WO1993016080A1 - Nouveau derive de carbapenem - Google Patents

Nouveau derive de carbapenem Download PDF

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Publication number
WO1993016080A1
WO1993016080A1 PCT/JP1993/000126 JP9300126W WO9316080A1 WO 1993016080 A1 WO1993016080 A1 WO 1993016080A1 JP 9300126 W JP9300126 W JP 9300126W WO 9316080 A1 WO9316080 A1 WO 9316080A1
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Prior art keywords
group
pharmaceutically acceptable
compound
lower alkyl
formula
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PCT/JP1993/000126
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English (en)
Japanese (ja)
Inventor
Tokuo Koide
Ei-Ichi Nakai
Masaki Yokota
Tomio Araki
Tetsuya Maeda
Kiyoshi Susaki
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Yamanouchi Pharmaceutical Co., Ltd.
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Publication of WO1993016080A1 publication Critical patent/WO1993016080A1/fr

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    • 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
    • C07D477/14—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 hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3

Definitions

  • the present invention relates to a novel carbanemine derivative, and more particularly, to a 1 ⁇ -methylcarbapanem derivative having a —configuration methyl group introduced at the 1-position of a carbanemene skeleton, and a method for producing the compound.
  • the present invention relates to an antibacterial agent containing the compound as an active ingredient.
  • chenamycin which is obtained as a fermentation product of Streptomyces catt leya. Although this chenamycin has excellent antibacterial activity against a wide range of Gram-positive and negative bacteria, its chemical stability is poor and it has not yet been put to practical use.
  • imidenem in which the amino group on the 2-position side chain of chenamycin was formimidylated, appeared as a practical antibacterial agent. Although this compound has excellent antibacterial activity and chemical stability to some extent, it is easily degraded and inactivated by renal dehydrobeptidase (DHP) in vivo, and is used in combination with cilastatin, a type of DHP inhibitor. It is formulated with Midianem Z Cilastatin.
  • DHP renal dehydrobeptidase
  • the present invention differs from these compounds in that 1-propenyl group, which is structurally different from 1-methylcarbane skeleton, is bonded to the nitrogen atom on the heterocycle at the 2-position to form a quaternary ammonium group.
  • the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable hydrate thereof. And a method for producing the compound, and a pharmaceutical composition comprising the compound as an active ingredient.
  • R'R 2 same or different lower alkyl group
  • n an integer from 3 to 7
  • examples of the substituent in the “substituted or unsubstituted pyridinium group” include a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a hydroxyl group, and an amino group.
  • the term "lower” means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, as the “lower alkyl group”, specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amyl group) ) Group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl
  • the “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, and specifically includes a vinyl group, an aryl group, a 1-propyl group, a 2-propenyl group, a 1-propyl group.
  • “Lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl group , 1-methyl-2-butynyl, 1-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl And a 5_hexynyl group.
  • the “lower alkoxy group” includes methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentyloxy and the like.
  • the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • lower alkylthio group examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.
  • the "mono- or di-lower alkylamino group” include, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, and a tert-butylamino group.
  • Pentyl (amyl) amino group isopentylamino group, neopentylamino group, tert-pentylamino g, dimethylamino group, getylamino group, ethylmethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group And diisobutylamino groups.
  • Pentyl (amyl) amino group isopentylamino group, neopentylamino group, tert-pentylamino g, dimethylamino group, getylamino group, ethylmethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group And diisobutylamino groups.
  • amino lower alkyl group is a group in which an amino group is substituted at an arbitrary position of the above lower alkyl group, and specifically, an aminomethyl group, an aminoethyl group, an aminopropyl group , Aminobutyl, aminopentyl and the like.
  • an alkylene group having 1 to 6 carbon atoms is preferable, and specifically, a methylene group, an ethylene group, a methylmethylene group, a trimethylene group is preferable.
  • aryl group examples include a phenyl group and a naphthyl group.
  • Examples of the “mono- or di-substituted amino group” include an amino group having one or two substituents selected from an acyl group, an aralkyl group and the like.
  • lower alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and the like.
  • acyl group examples include an acetyl group, a propionyl group, a benzoyl group and the like.
  • the “N—lower alkyl-substituted rubamoyl group” includes, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylpower rubamoyl group, N, N, —dimethylcarbamoyl group or N, N-diethyl And a rucarbamoyl group.
  • Examples of the “lower alkylsulfonyl group” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group and a butylsulfonyl group.
  • Examples of the “lower alkylsulfinyl group” include a methylsulfinyl group, an ethylsulfinyl group, a butylsulfinyl group and an isopropylsulfinyl group.
  • ester residue examples include an ester residue which is metabolized and hydrolyzed in a living body, or an ester residue which can serve as a protecting group for a carboxyl group.
  • ester residues that are metabolized and hydrolyzed in vivo include lower alkanoyloxy lower alkyl groups, lower alkenyl lower alkyl groups, cycloalkyl carboxy lower alkyl groups, lower alkenoyloxy lower alkyl groups.
  • Alkyl group lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxycarbonyloxy lower alkyl group, benzoyloxy Lower alkyl group, 2-oxotetrahydrofuran-5-yl group, 2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyalkyl,
  • ester residues such as a tyl group and a 3-phthalidyl group are exemplified.
  • ester residue which can serve as a protecting group for a carboxyl group include, for example, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a nitrobenzyl group, a lower alkoxybenzhydryl group, and the like.
  • the lower alkylene group has 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms, the lower alkanoyl group has 2 to 6 carbon atoms, and the cycloalkyl group has 3 to 8 carbon atoms. Particularly, those having 3 to 6 carbon atoms are mentioned. -1
  • particularly preferred compounds are 1, 2, 5, 6, 7, and 8 compounds. These compounds are described in the process diagrams and It can be synthesized by a method similar to the synthesis route described in the examples.
  • the compound of the present invention has a group represented by the formula 1 NJ which is a substituent at the 2-position and a group represented by the formula 1) which is capable of forming an inner salt by a carboxy anion or an anion at the 3-position.
  • a group represented by the formula 1 NJ which is a substituent at the 2-position
  • a group represented by the formula 1) which is capable of forming an inner salt by a carboxy anion or an anion at the 3-position.
  • Salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Examples include acid addition salts with organic acids such as maleic acid, lactic acid, lingic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • formic acid acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid
  • Examples include acid addition salts with organic acids such as maleic acid, lactic acid, lingic acid, citric acid, tartaric acid, carbonic acid
  • salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolamine; and basic amino acids such as lysine and orditin. Salts with acids include ammonium salt.
  • the compound of the present invention has an asymmetric carbon atom and a double bond (a propyl group at the 2-position), and thus has a plurality of isomers.
  • the present invention includes separated or mixtures of these isomers.
  • Particularly preferred isomers in the ring of the present invention are 1 S, 5 R and 6 S, in which the propenyl group at the 2-position has a trans configuration (E).
  • the compound of the present invention also includes pharmaceutically acceptable solvates or hydrates thereof.
  • R 3 represents a carboxyl-protecting group
  • X represents a halogen atom. The same applies hereinafter.
  • the compound (III) of the present invention is obtained by phosphorylating 3-hydroxy-1-propene-1-ylcarbapanem represented by the general formula (II), followed by halogenation to give the compound represented by the general formula (III). Change the benyl halide (Step 1), and then react the probenyl halide with the corresponding pyridine or bridged ring derivative represented by the general formula (V) to obtain a compound represented by the general formula (lb).
  • the compound can be produced by removing the protecting group R 3 of the compound (deprotection step) if necessary (second step).
  • a phosphate esterifying agent (a reactive derivative of phosphoric acid) is allowed to act under cooling in an inert solvent in the presence of an acid scavenger (such as dimethylaminopyridine).
  • an acid scavenger such as dimethylaminopyridine.
  • Rogen donors eg, halogenated compounds such as alkali metals and alkaline earth metals, halogenated silanol compounds such as trialkylsilyl halides, or trialkyltin halides, dialkyltin dihalide tins or monoalkyltin trihalide halides
  • the reaction is carried out under cooling or at room temperature to produce 3-halogeno-1-propene-1-ylbenzene compound (III).
  • reaction in the second step is carried out by stirring the compound (III) and a corresponding amount or an excess amount of the compound (V) in an inert solvent.
  • aromatic hydrocarbons such as benzene, toluene and xylene are preferable, but dimethyl ether, dioxane, tetrahydrofuran, cyclohexane, cyclohexane, chloroform, dichloromethane, acetonitrile, dimethyl are preferable.
  • examples include sulfoxide, N, N-dimethylformamide, hexamethylphosphamide, and ethanol. Also, a mixture thereof may be used.
  • the first step and the second step may be performed continuously.
  • the reaction may be performed after the first and second steps are performed.
  • the removal of the protecting group can then be carried out by 1) reduction using zinc or iron, 2) liquid reduction or 3) catalytic reduction using palladium-carbon or palladium hydroxide-carbon. it can.
  • compound (IV) is added to a buffer solution (an inert solvent is added if necessary), and then an amount of zinc or iron corresponding to the reaction is added, and the mixture is cooled or heated. Can be performed by stirring under o
  • the reduction method can be performed by adding compound (IV) to liquid ammonia, then adding sodium metal and stirring.
  • the reduction method in 3) is based on palladium-carbon or palladium hydroxide. It can be performed under cooling or heating in the presence of a catalyst such as carbon.
  • the reaction time of the above reaction varies depending on the reaction conditions such as the raw materials and the reaction reagents, but it is several tens to several tens of hours, preferably several tens to several hours.
  • Y means a phenyl group, the lower alkyl group or the lower alkoxy group.
  • the compound (I) of the present invention can be produced by subjecting the phosphorane represented by the general formula (VI) to a Wittig reaction, and then optionally removing a protecting group.
  • the Wittig reaction can be carried out by heating compound (VI) usually in an inert solvent.
  • the inert solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, but the solvents described in the first production method can also be used.
  • the reaction temperature is preferably in the range of 50 to 200 ° C, but the reaction can be adjusted by cooling or heating as appropriate.
  • the protective group can be removed in the same manner as in the first production method.
  • Isolation and purification of the target substance from the reaction solution are carried out in a conventional manner by appropriately combining extraction with an organic solvent, chromatography, crystallization, and the like.
  • Is carried out by reacting an alcohol or an esterifying agent such as a halide, sulfonate, sulfite, diazo compound or the like by an ordinary method, or, when compound (I) has a salt, by a conventional salt-forming reaction. Can be obtained by adding.
  • the compound of the present invention has excellent antibacterial activity and belong to Gram positive and negative Inhibits the growth of a wide range of pathogenic microorganisms. That is, the compound of the present invention has an excellent antibacterial activity equivalent to or higher than imidenem / cilastatin (I PMZC S), which has the highest antibacterial activity as a carbanadem derivative, and a protective effect against infection. .
  • I PMZC S imidenem / cilastatin
  • the compound of the present invention is stable against DHP-I in the kidney, and its pharmacokinetics, particularly the excretion pathway, the distribution characteristics in the tissue, etc. are comparable to those of IPM / cs or other active leubadenem compounds. In comparison, it has a much better profile, low toxicity, and can be a clinically useful antibacterial agent without being combined with a DHP inhibitor. In particular, it is expected to have excellent clinical effects as an antibacterial agent for diseases such as urinary tract infections.
  • the usefulness of the compound of the present invention has been confirmed by the following experiments. In the following experiment, among the compounds of the present invention, the 2-position was (E) -31- (pyridine-11-)-1-propene-1-yl and the 3-position was a carboxy anion. Went with things.
  • the compound of the present invention exhibited an antibacterial activity (MIC) equivalent to or higher than that of imidenem / cilastatin (IPMZCS).
  • mice Each group consisted of 10 mice, which were dissolved in physiological saline using IPM / CS as a comparative drug.
  • the compound of the present invention had a good ED50 value almost equivalent to that of IPMZCS.
  • the bioassay method was performed by the agar well method using B. subtilis ATCC 6633 as a test bacterium and antibiotic medium 1 or citrate medium (pH 6.5) as a medium. Calibration curves were prepared using control plasma or 1 / 15M phosphate buffer (PH7).
  • the compound of the present invention was sufficiently stable even in the absence of cilastatin, and was twice as stable in mice and about 10-fold in rats as compared to IPM / CS.
  • the compound of the present invention was prepared in physiological saline for injection (2 mg / ml), One OmgZkg was administered once intravenously. After administration of the drug, urine was collected at a predetermined time and used for bioassay.
  • the compound of the present invention exhibited a good urinary excretion rate of about twice that of IPM / CS.
  • the compound of the present invention was prepared in a physiological saline solution for injection (lmgZml), and 1 Omg / kg was subcutaneously administered once.
  • a physiological saline solution for injection (lmgZml)
  • 1 Omg / kg was subcutaneously administered once.
  • blood was killed from the inferior vena cava and the heart, lung, liver, kidney, and spleen were removed. Heparin was added to the blood, the plasma was separated, and used for bioassay.
  • To each tissue add 3 times the wet weight of 50 ⁇ g / m1 cilastatin in 115 M phosphate buffer (pH 7), homogenize with a homogenizer, and centrifuge at 300 rpm for 15 minutes. The drug concentration in the supernatant was measured by the bioassay method.
  • the compound of the present invention Compared to IPM / CS, the compound of the present invention showed about 6-fold better value in Cmax in the kidney, about 9-fold in AUC, and about 3-fold in half-life (T1 ⁇ 2min) .
  • the compound of the present invention showed a favorable value in plasma as compared with I PMZC S.
  • mice Three d dY mice (4 weeks old, male) were used per group.
  • the drug was dissolved in physiological saline for injection, and administered locally at 100 zg / animal and 300 g / animal into the left ventricle of the mouse.
  • the administered liquid volume was 20 to 1 in all cases, and the control group received only physiological saline for injection.
  • Intracerebroventricular administration was performed under anesthesia and the drug was injected vertically into the skull position 3 mm behind the posterior margin of the left eye and 0.5 mm outside the longitudinal midline. After that, behavioral observation was performed for 30 minutes to determine the presence or absence of convulsions and death.
  • the convulsant-inducing effect of the compound of the present invention was weaker than that of IPM, and there was no death at any dose, confirming that the central toxicity of the compound of the present invention was low.
  • Preparations containing one or more of the compounds represented by the general formula (I) as an active ingredient are prepared using carriers, excipients, and other additives that are usually used in formulation.
  • Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, Examples include ethylene glycol and other commonly used ones.
  • Administration can be either oral administration, such as tablets, pills, capsules, granules, powders, or liquids, or parenteral administration, such as injections such as intravenous and intramuscular injections, suppositories, and transdermal agents. Good.
  • the dose is appropriately determined depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration, but is generally about 250 to 150 Omg per day.
  • reaction mixture was diluted with cold water, cold saturated aqueous sodium bicarbonate solution, cold 0. Washing was performed in the order of IN hydrochloric acid and cold water. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the pH was adjusted to 6.1 by adding an aqueous solution of sodium dihydrogen phosphate, and the mixture was stirred at room temperature for 30 minutes. This was filtered through celite with water and ethyl acetate, and the aqueous layer was further washed with ethyl acetate. This was applied to a resin column chromatograph of Amberlite IR120B (manufactured by Organo) of 60 ml and eluted with 140 ml of water. This was concentrated under reduced pressure to 15 ml, adsorbed on Diaion HP-20 (100 ml), eluted with water and then with 10% aqueous acetate-water, and the target fraction was collected and depressurized.
  • Amberlite IR120B manufactured by Organo
  • N-Dimethylaminopyridine (167 mg) was added to 75 ml of a dichloromethane solution containing 500 mg of 2-l-emu-3-carboxylate in dichloromethane at -40 ° C under argon atmosphere. While maintaining the temperature, a solution of 500 mg of diphenylphosphoryl chloride in 2 ml of dichloromethane was added dropwise.
  • Example 6 The compound of Example 6 was obtained in the same manner as in Example 5.
  • reaction solution was filtered, the filtrate was washed with ethyl acetate, and the resulting aqueous layer was replaced with sodium ion. 40 ml) and eluted with 200 ml of water.
  • the resulting aqueous solution was concentrated under reduced pressure to about 30 ml, and the solution was subjected to HP-20 The fraction eluted with 10% acetonitrile-water is freeze-dried, and (1S, 5R, 6S) —6 — ((1R) —1—hydroxyxethyl 1) 2-((E)-3-(4-dimethylamino 1-1 -pyridinio 1-1-propionyl)-1-force lubapen-2-emu 3-1-carboxylate 51 mg was obtained.
  • 1 capsule 285 mg Mix the above ingredients and fill it into a normal hard gelatin capsule to make a capsule.
  • Compound of the present invention 200 mg Sucrose 790 mg Hydroxypropyl cellulose 5 mg Flavor 5 mg Total: l OOOmg
  • the above ingredients are mixed to form a dry syrup.
  • An appropriate amount of water for injection is added to 10 g of the compound of the present invention to make a volume of 100 ml, and the solution is filtered through a membrane filter.
  • One vial is filled with 250 mg of the sterilized compound of the present invention as powder. Before use, add about 2 to 4 ml of water for injection to make an injection.

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Abstract

Dérivé de carbapenem répondant à la formule générale (I), ou son sel. Dans ladite formule, (a) représente pyridinium éventuellement substitué, (b), (c), (d) ou (e); R1 et R2 sont identiques ou différents et chacun représente alkyle inférieur; n est un nombre entier compris entre 3 et 7; R représente hydrogène, une charge ionique ou un reste d'ester; et la ligne sinueuse représente la forme cis ou trans. Ce composé présente une excellente activité antibactérienne dirigée contre une grande diversité de bactéries Gram positif ou négatif, et est donc utilisable comme agent antibactérien.
PCT/JP1993/000126 1992-02-06 1993-02-03 Nouveau derive de carbapenem WO1993016080A1 (fr)

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JP5635592 1992-02-06
JP4/56355 1992-02-06

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WO1993016080A1 true WO1993016080A1 (fr) 1993-08-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1027352A1 (fr) * 1997-10-23 2000-08-16 Merck & Co., Inc. Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement
EP1084105A1 (fr) * 1998-06-02 2001-03-21 Merck & Co., Inc. Composes antibacteriens de carbapenem, compositions renfermant ces composes, et methodes de traitement

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JPH01197483A (ja) * 1987-02-02 1989-08-09 Merck & Co Inc ２−（ヘテロアリーリウムアルキル）フエニルカルバペネム抗菌剤
JPH02145585A (ja) * 1988-11-23 1990-06-05 Merck & Co Inc ２―〔４―（ｎ―シアノスルフアモイルメチル）―１―ピリジニウム〕エチルチオカルバペネム類
JPH02289571A (ja) * 1989-04-24 1990-11-29 Fujisawa Pharmaceut Co Ltd ３―アルケニル―１―アザビシクロ［３．２．０］ヘプト―２―エン―２―カルボン酸誘導体およびその製造法、並びにそれを含む抗菌性薬剤

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61151191A (ja) * 1984-12-13 1986-07-09 メルク　エンド　カムパニー　インコーポレーテツド ２‐ヘテロアリーリウム脂肪族置換基を有するカルバペネムおよび１‐メチルカルバペネム類
JPH01197483A (ja) * 1987-02-02 1989-08-09 Merck & Co Inc ２−（ヘテロアリーリウムアルキル）フエニルカルバペネム抗菌剤
JPS63303981A (ja) * 1987-05-21 1988-12-12 メルク　エンド　カムパニーインコーポレーテツド ２−（置換メチル）−１−アルキルカルバペネム誘導体
JPH02145585A (ja) * 1988-11-23 1990-06-05 Merck & Co Inc ２―〔４―（ｎ―シアノスルフアモイルメチル）―１―ピリジニウム〕エチルチオカルバペネム類
JPH02289571A (ja) * 1989-04-24 1990-11-29 Fujisawa Pharmaceut Co Ltd ３―アルケニル―１―アザビシクロ［３．２．０］ヘプト―２―エン―２―カルボン酸誘導体およびその製造法、並びにそれを含む抗菌性薬剤

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1027352A1 (fr) * 1997-10-23 2000-08-16 Merck & Co., Inc. Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement
EP1027352A4 (fr) * 1997-10-23 2001-09-19 Merck & Co Inc Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement
EP1084105A1 (fr) * 1998-06-02 2001-03-21 Merck & Co., Inc. Composes antibacteriens de carbapenem, compositions renfermant ces composes, et methodes de traitement
EP1084105A4 (fr) * 1998-06-02 2002-10-30 Merck & Co Inc Composes antibacteriens de carbapenem, compositions renfermant ces composes, et methodes de traitement

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