EP0722447A1 - Derives de 3-pyrrolidinylthio-carbapenem et leur activite antimicrobienne - Google Patents

Derives de 3-pyrrolidinylthio-carbapenem et leur activite antimicrobienne

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Publication number
EP0722447A1
EP0722447A1 EP94927783A EP94927783A EP0722447A1 EP 0722447 A1 EP0722447 A1 EP 0722447A1 EP 94927783 A EP94927783 A EP 94927783A EP 94927783 A EP94927783 A EP 94927783A EP 0722447 A1 EP0722447 A1 EP 0722447A1
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EP
European Patent Office
Prior art keywords
methyl
hydroxymethyl
ethyl
compound
hydroxyethyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94927783A
Other languages
German (de)
English (en)
Inventor
Masayoshi 7-17 Higashitokiwadai 7-chome MURATA
Hideo 16-3-301 Yuhigaoka 2-chome TSUTSUMI
Keiji 14-18 Kosobecho 3-chome MATSUDA
Kohji 1-7-1-915 Sumiregaoka HATTORI
Takashi 2-21-1-1208 Kamishinden NAKAJIMA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0722447A1 publication Critical patent/EP0722447A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B19/00—Driving, starting, stopping record carriers not specifically of filamentary or web form, or of supports therefor; Control thereof; Control of operating function ; Driving both disc and head
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B19/00—Driving, starting, stopping record carriers not specifically of filamentary or web form, or of supports therefor; Control thereof; Control of operating function ; Driving both disc and head
    • G11B19/02—Control of operating function, e.g. switching from recording to reproducing
    • G11B19/12—Control of operating function, e.g. switching from recording to reproducing by sensing distinguishing features of or on records, e.g. diameter end mark
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B7/00—Recording or reproducing by optical means, e.g. recording using a thermal beam of optical radiation by modifying optical properties or the physical structure, reproducing using an optical beam at lower power by sensing optical properties; Record carriers therefor
    • G11B7/08—Disposition or mounting of heads or light sources relatively to record carriers
    • G11B7/09—Disposition or mounting of heads or light sources relatively to record carriers with provision for moving the light beam or focus plane for the purpose of maintaining alignment of the light beam relative to the record carrier during transducing operation, e.g. to compensate for surface irregularities of the latter or for track following
    • G11B7/0925—Electromechanical actuators for lens positioning
    • G11B7/0935—Details of the moving parts
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B7/00—Recording or reproducing by optical means, e.g. recording using a thermal beam of optical radiation by modifying optical properties or the physical structure, reproducing using an optical beam at lower power by sensing optical properties; Record carriers therefor
    • G11B2007/0003—Recording, reproducing or erasing systems characterised by the structure or type of the carrier
    • G11B2007/0006—Recording, reproducing or erasing systems characterised by the structure or type of the carrier adapted for scanning different types of carrier, e.g. CD & DVD
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel azabicyclo compounds and pharmaceutically acceptable salts thereof.
  • one object of the present invention is to provide novel 3-pyrrolidinylthio-l-azabicyclo- [3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms and are usef l as antimicrobial agents.
  • Another object of the present invention is to provide processes for the preparation of novel 3-pyrrolidinylthio- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and salts thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said 3-pyrrolidinylthio-l-azabicyclo- [3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
  • Still further object of the present invention is to provide a use of said 3-pyrrolidinylthio-l-azabicyclo- [3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof as a medicament and in the treatment of infectious diseases by pathogenic microorganisms in human being or animal.
  • R 1 is carboxy, COO- or protected carboxy
  • R-2 is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R-* ** " is hydrogen or lower alkyl, R ⁇ is 2(or 3)-methylpyridin-4-ylmethyl, 2- cyanopyridin-4-ylmethyl, 2- carbamoylpyridin-4-ylmethyl, [1,2(or 1,3)- di ethyl-4-pyridinio]methyl, (l-methyl-2- cyano-4-pyridinio) ethyl, (l-methyl-2- carbamoyl-4-pyridinio)methyl, [l-(2- 5 procected hydroxyethy1)-4-pyridinio]methyl,
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g.
  • a salt with an acid such as inorganic acid addition salt (e.g.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, trifluoromethanesulfonate etc.
  • a salt with a basic or acidic amino acid e.g. arginine, aspartic acid , glutamic acid, etc.
  • the said intermolecular quaternary salt can be formed, for example, between the quaternary nitrogen atom in R 4 and counter anion such as halide (e.g. iodide, chloride, etc.), trihalo(lower)alkyl (e.g. trifluoro ethyl, etc.), and the like.
  • halide e.g. iodide, chloride, etc.
  • trihalo(lower)alkyl e.g. trifluoro ethyl, etc.
  • the said intramolecular quaternary salt can be formed, for example, between the quaternary nitrogen atom in R 4 and COO " group of R 1 .
  • the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
  • R R 3, R4 and R5 are each as defined above,
  • R is protected carboxy, is protected hydroxy(lower)alkyl
  • cyanopyridin-4-ylmethyl 2- carbamoylpyridin-4-ylmethyl, [2- (hydroxymethyl)pyridin-4- 1]methyl, 2- (imidazol-l-yl)propyl, 2-(1-methylimidazol- 5-yl)ethyl, [1-methyl-2- (hydroxymethyl)imidazol-5-yl]methyl, (1- methyl-2-carbamoylimidazol-5-yl)methyl, [1- methyl-4-(hydroxymethyl)pyrazol-5- yl]methyl, [1-methyl-5-
  • R + is [1,2(or 1,3)-dimethyl-4- pyridinio]methyl, (l-methyl-2-cyano-4- pyridinio)methyl, (l-methyl-2-carbamoyl-4- pyridinio)methyl, [1-(2-protected hydroxyethyl)-4-pyridinio]methyl, [1-(2- hydroxyethyl)-4-pyridinio]methyl, [1- (carbamoylmethyl)-4-pyridinio]methyl, [2- (hydroxymethyl)-l-methyl-4- pyridinio]methyl, 2- ( 1,3-dimethyl-4- imidazolio)ethyl, 2- (3-methyl-l- imidazolio)propyl, [1,3-dimethyl-2- (hydroxymethyl)-4-imidazolio]methyl, (1,3- dimethyl-2-carbamoyl-4-imidazolio)methyl, 2-(1-carbamo
  • R 4 is [l-(2-protected hydroxyethyl)-4- pyridinio]methyl, or 2-(2-protected i ino- 3-methylimidazolin-l-yl)ethyl
  • R c is [1-(2-hydroxyethyl)-4-pyridinio]methyl, or 2-(2-imino-3-methylimidazolin-l-yl)ethyl
  • Rg is imino-protective group
  • R° is methyl, carbamoylmethyl, 2-hydroxyethyl, 2- protected hydroxyethyl, and X is an acid residue.
  • the compound (III) used in the Process 1 is new and can be prepared, for example, by the following methods or a conventional manner.
  • R 4 and R5 are each as defined above, and R 7 .s mercapto-protective group.
  • lower is intended to mean 1 to 6, preferably 1 to 4 carbon atom(s), unless otherwise indicated.
  • Suitable "hydroxy(lower)alkyl” may include straight or branched lower alkyl having hydroxy group such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 1- (hydroxymethyl)ethyl, 1-hydroxy-1-methylethyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like, in which more preferable example may be hydroxyfC ⁇ -C ⁇ alkyl and the most preferable one may be 2- hydroxyethyl.
  • Suitable "lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferable example may be C..-C. alkyl and the most preferable one may be methyl.
  • Suitable "ercapto-protective group” may include acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.
  • the aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g.
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, ethacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.)
  • alkenoyl such as lower alkenoyl (e.g. acryloyl, ethacryloyl, crotonoyl, etc.)
  • cycloalkanecarbonyl such as cycl
  • the aromatic acyl may include Cb,-C_1, A 1) aroyl (e.g. benzoyl, toluoyl, xyloyl, etc.), N-(Cg-C 10 )arylcarbamoyl (e.g. N-phenylcarbamoyl, N-tolylcarbamoyl,
  • the aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc. ) , and the like.
  • aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc. ) , and the like.
  • acyl groups may be further substituted with one or more suitable substituent(s) such as nitro, and the like, and preferable acyl having such substituent(s) may be nitroaralkoxycarbonyl (e.g. nitrobenzyloxycarbonyl, etc. ) , and the like.
  • suitable substituent(s) such as nitro, and the like
  • preferable acyl having such substituent(s) may be nitroaralkoxycarbonyl (e.g. nitrobenzyloxycarbonyl, etc. ) , and the like.
  • mercapto-protective group thus defined may be C..-C, alkanoyl and C 8 -C.
  • Q aroyl and the most preferable one may be acetyl and benzoyl.
  • Suitable "acid residue” may include an inorganic acid residue such as azido, halogen (e.g. chlorine, bromine, fluorine or iodine), and the like, an organic acid residue such as acyloxy (e.g.
  • Suitable “protected carboxy” may include esterified carboxy wherein “esterified carboxy” can be referred to the ones as mentioned below.
  • ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s) , for example, lower alkanoyloxy(lower)alkyl ester [e.g.
  • 2-mesylethyl ester, etc. mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester [e.g.
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydrox ⁇ -3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g.
  • phenyl ester 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
  • More preferable example of the protected carboxy thus defined may be C--C. alkenyloxycarbonyl and phenyl(or nitrophenyl) (C--C.)alkoxycarbonyl, and the most preferable one may be allyloxycarbonyl.
  • Suitable "imino-protective group” may include acyl as mentioned in the explanation of mercapto-protective group, in which more preferable example may be C ⁇ -C. alkenyloxycarbonyl and the most preferable one may be allyloxycarbonyl.
  • Suitable hydroxy-protective group may include aforementioned acyl, tri(lower)alkylsilyl, and the like, in which more preferable example may be lower alkenyloxycarbonyl and tri(lower)alkylsilyl, and the most preferable one may be allyloxycarbonyl and t-butyldimethylsilyl.
  • R 1, R2, R3, R4 and R5 are as follows.
  • R is carboxy or esterified carboxy
  • R is 1-hydroxyethyl
  • R is methyl
  • R 4 is 2(or 3)-methylpyridin-4-ylmethyl, 2-cyanopyridin-4- ylmethyl, 2-carbamoylpyridin-4-ylmethyl, [1,2(or l,3)-dimethyl-4-pyridinio]methyl, (1-methyl-2-cyano- 4-pyridinio)methyl, (l-methyl-2-carbamoyl-4- pyridinio) ethyl, [l-(2-protected hydroxyethyl)-4- pyridinio]methyl, said protected hydroxy being acyl or tri(lower)alkylsilyloxy, [l-(2-hydroxyethyl)-4- pyridinio] ethyl, [1-(carbamoylmethyl)-4- pyridinio] ethyl, [2-(hydroxymethyl)pyridin-4- yl]methyl, [2-(hydroxymethyl)-l-methyl-4- pyri
  • R is hydrogen or esterified carboxy.
  • R 1, R2, R3, R4 and R5 are as follows.
  • R is carboxy
  • R is 1-hydroxyethyl
  • R is methyl
  • the compound (I) or salts thereof can be prepared by reacting the compound (II) or a reactive derivative at the oxo group thereof or salts thereof with the compound (III) or salts thereof.
  • Suitable salts of the compound (II) may be salts with bases such as those given for the compound (I) .
  • the reactive derivative at the oxo group of the compound (II) can be represented by the following formula (II 1 ), which is preferably used in this reaction and can be prepared by reacting the compound (II) or salts thereof with an acylating agent. iO -
  • R , R 2 and R3 are each as defined above, and
  • R ⁇ is acyl as exemplified for the imino-protective group and further 0,0-substituted phosphono derived from, for example, organic phosphoric acid mentioned hereinbelow.
  • Suitable acylating agents may include conventional ones which can introduce the acyl group as mentioned above into the compound (II) , and preferable acylating agents may be organic sulfonic or phosphoric acid or its reactive derivative such as acid halide, acid anhydride, and the like, for example, arenesulfonyl halide (e.g. benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc.), arenesulfonic anhydride (e.g.
  • benzenesulfonic anhydride p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, etc.
  • lower alkanesulfonyl halide which may have additional halogen (e.g. methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.), lower alkanesulfonic anhydride which may have halogen (e.g.
  • methanesulfonic anhydride ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.
  • di(lower)alkyl phosphbrohaloridate e.g. diethyl phosphorochloridate, etc.
  • diaryl phosphorohaloridate e.g. diphenyl phosphorochloridate, etc.
  • This acylation reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixture thereof.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as carbodiimide compound [e.g. N,N'- diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'- dicyclohexylcarbodiimide, N-cyclohexyl-N'- morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethyl- aminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethyl- aminopropyDcarbodiimide, etc.]; N,N'-carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole) ; keteneimine compound (e.g.
  • This acylation reaction may be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine, N,N-diisopropyl-N- ethylamine, etc.), pyridine compound [e.g.
  • an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
  • tri(lower)alkylamine e.g. trimethylamine, triethylamine, N,
  • N,N-di(lower)alkylamin ⁇ pyridine such as N,N-dimethylaminopyridine, etc.
  • quinoline N-lower alkylmorpholine (e.g. N-methylmorpholine, etc.), N,N- di(lower)alkylbenzylamine (e.g. N,N-dimethylbenzylamine, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium butoxide, etc.), and the like.
  • reaction temperature of this acylation reaction is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (II') or salts thereof can be used with or without isolation for the subsequent reaction with the compound (III) or salts thereof.
  • Suitable salts of the compound (III) may be the same as those for the compound (I) and silver salt.
  • the reaction of the compound (II) or its reactive derivative or salts thereof with the compound (III) or salts thereof can be carried out in the presence of an organic or inorganic base such as those given in the explanation of the acylation reaction as stated above.
  • This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as those given in the explanation of the acylation reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to a removal reaction of the carboxy-protective group on R a -
  • Suitable salts of the compounds (I-a) and (I-b) may be the same as those for the compound (I) .
  • the present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
  • Suitable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride. etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g.
  • an alkalimetal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride.
  • sodium carbonate, potassium carbonate, etc. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
  • an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.).
  • organic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • the acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. phenol, anisole, etc.).
  • the hydrolysis can be carried out in the presence of tri(lower)alkylammonium halide (e.g. tributylammonium fluoride, etc.).
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
  • the reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g.
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • the reaction is preferably carried out around neutral condition.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • dioxane etrahydrofuran
  • acetic acid e.g. phosphate buffer, acetate buffer, etc.
  • buffer solution e.g. phosphate buffer, acetate buffer, etc.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the carboxy-protective group is allyl group, it can be deprotected by hydrogenolysis using a palladium compound.
  • Suitable palladium compound used in this reaction may be palladium on carbon, palladium hydroxide on carbon, palladium chloride, a palladium-ligand complex such as tetrakis(triphenylphosphine)palladiu (0) , bis(dibenzylideneacetone)palladium(0) , di[l,2-bis(diphenyl phosphino)ethane]palladium(0) , tetrakis(triphenyl phosphite)palladium(0) , tetrakis(triethyl phosphite)- palladium(0) , and the like.
  • a palladium-ligand complex such as tetrakis(triphenylphosphine)palladiu (0) , bis(dibenzylideneacetone)palladium(0) , di[l,2-bis(diphenyl phosphino)ethane]palladium(0) , te
  • the reaction can preferably be carried out in the presence of a scavenger of allyl group generated in situ, such as amine (e.g. morpholine, N-methylaniline, etc.), an activated methylene compound (e.g. dimedone, benzoylacetate, 2-methyl-3-oxovaleric acid, etc.), a cyanohydrin compound (e.g. ⁇ -tetrahydropyranyloxybenzyl cyanide, etc.), lower alkanoic acid or a salt thereof (e.g. formic acid, acetic acid, ammonium formate, sodium acetate, etc.), N-hydroxysuccinimide, and the like.
  • a base such as lower alkyla ine (e.g. butylamine, triethyamine, etc.), pyridine, and the like.
  • This reaction can also be carried out in the presence of a conventional reducing agent such as sodium borohydride, tributyltin hydride, and the like.
  • a conventional reducing agent such as sodium borohydride, tributyltin hydride, and the like.
  • the reaction can preferably be carried out in the presence of the corresponding ligand (e.g. triphenylphosphine, triphenyl phosphite, triethyl phosphite, etc.).
  • the corresponding ligand e.g. triphenylphosphine, triphenyl phosphite, triethyl phosphite, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, acetic acid, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, acetic acid, etc., or a mixture thereof.
  • the removal reaction can be selected according to the kind of carboxy-protective group to be removed.
  • the present process includes within the scope thereof a case that the i ino-protective group of R is removed at the same time during the reaction.
  • the compound (I-d) or salts thereof can be prepared by subjecting the compound (I-c) or salts thereof to a removal reaction of the imino-protective group on R .
  • Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I) .
  • This reaction is usually carried out by a conventional method such as hydrolysis, reduction and the like.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the present process includes within the scope thereo)ff aa ccaassee tthhaatt tthhee ccaarrbbooxxyy--pprrootteeccttiivvee ggnroup on R is removed at the same time during the reaction.
  • the compound (I-f) or salts thereof can be prepared by reacting the compound (I-e) or salts thereof with the compound (IV) .
  • Suitable salts of the compounds (I-e) and (I-f) may be the same as those for the compound (I) .
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dioxane, tetrahydrofuran, acetone, acetonitrile, etc., or a mixture thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
  • the compound (I-h) or salts thereof can be prepared by subjecting the compound (I-g) or salts thereof to a
  • Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I) .
  • This reaction is usually carried out by a conventional method such as hydrolysis, reduction and the like.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the present process includes within the scope thereof a case that the carboxy-protective group on R and/or imino-protective group of R are removed at the same time during the reaction.
  • the compound (I-j) or salts thereof can be prepared by reacting the compound (I-i) or salts thereof with acid anhydride.
  • Suitable salts of the compounds (I-i) and (I-j) may be the same as those for the compound (I) .
  • Said acid anhydride is used only for preparing reactive derivative at the hydroxy group of the compound (I-i).
  • Suitable reagent which can prepare following reactive derivatives at the hydroxy group of the compound (I-i), can be used in this reaction.
  • Suitable reactive derivative at the hydroxy group of the compound (I-i) may include a conventional one such as halide (e.g. iodide, etc.), trifluoromethanesulfonate prepared by, for example, reactive with trifluoromethanesulfonic anhydride, and the like.
  • This reaction can be carried out in the presence of a base such as those mentioned in the explanation of Process 2.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
  • a liquid base can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (I- ) or salts thereof can be prepared by subjecting the compound (I-k) or salts thereof to a
  • Suitable salts of the compounds (I-k) and (I-i) may be the same as those for the compound (I) .
  • This reaction is usually carried out by a conventional method such as hydrolysis, reduction and the like.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the present process includes within the scope thereof a case that the protective groups on R , R 4 and/or R *** - 1 is(are) removed at the same time during the reaction.
  • the compound (Ill-a) or salts thereof can be prepared by reacting the compound (IV) or a reactive derivative at the hydroxy group thereof or salts thereof with the compound (V) or salts thereof.
  • Suitable salts of the compounds (III-a) and (IV) may be the same as those for the compound (I).
  • Suitable salts of the compound (V) may be salts with bases such as those given for the compound (I) .
  • Suitable reactive derivative at the hydroxy group of the compound (IV) may include a conventional one such as halide (e.g. chloride, bromide, iodide, etc.), sulfonate (e.g. ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.), and the like, in which more preferable example may be sulfonate.
  • the starting compound (IV) of this method is new and can be prepared by the methods described in the Preparations mentioned below.
  • the compound (V) may be ar(lower)alkanethiol such as mono- or di- or triphenyKlower)alkanethiol (e.g. phenylmethanethiol, diphenylmethanethiol, triphenylmethanethiol, etc.), thio(lower)alkanoic S-acid (e.g. thioacetic S-acid, etc.) or salts thereof, thioarenoic S-acid or salts thereof (e.g.
  • thiobenzoic S-acid, etc. in which more preferable example may be triphenyl(C.,- C.)alkanethiol, thio(C,-C.)alkanoic S-acid or alkali metal salts thereof and thio(C 8 -C. 0 )arenoic S-acid or alkali metal salts thereof, and the most preferable one may be triphenylmethanethiol, thioacetic S-acid and potassium thioacetate.
  • the starting compound (IV) of the present reaction is preferably used in the form of its reactive derivative at the hydroxy group, and in, such a case, this reaction is usually carried out in the presence of an organic or inorganic base such as those exemplified in the explanation of Process 2.
  • suitable example of compound (V) may be thio(lower)alkanoic S-acid or thioarenoic S-acid
  • this reaction is preferably carried out in the presence of a conventional condensing agent such as combination of triarylphosphine (e.g. triphenylphosphine, etc.) and di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, etc.).
  • a conventional condensing agent such as combination of triarylphosphine (e.g. triphenylphosphine, etc.) and di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, etc.).
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, methanol, ethanol, propanol, pyridine, N,N-dimethylformamide, 4-methyl-2- pentanone, tetrahydrofuran, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as dichloromethane, methanol, ethanol, propanol, pyridine, N,N-dimethylformamide, 4-methyl-2- pentanone, tetrahydrofuran, etc., or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (III) or salts thereof can be prepared by subjecting the compound (III-a) or salts thereof to elimination reaction of the mercapto-protective group.
  • This elimination reaction can be carried out by a conventional method as described below, which can be selected according to the kind of mercapto-protective group to be eliminated.
  • the protective groups may be ar(lower)alkyl group
  • it can generally be eliminated by treating, for example, with a silver compound (e.g. silver nitrate, silver carbonate, etc.).
  • a silver compound e.g. silver nitrate, silver carbonate, etc.
  • the reaction with the silver compound as stated above is preferably carried out in the presence of an organic base (e.g. pyridine, etc.).
  • the resultant silver salt of compound (III) can be transformed into its alkali metal salt, if necessary, by reacting with alkali metal halide (e.g. sodium iodide, potassium iodide, etc.).
  • alkali metal halide e.g. sodium iodide, potassium iodide, etc.
  • the protective groups may be acyl group
  • it can generally be eliminated by solvolysis such as hydrolysis using an acid or base, alcoholysis using a base, and the like.
  • Suitable acid or base used in these reactions may be the same such as those given in the explanation of hydrolysis of the Process 2.
  • the hydrolysis is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, etc.), pyridine, N,N-dimethylformamide, etc., or a mixture thereof, and further in case that the base or acid to be used is in liquid, it can also be used as a solvent.
  • the alcoholysis is usually carried out in a conventional alcohol such as methanol, ethanol, and the like.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the object compounds obtained according to the above Processes can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
  • the object compound (I) and pharmaceutically acceptable salts thereof of the present invention are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as antimicrobial agents.
  • the object compound (I) possessing more potent antimicrobial activity can be represented by the following formula :
  • R 2, R3 and R4 are each as defined above, and pharmaceutically acceptable salts thereof.
  • the compound (I) possessing the most potent antimicrobial activity can be represented by the following formula:
  • R 3 and R4 are each as defined above, and pharmaceutically acceptable salts thereof.
  • the object compound (I) and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between 1 mg and about 4,000 mg or even more per day may be administered to a patient.
  • An average single dose of about 1 mg, 10 mg, 50 mg, 100 mg, 250 g, 500 mg, 1000 mg, 2000 mg, of the object compound (I) of the present invention may be used in treating diseases infected by pathogenic microorganisms.
  • IR (Film) 3450, 3315, 2950, 2930, 2850, 1695, 1605, 1560 era "1
  • IR (Film) 3055, 2940, 2235, 1700, 1650, 1595,
  • the resin was filtered off and washed with a mixture of ethanol (50 ml) and dichloromethane (50 ml). The filtrate and washing were collected and evaporated in vacuo to give a residue.
  • ethanol 140 ml
  • hydrazine hydrate 4.1 ml
  • the resulting precipitates were filtered off and washed with ethanol (20 ml).
  • the filtrate and washing were combined and evaporated in vacuo to give a residue.
  • the residue was dissolved in ethyl acetate (100 ml).
  • the mixture was stirred at 80-90°C for 3 hours .
  • the reaction mixture was poured into ice- water (200 ml) and extracted three times with ethyl acetate (200 ml).
  • the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo.
  • the resulting residue was chromatographed on silica gel (200 g) eluting with a mixture of chloroform and methanol (19:1, V/V).
  • the mixture was diluted with dichloromethane (60 ml) and ion exchange resin amberlyst A-26 (Cl * type) (which is pretreated with methanol and dichloromethane, and dried) (30 ml) was added. The mixture was stirred at room temperature for 40 minutes and filtered. The resin was washed with a mixture of dichloromethane and methanol
  • Example 2-8) (4R,5S,6S)-3-[ (2R,4S)-2- ⁇ (1,2-Dimethyl-4- pyridinio)methyl ⁇ pyrrolidin-4-yl]thio-6-[ (1R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid chloride was obtained in the same procedure as that of Example 2-5).
  • IR (KBr) 3429, 1770, 1697, 1645 cm" 1
  • Example 3-1) To a solution of allyl (4R,5S,6S)-3-[ (2R,4S)-1- allyloxycarbonyl-2-[ ⁇ 1-(2-t-butyldimethylsilyloxyethyl)-4- pyridinio ⁇ methyl]pyrrolidin-4-yl]thio-6-[ (1R)-1- hydroxyethyl-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- 2-carboxylate trifluoromethanesulfonate in tetrahydrofuran (80 ml) were added acetic acid (2.28 ml) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 38 ml) at room temperature.
  • the aqueous layer was concentrated and chromatographed on Diaion HP-20 (Trademark, made by Mitsubishi Kasei Co.) ( I t ) eluting with a mixture of water and acetonitrile (95:5).
  • the fractions containing the desired compound were collected and passed through ion exchange resin (Amberlyst A-26 (Cl- type)) (30 ml). Obtained solution was concentrated and lyophilized.
  • Example 3-2 (4R,5S,6S)-3-[ (4S)-2-[l-(Carbamoylmethyl)-4- pyridinio]methylpyrrolidin-4-yl]thio-6-[ (1R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid chloride was obtained in 11.3% yield in substantially similar manner as that of Example 3-8).
  • IR (Nujol) 1750, 1690 cm -1
  • the solution was adjusted to pH 3.5 by addition of IN hydrochloric acid and chromatographed on SP-205 (Trademark, made by Mitsubishi Chemical Industries) (60 ml) and eluted with 5-10% aqueous acetonitrile.
  • Example 3-5 The following compound was obtained by the similar manner to that of Example 3-3).
  • Example 3-6 The following compound was obtained by the similar manner to that of Example 3-4).
  • Example 3-7) To a solution of allyl (4R,5S,6S)-3-[ (2R,4S)-1- allyloxycarbonyl-2- ⁇ (2S)-2-(3-methyl-l- imidazolio)propyl ⁇ pyrrolidin-4-yl ⁇ thio-6-[ (1R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate iodide (1.65 g), triphenylphosphine (126 mg), acetic acid (0.55 ml) and tetrakis(triphenylphosphine)palladium(0) (111 mg) was added tributyltin hydride (2.59 ml) with stirring at ambient temperature.
  • Example 4-3) (4R,5S,6S)-3-[(2R,4S)-2- ⁇ (2-Hydroxymethyl-l,3- dimethyl-4-imidazolio)methyl ⁇ pyrrolidin-4-yl]thio-6-[ (IR)- 1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid chloride (485 mg) was obtained in substantially the same manner as that of Example 4-1). IR (Nujol) : 1730 crn -1
  • the precipitate was dissolved in water (200 ml) and washed with ethyl acetate (100 ml x 2).
  • the aqueous layer was applied to a column of Amberlist A-26 (Cl-) (60 ml).
  • the eluate and washing were concentrated in vacuo to ca. 500 ml.
  • the obtained solution was adjusted to pH 6 with 5% aqueous sodium carbonate and the solution was chromatographed on nonionic adsorption resin, Diaion HP-20 (600 ml) eluting in turn with water and 10% aqueous acetonitrile.
  • the fractions containing the desired compound were collected and adjusted to pH 8.0 with 5% aqueous sodium carbonate.
  • the precipitate was dissolved in water (250 ml) and washed with dichloromethane (x 2).
  • the aqueous solution was adjusted to pH 6 with IN-hydrochloric acid and chromatographed on nonionic adsorption resin, Diaion SP-205 (Trademark, made by Mitsubishi Kasei Co.) (620 ml) eluting in turn with water and 10% aqueous acetone.
  • Diaion SP-205 Trademark, made by Mitsubishi Kasei Co.
  • the fractions containing the desired compound were collected and concentrated in vacuo.
  • the resulting residue was passed through ion exchange resin, Amberlist A-26 (Cl- tyP e ) (60 m l) eluting with water.
  • Example 5-1) A solution of (2R,4S)-l-Allyloxycarbonyl ⁇ 2-[ (2- methyl-l-carbamoylmethyl-3-pyrazoliomethyl]-4- (tritylthio)pyrrolidine trifluoromethanesulfonate (284 mg) in dichloromethane (3 ml) was cooled to 0°C and treated successively with trifluoroacetic acid (444.7 mg) and triethylsilane (54.4 mg) . After 10 minutes at 0°C and 30 minutes at ambient temperature the mixture was evaporated under reduced pressure. The residue was washed three times with n-hexane (5 ml) and concentrated in vacuo.
  • Example 5-2 (4R,5S,6S)-3-[ (2R,4S)-2- ⁇ (l-Methyl-2- carbamoylmethyl-4-pyrazolio)methyl ⁇ pyrrolidin-4-yl]thio-6- [ (IR)-1-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid chloride (100 mg) was obtained by the same procedure as Example 5-1) .
  • Example 6-2 To a solution of allyl (4R,5S,6S)-3-[ (2R,4S)-1- allyloxycarbonyl-2- ⁇ (1-methyl-l,2,3-triazol-5- yl)methyl ⁇ pyrrolidin-4-yl]thio-6-[ (IR)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.03 g) in dichloromethane (20 ml) was added methyl trifluoromethanesulfonate (0.264 ml) at room temperature. The mixture was stirred for 30 minutes. Dichloromethane was evaporated under reduced pressure.
  • the aqueous solution was adjusted to pH 6 with IN-hydrochloric acid and chromatographed on nonionic adsorption resin Diaion SP-205 (Trademark, made by Mitsubishi Kasei Co.) (50 ml) eluting in turn with water and 8% aqueous acetone.
  • Diaion SP-205 Trademark, made by Mitsubishi Kasei Co.
  • the fractions containing the desired compound were collected and concentrated in vacuo.
  • the resulting residue was passed through ion exchange resin, Amberlist A-26 (Cl- type, Trademark, made by Rohm and Haas Co. Ltd.) (5 ml) eluting with water.
  • the solid was dissolved in water (5 ml) and the solution was chromatographed on nonionic adsorption resin, Diaion HP-20 (Trademark, made by Mitsubishi Chemical Industries) (10 ml) eluting in turn with water (30 ml) and 5% aqueous acetone (60 ml). The fractions containing the desired compound were collected and evaporated in vacuo. The resulting residue (20 ml) was passed through ion exchange resin, Amberlist A-26 (Cl- type, Trademark, made by Rohm and Haas Co., Ltd.) (5 ml) eluting with water (40 ml).
  • Example 9-4) To a solution of allyl (4R,5S,6S)-3-[ (2R,4S)-1- allyloxycarbonyl-2- ⁇ 2-(l-methylimidazol-5- yl)ethyl ⁇ pyrrolidin-4-yl]thio-6-[ (IR)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (4.33 g) in acetone (20 ml) was added iodoacetamide (4.41 g) with stirring at ambient temperature and then allowed to stand overnight.
  • Example 9-5) (4R,5S,6S)-3-[(2R,4S)-2- ⁇ 2-(l-Carbamoylmethyl-3- methyl-4-imidazolio)ethyl ⁇ pyrrolidin-4-yl]thio-6-[ (IR)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid chloride (201 mg) was obtained in substantially the same manner as that of Example 3-7). IR (Nujol) : 1730, 1670, 1550 cm -1

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Abstract

L'invention concerne un composé de formule (I), dans laquelle R1 représente carboxy, etc., R2 représente hydroxyalkyle (inférieur), etc., R3 représente hydrogène ou alkyle inférieur, R4 représente 2(ou 3)-méthylpyridin-4-ylméthyle, etc., et R5 représente hydrogène ou un groupe imino-protecteur. Ce composé et ses sels pharmaceutiquement acceptables s'utilisent comme agents antimicrobiens.
EP94927783A 1993-10-08 1994-09-27 Derives de 3-pyrrolidinylthio-carbapenem et leur activite antimicrobienne Withdrawn EP0722447A1 (fr)

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KR100473365B1 (ko) * 2002-10-18 2005-03-10 주식회사 하원제약 옥사디아졸고리를 포함하는 피롤리딘 치환체를 가지는1-베타메틸카바페넴 유도체 및 그 제조방법

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US4963544A (en) * 1988-05-23 1990-10-16 Fujisawa Pharmaceutical Company, Ltd. 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds
EP0636133A1 (fr) * 1992-04-13 1995-02-01 Fujisawa Pharmaceutical Co., Ltd. 3-pyrrolidinylthio-carbapenemes substitues, utilises comme agents antimicrobiens
JPH0737259A (ja) * 1993-07-23 1995-02-07 Ricoh Co Ltd 光ディスク装置の構成方法

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