WO2002092605A1 - Cristal d'hydrate de compose de $g(b)-lactame - Google Patents

Cristal d'hydrate de compose de $g(b)-lactame Download PDF

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Publication number
WO2002092605A1
WO2002092605A1 PCT/JP2002/004595 JP0204595W WO02092605A1 WO 2002092605 A1 WO2002092605 A1 WO 2002092605A1 JP 0204595 W JP0204595 W JP 0204595W WO 02092605 A1 WO02092605 A1 WO 02092605A1
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WO
WIPO (PCT)
Prior art keywords
hydrate
aqueous solution
crystal
crystals
salt
Prior art date
Application number
PCT/JP2002/004595
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English (en)
Japanese (ja)
Inventor
Akihiro Shimabayashi
Shigetoshi Yaguchi
Original Assignee
Otsuka Chemical Co., Ltd.
Taiho Pharmaceutical Co., Ltd.
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 Otsuka Chemical Co., Ltd., Taiho Pharmaceutical Co., Ltd. filed Critical Otsuka Chemical Co., Ltd.
Publication of WO2002092605A1 publication Critical patent/WO2002092605A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to hydrate crystals of i9-lactam compounds.
  • zobactam has very weak antibacterial activity by itself and is not used as an antibacterial agent by itself. However, it binds irreversibly to various types of bacteria produced by] 3-lactamase, and j8-lactamase. Has the effect of inhibiting the activity of For this reason, it can be used in combination with various existing antibacterial agents inactivated by ⁇ -lactamase, and can exert the original antibacterial action of the various antibacterial agents on 3-lactamase producing bacteria.
  • R represents a benzyl group having an electron-donating group as a substituent on the phenyl ring, a diphenylmethyl group or a tert-butyl group which may have an electron-donating group on the phenyl ring.
  • zopactam is a poorly water-soluble compound, and has the property of becoming water-soluble when converted to a salt form. Utilizing this property, Zobactam is isolated and purified.
  • a basic compound, water and a hydrophobic organic solvent are added to a reaction mixture containing tazopactam to be formed, and the zobactam is converted into a salt form, extracted into an aqueous layer, and then extracted with water.
  • the desired zopactam is crystallized by making the layer acidic.
  • the tazobactam crystals obtained by the method described in the above patent publication have poor stability, and have a problem that when stored at room temperature for a long period of time, they are decomposed and their purity is reduced.
  • evening zobactam produced by the above method is stored in a refrigerator and other measures are taken to avoid a decrease in purity.
  • An object of the present invention is to provide a tazopactam crystal having excellent storage stability.
  • the present inventor has made intensive studies to achieve the above object.
  • the ratio of the organic solvent contained in the aqueous solution was adjusted to a specific level or less, and the pH of the aqueous solution was maintained while maintaining the liquid temperature of the aqueous solution at a specific temperature or lower. It has been found that by adjusting the value to a specific value or less, a tazobactam hydrate crystal having excellent storage stability can be obtained.
  • the present invention has been completed based on such knowledge.
  • equation (1) (1)
  • a hydrate crystal of a lactam compound is provided.
  • the hydrate crystal of the 3-lactam compound represented by the formula (1) of the present invention] is composed of S, S-dioxide of 2-methyl-12-triazolylmethylpentanum-13-carboxylic acid, Further, it is a crystal having crystallization water.
  • the hydrate crystal has a peak at the next lattice plane spacing, and the relative intensity of the peak is as follows. Those having a diffraction spectrum are preferred.
  • the measurement of the X-ray diffraction spectrum was performed using an X-ray diffraction spectrometer (RINT 2000 ZPC (trade name) manufactured by Rigaku Corporation).
  • RINT 2000 ZPC trade name
  • the method for producing the hydrate crystal of the 3-lactam compound represented by the formula (1) (hydrate crystal of tazopactam) of the present invention will be described below.
  • the hydrate crystals of tazobactam of the present invention are prepared, for example, by adjusting the content of an organic solvent in an aqueous solution containing zopactam salt to 0.1% by weight or less, cooling the aqueous solution, and then adding an acid to the aqueous solution. It is produced by crystallization of zozobactam crystals.
  • An aqueous solution containing a tazopactam salt is prepared by reacting a 3-lactam compound represented by the formula (2) with cresol according to the method described in, for example, Japanese Patent No. 2,648,750. Then, a hydrophobic organic solvent such as methyl isobutyl ketone is added to the reaction mixture containing tazopactam, the mixture is cooled to 0 to 5 ° C, and a basic compound such as sodium hydrogen carbonate and water are added and mixed. It can be easily prepared by separating the aqueous layer.
  • a hydrophobic organic solvent such as methyl isobutyl ketone
  • an aqueous solution containing a tazopactam salt is prepared by treating an evening zobactam produced according to the specification of Japanese Patent No. 2648750 with a basic conjugate to give an evening zopactam salt. It may be prepared by dissolving in water.
  • alkali metal bicarbonates such as sodium hydrogencarbonate and potassium bicarbonate
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • carbonate examples thereof include alkaline earth metal carbonates such as calcium.
  • alkali metal bicarbonates such as sodium bicarbonate are preferred.
  • One of these basic compounds can be used alone, or two or more can be used in combination.
  • the evening zopactam salt of the present invention includes alkali metal salts such as sodium and potassium salts of tazopactam and earth metal salts such as calcium salts.
  • the concentration of the tazobactam salt contained in the aqueous solution is not limited, and can be appropriately selected from a wide range.
  • the concentration of zobactam salt in aqueous solution Considering the crystallization efficiency and workability of the target hydrate, it is usually 1 to 50% by weight, preferably 5 to 20% by weight.
  • This organic solvent includes both a hydrophobic organic solvent used in preparing the above aqueous solution and cresol, which is a raw material for producing zobactam.
  • the aqueous solution containing zobactam salt may be treated with an adsorbent.
  • adsorbent known ones can be widely used, and examples thereof include a synthetic resin adsorbent and activated carbon.
  • Examples of the synthetic resin adsorbent include a crosslinked polymer composed of styrene and divinylbenzene, and a crosslinked polymer composed of methacrylic acid ester and ethylene glycol dimethacrylate.
  • Commercially available synthetic resin adsorbents used in the present invention include, for example, Amberlite XAD (trade name, manufactured by Rohm & Haas), Diaion HP (trade name, manufactured by Mitsubishi Chemical Corporation), and the like. .
  • Specific examples of the method of treating an aqueous solution containing tazopactam salt with an adsorbent include, for example, a method in which an adsorbent is packed in a column or the like, and an aqueous solution of tazobactam salt is passed once or twice or more. Examples thereof include a method of adding an adsorbent to an aqueous solution of salt and mixing the adsorbent.
  • the amount of the adsorbent used can be appropriately selected according to the amount of the aqueous solution of the tazopactam salt to be treated. This process is usually performed at a temperature of 20 to 30.
  • an acid is added to the aqueous solution while cooling the aqueous solution in which the organic solvent content is adjusted to usually 0.1% by weight or less, preferably 0.08% by weight or less. Precipitate hydrate crystals.
  • the cooling temperature of the aqueous solution of zopactam salt is usually 10 ° C. or lower, preferably 0 to 5 t. If the temperature of the aqueous solution of tazopactam salt is higher than the specified temperature, then the pH was adjusted to 3 or less by adding an acid to the aqueous solution. However, the desired hydrate crystals of zopactam cannot be precipitated.
  • the pH value of the aqueous solution containing zobactam salt is maintained at 3 or less.
  • the pH of the aqueous solution is adjusted to preferably about 0.5 to 1.5, more preferably about 0.6 to 1. Is good.
  • Examples of the acid used include inorganic acids such as nitric acid, hydrochloric acid, and sulfuric acid, and organic acids such as trifluoroacetic acid. Of these, inorganic acids are preferred, and hydrochloric acid is most preferred. These acids can be used alone or in combination of two or more.
  • the evening zopactam hydrate crystals of the present invention have excellent storage stability, and do not substantially decompose even when stored at room temperature for a long period of time.
  • the tazobactam hydrate crystal of the present invention has an excellent property that the antibacterial agent used in combination with the crystal can sufficiently exhibit the antibacterial performance.
  • the tazobactam hydrate crystal of the present invention binds irreversibly to various types of 6-lactamase produced by bacteria and has an action of inhibiting the activity of lactase. Therefore, it can be used in combination with existing various antibacterial agents which are inactivated by lactamase, and can exhibit the original antibacterial action of the various antibacterial agents against 3-lactamase-producing bacteria. '
  • Example 1 described in Japanese Patent No. 26488750, a crystal of 2-methyl-2-triazolylmethylpenam-13-carboxylic acid S, S-dioxide (Zobactam) was produced.
  • the X-ray diffraction spectra of the tazobactam white crystals obtained above were as follows.
  • This aqueous solution was passed through a column filled with 10 ml of a synthetic resin adsorbent (trade name: Diaion HP-20, manufactured by Mitsubishi Chemical Corporation), and then 3 Om1 of water was passed through the column. The fractions were combined.
  • the m_cresol concentration in this solution was measured by high performance liquid chromatography and found to be about 0.044% by weight.
  • the concentration of methyl isobutyl ketone measured by gas chromatography was about 0.036% by weight.
  • the X-ray diffraction spectrum of the white crystals of zobactam hydrate was as follows.
  • Each 10 g of the evening zobactam crystals obtained in Reference Example 1 and Example 1 were placed in separate test tubes, sealed, and stored at room temperature for one year. During this time, the room temperature fluctuated between 10 and 34 ° C.
  • the tazobactam hydrate crystal of the present invention is superior in storage stability to the conventional tazobactam crystal.

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

Abstract

La présente invention concerne des cristaux de l'hydrate de composé de β-lactame représenté par la formule (I). Pour produire cet hydrate cristallin, on régule une solution aqueuse contenant un sel de tazobactame de façon empêcher la teneur en solvant organique de dépasser 0,1 % de la masse, on refroidit la solution aqueuse, puis on ajoute un acide à la solution aqueuse de façon à cristalliser l'hydrate. Cet hydrate de composé de β-lactame présente une excellente stabilité au stockage.
PCT/JP2002/004595 2001-05-14 2002-05-13 Cristal d'hydrate de compose de $g(b)-lactame WO2002092605A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001142760A JP2002338578A (ja) 2001-05-14 2001-05-14 β−ラクタム化合物の水和物結晶
JP2001-142760 2001-05-14

Publications (1)

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WO2002092605A1 true WO2002092605A1 (fr) 2002-11-21

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AR (1) AR034333A1 (fr)
WO (1) WO2002092605A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035539A1 (fr) * 2003-10-09 2005-04-21 Otsuka Chemical Co., Ltd. Cristal de penicilline et procede de production correspondant
US7547777B2 (en) 2003-10-10 2009-06-16 Otsuka Chemical Co., Ltd. Penam crystals and process for producing the same
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4158044B2 (ja) * 2003-10-09 2008-10-01 大塚化学株式会社 ペニシリン結晶及びその製造法
RU2671485C2 (ru) * 2012-09-27 2018-11-01 Мерк Шарп И Доум Корп. Антибиотические композиции тазобактама аргинина

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012601A1 (fr) * 1993-11-06 1995-05-11 Taiho Pharmaceutical Co., Ltd. Derives cristallin de penicilline, sa production et son utilisation
CN1236781A (zh) * 1999-01-12 1999-12-01 中国药品生物制品检定所 他唑巴坦半水合物的制备与应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012601A1 (fr) * 1993-11-06 1995-05-11 Taiho Pharmaceutical Co., Ltd. Derives cristallin de penicilline, sa production et son utilisation
CN1236781A (zh) * 1999-01-12 1999-12-01 中国药品生物制品检定所 他唑巴坦半水合物的制备与应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 133, 2000, Columbus, Ohio, US; abstract no. 133:232796, "Preparation and application of tazobactam semihydrate" *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035539A1 (fr) * 2003-10-09 2005-04-21 Otsuka Chemical Co., Ltd. Cristal de penicilline et procede de production correspondant
US7692003B2 (en) 2003-10-09 2010-04-06 Otsuka Chemical Co., Ltd. Penicillin crystals and process for producing the same
KR101098491B1 (ko) 2003-10-09 2011-12-26 다이호야쿠힌고교 가부시키가이샤 페니실린 결정 및 그의 제조 방법
US7547777B2 (en) 2003-10-10 2009-06-16 Otsuka Chemical Co., Ltd. Penam crystals and process for producing the same
KR101109177B1 (ko) 2003-10-10 2012-02-17 다이호야쿠힌고교 가부시키가이샤 페남 결정 및 그 제조법
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9320740B2 (en) 2013-03-15 2016-04-26 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9925196B2 (en) 2013-03-15 2018-03-27 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US10420841B2 (en) 2013-03-15 2019-09-24 Merck, Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US11278622B2 (en) 2013-03-15 2022-03-22 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US10933053B2 (en) 2013-09-09 2021-03-02 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane

Also Published As

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AR034333A1 (es) 2004-02-18
JP2002338578A (ja) 2002-11-27

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