WO1991016311A1 - Derive d'acide 7-(hydrazino substitue)-4-oxoquinoline-3-carboxylique, son sel et son ester - Google Patents

Derive d'acide 7-(hydrazino substitue)-4-oxoquinoline-3-carboxylique, son sel et son ester Download PDF

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Publication number
WO1991016311A1
WO1991016311A1 PCT/JP1990/000521 JP9000521W WO9116311A1 WO 1991016311 A1 WO1991016311 A1 WO 1991016311A1 JP 9000521 W JP9000521 W JP 9000521W WO 9116311 A1 WO9116311 A1 WO 9116311A1
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WO
WIPO (PCT)
Prior art keywords
group
acid
salt
ester
carboxylic acid
Prior art date
Application number
PCT/JP1990/000521
Other languages
English (en)
Japanese (ja)
Inventor
Rajeshwar Singh
George Thomas
Ronald G. Micetich
Original Assignee
Taiho Pharmaceutical Company, Limited
Synphar Laboratories, Inc.
Fathi-Afshar, Rakhshandeh
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 Taiho Pharmaceutical Company, Limited, Synphar Laboratories, Inc., Fathi-Afshar, Rakhshandeh filed Critical Taiho Pharmaceutical Company, Limited
Priority to PCT/JP1990/000521 priority Critical patent/WO1991016311A1/fr
Publication of WO1991016311A1 publication Critical patent/WO1991016311A1/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
    • 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

Definitions

  • the present invention relates to a 7-substituted hydrazino 4-oxo-quinoline-13-carbonic acid derivative, a salt and an ester thereof useful as an antibacterial agent having a broad spectrum.
  • the present inventor has shown that certain 7-substituted hydrazino-4-oxoquinoline-3-carboxylic acid derivatives have high antibacterial activity against both gram-positive and gram-negative bacteria in a broad spectrum. It was found that the present invention was completed.
  • the present invention provides a compound represented by the general formula (I):
  • R ii C i -CA alkyl group, C 3 -C 6 represents an alicyclic hydrocarbon group or a phenyl group which may be substituted with a halogen atom, and X represents CH, CF or N.
  • — Represents a morpholino group or a C ⁇ -C 4 alkyl group.
  • ester residue constituting the ester of the compound of the present invention examples include a C, 1 C 4 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a t-butyl group. Can be exemplified.
  • the salt of the compound of the present invention is a pharmaceutically acceptable acid addition salt and Z or a base salt
  • the base salt is, for example, sodium, potassium, magnesium, calcium or the like.
  • alkaline metals and alkaline earth metals silver, zinc Examples thereof include salts with heavy metals such as lead, cobalt, and cerium.
  • Pharmaceutically acceptable acid addition salts include, for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, lingoic acid, dalconic acid, fumaric acid, succinic acid And salts with inorganic or organic acids such as ascorbic acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • R i above-a C 4 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group; the alkyl group, C 3 - C 6 alicyclic hydrocarbon group, such as cyclopropyl group, cyclobutyl group, C 3, such as cyclopentyl group, cyclohexyl group -
  • C 6 cycloalkyl groups can be mentioned.
  • the halogen atom which may be substituted with a phenyl group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the C 1 -C 4 alkyl group which may be substituted with a 1-piperazinyl group include the above-mentioned alkyl groups.
  • R ⁇ is an ethyl group, a cyclopropyl group, a 4-fluorophenyl group and a 2,4-difluorophenyl group, and
  • physiologically acceptable compounds of the general formula (I) have pharmacological properties which are particularly useful as antibacterial agents.
  • the compounds of general formula (I) of the present invention can be used as active ingredients in medicaments formed with a pharmaceutically acceptable carrier.
  • the compound of the general formula (I) of the present invention is produced, for example, as follows.
  • R i and X are the same as above, and L represents a leaving group such as a chlorine atom or a fluorine atom.
  • L represents a leaving group such as a chlorine atom or a fluorine atom.
  • the compound of the general formula ( ⁇ ) and the compound of the general formula (m) are reacted with or without a solvent until the reaction is completed.
  • the above reaction is preferably performed in the presence of a proton receptor such as pyridine, diazabicycloundecene, N-methylpyrrolidin-12-one, picolin and the like.
  • Solvents that can be used in this reaction include non-reactive solvents, For example, acetonitrile, tetrahydrofuran, ethanol, methanol, black form, methylene chloride, pyridin, picolin, N-methylpyrrolidine 1-2— ON, water, dimethyl sulfoxide, dimethylformamide, and the like. Also, any mixture of these solvents can be used.
  • non-reactive solvents For example, acetonitrile, tetrahydrofuran, ethanol, methanol, black form, methylene chloride, pyridin, picolin, N-methylpyrrolidine 1-2— ON, water, dimethyl sulfoxide, dimethylformamide, and the like.
  • any mixture of these solvents can be used.
  • the reaction conditions are generally about 0 to 150, although the reaction temperature depends on the nature of the leaving group L of the compound of the general formula ( ⁇ ) and the degree of reactivity of the compound ( ⁇ ).
  • the thus-obtained compound represented by the general formula (I) of the present invention can be used in the form of a pharmaceutically acceptable salt, according to a usual salt-forming reaction, esterification reaction and deesterification reaction carried out in the art. Can be converted to ester and free acid forms.
  • the compounds of the present invention may exist in solvated and unsolvated forms such as hydrates.
  • solvated forms such as hydrates, are equivalent to unsolvated forms.
  • the structure of the compound of the present invention was confirmed by a wide range of high magnetic field-nuclear magnetic resonance spectroscopy, source analysis, mass spectrometry, and the like.
  • the compound of the general formula (I) of the present invention is useful as an antibacterial agent to be administered to a patient having a bacterial infection, and can be used in various pharmacological compositions depending on the purpose of treatment.
  • various administration forms containing one or more pharmaceutically effective amounts of the compound of the present invention, a salt thereof, and an ester thereof and various pharmaceutically acceptable carriers can be employed.
  • the administration form may be any of oral preparations such as tablets, capsules, powders, granules, fine granules, solutions, suspensions and the like, and parenteral preparations such as injections, suppositories, ointments and the like.
  • Each dosage form can be manufactured by a conventional formulation method known to those skilled in the art.
  • the excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to the active ingredient of the present invention. Tablets, capsules, powders, granules, fine granules, etc. can be produced by the method.
  • a flavoring agent, a buffer, a stabilizing agent, a flavoring agent, and the like can be added to the active ingredient of the present invention, and then an internal liquid solution, a syrup, etc. can be produced by a conventional method.
  • a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the active ingredient of the present invention, and intravenous, intramuscular, subcutaneous, Intradermal and intraperitoneal injections can be produced.
  • the active ingredient of the present invention may contain a base and, if necessary, an interface. After the addition of the activator and the like, suppositories can be prepared in a conventional manner.
  • Excipients used in the manufacture of solid dosage forms for oral use include, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboquin methylcellulose, glycerin, and alginic acid.
  • Disintegrators include dried starch, agar powder, sodium bicarbonate, calcium carbonate, lactose, etc., and flavoring agents include sucrose, citric acid, tartaric acid, etc. Other coloring agents, flavoring agents, etc. Can be used.
  • the flavoring agents used in the production of oral liquid preparations may be those mentioned above, such as sodium citrate as a buffering agent, and tragacanth as a stabilizer. Arabia, gelatin and the like.
  • pH adjusting agent and the buffer used in the production of an injection examples include sodium citrate, sodium sodium sulfate, sodium phosphate and the like.
  • Stabilizers include sodium pyrosulfate, EDTA, thioglycolic acid, thiomilk Acids and the like.
  • Local anesthetics include proforce hydrochloride, lidocaine hydrochloride and the like. .
  • Bases for producing suppositories include, for example, oily bases such as macrogol, lanolin, cocoa butter, fatty acid triglyceride, and ditbuzonole (hard fat, manufactured by Dynamite Nobel). Agents can be used.
  • the amount of the compound of the present invention to be incorporated in each of the above-mentioned dosage unit forms is not fixed depending on the condition of the patient to which the present invention is to be applied or on the dosage form thereof. ⁇ 500 rag, about 1 ⁇ for injection
  • the daily dose of a drug having the above-mentioned dosage form varies depending on the patient's condition, weight, age, sex, etc., and cannot be determined unconditionally. ⁇ 100 m, preferably 10 ⁇
  • the dose should be about 80 Omg, and it is preferable to administer it in 2 to 4 divided doses.
  • the compounds of the general formula (I) exhibit antibacterial activity against various pathogenic microorganisms, and are useful for treating diseases caused by such microorganisms in humans and animals.
  • TFA trifluoroacetic acid
  • the antimicrobial activity at the mouth of the intestine was determined by the following agar plate two-fold dilution method.
  • 400 mg tablets of 400 m per tablet were prepared in the above mixing ratio by a usual method.

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

Abstract

L'invention se rapporte à un dérivé d'acide 7-(hydrazino substitué)-4-oxoquinoline-3-carboxylique et à des sels et à des esters de ce dérivé, qui est utilisé comme agent antibactérien et qui est représenté par la formule générale (I) où R1 représente un groupe alkyle C1 à C4, un groupe d'hydrocarbure alicyclique C3 à C6, ou un groupe phényle éventuellement substitué par un ou des atomes d'halogène; X représente CH, CF ou N; et $(1,3)$N- représente un groupe morpholino ou un groupe 1-pipérazinyle éventuellement substitué par un ou des groupes alkyle C1 à C4, à condition que le cas où R1 représente un éthyle et X représente CH soit exclu.
PCT/JP1990/000521 1990-04-20 1990-04-20 Derive d'acide 7-(hydrazino substitue)-4-oxoquinoline-3-carboxylique, son sel et son ester WO1991016311A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP1990/000521 WO1991016311A1 (fr) 1990-04-20 1990-04-20 Derive d'acide 7-(hydrazino substitue)-4-oxoquinoline-3-carboxylique, son sel et son ester

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1990/000521 WO1991016311A1 (fr) 1990-04-20 1990-04-20 Derive d'acide 7-(hydrazino substitue)-4-oxoquinoline-3-carboxylique, son sel et son ester

Publications (1)

Publication Number Publication Date
WO1991016311A1 true WO1991016311A1 (fr) 1991-10-31

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WO (1) WO1991016311A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7498341B2 (en) * 2004-01-31 2009-03-03 Sanofi Aventis Deutschland Gmbh Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments
CN110551124A (zh) * 2019-06-14 2019-12-10 山东省联合农药工业有限公司 一种喹诺酮类化合物或其农药学上可接受的盐及其制备方法与用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61277669A (ja) * 1985-05-30 1986-12-08 バイエル・アクチエンゲゼルシヤフト ７−アゾリル−１−シクロプロピル−１，４−ジヒドロ−４−オキソ−３−キノリンカルボン酸及び−１，８−ナフチリジン−３−カルボン酸類
JPH01165584A (ja) * 1987-12-23 1989-06-29 Fujimoto Seiyaku Kk 新規な１，８−ナフチリジン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61277669A (ja) * 1985-05-30 1986-12-08 バイエル・アクチエンゲゼルシヤフト ７−アゾリル−１−シクロプロピル−１，４−ジヒドロ−４−オキソ−３−キノリンカルボン酸及び−１，８−ナフチリジン−３−カルボン酸類
JPH01165584A (ja) * 1987-12-23 1989-06-29 Fujimoto Seiyaku Kk 新規な１，８−ナフチリジン誘導体

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 105, No. 1, refer to the Abstract No. 6425a; & J. HETEROCYCL. CHEM., Vol. 22, No. 4, 1029-32(1985). *
CHEMICAL ABSTRACTS, Vol. 110, No. 19, Refer to the Abstract No. 173064s; & J. HETEROCYCL. CHEM., Vol. 25, No. 5, 1543-6(1988). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7498341B2 (en) * 2004-01-31 2009-03-03 Sanofi Aventis Deutschland Gmbh Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments
CN110551124A (zh) * 2019-06-14 2019-12-10 山东省联合农药工业有限公司 一种喹诺酮类化合物或其农药学上可接受的盐及其制备方法与用途

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