WO2003000681A1 - Compose antibacterien comprenant un squelette quinolinecarboxamide - Google Patents

Compose antibacterien comprenant un squelette quinolinecarboxamide Download PDF

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Publication number
WO2003000681A1
WO2003000681A1 PCT/JP2002/006395 JP0206395W WO03000681A1 WO 2003000681 A1 WO2003000681 A1 WO 2003000681A1 JP 0206395 W JP0206395 W JP 0206395W WO 03000681 A1 WO03000681 A1 WO 03000681A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
atom
quinolinecarboxamide
independently
Prior art date
Application number
PCT/JP2002/006395
Other languages
English (en)
Japanese (ja)
Inventor
Minoru Yasuda
Koichi Ikesue
Yutaka Maeda
Toshio Yoshida
Mihoko Nakashima
Hiroto Hara
Kazuteru Yokose
Original Assignee
Rrf Research Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rrf Research Inc. filed Critical Rrf Research Inc.
Publication of WO2003000681A1 publication Critical patent/WO2003000681A1/fr

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to a compound having a novel quinolinecarboxamide skeleton that exhibits an excellent antibacterial action.
  • Resistant Gram-positive bacteria such as MRSA (methicillin-resistant Staphylococcus aureus) and VRE (vancomycin-resistant enterococcus) are resistant to treatment with existing antimicrobial agents. Therefore, development of an antibacterial agent having a strong antibacterial activity against such resistant Gram-positive bacteria has been desired.
  • An object of the present invention is to provide an antibacterial agent having a novel quinolinecarboxamide skeleton.
  • the present invention relates to a compound having a quinolinecarboxamide skeleton represented by the following formula (I) or a salt thereof.
  • R! Is a pyridyl group, a pyrazyl group, a pyrazolyl group, a quinolyl group, or an isoquinolyl group;
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a nitro group or a hydroxyl group, and R 6 is a lower alkyl group, a lower alkenyl group or an aralkyl group Or R 5 and R 6 may together form a hetero atom with the carbon and nitrogen atoms to which they are attached,
  • R 7 is independently a hydrogen atom or a benzoyl group
  • the present invention also relates to a pharmaceutical composition such as an antibacterial agent, which comprises a compound having a quinolinecarboxamide skeleton represented by the following formula (I) or a salt thereof.
  • R 2 s 3 s R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a nitro group or a hydroxyl group;
  • R 6 is a lower alkyl group, a lower alkenyl group, or an aralkyl group; Or R 5 and R 6 may be taken together to form a heterocycle with the carbon atom and the nitrogen atom to which they are attached,
  • R 7 is independently a hydrogen atom or a benzoyl group.
  • the present invention also provides a method for producing a compound having a quinolinecarboxamide skeleton or a salt thereof, comprising the following steps:
  • R is a lower alkyl group
  • R 2 s R 3 , R 4 , R 5 and R 6 are as defined above.
  • the compound having a quinolinecarboxamide skeleton or a salt thereof (hereinafter, simply referred to as “the compound of the present invention”) of the present invention is a compound having a novel chemical structure.
  • the compounds of the present invention can form salts such as the sodium salt.
  • the compounds of the present invention show strong antibacterial activity against Gram-positive bacteria. Further, the present invention shows a strong antibacterial activity against resistant Gram-positive bacteria.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the pyridyl group, virazyl group, pyrazole group, quinolyl group, or isoquinolyl group may be substituted with any substituent within a range that does not affect the antibacterial properties of the compound.
  • substituents include a lower alkyl group, a halogen atom, a cyano group, and the like.
  • the lower alkyl group is a saturated alkyl group having 1 to 8, preferably 1 to 5, and more preferably 1 to 3 carbon atoms, and may be linear or branched. .
  • examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and a pentyl group.
  • a lower alkyl group is preferably exemplified.
  • the lower alkyl group may be substituted with any substituent within a range that does not affect the antibacterial properties of the compound.
  • Such a substituent includes, for example, a halogen atom.
  • a lower alkenyl group corresponds to a lower alkyl group, has one double bond, and is an unsaturated aliphatic group.
  • Such a lower alkenyl group is an alkenyl group having 1 to 8, preferably 1 to 5, and more preferably 1 to 3, and is linear or branched. Is also good.
  • examples of the lower alkenyl group include a vinyl group, an n-propenyl group, an isopropenyl group, an n-butenyl group, an isobutenyl group, a sec-butenyl group, a tert-butenyl group, and a pentenyl group.
  • lower alkenyl groups such as.
  • the lower alkenyl group may be substituted with any substituent within a range that does not affect the antibacterial properties of the compound.
  • Such a substituent includes, for example, a halogen atom.
  • An aralkyl group is an arylalkyl group in which an alkyl group is substituted with an aryl group.
  • the aryl group is, for example, a phenyl group or a naphthyl group.
  • the alkyl group is as described above. Specific examples of the aralkyl group include a benzyl group.
  • the aralkyl group may be substituted with any substituent in the aralkyl group within a range that does not affect the antibacterial properties of the compound. Examples of such a substituent include a halogen atom, an alkyl group, a lower alkoxy group and the like.
  • the benzoyl group may be substituted by an alkanol group, a halogen atom, a lower alkoxy group or the like.
  • the benzene ring may be substituted with any substituent within a range that does not affect the antibacterial properties of the compound. Examples of such a substituent include a halogen atom, an alkyl group, a lower alkoxy group and the like.
  • An alkanoyl group is an acyl group derived from an alkanoic acid.
  • the alkyl group bonded to the carbonyl group includes a linear or branched alkyl group.
  • Examples of such an alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and a pentyl group.
  • higher alkyl groups such as decyl group, dodecyl group, tridecyl group and pendecyl group are included.
  • such an alkyl group may be substituted with any substituent within a range that does not affect the antibacterial property of the compound.
  • a substituent includes, for example, a halogen atom.
  • a lower alkoxy group is an alkoxy group consisting of an oxygen atom bonded to a lower alkyl group.
  • the lower alkyl group constituting the lower alkoxy group is the same as the above lower alkyl group.
  • Examples of the lower alkoxy group include linear or branched chains such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and pentyloxy.
  • a chain lower alkoxy group is exemplified.
  • the lower alkyl group constituting the lower alkoxy group may be substituted with any substituent within the range that does not affect the antibacterial properties of the compound, as described above. Such substituents include, for example, halogen atoms.
  • R 5 and R 6 may together form a hetero atom containing a carbon atom and a nitrogen atom together with the carbon atom and the nitrogen atom to which these substituents are bonded.
  • a hetero ring includes a 5- or 6-membered ring, and may contain a double bond.
  • Examples of such a hetero ring include a 6-membered hetero ring, specifically, a pyridyl group, a dihydropyridyl group, a tetrahydropyridyl group, and the like.
  • R 5 and R 6 are taken together, for example, as an aliphatic group which may have a double bond, at both ends of which the carbon atom or R 5 to which R 5 and R 6 are bonded, respectively.
  • a hetero atom may be formed by combining with a nitrogen atom.
  • Examples of such a divalent group formed by combining R 5 and R 6 with each other include a propylene group. This propylene group is bonded to the carbon atom and the nitrogen atom to which R 5 and R 6 are bonded to form dihydropyridine ⁇ as a condensed ring.
  • Compound (I) of the present invention is basically prepared by the method described in J. Org. Chem. Vol. 41, 825 (1976), It can be synthesized according to the synthesis method described in J. Heterocyclic Chem. Vol. 16, 1605 (1979), Vol. 18, 917 (1981). For example, it can be synthesized according to the following scheme 1.
  • compound (IV) is dissolved in a solvent such as DMSO or DMF, and treated with a base such as sodium hydride, and then R 6 -X is replaced with iodine, bromine atom, etc.
  • the compound (V) in which the nitrogen atom is alkylated (R 6 ) can be obtained by reacting with an alkyl halide such as a halogen atom), an alkenyl halide, or an aralkyl halide.
  • Compound (V) is then added to a reaction solution obtained by treating getyl malonate with sodium hydride or the like in a solvent such as DMF, and heated at about 110 ° C to give 2-quinolone-1-.
  • Compound ( ⁇ ) having a carboxylate skeleton can be obtained.
  • This compound ( ⁇ ) is then mixed with an amine such as Ri—NH 2 (III), and heated, for example, at about 150 ° C. to convert the compound (I) of the present invention into a crystalline compound.
  • the starting compound (I) is a known compound, and is easily available in the market or can be synthesized.
  • Table 2 and Table 3 below show the NMR data of the obtained compounds for the compounds of the above specific examples.
  • the compound of the present invention can be used as a salt.
  • Such salts include, for example, salts of alkali metals (eg, sodium, potassium, etc.) and alkaline earth metals (eg, potassium, magnesium, etc.).
  • the compound of the present invention is an antibacterial agent useful for treating local or systemic infections of humans and animals caused by, for example, Gram-positive bacteria, resistant Gram-positive bacteria, and the like.
  • Gram-positive bacteria include, for example, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus huei squirrel, Enterococcus huesium, and pyogenic streptococci.
  • the compounds of the present invention are also effective against these resistant bacteria, for example, methicillin-resistant Staphylococcus aureus.
  • the compound of the present invention may be used alone or together with pharmaceutically acceptable auxiliaries, diluents, binders, etc., for example, tablets, dragees, capsules, injections, creams, ointments, liquids, powders. And the like can be used in the form of general pharmaceutical compositions such as
  • the compounds of the present invention can be used alone or as a mixture of a plurality of different compounds.
  • dissolving agents or solubilizing agents which can constitute aqueous or in-use dissolving dosage forms (eg, distilled water for injection, physiological saline, propylene glycol, etc.); Pharmaceutical ingredients such as regulators (eg, inorganic or organic acids or bases), tonicity agents (eg, salt, glucose, glycerin, etc.) and stabilizers are used.
  • regulators eg, inorganic or organic acids or bases
  • tonicity agents eg, salt, glucose, glycerin, etc.
  • excipients eg, lactose, D-mannitol, corn starch, crystalline cellulose, etc.
  • disintegrants eg, carboxymethylcellulose, carboxymethylcellulose calcium, etc.
  • binders Eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • coating agents eg, hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.
  • plasticizers eg, For example, pharmaceutical ingredients such as polyethylene glycol and the like (eg, polyethylene glycol, hard fat, etc.) are used.
  • ointments for example, ointments, creams, and preparation components suitable as patches (eg, white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.) are used.
  • preparation components suitable as patches eg, white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.
  • the compound of the present invention varies depending on, for example, symptoms, age, body weight, etc., but in the case of systemic administration, the body weight is usually lk per adult per day, for example, 0.1 to 100 mg, preferably 0.1 to 100 mg. 0, 5-3 O mg can be administered.
  • the concentration of the active ingredient in topical treatment is, for example, 0. -20% by mass, preferably 0.5-10% by mass.
  • the compounds of the present invention can be used as germicidal disinfectants.
  • the compound of the present invention is, for example, in a medium such as water or ethanol in an amount of, for example, 0.01 to 10% by mass, preferably 0.05 to 5% by mass. Can be used.
  • the compounds of the present invention can be used not only in the medical field but also in the field of agrochemicals.
  • Example 1 A mixture of ethyl 1-aryl-1 1,2-dihydro-14-hydroxy-12-oxo-1 3_quinolinecarboxylate (104mg) and 2-aminoviridine (37mg) was stirred at 150 ° C for 30 minutes. . The resulting crystals were recrystallized from chloroform to give 94 mg of 1-aryl-11,2-dihydro-14-hydroxy-2-oxo-1-N-pyridyl-3-quinolinecarboxamide.
  • Antibacterial test method minimum inhibitory concentration, MIC measurement
  • the compounds of the present invention have excellent antibacterial activity against Gram-positive bacteria and resistant Gram-positive bacteria.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un composé qui comprend un squelette quinolinecarboxamide et qui présente d'excellentes qualités antibactériennes contre les bactéries Gram positif et les bactéries Gram positif résistantes. Le composé selon l'invention est représenté par la formule (I) dans laquelle R1 représente pyridyle, pyrazyle, pyrazole, quinolyle ou isoquinolyle; R2, R3, R4 et R5 représentent chacun indépendamment hydrogène, halogéno, nitro ou hydroxy ; R6 représente alkyle inférieur, alcényle inférieur ou aralkyle, à condition qu'il puisse être lié à R5 pour former un hétérocycle en coopération avec les atomes de carbone ou d'azote liés à ce dernier; et R7 représente indépendamment hydrogène ou benzoyle. Formule (I)
PCT/JP2002/006395 2001-06-26 2002-06-26 Compose antibacterien comprenant un squelette quinolinecarboxamide WO2003000681A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-192416 2001-06-26
JP2001192416A JP2003012667A (ja) 2001-06-26 2001-06-26 キノリンカルボキサミド骨格を有する抗菌剤

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8962598B2 (en) 2010-10-14 2015-02-24 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators
CN113307768A (zh) * 2021-04-29 2021-08-27 中国农业科学院兰州畜牧与兽药研究所 喹诺酮类衍生物及其制备方法和用途

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US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
NZ587551A (en) 2004-06-24 2012-01-12 Vertex Pharma 5-Amino-phenol derivatives such as 5-amino-2,4-di-tert-butyl-phenol
JP5003014B2 (ja) * 2005-07-14 2012-08-15 住友化学株式会社 カルボキサミド化合物及びその植物病害防除用途
PL3219705T3 (pl) 2005-12-28 2020-08-10 Vertex Pharmaceuticals Incorporated Kompozycje farmaceutyczne amorficznych postaci n-[2,4-bis(1,1-dimetyloetylo)-5-hydroksyfenylo]-1,4-dihydro-4-oksochinolino-3-karboksyamidu
JP2009544732A (ja) * 2006-07-26 2009-12-17 ノバルティス アクチエンゲゼルシャフト ウンデカプレニルピロホスフェートシンターゼの阻害剤
KR101852173B1 (ko) 2009-03-20 2018-04-27 버텍스 파마슈티칼스 인코포레이티드 낭성 섬유증 막횡단 전도도 조절자의 조정자의 제조 방법
CN109966264A (zh) 2012-02-27 2019-07-05 沃泰克斯药物股份有限公司 药物组合物及其施用
WO2016020836A1 (fr) * 2014-08-06 2016-02-11 Novartis Ag Dérivés de quinolone comme antibactériens
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator

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EP0059698A1 (fr) * 1981-03-03 1982-09-08 Ab Leo Carboxamides hétérocycliques, compositions contenant de tels composés, procédés pour leur préparation et méthodes pour le traitement à l'aide de ceux-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0059698A1 (fr) * 1981-03-03 1982-09-08 Ab Leo Carboxamides hétérocycliques, compositions contenant de tels composés, procédés pour leur préparation et méthodes pour le traitement à l'aide de ceux-ci

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8962598B2 (en) 2010-10-14 2015-02-24 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators
CN113307768A (zh) * 2021-04-29 2021-08-27 中国农业科学院兰州畜牧与兽药研究所 喹诺酮类衍生物及其制备方法和用途
CN113307768B (zh) * 2021-04-29 2023-12-12 中国农业科学院兰州畜牧与兽药研究所 喹诺酮类衍生物及其制备方法和用途

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