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WO1993019072A1 - Derive de carbapenem - Google Patents

Derive de carbapenem Download PDF

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Publication number
WO1993019072A1
WO1993019072A1 PCT/JP1993/000306 JP9300306W WO9319072A1 WO 1993019072 A1 WO1993019072 A1 WO 1993019072A1 JP 9300306 W JP9300306 W JP 9300306W WO 9319072 A1 WO9319072 A1 WO 9319072A1
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Prior art keywords
group
compound
lower alkyl
pharmaceutically acceptable
formula
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PCT/JP1993/000306
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English (en)
Japanese (ja)
Inventor
Ei-Ichi Nakai
Tokuo Koide
Masaki Yokota
Tomio Araki
Tetsuya Maeda
Kiyoshi Susaki
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Publication of WO1993019072A1 publication Critical patent/WO1993019072A1/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
    • C07D477/16—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 sorbaenem derivative, and more specifically, a 1 S-methylcarbanemine derivative having an S-configuration methyl group introduced at the 1-position of the carbavanene skeleton, and a method for producing the compound An antimicrobial agent containing the compound as an active ingredient.
  • the earliest potent varpenem antibiotics include chenamycin, which is obtained as a fermentation product of Streptomyces cattleya. 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 [Autimi crob. Agents Chemother., 2_ 2, 62 (1982); ibid., 23, 300, (1983)].
  • imidenem J. Med. Chem. 2 ⁇ 1435, (1979)
  • imidenem in which the amino group of the side chain 2 of this chenamycin is formimidylated, has emerged as a practical antibacterial agent.
  • the compound has a certain level of excellent antibacterial activity and chemical stability, it is susceptible to degradation inactivation by renal aldehyde oral peptidase (DHP) in vivo.
  • DHP renal aldehyde oral peptidase
  • IPMZC S iminenum Z sylastin
  • the present invention is structurally different from these compounds, and a nitrogen atom represented by the formula at the 2-position of the 1-methylcarbadium skeleton.
  • a Te-ring group into a bicyclic ring containing a molecule, it has superior antibacterial activity compared to known carbanem derivatives, and has clinical utility with excellent DHP stability and pharmacokinetics It provides a compound with a high valency.
  • the present invention provides a compound represented by the following general formula (I): Derivatives thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, pharmaceutically acceptable hydrates thereof, methods for producing the compounds, and pharmaceutical compositions containing the compounds as active ingredients About.
  • Nitrogen atom or group represented by formula CH Broken line: One of the broken lines represents a single bond, and the other represents a double bond.
  • R hydrogen atom, negative charge or ester residue The same applies hereinafter.
  • FIG. 1 is a graph comparing the distribution of the compound of the present invention and a compound on the market or under development in tissues of a mouse.
  • the vertical axis represents concentration (s / 1)
  • the horizontal axis represents time (min).
  • Examples include the following heterocyclic groups ⁇
  • R 2 is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an acyl lower alkyl group, a carbamoyl lower alkyl group, a carbamoyl group, or a lower alkyl carbamoyl group;
  • R 3 is absent or One or more of the same or different lower alkyl groups, lower alkenyl groups, lower alkynyl groups, hydroxyl lower alkyl groups, rubamoyl lower alkyl groups, halogen atoms, nitro groups, cyano groups, lower alkoxy groups, A substituent selected from a rubamoyl group, a lower alkyl group, a rubamoyl group, and a trihalogenomethyl group.
  • R 3 is absent or a group selected from the above-listed groups, and is the same or different and has 1 to plural, preferably 1 to 3 substituents. Means a group. Where R 3 is Any ring atom of the bicyclic heterocyclic group may be substituted.
  • the term “lower” means a straight chain or a functional 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 ibutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amido) ) 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, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,
  • the “lower alkenyl group” is a linear 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, Butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylaryl group, 1-methyl-1-propenyl group, 1-methylaryl group, 1,1-dimethylvinyl group, 1-1 Pentenyl group, 2-pentenyl group, 3-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 2-methyl-1-butenyl 1-methyl-2-butenyl group, 2-methyl-3-butenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethylaryl group , 1,2-Dimethyl-1 mono
  • the “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, 3-butynyl group, 1-methyl-12-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 group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4 Examples include a hexyl group and a 5-hexynyl group.
  • alkyl lower alkyl group examples include, for example, an acetyl group, a propionyl group, a benzoyl group, etc., which are substituted at any position of the lower alkyl group, and include, for example, an acetylmethyl group, an acetylethyl group, an acetylpropyl Group, propionylpropyl group, benzoylmethyl And a propionylethyl group, and more preferably an acetylmethyl group and an acetylethyl group.
  • the “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy, and 2-methylbutoxy. , 1,2-dimethylpropoxy, 11-ethylpropoxy, hexyloxy, and the like. Of these groups, methoxy, ethoxy, propoxy, and isopropoxy groups are preferred. Preferred are a methoxy group and an ethoxy group.
  • lower alkyl rubamoyl group examples include a methylcarbamoyl group, an ethylcarbamoyl group, a propyl rubamoyl group, a 1-methylpropyl rubamoyl group, and an isopropylpropyl rubamoyl group.
  • the “lowermoyl lower alkyl group” is a lower alkyl group in which an arbitrary position of the lower alkyl group is substituted with a lower-level alkyl group, for example, a lower-level alkyl group, a lower-level alkyl group, a lower-level alkyl group or the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • ester residue is an ester residue that is metabolized and hydrolyzed in a living body, and is, for example, a lower alkanoyloxy lower alkyl group, a lower alkenoyl lower alkyl group, or a cycloalkyl carboxy lower alkyl group.
  • Lower alkenyloxy lower alkyl group lower alkoxy lower alkanoyloxy lower alkenyl group, lower alkoxy lower alkenyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alk Coxy lower alkoxy lower alkyl group, benzoyl lower alkyl group, 2-oxotetrahydrofuran-5-yl group, 2-oxo-1-5-alkyl-1,3-dioxolen-1-4-alkyl
  • the lower alkylene group has 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms
  • the lower alkanoyl group has 2 to 6 carbon atoms
  • the cycloalkyl group has 3 to 8 carbon atoms. Particularly, those having 3 to 6 carbon atoms are mentioned.
  • the compound of the present invention can form an inner salt with the 3-position carboxy anion depending on the type of the heterocyclic ring as the 2-position substituent. Or a salt with another acid or base depending on the type of the heterocyclic ring which is the substituent at the 2-position, or when the ester residue is replaced.
  • Salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Acid addition salts with organic acids such as acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methsulfonic acid, ethanesulfonic acid, and glumic acid can be mentioned.
  • Examples of the salt with a base 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 ordinine. Salt and ammonium salt.
  • the compound of the present invention has a double bond depending on the type of asymmetric carbon atom or substituent, and thus has a plurality of isomers.
  • the present invention includes separated or mixtures of these isomers.
  • Particularly preferred isomers in the kerbaenem ring of the present invention are 1 R, 5 S and 6 S.
  • the compound of the present invention also includes pharmaceutically acceptable solvates or hydrates thereof.
  • the compound of the present invention can be synthesized by a conventionally known method other than the following production method.
  • R 4 is a carboxyl-protecting group
  • R 5 is
  • the compound (I) of the present invention can be prepared by reacting the compound represented by the general formula (VI) with diphenylphosphoryl chloride (Step I-1) or oxidizing the compound (VII) using an appropriate oxidizing agent. Then, after the compound (II) is obtained (Step I-12), a substitution reaction with the thiol compound (III) is carried out (Step II), and if necessary, the protecting group is removed. Alternatively, (Step III) can be obtained by subjecting it to a salt formation reaction.
  • This step is a step of reacting compound (VI) with diphenylphosphoryl chloride.
  • Solvents used for this reaction include ketones such as acetone and methylethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, and a mixed solvent thereof. Good.
  • a base can be added to promote the reaction.
  • the base in this case include organic bases such as triethylamine, diisopropylethylamine, DBU, N-methylmorpholine, and quinuclidine; inorganic bases such as hydroxylated lime, sodium hydroxide, and carbonated lime; sodium methoxide;
  • the reaction temperature of c which is a metal alcoholate or the like, is set under cooling to room temperature, preferably under cooling.
  • This step is a step of oxidizing compound (VH) to obtain compound (II).
  • Oxidation of the compound ( ⁇ ) is carried out by halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, tetrabasic carbon, etc., ketones such as acetone and methyl ethyl ketone, acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, tetrabasic carbon, etc.
  • ketones such as acetone and methyl ethyl ketone
  • acetic acid pyridine
  • dimethylformamide dimethyl sulfoxide
  • acetonitrile tetrahydrofuran
  • the reaction temperature is from cooling to heating.
  • examples of the carboxyl-protecting group include a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a nitrobenzyl group, a lower alkoxybenzhydryl group and the like.
  • the compound (II) may be isolated once, or may be reacted with the compound (III) without isolation after the reaction in the first step.
  • thiol compound of the compound (III) a monomer represented by the general formula (II) may be reacted, and two molecules of the compound represented by the general formula (III) may be an S—S disulfite.
  • the compound bonded by a sulfide bond may be reacted with a compound that cleaves a disulfide bond, such as trimethylmer.
  • the solvent described in Step I-11 is preferably used.
  • the reaction may be performed in the presence of a base, and in this case, the base described in Step I-1 may be used.
  • the alkali metal represented by M include potassium and sodium.
  • This step is for removing the protecting group when compound (VIII) has a protecting group. That is, when a protecting group of R 4 has a p-nitrobenzyl group, a benzyl group, a benzhydryl group, or the like, the removal of these protecting groups can be achieved by 1) reduction of compound (VIII) using zinc or iron, 2) Liquid reduction or 3) catalytic reduction using palladium monocarbon or palladium hydroxide-carbon.
  • the reduction method 2) can be carried out by adding compound (VIII) to liquid ammonia, then adding metallic sodium and stirring.
  • the reduction method 3) can be performed under cooling or heating in the presence of a catalyst such as palladium-carbon or palladium hydroxide-carbon.
  • the reaction time of the above reaction varies as appropriate depending on the reaction conditions such as the raw materials and the reaction reagents, but it can be from tens to tens of hours, preferably from tens of minutes to several hours.
  • a compound represented by the general formula (IV) is reacted with a halogen compound represented by the general formula (V) to obtain a compound represented by the general formula (IX).
  • a compound represented by the general formula (Ia) is obtained by carrying out a sulfurization reaction or a salt formation reaction.
  • examples of the halogen atom represented by X include a chlorine atom, a bromine atom and an iodine atom.
  • the reaction proceeds without solvent, but is not involved in the reaction, and is preferably performed in an organic solvent.
  • Suitable organic solvents that do not participate in the reaction include benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloromethane, methanol and ethanol.
  • Compound (IV) is preferably used in an equimolar amount or a slight excess with respect to compound (V).
  • secondary or tertiary bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, dimethylamine, and bases such as carbonated lime, sodium carbonate, and sodium hydrogen carbonate are added.
  • bases such as carbonated lime, sodium carbonate, and sodium hydrogen carbonate are added.
  • this method it may be advantageous to increase the amount of compound (V) to promote the reaction smoothly, and this method can be employed if necessary.
  • reaction temperature and reaction time depend on the starting compounds ([V) and
  • reaction conditions such as the type of (V) and the type of solvent.
  • This reaction is usually performed at room temperature, under heating, or under heating to reflux.
  • Isolation and purification of the target substance from the reaction solution are performed by a conventional method by appropriately combining extraction with an organic solvent, chromatography, crystallization, and the like.
  • the compound (I) has an ester residue
  • the compound (I) is reacted with an esterifying agent such as an alcohol or a halide thereof, a sulfonate, a sulfate, a diazo compound, or the like, or the compound (I) is converted into a salt. If it does, use a conventional salt formation reaction. Can be obtained.
  • an esterifying agent such as an alcohol or a halide thereof, a sulfonate, a sulfate, a diazo compound, or the like
  • the compound of the present invention is excellent against a wide range of Gram-positive and Gram-negative bacteria. It has excellent antibacterial activity, excellent plasma concentration, distribution in each tissue and stability in each tissue, high urinary excretion rate, and a good pharmacokinetic profile. Therefore, it exhibits an anti-infection activity against various bacteria reflecting the strong antibacterial activity of in vitro, and is useful as an antibacterial agent for the treatment and prevention of infectious diseases targeting a wide range of bacteria.
  • the compounds of the present invention also include compounds that exhibit a good infection protective action against methicillin-resistant Staphylococcus aureus.
  • the compound of the present invention is stable against DHP-1, and a stable effect is expected with a single agent without being combined with a DHP-1 inhibitor such as cilastatin.
  • the usefulness of the compound of the present invention has been confirmed by the following experiments.
  • the 2-position of the compound of the present invention is (1-methylimidazo [1,2-a] pyridine-12-io) methylthio group, This was performed for the carboxy anion at the 3-position.
  • the compound of the present invention has good antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria.
  • gram-negative bacteria showed better antibacterial activity than IPM / CS.
  • mice Each group consisted of 10 mice, and dissolved in physiological saline using I PMZCS as a comparative drug.
  • mice Each group consisted of 4 mice, which were dissolved in saline using I PMZCS as a comparative drug.
  • 1Z15M phosphate buffer (pH 7) 1.5 times the renal wet weight of ICR male mice and SD male rats was added, and a 40% renal homogenate was prepared using a homogenizer.
  • drug solution 51 volumes
  • incubate for 2 hours at 37.
  • the reaction was performed by adding an equal volume of 100 / gZml cilastatin in 1/15 M phosphate buffer (pH7). This was centrifuged at 3000 rpm for 15 minutes, and the drug concentration in the supernatant was measured by the bioassay method.
  • a lung homogenate was prepared, and the stability of the drug was measured.
  • 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.
  • the calibration curve was prepared using control plasma or 115 M phosphate buffer (pH 7).
  • the compound of the present invention is sufficiently stable even in the absence of cilastatin, and is 2.1 times in the lung and 2.7 times in the kidney compared to IPMZCS.
  • the compound of the present invention was prepared in a physiological saline solution for injection (2 mgZml), and 1 OmgZkg was administered once intravenously. At predetermined times after drug administration, urine was collected and provided for bioassay.
  • mice As a result, about 66% of the dose of the compound of the present invention was excreted in urine by 24 hours after administration. This was about 6 times better than I PMZCS. (5) Tissue distribution in mice
  • the compound of the present invention was prepared in a physiological saline solution for injection (1 mgZm 1), and a single dose of 1 Omg / kg was subcutaneously administered.
  • a physiological saline solution for injection (1 mgZm 1)
  • a single dose of 1 Omg / kg was subcutaneously administered.
  • 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-containing 1/15 M phosphate buffer (pH7), homogenize with a homogenizer, and centrifuge at 3000 rpm for 15 minutes. The concentration was measured by the bioassay method.
  • the compound of the present invention showed a favorable transition in plasma concentration and a high AUC value even when compared with a compound on the market or under development.
  • the compound of the present invention showed good distribution in heart, lung, liver, kidney, and spleen tissues, and was 1.3 to 2.1 times at C max and 1.7 to 2.7 times at AUC, halved compared to I PMZCS. In the period (Tl / 2), the value was superior by 1.6 to 2.4 times.
  • mice Three ddY mice (4 weeks old, male) were used per group.
  • the drug was dissolved in physiological saline for injection and administered locally in the left ventricle of the mouse at 200 g Zanimal.
  • the administration volume was 201 in each case, and the control group received only saline for injection.
  • the lateral ventricle was injected under anesthesia under vertical anesthesia at 3 mm behind the posterior margin of the left eye and vertically into the skull position 0.5 mm outside the longitudinal midline. Thereafter, behavioral observation was performed for 30 minutes to determine the presence or absence of convulsions and death.
  • Formulations containing one or more of the compounds represented by the formula (I) as an active ingredient can be prepared using carriers, excipients, and other additives that are usually used in formulation. Is done.
  • Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, arabic gum, olive oil, sesame oil, cocoa butter (1) Ethylene glycol and others commonly used.
  • Administration can be in the form of tablets, pills, capsules, granules, powders, liquids, etc., or intravenous injections, intravenous injections, intramuscular injections, etc., non-oral administrations such as suppositories, transdermals, etc. You may.
  • the dosage is appropriately determined depending on the individual case in consideration of the symptoms, age of the administration subject, sex, and the like, but is generally about 250 to 150 Omg per day.
  • the solvent was distilled off under reduced pressure, and the resulting residue was added with 3 ml of tetrahydrofuran, 3 ml of 0.05M potassium phosphate buffer solution at pH 7 and 0.63 g of 20% palladium hydroxide on carbon, and hydrogenated at room temperature and normal pressure. Stirred for hours. After filtering off the palladium and distilling off tetrahydrofuran under reduced pressure, the remaining aqueous solution was washed with ethyl acetate and then adsorbed on DIAION HP-20.
  • the port-form layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (formaldehyde Z methanol) to give 2.74 g (9.6 Ommo 1) of 3- (4-methoxybenzylthiomethyl) imidazo [1,2-b] pyridazine. .
  • Mass spectrometry value (FAB, Pos, mZz): 389 ((M11) + )
  • Example 17 Paramethoxybenzyl (1R, 5S, 6S) —6-((1R) -1-hydroxyethyl) obtained in (1) of 11-Methyl 2-([imidazo [ 1,2-b] [1,2,4] triazine-6-ylmethyl) thio] 1-1-methylcarbapene-2-hemo-3-carboxylate, using methyl iodide in the same manner as in Example 4.
  • Mass spectrometry value (FAB, Pos, m / z): 300 ((M + 1) +) (5) Obtained 2- (p-methoxybenzylthiomethyl) imidazo [1,2-a] 10 ml of anisol, 50 ml of trifluoroacetic acid and 1.42 ml of trifluoromethanesulphonic acid were added to 2.40 g (8.0 mmo1) of pyrimidine at 0 at 0 and stirred for 2 hours.
  • Mass spectrometry value (FAB, Pos, m / z): 524 ((M + l) + ) (2) Obtained paramethoxybenzyl (1 R, 5 S, 6 S)-6-((1 R ) — 1-Hydroxyethyl] — 1-methyl-2-C (6-methylimidazo [1,2—a] pyridazine-l-ylmethyl) To 0.3 mmo 1), 5 ml of methylene chloride was added, and the mixture was stirred at 0 ° C. To this, 0.1 ml of methyl trifluoromethanesulfonate (1.0 mmol) was added.
  • the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate (9: 1). The solvent was distilled off under reduced pressure to obtain 54.8 g of ethyl 3-bromo-2-ketobutyrate.
  • Example 25 Paranitrobenzyl (1R, 5S, 6S) of (2) —6 — ((1R) —1-hydroxyethyl) —2-C (3-methylimidazo [1,2-a] Pyrimidine-12-yl) methylthio] -11-methylcarbapene-12-em-carboxylate was treated in the same manner as in Example 4 to give (1R, 5S, 6S) -6- ((1 R)-1-hydroxyethyl) 1-2-[(1, 3-dimethylimidazo [1, 2-a] pyrimidine-1-io) methylthio] 1-1-methylcarbabene 2-hem- Obtain the carboxylate.

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Abstract

On décrit un dérivé de carbapenem ou un de ses sels. Il est représenté par la formule générale (I) et présente une excellente activité antibactérienne contre une grande variété de bactéries à Gram positif ou négatif, et on peut donc l'utiliser en tant qu'agent antibactérien.
PCT/JP1993/000306 1992-03-17 1993-03-15 Derive de carbapenem Ceased WO1993019072A1 (fr)

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JP4/91774 1992-03-17
JP9177492 1992-03-17

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033888A1 (fr) * 1996-03-11 1997-09-18 Takeda Chemical Industries, Ltd. Composes de carbapenem, leur production et leur utilisation
US6174877B1 (en) 1996-01-12 2001-01-16 Takeda Chemical Industries, Ltd. Carbapenem compound, their production and use
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
CN109776527A (zh) * 2019-02-21 2019-05-21 药雅科技(上海)有限公司 一种5-溴-7-氮杂吲哚的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60104088A (ja) * 1983-11-11 1985-06-08 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物およびその製造法
JPS6425779A (en) * 1987-04-11 1989-01-27 Lederle Japan Ltd (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60104088A (ja) * 1983-11-11 1985-06-08 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物およびその製造法
JPS6425779A (en) * 1987-04-11 1989-01-27 Lederle Japan Ltd (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174877B1 (en) 1996-01-12 2001-01-16 Takeda Chemical Industries, Ltd. Carbapenem compound, their production and use
WO1997033888A1 (fr) * 1996-03-11 1997-09-18 Takeda Chemical Industries, Ltd. Composes de carbapenem, leur production et leur utilisation
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
CN109776527A (zh) * 2019-02-21 2019-05-21 药雅科技(上海)有限公司 一种5-溴-7-氮杂吲哚的合成方法

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