WO1992009579A1 - Compose d'acide quinolonecarboxylique et son utilisation - Google Patents

Compose d'acide quinolonecarboxylique et son utilisation Download PDF

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Publication number
WO1992009579A1
WO1992009579A1 PCT/JP1991/001645 JP9101645W WO9209579A1 WO 1992009579 A1 WO1992009579 A1 WO 1992009579A1 JP 9101645 W JP9101645 W JP 9101645W WO 9209579 A1 WO9209579 A1 WO 9209579A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
oxo
dihydro
methoxy
acid
Prior art date
Application number
PCT/JP1991/001645
Other languages
English (en)
Japanese (ja)
Inventor
Kazuhiko Araki
Tsuyoshi Kuroda
Satoru Uemori
Akihiko Moriguchi
Yoshifumi Ikeda
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Japan Tobacco 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 Yoshitomi Pharmaceutical Industries, Ltd., Japan Tobacco Inc. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Publication of WO1992009579A1 publication Critical patent/WO1992009579A1/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
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel quinolone carboxylic compound useful as an antibacterial agent, a salt or ester thereof, and a pharmaceutical use thereof.
  • MRSA Methicillin-resistant staphylococci
  • new quinoline antibacterial agents represented by ofloxacin and ciprofloxacin in recent years are widely used for various infectious diseases because of their broad antibacterial spectrum and strong antibacterial activity, and their excellent utility has been recognized. Have been. However, several years after these new quinolone antibacterial agents have appeared in clinical practice, increasing their use and increasing resistance to causative bacteria have become a problem. Furthermore, the therapeutic effect of new quinoline antibacterial agents on MRSA is also expected.In spite of a certain effect in the initial stage, MRSA becomes more resistant to new quinoline antibacterial agents and new antibacterial agents are developed. Raises the problem.
  • the main side effects of new quinolone antibacterial agents are digestive symptoms such as sucking, stomach discomfort, abdominal pain, anorexia, rash, systemic redness, itching, photosensitivity such as photosensitivity, dizziness and lightheadedness Central nervous symptoms such as insomnia, tinnitus, etc. are known.
  • the present inventors have conducted intensive studies in view of the above problems, and found that a novel quinoline carboxylic acid compound in which a 7-cyclic amino group of the quinoline skeleton is substituted with a hydroxyalkyl group is a gram-negative bacterium.
  • Antibacterial activity against Gram-positive bacteria as well as strong antibacterial activity against Stronger than carboxylic acids it has excellent antibacterial activity, especially against Gram- ⁇ bacteria, including MRSA and Newquinone-resistant bacteria. They have found and completed the present invention.
  • the present invention relates to the general formula
  • Z is human Dorokishi 0 Bok 4 alkyl substituted Azechijin one 1 one I le, pyrosulfate lysine one 1 one I le, Piperi Gino Hexhydridoazepine, morpholino or hexahydro draw 1,4-oxazepine.
  • preferred compounds of the present invention include
  • C 4 alkoxy is methoxy, ethoxy, broboxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.
  • fluoro-substituted C ⁇ alkoxy is fluoromethoxy, difluoromethoxy, trifluoromethoxy, etc.
  • the salt of the compound of the general formula (I) is a metal salt, for example, an alkali metal salt or an alkaline earth metal salt (a salt of sodium, potassium, calcium, magnesium, etc.), or a heavy metal salt (Salts such as copper, zinc, iron, gold, silver, platinum, and manganese). Pharmaceutically acceptable salts are preferred as these salts.
  • the compound of the general formula (I) of the present invention may exist as its corresponding hydrate (monohydrate, 1Z dihydrate, 3Z dihydrate, etc.) or other solvates. sell.
  • the ester of the compound of the general formula (I) is a compound in which rubonic acid at the 3-position of the quinolone skeleton is esterified with an alkyl ester, an aralkyl ester or a group that can be hydrolyzed in vivo.
  • C1-C6 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc .; halogen, alkyl, alkoxy (methoxy, Shows alkoxy with 1 to 6 carbon atoms such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, and hexyloxy.).
  • the compound of the general formula (I) of the present invention can be synthesized by the following production method.
  • X 1 represents a halogen of chlorine, bromine, fluorine, or iodine, and other symbols are as defined above.
  • compound (I) (Hereinafter also referred to as compound (I).
  • Compound (I) is described in JP-A-62-252772, JP-A-2-124873, and JP-A-2-231476. And the general formula
  • the compound (dish) is used in an amount of 1 to 8 times the molar amount of the compound (I), and the solvent is used in the absence of a solvent or in the presence of an appropriate solvent at 0 to 200, preferably 30 to 150 to 1 to 48 Do it over time.
  • suitable solvents include water, alcohols (such as methanol, ethanol, and brovanol), acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric amide, and 1-methyl-2-pyrrolidone. Can be used.
  • triethylamine, 1,8-diazavic mouth [5.4.0] organic base such as dedeca-7-ene or potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate as a deoxidizing agent
  • organic base such as dedeca-7-ene or potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate as a deoxidizing agent
  • An inorganic base such as lime may be used.
  • compound (IV) (Hereinafter, also referred to as compound (IV).
  • Compound () is disclosed in Japanese Patent Application Laid-Open Nos. 63-316, 157, 2-1-2,873, and 2- The compound can be synthesized by the method described in Japanese Patent Publication No. 2314776.
  • the compound (Iff) is used 1 to 8 times by mole the compound (17), and 0 to 150 in the absence of a solvent or in the presence of a suitable solvent.
  • C preferably at 30 to 100 for 1 to 48 hours.
  • Suitable solvents include water, alcohols (methanol, ethanol, brovanol, etc.), acetonitrile, pyridine, dimethylphos.
  • Lumamide, dimethylsulfoxide, hexamethylphosphoric amide, 1-methyl-2-pyrrolidone and the like can be used.
  • triethylamine, 1,8-diazavic mouth [5,4,0] organic base such as dendecar 7-ene or potassium carbonate, sodium carbonate, sodium hydrogen carbonate, or hydrogen carbonate
  • organic base such as dendecar 7-ene or potassium carbonate
  • sodium carbonate sodium hydrogen carbonate
  • hydrogen carbonate An inorganic base such as sodium bicarbonate may be used.
  • the base acting on compound (V) may be triethylamine, an organic base such as 1,8-diazabicyclo [5.4.0] pentaca 7 -ene, or an organic base such as sodium hydride, potassium carbonate, sodium carbonate and carbonate.
  • organic bases such as sodium hydride, potassium carbonate, sodium carbonate and carbonate.
  • inorganic bases such as hydrogen hydride, sodium hydrogen carbonate, sodium hydroxide, and hydroxide hydroxide.
  • Suitable solvents include water, alcohols (methanol, ethanol, blobanol, etc.) or mixtures thereof.
  • compound (VI) (Wherein, X 2 represents halogen, and other symbols are as defined above.) (Hereinafter also referred to as compound (VI).
  • Compound (VI) is described in Japanese Patent Application No. 2-32427. In the method described in the specification of No. 3 or in the present specification, the compound can be synthesized by the production method 1 or 2 using the halogenated 8-position corresponding to the compound (I) or (HI). And general formula
  • the compound (W) is used in an amount of 1 to 8 times the amount of the compound (VI), and 0 to 200 ° C., preferably 30 to 15 O Do this for 1-48 hours at 'C.
  • Suitable solvents include acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric amide, 1-methyl-2-pyrrolidone, and the like.
  • an organic base such as triethylamine, 1,8-diazabicyclo [5.4.0] pentaca 7 -ene or a sodium hydride, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, hydrogen hydrogen carbonate is used as a deoxidizing agent.
  • the use of an inorganic base such as sodium is preferred.
  • the hydroxyl group of the hydroxy C-alkyl group substituted on the ring-bound amino group at the 7-position of the quinolone skeleton is trialkylsilyl (trimethylsilyl, tert-butyldimethylsilyl, etc.), low ⁇ alkyl (methyl, ethyl, isopropyl, tertiary butyl, etc.), aryl, aralkyl (benzyl, phenylethyl, etc.), acyl (formyl, acetyl, propionyl, benzoyl, etc.), alkoxyalkyl (methoxymethyl, ethoxymethyl, etc.) Protected by known protecting groups in organic synthesis such as propoxymethyl, methoxethyl, and methoxypropyl.
  • the protecting group can be removed by a conventional method after the synthesis reaction, for example, hydrolysis with an acid or alkali, or reduction reaction.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and aluminum chloride, and organic acids such as formic acid, acetic acid, and trifluoroacetic acid.
  • the alkali include inorganic bases such as sodium hydroxide, hydroxide hydroxide, sodium carbonate, and hydrogen carbonate, and organic bases such as triethylamine.
  • the reduction reaction include catalytic reduction.
  • reaction can be carried out in water, alcohols such as methanol, ethanol, propanol, etc .; hydrogen chlorides, such as methylene chloride, ⁇ -form, hydrogen tetrachloride, or mixtures thereof; or An acid or acid is used as a solvent, and the reaction is carried out in the range of 0 to 200 ° C., preferably 30 to 120 ° C.
  • the compound of the general formula (I) may be used, if desired, according to a conventional method, such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide.
  • an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide
  • an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide.
  • the above-mentioned salt can be obtained by treating with a material, a hydroxide of heavy metal such as copper, zinc, iron, gold, silver, platinum and manganese.
  • the ester compound with which the compound of the general formula (I) reacts can be obtained by reacting the carboxylic acid compound of the compound (I) with the corresponding ester residue which is halogenated or organic sulfonyloxy in a conventional manner. it can.
  • the compound having an asymmetric carbon is usually produced as a racemic compound, and the optical isomer is classified into fractionated crystals, chromatographies. It can be separated by a conventional method such as chromatography, and can also be produced using an optically active starting compound.
  • the compound of the present invention When used as an antibacterial agent, it is orally administered in the form of a conventional preparation containing a therapeutically effective amount of the compound of the present invention and an organic or inorganic, solid or liquid pharmaceutically acceptable carrier. It can be administered parenterally or externally.
  • Such preparations include, for example, solid preparations such as tablets, granules, powders, and capsules and liquid preparations such as suspensions, syrups, emulsions, and lemonade.
  • the above preparation may contain an auxiliary agent, a lubricant, other lactose, magnesium stearate, clay, sucrose, corn starch, talc, stearate, gelatin, agar, pectin, peanut oil, It may contain commonly used additives such as cocoa butter, ethylene glycol and the like.
  • the dosage of the compound of the present invention will vary depending on the age and the illness of the patient, or the type of the disease and the type of the administered compound, but is generally 1 B3 ⁇ 4 to about 400 m / day or more. Can be administered to the patient.
  • the average dose per side of the compound of the invention is about 50 ng, 100 ⁇ ? , 250 mg, 500 ng, 1000 mgr, 2000 Om, and can be used for treatment of diseases caused by pathogenic microorganisms.
  • test compounds used are as follows.
  • CPFX 1-cyclobutyral pill-1 6-fluoro-1,4-dihydro 7- (1-piperadur) 1-44-oxoquinoline-3 mono-rubonic acid (cibrofloxacin)
  • Table 1 shows the results.
  • the compound of the general formula (I), its salt or its ester of the present invention has not only a strong antibacterial activity against Gram-negative bacteria but also an antibacterial activity against Gram- picking bacteria. It is stronger than doncarboxylic acid, and has good antibacterial activity, especially against Gram III bacteria including MRSA and new quinoline resistant bacteria. Further, when the medium pH is related to the acidic side in the in vitro antibacterial activity test, the antibacterial activity of the conventional compound of the present invention is reduced, whereas the antibacterial activity of the compound of the present invention is enhanced on the acidic side.
  • Example 8 1-cyclobutyral pill-1-6-fluoro-8-fluoromethoxy-1,4-dihydroxy 7- (2-hydroxymethylmorpholino) -1,4-oxo-1-3-quinolinecarboxylic acid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composé d'acide quinolonecarboxylique représenté par la formule générale (I), son sel ou son ester, et son utilisation en médecine. Dans la formule, R représente alcoxy C1-C4 ou alcoxy C1-C4 fluoré; Z représente azétidin-1-yle à substitution C1-C4 hydroxyalkyle, pyrrolidin-1-yle, pipéridino, hexahydroazépin-1-yle, morpholino ou hexahydro-1,4-oxazépin-1-yle. Ce composé est un agent antibactérien très utile car il présente une puissante action antibactérienne contre les bactéries Gram négatif, une action antibactérienne contre les bactéries Gram positif plus puissante que celle de l'acide pyridonecarboxylique que l'on utilise habituellement, une excellente action antibactérienne notamment contre les bactéries Gram positif comprenant le MRSA et les bactéries résistantes au neuroquinolone, et une meilleure action antibactérienne en milieu acide.
PCT/JP1991/001645 1990-11-30 1991-11-29 Compose d'acide quinolonecarboxylique et son utilisation WO1992009579A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/341113 1990-11-30
JP34111390 1990-11-30

Publications (1)

Publication Number Publication Date
WO1992009579A1 true WO1992009579A1 (fr) 1992-06-11

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005026145A2 (fr) * 2003-09-12 2005-03-24 Warner-Lambert Company Llc Agents antibacteriens a base de quinolone
US6897315B2 (en) 1997-11-24 2005-05-24 Bayer Healthcare Aktiengesellschaft Method for producing 8-methoxy-quinolinecarboxylic acids
US7902227B2 (en) 2007-07-27 2011-03-08 Janssen Pharmaceutica Nv. C-7 isoxazolinyl quinolone / naphthyridine derivatives useful as antibacterial agents

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5967269A (ja) * 1982-09-09 1984-04-16 ワ−ナ−−ランバ−ト・コンパニ− 抗細菌化用化合物
JPS60214777A (ja) * 1984-02-17 1985-10-28 ワ−ナ−−ランバ−ト・コンパニ− 抗菌剤
JPS60258163A (ja) * 1984-05-30 1985-12-20 バイエル・アクチエンゲゼルシヤフト 免疫刺激剤
JPS61263959A (ja) * 1985-05-15 1986-11-21 バイエル・アクチエンゲゼルシヤフト １−アリ−ル−４−キノロン−３−カルボン酸
JPS62252772A (ja) * 1986-01-21 1987-11-04 Kyorin Pharmaceut Co Ltd 選択毒性に優れた８−アルコキシキノロンカルボン酸およびその塩並びにその製造方法
JPS63198664A (ja) * 1986-03-31 1988-08-17 Sankyo Co Ltd キノロンカルボン酸誘導体

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5967269A (ja) * 1982-09-09 1984-04-16 ワ−ナ−−ランバ−ト・コンパニ− 抗細菌化用化合物
JPS60214777A (ja) * 1984-02-17 1985-10-28 ワ−ナ−−ランバ−ト・コンパニ− 抗菌剤
JPS60258163A (ja) * 1984-05-30 1985-12-20 バイエル・アクチエンゲゼルシヤフト 免疫刺激剤
JPS61263959A (ja) * 1985-05-15 1986-11-21 バイエル・アクチエンゲゼルシヤフト １−アリ−ル−４−キノロン−３−カルボン酸
JPS62252772A (ja) * 1986-01-21 1987-11-04 Kyorin Pharmaceut Co Ltd 選択毒性に優れた８−アルコキシキノロンカルボン酸およびその塩並びにその製造方法
JPS63198664A (ja) * 1986-03-31 1988-08-17 Sankyo Co Ltd キノロンカルボン酸誘導体

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6897315B2 (en) 1997-11-24 2005-05-24 Bayer Healthcare Aktiengesellschaft Method for producing 8-methoxy-quinolinecarboxylic acids
US7115744B2 (en) 1997-11-24 2006-10-03 Bayer Healthcare Aktiengesellschaft Method for producing 8-methoxy-quinolinecarboxylic acids
WO2005026145A2 (fr) * 2003-09-12 2005-03-24 Warner-Lambert Company Llc Agents antibacteriens a base de quinolone
WO2005026145A3 (fr) * 2003-09-12 2005-06-16 Warner Lambert Co Agents antibacteriens a base de quinolone
US7902227B2 (en) 2007-07-27 2011-03-08 Janssen Pharmaceutica Nv. C-7 isoxazolinyl quinolone / naphthyridine derivatives useful as antibacterial agents

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