WO2009030106A1 - Dérivés d'acide 7-(4-oximino-3-amino-1-pipéridyl)quinoléinecarboxylique et leurs procédés de préparation - Google Patents

Dérivés d'acide 7-(4-oximino-3-amino-1-pipéridyl)quinoléinecarboxylique et leurs procédés de préparation Download PDF

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Publication number
WO2009030106A1
WO2009030106A1 PCT/CN2008/001526 CN2008001526W WO2009030106A1 WO 2009030106 A1 WO2009030106 A1 WO 2009030106A1 CN 2008001526 W CN2008001526 W CN 2008001526W WO 2009030106 A1 WO2009030106 A1 WO 2009030106A1
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WIPO (PCT)
Prior art keywords
compound
formula
group
acid
amino
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PCT/CN2008/001526
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English (en)
Chinese (zh)
Inventor
Huiyuan Guo
Xiuyun Wang
Jin Jiang
Yucheng Wang
Bingquan Liu
Mingliang Liu
Chunbo Li
Original Assignee
Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences
Beijing Double-Crane Pharmaceutical Co., Ltd
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Application filed by Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences, Beijing Double-Crane Pharmaceutical Co., Ltd filed Critical Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences
Publication of WO2009030106A1 publication Critical patent/WO2009030106A1/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 invention further relates to a process for the preparation of a compound of formula (I), as shown in Scheme 1, wherein a compound of formula (I) can be prepared by reacting a compound of formula ( ⁇ ) with a compound of formula (III) or a salt thereof.
  • Preferred acid acceptors for use in the reaction include inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride and the like, and organic bases such as triethylamine, diisopropylethylamine, pyridine, hydrazine. , ⁇ -dimethylaminopyridine, hydrazine, hydrazine-dimethylaminoaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,4-diaza Double ring [2, 2, 2] Xin (DABCO) and so on.
  • inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride and the like
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, hydrazine. , ⁇ -dimethylaminopyridine, hydrazine, hydrazin
  • a compound of formula (IV) can be hydrolyzed in a solvent in the presence of an organic or inorganic acid or base at a temperature of from 0 to 15 (TC temperature to remove the protecting group to give a compound of formula (I).
  • the acid may be related to a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., an organic acid such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, etc.
  • P represents an amino protecting group.
  • R, R 2 and protecting groups are as described above.
  • 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride is added to an organic base such as triethylamine in a solvent such as ethanol to make the reaction system weakly alkaline, and then a reducing agent such as: Potassium borohydride is subjected to a reduction reaction to obtain (1).
  • an effective amount of the inventive compound contained in each dose is from 0.1 to 1000 mg, and each dose refers to each preparation unit, such as each tablet of a tablet, each capsule , can also refer to each dose, such as taking 100mg each time.
  • Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling wax, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, and capsules represent the most advantageous oral solid formulations.
  • Liquid preparations of the invention include solutions, suspensions and emulsions.
  • injections for parenteral administration The preparation may be in the form of water or a water-propylene glycol solution, adjusted for its isotonicity, pH, etc. to suit physiological conditions of the living body.
  • Liquid preparations can also be prepared in the form of solutions in polyethylene glycol, aqueous solutions.
  • the preparation of an aqueous suspension suitable for oral administration can be prepared by dissolving the active ingredient in water by adding an appropriate amount of a coloring agent, a flavoring agent, a stabilizer and a thickening agent to prepare cellulose, sodium carboxymethylcellulose and other known suspending agents. .
  • the active compound of the formula (I) of the present invention When used as a medicament for treating a bacterial infection, it is preferred to give an amount of 6 to 14 mg/kg of body weight in the first stage.
  • the dosage administered may vary depending on the needs of the patient, the severity of the infection to be treated, the selected compound, and the like.
  • the preferred dosage for a particular situation can be determined in a conventional manner. Generally, the amount of treatment initiated is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For convenience, the total daily dose can be divided into several parts, administered in divided doses.
  • MH agar medium is dissolved and quantitatively injected into the liquid-containing plate to mix, the final concentration of the drug is 0.03, 0.06, 0.125...128 ? g /ml, after the medium in the plate was solidified, the experimental bacteria (105 cfU / dot) were inoculated with a multi-point inoculator, and the result was observed after incubation at 35 ° C for 18 hours, and the minimum concentration of the drug contained in the aseptically grown plate was the lowest. Inhibitory concentration (MIC).
  • Table 1 lists the in vitro antibacterial activity of four representative compounds of the compounds of formula (I) of the present application against various Gram-positive strains, and the two new quinolone antibacterial drugs gemifloxacin and balofloxacin And a representative compound of two structural similarities in CN1850823A was compared.
  • Table 1 It can be seen that the in vitro activity of the compound of the formula (I) of the present invention against these Gram-positive bacteria is 2-32 times that of the newly approved quinolone antibacterial drugs gemifloxacin and balofloxacin in recent years, and is similar to the two structures in CN1850823A. Representative compounds are 8-128 times.
  • the compounds of formula (I) of the present invention also exhibit much better activity than gemifloxacin and balofloxacin for clinically increasing MRSA and MRSE.
  • Table 2 shows the solubility in water of Representative Example 17 selected from the compounds of formula (I) of the present invention, and is compared with the recently approved quinolone drug, balofloxacin.
  • the compound of the present invention has a water solubility of 6 times that of balofloxacin. Therefore, they can be used not only as an oral preparation but also as an injection for the treatment of infectious diseases.
  • mice were subjected to acute toxicity experiments, and solutions containing various concentrations of the compounds of Examples 18 and 19 were orally administered to male mice at a dose of 0.1 ml/10 g body weight. After 7 ⁇ , the number of dead rats was counted separately, and the half lethal dose (LD 5Q ) of each compound was calculated by Bliss program. The results are shown in Table 3. Table 3 Acute oral toxicity of experimental compounds in mice
  • the configuration of the molecule exists in the Z-type or E-type.
  • the single-phase X-ray diffraction analysis of the 7-position side chain compound indicates that the present invention
  • the 7-(4-indolyl-3-amino-1-piperidinyl)quinolone compound exists in the E configuration.
  • the following is a single crystal X-ray diffraction analysis data of the compound of Example 10.
  • the sample crystal is colorless and transparent column.
  • Diffraction intensity data collected with MAC DIP-2030K surface detector, ⁇ radiation, graphite monochromator, collimation tube Crystal and IP board distance is 100mm, tube pressure is 50kV, tube flow is 80mA, ⁇ scan, maximum 2 ⁇ angle is 50.0°, scanning range is 0-180°, swing angle is 6°, interval is 6°, scanning speed is 0.9 . /min, each screen is scanned once, and a total of 30 images are taken.
  • the independent diffraction points are 3649, and the observable points (
  • Figure 1 shows the relative configuration of the single molecule of the compound
  • Figure 2 shows the bimolecular overlay
  • Figure 3 shows the ellipsoid of the A and B molecules
  • Figure 4 shows the unit cell stack along the a-axis.
  • Table 4 shows the atomic coordinates and the equivalent temperature factor.
  • Table 5 shows the bond length and bond angle between the bonding atoms.
  • Figure 1 is a single molecule (A) relative configuration diagram of the compound of Example 10 of the present application.
  • Figure 2 is a bimolecular (A, B) superimposed pattern of the compound of Example 10 of the present application;
  • Figure 3a is a molecular ellipsoid diagram of the compound of Example 10 of the present application.
  • Figure 3b is a B molecule ellipsoid of the compound of Example 10 of the present application.
  • Fig. 4 is a view showing the cell packing of the molecule of the compound of Example 10 in the a-axis direction.
  • Triethylamine (1.4 ml) was added dropwise to a solution of ethyl 1-benzyl-4-oxo-piperidine-3-carboxylate (6.0 g, 20 mmol) and 95% ethanol (20 ml). Then, potassium borohydride (1.7 g, 27 mmol) was added in portions, and the mixture was poured, evaporated, evaporated, evaporated, evaporated.
  • Example 3 The compound (7.0 g, 34.0 mmol) was dissolved in water (15 ml), pH was adjusted to about 8.5 with sodium hydroxide, dioxane (20 ml) was added, and di-tert-butyl pyrocarbonate (BOC 2 ) was added in portions. 0) (19.0g), maintain pH at about 8.5, react at 60 °C for 1h, concentrate under reduced pressure, add water (30ml), dichloromethane (3 X 20ml), dry over anhydrous magnesium sulfate, filter, steam under vacuum The solvent was removed to give 8.6 g of product as colorless oil.
  • Example 5 The compound of Example 5 (5.2 g, 24 mmol) was dissolved in water (15 ml), pH was adjusted to about 8.5 with sodium hydroxide, dioxane (20 ml) was added, and BOC 2 0 (7.0 g) was added in portions to maintain the pH. 8.5 or so, react at 60 ° C for 1 h, concentrate under reduced pressure, add water (40 ml), dichloromethane (3 x 20 ml), extract, dry over anhydrous magnesium sulfate, filtered, concentrated, then petroleum ether, 6.5 g of white solid product The rate is 85.5%, mp: 113 ⁇ 116 °C.
  • Example 7 The compound of Example 7 (0.5 g, 1.59 mmol) and methoxylamine hydrochloride (0.4 g, 4.78 mmol) were reacted in pyridine at 70 ° C for 3 h, and the solvent was evaporated. 1M hydrochloric acid, saturated NaHC0 3 solution and water, the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to give the crude product, the VLC method (ethyl acetate and petroleum ether gradient) to give 0.53 g of product as a white solid, The yield was 97%. Mp: 114 ⁇ 116 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (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 des dérivés d'acide 7-(4-oximino-3-amino-1-pipéridyle)quinoléinecarboxylique, leurs procédés de préparation, leurs utilisations pharmaceutiques et des agents antibactériens et additifs alimentaires comprenant lesdits composés. Plus précisément, l'invention concerne de nouveaux dérivés d'acide fluoroquinolone formique, dans lesquels la position 7 est 4-oximino-3-amino-1-pipéridyle, la position 8 métoxyle et la position 1 cyclopropyle. Comparés avec les médicaments antibactériens fluoroquinolone classiques, les composés selon l'invention présentent une excellente activité de résistance aux bactéries gram-pos et activité antibactérienne à large spectre.
PCT/CN2008/001526 2007-09-03 2008-08-25 Dérivés d'acide 7-(4-oximino-3-amino-1-pipéridyl)quinoléinecarboxylique et leurs procédés de préparation WO2009030106A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710145608.3 2007-09-03
CNB2007101456083A CN100497331C (zh) 2007-09-03 2007-09-03 7-(4-肟基-3-氨基-1-哌啶基)喹啉羧酸衍生物及其制备方法

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WO2009030106A1 true WO2009030106A1 (fr) 2009-03-12

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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100497331C (zh) * 2007-09-03 2009-06-10 北京双鹤药业股份有限公司 7-(4-肟基-3-氨基-1-哌啶基)喹啉羧酸衍生物及其制备方法
CN101812052B (zh) * 2010-03-18 2012-10-03 中国医学科学院医药生物技术研究所 含有靛红取代的喹啉羧酸衍生物及其制备方法
CN101863876B (zh) * 2010-04-23 2012-12-12 中国医学科学院医药生物技术研究所 有7-(3-氨基-4-肟基)-1-哌啶基取代基的氟喹诺酮及其组合物的应用
CN101974578B (zh) * 2010-10-21 2014-06-11 杭州师范大学 一种复合酶催化水解制备喹诺酮类羧酸中间体的方法
CN103086955B (zh) * 2013-02-19 2014-10-15 中国医学科学院医药生物技术研究所 3-氨基-4-烷氧亚胺基哌啶的制备方法
CN103467448B (zh) * 2013-09-18 2015-04-15 浙江司太立制药股份有限公司 7-(3-氨基-4-烷氧亚胺基-1-哌啶基)-1-[(1r,2s)-2-氟环丙基]喹诺酮羧酸类化合物及其制备方法
CN103739591B (zh) * 2014-01-02 2015-07-15 浙江司太立制药股份有限公司 7-(3-酰胺基-4-甲肟基-1-哌啶基)氟喹诺酮羧酸及其制备方法

Citations (4)

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CN1114959A (zh) * 1994-06-16 1996-01-17 Lg化学株式会社 有7-(4-氨基甲基-3-肟)吡咯烷取代基的新喹啉羧酸衍生物和其制法
CN1850823A (zh) * 2006-05-19 2006-10-25 中国科学院上海药物研究所 一类含有肟基的喹诺酮类化合物及其制备方法和用途
CN101070322A (zh) * 2007-03-26 2007-11-14 中国医学科学院医药生物技术研究所 7－(4－肟基－3－氨基－1－哌啶基)新喹啉羧酸衍生物及其制备方法和医药用途
CN101117336A (zh) * 2007-09-03 2008-02-06 中国医学科学院医药生物技术研究所 7-(4-肟基-3-氨基-1-哌啶基)喹啉羧酸衍生物及其制备方法

Patent Citations (4)

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CN1114959A (zh) * 1994-06-16 1996-01-17 Lg化学株式会社 有7-(4-氨基甲基-3-肟)吡咯烷取代基的新喹啉羧酸衍生物和其制法
CN1850823A (zh) * 2006-05-19 2006-10-25 中国科学院上海药物研究所 一类含有肟基的喹诺酮类化合物及其制备方法和用途
CN101070322A (zh) * 2007-03-26 2007-11-14 中国医学科学院医药生物技术研究所 7－(4－肟基－3－氨基－1－哌啶基)新喹啉羧酸衍生物及其制备方法和医药用途
CN101117336A (zh) * 2007-09-03 2008-02-06 中国医学科学院医药生物技术研究所 7-(4-肟基-3-氨基-1-哌啶基)喹啉羧酸衍生物及其制备方法

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