2A and R 2B each independently have a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituent
  • R 2A and R 2B taken together have a methylidene having the following substituents: Or b-2)
  • Formula (I) is: Wherein -Z- is a single bond; Y is CH; -W- is -S-, -S-CH 2 -or -CH 2 -S-; -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is; R 4A and R 4B are each independently a hydrogen atom, hydroxy, acetyloxy, carbamoyloxy, methyl, or amino; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: (Wherein each definition has the same meaning as above) Is; R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (Wherein each definition has the same meaning as above) Is; R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy; and R 17
  • -Z- is a single bond; Y is CH; -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -; -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is; R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: Where X is CCl, CF or CBr; For R 2A and R 2B a) each R 2A is independently substituted or unsubstitute
  • -Z- is a single bond; Y is CH; -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 - is the be; -T- is -CR 5A R 5B -CR 6A R 6B -or -O-; R 5A , R 5B , CR 6A and R 6B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted Of amino; R 1 is the following formula: (Wherein each definition has the same meaning as above) Is; For R 2A and R 2B a) each R 2A is independently substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alky
  • -Z- is a single bond; Y is CH; -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -; -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is; R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: Where each definition is as defined above; For R 2A and R 2B a) each R 2A is independently substituted or unsubstituted amino, sulf
  • the compounds (I) and (IA) of the present invention are not limited to specific isomers, but all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical Isomers, rotamers, geometric isomers, etc.), racemates or mixtures thereof.
  • Formula (II) has all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, except where stereo designations are specified) , Geometric isomers, etc.), racemates or mixtures thereof.
  • Is Etc Preferably, It is. More preferably, It is.
  • substitution positions on the skeletons of formula (I) and formula (II) are as follows.
  • the ⁇ -position side chain and the ⁇ -position side chain represent groups bonded to the ⁇ -position and ⁇ -position of the following mother nucleus.
  • the ester form of the formula (I), (IA) or (II) preferably includes an ester form of carboxy on the ⁇ -position and / or carboxy on the ⁇ -position side chain.
  • Esters in carboxy on the ⁇ -position side chain have the formula: (In the formula, each symbol is as defined above.) Substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituent at the end of R 1 or R 2A or R 2B represented by In which carboxy in carbonyloxy or the like having an ester structure has an ester structure (for example, in the case of carboxy (—COOH), a structure of —COOR P1 shown together with R P1 indicating an ester residue such as a carboxy protecting group) And esters that are easily metabolized in the body to form a carboxy
  • Protecting groups such as carboxy described above include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected, such as lower alkyl (eg, methyl, ethyl, t-butyl), lower alkylcarbonyloxymethyl (eg, pivaloyl), An optionally substituted arylalkyl (eg, benzyl, benzhydryl, phenethyl, p-methoxybenzyl, p-nitrobenzyl), a silyl group (eg, t-butyldimethylsilyl, diphenyl t-butylsilyl) and the like can be mentioned.
  • lower alkyl eg, methyl, ethyl, t-butyl
  • lower alkylcarbonyloxymethyl eg, pivaloyl
  • Protecting groups for amino groups include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected, such as lower alkyloxycarbonyl (eg, t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), substituted Aralkylanoyl (eg: benzoyl, p-nitrobenzoyl), acyl (eg: formyl, chloroacetyl) and the like which may be used may be mentioned.
  • the amino-protecting group also includes a group that is easily metabolized in the body to become amino.
  • One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), (IA) or (II) may be replaced by hydrogen, carbon and / or isotopes of other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compounds of formula (I), (IA) or (II) also include compounds substituted with such isotopes.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I), (IA) or (II).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • Radiolabeled compounds of the compounds represented by formula (I), (IA) or (II) can be prepared by methods well known in the art.
  • a tritium-labeled compound represented by the formula (I), (IA) or (II) is represented by the formula (I), (IA) or (II) by, for example, catalytic dehalogenation reaction using tritium. It can be prepared by introducing tritium into a specific compound.
  • This method is a precursor in which a compound of formula (I), (IA) or (II) is appropriately halogen-substituted in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. It includes reacting the body with tritium gas.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • the salt of the compound represented by the formula (I), (IA) or (II) means that the ⁇ -position carboxy group and / or the ⁇ -position carboxy group and / or the ⁇ -position side chain amino group is an inorganic acid or an organic acid. Includes those forming a salt.
  • a compound represented by the formula (I), (IA) or (II) and an alkali metal for example, Lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanol) Amine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, iodine) Hydrofluoric acid etc.) and organic acids (eg formic acid, acetic acid) Propionic acid, tri
  • the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystalline polymorph.
  • the present invention also encompasses such various solvates and polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I), (IA) or (II).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing a compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is hydrolyzed by a compound, gastric acid, etc., which is enzymatically oxidized, reduced, hydrolyzed and converted to a compound represented by the formula (I), (IA) or (II) under physiological conditions in vivo. The compound etc.
  • the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof has a hydroxy group, for example, a compound having a hydroxy group and an appropriate acyl halide, an appropriate acid anhydride
  • examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and a mixed anhydride, or reacting with a condensing agent.
  • CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p— CH 3 —O—PhSO 3 —, PhSO 3 —, and p—CH 3 PhSO 3 — can be mentioned.
  • the present invention relates to (A) a compound represented by formula (I), (IA) or (II), an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (B) ⁇ - There is provided a medicament characterized by combining a compound having a lactamase inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound having a ⁇ -lactamase inhibitory action include a compound having a metallo ⁇ -lactamase inhibitory action and a compound having a serine ⁇ -lactamase inhibitory action, and a compound having a serine ⁇ -lactamase inhibitory action is preferable.
  • Specific examples of the compound having ⁇ -lactamase inhibitory action include clavulanic acid, sulbactam, tazobactam, dipicolinic acid (DPA), 3-aminophenylboronic acid (APB), ethylenediaminetetraacetic acid (EDTA), abibactam (AVI) and the like.
  • compounds having ⁇ -lactamase inhibitory activity described in Expert Opinion Therapeutic Patents (2013), 23 (11), 1469-1481 can be mentioned.
  • the compounds of the present invention represented by the formulas (I) and (IA) have side chain sites bonded to the ⁇ -position and ⁇ -position of the skeleton of the intermediate shown below Can be obtained.
  • the protecting group P include protecting groups described in the following general synthesis. Preferred examples include a benzhydryl group, a paramethoxybenzyl group, a trityl group, a 2,6-dimethoxybenzyl group, a methoxymethyl group, Examples thereof include a benzyloxymethyl group and a 2- (trimethylsilyl) ethoxymethyl group.
  • the leaving group include halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • Process 2 It subjected the compound protecting group P 3 of (V) under acidic conditions deprotection reaction to obtain subsequently a compound by subjecting the intramolecular cyclization reaction under condensing agent present in the (VI).
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • dichloromethane examples include organic acids and inorganic acids.
  • Trifluoroacetic acid examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 0 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 3 Compound (VII) is obtained by subjecting the carboxy protecting group P 1 containing an acyl group of compound (VI) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 4 Compound (IX) is obtained by subjecting Compound (VII) to a condensation reaction with Compound (VIII) in the presence of a base.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • dichloromethane examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, phenyl phosphate dichloride, and the like.
  • the base used include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferable.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • reaction solvent examples include, for example, ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-acetate).
  • ethers eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether
  • esters eg, ethyl formate, ethyl acetate, n-acetate.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, carbon tetrachloride
  • hydrocarbons eg, n-hexane, benzene, toluene
  • amides eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • ketones eg acetone, methyl ethyl ketone
  • nitriles eg acetonitrile, propionitrile
  • nitros eg nitromethane, nitroethane, nitrobenzene
  • dimethyl sulfoxide Water It is shown.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • R 16a and R 16b are each independently a hydrogen atom or substituted or unsubstituted alkyl, R 16A is cyano or tetrazolyl optionally having a protecting group, and other symbols are as defined above.
  • Process 1 P 2 of compound (VI) can be deprotected by catalytic reduction or acidic conditions with a protecting group.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (Eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides ( Examples: formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile),
  • ethers eg, anisole, dioxane, tetrahydrofuran,
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • an organic acid or an inorganic acid can be used as the acid. Examples thereof include trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • the carboxylic acid of compound (VII) can be converted to an amide.
  • the activating agent for carboxylic acid include thionyl chloride, oxalyl chloride, ethyl chlorocarbonate, di-tert-butyl dicarbonate, carbonyldiimidazole, dicyclohexylcarbodiimide and the like. Preferred is di-tert-butyl dicarbonate.
  • amidating agent examples include ammonia, ammonium chloride, ammonium formate, and ammonium carbonate. Ammonium carbonate is preferred.
  • base examples include pyridine, dimethylaminopyridine, picoline, triethylamine, diisopropylethylamine and the like. Pyridine is preferred.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 3 The amide group of compound (VII) can be converted to a tetrazolyl optionally having a protecting group via a cyano group or a cyano group. Conversion to a cyano group can be performed using a dehydrating reagent.
  • Examples of the dehydrating reagent include thionyl chloride, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, phosphorus pentachloride, diphosphorus pentoxide, and the like. Preferred is trifluoroacetic anhydride.
  • a base may coexist in the reaction. Examples of the base include pyridine, picoline, triethylamine, lutidine, diisopropylethylamine and the like. Pyridine is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Subsequent conversion to tetrazolyl can be done using trimethylsilyl azide, sodium azide, hydrazoic acid, diphenylphosphoric acid azide. Trimethylsilyl azide is preferred.
  • Dibutyltin oxide can coexist as a catalyst.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • the tetrazolyl group can be protected as necessary.
  • a protecting group similar to the protecting group for carboxy group can be used. Preferred protecting groups include benzhydryl, p-methoxybenzyl and the like.
  • Process 4 Compound (VII) is obtained by subjecting carboxy protecting group P 1 containing an acyl group of compound (IX) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 1 Compound (XI) can be led to compound (XII) by oxidation.
  • the oxidizing agent include selenium dioxide and oxon.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 2 Compound (XIV) can be led to compound (XIV) by alkylation reaction of compound (XII) and compound (XIII) and subsequent cyclization reaction.
  • the base include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 10 to 30 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 3 By reacting compound (XIV) with ⁇ -haloacetic acid halide, compound (XV) can be derived.
  • the base used include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 0 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 4 The halide of compound (XV) can be converted to a phosphonium salt and subsequently led to compound (XV) by intramolecular cyclization that occurs in the presence of a base.
  • Examples of the phosphonium salt formation include triphenylphosphine, triethylphosphine, tributylphosphine, and the like, and triphenylphosphine is preferable.
  • Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
  • Sodium bicarbonate is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 10 to 30 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 5 Reduction of the double bond of compound (XVI) can lead to compound (XVII).
  • the reduction is performed using catalytic hydrogenation or a reducing agent, and examples of the reducing agent include sodium borohydride, lithium borohydride, and borohydride.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • Step 6 Compound (VII) is obtained by subjecting amino protecting group P 1 containing a carbonyl group of compound (IX) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • Step 1-1 The compound (XIX) or compound (XXII) can be derived by acylating the cyclic amide nitrogen atom of the compound (XIX) or compound (XX) in the presence of a base.
  • the acylating agent include tert-butyl 2-chloro-2-oxoacetate.
  • the base include triethylamine, diisopropylethylamine, pyridine, lutidine and the like.
  • Diisopropylethylamine is preferable.
  • the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg,
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Step 1-2 Ozonolysis of the double bond of compound (XXII) can lead to compound (XXIII).
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • the reaction temperature is usually about ⁇ 100 to 0 ° C., preferably about ⁇ 70 to ⁇ 40 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 2 The compound (XXIV) typified by the compound (XXI) or the compound (XXIII) can be cyclized with a reducing agent to lead to the compound (XXV).
  • the reducing agent include samarium iodide.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • the reaction temperature is usually about ⁇ 100 to 0 ° C., preferably about ⁇ 70 to ⁇ 40 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 3 The dihydroxy group of compound (XXV) can be led to a cyclic carbonate structure by an acylating agent.
  • the acylating agent include carbonyldiimidazole and triphosgene.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • Process 4 Compound (VII) is obtained by subjecting amino protecting group P 1 containing a carbonyl group of compound (XXVI) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • Process 1 Compound (XXVIII) is obtained by subjecting the amine body to a condensation reaction with compound (VII) in the presence of a base.
  • the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone,
  • ethers eg, anisole, dioxane
  • solvents may be used alone or in combination of two or more.
  • the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, and phenyl phosphate dichloride.
  • the base include triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 2 Compound (XXIX) is obtained by oxidizing compound (XXVIII).
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulf
  • solvents may be used alone or in combination of two or more.
  • the oxidizing agent include peracetic acid, m-chloroperbenzoic acid, hydrogen peroxide, sodium tungstate, and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 3 All protecting groups of compound (XXIX) are subjected to a deprotection reaction under acidic conditions to give compound (I).
  • the acid an organic acid or an inorganic acid can be used.
  • reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • the obtained compound (I) or (IA) can be further chemically modified to synthesize ester forms, or pharmaceutically acceptable salts or solvates thereof.
  • the compound of the present invention has a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.
  • the compound of the present invention is a gram-negative bacterium, preferably a gram-negative bacterium of the family Enterobacteriaceae (E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.) (Hemophilus, Moraxella, etc.) and glucose non-fermenting Gram-negative bacteria (Pseudomonas other than Pseudomonas aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.).
  • the compounds of the present invention are stable against ⁇ -lactamases belonging to classes A, B, C and D produced by these gram-negative bacteria.
  • the compound of the present invention also has antibacterial activity against gram-positive bacteria including methicillin-sensitive Staphylococcus aureus (MRSA), penicillin-resistant pneumococcus (PRSP) and the like.
  • MRSA methicillin-sensitive Staphylococcus aureus
  • PRSP penicillin-resistant pneumococcus
  • Further preferable compounds have characteristics such as high blood concentration, long duration of effect, and / or remarkable tissue transferability as pharmacokinetics.
  • Preferred compounds are safe in terms of side effects such as no fever and no nephrotoxicity.
  • preferred compounds have high water solubility and good pharmacokinetics, and are suitable as injections and oral drugs.
  • the compound of the present invention can be administered orally or parenterally.
  • the compound of the present invention is any of ordinary preparations, for example, solid preparations such as tablets, powders, granules and capsules, liquid preparations, oil suspensions, or liquid preparations such as syrups and elixirs. It can also be used as a dosage form.
  • the compound of the present invention can be used as an aqueous or oily suspension injection or nasal solution.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.
  • the formulations of the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.
  • the compound of the present invention can be administered parenterally or orally as an injection, capsule, tablet or granule, but is preferably administered as an injection.
  • the dose is usually about 0.1 to 100 mg / day, preferably about 0.5 to 50 mg / day per kg of the body weight of the patient or animal, if desired divided into 2 to 4 times a day.
  • the carrier is, for example, distilled water, physiological saline or the like, and a base for adjusting pH may be used.
  • Carriers when used as capsules, granules, tablets are known excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.).
  • excipients eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.
  • binders eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • Boc tert-butoxycarbonyl
  • DMF N, N-dimethylformamide
  • DMA N, N-dimethylacetamide
  • DMAP N, N-dimethyl-4-amino Pyridine
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • HMPA hexamethylphosphoric triamide
  • HOBt 1-hydroxybenzotriazole
  • mCPBA m-chloroperbenzoic acid
  • Me methyl
  • TBS tert-butyldi
  • the LCMS analysis obtained in the examples was measured under the following conditions. Measurement condition 1: Column: ACQUITY UPLC® BEH C18 (1.7 ⁇ m id 2.1 ⁇ 50 mm) (Waters) Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, [B] was 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes Thereafter, 100% solvent [B] was maintained for 0.5 minutes.
  • Measurement condition 2 Column: Shim-pack XR-ODS (2.2 ⁇ m, id 50 ⁇ 3.0 mm) Flow rate: 1.6 mL / min PDA detection wavelength: 254 nm
  • Step 2 Synthesis of Compound 3c
  • a solution of Compound 3b (4.79 g, 12.7 mmol) in tetrahydrofuran (24 mL) was added dropwise a solution of diphenyldiazomethane (2.60 g, 13.4 mmol) in tetrahydrofuran (24 mL) over 20 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 3c (3.37 g, yield 49%) as a white solid. .
  • Step 3 Synthesis of Compound 3f After cooling a suspension of phosphorus pentachloride (1.04 g, 5.0 mmol) in dichloromethane (6.8 mL) to ⁇ 78 ° C., pyridine (0.444 mL, 5.5 mmol) was added, Then, a solution of compound 3c (1.36 g, 2.5 mmol) in dichloromethane (6.8 mL) was added dropwise. After stirring at ⁇ 10 ° C. for 1 hour, the reaction mixture was cooled to ⁇ 78 ° C. and methanol (6.8 mL) was added. After stirring at ⁇ 30 ° C.
  • Step 4 Synthetic compound 3f (367 mg, 0.39 mmol) in dichloromethane (3.7 mL) was cooled to ⁇ 40 ° C., then anisole (0.344 mL, 3.15 mmol) and 2 mol / L aluminum chloride were used. / Nitromethane solution (1.58 mL, 3.15 mmol) was sequentially added, and the mixture was stirred for 30 minutes under ice cooling. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated.
  • Step 2 Synthesis of Compound I-004
  • Compound 4a (295 mg, 0.35 mmol) in dichloromethane (3.0 mL) was cooled to ⁇ 20 ° C., then anisole (0.385 mL, 3.5 mmol) and 2 mol / L titanium chloride.
  • Dichloromethane solution (1.23 mL, 2.47 mmol) was sequentially added, and the mixture was stirred for 40 minutes under ice cooling. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated.
  • Step 2 Compound 4 of Compound 4 (18.0 g, 27.2 mmol) was dissolved in dichloromethane (180 mL), cooled to 50 ° C. below freezing, and anisole (11.9 mL, 109 mmol) and 2 mol / L aluminum chloride-nitromethane solution (47.7 mL, 95.0 mmol) was added dropwise and stirred at the same temperature for 20 minutes. Purified water was added to the reaction solution, and the target product was extracted with dichloromethane. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to obtain Compound 4. The entire amount obtained was used in the next reaction without purification.
  • Step 3 Synthesis of Compound 5
  • the residue obtained in the entire reaction was dissolved in dichloromethane (130 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.21 g, 27.2 mmol) was added thereto at room temperature. For 1 hour 30 minutes. To this solution was again added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.61 g, 13.6 mmol), and the mixture was stirred at room temperature for 1 hour. Purified water was added to the reaction solution, and the target product was extracted with dichloromethane.
  • Step 4 Synthesis of Compound 6
  • Compound 6 (2.80 g, 5.88 mmol) was suspended in dichloromethane (30.0 mL), 4 mol / L hydrochloric acid-ethyl acetate (22.0 mL, 88.0 mmol) was added, and the mixture was stirred at room temperature. Stir for minutes. The resulting solid was collected by filtration and washed with ethyl acetate to obtain Compound 8 as an inseparable mixture.
  • Step 5 Synthesis of Compound 8
  • Compound 8 (202 mg) was suspended in dichloromethane, cooled to 0 ° C., compound 9 (189 mg, 0.538 mmol) and N-methylmorpholine (0.118 mL, 1.08 mmol) were added overnight.
  • Stir with. 5% multistory water and tetrahydrofuran were added to the reaction solution, and the target product was extracted from the aqueous layer with dichloromethane.
  • the collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography to give a compound.
  • Step 2 Synthesis of Compound 1c
  • Compound 1b (13.87 g, 35.2 mmol) was treated in the same manner as in Step 2 of Synthesis Example of Compound I-031 to give Compound 1c (9.64 g, yield 67.4%). Obtained as a clear colorless oil.
  • Step 3 Synthesis of Compound 1e
  • acetone 50.2 mL
  • Compound 1d 5.02 g, 21.26 mmol
  • hexamethylphosphoric triamide (12.95 mL)
  • Water was added and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Step 5 Synthesis of Compound 1h
  • Compound 1f-isomer B and Compound 1f-isomer C mixture 500 mg, 1.09 mmol
  • compound 1g 525 mg, 1.31 mmol
  • To give compound 1h-isomer C 96.7 mg, 12.3% yield) as a single isomer.
  • Step 6 Synthesis of Compound I-009
  • Compound 1h—isomer C 90.2 mg, 0.125 mmol
  • Step 7 of the synthesis of Compound I-031 was treated in the same manner as in Step 7 of the synthesis of Compound I-031 to give compound I-009 (14.2 mg, yield). 21.0%) was obtained as a brown solid.
  • Process 3 Compound 4 (590 mg) was dissolved in dichloromethane (6.0 mL), cooled to 20 degrees below freezing, and anisole (1.03 mL, 9.45 mmol) and a 2 mol / L aluminum chloride-nitromethane solution (4.72 mL, 9.45 mmol). ) And stirred at -20 degrees for 30 minutes. Purified water and diisopropyl ether were added to the reaction solution. Acetonitrile was added to the reaction solution, and the aqueous layer was separated. The organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and the pH was adjusted to 1.3 using 2 mol / L hydrochloric acid.
  • HP20SS was added to the aqueous layer and concentrated.
  • the concentrated suspension was subjected to column chromatography connecting HP20SS and ODS and eluted with water-acetonitrile, and fractions containing the desired product were collected.
  • the aqueous solution was adjusted to pH 9.0 using a 2 mol / L aqueous sodium hydroxide solution, and a piece of dry ice was added to adjust the pH to 5.2. This aqueous solution was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound I-018 as a powder.
  • Step 4 Synthesis of Compound 29f
  • the system was replaced with nitrogen gas, dimethyl sulfide (7.77 mL, 105 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 5 minutes.
  • prenyl alcohol (5.33 mL, 53 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 1.5 hours.
  • reaction mixture was raised to about 0 ° C., 5% aqueous sodium carbonate solution was added, and the mixture was stirred at room temperature for 5 minutes.
  • Dichloromethane was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure.
  • the resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 29f (6.67 g, yield 41%) as a colorless oil.
  • Step 5 Compound 29g Synthesis compound 29f (6.67 g, 14.4 mmol) in dichloromethane (33 mL) was added with N, N, N′N′-tetramethylmethanediamine (7.82 mL, 57.4 mmol) under ice cooling. ) was added, and acetic anhydride (6.78 mL, 71.8 mmol) and acetic acid (5.75 mL, 100 mmol) were slowly added in this order. After stirring at room temperature for 3 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 7 Synthesis of Compound 29k
  • Compound 29i 700 mg, 0.98 mmol
  • dichloromethane 3.5 mL
  • trifluoroacetic acid 3.5 mL
  • dichloromethane 3.5 mL
  • dichloromethane 3.5 mL
  • ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • the organic layer was washed 4 times with water, then with saturated brine, and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure to obtain Compound 29j as a white foam.
  • the obtained 29j was used in the next reaction without purification.
  • Step 8 Synthesis of Compound 29n
  • Compound 29n (255 mg, 82% yield) was converted into white foam from Compound 29k (212 mg, 0.37 mmol) and Compound 29m (178 mg, 0.44 mmol) in the same manner as in Step 3 of Example 1. Obtained.
  • Step 3 Synthesis of Compound 1e
  • Compound 1c (10.0 g, 25.5 mmol) in acetone (100 mL)
  • Compound 1d (6.02 g, 25.5 mmol) and hexamethylphosphoric triamide (15.5 mL, 89 mmol) were added.
  • the mixture was further stirred at room temperature for 1 hour.
  • Water was added and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 1e (2.1 g, yield: 13.1%).
  • Step 4 Synthesis of Compound 1f Under a nitrogen atmosphere, a solution of compound 1e (6.80 g, 10.8 mmol) in dichloromethane (34 mL) was cooled to ⁇ 10 ° C. A solution of TFA (34 mL, 441 mmol) in dichloromethane (34 mL) was added dropwise thereto, and the mixture was stirred at ⁇ 10 ° C. for 30 minutes. Water was added and extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and a solution of the obtained residue in dichloromethane (50 mL) was cooled to 0 ° C.
  • Step 5 Synthesis of Compound 1i
  • triphenylphosphine 8.80 g, 33.5 mmol
  • DIAD 6.52 mL, 33.5 mmol
  • hydroxyacetic acid benzhydryl were added thereto, and the mixture was stirred at 0 ° C. for 1 hour.
  • the reaction mixture was poured into a hexane-ethyl acetate mixture, and the resulting insoluble material was filtered.
  • Step 7 Synthesis of Compound I-031
  • a suspension of phosphorus pentachloride (0.754 g, 3.62 mmol) in dichloromethane (10 mL) was cooled to ⁇ 40 ° C., and pyridine (0.584 mL, 7.24 mmol) was added.
  • Compound 1f (0.805 g, 1.81 mmol) was then added.
  • the reaction mixture was cooled to ⁇ 78 ° C., and methanol (8.1 mL) was added.
  • an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • Step 2 Synthesis of Compound 34c
  • tetrahydrofuran 2.0 mL
  • chlorosulfonyl isocyanate 43 ⁇ L, 0.50 mmol
  • sodium hydrogen carbonate 116 mg, 1.38 mmol
  • water 200 ⁇ L
  • the mixture was further stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 2 Synthesis of Compound I-35
  • Compound I-35 (37 mg, 33% yield) was obtained as a white powder from Compound 35a (161 mg, 0.21 mmol) in the same manner as in Step 3 of Example 2.
  • reaction solution was dissolved in water, 2 mol / L hydrochloric acid and acetonitrile, and then washed with diisopropyl ether.
  • HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure.
  • the resulting mixture was subjected to ODS column chromatography and eluted with water / acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure and lyophilized to give compounds I-36 and I-37 as white powders.
  • Step 2 Synthesis of Compound 39c
  • Compound 39b (135 mg, 0.207 mmol) was dissolved in dichloromethane (1.50 mL) and cooled to 30 degrees below freezing. Pyridine (0.050 mL, 0.621 mmol) was added to this solution, and then trifluoroacetic anhydride (0.044 mL. 0.311 mmol) was added, followed by stirring at 30 ° C. for 45 minutes. To this reaction solution were added pyridine (0.033 mL, 0.414 mmol) and trifluoroacetic anhydride (0.029 mL. 0.207 mmol), and the mixture was stirred at 0 ° C. for 2 hours and 30 minutes.
  • Step 3 Synthesis of Compound 39d
  • Compound 39c 120 mg, 0.189 mmol was dissolved in 1,4-dioxane (1.20 mL), trimethylsilyl azide (0.050 mL, 0.379 mmol) and dibutyltin oxide (4.71 mg, 0.0189 mmol) was added and stirred at 70 degrees.
  • purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with ethyl acetate.
  • the collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to give compound 39d.
  • Process 4 Compound 39d (128 mg, 0.189 mmol) was dissolved in dichloromethane (1.0 mL), cooled to 30 ° C. below freezing, and anisole (0.124 mL, 1.13 mmol) and 2 mol / L aluminum chloride-nitromethane solution (0.567 mL) were cooled. 1.13 mmol) and stirred at 0 degrees for 45 minutes. Purified water and diisopropyl ether were added to the reaction solution. Acetonitrile, 2 mol / L hydrochloric acid was added to the reaction solution to dissolve the precipitate, and then the aqueous layer was separated.
  • the organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and HP20SS was added to the combined aqueous layer and concentrated.
  • the concentrated suspension was subjected to column chromatography in which HP20SS and ODS were connected, and eluted with water-acetonitrile. Fractions containing the target product were collected, and the pH was adjusted to 6.5 using 0.2 mol / L aqueous sodium hydroxide solution. A piece of dry ice was added. This solution was concentrated under reduced pressure, and the concentrate was lyophilized to obtain Compound I-39 as a powder.
  • Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was extracted with an aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted again with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 3 Synthesis of Compound I-40 Dimedone (616 mg, 4.39 mmol) and tetrakis (triphenylphosphine) palladium (0) (169 mg, 0.146 mmol) were added to a DMF solution of the composition of compound 40c (500 mg) at room temperature. The mixture was stirred for 30 minutes. To this, compound 40d (770 mg, 2.20 mmol) was added and stirred at room temperature for 1 hour. Insoluble matters in the reaction solution were removed by Celite filtration. Diisopropyl ether, acetonitrile and dilute hydrochloric acid were sequentially added to the filtrate and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated.
  • Step 4 Synthesis of Compound I-41 Dimedone (689 mg, 4.91 mmol) and tetrakis (triphenylphosphine) palladium (0) (379 mg, 0.328 mmol) were added to a DMF solution of 41 g of the composition compound (600 mg), at room temperature. Stir for 1 hour. To this, compound 1d (861 mg, 2.46 mmol) was added and stirred at room temperature for 1 hour. Insoluble matters in the reaction solution were removed by Celite filtration. Diisopropyl ether, acetonitrile and dilute hydrochloric acid were sequentially added to the filtrate and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated.
  • Step 2 Synthesis of Compound I-42
  • Compound I-42 was synthesized by the method described in EP253337A using Compound 42b (100 mg, 0.18 mmol) and Compound 42d (184 mg, 0.52 mmol) and purified by ODS column chromatography. This gave compound I-42 (15 mg, 19%).
  • Step 2 Compound 43c
  • Compound 43b (6.85 g, 33.7 mmol) and t-butyldimethylsilyl chloride (7.62 g, 50.6 mmol) were added to a solution of imidazole (3.44 g, 50.6 mmol) in dichloromethane (192 mL) at 0 ° C. And left at room temperature overnight.
  • Water was added and extracted with ethyl acetate.
  • the organic layer was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure.
  • Step 3 Compound 43e To a solution of compound 43c (11.32 g, 35.7 mmol) in tetrahydrofuran (192 mL) was added 8N aqueous sodium hydroxide solution (8.91 mL, 71.3 mmol) at 0 ° C., and the mixture was allowed to stand overnight at room temperature. A 1N aqueous hydrochloric acid solution (78 mL, 78 mmol) was added at 0 ° C., the mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate.
  • Step 4 Compound 43f A solution of compound 43e (5.0 g, 10.65 mmol) in tetrahydrofuran (50 mL) was added acetic acid (0.913 mL, 15.97 mmol) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 15.97 mL, 15.97 mmol) at 0 ° C. ) And stirred at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic layer was washed sequentially with an 8.4% aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • Step 5 Compound 43g To a solution of compound 43f (3.2 g, 9.0 mmol) in tetrahydrofuran (32 mL) at room temperature was added 2-hydroxyindoline-1,3-dione (1.763 g, 10.81 mmol) and triphenylphosphine (2.83 g, 10 .81 mmol) was added, and diisopropyl azodicarboxylate (2.10 mL, 10.81 mmol) was added dropwise, followed by stirring at room temperature for 1.5 hours.
  • Step 6 Compound 43k To a solution of compound 43g (2.96 g, 5.91 mmol) in dichloromethane (20.7 mL), methylhydrazine (0.351 mL, 6.50 mmol) was added at once at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. The obtained solution was filtered and washed with dichloromethane (8.9 mL), methanol (14.8 mL) was added to the obtained dichloromethane solution, and compound 43h (1.545 g, 5.67 mmol) was added at 0 ° C. And stirred at 0 ° C. for 1 hour.
  • Step 7 Compound I-43
  • Compound I-43 In the same manner as in Step 4 of Example 1, using Compound 43k, Compound I-43 (252.5 mg, 29.6%) was obtained as a white solid.
  • Step 2 Synthesis of Compound 45c
  • a solution of Compound 45b (8.07 g, 33 mmol) in tetrahydrofuran (32 mL) was added dropwise a solution of diphenyldiazomethane (7.12 g, 37 mmol) in tetrahydrofuran (24 mL).
  • the mixture was stirred at room temperature for 5 days and concentrated under reduced pressure.
  • the resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 45c (4.80 g, yield 35%) as a white solid.
  • Step 4 To a solution of compound 45f and 45 g of compound 45d (4.83 g, 10.7 mmol) in acetone (48 mL), compound 45e (2.79 g, 11.8 mmol), hexamethylphosphoric triamide (6.54 mL, 37 .6 mmol) was added. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure.
  • Step 5 Synthesis of compound 45i
  • dichloromethane 4.7 mL
  • trifluoroacetic acid 2.4 mL, 30.9 mmol
  • the reaction mixture was added to an ice-cooled mixture of aqueous sodium bicarbonate and dichloromethane.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration, and the compound 45h was obtained by concentrating under reduced pressure.
  • the obtained 45 h was used in the next reaction without purification.
  • the total amount of the obtained 45 h was dissolved in a dichloromethane (6.8 mL) solution, and then EDC hydrochloride (217 mg, 1.13 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure.
  • Step 6 Synthesis of Compound 45l After cooling a solution of Compound 45k (361 mg, 0.90 mmol) in dimethylacetamide (1.8 mL) to ⁇ 20 ° C., triethylamine (0.156 mL, 1.12 mmol) methanesulfonyl chloride (0.082 mL) 1.05 mmol). Solution A was obtained by stirring at ⁇ 20 ° C. for 30 minutes. After cooling a suspension of phosphorus pentachloride (312 mg, 1.5 mmol) in dichloromethane (1.8 mL) to ⁇ 78 ° C., pyridine (0.133 mL, 1.65 mmol) was added, followed by compound 45i (354 mg, 0.
  • Step 7 Synthesis of Compound I-45 After cooling a solution of Compound 45l (407 mg, 0.55 mmol) in dichloromethane (4 mL) to ⁇ 40 ° C., anisole (0.48 mL, 4.4 mmol), 2 mol / L aluminum chloride / nitromethane The solution (2.2 mL, 4.4 mmol) was added in order and stirred at ⁇ 30 ° C. for 30 minutes. Diisopropyl ether, ice water, and acetonitrile were added to the reaction solution and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated.
  • Step 3 Synthesis of Compound 47e
  • a solution of Compound 47d (20.8 g, 33.5 mmol) in tetrahydrofuran (208 mL) was degassed under reduced pressure, and then morpholine (6.42 mL, 73.7 mmol), Pd (PPh 3 ) 4 (1. 94 g, 1.68 mmol) was added in order.
  • Boc 2 O (21.8 mL, 94 mmol) was added.
  • the mixture was further stirred at room temperature for 1.5 hours and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 47e (20.12 g, 94% yield) as a white foam.
  • Step 3 Synthesis of Compound 48g After cooling a suspension of phosphorus pentachloride (611mg, 2.94mmol) in dichloromethane (3.3mL) to -78 ° C, pyridine (0.261mL, 3.2mmol) was added, and then compound A solution of 48d (658.2 mg, 1.47 mmol) in dichloromethane (3.3 mL) was added dropwise. After stirring at ⁇ 10 ° C. for 2 hours, the reaction mixture was cooled to ⁇ 78 ° C. and ethanol (3.3 mL) was added. After stirring at ⁇ 30 ° C.
  • the organic layer was washed successively with an 8.4% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 48 g (453.7 mg, yield 43.4%) of a compound as a yellow oil.
  • Step 4 Synthesis of Compound I-48 48 g (453.7 mg, 0.64 mmol) in dichloromethane (6.8 mL) was cooled to ⁇ 30 ° C., then anisole (0.833 mL, 7.63 mmol) and 2 mol / L. An aluminum chloride / nitromethane solution (3.81 mL, 7.63 mmol) was sequentially added, and the mixture was stirred at ⁇ 30 ° C. for 20 minutes. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated.
  • Step 2 A solution of compound 50m and 50n in 50 ml of synthetic compound 50j (21.0 g, 51.9 mmol) in dichloromethane (420 mL) is stirred for 40 minutes while blowing ozone gas at ⁇ 78 ° C. Nitrogen was blown into the obtained blue solution for 5 minutes, dimethyl sulfide (11.5 mL, 156 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 15 minutes, stirred at 0 ° C. for 1 hour, added with ice water, and extracted with ethyl acetate. . The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 3 Synthesis of Compound I-50
  • Compound I-50 (169.9 mg, 27.3% yield (2 steps)) was obtained as a yellow solid.
  • Step 2 Synthesis of Compound 52c Selenium oxide (IV) (40.4 g, 364 mmol) was added to a solution of compound 52b (41.5 g, 165 mmol) in dioxane (215 mL), and the mixture was stirred at 80 ° C. for 15 hours. The reaction solution was cooled to room temperature, and the insoluble material was filtered through celite and washed with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52c (21.3 g, 46%).
  • Step 4 Compound 52g Synthetic compound 52e (5.54 g, 13.2 mmol) in dichloromethane (55 mL) was ice-cooled, bromoacetyl bromide (2.06 mL, 23.7 mmol) was added, and then triethylamine (3.29 mL). 23.7 mmol). After stirring for 2 hours under ice cooling, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure.
  • Step 5 Synthesis of Compound 52h Triphenylphosphine (2.45 g, 9.33 mmol) was added to a DMF (42 mL) solution of compound 52 g (4.21 g, 7.78 mmol). After stirring at room temperature for 1 to 5 hours, 8.4% aqueous sodium hydrogen carbonate solution (20.0 mL, 20.0 mmol) was added. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure.
  • reaction mixture A Pyridine (0.051 mL, 0.629 mmol) was added to the dichloromethane solution of 52j obtained in step 7 under ice-cooling, and then reaction mixture A was added dropwise. After stirring at 0 ° C. for 40 minutes, water was added and dichloromethane was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound 53d
  • a mixture of Compound 53d and 53d-ii (25.88 g, Yield 58%) was mixed with white from a mixture of Compound 53c and 53c-ii (21 g, 83 mmol) in the same manner as in Step 2 of Example 6. Obtained as a foam.
  • Step 3 Synthesis of Compound 53e
  • a mixture of Compound 53e and 53e-ii (6.11 g, yield 36%) was prepared in the same manner as in Step 4 of Example 6 from a mixture of Compound 53d and 53d-ii (25.9 g, 48 mmol).
  • Step 4 Synthesis of Compound 53g
  • a solution of a mixture of compound 53e and 53e-ii (6.11 g, 17.5 mmol) in dichloromethane (30 mL) was added N, N, N′N′-tetramethylmethanediamine (7 .17 mL, 52.6 mmol) was added, and acetic anhydride (6.30 mL, 66.6 mmol) and acetic acid (5.32 mL, 93 mmol) were added dropwise in this order.
  • ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 5 Synthesis of Compound I-53 Synthesis was performed from 53 g of Compound I in the same manner as in Steps 5 to 7 of Example 19 to obtain Compound I-53.
  • Step 2 Synthesis of Compound 54d
  • Compound 54c (corresponding to 28.7 mmol) obtained was dissolved in tetrahydrofuran (30 ml), and acetic acid (4.92 ml, 86 mmol) and 1 mol / L TBAF tetrahydrofuran solution (86 ml, 86 mmol) were added. . After stirring for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 5 Synthesis of Compound 54h Compound 54h (1.60 g, 92 g) was obtained in the same manner as in Step 3 of Example 12 using Compound 54f (1.04 g, 2.25 mmol) and Compound 54 g (1.00 g, 2.25 mmol). %) Crude product as a mixture of about 1.2: 1.
  • Step 2 Synthesis of Compound 55c
  • Compound 55b (19.1 g, 89.0 mmol) was suspended in tetrahydrofuran (38 mL), 4-methoxyphenylmethanol (36.8 g, 267 mmol) was added, and the mixture was stirred at 50 ° C. for 10 hours.
  • purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with dichloromethane.
  • the collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure.
  • the obtained residue was subjected to silica gel chromatography to obtain compound 55c.
  • Step 4 Synthesis of Compound 55e
  • Compound 55e was synthesized in the same manner as in Step 3 of Example 6 using Compound 55d (20.2 g, 31.7 mmol). (Yield 5.01 g, Yield 35%)
  • Step 5 Synthesis of Compound I-55
  • Compound I-55 was synthesized in the same manner as in Step 5 of Example 6 using Compound 55e.
  • MS (m + 1) 500.95, retention time: 0.32 minutes, measurement condition 1
  • Test Example 1 In vitro antibacterial activity of the compound of the present invention was confirmed.
  • the minimum inhibitory concentration (MIC) is measured according to the method recommended by CLSI (Clinical and Laboratory Standards Institute), the inoculum is 1 ⁇ 10 5 CFU / mL, the test medium is cation-adjusted Mueller Hinton broth, It was carried out by a micro liquid dilution method. The strains used are shown in the table below. (result) The test results are shown in Tables 20 and 21. In the table, the unit of the numerical value of the inhibitory activity is ⁇ g / mL.
  • the compound represented by the formula (I), (IA) or (II) has a broad antibacterial spectrum, particularly a strong antibacterial spectrum against gram-negative bacteria, and / or multidrug resistance. It exhibits strong antibacterial activity against bacteria, particularly crumb B type metallo- ⁇ -lactamase producing Gram negative bacteria, and / or strong antibacterial activity against substrate-specific extended ⁇ -lactamase (ESBL) producing bacteria. It is also effective against multi-drug resistant bacteria including carbapenemase resistance, and has high stability against ⁇ -lactamase producing gram-negative bacteria.
  • Test Example 1-2 In vitro antibacterial activity was confirmed in order to confirm the combined effect of the compound of the present invention and a compound having ⁇ -lactamase inhibitory action.
  • Test method Minimum growth inhibitory concentration (MIC: ug / mL) is measured according to the CLSI (Clinical and Laboratory Standards Institute) method. Implemented by law.
  • the amount of the compound having ⁇ -lactamase inhibitory action was 3-aminophenylboronic acid: 400 ug / ml and abibactam: 4 ug / ml.
  • the strains used are shown in the table below.
  • the test results are shown in Table 24. In the table, the unit of the numerical value of the inhibitory activity is ug / ml, APB means 3-aminophenylboronic acid, and AVI means abibactam.
  • the compound of the present invention represented by the formula (I), (IA) or (II) in combination with a compound having ⁇ -lactamase inhibitory activity, it has a broader antibacterial spectrum, It exhibits strong antibacterial activity against strains producing all types of ⁇ -lactamases of class A, B, C and D. That is, it exhibits strong antibacterial activity against crumb B-type metallo- ⁇ -lactamase-producing gram-negative bacteria and / or strong antibacterial activity against substrate-specific extended ⁇ -lactamase (ESBL) -producing bacteria. It is also effective against multidrug-resistant bacteria including carbapenemase resistance, and shows high stability against various ⁇ -lactamase-producing gram-negative bacteria.
  • ESBL substrate-specific extended ⁇ -lactamase
  • Test Example 2 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • Test Example 4 Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
  • the compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.
  • Test Example 5 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in the K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ mol / L or more was designated as (+), and the case where it was 3 ⁇ mol / L or less was designated as ( ⁇ ).
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated. Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Test Example 7 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role, was investigated. Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of ⁇ 80 mV by whole cell patch clamp, a +40 mV depolarization stimulus was applied for 2 seconds, followed by a ⁇ 50 mV repolarization.
  • I Kr delayed rectifier K + current
  • the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 10 About 5 mg of visual solubility test compound is weighed into three microscopic test tubes, and each medium (water for injection, saline feed, 0.5% glucose solution) is added to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be ⁇ 1%. Measure and record the pH with 1% test solution.
  • Test Example 11 pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method) This is a separation method using capillary zone electrophoresis technology and free migration of each sample component in a buffer solution containing an electrolyte. After injecting a compound solution into a fused silica capillary filled with a buffer solution adjusted to pH 2.5 to 11.5 and then applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow).
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • the compound according to the present invention has a broad antibacterial spectrum particularly against gram-negative bacteria and is effective as an antibacterial drug having high stability against ⁇ -lactamase-producing gram-negative bacteria. In addition, since it has good pharmacokinetics and high water solubility, it is particularly effective as an injection or oral drug.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des composés à spectre anti-bactérien puissant contre un grand nombre de bactéries, comprenant des bactéries à gram négatif et des bactéries à gram positif ; et des compositions pharmaceutiques à activité antibactérienne contre les bactéries résistantes au carbapénem. L'invention porte sur les éléments suivants : un composé représenté par la formule (I) : (dans la formule, -Z- est une liaison simple ou -CR7AR7B-, R7A et R7B sont chacun de façon indépendante un atome d'hydrogène ou similaire, Y est N ou CH, -W- est -S-, -S-CH2-, -CH2-S- ou -CH2-, -T- est -CR4AR4B- ou -CR5AR5B-CR6AR6B-, R4A, R4B, R5A, R5B, R6A et R6B sont chacun de façon indépendante un atome d'hydrogène ou similaire, R16 est un groupement carboxyl, un groupement tetrazolyl, ou similiare, R17 est un atome d'hydrogène ou similaire, R1 est un groupement hétérocyclique substitué ou non substitué, ou similaire, R2A et R2B sont chacun de façon indépendante un atome d'hydrogène ou similaire ou R2A et R2B se lient l'un à l'autre pour former un groupement méthylidene substitué ou non substitué, ou similaire, et R3 est un atome d'hydrogène ou similaire) ; des esters dudit composé ; et des sels et hydrates pharmaceutiquement acceptables de celui-ci.
PCT/JP2016/063138 2015-04-28 2016-04-27 Composés tricycliques et utilisations de ceux-ci WO2016175223A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2017515564A JPWO2016175223A1 (ja) 2015-04-28 2016-04-27 三環性化合物、およびそれらの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015-090941 2015-04-28
JP2015090941 2015-04-28

Publications (1)

Publication Number Publication Date
WO2016175223A1 true WO2016175223A1 (fr) 2016-11-03

Family

ID=57199259

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/063138 WO2016175223A1 (fr) 2015-04-28 2016-04-27 Composés tricycliques et utilisations de ceux-ci

Country Status (2)

Country Link
JP (1) JPWO2016175223A1 (fr)
WO (1) WO2016175223A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922436A (zh) * 2015-06-30 2018-04-17 盐野义制药株式会社 具有亚磺酰基或磺酰基的三环性化合物
WO2018123920A1 (fr) * 2016-12-26 2018-07-05 塩野義製薬株式会社 Composé tricyclique présentant du sulfinyle et composition pharmaceutique le contenant
CN112500421A (zh) * 2020-12-15 2021-03-16 河南科技大学第一附属医院 一种可用于杀菌消毒的苯并吡喃脲类化合物的制备方法及应用
CN112574215A (zh) * 2020-12-15 2021-03-30 河南科技大学第一附属医院 一种用于医院消毒的苯并噁唑类化合物的制备方法和应用
CN112661720A (zh) * 2020-12-28 2021-04-16 山东金城柯瑞化学有限公司 头孢克肟侧链酸结晶工艺

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63107956A (ja) * 1986-06-17 1988-05-12 Takeda Chem Ind Ltd ３環性ペナム化合物，その製造法及び用途
JPS63152384A (ja) * 1986-07-15 1988-06-24 Takeda Chem Ind Ltd ３環性セファムまたはイソセファム化合物，その製造法および用途
JPH01226887A (ja) * 1988-03-07 1989-09-11 Takeda Chem Ind Ltd ３環性セファムまたはイソセファム化合物，その製造法およびエラスターゼ阻害剤
WO2008016007A1 (fr) * 2006-07-31 2008-02-07 Meiji Seika Kaisha, Ltd. INHIBITEUR DE LA MÉTALLO-β-LACTAMASE
WO2014179885A1 (fr) * 2013-05-07 2014-11-13 Mcmaster University Inhibiteurs d'enzymes métallo-ss-lactamase
WO2014198849A1 (fr) * 2013-06-13 2014-12-18 Antabio Sas Acides thiazole carboxyliques antibactériens

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63107956A (ja) * 1986-06-17 1988-05-12 Takeda Chem Ind Ltd ３環性ペナム化合物，その製造法及び用途
JPS63152384A (ja) * 1986-07-15 1988-06-24 Takeda Chem Ind Ltd ３環性セファムまたはイソセファム化合物，その製造法および用途
JPH01226887A (ja) * 1988-03-07 1989-09-11 Takeda Chem Ind Ltd ３環性セファムまたはイソセファム化合物，その製造法およびエラスターゼ阻害剤
WO2008016007A1 (fr) * 2006-07-31 2008-02-07 Meiji Seika Kaisha, Ltd. INHIBITEUR DE LA MÉTALLO-β-LACTAMASE
WO2014179885A1 (fr) * 2013-05-07 2014-11-13 Mcmaster University Inhibiteurs d'enzymes métallo-ss-lactamase
WO2014198849A1 (fr) * 2013-06-13 2014-12-18 Antabio Sas Acides thiazole carboxyliques antibactériens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAMASHITA, Y. ET AL.: "NO cations as highly efficient catalysts for carbon-carbon bond forming reactions", CHEMISTRY LETTERS, vol. 38, no. 7, 2009, pages 678 - 679, XP055326422 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922436A (zh) * 2015-06-30 2018-04-17 盐野义制药株式会社 具有亚磺酰基或磺酰基的三环性化合物
US20180186814A1 (en) * 2015-06-30 2018-07-05 Shionogi & Co., Ltd. Tricyclic compound having sulfinyl or sulfonyl
WO2018123920A1 (fr) * 2016-12-26 2018-07-05 塩野義製薬株式会社 Composé tricyclique présentant du sulfinyle et composition pharmaceutique le contenant
CN112500421A (zh) * 2020-12-15 2021-03-16 河南科技大学第一附属医院 一种可用于杀菌消毒的苯并吡喃脲类化合物的制备方法及应用
CN112574215A (zh) * 2020-12-15 2021-03-30 河南科技大学第一附属医院 一种用于医院消毒的苯并噁唑类化合物的制备方法和应用
CN112661720A (zh) * 2020-12-28 2021-04-16 山东金城柯瑞化学有限公司 头孢克肟侧链酸结晶工艺

Also Published As

Publication number Publication date
JPWO2016175223A1 (ja) 2018-02-15

Similar Documents

Publication Publication Date Title
WO2016175223A1 (fr) Composés tricycliques et utilisations de ceux-ci
US9289419B2 (en) Substituted heterocyclic compounds as tropomyosin receptor kinase a (TrkA) inhibitors
CN108778273B (zh) 二环芳基单环β-内酰胺化合物及其用于治疗细菌感染的用途的方法
US11433055B2 (en) Chromane monobactam compounds for the treatment of bacterial infections
US20180362543A1 (en) Hiv replication inhibitor
JPWO2016021629A1 (ja) ＴｒｋＡ阻害活性を有する複素環および炭素環誘導体
TW200305422A (en) Broad spectrum cefem compounds
JPWO2017135399A1 (ja) ＴｒｋＡ阻害活性を有する含窒素複素環および炭素環誘導体
WO2015056782A1 (fr) Nouveau dérivé d'alkylène
WO2019093450A1 (fr) Dérivé de diazabicyclooctane
KR102435777B1 (ko) 카르바페넴 화합물
WO2017002903A1 (fr) Composé tricyclique présentant un sulfinyle ou un sulfonyle
US4891427A (en) Tricyclic cepham compounds
JP3238209B2 (ja) チオメチルチオカルバセファロスポリン誘導体
JP2018104420A (ja) スルフィニルまたはスルホニルを有する三環性化合物を含有する医薬組成物
JP2531183B2 (ja) ３環性ペナム化合物，その製造法及び用途
JP3743680B2 (ja) 新規なセフェム化合物、その製造方法及び抗菌剤
TW201930314A (zh) 具有亞磺醯基的三環性化合物及含有該三環性化合物的醫藥組成物
WO2013001830A1 (fr) Dérivé antibiotique nucléoside
WO1994022874A1 (fr) Derive de cephalosporines
JPS62215583A (ja) ピラゾリジノン誘導体およびその製造法
WO1987000527A1 (fr) Composes antibacteriens, leur utilisation et procede de preparation
HU197742B (hu) Eljárás izoxazolidinil-tetrahidrofurán-kárbonsav antibiotikum-származékok, és hatóanyagként e vegyületeket tartalmazó gyógyszerkészítmények előállítására

Legal Events

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

Ref document number: 16786499

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017515564

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16786499

Country of ref document: EP

Kind code of ref document: A1