WO2003076428A1 - Derive d'acide quinolone-carboxylique - Google Patents

Derive d'acide quinolone-carboxylique Download PDF

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Publication number
WO2003076428A1
WO2003076428A1 PCT/JP2002/002181 JP0202181W WO03076428A1 WO 2003076428 A1 WO2003076428 A1 WO 2003076428A1 JP 0202181 W JP0202181 W JP 0202181W WO 03076428 A1 WO03076428 A1 WO 03076428A1
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Prior art keywords
compound
formula
water
fluoro
methoxy
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PCT/JP2002/002181
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English (en)
Japanese (ja)
Inventor
Sadahiro Shimizu
Yuichiro Tani
Toshifumi Akiba
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Daiichi Pharmaceutical Co., Ltd.
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Publication date
Application filed by Daiichi Pharmaceutical Co., Ltd. filed Critical Daiichi Pharmaceutical Co., Ltd.
Priority to AU2002236267A priority Critical patent/AU2002236267A1/en
Priority to JP2003574645A priority patent/JPWO2003076428A1/ja
Priority to PCT/JP2002/002181 priority patent/WO2003076428A1/fr
Publication of WO2003076428A1 publication Critical patent/WO2003076428A1/fr

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    • 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
    • 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 method for producing an optically active quinolone carboxylic acid derivative having high antibacterial activity and safety and good stability, and an intermediate for producing the same.
  • Quinolone carboxy derivatives are known as synthetic antibacterial agents.
  • compounds of the following general formula (I) having a 1,2-cis-12-halogenocyclopropyl group at the 1-position nitrogen atom of the quinoline skeleton are highly potent antibacterial agents. It is known to be useful as a pharmaceutical because of its high activity and high safety (Patent Nos. 271,595 and 297)
  • R 1 represents an amino group, a methylamino group, a hydroxyl group, a thiol group or a hydrogen atom
  • R 2 is a substituent selected from the following group
  • R 3 , R 4 , R 5 and R s each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R le and R 11 independently represent a hydrogen atom or 1 carbon atom.
  • taste alkyl group of ⁇ 6, R 12 and R 13 means the independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • a 3-hydroxypiperidinyl group which may have an alkyl group having 1 to 6 carbon atoms.
  • A means the CX 3 or nitrogen atom.
  • X 1 and X 2 each independently represent a halogen atom;
  • X 3 represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group or a hydrogen atom I do.
  • Z is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, a phenylalkyl group having 1 to 6 carbon atoms, a phenyl group, an acetomethyl group, and a bivaloyloxymethyl group.
  • Fluoroquinolones are evolving into chemotherapeutic drugs that are effective against almost systemic infections. Under such circumstances, there is a need for a compound having higher antibacterial activity and safety, and also having excellent stability to light and humidity. Disclosure of the invention
  • Compound (A) is a free compound having the structure of the following formula (A). ]
  • the monohydrochloride monohydrate is significantly more effective than other acid addition salts in terms of not only antibacterial activity and safety but also stability against light and humidity. It was found to be excellent and useful as an antibacterial agent, and a patent application was filed earlier (Japanese Patent Application No. 2000-097690).
  • the hydrochloride of compound (A) includes 'monohydrochloride' pentahydrate in addition to monohydrochloride ⁇ monohydrate, and these two hydrates By properly adjusting the conditions during the crystal production, they found that they could be selectively produced, and completed the present invention.
  • compound (1) is the monohydrochloride ⁇ 2.5 hydrate of compound ( ⁇ ). ].
  • the present invention is characterized in that the compound having the structure represented by the formula ( ⁇ ) is treated in a water-containing solvent whose water content is adjusted in the presence of hydrochloric acid, if desired, or recrystallized from the water-containing solvent.
  • (1) 1 7 — [(7S) 1—7—amino—5—azapi mouth [2. 4] Heptane—5—yl] 1—6—Fluoro; 1 [(1 R, 2 S) 1 2 —Fluoro-1-cyclopropyl] — 1,4-dihydro-8-methoxy-4-oxo—3-quinolinecarboxylic acid ⁇ monohydrochloride ⁇ monohydrate [Hereinafter, Compound (2).
  • Compound (2) is the monohydrochloride monohydrate of compound (II). Or a method for producing compound (1). Further, the present invention provides a method for treating a compound having a structure represented by the formula (A) in a water-containing solvent having a water content of 1 to 5% in the presence of hydrochloric acid, if necessary, or recrystallizing from the water-containing solvent. And a process for producing the compound (2).
  • the present invention provides that a compound having a structure represented by the formula (A) is treated in a water-containing solvent having a water content of 20 to 40% in the presence of hydrochloric acid, if necessary, or recrystallized from the water-containing solvent. And a process for producing the compound (1) characterized by the following. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a view showing a powder X-ray diffraction spectrum of the compound (1).
  • FIG. 2 is a view showing an infrared absorption spectrum of the compound (1).
  • FIG. 3 is a graph showing a change in weight of the compound (1) under the condition of 5 to 95% RH.
  • FIG. 4 is a view showing a powder X-ray diffraction spectrum of the compound (2).
  • FIG. 5 is a diagram showing an infrared absorption spectrum of the compound (2).
  • the compound (1) and the compound (2) of the present invention can be produced, for example, according to the following reaction formula.
  • the compound (3) is reacted with the compound (4) to obtain a compound (A), which is then treated in a water-containing solvent having a controlled water content in the presence of hydrochloric acid if desired, or Compound (1) or compound by recrystallization from aqueous solvent
  • the compound (1) and the compound (2) can be selectively converted to each other by treating in a water-containing solvent having a controlled water content.
  • the starting compounds (3) and (4) can both be obtained by the method described in Japanese Patent No. 2714597.
  • the reaction between compound (3) and compound (4) can be carried out with or without a solvent.
  • the solvent that can be used in the reaction is not particularly limited as long as it is inert to the reaction.
  • Such solvents include, for example, sulfoxides such as dimethyl sulfoxide, nitrogen-containing heterocyclic compounds such as pyridine, nitriles such as acetonitrile, alcohols such as ethanol, halogenated hydrocarbons such as chloroform, dimethylformamide, and the like.
  • Amines such as dimethylacetamide and N-methylpyrrolidone
  • ethers such as tetrahydrofuran, water, 3-methoxybutanol and the like, and these may be used as a mixture.
  • the reaction is preferably performed in the presence of an acid acceptor such as an inorganic base or an organic base.
  • the base may be any of an inorganic base and an organic base.
  • the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and hydrogen hydrogen carbonate. Hydroxides, carbonates, hydrogencarbonates and the like of alkali metals such as potassium.
  • organic base examples include trialkylamines such as triethylamine, tripropylamine, triptylamine, N, N-diisopropylethylamine, dialkylanilines such as getylaniline and dimethylaniline, N-methylmorpholine, Pyridine, N, N-dimethylaminopyridine and the like can be exemplified.
  • the reaction can be carried out usually at room temperature to 100 ° C., and preferably at room temperature to about 40 ° C.
  • the reaction time may be in the range of 30 minutes to 48 hours, and usually ends in about 30 minutes to 20 hours.
  • the product is dissolved in aqueous ethanol, triethylamine is added, and the mixture is heated under reflux for several hours.
  • the hydrous ethanol may be replaced with another protic solvent, for example, hydrous isopropanol, which is a protonic solvent which can be mixed with water, and which can dissolve compound (4) at least when heated. Is preferred. Also, it is not necessary to add triethylamine.
  • the present inventors investigated the stability of the crystals of the compounds (1) and (2) in an aqueous solvent. I examined it.
  • the study method is as follows.
  • 40% aqueous 2-propanol is a mixture of 6 volumes of 2-propanol and 4 volumes of water.
  • the treatment was performed for 1 to 3 days. However, it was also revealed that one to three days are not necessarily required for crystal conversion, and that the conversion may actually be completed within one day.
  • the treatment was performed at 0 ° C to 70 ° C.
  • the compound (1) should be treated in a solvent having a water content of 20% to 40% in order to obtain a single compound. Also, the compound
  • treat means that a mixture of crystals and a solvent in a slurry state is stirred at a selected temperature for a certain period of time.
  • the crystals may be dissolved and then crystallized to form a slurry state, or the solvent and the crystals may be simply mixed.
  • the raw materials used in this treatment may be any as long as they have the structure represented by the formula (A).
  • an unpurified product (so-called crude crystal) immediately after producing the compound represented by the formula (A), and a free form of the compound having the structure represented by the formula (A) (compound (A))
  • It may be a hydrate, a hydrochloride, a hydrate of a salt, or a crystal of the formula (1) or the formula (2) itself. These may be in the form of crystals or simply solids.
  • the acid is weaker than hydrochloric acid, the acid exchange is considered to occur in the solution, so that an acid addition salt other than the hydrochloride may be used.
  • hydrochloric acid need not be added.
  • the solvent that can be used in the method of the present invention is not particularly limited as long as it is a solvent that dissolves crystals and is miscible with water.
  • examples include lower alcohols such as methanol, ethanol, and propanols. Can be. Of these, 2-propanol is most preferred.
  • the condition in which only the compound (1) or the compound (2) is present in the slurry state is the condition for crystallization
  • the water content of the compound (A) was adjusted in the presence of hydrochloric acid if desired.
  • the conditions for crystallization refer to the conditions for dissolving the crude crystal in a solvent, followed by a treatment such as activated carbon treatment or concentration, as necessary, to crystallize the crystal.
  • compound (A) is mixed with water-containing 2-propanol adjusted to the above-mentioned water content, hydrochloric acid is added and dissolved by heating, and if necessary, treatment such as activated carbon treatment or concentration is performed to crystallize the crystal. After precipitation, a single crystal consisting of only compound (1) or compound (2) can be selectively produced by filtration.
  • the hydrochloric acid may be a hydrochloric acid gas or a hydrochloric acid aqueous solution.
  • the amount of hydrochloric acid used may be at least one equivalent to compound (A).
  • Compounds (1) and (2) obtained as described above are compounds 9a, 9b, 13b, 18a, 18b, 26bb, 26aa, 26ba described in Japanese Patent No. 2917010. , 26 ab, 31 a, 31 b, 34 b, 54 b, 56 b, 52 bb and 85 bb have excellent antibacterial activity and are useful as antibacterial agents. Of these, compound (2) is preferable to compound (1) in terms of stability against light and humidity.
  • Compound (2) shows characteristic peaks near 6.9, 10.9, 14.4, 23.1, 26.9 and 27.8 (°) as diffraction angle (20) by powder X-ray diffraction.
  • compound (1) shows a characteristic peak near 5.4 (°) as the diffraction angle (20) by powder X-ray diffraction, while it is crystalline.
  • Compound (2) does not absorb or desorb moisture under the humidity condition of 5 to 95% RH, and has good stability to humidity.
  • OmL (1 32 Ommo 1) were dissolved in anhydrous 50 mL of tetrahydrofuran, and then prepared under ice-cooling in this solution.
  • a solution of the obtained acid chloride in 50 mL of anhydrous tetrahydrofuran was added dropwise. After completion of the dropwise addition, the reaction suspension was heated to reflux for 5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, 150 OmL of water and 150 OmL of dichloromethane were added to the residue, and the mixture was stirred.
  • the dichloromethane layer was separated, and the aqueous layer was extracted with 100 OmL of dichloromethane.
  • the combined dichloromethane layer was washed with 150 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel chromatography.
  • the crystals were washed with an excess of purified water, a small amount of cold ethanol, and an excess of ethyl ether in that order, and dried under reduced pressure at 70 to obtain 213.4 g (81.8%) of the title compound as a white powder.
  • the moisture absorption and desorption behavior of compound (1) was measured using a water adsorption analyzer (mode 1 SGA-100, manufactured by VTI) using about 10 mg of the sample.
  • the measurement temperature was 25 ° C, and the relative humidity was changed in the range of 5 to 95% by 5% or 10%.
  • the equilibrium condition was that the weight change within 30 minutes was within 0.03%, and the maximum equilibrium time was 180 minutes, and the weight change of the sample under each relative humidity was measured.
  • FIG. 3 it can be seen that compound (1) does not absorb and desorb at 40% RH or less, and exists as a pentahydrate in this range.
  • compound (1) When the solubility of compound (1) in water was examined, compound (1) showed a high solubility of 47.1 rag / mL or more in water.
  • Fig. 4 shows the powder X-ray diffraction results of compound (2) (using X'pert powder X-ray diffractometer manufactured by Ph 1 ips), and the IR spectrum (using FT-IR, FT-720 manufactured by Horiba) Is shown in FIG.
  • the thermal analysis of compound (2) showed that the weight loss was 4.2% by weight, which almost coincided with the theoretical value as a monohydrate (3.9%).
  • the water content was determined by Karl Fischer's method to be 4.11%, which was consistent with the result of thermal analysis.
  • compounds (2) and (1) which have excellent antibacterial activity and safety, and also have excellent stability against light and humidity, are useful as antibacterial agents.

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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

L'invention concerne un dérivé d'acide quinolone-carboxylique, le monochlorhydrate 2.5-hydraté d'acide (-)-7-[(7S)-Amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4dihydro-8-méthoxy-4-oxo-3-quinoléine-carboxylique, représenté par la formule générale (1) ; ainsi qu'un procédé servant à la production du monohydrate de monochlorhydrate de ce composé. Ce procédé permet d'obtenir un composé stable présentant une excellente activité antibactérienne et une excellente stabilité à la lumière et à l'humidité, et offrant une excellente protection antibactérienne. Ce composé peut être utilisé comme agent antibactérien.
PCT/JP2002/002181 2002-03-08 2002-03-08 Derive d'acide quinolone-carboxylique WO2003076428A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2002236267A AU2002236267A1 (en) 2002-03-08 2002-03-08 Quinolonecarboxylic acid derivative
JP2003574645A JPWO2003076428A1 (ja) 2002-03-08 2002-03-08 キノロンカルボン酸誘導体
PCT/JP2002/002181 WO2003076428A1 (fr) 2002-03-08 2002-03-08 Derive d'acide quinolone-carboxylique

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1757598A1 (fr) * 2004-05-13 2007-02-28 Daiichi Pharmaceutical Co., Ltd. Dérivé de pyrrolidine substituée
US8003666B2 (en) * 2006-03-27 2011-08-23 Daiichi Sankyo Company, Limited Hydrate for medical purposes
WO2012018105A1 (fr) * 2010-08-06 2012-02-09 第一三共株式会社 Cristal de composé antibactérien
WO2013069297A1 (fr) * 2011-11-10 2013-05-16 杏林製薬株式会社 Cristal de l'acide 7-{(3s,4s)-3-[(cyclopropylamino)méthyl]-4- fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroéthyl)-8-méthoxy-4-oxo-1,4- dihydroquinoléine-3-carboxylique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058876A1 (fr) * 2000-02-09 2001-08-16 Daiichi Pharmaceutical Co., Ltd. Agents antibacteriens acidoresistants renfermant des acides pyridonecarboxyliques comme principe actif
WO2001072738A1 (fr) * 2000-03-31 2001-10-04 Daiichi Pharmaceutical Co., Ltd. Derive d'acide quinolone-carboxylique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058876A1 (fr) * 2000-02-09 2001-08-16 Daiichi Pharmaceutical Co., Ltd. Agents antibacteriens acidoresistants renfermant des acides pyridonecarboxyliques comme principe actif
WO2001072738A1 (fr) * 2000-03-31 2001-10-04 Daiichi Pharmaceutical Co., Ltd. Derive d'acide quinolone-carboxylique

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1757598A4 (fr) * 2004-05-13 2010-07-21 Daiichi Seiyaku Co Dérivé de pyrrolidine substituée
US7977327B2 (en) 2004-05-13 2011-07-12 Daiichi Sankyo Company, Limited Substituted pyrrolidine derivative
EP1757598A1 (fr) * 2004-05-13 2007-02-28 Daiichi Pharmaceutical Co., Ltd. Dérivé de pyrrolidine substituée
US8455482B2 (en) 2004-05-13 2013-06-04 Daiichi Sankyo Company, Limited Substituted pyrrolidine derivative
US8003666B2 (en) * 2006-03-27 2011-08-23 Daiichi Sankyo Company, Limited Hydrate for medical purposes
US8674107B2 (en) 2010-08-06 2014-03-18 Daiichi Sankyo Company, Limited Crystal of anti-bacterial compound
WO2012018105A1 (fr) * 2010-08-06 2012-02-09 第一三共株式会社 Cristal de composé antibactérien
US20140288310A1 (en) * 2011-11-10 2014-09-25 Kyorin Pharmaceutical Co., Ltd 7--6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
WO2013069297A1 (fr) * 2011-11-10 2013-05-16 杏林製薬株式会社 Cristal de l'acide 7-{(3s,4s)-3-[(cyclopropylamino)méthyl]-4- fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroéthyl)-8-méthoxy-4-oxo-1,4- dihydroquinoléine-3-carboxylique
JPWO2013069297A1 (ja) * 2011-11-10 2015-04-02 杏林製薬株式会社 ７−｛（３ｓ、４ｓ）−３−［（シクロプロピルアミノ）メチル］−４−フルオロピロリジン−１−イル｝−６−フルオロ−１−（２−フルオロエチル）−８−メトキシ−４−オキソ−１、４−ジヒドロキノリン−３−カルボン酸の結晶
US9090587B2 (en) * 2011-11-10 2015-07-28 Kyorin Pharmaceutical Co., Ltd. 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluorodethyl)-acid crystal
CN104945375A (zh) * 2011-11-10 2015-09-30 杏林制药株式会社 7-{(3s,4s)-3-[(环丙基氨基)甲基]-4-氟吡咯烷-1-基}-6-氟-1-(2-氟乙基)-8-甲氧基-4-氧-1,4-二氢喹啉-3-羧酸晶体
US20150284361A1 (en) * 2011-11-10 2015-10-08 Kyorin Pharmaceutical Co., Ltd. 7--6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
JP2016027045A (ja) * 2011-11-10 2016-02-18 杏林製薬株式会社 ７−｛（３ｓ、４ｓ）−３−［（シクロプロピルアミノ）メチル］−４−フルオロピロリジン−１−イル｝−６−フルオロ−１−（２−フルオロエチル）−８−メトキシ−４−オキソ−１、４−ジヒドロキノリン−３−カルボン酸の結晶
US9328089B2 (en) 2011-11-10 2016-05-03 Kyorin Pharmaceutical Co., Ltd. 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-YL}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
JP2017160243A (ja) * 2011-11-10 2017-09-14 杏林製薬株式会社 ７−｛（３ｓ、４ｓ）−３−［（シクロプロピルアミノ）メチル］−４−フルオロピロリジン−１−イル｝−６−フルオロ−１−（２−フルオロエチル）−８−メトキシ−４−オキソ−１、４−ジヒドロキノリン−３−カルボン酸の結晶
USRE47785E1 (en) 2011-11-10 2019-12-31 Kyorin Pharmaceutical Co., Ltd. 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal

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