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WO2018216822A1 - Nouveaux dérivés d'imidazole - Google Patents

Nouveaux dérivés d'imidazole Download PDF

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Publication number
WO2018216822A1
WO2018216822A1 PCT/JP2018/021100 JP2018021100W WO2018216822A1 WO 2018216822 A1 WO2018216822 A1 WO 2018216822A1 JP 2018021100 W JP2018021100 W JP 2018021100W WO 2018216822 A1 WO2018216822 A1 WO 2018216822A1
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group
compound
imidazol
methyl
substituted
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Inventor
Hajime Takashima
Toru Sasaki
Nozomi Tanaka
Norikazu Otake
Risa Tsuruta
Yousuke Yamada
Yohei Matsuda
Yuya Ogata
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D491/20—Spiro-condensed systems

Definitions

  • This invention relates to novel imidazole derivatives or salts thereof, which exhibit an activity for inhibiting uridyldiphospho(UDP)-3 _ 0-acyl-N-acetylglucosamine deacetylase (LpxC) and antimicrobial pharmaceuticals comprising the same.
  • LpxC 0-acyl-N-acetylglucosamine deacetylase
  • Gram-negative bacteria have an outer membrane composed of a lipid bilayer inexistent in gram-positive bacteria, and thus are more resistant to drugs, as compared with gram- positive bacteria, due to the problem of drug permeability. Gram-negative bacteria are also known to have a plurality of drug efflux proteins, which are known to be involved in drug resistance (Non-Patent Document l). Furthermore, lipopolysaccharide (LPS), one of the main constituents of the outer membrane, is involved in toxicity as an endotoxin.
  • LPS lipopolysaccharide
  • Non-Patent Document 2 and 3 Emergence of multi-drug resistant gram-negative bacteria including Pseudomonas aeruginosa and Enterobacteriaceae has become a major healthcare problem worldwide, because there have been few useful therapeutic drugs. Hence, there is a keen demand for the development of a drug having a novel mechanism of action.
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase is an enzyme in charge of the synthesis of lipid A (hydrophobic anchor of LPS which is the constituent of the outer membrane).
  • Lipid A biosynthesis consists of reactions in ten stages, and LpxC catalyzes the second stage of the biosynthesis reactions to remove the acetyl group of UDP-3 -acyl-N- acetylglucosamine (Non-Patent Document 4).
  • Lipid A is a component essential for the formation of the outer membrane, and is consequently indispensable for the survival of gram-negative bacteria (Non-Patent Document 5).
  • LpxC is a rate-determining enzyme in the process of lipid A biosynthesis, and is an indispensable enzyme for lipid A biosynthesis.
  • a drug inhibiting the activity of LpxC is highly expected to be an antimicrobial agent effective against gram-negative bacteria including multi-drug resistant strains, because such a drug has a mechanism of action different from those of conventional drugs.
  • LpxC has been the focus of several pharmaceutical drug development programs over the last decade. LpxC has the catalytic zinc ion in its active site and many of the potent LpxC inhibitors identified so far contain a zinc-binding hydroxamic acid group.
  • Patent Document 1- International Publication 15/085238 pamphlet.
  • Non-Patent Document 2 J. Antimicrob. Chemother. (2003) Jan 14, 51, pp. 347-352.
  • Non-Patent Document 3 Virulence. (2017), 8(4), pp. 460-469.
  • Non-Patent Document 4 J. Biol. Chem. (1995) Dec 22, 270, pp. 30384-30391.
  • Non-Patent Document 5 J. Bacteriol. (1987), 169, pp. 5408-5415.
  • Non-Patent Document 6 Cold Spring Harb Perspect Med. (2016), July l; 6(7), a025304.
  • An object of the present invention is to find novel compounds that do not contain a hydroxamic acid group and inhibit LpxC or pharmaceutically acceptable salts thereof, and provide new pharmaceutical drugs that exhibit antimicrobial activity against gram-negative bacteria including multi-drug resistant strains and that are useful in treating bacterial infections.
  • Z represents a hydroxyl group or an amino group
  • R 1 represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 haloalkyl group or a cyclopropyl group,
  • R 2 represents a hydrogen atom, -COOH or -CONH2, provided that R 1 and R 2 are not a hydrogen atom at the same time,
  • R 3 represents a hydrogen atom or a C1-4 alkyl group
  • R 4 represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 hydroxyalkyl group or a C1-4 aminoalkyl group (the amino group of the Ci 4 aminoalkyl group may be substituted with a C2 4 alkanoyl group or a Ci-4 alkylsulfonyl group),
  • R 5 represents a hydrogen atom
  • R 4 and R 5 may form a Ci-4 alkylidene group together
  • a 1 represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group (the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group and the 1,4-phenylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom and a Ci-4 alkyl group") or a benzoisoxazolylene group,
  • W 1 represents W 2 -A 2 -, a Ci-8 alkyl group (the Ci-e alkyl group may be substituted with a hydroxyl group), a chlorine atom or a bromine atom,
  • a 2 represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group or a divalent group selected from the following formula [2A] X
  • the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group, the 1,4-phenylene group and the divalent group selected from the formula [2A] may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a C alkyl group and a Ci-4 hydroxyalkyl group"
  • G represents N or CH
  • W 2 represents Re-X"-, R6-X i -Yi-Xn-, R6-X 2 -Y 2 -X i -Y i -XH- Q- ⁇ ⁇ -, Q-X"-Y i -X»- or ⁇ 3 ⁇ 4- ⁇ - ⁇ 2 - ⁇ - ⁇ - ⁇ "- or ⁇ 3 ⁇ 4- ⁇ 3- ⁇ 2- ⁇ 2- ⁇ - ⁇ - ⁇ ⁇ -
  • Y 3 represents -NR 7 -
  • X 1 and X 2 are the same or different and each represent a Ci-8 alkylene group or a C3-9 cycloalkylene group (the Ci-8 alkylene group and the C3-9 cycloalkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group or an amino group"),
  • X 11 and X 12 are the same or different and each represent a Ci-s alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group and an amino group"), a C3-9 cycloalkylene group, or a bond,
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-4 hydroxyalkyl group, an amino group, a Ci-4 aminoalkyl group, a carbamoyl group, -SO2NH2, or
  • R 7 represents a hydrogen atom, C1-4 hydroxyalkyl group or a Ci- 4 alkyl group
  • Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the ring-constituting atoms may optionally contain 1 or 2 oxygen or sulfur atoms, or an oxygen-containing 4- to 7-membered saturated heterocyclic group (the nitrogen-containing 4- to 7-membered saturated heterocyclic group and the oxygen- containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 or 2 oxo groups and may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, Ci-4 alkyl group, Ci-4 alkoxy group, a Ci-s hydroxyalkyl group or a Ci-4 alkylsulfonyl group", and
  • Z represents a hydroxyl group or an amino group
  • R 1 represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 haloalkyl group or a cyclopropyl group,
  • R 2 represents a hydrogen atom, -COOH or -CONH2, provided that R 1 and R 2 are not a hydrogen atom at the same time,
  • R 3 represents a hydrogen atom or a C1-4 alkyl group
  • R 4 represents a hydrogen atom, a Ci-4 alkyl group, a Ci-4 hydroxyalkyl group or a Ci-4 aminoalkyl group (the amino group of the Ci-4 aminoalkyl group may be substituted with a C2 4 alkanoyl group or a Ci-4 alkylsulfonyl group),
  • R 5 represents a hydrogen atom
  • R 4 and R 5 may form a Ci alkylidene group together
  • a 1 represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group (the divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group and the 1,4-phenylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom and a Ci-4 alkyl group") or a benzoisoxazolylene group,
  • W 1 represents W 2 -A 2 -, a Ci-e alkyl group (the Ci-8 alkyl group may be substituted with a hydroxyl group), a chlorine atom or a bromine atom,
  • a 2 represents a divalent 5-membered heteroaromatic group, a 1,4-divalent 6-membered heteroaromatic group, a 1,4-phenylene group or a divalent group selected from the following formula [2]
  • divalent 5-membered heteroaromatic group, the 1,4-divalent 6-membered heteroaromatic group, the 1,4-phenylene group and the divalent group selected from the formula [2] may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group"),
  • G represents N or CH
  • W 2 represents R6-X"- Re- ⁇ - ⁇ - ⁇ - R6-X 2 -Y 2 -X i -Y i -Xn- Q- ⁇ ⁇ -, Q-X"-Y i -X"- or ⁇ 3 ⁇ 4- ⁇ ⁇ - ⁇ 2 - ⁇ ⁇ - ⁇ ⁇ - ⁇ ⁇ -,
  • X 1 and X 2 are the same or different and each represent a Ci-8 alkylene group, a C3 9 cycloalkylene group (the Ci-8 alkylene group and the C3 9 cycloalkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group or an amino group"),
  • X u and X 12 are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group and an amino group"), a C3 9 cycloalkylene group, or a bond,
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, -SO2NH2, or -COOR 7 ,
  • R 7 represents a hydrogen atom, Ci-4 hydroxyalkyl group or a C1-4 alkyl group
  • Q represents a nitrogen-containing 4- to 7-membered saturated heterocyclic group wherein the ring-constituting atoms may optionally contain 1 or 2 oxygen or sulfur atoms, or an oxygen-containing 4- to 7-membered saturated heterocyclic group (the nitrogen-containing 4- to 7-membered saturated heterocyclic group and the oxygen- containing 4- to 7-membered saturated heterocyclic group may be substituted with 1 or 2 oxo groups and may be substituted with 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci 4 alkoxy group, a C hydroxyalkyl group or a alkylsulfonyl group", and
  • R A1 , R A2 , R A3 , R A4 , R A5 and R A6 are the same or different and each represent a hydrogen atom, halogen atom or a methyl group!
  • a 2 is a 1,4-phenylene group wherein the 1,4-phenylene group may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a_Ci-4 alkyl group and a C.i-4 hydroxyalkyLgroup"; _
  • W 2 is R6-X 11 -, RG-X ! -Y 1 - R6-X 2 -Y -X i -Y i -, or Q-X ⁇ -Y 1 - wherein Y 1 represents -0-, Y 2 represents -0- or -NR 7 wherein R 7 represents a hydrogen atom, Ci-4 hydroxyalkyl group or a C alkyl group, X 1 and X 2 are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups), X 11 and X 12 are the same or different and each represent a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) or a bond, R 6 is a hydroxyl group, an amino group a carbamoyl group, and Q represents a nitrogen-containing 4 ⁇ to 7
  • W 2 is R 6 -X H - Rs-X ! -Y ! -X 11 -, wherein Y 1 represents -0-, X 1 represents a Ci-e alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups), X 11 represents a Ci-s alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) and R 6 is a hydrogen or a hydroxyl group, '
  • a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items (1) to (19);
  • the compound or the pharmaceutically acceptable salt thereof according to the present invention has a strong LpxC -inhibiting action and exhibits potent antimicrobial activity against gram-negative bacteria including Pseudomonas aeruginosa.
  • the compound or its pharmaceutically acceptable salt is useful as a pharmaceutical composition and as an antimicrobial agent against these bacteria.
  • n- means normal, "r” iso, “sec-” secondary, “tert-” tertiary, “c-” cyclo, "0-" ortho, “nr” meta, and “p-” para.
  • the "halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the "Ci-4 alkyl group” refers to a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Its examples are a methyl group, an ethyl group, a n-propyl group, a n-butyl group, an isopropyl group, an isobutyl group, a tert-butyl group and a sec-butyl group.
  • the "Ci-6 alkyl group” refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. Its examples are a n-pentyl group, a n-hexyl group, an isopentyl group, a neopentyl group, a tert-pentyl group and a 1,2-dimethylpropyl group, in addition to the above-mentioned examples of the "Ci-4 alkyl group”.
  • the "Ci-8 alkyl group” refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms. Its examples are a n-heptyl group and a n-octyl group, in addition to the above-mentioned examples of the "Ci-6 alkyl group”.
  • C2-8 alkenyl group refers to a straight-chain or branched-chain alkenyl group with 2 to 8 carbon atoms which has one or more double bonds at any position(s) of the above- mentioned "Ci-e alkyl group”. Its examples are a vinyl group, a 1-propenyl group, a 2- propenyl group, an isopropenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 2- pentenyl group, a 3-pentenyl group, a 2-hexenyl group, a 2"heptenyl group and a 2-octenyl group.
  • C2-8 alkynyl group refers to a straight-chain or branched-chain alkynyl group with 2 to 8 carbon atoms which has one or more triple bonds at any position(s) of the above-mentioned "Ci-e alkyl group”.
  • ethynyl group a 1-propynyl group, a 2-propynyl group, a l'butynyl group, a 3"butynyl group, a 1-pentynyl group, a 4-pentynyl group, a 1- hexynyl group, a 5-hexynyl group, a 1-heptynyl group and a 1-octynyl group.
  • the "C3 6 cycloalkyl group” refers to a cycloalkyl group having 3 to 6 carbon atoms.
  • the C3-6 cycloalkyl group include includes not only a monocyclic cycloalkyl group but also a fused cycloalkyl group and a bridged cycloalkyl group. Its examples are a c-propyl group, a c-butyl group, a c-pentyl group, a c-hexyl group and a bicyclo[l.l.l]pentanyl group.
  • the "C3 9 cycloalkyl group” refers to a cycloalkyl group having 3 to 9 carbon atoms.
  • the C3 9 cycloalkyl group include includes not only a monocyclic cycloalkyl group but also a fused cycloalkyl group and a bridged cycloalkyl group. Its examples are a cheptyl group, a c-octyl group, a bicyclo[2.2.2]octanyl group, a norbornyl group and an adamantyl group, in addition to the above-mentioned examples of the "C3-6 cycloalkyl group”.
  • the "Ci-4 alkoxy group” refers to a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms. Its examples are a methoxy group, an ethoxy group, a 1-propoxy group, an isopropoxy group, a 1-butoxy group, a 1-methyl- 1-propoxy group and a tert-butoxy group.
  • the "Ci-6 alkoxy group” refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms. Its examples are a 1-pentyloxy group and 1-hexyloxy group, in addition to the above-mentioned examples of the "Ci-4 alkoxy group”.
  • Ci-4 haloalkyl group refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-4 alkyl group” has been or have been substituted with a halogen atom or halogen atoms.
  • fluoromethyl group a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a pentafluoroethyl group, a 3,3,3-trifluoropropyl group, a perfluoropropyl group, a 4- fluorobutyl group, a 4-chlorobutyl group and a 4-bromobutyl group.
  • the "Ci-4 hydroxyalkyl group” refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-4 alkyl group” has been or have been substituted with a hydroxyl group or hydroxyl groups. Its examples are a hydroxymethyl group, a 1- hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 1-hydroxybutyl group, a 2-hydroxybutyl group, a 3"hydroxybutyl group and a 4- hydroxybutyl group.
  • the "Ci-8 hydroxyalkyl group” refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-8 alkyl group” has been or have been substituted with a hydroxyl group or hydroxyl groups. Its examples are a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group and a hydroxyoctyl group, in addition to the above-mentioned examples of the "Ci-4 hydroxyalkyl group”.
  • C2-4 hydroxyalkyl group is the same as Ci-4 hydroxyalkyl group except for a hydroxymethyl group.
  • the "Ci-4 aminoalkyl group” refers to an alkyl group in which one or more of the hydrogen atoms of the above-mentioned "Ci-4 alkyl group” has been or have been substituted with a an amino group or amino groups. Its examples are an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 2-aminopropyl group, a 3-aminopropyl group, a 1-aminobutyl group, a 2-aminobutyl group, a 3-aminobutyl group and a 4-aminobutyl group.
  • C2-4 alkanoyl group refers to a straight-chain or branched-chain alkanoyl group having 2 to 4 carbon atoms. Its examples are an acetyl group, a propionyl group, a butyryl group and a pivaloyl group.
  • Ci 4 alkylsulfonyl group refers to a straight-chain or branched-chain alkylsulfonyl group having 1 to 4 carbon atoms. Its examples are a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group.
  • the "Ci-4 alkylidene group” refers to a straight-chain or branched-chain alkylidene group having 1 to 4 carbon atoms, and includes, for example, a methylidene group, an ethylidene group, a n-propylidene group, a n-butylidene group and an isopropylidene group.
  • aryl group refers to a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms. Its examples are a phenyl group, a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group and a pyrenyl group.
  • the "partially saturated fused polycyclic hydrocarbon ring group” refers to a fused polycyclic hydrocarbon ring group having a part hydrogenated. Its examples are an indanyl group and an acenaphthenyl group.
  • heterocyclic group refers to a cyclic group which contains, as a ring-constituting atom(s), any 1 to 5 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. If the hetero atom is a sulfur atom, a dioxide compound is also included in the present invention.
  • saturated heterocyclic group refers to a heterocyclic group having a ring constituted only by saturated bonds, and may be substituted with 1 to 2 oxo groups.
  • nitrogen-containing 4- to 7-membered saturated heterocyclic group refers to a saturated heterocyclic group which consists of 4 to 7 atoms as ring-constituting atoms and contains 1 or 2 nitrogen atoms.
  • This nitrogen-containing 4- to 7-membered saturated heterocyclic group may contain 1 or 2 oxygen atoms or 1 or 2 sulfur atoms as ring- constituting atoms, and may be substituted with 1 or 2 oxo groups.
  • a fused ring group and a spiro ring group are also included.
  • azetidinyl group a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a homopiperazinyl group, a homomorpholinyl group, an imidazolidyl group, a pyrazolidinyl group, an oxazolidinyl group, an 2-oxo-oxazolidinyl group, an isoxazolidinyl group, a 2-oxa-6-azaspiro[3.3]heptanyl group, a l-oxa-6-azaspiro[3.3]heptanyl group, a 6-oxa-l-azaspiro[3.3]heptanyl group, a 1- azaspiro[3.3]heptanyl group, a 2-azaspiro[3.3]heptyl group, a 2,6'diazaspiro[3.3]heptyl and 3-azabicyclo[3.1.0
  • the "oxygen-containing 4- to 7-membered saturated heterocyclic group” refers to a saturated heterocyclic group which consists of 4 to 7 atoms as ring-constituting atoms and contains 1 or 2 oxygen atoms. Its examples are an oxetanyl group,' a tetrahydrofuranyl group and a tetrahydropyranyl group.
  • the "5-membered heteroaromatic group” refers to an aromatic ring group which consists of 5 atoms as ring-constituting atoms and contains at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. Its examples are a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a 1,3,4-thiadiazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group and a tetrazolyl group.
  • the "6-membered heteroaromatic group” refers to an aromatic ring ring group which consists of 6 atoms as ring-constituting atoms and contains at least one nitrogen atom. Its examples are a pyridyl group, a pyridazinyl group, a pyrimidinyl group and a pyrazinyl group.
  • the "Ci-4 alkylene group” refers to a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms. Its examples are -CH2-, "(CH k, -(CHs s-, -GH 2 -CH(CH 3 )-, -CiCHs , - (CH 2 ) 4 -, -(CH2)2-CH(CH 3 )-, -CH2-CH(CH 3 )-CH 2 - and -CH(CH 3 )-(CH 2 ) 2 -.
  • the "Ci-8 alkylene group” refers to a straight-chain or branched-chain alkylene group having 1 to 8 carbon atoms. Its examples are -(CH 2 )5-, -(CH 2 ) 3 -CH(CH 3 )-, -(CH2) 2 -CH(C 2 H 5 ) -, ⁇ (CH 2 ) 6 -, -(CH 2 )3-CH(CH 3 )-CH 2 -, and -CH 2 -CH(CH 3 )-(CH 2 ) 3 -, C )r, -(CH 2 ) 5 -CH(CH 3 )-, - (CH 2 )4 _ CH(C 2 H5)-, -(CH 2 )8-, in addition to the above-mentioned examples of the "Ci-4 alkylene group”.
  • the "C 2 -8 alkynylene group” refers to a straight-chain or branched-chain alkynylene group having 2 to 8 carbon atoms which has one or more triple bonds in the chain. Its example is a divalent group having a triple bond formed by further eliminatins-, a hydrogen atom from the carbon atom in the double bond moiety of the "C 2 -8 alkenylene group” mentioned above.
  • the "C 3 -G cycloalkylene group” refers to a divalent group formed by further eliminating any one hydrogen atom from the C 3 6 cycloalkyl group. Two bonds where hydrogen atoms are eliminated may be attached on the same carbon atom.
  • a 1, 1-c-propylene group a 1,2-c-propylene group, a ⁇ , ⁇ -butylene group, a 1,2-cbutylene group, a 1,3-c- butylene group, a 1,2-c-pentylene group, a 1, 1-c-hexylene group, a 1.2'C-hexylene group, a 1,3-c-hexylene group and a 1,4'c-hexylene group.
  • the "C 3 -9 cycloalkylene group” refers to a divalent group formed by further eliminating any one hydrogen atom from the C 3 -9 cycloalkyl group. Its examples are a 1,4-c-heptylene group, a l,3-bicyclo[l. l.l]pentanylene group, a l,4-bicyclo[2.2.2]octanyl group, a 1,4-norbornylene group and a 1,4-adamantylene group, in addition to the above mentioned examples of the "C 3 -6 cycloalkylene group”.
  • the "divalent 5-membered heteroaromatic group” refers to a divalent group formed by further eliminating any one hydrogen atom from the 5-membered heteroaromatic group. Its examples are a 2,5-thienylene group, a 2,5-pyrrolylene group, a 2,5-thiazolylene group, an 3,5-isothiazolylene group, a 3,5-pyrazolylene group, a 2,5-imidazolylene group, a 1,5" furylene group, a 2,5-oxazolylene group, a 3,5-isoxazolylene group, a 2,5-(l,3,4-oxadiazolyl)- ene and a 2,5-(l,3,4-thiadiazolyl)-ene group.
  • the "1,4-divalent 6-membered heteroaromatic group” refers to a divalent group formed by further eliminating one hydrogen atom at the p -position from the 6-membered heteroaromatic group. Its examples are 2,5-pyridylene group, a 3,6-pyridazinylene group, a 2,5-pyrimidinylene group and a 2,5-pyrazinylene group.
  • the "optionally protected hydroxyl group” means an unprotected or protected hydroxyl group.
  • the "protected hydroxyl group” means a hydroxyl group protected with a “protective group for a hydroxyl group”.
  • the “optionally protected amino group” means an unprotected or protected amino group.
  • the “protected amino group” means an amino group protected with a “protective group for an amino group”.
  • the "optionally protected carboxy group” means an unprotected or protected carboxy group.
  • the "protected carboxy group” means a carboxy group protected with a “protective group for a carboxy group”.
  • the "protected imidazole group” means an imidazole group protected with a “protective group for an imidazole group”.
  • the "protective group for a hydroxyl group”, the “protective group for an amino group”, the “protective group for a carboxy group” and the “protective group for an imidazole group” include all groups usable usually as protective groups for a hydroxyl group, an amino group, an carboxy group and an imidazole group, respectively, and includes, for example, the groups described in P.G.M. Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., 2014, John Wiley Sons, Inc.
  • the “leaving group” includes, for example, a halogen atom, a methnesulfonyloxy group, "a ethanesulfonyloxy group, a isopropanesulfonyloxy group, a trifluoromethanesulfonyloxy group, benzensulfonyloxy group and a p-toluenesulfonyloxy group.
  • the "antimicrobial agent” refers to a substance which has the ability to act on bacteria, such as gram-positive bacteria or gram-negative bacteria, thereby suppressing their growth or destroying them.
  • the antimicrobial agent may be one which keeps down propagation of bacteria, or kills some of bacteria to decrease their count.
  • Examples of gram-positive bacteria are the genus Staphylococcus (Staphylococcus aureus, Staphylococcus epidermidis, etc.), the genus Streptococcus (Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, etc.), and the genus Enterococcus (Enterococcus faecalis, Enterococcus faecium, etc.).
  • Staphylococcus Staphylococcus aureus, Staphylococcus epidermidis, etc.
  • the genus Streptococcus Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, etc.
  • Enterococcus Enterococcus faecalis, Enterococcus faecium, etc.
  • Examples of gram-negative bacteria are the genus Pseudomonas (Pseudomonas aeruginosa, etc.), the genus Escherichia (Escherichia coli, etc.), the genus Klebsiella (Klebsiella pneumoniae, Klebsiella oxytoca, etc.), the genus Haemophilus (Haemophilus influenzae, Haemophilus parainfluenzae, etc.), the genus Bordetella (Bordetella pertussis, Bordetella bronchiseptica, etc.), the genus Serratia (Serratia marcescens, etc.), the genus Proteus (Proteus mirabilis, etc.), the genus Enterobacter (Enterobacter cloacae, etc.), the genus Campylobacter (Campylobacter jejuni, etc.), the genus Citrobacter, the gen
  • Preferred R 2 is a hydrogen atom.
  • Preferred R 1 is a methyl group, an ethyl group, a difluoromethyl group or a trifluoromethyl group, and more preferred R 1 is a methyl group.
  • Preferred Z is a hydroxyl group.
  • Preferred R 3 is a hydrogen atom.
  • Preferred R 4 is a hydrogen atom, a hydroxy methyl group or an aminomethyl group.
  • Preferred R 5 is a hydrogen atom.
  • Preferred A 1 is a divalent group selected from the following formula [6],
  • R A1 , R A2 , R A3 , R A4 , R A5 and R A6 are the same or different and each represent a hydrogen atom, halogen atom or a methyl group, and more preferred A 1 is a divalent group represented by the following formula [7]
  • Preferred L 1 is a bond
  • Preferred W 1 is W -A 2 -.
  • Preferred A 2 is a divalent group selected from the following formula [8] wherein G represents N or CH, the above formula [2] may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group", and more preferred A 2 is a 1,4-phenylene group wherein the 1,4-phenylene group may be substituted by 1 to 3 substituents which are the same or different and are selected from "a halogen atom, a hydroxyl group, a Ci-4 alkyl group and a Ci-4 hydroxyalkyl group".
  • Preferred W 2 is R6-X"- Re- ⁇ - ⁇ - R6-X 2 -Y -X i -Y i - or Q-X i -Y i - wherein Y i represents -0-, Y 2 represents -O- or -NR 7 wherein R 7 represents a hydrogen atom, Ci-4 hydroxyalkyl group or a Ci-4 alkyl group, X 1 and X 2 are the same or different and each represent a Ci-e alkylene group (the Ci-s alkylene group may be substituted with 1 to 3 hydroxyl groups), X u and X 12 are the same or different and each represent a Ci-8 alkylene group (the Ci-e alkylene group may be substituted with 1 to 3 hydroxyl groups) or a bond, R 6 is a hydroxyl group, an amino group a carbamoyl group, and Q represents a nitrogen- containing 4- to 7-membered saturated heterocyclic group wherein the nitrogen-containing 4- to 7-member
  • W 2 is R ⁇ X ! -Y 1 - wherein Y 1 represents -(CH2)mO-, m is 0 to 3, X 1 represents a C3 6 cycloalkyl group and R 6 represents an amino . group or filinga Ci-4 aminoalkyl group, more preferred W 2 is R ⁇ X ! -Y 1 -, wherein Y 1 represents -(CH2)mO- wherein m is 0 or 1, X 1 represents a cyclopropyl group and R 6 represents an amino group.
  • W 2 is R 6 -X u - e-X ! -Y ! -X 11 -, wherein Y 1 represents -0-, X 1 represents a Ci-8 alkylene group (the Ci-e alkylene group may be substituted with 1 to 3 hydroxyl groups), X 11 represents a Ci-8 alkylene group (the Ci-8 alkylene group may be substituted with 1 to 3 hydroxyl groups) and R 6 is a hydrogen or a hydroxyl group.
  • a preferred embodiment of the compound according to the present invention is as follows *
  • the compounds represented by the formula [l] of the present invention have asymmetric carbon at the 2-position of the imidazole group.
  • the compounds of the present invention may be used in racemic form or as a specific enantiomer.
  • the compounds repre [10] are preferred '
  • the compounds of the present invention can exist as tautomers, stereoisomers such as geometrical isomers, and optical isomers, and the present invention includes them.
  • the present invention also includes various hydrates, solvates and polymorphic substances of the compounds of the invention and their salts.
  • the pharmaceutically acceptable salts refer to salts which are used in chemotherapy and prevention of bacterial infections.
  • Their examples are salts with acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, malonic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosic acid), laurylsulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydriodic acid, nicotinic acid, oxalic
  • the compound of the present invention can be made into a medicinal preparation upon combination with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkylparahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soy oil, and various other seed oils.
  • the above carriers, excipients or diluents can be mixed, as needed, with commonly used additives such as thickeners, binders, disintegrants, pH regulators, and solvents, and can be prepared as an oral or parenteral drug, such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, or skin patches, by a customary pharmaceutical technology.
  • the compound of the present invention can be administered intravenously, orally or parenterally to an adult patient in a dose of 10 to 5,000 mg as a single daily dose or as divided portions per day. This dose can be increased or decreased, as appropriate, according to the type of the disease to be treated, or the age, body weight, symptoms, etc. of the patient.
  • the compound of the present invention can also be used in combination with other drugs.
  • the compound of the present invention can be synthesized, for example, by methods to be shown below, but the present invention is in no way limited to these methods of manufacturing the compound.
  • a compound represented by the general formula (II -A) (where R IIa is a leaving group, and the other symbols are as defined above) and a compound represented by the general formula (II-B) (where R IIb is a protecting group for an imidazole group, R IIc is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence or absence of a base, followed by an appropriate treatment for R IIb deprotection, whereby a compound represented by a general formula (II -D) (where the symbols are as defined above) can be obtained via an intermediate compound represented by a general formula (II-C) (where the symbols are as defined above).
  • a deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula ( ⁇ ) (where the symbols are as defined above) can be obtained.
  • a compound represented by the general formula (III-A) (where R IIIa is a leaving group, R IIIb is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) and a boronic acid compound represented by the general formula ( ⁇ ) (where _the_symbols are as defined above) are reacted -in-t-he presence of a catalyst ⁇ in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by a general formula (III-C) (where the symbols are as defined above) can be obtained.
  • a corresponding boronic ester compound can be used instead of a boronic acid compound represented by the general formula (III-B).
  • a deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (III-D) (where the symbols are as defined above) can be obtained.
  • a compound represented by the general for ula (IV-A) (where R IVa is a leaving group, R IVb is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) and a compound represented by the general formula (I B) (where the symbols are as defined above) are reacted in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by a general formula (IVC) (where the symbols are as defined above) can be obtained.
  • a deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (IV-D) (where the symbols are as defined above) can be obtained.
  • a compound represented by the general formula (V-A) (where R Va is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) and a compound represented by the general formula (V-B) (where is a leaving group, and the symbols are as defined above) are reacted in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand, whereby a compound represented by a general formula (V-C) (where the symbols are as defined above) can be obtained.
  • a deprotection reaction is performed under appropriate conditions in accordance with the type of this protective group, whereupon the target compound represented by the general formula (V-D) (where the symbols are as defined above) can be obtained.
  • a compound represented by the general formula (VI -A) (where R ⁇ 3 is a leaving group or a protected ethynyl group, RTM is a leaving group or a hydroxyl group, and the other symbols are as defined above) and a compound represented by the general formula (VTB) (where ⁇ 1 is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence of a base (when R VIb is a leaving group) or in the Mitsunobu reaction condition (when R VIb is a hydroxyl group), whereby a compound represented by a general formula (VI- C) (where the symbols are as defined above) can be obtained.
  • RV 13 is a protected ethynyl group
  • R VIa can be transformed to an unprotected ethynyl group by a deprotection reaction under appropriate conditions in accordance with the type of the protective group.
  • Vll-A Vll-B
  • Vll-C Vll-C
  • a compound represented by the general formula (VII-A) (where R V " 3 is a leaving group or a protected ethynyl group, R ⁇ TM is a leaving group, and the other symbols are as defined above) and a compound represented by the general formula (VII-B) (where B 110 is a protecting group for an imidazole group, R VIId is a protected hydroxyl group or a protected amino group, and the other symbols are as defined above) are reacted in the presence or absence of a base, followed by an appropriate RTM 0 deprotection treatment, whereby a compound represented by a general formula (VII-C) (where the symbols are as defined above) can be obtained.
  • Vlll-A (Vlll-B) (Vlll-C)
  • a compound represented by the general formula _(VIII:A) (where.R VIIIa is a leaving group or a protected ethynyl group, and the other symbols are as defined above), a compound represented by the general formula (Vffl-B) (where R n ib is a protected hydroxyl group or a protected amino group) and glyoxal are reacted in the presence of an ammonia source such as ammonia solution or ammonium bicarbonate, whereby a compound represented by a general formula (VlirO (where the symbols are as defined above) can be obtained.
  • an ammonia source such as ammonia solution or ammonium bicarbonate
  • imidazole compounds represented by the general formulas (I-B), (II-B), CVTB) and (VII- B) can be obtained, for example, by the methods described in Scheme IX or X.
  • a compound represented by the general formula (IX-A) (where R IXa is a protected hydroxyl group or a protected amino group) and a compound represented by the general formula (IX - B) (where R 3 is as defined above) are reacted in the presence of an ammonia source such as ammonia solution or ammonium bicarbonate, whereby a compound represented by a general formula ( ⁇ -C) (where the symbols are as defined above) can be obtained.
  • the compound represented by the general formula (IX-C) is subjected to a protection reaction under approximate conditions according to the type of the protective group R IXb , whereby a compound represented by a general formula (IX"D) (where the symbols are as defined above) can be obtained.
  • a compound represented by a general formula (X"C) (where the symbols are as defined above) can be obtained.
  • the compound represented by the general formula (X"C) is subjected to a ring-forming reaction under approximate conditions in the presence of an ammonia source such as ammonia solution or ammonium bicarbonate, whereby a compound represented by a general formula (X-D) (where the symbols are as defined above) can be obtained.
  • the compound represented by the general formula (X-D) is subjected to a protection reaction under approximate conditions according to the type of the protective group R 5 ⁇ , whereby a compound represented by a general formula (X-E) (where the symbols are as defined above) can be obtained.
  • the sequence of the reaction steps can be changed as needed. If an amino group, a hydroxyl group, a formyl group, and a carboxy group are present in the compounds obtained in the respective reaction steps and their intermediates, the reactions can be performed, with the protective groups for them being removed for deprotection or being used in appropriately changed combinations.
  • examples of the base used in any of the above reactions are sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, potassium hydroxide, NaOH, lithium hydroxide, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium hydride, trie thy lamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine, and N-methylmorpholine.
  • the acid examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and polyp hosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and polyp hosphoric acid
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid.
  • Examples of the condensing agent are o-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafiuorophosphate, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro-l-methylpyridinium iodide, 4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methylmorpholine chloride, ⁇ r(7- azabenzotriazol-l-ylVN.N.N ⁇ N'-tetramethyluronium hexafiuorophosphate, and benzotriazol- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafiuorophosphate.
  • Examples of the activator used in employing the method conducted via an acid chloride or an acid anhydride are thionyl chloride, oxalyl chloride, phosphoryl chloride, acetic anhydride, and chloroformic esters.
  • the catalyst examples include palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium(II) dichloride,, bis(benzonitrile)dichloropalladium, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium,
  • ligand examples include trrtert-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tritolylphosphine, tributyl phosphite, tricyclohexyl phosphite, triphenyl phosphite, 1, l'-bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)- 1, l'-binaphthyl, 2-dicyclohexylphosphino-2',6'"dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl, and 2-(drtert- butylphosphino)bi
  • oxidizing agent examples include inorganic and organic peroxides such as potassium permanganate, chromium oxide, potassium dichromate, hydrogen peroxide, nv chloroperbenzoic acid, urea hydrogen peroxide adduct/phthalic anhydride, tert-butyl hydroperoxide, and cumene hydroperoxide, selenium dioxide, lead(IV) acetate, tert-butyl hypochlorite, sodium hypochlorite, and l, l,l-triacetoxy- l, l-dihydro-l,2-benziodoxol-3(lH)' one.
  • organic peroxides such as potassium permanganate, chromium oxide, potassium dichromate, hydrogen peroxide, nv chloroperbenzoic acid, urea hydrogen peroxide adduct/phthalic anhydride, tert-butyl hydroperoxide, and cumene hydroperoxide, selenium dioxide, lead(IV)
  • Examples of the reducing agent are hydrogenated complex compounds such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, and diisobutylaluminum hydride, boranes, sodium, and sodium amalgam.
  • hydrogenated complex compounds such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, and diisobutylaluminum hydride, boranes, sodium, and sodium amalgam.
  • metal salt examples include zinc chloride, zirconium chloride, indium chloride, and magnesium chloride.
  • the solvent is not limited, if it is stable under the reaction conditions concerned, is inert, and does not impede the reaction.
  • the solvent are polar solvents (e.g., water and alcoholic solvents such as methanol, ethanol and isopropanol), inert solvents (e.g., halogenated hydrocarbon-based solvents such as chloroform, methylene chloride, dichloroethane and carbon tetrachloride, ether-based solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane, aprotic solvents such as dimethylformamide, dimethyl sulfoxide, ethyl acetate, tert-butyl acetate, acetonitrile and propionitrile, aromatics such as benzene, toluene and anisole, or hydrocarbons such as cyclohexane), and mixture
  • the reaction can be performed at an appropriate temperature selected-from a range of from - 78°C to the boiling point of the solvent used in the reaction, at ordinary pressure or under pressurized conditions, and under microwave irradiation or the like.
  • a microwave synthesizer Initiator* (Biotage) was used for a microwave irradiation.
  • OH-type silica gel column chromatography's were performed using SNAP Ultra (Biotage) or using REVELERIS 40 ⁇ (Grace), and amino-type type silica gel chromatography's were performed using SNAPCartridge ISOLUTE Flash-NH 2 (Biotage) or Grace REVELERIS Amino 40 ⁇ (Grace).
  • Preparative chromatography's were performed using PLC Silica gel 60F254 (Merck), and amino-type preparative chromatography's were performed using NH2 Silica Gel 60 F 254 Plate- Wako (Wako).
  • the prep-HPLC purifications were performed using Agilent 1260 Infinity or Agilent 6130 (ionization method: Electron Spray Ionization (ESI)), and Agilent 385-ELSD were used when the ELSD detector was attached.
  • Mass spectra (MS) and the retention time (RT, minutes) were run on LOMS systems with one of the following Methods and Conditions:
  • a Agilent 1290 Infinity for LC system Agilent 6130 or 6150 for Quadrupole LC/MS system, and Agilent 385-ELSD when a ELSD detector is attached.
  • Ionization method ESI/APCI (atmospheric pressure chemical ionization) dual source. Eluents: A(H 2 0 + 0.1% HCOOH), B(CH 3 CN + 0.1% HCOOH).
  • Ionization method ESI/APCI (electrospray ionization / atmospheric pressure chemical ionization) dual source.
  • (+)-CSA (+)-10-camphorsulfonic acid
  • DIBAL Diisobutylaluminum hydride
  • DIPEA N,N-diisopropylethylamine
  • HATU 0-(7-azabenzotriazol-l-yl)"N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HMDS Hexamethyldisilazane
  • MgSO ⁇ i Magnesium sulfate anhydrous
  • PEPPSI (1,3 bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride
  • PdCl2(CH 3 CN)2 Bis(acetonitrile)palladium(II) dichloride
  • PdCl2(PPh 3 )2 Bis(triphenylphosphine)palladium(II) dichloride
  • Pd(PPh 3 )4 Tetrakis(triphenylphosphine)palladium(0)
  • T3P Propylphosphonic anhydride
  • TBDPS Tert-butyldiphenylsilyl
  • TBS Tert-butyldimethylsilyl
  • TrCl Triphenylmethyl chloride
  • TsCl 4-Methylbenzenesulfonyl chloride
  • WSC -HCl l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the enantiomeric excess (ee) was identified by the following method.
  • the race mic compound (Intermediate-3) has retention time of 4.45 and 5.00 min while the title compound has retention time of 5.00 min.
  • a microwave vial was charged with 3-(4-iodophenoxy)azetidine (l.0-g), DIPEA (0.82 mL) and acetonitrile (12 mL).
  • the vial was sealed with a Teflon® cap and the mixture was irradiated in a microwave reactor at 110 °C for 30 minutes.
  • the mixture was diluted with chloroform followed by washing with water and brine.
  • the organic layer was dried over MgS04, filtered, and concentrated in vacuo.
  • the residue was purified by OH-type silica gel column chromatography (0 ⁇ 0 % MeOH in CHCI3) to give the title compound (2.4 g, 74 % yield) as pale yellow oil.
  • I- 17 corresponds to Intermediate- 1 to Intermediate- 17, respectively.
  • Table 2A Reference Compound List (Rl - R15). Reference compound ID, chemical structures, ⁇ -NMR data, MS data and LCMS retention time (minute) data are shown.
  • Table 2B List of Reference Compounds (R16-R70). Reference Compound ID, chemical structures, MS data, LCMS retention time (minutes) data and LCMS (MS) condition are shown.
  • R4 l- ⁇ l-[3-(4-Chlorophenyl)propyl]-4-methyl-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R6 l-(3-(4-Chlorophenyl)propyl)-2-isopropyl-lH-imidazole
  • R7 l-[l-(3-Phenylpropyl)-lH-imidazol-2-yl]ethan-l-ol
  • R13 4- ⁇ [3-( ⁇ 2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl ⁇ methyl)-l,2-oxazol-5-yl]ethynyl ⁇ -l-(3- hydroxypropyl)pyridin-2(lH)-one
  • R14 4- ⁇ [3-( ⁇ 2-[(lS)-l-hydroxyethyl]-lH-imidazol-l-yl ⁇ methyl)-l,2-oxazol-5- yl] ethy ny l ⁇ pyridin- 2 ( 1H) -one
  • R17 l- ⁇ l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl ⁇ methanamine--hydrogen chloride (1/2)
  • R22 l-[l-(l-phenylethyl)-lH-imidazol-2-yl]ethan-l-ol
  • R25 2-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]-l-(4-phenylpiperazin-l-yl)ethan-l-one
  • R26 6- ⁇ [2-(l-hydroxyethyl)- IH-imidazol- 1-yllmethyl ⁇ - l-methylpyridin-2(lH)-one
  • R28 l- ⁇ l-[([l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R29 l- ⁇ l-[(l-methyl-lH-benzimidazol-2-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R32 l- ⁇ l-[(quinolin-2-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R33 l- ⁇ l-[(l,3-benzothiazol-2-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R36 3- ⁇ [2-(l-hydroxyethyl)- lH-imidazol- 1-yUmethyl ⁇ - l-methylquinoxalin-2(lH)-one
  • R37 l- ⁇ l-[(lH-pyrrolo[2,3-b]pyridin-6-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R40 3- ⁇ [2-(l-hydroxyethyl)-lH-imidazol-5-yl]methyl ⁇ -l-methyl-6-(4-methylphenyl)pyridin- 2(lH)-one .
  • R42 l- ⁇ l-[(quinoxalin-2-yl)methyl]-lH-imidazol"2-yl ⁇ ethan-l-ol
  • R43 l- ⁇ l-[(4,5,6,7-tetrahydro-l,2-benzoxazol-3-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R44 l- ⁇ l-[(imidazo[l,2-a]pyridin-2-yl)methyl]-lH-imidazol-2-yl ⁇ ethan-l-ol
  • R48 l- ⁇ l-[([l,l'-biphenyl]-4-yl)methyl]-lH-l,2,4-triazol-5-yl ⁇ ethan-l-ol
  • R66 l- ⁇ l-[3-(4-chlorophenyl)propyl]-lH-imidazol-2-yl ⁇ -2-(methanesulfonyl)ethan-l-ol
  • R67 2-benzyl-3-[2-(l-hydroxyethyl)-lH-imidazol-l-yl]propan-l-ol
  • Step-1) l-(l-(2-([l,l'-Biphenyl]-4-yl)ethyl)-lH-imidazol-2-yl)ethanone
  • Compound-53 was separated with chiral SFC to afford the first eluting isomer (Compound- 54, 17 mg, > 99 % ee) and the second eluting isomer (Compound-55, 13 mg, > 99 % ee).

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Abstract

L'invention concerne de nouveaux composés représentés par la formule générale suivante [l] ou des sels pharmaceutiquement acceptables de ceux-ci, qui inhibent LpxC, ainsi que des médicaments pharmaceutiques comprenant ces composés ou les sels pharmaceutiquement acceptables de ceux-ci, présentant une activité antimicrobienne contre des bactéries à Gram-négatif comprenant des souches résistantes à des médicaments multiples et qui sont utiles dans le traitement d'infections bactériennes.
PCT/JP2018/021100 2017-05-25 2018-05-25 Nouveaux dérivés d'imidazole Ceased WO2018216822A1 (fr)

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WO2020105660A1 (fr) * 2018-11-21 2020-05-28 大正製薬株式会社 Nouveau dérivé d'imidazole
WO2020111252A1 (fr) * 2018-11-30 2020-06-04 国立大学法人九州大学 Composé inhibiteur de dock1 et son utilisation
CN111909170A (zh) * 2020-09-11 2020-11-10 吉林奥来德光电材料股份有限公司 一种有机电致发光化合物、其制备方法以及包含该有机电致发光化合物的有机电致发光器件
US11311523B2 (en) 2015-02-27 2022-04-26 Kyushu University, National University Corporation Pyridinone compound and use thereof
WO2022173756A1 (fr) * 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2022173758A1 (fr) 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2023011574A1 (fr) 2021-08-05 2023-02-09 浙江海正药业股份有限公司 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation
WO2024036176A1 (fr) * 2022-08-10 2024-02-15 Blacksmith Medicines, Inc. Composés antibactériens
WO2024153173A1 (fr) * 2023-01-19 2024-07-25 浙江海正药业股份有限公司 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation
US12227475B2 (en) 2021-04-27 2025-02-18 X-Biotix Therapeutics, Inc. Aza-heterocyclyl carboxamide and related compounds and their use in treating medical conditions
US12325699B2 (en) 2018-09-20 2025-06-10 Blacksmith Medicines, Inc. Antibacterial compounds
WO2025174868A1 (fr) * 2024-02-13 2025-08-21 Blacksmith Medicines, Inc. Composés antibactériens
WO2025174875A1 (fr) * 2024-02-13 2025-08-21 Blacksmith Medicines, Inc. Composés antibactériens

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11311523B2 (en) 2015-02-27 2022-04-26 Kyushu University, National University Corporation Pyridinone compound and use thereof
US12325699B2 (en) 2018-09-20 2025-06-10 Blacksmith Medicines, Inc. Antibacterial compounds
WO2020105660A1 (fr) * 2018-11-21 2020-05-28 大正製薬株式会社 Nouveau dérivé d'imidazole
WO2020111252A1 (fr) * 2018-11-30 2020-06-04 国立大学法人九州大学 Composé inhibiteur de dock1 et son utilisation
CN113164444A (zh) * 2018-11-30 2021-07-23 国立大学法人九州大学 Dock1抑制化合物及其用途
JPWO2020111252A1 (ja) * 2018-11-30 2021-10-14 国立大学法人九州大学 Ｄｏｃｋ１阻害化合物およびその用途
CN111909170A (zh) * 2020-09-11 2020-11-10 吉林奥来德光电材料股份有限公司 一种有机电致发光化合物、其制备方法以及包含该有机电致发光化合物的有机电致发光器件
WO2022173756A1 (fr) * 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2022173758A1 (fr) 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
JP2024507139A (ja) * 2021-02-11 2024-02-16 ブラックスミス メディシンズ，インク． 抗菌性化合物
US12227475B2 (en) 2021-04-27 2025-02-18 X-Biotix Therapeutics, Inc. Aza-heterocyclyl carboxamide and related compounds and their use in treating medical conditions
WO2023011574A1 (fr) 2021-08-05 2023-02-09 浙江海正药业股份有限公司 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation
JP2024528245A (ja) * 2021-08-05 2024-07-26 浙江海正薬業股▲ふん▼有限公司 芳香族アセチレン系誘導体及びその製造方法と用途
JP7700363B2 (ja) 2021-08-05 2025-06-30 浙江海正薬業股▲ふん▼有限公司 芳香族アセチレン系誘導体及びその製造方法と用途
WO2024036176A1 (fr) * 2022-08-10 2024-02-15 Blacksmith Medicines, Inc. Composés antibactériens
WO2024153173A1 (fr) * 2023-01-19 2024-07-25 浙江海正药业股份有限公司 Dérivé d'acétylène aromatique, son procédé de préparation et son utilisation
WO2025174868A1 (fr) * 2024-02-13 2025-08-21 Blacksmith Medicines, Inc. Composés antibactériens
WO2025174875A1 (fr) * 2024-02-13 2025-08-21 Blacksmith Medicines, Inc. Composés antibactériens

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