EP0000828A1 - Synthetische beta-Lactam Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende Arzneipräparate - Google Patents

Synthetische beta-Lactam Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende Arzneipräparate Download PDF

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Publication number
EP0000828A1
EP0000828A1 EP78300231A EP78300231A EP0000828A1 EP 0000828 A1 EP0000828 A1 EP 0000828A1 EP 78300231 A EP78300231 A EP 78300231A EP 78300231 A EP78300231 A EP 78300231A EP 0000828 A1 EP0000828 A1 EP 0000828A1
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Prior art keywords
ene
hept
carboxylate
oxo
group
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French (fr)
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EP0000828B1 (de
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Roger John Ponsford
Robert Southgate
Patricia Margaret Roberts
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Beecham Group PLC
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Beecham Group PLC
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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
    • 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
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings

Definitions

  • the present invention relates to ⁇ -lactam antibacterials, to a process for their preparation and to compositions containing them.
  • An apt group of compounds within formula (II) includes those wherein:
  • a further apt group of compounds within formula (II) includes those wherein:
  • Suitable esterifying groups R 1 include alkyl groups of up to 12 carbon atoms, alkenyl groups of up to 12 carbon atoms, alkynyl groups of up to 12 carbon atoms, phenyl or benzyl groups or any of the aforesaid inertly substituted by lower alkoxyl, lower acyloxyl,halogen, nitro or the like.group. Used herein 'inertly substituted' means that the resulting group is stable and will not undergo rapid decomposition.
  • Particularly suitable esterifying groups R 1 include lower alkyl groups optionally substituted by lower alkoxyl, the benzyl group optionally substituted by lower alkoxyl, nitro, chloro or the like,and those groups which are known to give rise to rapid in-vivo hydrolysis in penicillin esters.
  • Certain preferred esterifying groups R 1 include methyl, ethyl, methoxymethyl, 2-methoxyethyl, benzyl, methoxybenzyl, nitrobenzyl and the like.
  • esterifying groups R 1 include those which give rise to in-vivo hydrolysable esters such as acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl, phthalidyl and the like.
  • a preferred group R 1 of those giving rise to in-vivo hydrolysable esters is the phthalidyl group.
  • Preferred groups R 1 are those such that CO 2 R 1 is a carboxylic acid salt.
  • the group C0 2 R 10 may also be a carboxylic acid salt.
  • CO 2 R 1 is a carboxylic acid salt in compounds of the formula (II) also containing the group CO 2 R 10
  • C0 2 R 10 is usually also a carboxylic acid salt, and normally R 1 and R 10 are like cations.
  • salts of compounds of formula (II) are conventional pharmaceutically acceptable salts such as the alkali metal and alkaline earth metal salts, in particular the sodium, potassium, calcium and magnesium salts; ammonium and substituted ammonium salts, for example the t-butylamine salt.
  • Particularly suitable salts are the potassium and sodium salts, especially the sodium salts.
  • R 2 is a phenyl group, optionally mono-substituted.
  • Suitable groups R 2 include the phenyl, p-chlorophenyl, m-chlorophenyl, p-nitrophenyl, m-nitrophenyl, p-ethoxy- carbonylphenyl, p-fluorophenyl, p-methylphenyl, p-aminophenyl, p-acetamidophenyl, p-(4'-nitrobenzyloxycarbonyl- amino)phenyl, p-methoxyphenyl and like groups.
  • a preferred sub-group of compounds within formula (II) is of formula (IV): wherein:
  • R 1 1 include acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl, phthalidyl and the like.
  • R 1 1 is preferably phthalidyl.
  • Suitable groups R 2 are as so described under formula (II).
  • a second preferred sub-group of compounds within formula (II) is of formula (V): wherein:
  • Particularly suitable salts are the potassium and sodium salts, especially the sodium salts.
  • Suitable groups R 2 are as so described under formula (II).
  • a sub-group of compounds within formula (II) of interest is of formula (VI): wherein:
  • a suitable group R 3 1 is tert-butyl.
  • Another suitable group R 3 1 is methyl.
  • An additional suitable group R 3 1 is benzyl.
  • a suitable group R 3 1 is p-nitrobenzyl.
  • One more suitable group R 3 1 is phthalidyl.
  • a further suitable group R 3 1 is pivaloyloxymethyl.
  • R 3 1 is sodium.
  • p-Nitrobenzyl is a preferred group R 3 1 .
  • Phthalidyl is also a preferred group R 3 1 .
  • Sodium is another preferred group R 3 1 .
  • a suitable group R 1 2 is p-acetamidophenyl.
  • R 1 2 is phenyl
  • a suitable group R 1 2 is p-nitrophenyl.
  • One more suitable group R 2 is p-aminophenyl.
  • a further suitable group R 1 2 is p-(4'-nitrobenzyloxy- carbonylamino)phenyl.
  • a reaction sequence leading to the compounds of this invention is as follows:
  • R 4 , R 5 and R 6 are each phenyl groups.
  • the ring closure is normally brought about by heating the compound of the formula (VII) in an inert solvent; for example temperatures of 90-120°C and more suitably 100-110°C may be employed in a solvent such as toluene or the like.
  • the reaction is best carried out under dry conditions under an inert gas.
  • the ester of the compound (II) produced may be isolated by any standard method such as fractional crystal - lisation or chromatography. We have found that it is most convenient to separate the desired product by column chromatography.
  • the ester employed is preferably one which is readily converted to the parent acid or its salt by mild methods of hydrogenolysis.
  • the invention includes a process for preparing a salt or free acid of a compound (II) which process comprises de-esterifying an ester of a compound of formula (II).
  • Particularly suitable esters for use in this process include benzyl esters, optionally substituted in the para position by a lower alkoxy, or nitro group or a halogen atom.
  • a preferred ester for use in this process is the p-nitrobenzyl ester.
  • Esters of compounds (II) may be de-esterified by conventional methods of hydrogenolysis.
  • Suitable methods include hydrogenation in the presence of a transition metal catalyst.
  • the pressure of hydrogen used in the reaction may be low, medium or high but in general an approximately atmospheric or slightly superatmospheric pressure of hydrogen is preferred.
  • the transition metal catalyst employed is preferably palladium on charcoal or on calcium carbonate.
  • the hydrogenation maybe effected in a suitable solvent in which the ester is soluble such as aqueous dioxan or the like. If this hydrogenation is carried out in the presence of a base then a salt of compounds (II) is produced.
  • Suitable bases for inclusion include NaHC0 3 , KHC0 3 , Na 2 C0 3 , K 2 CO 3 , CaC0 3 , MgCO 3 , LiHCO 3 , NH 4 OCOCH 3 and the like.
  • Suitable bases which may be used to neutralise acids within formula (II) include LiOH, NaOH, NaHCO 3 , KOH, Ca(OH) 2 and Ba(OH) 2 .
  • the salts of acids (II) may be converted to esters in conventional manner, for example by reaction with a reactive halide such as bromophthalide in solution in dimethylformamide or like solvent.
  • a reactive halide such as bromophthalide in solution in dimethylformamide or like solvent.
  • the substituent group or groups within the group R 2 in the compounds of formula (II) may be varied by conventional reactions.
  • a substituent when a substituent is a nitro group it may be reduced in a conventional manner to an amino group, for example by catalysed hydrogenation.
  • an amino group may be acylated to give a substituted amido group, for example by treatment with an acyl halide in the presence of an organic base.
  • Substituents NHC0 2 R3 where R 3 is a benzyl group substituted as hereinbefore described may be converted to amino groups, for example by hydrogenolysis.
  • the compound of the formula (VII) may be prepared by the reaction of a corresponding compound of the formula (VIII): wherein R 4 , R 5 and R 6 are as defined in relation to formula (VII) with a diloweralkylphosphorochloridate and a triloweralkylamine followed by reaction with a derivative of the formula (IX): where L 0 is a sodium or thallium (I) cation or an ammonium ion substituted by up to three organic groups, and R 2 is as defined in relation to formula (II).
  • L 0 is a substituted ammonium ion, it is preferably a tertiary ammonium ion, such as the triethylammonium ion. It is conveniently generated in situ by the reaction of a compound of the formula HSR 2 with an amine, preferably a tertiary amine.
  • L ⁇ is a thallium (I) cation.
  • L ⁇ is a sodium cation.
  • a particularly suitable diloweralkylphosphorochloridate is uiethylphosphorochloridate.
  • a particularly suitable triloweralkylamine is triethylamine.
  • the reaction is generally carried out in an inert organic solvent such as tetrahydrofuran at a non-extreme temperature such as 0 to 40°C, for example 15-25°C.
  • an inert organic solvent such as tetrahydrofuran at a non-extreme temperature such as 0 to 40°C, for example 15-25°C.
  • the compound of the formula (VIII) may be prepared by the reaction of the compound of the formula (X): wherein R 4 1 , R 4 , R 5 and R 6 are as defined in relation to formula (VIII) with ozone in the presence of trifluoroacetic acid followed by m-chloroperbenzoic acid.
  • the ozonolysis is generally performed at a depressed temperature such as -40 to -80°C, for example about -70°C and in solution in an inert solvent such as methylene chloride. Excess ozone is removed by flushing with an inert gas and thereafter a solution of the peracid is added to the reaction mixture.
  • the compound of the formula (X) may be prepared from the corresponding compound of the formula (XI): wherein R 4 1 is as defined in relation to formula (X) with a phosphine of the formula (XII): where R 4 , R 5 and R 6 are as defined in relation to formula (X).
  • This reaction is normally effected in the presence of at least one equivalent of a base of relatively low nucleophilicity such as 2,6-lutidine at an ambient temperature in a dry solvent such as dioxan, tetrahydrofuran or the like.
  • a base of relatively low nucleophilicity such as 2,6-lutidine
  • the compound of the formula (XI) may be prepared from the corresponding carbinol of the formula (XIII): wherein R 4 1 is as defined in relation to formula (XI) by reaction with thionyl chloride.
  • This reaction is also normally effected in the presence of at least one equivalent of a base of relatively low nucleophilicity in a dry solvent such as dioxan or tetrahydrofuran but in this instance the reaction is performed at a depressed temperature, for example -30 to -10°C.
  • the preceding carbinol may be prepared by the reaction of a compound of the formula (XIV): with a glyoxylic acid ester of the formula (XV): wherein R 4 1 is as defined in relation to formula (VII).
  • this reaction is carried out in an inert solvent at an elevated temperature, for example in dry benzene under reflux.
  • the compound of the formula (XIV) may be prepared as described in Description 1 hereinafter.
  • the present invention provides the compounds of the formulae (VII) and (VIII), as useful intermediates.
  • the process for the preparation of these compounds also forms part of this invention.
  • the present invention also provides a pharmaceutical composition which comprises a compound of the formula (II) as hereinbefore defined and a pharmaceutically acceptable carrier.
  • composition of the invention includes those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in domestic animals or humans.
  • compositions of this invention include tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colours, flavours, preservatives, disintegrants and the like in accordance with conventional pharmaceutical practice in the manner well understood by those skilled in the art of formulating antibacterial agents.
  • the compound of the formula (II) present in such compositions will be in-vivo hydrolysable to the parent acid or its salt.
  • composition of this invention may beneficially also comprise a penicillin or cephalosporin.
  • penicillins for use in these compositions include amoxycillin trihydrate and sodium amoxycillin.
  • the present invention also provides a method of treatment and/or prophylaxis of bacterial infections in human beings or domestic animals, which method comprises the administration to the sufferer of an effective amount of a compound of the formula (II).
  • 1,4 Pentadiene(d1) (30g) and chlorosulphonyl isocyanate (d2)(35.4 ml) were mixed and allowed to stand at room temperature for 3 days, in a pressure bottle.
  • the thick, dark syrup obtained was diluted with methylene chloride (500ml) and added dropwise to a stirred solution of sodium sulphite (66g) in water (240ml).
  • the chloride (d 14) was dissolved in dry dioxane (80 ml) and treated with triphenylphosphine (8.2 g) and 2,6-lutidine (3.7 ml). The reaction mixture was stirred overnight and then filtered; the filtrate concentrated and re-dissolved in ethyl acetate (100 ml). This solution was washed free of base with N/10 hydrochloric acid (ca 100 ml) and then washed with brine and dried over sodium sulphate. The solution was concentrated and then chromatographed on silica gel 60 ( ⁇ 230 mesh) eluting with ethyl acetate/60-80° petroleum ether 7:3 to give a foam.
  • the acid (2a) was further characterised by treatment with benzyl bromide and potassium carbonate in dimethylformamida: to give the benzyl ester (2b), obtained as white crystals (ex ether) m. p . 176.5-178°C. ⁇ max (CHCl 3 ) 1735 , 16 4 0 , 1610 cm -1 . (Found: C, 72.20; H, 6.59; N, 2.28; C 36 H 36 NO 5 P re- quires C, 72.83; H, 6.11; N, 2.36%).
  • the acid (2a) (754mg; 1.5 mmol) was dissolved in dry THF (15ml) containing Et 3 N (167m g ; 1.6 mmol) and stirred at RT.
  • a solution of diethylphosphorochloridate (272mg; 1.6mmol) in THF (5ml) was added dropwise to the solution under argon. Stirring was continued for 3h.
  • the solution was filtered, and to the solution was added thallium (I) phenylthiolate (500mg; 1.6 mmol). Stiring was continued overnight.
  • This foam was taken up in dry methylene chloride (70ml), and stirred with basic alumina (8g), for 2 hours.
  • the acid (8a) was characterised by treatment with benzyl bromide and potassium carbonate in dimethylformamide to give the benzyl ester (8b), as white crystals (ex ethyl acetate/petroleum ether), mp 146-8°C, ⁇ max (CHCl 3 ) 1740, 1620cm -1 (Found: C, 71.71; H, 5.67; N, 2.44. C 33 H 30 NO 5 P requires C, 71.87; H, 5.44: N, 2.54%.
  • the phosphorane (13) (150mg) was refluxed in dry toluene (100ml) under argon for nine hours. The solvent was evaporated and the product chromatographed on Merck Kieselgel 60 using ethyl acetate/petol as eluant to yield the title compound (14) as the major product (25 mg ; 30%), ⁇ max (CHC13) 1790, 1705 cm -1 .
  • the phosphorane (2.82g) in dry methylene chloride (125ml) was treated with trifluoroacetic acid (4ml) at 0°. The solution was cooled to -70° and treated with ozone until blue. Argon was passed through to remove excess ozone, and m-chloroperbenzoic acid (0.9g) in methylene chloride (20ml) was. added, and the mixture was stirred at RT overnight. The. solvent was evaporated, and the resulting white solid was dissolved in ethyl acetate and chromatographed on silica gel. Elution with 10% ethanol/ethyl acetate gave the product as the trifluoroacetic acid salt.
  • the phosphorane (17) (550mg) was refluxed in dry toluene (500ml) for 24 hours with removal of water (Dean-Stark) under argon. The solvent was evaporated and the product chromatographed on florisil (200-300 U.S. mesh) using ethyl acetate/petrol (60-80°) as eluant to yield the title compound (52mg; 18%) as a crystalline solid from benzene/petrol (60-80°C) mp 112-4°C. ⁇ max (CHC1 3 ) 1 79 0, 1705 cm -1 .
  • This thioester (19) was also prepared substituting the sodium thiolate mixture by solid thallium (I)p-acet- amidophenylthiolate. A comparable yield was obtained.
  • the phosphorane (19) (136mg) was suspended in dry toluene (10ml) and the mixture was evaporated to dryness. The residue was suspended in dry toluene (60ml), and the mixture was degassed and heated, under argon, under reflux with a Dean-Stark head. After 5 hours the pale yellow solution was cooled to room temperature, and the solvent was evaporated. The residue was taken up in ethyl acetate (12ml), and-left overnight at 5°, when buff coloured crystals were obtained. These were collected (97.5mg) and shown by thin layer chromatography to be recovered starting material.
  • the acid (12, prepared as in Example 4a) (1.675g) in dry tetrahydrofuran (80ml), under argon, was treated with triethylamine (0.472g) and diethylphosphorochloridate (0.807g). After stirring at room temperature for 3 hours the reaction mixture was added to freshly prepared sodium p-amino-phenylthiolate in tetrahydrofuran [prepared by treating p-aminophenylthiol (0.428g) in dry tetrahydrofuran (30ml)/hexamethylphosphoramide (0.505g), under argon at 0°, with sodium hydride (0.165g of a 50% suspension in oil)].
  • the phosphorane (21) (0.461g) was taken up in dry toluene, and the mixture was evaporated to dryness.
  • the residue was suspended in dry toluene (250ml), and the mixture was degassed and heated to reflux. A pale yellow solution was obtained. After refluxing for 6.5 hours the solution was left in the refrigerator overnight.
  • the toluene solution was decanted from some gummy material and evaporated to dryness. Trituration of the residue with dry diethyl ether gave recovered (21) as a solid (414mg). .
  • the phosphorane (23) (850mg) was suspended in dry toluene (500ml) and heated under an atmosphere of argon under reflux using a Dean-Stark apparatus to remove water. A clear, pale yellow solution was obtained. After refluxing for 6.5 hours the slightly darker solution was cooled and reduced by evaporation to about 150ml. On storing overnight at 5°, recovered starting material (551mg) was precipitated. The solution was evaporated, and the residue was chromatographed on florisil (200-300 U.S. mesh).
  • the p-nitrobenzyl ester (18) (70mg) was dissolved in 30% aqueous dioxan containing 5% Pd/C (90mg) prenyarogenated for twenty minutes].
  • the solution was hydrogenated at ambient temperature and pressure for one hour. Examination of the solution by u.v. showed a shift of chromo- phoric absorption of 316 nm and 266 nm for the p-nitrobenzyl ester to 314 nm and 251 nm respectively for the product.
  • the solution was treated with one equivalent of NaHC0 3 (14.7mg) in water (2ml) and filtered through keiselguhr.
  • the sodium salt (14mg) was dissolved in DMF (2ml) and treated with bromophthalide (10mg). The solution was stirred at RT for 3 hours, the solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with brine (2 x 5ml).
  • the phosphorane (d1.5, prepared as in Description 5) (258mg) was dissolved in dry methylene chloride (15ml) containing trifluoracetic acid (0.8ml) and stirred at RT. for ten minutes. The solution was cooled to -70° and ozonised for 15 minutes until a blue colour persisted. Argon was passed through the solution to remove excess ozone and m-chloroperbenzoic acid (90mg) in methylene chloride (5ml) was added. The mixture was allowed to warm up to RT. and stirred overnight. The solvent was evaporated and the residue chromatographed (Kieselgel 60, ⁇ 230 mesh) to yield the phosphorane acid (29) as the trifluoroacetic acid salt.
  • the salt was dissolved in methylene chloride and stirred with basic alumina (500m g ) for one hour. The solution was filtered and evaporated to yield the phosphorane-acid (29) as a colourless foam (198 mg) ⁇ max (CHC1 3 ) 1730, 1600cm -1 .
  • the phosphorane (30) (218mg) was refluxed in dry toluene (250ml) under argon for 18 hours.
  • the solvent was evaporated and the residue chromatographed on florisil (200-300 U.S. mesh) using slight pressure and ethyl acetate/petrol (60-80) as eluant.

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EP78300231A 1977-08-06 1978-08-02 Synthetische beta-Lactam Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende Arzneipräparate Expired EP0000828B1 (de)

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EP0000828B1 EP0000828B1 (de) 1983-03-09

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Cited By (8)

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FR2371542A1 (fr) * 1976-11-19 1978-06-16 Bayer Ag Colorants de l'isothiazolanthrone et leur application
EP0037080A1 (de) * 1980-03-27 1981-10-07 Merck & Co. Inc. 4-(3-Carboxy-2-oxopropyl)-azetidino-2-one und Verfahren zu ihrer Herstellung
EP0037592A2 (de) * 1978-07-26 1981-10-14 Beecham Group Plc Beta-lactam-Verbindungen
EP0001628B1 (de) * 1977-10-19 1984-01-18 Merck & Co. Inc. 3,6-Disubstituierte 7-oxo-1-azabicylo-(3.2.0.)-2-hepten-2-carbonsäure, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen
US4992542A (en) * 1984-01-24 1991-02-12 Merck & Co., Inc. 2-substituted-6-carbadethiapen-2-em-3-carboxylic acids
EP0499196A1 (de) * 1991-02-13 1992-08-19 Fujisawa Pharmaceutical Co., Ltd. Zwischenprodukte und Verfahren zur Herstellung von Carbapenem-Derivaten
EP0587436A1 (de) * 1992-09-09 1994-03-16 Sankyo Company Limited Verfahren zur Herstellung von Carbapenem- und Penemverbindungen und beteiligte Verbindungen in diesem Verfahren
US5541317A (en) * 1991-05-31 1996-07-30 Sankyo Company, Limited Azetidinone compounds useful in the preparation of carbapenem antibiotics and process for preparing carbapenem and penem compounds

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Publication number Priority date Publication date Assignee Title
JPS56142260A (en) * 1980-04-09 1981-11-06 Toyama Chem Co Ltd 2-azetidinone and its preparation
JPS56145271A (en) * 1980-04-11 1981-11-11 Dai Ichi Seiyaku Co Ltd 2-azetidinone derivative
JPS57103057A (en) * 1980-12-19 1982-06-26 Meito Sangyo Kk Automatic measuring method for hdl-cholesterol and its precipitant

Citations (1)

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Publication number Priority date Publication date Assignee Title
FR2371449A1 (fr) * 1976-11-19 1978-06-16 Merck & Co Inc Acide 1-carba-2-penem-3-carboxylique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2371449A1 (fr) * 1976-11-19 1978-06-16 Merck & Co Inc Acide 1-carba-2-penem-3-carboxylique

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2371542A1 (fr) * 1976-11-19 1978-06-16 Bayer Ag Colorants de l'isothiazolanthrone et leur application
EP0001628B1 (de) * 1977-10-19 1984-01-18 Merck & Co. Inc. 3,6-Disubstituierte 7-oxo-1-azabicylo-(3.2.0.)-2-hepten-2-carbonsäure, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen
EP0038087A2 (de) * 1978-07-26 1981-10-21 Beecham Group Plc Beta-Lactam enthaltende Verbindungen, ihre Herstellung und Verwendung
EP0037592A2 (de) * 1978-07-26 1981-10-14 Beecham Group Plc Beta-lactam-Verbindungen
EP0038087A3 (de) * 1978-07-26 1981-10-28 Beecham Group Plc Beta-Lactam enthaltende Verbindungen, ihre Herstellung und Verwendung
EP0037592A3 (de) * 1978-07-26 1982-03-03 Beecham Group Plc Beta-lactam-Verbindungen
EP0037080A1 (de) * 1980-03-27 1981-10-07 Merck & Co. Inc. 4-(3-Carboxy-2-oxopropyl)-azetidino-2-one und Verfahren zu ihrer Herstellung
US4992542A (en) * 1984-01-24 1991-02-12 Merck & Co., Inc. 2-substituted-6-carbadethiapen-2-em-3-carboxylic acids
EP0499196A1 (de) * 1991-02-13 1992-08-19 Fujisawa Pharmaceutical Co., Ltd. Zwischenprodukte und Verfahren zur Herstellung von Carbapenem-Derivaten
US5306816A (en) * 1991-02-13 1994-04-26 Fujisawa Pharmaceutical Co., Ltd. Processes for preparing carbapenem derivatives
US5541317A (en) * 1991-05-31 1996-07-30 Sankyo Company, Limited Azetidinone compounds useful in the preparation of carbapenem antibiotics and process for preparing carbapenem and penem compounds
US5614624A (en) * 1991-05-31 1997-03-25 Sankyo Company, Limited Carbapenem
US5681951A (en) * 1991-05-31 1997-10-28 Sankyo Company, Limited Metal catalyzed displacement process
US5719275A (en) * 1991-05-31 1998-02-17 Sankyo Company, Limited Silyl enol ether alkylation process
EP0587436A1 (de) * 1992-09-09 1994-03-16 Sankyo Company Limited Verfahren zur Herstellung von Carbapenem- und Penemverbindungen und beteiligte Verbindungen in diesem Verfahren

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EP0000828B1 (de) 1983-03-09
DE2862198D1 (en) 1983-04-14
JPS5448786A (en) 1979-04-17

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