WO1995005380A1 - Derives cristallins de carbapenem - Google Patents

Derives cristallins de carbapenem Download PDF

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Publication number
WO1995005380A1
WO1995005380A1 PCT/JP1994/001361 JP9401361W WO9505380A1 WO 1995005380 A1 WO1995005380 A1 WO 1995005380A1 JP 9401361 W JP9401361 W JP 9401361W WO 9505380 A1 WO9505380 A1 WO 9505380A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
oxo
ester
pyrrolidinylthio
emu
Prior art date
Application number
PCT/JP1994/001361
Other languages
English (en)
Japanese (ja)
Inventor
Isao Kawamoto
Masao Miyauchi
Rokuro Endo
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU74671/94A priority Critical patent/AU7467194A/en
Publication of WO1995005380A1 publication Critical patent/WO1995005380A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms

Definitions

  • the present invention relates to a crystal of a potent antioxidant compound useful as a pharmaceutical antibacterial compound and an antibacterial agent containing the same.
  • 1-methylcarbapanem derivatives having the formula: This is an orally active rubavenem compound having excellent antibacterial activity not only for gram-negative bacteria but also for gram-positive bacteria by oral administration, and its practical application is under study. In order to make this a practical drug, it must be easy to handle and stable under normal conditions.
  • the present inventors have conducted various studies, and have obtained the compound of the present invention as a stable crystal. And completed the present invention.
  • the present invention relates to crystalline (1R, 5S, 6S) -2-([(4R) -12-oxo-11-methyl-41-pyrrolidinylthio] 16-[(1R) 1- '1-Hydroxitytyl] 1-methyl-1 1-lubapen-1 2-emu 3-bivaloyloxymethyl ester of rubonic acid, the crystal of which is ⁇ -ray of copper with a wavelength of 1.54 A In X-ray powder diffraction obtained by irradiation, the main peaks are shown at the interplanar spacing of 15.50, 6.66, 5.13, 4.80, 4.31, 3.93 3. , and
  • the present invention provides crystalline (1R, 5S, 6S) -2 — [(4S) -2-oxo-11-methyl-4,1-pyrrolidinylthio] -16 — [(1R) 1-1-hydroxyxethyl] having the above formula.
  • the interplanar spacings were 18.4 1, 10.0 5, 5.64, 5.50, 5.0 1, 4.93, 4.53, 4.35, The main peak is shown at 3-87 7.
  • the crystalline compound of the present invention comprises (1R, 5S, 6S) -2-[(4R) -12-oxo-1-methyl-4-1-pyrrolidinylthio] -16-[(1R) 1-1-hydroxyxethyl] 1 1- Chill 1 1-Rubapen 2-Emu 3-Sodium salt of rubonic acid (JP-A-2-497883) or (1R, 5S, 6S) —2 — [(4S) 1-2-oxo 1-4-Pyrrolidinylthio] — 6 — [(1R) 1-1-Hydroxitytyl-1-1-methyl-1 sodium levapen-12-em-3-sodium salt of carboxylic acid (Japanese Unexamined Patent Publication No.
  • the solvent used in the esterification reaction is not particularly limited as long as it does not participate in the reaction.
  • Examples thereof include dimethyl acetate amide, dimethyl formamide, dimethyl sulfoxide, acetonitril, and tetraethyl.
  • Examples thereof include hydrofuran and the like and a mixed solvent thereof.
  • the reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction. Usually, the reaction is carried out at a temperature of from 120 to 40 ° C.
  • the reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually 15 minutes to 40 hours.
  • Solvents used to crystallize the residue obtained from the reaction solution include nitriles such as acetonitrile and halogenated carbons such as dichloromethane as good solvents.
  • nitriles such as acetonitrile and halogenated carbons such as dichloromethane
  • examples include hydrogen, dialkyl sulfoxides such as dimethyl sulfoxide, dimethylformamide, amides such as dimethyl acetate, and alcohols such as methanol, and poor solvents such as ethanol and water.
  • a particularly preferred crystallization solvent is a mixed solvent of water and a small amount of acetonitrile, and in the case of compound (II), a particularly preferred crystallization solvent is ethyl acetate. is there.
  • the obtained crystals are washed, dried and isolated by a conventional method.
  • the thus-obtained crystals of the compound (I) of the present invention have a melting point of about 19 ° C., and are determined by powder X-ray diffraction to have an interplanar spacing of 15.50, 6.66,5.
  • the crystal of the present invention is a stable crystal that is practically easy to handle, and exhibits an antimicrobial spectrum that shows a broad antibacterial spectrum against gram-positive and gram-negative bacteria and cephalosporinase-producing bacteria by oral administration. Useful. Its antibacterial activity was measured by equilibration in equine serum at 37 ° C for 1 hour, and then the activity was measured by agar plate dilution method.For example, Staphylococcus aureus, enterococci, etc.
  • the crystals of the present invention are useful as oral antibacterial agents for treating bacterial infections caused by these pathogenic bacteria.
  • the crystal of the present invention is used as an active ingredient in an excipient such as starch, lactose, sucrose, calcium carbonate, calcium phosphate, polyethylene glycol, etc., for example, gum arabic, carboxymethylcellulose, hydroxypro by conventional pharmaceutical methods.
  • Binders such as pircellose, gelatin, polyvinylpyrrolidone, lubricants such as magnesium stearate, talc, sodium raurylsulfate, polyethylene glycol, for example, carboxy Oral preparations such as capsules, powders, granules and tablets can be manufactured by mixing with various additives such as disintegrants such as methylcellulose calcium, alginic acid or a salt thereof, coloring agents, flavors, sweeteners and the like. .
  • the dose varies depending on age, body weight, symptoms, etc., but is about 50 mg to 2 g per adult, and can be given in 2 to 4 divided doses.
  • the ethyl acetate layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was subjected to reverse phase column chromatography (manufactured by Nacalai Tesque, Cosmo Seal 75 C18 PREP, 20 ml), and the fraction eluted with 40% acetate 2 water was used.
  • the fraction containing the desired compound was concentrated (about 2 ml) and left at room temperature to precipitate crystals. This was filtered off, washed with water, and dried to give the desired compound (50 mg) as colorless crystals.
  • the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue purified by reverse phase Karamukuroma chromatograph I chromatography (Nacalai Tesque, co Sumoshi Ichiru 7 5 (3 18 - ⁇ ⁇ ⁇ ⁇ , subjected to 4 0 ml), '4 0% ⁇ Se Bok two Bok Li Le monohydrate From the eluted fraction, the fraction containing the desired compound was concentrated, extracted with ethyl acetate, dried and concentrated. The residue was dissolved by heating in ethyl acetate (2 ml), and crystals were precipitated when left at room temperature. This was collected by filtration and dried to give the desired compound (107 mg) as colorless crystals.
  • Crystalline powder of the ester produced by the method of the present invention and JP-A-2-4 The amorphous powder obtained by the method described in 9783 was stored in a silica gel desiccator at 60 ° C and the residual ratio after 28 days (4 weeks) was measured.
  • the residual amount of the ester compound was measured using high performance liquid chromatography (HPLC).
  • the reaction solution was concentrated, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and developed with ethyl acetate-methanol 9: 1. The target fraction is concentrated and dried under reduced pressure to give the title compound as a powder (25 1 mg).
  • the vertical axis shows the diffraction intensity in cps unit, and the horizontal axis shows the value of the diffraction angle 2 ⁇ .

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

Abstract

Pivaloyloxyméthyl(1R, 5S, 6S)-2-[(4R)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyéthyl]-1-méthyl-1-carbapen-2-em-3-carboxylate cristallin répondant à la formule (I), pivaloyloxyméthyl(1R, 5S, 6S)-2-[(4R)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyéthyl]-1-méthyl-1-carbapen-2-em-3-carboxylate cristallin comme isomère de celui-ci, et procédé de production de ces composés. Les composés sont stables et utilisables comme agent antibactérien précieux.
PCT/JP1994/001361 1993-08-18 1994-08-17 Derives cristallins de carbapenem WO1995005380A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74671/94A AU7467194A (en) 1993-08-18 1994-08-17 Crystalline carbapenem derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP5/203974 1993-08-18
JP20397493 1993-08-18
JP5/203973 1993-08-18
JP20397393 1993-08-18

Publications (1)

Publication Number Publication Date
WO1995005380A1 true WO1995005380A1 (fr) 1995-02-23

Family

ID=26514209

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001361 WO1995005380A1 (fr) 1993-08-18 1994-08-17 Derives cristallins de carbapenem

Country Status (2)

Country Link
AU (1) AU7467194A (fr)
WO (1) WO1995005380A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034868A1 (fr) * 1995-05-03 1996-11-07 Smithkline Beecham Plc Ester de carbapenems

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0249783A (ja) * 1988-05-10 1990-02-20 Sankyo Co Ltd １―メチルカルバペネム誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0249783A (ja) * 1988-05-10 1990-02-20 Sankyo Co Ltd １―メチルカルバペネム誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034868A1 (fr) * 1995-05-03 1996-11-07 Smithkline Beecham Plc Ester de carbapenems

Also Published As

Publication number Publication date
AU7467194A (en) 1995-03-14

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