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WO1996023775A1 - Nouveaux derives d'acide pyridonecarboxylique ou de ses sels et agent antibacterien contenant ces derives en tant qu'ingredient actif - Google Patents

Nouveaux derives d'acide pyridonecarboxylique ou de ses sels et agent antibacterien contenant ces derives en tant qu'ingredient actif Download PDF

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Publication number
WO1996023775A1
WO1996023775A1 PCT/JP1996/000152 JP9600152W WO9623775A1 WO 1996023775 A1 WO1996023775 A1 WO 1996023775A1 JP 9600152 W JP9600152 W JP 9600152W WO 9623775 A1 WO9623775 A1 WO 9623775A1
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Prior art keywords
amino
dihydro
group
title compound
properties
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PCT/JP1996/000152
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English (en)
Japanese (ja)
Inventor
Akira Yazaki
Jiro Yoshida
Yoshiko Niino
Yoshihiro Ohshita
Norihiro Hayashi
Hirotaka Amano
Yuzo Hirao
Yasuhiro Kuramoto
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Wakunaga Seiyaku Kabushiki Kaisha
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Priority to CA002211681A priority Critical patent/CA2211681C/fr
Priority to AU52600/96A priority patent/AU5260096A/en
Publication of WO1996023775A1 publication Critical patent/WO1996023775A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 pyridone carboxylic acid derivative or a salt thereof having excellent antibacterial activity and oral absorption, and an antibacterial agent containing the same.
  • the present invention has been made in view of the above circumstances, and is a novel pyridone carbonyl that satisfies antibacterial activity, intestinal absorption, metabolic stability and side effects, particularly phototoxicity and cytotoxicity. Acid derivatives or And an antibacterial agent containing the same.
  • the present inventors have conducted intensive studies to obtain a compound that can be a clinically excellent synthetic antibacterial agent.
  • the compound represented by the following general formula (1) was converted to a compound represented by the following formula:
  • the present inventors have found that they have excellent antibacterial properties against negative bacteria and Gram-positive bacteria, are extremely low-toxic and are useful as synthetic antibacterial agents, and have accomplished the present invention. It is a thing.
  • R 1 represents a hydrogen atom or a carboxyl protecting group
  • R 2 represents a nitro group or a substituted or unsubstituted amino group
  • R 3 represents a halogen atom
  • R 4 and R 5 are the same or different and may be a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 6 is a hydrogen atom
  • R 7 represents a hydrogen atom or a halogen atom
  • Z represents a halogen atom or It represents a saturated cyclic amino group which may have a substituent.
  • the present invention also provides an antibacterial agent containing the pyridone carboxylic acid derivative or a salt thereof as an active ingredient.
  • the term “lower” in the substituent of the pyridone carboxylic acid derivative represented by the above general formula (1) of the present invention means that when the substituent is a chain, it has 1 carbon atom.
  • the compounds having 1 to 7 carbon atoms are preferred, and those having 1 to 5 carbon atoms are particularly preferable. When they are cyclic, those having 3 to 7 carbon atoms are meant.
  • the carboxyl protecting group represented by R ′ is an ester residue of a carboxylate ester, which is relatively easily cleaved to give a corresponding free radical.
  • Examples are those which generate a carboxyl group, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, and an n-butyl group.
  • Groups i — butynole group, t — lower alkyl group such as butynole group, pentyl group, hexyl group, heptyl group; vinyl group, aryl group, 1-propyl group, butenyl group, phenyl group Lower alkenyl groups such as phenyl, hexeninole and heptenyl; aralkyl having 7 to 11 carbon atoms such as benzyl; and 6 to 1 carbons such as phenyl and naphthyl.
  • By treating under mild conditions such as hydrolysis and catalytic reduction of aryl groups, etc.
  • Examples of the substituent in the substituted amino group represented by R 2 include a methyl group, an ethyl group, n-propyl group, i-propyl group, n-butynole group, and i- Butynole group, t-butynole group, pentyl group, hexyl group, heptyl group and other lower alkyl groups; vinyl group, aryl group, 1-propeninole group, butenyl group, phenyl group Lower alkenyl groups such as benzyl, hexenyl and heptenyl; alkenyl having 7 to 11 carbon atoms such as benzyl and 1-phenylethyl; phenyl A C6-C14 aryl group such as a naphthyl group or a naphthyl group; a honoleminole group, an acetyl group, a propionyl group, a butyryl group, an
  • Lower alkanol groups lower alkyl groups such as methoxycarbonyl and ethoxycarbonyl groups; Xylonolebonyl group; Benzoyl group, naphthoyl, etc. C7-C15 aryl group; Glycinole, Mouth Ixinole, Noxinolole, Alara Families such as ginore, feninore alaninore, araninore araranil, glycirl varinole, grisill glycirl Acid residues or oligopeptide residues and their Amino acid residue or oligopeptide residue whose functional group is protected by a commonly used protecting group in peptide chemistry such as acyl group or lower aralkyl, or cyclic amino group Group.
  • These substituents can be arbitrarily selected from one or two same or different substituents. Compounds protected with such amino acid residues or peptide residues are expected to have improved water solubility
  • R 2 is an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoinorea amino group, an amino acid-substituted amino group, and an oligo group. Gopeptide-substituted amino groups. More preferred examples of R 2 include an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a holinoamino group, Glycine amino group, loycin amino group, norino amino group, aranyl amino group, aranyl alanyl amino group, and the like. Of these, amino groups are particularly preferred.
  • Examples of the halogen atom represented by R 3 , R 4 , R 5 , R 6, and R 7 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a fluorine atom or a chlorine atom is preferred, and a fluorine atom is particularly preferred.
  • Examples of the lower alkyl group represented by R 4 , R 5 , R 6 and X include a methylenol group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, t A monobutyl group, a pentyl group, a hexyl group, a heptyl group, and the like, with a methyl group being preferred.
  • Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, a t-butoxy group and the like.
  • R 4 and R 5 are a halogen atom and a hydrogen atom, and more preferably, R 4 is a fluorine atom or a chlorine atom and R 5 is a hydrogen atom. It is particularly preferred that R 4 is a fluorine atom and R 5 is a hydrogen atom. Note that this R 4 is the same as R 2 . It is particularly preferable to substitute at position l.
  • halogen atom represented by X and Z examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and a chlorine atom are particularly preferred.
  • the saturated cyclic amino group which may have a substituent represented by Z further contains one or more hetero atoms such as a nitrogen atom, an oxygen atom, an thio atom and a carbonyl carbon atom in the ring. And may be monocyclic or bicyclic or tricyclic. Preferred is a 4- to 7-membered ring for a monocyclic ring, a 7 to 11-membered ring for a bicyclic ring, and a 9 to 15-membered ring for a tricyclic ring.
  • Examples of such cyclic amino groups include, for example, aziridin-1—yl, azetidin-11-inole, pyrrolidine-11-inole, and pyridinone.
  • the atoms constituting the ring of these saturated cyclic amino groups may be substituted with an appropriate substituent.
  • substitutable group include, for example, hydrogen.
  • the lower alkyl group which can be substituted for the saturated cyclic amino group includes, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group.
  • a group having 1 to 7 carbon atoms, such as a group is a lower alkoxy group.
  • C 1 to C 7, such as a group, an ethoxy group, and an n-propoxy group include halogen atoms such as a fluorine atom, a chlorine atom, and a bromine atom. .
  • the substituents on the saturated cyclic amino group are the same as those represented by R 2.
  • Particularly preferred examples of the substituted amino group and the substituted or unsubstituted amino lower alkyl group include a methylamino group and an ethylamino group.
  • Group dimethylamino group, aminomethyl group, 1-aminoethyl group, 2—aminoethyl group, 1-amino-1—ethyl group, methylamino Methyl group, methyl amino group, methyl amino group, methyl group, amino group, mouth amino group, valley
  • Examples include a non-amino group, an aranil-amino group, an aranyl-a-nitro-amino group, and the like.
  • saturated cyclic amino groups preferred groups include those represented by the following formulas (a) and (b).
  • Y represents an oxygen atom, a sulfur atom or NR 8 (where R 8 represents a hydrogen atom or a lower alkyl group), and e represents 3 to 5 Shows the number, f is indicates the number of 1 ⁇ 3, g is indicates the number of 0 ⁇ 2, J l, J 2 and J 3 is rather good be the same or different Ttei, hydrogen atom, arsenic (Indicates droxyl group, lower alkyl group, amino lower alkyl group, amino group, lower alkylamino group, lower alkoxy group, and halogen atom.)
  • the lower alkyl group, amino lower alkyl group, lower alkylamino group, lower alkoxy group, and halogen atom are those represented by R 2 to those similar to the groups shown by R 5 is exemplified.
  • Examples of the cyclic amino group represented by the formula (a) include azetidin-11-yl group, pyrrolidine-11-yl group, and piberidine-1
  • the cyclic amino group represented by the formula (b) includes, for example, a pyrazine-11-inole group, a morpholin-14-inole group, Thiomolephosphorin-14-inole group, homopirazine-1-1-inole group, N-thiazolidinyl group, N-oxazolidinyl group, etc. .
  • a cyclic amino group represented by the formula (a) is more preferred, and an azetidin-1-yl group or a pyrrolidine-11-yl group is particularly preferred.
  • 3 Aminoazetidine-1 1 — Inole group, 3 — Methylaminoazetidine 1 — Inole group, 3 — Dimethylaminoazetidine -1-ethyl group, 3-aminomethylazetidine 1-amino group, 3-amino 2-methylazetidine 1-1-inole group, 3 — Amino 1 3 — Methyl azetidin 1 1 — Inole group, 3 — Alaninole 1-amino-azetidine- 1-yl group, 3-phenol- 1-amino-azetidine 1-yl group, pyrrolidine- 1-yl group, 3 -Hydroxypyrrolidine-1 -yl group, 3,4 -Hydroxypyrrolidine-1 1 -Inole group, 3 -Methoxypropyl Gen 1 -yl group, 3-Methyl phenol pyrrolidine 1-1-Inole group, 3 -Hydrogen
  • R ' is a hydrogen atom
  • R 2 Gaa Mi R 3 a lower alkylamino group, a di-lower alkylamino group, a lower aminophenol amino group, an amino acid-substituted amino group or an oligopeptide-substituted amino group
  • R 3 Is a halogen atom
  • R 4 is a halogen atom
  • R 5 is a hydrogen atom
  • R 6 is a hydrogen atom
  • R 7 is a fluorine atom
  • A is a nitrogen atom
  • Pyridonic carboxylic acid derivatives or their salts (1) are acid addition salts Alternatively, both base addition salts can be formed. In addition, this salt also includes those which form a chelate salt with a boron compound.
  • the acid addition salts include (A) salts with mineral acids such as hydrochloric acid and sulfuric acid, and (B) formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, and fumaric acid.
  • Salts with organic acids such as acids and maleic acids, such as (C) methansulphonic acid, benzenesulphonic acid, p-trinorenence norephonic acid
  • Examples of salts with sulfonic acids such as mesitylenesorenoic acid and naphthalenesulfonate
  • examples of the base addition salts include, for example, (A ') sodium Salt with an alkaline metal such as limestone, salt with an alkaline earth metal such as (B ') canolemium, magnesium, and (C') aluminum.
  • Ammonium salt (D ') trimethylamine, triethylamine, tributinoreamin, pyridin, N, N—dimethinorea Lin, N — Methyl oleperidine, N — Methyl mono olein, Jethylamine, Cyclohexamine, Proline, J Benzenoremin, N — Benzenore 1/3 — phenamine, 1 — phenamine, N, N '— diphenylamine Salts with nitrogen-containing organic bases such as amines can be mentioned.
  • examples of the boron compound include boron halide such as boron fluoride, and lower alkoxyboron such as acetate boron.
  • the pyridone carboxylic acid derivative or a salt thereof (1) can exist not only in an unsolvated form but also as a hydrate or solvate. Accordingly, the compounds of the present invention include all of their crystal forms and hydrates or solvates.
  • the pyridone carboxylic acid derivative or its salt (1) can be present as an optically active substance. These optically active substances are also included in the compound of the present invention. Further, the compound (1) may exist as different stereoisomers (cis type, trans type). These stereoisomers are also included in the compounds of the present invention.
  • the pyridone carboxylic acid derivative or a salt thereof (1) is produced by an arbitrary method corresponding to the type of the substituent and the like, and examples thereof include the following. That's it.
  • Step 1 Among the compounds represented by the general formula (1), a compound in which R 1 is a hydrogen atom or a lower alkyl group and Z is a halogen atom can be produced, for example, by the following reaction formula It is manufactured by a series of process 1 represented by
  • R'a represents a lower alkyl group
  • R 9 represents a lower alkoxy group or a group _NR 12 R 13 (where R 12 and R ' 3 each represent a lower alkyl group. )
  • R indicates a lower alkyl group, respectively
  • L 1 is shows the C b gain down atom
  • Z 'is indicates Ha B gain down atom
  • R 2a is shows the substitution A Mi amino group
  • R 2, R 3 , R 4 , R s , R 6 , R 7 and A have the same meaning as described above.
  • the compounds (1a) and (1d) of the present invention are obtained by reacting the compound (A) with an orthoformate ester (H) such as ethyl orthoformate or methyl orthoformate.
  • H orthoformate ester
  • (J) is reacted, then cyclized, and the resulting compound (C) is converted into a compound (la) by dibolation, and reduced to give a compound (lb)
  • the compound (1c) is obtained by alkylating or acylating the compound, and the compound (1d) is obtained by hydrolyzing it.
  • compound (Id) can be obtained by hydrolyzing compound (lb).
  • the reaction between the compound (A) and the orthoformate ester (H) is usually carried out at 0 to 160 ° C., preferably at 50 to 150 ° C., and the reaction time is usually 10 minutes. ⁇ 48 hours, preferably 1-10 hours.
  • the amount of the orthoformate used is preferably at least equimolar to the compound (A), especially about 1 to 10 moles per mole of the compound (A).
  • the reaction with the compound (J) is carried out without a solvent or in a suitable solvent. It is also desirable to add a carboxylic anhydride such as acetic anhydride as a reaction aid.
  • the solvent used herein may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; pentane, hexane, heptane And aliphatic hydrocarbons such as ligroin; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; dimethylformamide And non-protonic polar solvents such as dimethinoresolelefoxide; methanol, ethanol, and prono. Examples of alcohols such as knoll.
  • This reaction is usually performed at 0 to 150 ° C, preferably at 0 to 100 ° C, and the reaction time is usually 10 minutes to 48 hours.
  • Compound (J) The amount of the compound to be used is at least equimolar to the compound (A), preferably from equimolar to 2 times mol.
  • compound (A) may be added to compound (A) such as N, N—dimethylformamide dimethinoreacetanol, and N—dimethylinoformolamide, etc.
  • compound (J) can be reacted to lead to compound (B).
  • the solvent used for the reaction with the acetals any solvent that does not affect the reaction may be used, and examples thereof include those described above. This reaction is usually performed at 0 to 150 ° C, preferably at room temperature to 100 ° C, and the reaction time is usually 10 minutes to 48 hours, preferably 1 to 10 hours. is there.
  • Compound (B) is subjected to a cyclization reaction to give compound (C).
  • This reaction is performed in a suitable solvent in the presence or absence of a basic compound.
  • a suitable solvent such as benzene, toluene and xylene.
  • Halogenated hydrocarbons such as carbon: methanol, ethanol, prono.
  • Examples include alcohols such as phenol and butanol; and non-protonic polar solvents such as dimethyl sulfonamide and dimethyl sulfoxide.
  • Alkali metals such as sodium metal, potassium metal, etc .; hydrogenated sodium, hydrogenated calcium;
  • metal water Inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; sodium methoxide, sodium Any phanolexide, such as trimuet or calcium, t-butoxy; sodium fluoride, calcium fluoride, etc.
  • the reaction temperature of this reaction is usually 0 to 200 ° C, preferably room temperature to 180 ° C, and the reaction is usually completed in 5 minutes to 24 hours.
  • the amount of the basic compound to be used is 1 mol or more, preferably 1 mol to 2 mol, per 1 mol of compound (B).
  • the compound (1a) of the present invention can be produced by subjecting the compound (C) to a nitration reaction. Nitrogenation is performed by a general method used for dinitrogenation of aromatic compounds. As the nitrifying agent, nitric acid or a mixed acid obtained by combining nitrate and sulfuric acid is used. And acetyl nitrate. The amount of the mixed acid used for the reaction is 1 equivalent to a large excess of sulfuric acid and 1 equivalent to a large excess of nitric acid with respect to 1 equivalent of the compound (C). This is done by adding (C). The reaction temperature is 110 ° C to 80 ° C. C ⁇ The reaction time is preferably 5 minutes to 5 hours.
  • Compound (1b) can be obtained by reducing compound (1a).
  • a commonly used method can be used.
  • a solution using zinc, iron, soot, soot (II) chloride or the like in an acidic solution can be used.
  • the compound (1d) in which R 1 is a hydrogen atom is obtained by hydrolyzing the compound (1b) or, if desired, alkylating or acylating the compound (lb). It can be obtained by disassembly.
  • the hydrolysis can be performed under any of the reaction conditions used in ordinary hydrolysis reactions. Examples include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
  • Basic compounds such as minerals: mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; or
  • the alkylation reaction for obtaining the compound (1C) of the present invention is carried out by using an anoalkylating agent such as dialkyl sulfate, alkyl chloride, alkyl bromide or the like, preferably sodium carbonate, corresponding to a desired alkyl group.
  • anoalkylating agent such as dialkyl sulfate, alkyl chloride, alkyl bromide or the like, preferably sodium carbonate, corresponding to a desired alkyl group.
  • a base such as lithium or potassium carbonate
  • a solution such as N, N-dimethylformamide, N-methizolepyrrolidone
  • This alkylation reaction is carried out in the presence of a carbonyl compound corresponding to the desired alkyl group, followed by a catalytic reduction method using platinum, Raney nickel, platinum black, and palladium carbon. You can also do this.
  • the acylation reaction can be carried out by any of the reactions commonly used for acylation of amino groups, such as acyl chloride corresponding to the desired acyl group.
  • an acid anhydride and a compound (lb) are converted into halogenated hydrocarbons such as methylene chloride, chlorophonolem, carbon tetrachloride, and chlorobenzene; benzene, Aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran and dioxane; or acetate trinoles, N, N—dimethinolehonolemamide Pyridin, picolin, N, N-dimethylaniline, N-methylmorpholin, dimethinoreamin at 0 ° C to room temperature in nonprotonic polar solvents such as In the presence or absence of a base such as triethylamine, sodium carbonate, carbonated rim, etc.
  • halogenated hydrocarbons such as methylene chloride, chlorophonolem, carbon tetrachloride, and chlorobenzene
  • Aromatic hydrocarbons such as toluene
  • ethers such
  • compound is a medium
  • R 6 Gaa Mi amino group is in the child that is the reaction using and R 6 Gaha b compound is gain down atom (A) as a starting material
  • the halogen atom is preferably obtained by subjecting the halogen atom to amino elimination.
  • the compound (1 b) is Ru can this and the force "5 also be synthesized in Tsu by the following methods. Condensation and cyclization
  • R 14 represents an amino protecting group
  • R ′ a , R 3 , R 4 , R 5 , R 6 , R 7 , R s , L ′, Z ′ and A are as defined above. That is, acrylate esters (D) obtained by reacting the above-mentioned compound (A) with orthoformates (H) and phenyl. The compound (L) is obtained by condensing and cyclizing a range amine (K), and then the compound (lb) is obtained by removing the amino-protecting group. ) Can be obtained.
  • reaction for obtaining the compound (L) from the compound (A) can be carried out under the same conditions as the above-mentioned reaction for obtaining the compound (C) from the compound (A).
  • Elimination of amino protecting groups (mainly acyl and carbamoyl) Is carried out by hydrolysis with an acid or an anolyte. This condition is the same as that described for the hydrolysis to compounds (lb) and (lc) above.
  • Step 2 Among the compounds represented by the general formula (1), a compound in which Z is a saturated cyclic amino group optionally having a substituent is represented by, for example, the following reaction formula Manufactured by Step 2.
  • Z 2 represents a saturated cyclic amino group which may have a substituent
  • R ′, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Z 1 And A have the same meaning as above.
  • the compound (0) can be obtained by aminating the compound (N) with a compound represented by the formula Z 2 —H.
  • This reaction is carried out using any aromatic hydrocarbons such as benzene, toluene, xylene, etc .; any phenols such as methanol, ethanol, etc .; Any ethers such as transhydran, dioxane, monoglyme; such as methylene chloride, chloroform, carbon tetrachloride Halogenated hydrocarbons; non-protonic, such as dimethyl alcohol, dimethyl alcohol, dimethyl alcohol, N-methyl pyrrolidone Polar solvent; In a solvent that does not affect the reaction, such as toluene and pyridin, a deoxidizing agent, if necessary, such as sodium carbonate, calcium carbonate, sodium hydrogen carbonate Um, triethylamine, 1,8-diazabicyclo [5.4.0] This is carried out at room temperature to 160 ° C in the presence of dendecene (DBU).
  • DBU dendecene
  • the reaction time is a few minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the amount of compound Z 2 —H to be used is preferably equimolar or more, preferably equimolar to 5 times mol, relative to compound (N).
  • R 1 is a carboxyl protecting group, it can be converted to a hydrogen atom by hydrolysis as desired.
  • Step 3 Among the compounds represented by the general formula (1), the compound in which R 1 is a carboxyl protecting group is produced, for example, by Step 3 shown in the following reaction formula.
  • R ′ b represents a carboxyl protecting group
  • L 2 represents a halogen atom
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A and Z Has the same meaning as above.
  • This reaction is performed with tri-tinoleamine, diisopropinoletinoleamine, dicyclohexylamine, DBU, sodium carbonate, potassium carbonate, It is preferable to carry out the reaction in the presence of a basic compound such as sodium hydroxide.
  • an amino group, imino group, hydroxy group, melcapto group, carboxyl group, etc. which are not involved in this reaction, are present in the starting compounds used in the above steps 1 to 3
  • these groups may be used in a protected form, and after completion of the reaction, the protecting group may be removed by a conventional method.
  • the protecting group may be any one that can be removed without destroying the structure of the compound of the present invention formed by the reaction, and may be a peptide, an amino group, or the like. Groups commonly used in the field of sugar and nucleic acid chemistry are used.
  • the starting compound (A) is produced by the method described in the following literature or a method analogous thereto.
  • the compound of the present invention thus obtained is isolated and purified according to a conventional method. Depending on the conditions of isolation and purification, it can be obtained in the form of a salt, free carboxylic acid or free amide, which can be converted into each other as desired to obtain the desired form.
  • the compound of the present invention is produced.
  • the compound (1) of the present invention or a salt thereof is a pharmaceutically acceptable carrier as an antibacterial agent for parenteral administration such as injection, rectal administration, ophthalmic administration and the like, or oral administration in solid or liquid form.
  • a composition can be formulated with it.
  • Examples of the form of the antibacterial composition of the present invention for injection include pharmaceutically acceptable sterile water or non-aqueous solution, suspension and emulsion.
  • suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene, and the like.
  • Such compositions may also contain adjuvants, such as preserving, wetting, emulsifying, and dispersing agents.
  • compositions may be sterile solid compositions that can be dissolved, for example, by filtration through a bacteria-retaining filter, or immediately before use, in a sterilizing agent or some other sterile injectable medium.
  • Bacteria can be sterilized by incorporating a sterilizing agent in the form described above.
  • Formulations for ophthalmic administration may preferably contain, in addition to the present compound, a solubilizing agent, a preservative, an isotonic agent, a thickening agent and the like.
  • Solid preparations for oral administration include capsules, tablets, pills, powders, and granules.
  • the compounds of the invention are generally mixed with at least one inert diluent, for example, sucrose, lactose or starch.
  • This preparation may also use an additional substance other than the inert diluent, such as Hitoshi Nisawa (eg, magnesium stearate) in the usual formulation.
  • a buffer may be used. Tablets and pills may be provided with an enteric coating.
  • Liquid dosage forms for oral administration include inert diluents commonly used by those skilled in the art, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and emulsions, including water. Xylants.
  • the compositions may also contain adjuvants such as wetting agents, emulsifying, suspending, and sweetening, flavoring, and flavoring agents. Flavors can also be included.
  • Formulations for rectal administration may preferably contain, in addition to the present compounds, excipients such as cocoa butter or a suppository box.
  • the dose of the compound (1) of the present invention depends on the properties of the compound to be administered, the administration route, the desired treatment period and other factors, but is generally about 0.1 l / day for an adult. ⁇ 100 mg Z kg, especially about 0.5 ⁇ : LOO mg Z kg is preferred. The daily dose can be divided into 2 to 4 divided doses, if desired.
  • the compound (1) of the present invention and its salt have extremely high antibacterial effects and low phototoxicity and cytotoxicity, so that they can be used as pharmaceuticals for humans and animals, as fish disease drugs, agricultural chemicals, food preservatives, etc. Can be widely used. Further, the compound of the present invention can be expected to have an antiviral activity, particularly an anti-HIV (human immunodeficiency virus) activity, and is considered to be effective in preventing or treating AIDS.
  • an antiviral activity particularly an anti-HIV (human immunodeficiency virus) activity
  • Echinole 7 Black mouth 6 — Fnoreo mouth 1, 4, 4-dihydro-1-41 (2, 4, 6 — Trifluorophenyl) 1-1, 8 — Naphthyridine 1 — Carboxylate:
  • Echinore 11 (2—Chloro 4-Frönöröfönönöre) 1 6,7—Gifnoreo Mouth 1, 1—4—Jhidro 41 Line 3 — Power Box Rate:
  • Etinole 2 — (2, 4, 5 — Trifnoreo benzol) 13 Ethoxy acrylate 2.46 g of a solution of chlorophonolem 13 Under ice-cooling, 5 ml of a solution of 1.2 ml of 2-chloro-4-anilineline was added dropwise to the ml under ice cooling, and the mixture was stirred at room temperature overnight. The solvent is distilled off, ethanol is added, and the crystals are collected by filtration, washed with ethyl ether, and then washed with ethyl alcohol 2 — (2, 4, 5 — trifluorobenzoyl).
  • the mixture was stirred at room temperature for 30 minutes to complete the nitration, and then the reaction solution was poured into 150 ml of a clog form and 100 ml of ice water while stirring. After stirring for minutes, liquid separation was performed, and the mouth layer layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated crystals are dispersed in ethanol and collected by filtration.Then, ethanol and diisopropyl ether are washed in this order. Thus, 2.08 g of the title compound was obtained.
  • Echinore 11 (2, 4 — diphenyl) 5 — 2-nitrophenyl 16 — 7, 7 — diphenyl 1, 4, 4 — dihydro 4 — oxo 1 quinolin 1 3 — card box rate:
  • Echinore 1 (2, 4 — Difluoro 1 5 — Nitrophenyl) 1 6, 7, 8 — Trif Norre 1 1, 4 — Dihydro 4 — OKI LINE LINE 3 — Power box:
  • Echinore 7 Krollo 6 — Phonore 1, 4 — Dihydro 1 4 1oxo 1 1 — (2, 3, 4 1 Trifnore 1 5 — 2 Tro 1, 8 — naphthyridine 1 3 — carboxylate:
  • Echinore 7 Black mouth 1 6 — Fenoole 1, 4 — Dihydro 1 4 — Oxo 1 1 — (2, 4, 6 — Trifnoreo mouth 13 — 2 Mouth fermentation)-1, 8-Naphthyridine 1-3-Carboxylate:
  • Echinore 7 Black mouth 1 6 — Phenorero 1, 4 — Dihydro 1 4 — Oxo 1 1 1 (2, 4, 6 — Trifluorene) 1 1
  • the title compound was obtained in the same manner as in Example 1 except that naphthyridine-13-potassium oleate was used.
  • 1 1 (3-Amino 4, 6-Difluorene) 1 7-Black 1-6-1-4-1-4 Oxo 1, 8 — Naphthyridine 1 3 — Power No. Revolving: Etino 7 — Black 1 6 — Noro 1 1 ((2,4) ⁇ 5 ⁇ ⁇ ⁇ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1. 1. Of 0 g with 280 mg of 10% palladium carbon, 50 ml of dichloromethane, 30 ml of ethanol and 2 ml of concentrated hydrochloric acid. The mixture was added and hydrogenated at room temperature overnight. Pyridine 2 ml was added, and the mixture was concentrated under reduced pressure.
  • Echinore 11 (3—Amino 1, 4, 6—Difluorophenyl) 1 7—Black mouth 6—Funoleo mouth 1, 4, 4-Dihydro 4
  • oxo-1,8-naphthyridine-13-potassium oxylate was added 4 ml of a mixture of 3N hydrochloric acid / monoacetic acid, and the mixture was heated under reflux for 2 hours. After adding 3 ml of distilled water and refluxing for 5 minutes, the precipitate was collected and washed with ethanol to obtain 0.54 g of the title compound.
  • Echinore 11 (2, 4 — diphenyl phenol 5 — nitric oxide phenol) 1 6, 7 — diphenyl phenol 1, 4 — dihydro 1 4 — oxo 3.7 g of quinolin-3-carboxylate was dissolved in 60 ml of acetic acid, and 400 mg of 10% paradium carbon was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 days. The catalyst was removed by filtration with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was collected by filtration and washed with getyl ether. 2.
  • Echinore 11 (3—Amino 4, 6—Diphenylolenophenyl) 1,6,7,8—Trif Noreo Mouth 1,4—Dihydro 1 4—O KIRO KI LIN LINE 1 3 — Power BOX:
  • Echinore 11 (2, 4 — diphenyleol 5 — dinitrophenyl) 1, 6, 7, 8 — Trifolenorex 1, 4 — dihydro 41 Kiso-kinolin 3-Power box box 2.2 g It was dissolved in evening water (20 ml), acetic acid (50 ml) and dichloroethane (10 ml), and 100% palladium carbon (200 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was collected by filtration and washed with getyl ether. 1.12 g of the title compound were obtained.
  • Echinore 11 (3—Amino 1-4, 6—Difluorophenyl) 1, 6, 7, 8—Trif Noreo Mouth 1, 4—Dihydro 1 41
  • the title compound was obtained in the same manner as in Example 19, except that quinoline-3—carboxylate was used.
  • No. 1 (3—Amino 4,5,6—Tri-no-re-open mouth) 1 7—Kuro-no-one 6—Fonore-ro 1,4—Dihydro ⁇ 4 1 oxo 1, 8 — naphthyridine 1 3 — carboxylate:
  • Echinore 7 Black mouth 6 — Phenole 1, 4 — Dihydro 1 — 1oxo 1 1 — (2, 3, 4 — Trif nore 5 — 2 Tro 1,8-Naphthyridine 13-Dissolve 80 mg of carboxylic acid in 80 ml of methanol and 1 ml of acetic acid. % Palladium carbon 8 O mg was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was collected by filtration and washed with diethyl ether. 200 mg of the title compound were obtained.
  • Echinore 11 (3—Amino 4, 5, 6—Triphenylamine mouth phenyl) 1-6, 7—Diphenyle 1,4—Dihydro 1 41 Okisokinori 3-Power box rate:
  • Echinore 1 (3—Amino 1, 2, 4, 6 — Tri-Fenole mouth, phenyl) 1-Cro mouth 16 — Fenoole 1, 4, 4 — 'Low 4 1-1, 1-8-Naphthyridine 1-3-
  • Echinore 1 1 (6—Chloro 4—Funoleo 1—3—Nitro 2 1) 7—Kuro 1 6—Fonole 1 1 4—Jihdro 4 —Oxo-1,8—Naphthyridine-13—The title compound was obtained in the same manner as in Example 16 except that carboxylate was used.
  • No. 1 (3 — Amino 4 — Black 1 6 — Black 1 6 7 — Black 6 — Black 6, 1 — 4 Mouth 4 1 oxo 1, 8 — naphthyridine 1 3 — force box rate: 1-(4-Black mouth 1-6-Fluoro 1-3-Nitro feninole) 1-7-Black mouth 1-6-Fluoro 1, 4-Dihydro 1 4 — Oxo 1, 8 — Naphthyridine 1 3 — Power The title compound was obtained in the same manner as in Example 16 except that oleboxylate was used.
  • Echinole 11 (3—Amino 14—Fonole 1) 2—Methylfour 2 1 7—Chloro 6—Fenole 1 1,4 1 ⁇ 4 — Oxo 1, 8 — Naphthyridine 1 3 — Carboxylate:
  • Echinole 11 (3-Amino 14-Fenole 1-7-Methyl phenol 2) 1 7-Chloro 6-Fenole 1-4-Dihydro 4-oxo-11,8-naphthyridine-13-force
  • the title compound was obtained in the same manner as in Example 17 except that oleboxylate was used.
  • Ethyl 7 Chlorine 11 (2, 4 — Diphnoreo mouth 1 5 — Holmylmethine) Aminophane 2 1) 6 — Phenole mouth 1, 1, 4 Hydro 1 4 1 oxo 1, 8 — naphthyridine 1 3 — force boxyrate:
  • Echizore 1 (3 — t — Butoxyl carbylamino 1, 2,4-difluorobenzene) 1 7 —Kuro 1-6 — oriole 1,4 Draw 4 — Oxo 1, 8 — Naphthyridine 1 3 — Carboxyrate:
  • No. 1 (3 — t — Butoksika Norreboninolea Min. 1, 4 — Jif Norelo Lenil) 1 7 — Chloro 6 — Flou mouth 1, 4 — J Hydro 4 — Oxo 1, 8 — Naphthyridine 1 3 — Forced boxylate 50 Omg was added to 8 ml of a mixture of 3N hydrochloric acid and acetic acid. The mixture was stirred and refluxed for 5 hours. 16 ml of distilled water was added, the mixture was heated under reflux for 10 minutes, and then allowed to cool.
  • Echinole 11 (2,4-Diphenyle 5-Methylamine) 1 6, 7 — diphnole 1, 4 — dihydro 1 4 1 oxo 1 quinoline 3 — carboxylate:
  • Echinore 1 (3—Amino I, 4,6—Gifnolelo Feninore) 1 6,7—Difnoleo Mouth 1,4, Jihidro 1 4—Oxo 1
  • the title compound was obtained in the same manner as in Example 42 except that quinoline 13-canolexylate was used.
  • Echinore 11 (2, 4 — Gifnoré Mouth 1 5 — Metnole Aminofen 2) _ 6, 7 — Gifnoreo Mouth 1, 4 — Jihydro 41
  • the title compound was obtained in the same manner as in Example 43, except for using oxo-quinoline 13-potassium chloride.
  • 1-1 (3-Amino 1, 4-6-diphenyle-phenyl) 1-7-Chloro 6-1-octane 4-Oxo 1-1, 4-Jihi Draw 1, 8 — Naphthyridine 1 3 — Forced boxyrate 500 mg with 500 mg of 37% formalin and 1 Oml of 1 , 2—Dichloroethane, 5 ml of methanol, 0.5 ml of acetic acid and hydrogenated with 0.08 g of 10% paradium carbon (64 hours). After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain the title compound.
  • Example 76 7 — [(3 S, 4 S) 1 3 — Amino 4 — Methyl pyrroline 1 1 ⁇ 1 1 — (2, 4 — Difnoreo 1-5 — Hole 1 6 — Fusoleol 1, 4 — Dihydro 1 4 — Oxo 1, 8 — Naphthyridine 1 3 — Power oleic acid : 7 — Chlorine 1 — (2, 4 — Diphnoreoroll 5 — Honoremilamiminofe 2) 1 6 — Phonore mouth 1, 4 — Dihydro 1 4 —Oxo-1,8—Naphthyridine-13—force The title compound was obtained in the same manner as in Example 54 except that oleic acid was used.
  • the mixture was allowed to stand at room temperature overnight, 50 ml of black-mouthed form and 10 ml of distilled water were added, the layers were separated, dried over magnesium sulfate anhydride, and concentrated under reduced pressure.
  • One-third of the foamed residue was dissolved in 6 ml of acetonitrile, and 1.5 ml of a 4N hydrogen chloride dioxane solution was added, followed by stirring at room temperature. .
  • a precipitate was formed in about 1 minute.
  • the mixture was stirred overnight, and the precipitate was collected by filtration.
  • the precipitate was dissolved in about 4 ml of distilled water, and a 10% aqueous solution of sodium hydroxide was added little by little to pH 8. To form a precipitate.
  • the mixture was heated under reflux for 1 hour, allowed to cool, and the precipitate was collected by filtration and washed with distilled water, ethanol and diisopropyl ether in that order to obtain 19.3 mg of the title compound as a
  • N — B oc — L Valine 220 mg, N — Methylene morpholin 106 mg in 5 ml of dichloromethane, bring to 120 ° C. With stirring, the mixture was added with isoforminol chloroformate 1401 and stirred for 20 minutes.
  • Ethanol 3 chloro-2,4,5 — Trifnoreo benzoyl acetate 5 g 3.9 g of orthoformic acid ethyl acetate, acetic anhydride 5 In addition to 5 g, the mixture was heated under reflux for 3 hours. After standing to cool, the mixture was concentrated under reduced pressure, and 20 ml of black hole foam was added to the residue. Under ice cooling, 2.3 ml of 2,4-difluoroaniline was added dropwise. The mixture was stirred at room temperature for 2 hours.
  • the title compound was obtained in the same manner as in Reference Example 6, except that ethenore 2, 3, 4, 5, 5 and 6-pentafeno benzoyl acetate were used.
  • 2,4, -Diphnoleo 1-5 Addition of 20.3 g of nitrobenzoic acid to 60 ml of dichloromethane, ogizarinolechloride 10 ml, N, N — dimethylol After adding 15 drops of muamide and stirring overnight, the solvent and excess reagent were distilled off under reduced pressure. The residue
  • Ethyl 8 Black mouth 6, 7 — Diphnoreolor 11 (2,4-Diphnoreo mouth 5 — 2 Trofene 2) 1 1,4 1 Jihide mouth 4 1 ⁇ ⁇ — 3 3 3 ⁇ ⁇ 3 3 : ::
  • Echinore 8 Black mouth 6, 7 — Giffnole 1 — (2, 4 — Giffnolero 1) 1 1, 4 — Jidro 4 — Oxo 2.5 g of quinoline 13-carboxylate was added to 15 ml of sulfuric acid, and under ice-cooling, 95 mg of nitric acid rim was added little by little, followed by stirring at room temperature overnight. Pour the reaction mixture into ice water and stir at room temperature. Stirred. The precipitate was collected by filtration and washed with water, ethanol, and getyl ether. 2.4 g of the title compound were obtained.
  • Ethyl 8 Black mouth 6, 7 — Diffusion 1 — (2,4 1 Diffusion 5 — Honore Minore a Minofue 1 1, 4 ⁇ 4 ⁇ 4 4 — — — — — — — — — — — — — — — — — — — — 3 — 8 ⁇ — — — — ⁇ — 8 Diphenyl chloro-5-Nitrophenyl) 1 1, 4 1 Dihydrochloride 1 4 1 oxoquinoline 1 3 — Power ureboki rate 2 g, 10% , 0 La di U beam di click carbon 2 0 O mg b b E data down 2 0 m 1, in addition to formic acid 1 0 ml, hydrogen stream under stirring for 3 hours at room temperature, the is added acetic anhydride al Stirred overnight.
  • the catalyst was removed by filtration with a membrane filter, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl ether, and the solid was collected by filtration and washed with ethanol and getyl ether to obtain 1.9 g of the title compound.
  • the reaction solution was concentrated under reduced pressure, 63 mg of potassium carbonate and 5 ml of N, N-dimethylformamide were added to the residue, and the mixture was heated with stirring at 90 ° C for 1 hour. . After allowing to cool, the reaction solution was added to ice water, the precipitated solid was collected by filtration, and this solid was dissolved in a clog port. The organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off. Ethanol and getyl ether were added to the residue, and the solid was collected by filtration and washed with diethyl ether. 1.2 g of the title compound were obtained.
  • Ethyl 5 Penzinoleone 1 1 1 (3—Ethoxyboninole Amino 4,6—Diphenyleole) 1 6,7—Diphneole Oro 1,4-dihydro-1-41-oxo quinoline 1-3-force norboxylate 50 O mg to 48% hydrobromic acid 5 ml, acetic acid 5 ml The mixture was heated under reflux overnight. After allowing to cool, the mixture was concentrated under reduced pressure, ethanol was added to the residue, and the solid was collected by filtration and washed with getyl ether. 130 mg of the title compound were obtained.
  • Ethyl 1 (3—Penzinole Okino Poninore Amino 4 and 6—Difluorene) 1 6 and 7—Difluoro 1 5— Memories 1, 4-1-1-4-1- Canole box:
  • Ethanol 2 Methylenol 1,3,4,6 — Trifnoreo benzobenzoyl acetate 2.6 g Orthoethyl formate 2.2 mg, Acetic anhydride 3
  • the mixture was heated and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure. To the residue was added 20 ml of a black hole mouth, and under ice-cooling, N-benzyloxy 2-4 of Reference Example 9 was added. A solution of 2.78 g of dimethylamine in 1 O ml of chloroform was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and to the residue were added 1.65 g of carbonated lithium and 10 ml of N, N-dimethyl honoleum amide, and the mixture was heated and stirred at 90 ° C for 1 hour. did. After cooling, the reaction solution was added to ice water, and the precipitated solid was collected by filtration. This solid was dissolved in chloroform, the organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off. Ethanol and ethyl ether were added to the residue, and the solid was collected by filtration and washed with getyl ether to obtain 2.4 g of the title compound.
  • Nozzle 1 [3 — (Penzinoreokibonboninoreamimino 1-4, 6 — Difnoreo Lofenizore)] — 6,7 — Difnoreo mouth — 5 — Memories 1, 4 ⁇ 4 4 4 4 1 ⁇ ⁇ ⁇ ⁇ ⁇
  • Echinore 1 (3—Penzinoleoxycarbonyl bonamino-4,6—Diphenylephenyl) 1—7—Cross mouth 1,4—Hydrogen ⁇ 4 1 oxo 1, 8 — naphthyridine 1 3 — carboxylate:
  • Echinole 2,6—Dichloronicotinoacetate 11.8 g was added to 8.8 ml of orthoformate and 13 ml of acetic anhydride, and the mixture was heated under reflux for 2 hours. did. The reaction solution was concentrated under reduced pressure. To 3.2 g of this compound was added 20 ml of toluene, and the N-benzyloxynanoboninole of Reference Example 9 was added to 2,4-diphenyleno-m-phenylene. Diamine 3. A solution of 10 ml of lg in toluene and 10 ml of ethanol was added dropwise, and after the addition was completed, the mixture was stirred at room temperature overnight.
  • Ethyl 11 (3—Penzinolekishonoronboniramino 1-4, 6—Gifnole Orofeninor) 1 7 _Chlor 1,4—Jihid
  • B 4-oxo-1,8-naphthyridine-13-canolepoxilate
  • the solid precipitated in the reaction solution was collected by filtration, and washed with ethanol, then with a cross-section film, and then with ethyl ether, to obtain 550 mg of the title compound.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • To the residue were added 2.1 g of anhydrous sodium carbonate and 4 ml of N, N-dimethylformamide, and the mixture was stirred at 90 ° C for 15 minutes. After allowing the mixture to cool, 50 ml of black hole holme and 300 ml of distilled water were added thereto, and the mixture was separated.Then, the black hole form layer was washed twice with 300 ml of distilled water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropyl ether in that order to obtain 647 mg of the title compound.

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Abstract

Dérivé d'acide pyridonecarboxylique représenté par la formule générale (1) ou un de ses sels et agent antibactérien contenant ledit dérivé, où R1 représente hydrogène ou un groupe de protection carboxy; R2 représente nitro ou amino éventuellement substitué; R3 représente halogéno; R4 et R5 peuvent être similaires ou différents et chacun représente hydrogène, halogéno, alkyle inférieur ou alcoxy inférieur; R6 représente hydrogène, halogeno, hydroxy, alkyle inférieur ou amino; R7 représente hydrogène ou halogéno; A représente azote ou -CX= (où X représente hydrogène, halogéno, alkyle inférieur ou alcoxy inférieur); Z représente halogéno ou amino cyclique saturé éventuellement substitué.
PCT/JP1996/000152 1995-01-30 1996-01-26 Nouveaux derives d'acide pyridonecarboxylique ou de ses sels et agent antibacterien contenant ces derives en tant qu'ingredient actif WO1996023775A1 (fr)

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CA002211681A CA2211681C (fr) 1995-01-30 1996-01-26 Nouveaux derives d'acide pyridonecarboxylique ou de ses sels et agent antibacterien contenant ces derives en tant qu'ingredient actif
AU52600/96A AU5260096A (en) 1995-01-30 1996-01-26 Novel pyridonecarboxylic acid derivatives or salts thereof and antibacterial agent containing the same as active ingredient

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JP1267395 1995-01-30
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011068A1 (fr) * 1995-09-22 1997-03-27 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives de l'acide pyridone-carboxylique ou leurs sels et agent antibacterien les contenant comme ingredient actif
WO1997038971A1 (fr) * 1996-04-16 1997-10-23 Wakunaga Pharmaceutical Co., Ltd. Nouvelles phenylenediamines et leur procede de preparation
WO1997040036A1 (fr) * 1996-04-19 1997-10-30 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives de l'acide pyridonocarboxylique ou des sels de cet acide et agents antibacteriens contenant ces substances en tant que composant actif
US6723734B2 (en) 1997-03-21 2004-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative
WO2006123792A1 (fr) * 2005-05-19 2006-11-23 Daiichi Sankyo Company, Limited Derives de 3-aminopyrrolidine tri ou tetrasubstitues
US7700617B2 (en) 1997-03-21 2010-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative
WO2017217441A1 (fr) * 2016-06-15 2017-12-21 湧永製薬株式会社 Nouveau dérivé de l'acide pyridonecarboxylique ou son sel correspondant
CN116606279A (zh) * 2023-03-13 2023-08-18 广东工业大学 一种氟喹诺酮类化合物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62135458A (ja) * 1985-10-07 1987-06-18 Fujisawa Pharmaceut Co Ltd 新規キノロン化合物およびその製造法
JPH0348682A (ja) * 1989-07-14 1991-03-01 Yoshitomi Pharmaceut Ind Ltd ピリドンカルボン酸化合物
JPH0366688A (ja) * 1989-08-03 1991-03-22 Yoshitomi Pharmaceut Ind Ltd １，４―ジヒドロ―４―オキソナフチリジン化合物
JPH03133960A (ja) * 1989-10-12 1991-06-07 Bayer Ag キノロンカルボン酸誘導体、それらを調製する方法および抗ウイルス剤としてのそれらの使用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62135458A (ja) * 1985-10-07 1987-06-18 Fujisawa Pharmaceut Co Ltd 新規キノロン化合物およびその製造法
JPH0348682A (ja) * 1989-07-14 1991-03-01 Yoshitomi Pharmaceut Ind Ltd ピリドンカルボン酸化合物
JPH0366688A (ja) * 1989-08-03 1991-03-22 Yoshitomi Pharmaceut Ind Ltd １，４―ジヒドロ―４―オキソナフチリジン化合物
JPH03133960A (ja) * 1989-10-12 1991-06-07 Bayer Ag キノロンカルボン酸誘導体、それらを調製する方法および抗ウイルス剤としてのそれらの使用

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011068A1 (fr) * 1995-09-22 1997-03-27 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives de l'acide pyridone-carboxylique ou leurs sels et agent antibacterien les contenant comme ingredient actif
US5998436A (en) * 1995-09-22 1999-12-07 Wakunaga Pharmaceuticals Co., Ltd. Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
US6133284A (en) * 1995-09-22 2000-10-17 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
US6156903A (en) * 1995-09-22 2000-12-05 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
WO1997038971A1 (fr) * 1996-04-16 1997-10-23 Wakunaga Pharmaceutical Co., Ltd. Nouvelles phenylenediamines et leur procede de preparation
US5994575A (en) * 1996-04-16 1999-11-30 Wakunaga Pharmaceutical Co., Ltd. Phenylenediamines and process for preparing the same
WO1997040036A1 (fr) * 1996-04-19 1997-10-30 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives de l'acide pyridonocarboxylique ou des sels de cet acide et agents antibacteriens contenant ces substances en tant que composant actif
US6211375B1 (en) 1996-04-19 2001-04-03 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or salts thereof and antibacterial agents containing the same as the active ingredient
US6723734B2 (en) 1997-03-21 2004-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative
US7700617B2 (en) 1997-03-21 2010-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative
US7563805B2 (en) 2005-05-19 2009-07-21 Daiichi Pharmaceutical Co., Ltd. Tri-, tetra-substituted-3-aminopyrrolidine derivative
WO2006123792A1 (fr) * 2005-05-19 2006-11-23 Daiichi Sankyo Company, Limited Derives de 3-aminopyrrolidine tri ou tetrasubstitues
US8211910B2 (en) 2005-05-19 2012-07-03 Daiichi Pharmaceutical Co., Ltd. Tri-, tetra-substituted-3-aminopyrrolidine derivative
JP5087394B2 (ja) * 2005-05-19 2012-12-05 第一三共株式会社 トリ−、テトラ−置換−３−アミノピロリジン誘導体
US8476429B2 (en) 2005-05-19 2013-07-02 Daiichi Sankyo Company, Limited Tri-, tetra-substituted-3-aminopyrrolidine derivative
KR101307717B1 (ko) 2005-05-19 2013-09-11 다이이찌 산쿄 가부시키가이샤 트리―, 테트라― 치환―3―아미노피롤리딘 유도체
WO2017217441A1 (fr) * 2016-06-15 2017-12-21 湧永製薬株式会社 Nouveau dérivé de l'acide pyridonecarboxylique ou son sel correspondant
JP6322772B1 (ja) * 2016-06-15 2018-05-09 湧永製薬株式会社 新規ピリドンカルボン酸誘導体又はその塩
CN109311818A (zh) * 2016-06-15 2019-02-05 湧永制药株式会社 新型吡啶酮羧酸衍生物或其盐
KR20190016962A (ko) 2016-06-15 2019-02-19 와쿠나가 세이야쿠 가부시키 가이샤 신규 피리돈카르복실산 유도체 또는 그 염
US10532984B2 (en) 2016-06-15 2020-01-14 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivative or salt thereof
AU2017285689B2 (en) * 2016-06-15 2021-01-07 Wakunaga Pharmaceutical Co., Ltd. Novel pyridonecarboxylic acid derivative or salt thereof
CN116606279A (zh) * 2023-03-13 2023-08-18 广东工业大学 一种氟喹诺酮类化合物及其制备方法和应用

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CA2211681C (fr) 2003-05-13
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KR19980701781A (ko) 1998-06-25
AU5260096A (en) 1996-08-21

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