WO1994005667A1 - Derives de carbapenem et procedes pour leur preparation - Google Patents

Derives de carbapenem et procedes pour leur preparation Download PDF

Info

Publication number
WO1994005667A1
WO1994005667A1 PCT/KR1993/000079 KR9300079W WO9405667A1 WO 1994005667 A1 WO1994005667 A1 WO 1994005667A1 KR 9300079 W KR9300079 W KR 9300079W WO 9405667 A1 WO9405667 A1 WO 9405667A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
methyl
lower alkyl
compound according
Prior art date
Application number
PCT/KR1993/000079
Other languages
English (en)
Inventor
Min Sun Chang
Jon In Lim
Nam Sik Kim
Hee Chan Shin
Gye Won Kim
Ji Young Kim
Jae Keol Rhee
Chon Woo Lee
Weon Bin Im
Dong Sung Kim
Original Assignee
Dong-A Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dong-A Pharmaceutical Co., Ltd. filed Critical Dong-A Pharmaceutical Co., Ltd.
Priority to JP6507064A priority Critical patent/JPH08502732A/ja
Priority to EP93919700A priority patent/EP0658162A1/fr
Publication of WO1994005667A1 publication Critical patent/WO1994005667A1/fr
Priority to KR1019950700834A priority patent/KR950702989A/ko

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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 carbapenem
  • Actinomycets, Streptomyces cattleya has antibacterial activity against gram negative gram positive bacteria.
  • Thienamycin has strong antibacterial activities, however, thienamycin itself is chemically unstable and has been reported to be decomposed in vivo by enzymes such as renal dehydropeptidase I (hereinafter referred to DHP-I), whereby the antibacterial activities decrease, and the urinary recovery is low (Antimicrob.
  • DHP-I renal dehydropeptidase I
  • ⁇ -lactam antibiotics exhibit selective antibacterial activity and show little or no toxic effects against animal cells. Therefore, they are widely used in treatment of infectious disease caused by bacteria. Especially useful one carbapenem compounds which have a broad antibacterial spectrum against gram positive and gram negative, and lower toxicity than other antibacterial agents.
  • the present invention provides novel carbapenem derivatives having an alkyloxyimino, a hydroxyimino or a hydrazono group at 2' position of pyrrolidine, which show having excellent antibacterial activities particularly against gram positive and gram negative together with high stability against DHP-I.
  • the present invention provides a compound of the formula (I)
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom, a metal or a nonmetal salt group, or a carboxy protecting group.
  • the metal or nonmetal salt group of the general formula (I) represents an alkali metal salt such as sodium salt or potassium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; an ammonium salt; an aliphatic salt such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N',N'-dibenzylethyleneamine salt, dibenzylamine salt; an acid addition salt, for example, an inorganic salt such as hydrochloride, hydrobromide, sulfate, phosphate; an organic salt such as formate, acetate, trifluoracetate, malate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate; or intermolecular quaternary salt.
  • an inorganic salt such as hydrochloride, hydrobromide, sulfate, phosphate
  • an organic salt such as
  • the carboxy protecting group may, for example, be a lower alkyl group or an esterified carboxyl group which is mentioned below.
  • the above-mentioned ester group includes at least one appropriate substituent, for example, a lower alkanoyloxy(lower)alkyl group such as an acetoxymethyl group, a propionyloxymethyl group, a butyryloxymethyl group, a valeryloxymethyl group, a pivaloyloxymethyl group, a hexanoyloxymethyl group; a lower alkanesulfonyl(lower)alkyl group such as a 2-methylethyl group; a mono(or di, or tri)halo(lower)alkyl group such as a 2-iodomethyl group, a 2 , 2 , 2- trichloroethyl group; a lower alkoxycarbonyloxy(lower)alkyl group such as a methoxycarbonyloxymethyl group, an ethoxyca rbonyloxymethyl group , a propoxycarbonyloxymethyl group, a t-butoxycarbonyloxy
  • “Lower” means that the number of carbon is 1 to 6.
  • the “Lower alkyl” includes a normal or a side alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, and hexyl.
  • “Lower alkoxy” also includes a normal alkoxy or a side alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy.
  • R 3 represents a hydrogen atom, an imino protecting group or a pharmaceutically acceptable salt.
  • An appropriate "imino protecting group” may be a carbamoyl, an aliphaticacyl, an aromaticacyl, heterocyclicacyl, an aliphaticacyl substituted with an aromatic group, an aliphaticacyl substituted with a heterocyclic group, all of which are derived from a carboxylic acid, a carbonic acid, a sulfonic acid, or a carbamic acid.
  • the aliphatic acyl includes a saturated or unsaturated acyclic or cyclicacyl, for example, a lower alkanoyl such as formyl, acetyl, propionyl, butyl, isobutyryl, valeryl, isovaleryl, pivaroyl, and hexanoyl; a lower alkylsulfonyl such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl; a carbamoyl; an N-alkylcarbamoyl such as methylcarbamoyl, and ethylcarbamoyl; a lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbon
  • the aromatic acyl includes an aroyl such as benzoyl, toluyl, and xyloyl; an N-arylcarbamoyl such as N-phenylcarbamoyl, N-tolylcarbamoyl, and N-naphtylcarbamoyl; an arensulfonyl such as benzensulfonyl, and tosyl.
  • the heterocyclic acyl includes a heterocyclic acyl such as proyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl.
  • the aliphatic acyl substituted with an aromatic group includes an aralkanoyl, for example, a phenyl(lower)alkanoyl such as phenylacetyl, phenylpropionyl, and phenylhexanoyl; an aralkoxycarbonyl , for exampl e , a phenyl(lower)alkoxycarbonyl such as a benzyloxycarbonyl, and penetyloxycarbonyl; an aryloxyalkanoyl, for example, a phenoxy(lower)alkanoyl such as phenoxyacetyl and phenoxypropinoyl.
  • aralkanoyl for example, a phenyl(lower)alkanoyl such as phenylacetyl, phenylpropionyl, and phenylhexanoyl
  • an aralkoxycarbonyl for exampl e ,
  • the aliphatic acyl substituted with a heterocyclic group includes a heterocyclic(lower)alkanoyl, for example, a heterocyclic(lower)alkanoyl such as thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, and thiadiazolylpropionyl.
  • a heterocyclic(lower)alkanoyl such as thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, and thiadiazolylpropionyl.
  • the above-mentioned acyl group can be substituted with one or more substitutents selected from the group consisting of a lower alkyl such as methyl, ethyl , propyl , i sopropyl , butyl , pentyl , and hexyl ; a halogen such as chlorine, bromine, iodine, and fluorine; a lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, and hexyloxy; a lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, and hexylthio; nitro.
  • a lower alkyl such as methyl, ethyl , propyl , i sopropyl , butyl , pentyl , and he
  • the preferable acyl group having such substitutes are selected from the group consisting of a mono(or di, or tri)halo alkanoyl such as chloroacetyl, bromoacetyl, dichloroacetyl, and trifluoroacetyl; a mono(or di or tri)haloalkoxycarbonyl such as chloromethoxycarbonyl, di chl o romethoxyca rbonyl , and 2 , 2 , 2 -trichloroethoxycarbonyl; a nitro(or halo, or lower alkoxy) ; an aralkoxycarbonyl such as nitrobenzyloxylcarbonyl, chlor Tavernzyloxycarbonyl, methoxybenzyloxycarbonyl, mono(or di, or tr i ) halo (lower )aklyl sulf onyl such as fluoromethylsulfonyl, difluoromethylsulfonyl, tri
  • the "imino protecting group” is preferably (C 1 -C 4 ) alkenyloxycarbonyl, phenyl(C 1 -C 4 )alkoxycarbonyl, o-nitro(or m-nitro, or p-nitro)benzyloxycarbonyl, and o-methoxy(or m-methoxy, or p-methoxy)benzyloxycarbonyl.
  • R 4 represents a hydrogen atom, lower alkyl group, a hydroxy group, a cyano group, a halogen group such as chlorine, bromine, iodine, and fluorine.
  • R 5 represents a hydroxy group, a lower alkoxy group, a protected or unprotected amino group, or one of the following general formula (1)-(4);
  • R 6 and R 7 are independently either a hydrogen atom or a lower alkyl group.
  • R 8 is a hydroxy group, a cyano group, a halogen atom such as chlorine, bromine, iodine, fluorine, or a heterocyclic group of a 5-or 6-membered ring containing 1 to 4 heteroatoms which may be optionally substituted with an appropriate substituent, a protected or unprotected amino group, a the following general formula,
  • R 9 is a lower alkylsulfonyl such as methylsulfonyl, halo(C 1 -C 4 )alkylsulfonyl, a phenyl(C 1 - C 4 )alkylsulfonyl such as a p-toluenesulfonyl, and a N,N-(lower)dialkylsulfamoyl such as a N,N-dimethylsulfamoyl.
  • R 6 is the same as defined above.
  • R 6 , R 7 are the same as defined above.
  • R 6 is the same as defined above
  • R 10 is a lower alkyl group, a lower alkylsulfonyl group, a halo lower alkylsulfonyl group, a phenyl (C 1 -C 4 )alkylsulfonyl group, an N-(lower)alkylsulfamoyl group, an N,N- (lower)dialkylsulfamoyl group, a heterocyclic group of a 5-or 6-membered ring containing 1 to 4 heteroatoms which may be optionally substituted by an appropriate substituent, a protected or unprotected amino group, of the following general formula, wherein R 11 is a , a , a halogen atom, a hydroxy group, a cyano group, the group of which can be substituted at one of the o-, m-, or p-positions of a phenyl group, and R 6 , R 7 are the same as defined
  • the heterocyclic group of a 5-or 6-membered ring containing 1 to 4 heteroatoms includes an unsaturated 5 or 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolidiyl, imidazolyl(such as 2-imidazole), imidazolinyl(such as 2-imidazolinyl), pyrazolyl, pyrazolinyl, pyridyl, pyridyl N-oxide, pyridinio, dihydropyridyl , tetrahydropyridyl ( such as 1,2,3,6-tetrahydropyridyl), pyrimidinyl, pyrimidinio, pyrazinyl, pyrazinio, pyridazinyl(such as 1,3,5-triazinyl-, 1,2,4-triazinyl and 1,2,3-triazinyl), te
  • the above-mentioned heterocyclic group can be substituted with 1 to 3 substituents selected from the group consisting of an amino group; an amino protecting group which is the same as the imino protecting group defined above; a lower alkylamino( such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino); ureido(lower)alkyl (such as ureidomethyl, ureidoethyl, ureidopropyl, ureidohexyl); carbamoyl; a lower alkyl as defined above; an amino(lower)alkyl(such as aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl); a hydroxy(lower)alkyl and protected hydroxy(lower)alkyl; an azido(lower)alkyl(such as azidomethyl, azid
  • the "protected hydroxy(lower)alkyl” includes a phenyl(C 1 -C 4 )alkoxycarbonyloxy(C 1 -C 4 )alkyl having a nitro group; a triphenyl(C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl having a nitro group; a tri(C 1 -C 4 )alkylsilyloxy(C 1 -C 4 )alkyl having a nitro group.
  • thiazolyl has the group of an amino or protecting amino group at the 2-position, or an 1,2,4- oxadiazolyl having the group of an amino or protecting amino group at the 3 position, the above-mentioned heterocyclic groups have "tautomeric isomers" as shown in the following formula;
  • R 12 is an amino or a protected amino group
  • R 13 is an imino or a protected imino group
  • 3-amino(or protected amino)-1,2,4-oxadi,zolyl is shown in the following formula, wherein the "protected amino group” includes the amino group which has one of the group of C1-C4 alkoxycarbonyl such as t-butyloxycarbonyl; a halo(C1-C3)alkoxycarbonyl such as 2-iodoethyloxycarbonyl, and 2,2,2-trichloroethyloxycarbonyl); a substituted or unsubstituted al(lower)alkyloxycarbonyl; a substituted or unsubstituted phenyl(C1-C3)alkyloxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, and p-nitorbenzyloxycarbonyl; tri(C1-C4)alkylsilyl such as trimethylsilyl and t-but
  • the present invention provides a process for preparing a compound of the following (IV),
  • R 14 is not difined above, reacting a compound of the following formula (II),
  • R 14 is hydrogen or a hydroxyl protecting group, with a compound of the following formula (III)
  • R 3 , R 4 and R 5 are the same as defined above, and provide useful steps to synthesize the above compound III. Further, the present invention confirms that a compound of the general formula (I) shows effective antibacterial activities and low toxicity (Tables 1, 2, 3).
  • the compound of the present invention has the basic structure as follows:
  • the present invention includes optical isomers based on the asymmetrical carbon atoms at the 1-position, 5-position, 6-position and 8-position of the carbapenem structure.
  • optical isomers based on the asymmetrical carbon atoms at the 1-position, 5-position, 6-position and 8-position of the carbapenem structure.
  • isomers is a preferred compound of a (5R,6R,8R) configuration, i.e., a compound having the same stereo-configuration (5R,6S) (5,6-trans) as thienamycin in which the carbon atom at the 8-position takes an R-configuration, or a compound of a (1R,5S,6S,8R) configuration where a methyl group is present at the 1-position.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the 2'-(N-substituted)pyrrolidin-4'-yl-thio group also includes all prossible isomers based on the asymmetrical carbon atoms at the 2- and 4-positions of the pyrrolidine structure.
  • preferred compounds are of a (2'S,4'S) configuration and a (2'R,4'S) configuration.
  • (lower)alkoxide group R 6 of group is a hydrogen atom or a
  • the compound of formula (II) should be converted to its reactive derivatives before reacting with the formula (III). That is, the compound of formula (II) is added to the inert organic solvent and reacted with activating agents under alkali conditions to obtain the activating derivatives of the formula (II-a),
  • the activating reagent to be used for the reaction may, for example, be an acid anhydride such as methanesulfonic anhydride, trifluromethanesulfonic anhydride, p-toluene sulfonic anhydride, and trifluoroacetic anhydride; or an acid chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride or diphenyl chlorophosphate. Particulary preferred is diphenylchlorophosphate.
  • A is a leaving group such as trifluoroacetoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or diphenoxyphosphoryloxy. Particularly preferred is a diphenoxyphosphoryloxy group.
  • the inert organic solvent to be used for the reaction may, for example, be methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, diethylether, tetrahydrofuran, dioxane, benzene, toluene, chlorobenzene, acetone, ethylacetate, acetonitrile, N,N-dimethylformamide, hexamethylphosphorictriamide or a mixture of such solvent.
  • Particulary preferred is acetonitrile, benzene, toluene, the mixture of toluene and benzene, or the mixture of toluene and ethylacetate.
  • the base to be used for the reaction may, for example, be trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]endec-7-ene(DBU), or 1,5-diazabicyclo[4,3,0]-non-5-ene(DBU), or pyridine 4 -dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline. Particularly preferred is N,N-diisopropylethylamine and triethylamine.
  • reaction temperature is not important, the reaction is conducted usually within a temperature range of from -40° to 50°C, preferably -20° to 20°C, and usually completed quantitatively in from 0.5 to 3 hours.
  • reaction product After completion of the reaction, the reaction product is treated to obtain the reactive derivative (Il-a) quantitatively.
  • the compound of the formula (II-a) may be reacted with the compound of the formula (III) without isolation.
  • the reaction is conducted using the above- mentioned inert organic solvent and the base and from 1 to 2 mol, preferably from 1 to 1.5 mol, of the base and from 0.8 to 1.2 mol of the compound of the formula (III) are used per mol of the compound of the formula(II-a).
  • the reaction is conducted usually within a temperature range of -40° to 50°C, preferably from -20° to 20°C and usually completed quantitatively in from 0.5 to 75 hours.
  • the compound of the formula (IV) can be prepared in one pot reaction from the compound of the formula (II), namely, without isolating the reactive derivative of the formula (II-a).
  • the base is employed per mol of the compound of the formula (II).
  • a compound of the formula (I) can be obtained, if necessary, by removing a protecting group for a hydroxyl group, an imino group and a carboxyl group.
  • the method varies depending upon the type of the protecting groups .
  • the removal can be conducted in accordance with methods known in the are, for example, by addition of a solvent for decomposition; by chemical reduction using salt of an amine, a metal such as zinc amalgam, a chromic compound such as chloro chromous, a formyl chromous together with an organic or inorganic acid such as acetic acid, propionic acid, hydrochloric acid, hydrosulfuric acid; or by catalytic hydrogenation using a platinum or palladium compound.
  • the protecting group of the hydroxyl group, amino group or the imino group is an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group
  • the protecting group for the carboxyl group is an aralkyl group such as a benzyl group, a p-nitrobenzyl group or a benzhydryl group.
  • Such protecting groups can be removed by catalytic hydrogenation by means of a platinum catalyst such as platinum oxide, platinum wire or platinum black, or a palladium catalyst such as palladium black, palladium black, palladium oxide, palladium carbon or palladium hydroxide carbon (Pearlman's catalyst).
  • the protecting group of the carboxyl group is an allyl group, allylisopropenyl
  • a palladium ligand complex catalyst such as palladium-carbon, palladium black, palladium hydroxide-carbon, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (O) , bis(dibenzylidenylacetone)-palladium (O), di(1,2-bis(diphenylphospino(ethane)palladium, and tetrakis(triphenylphosphine)palladium (O).
  • a palladium ligand complex catalyst such as palladium-carbon, palladium black, palladium hydroxide-carbon, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (O) , bis(dibenzylidenylacetone)-palladium (O), di(1,2-bis(dipheny
  • the reaction can be completed in from 0.5 to 8 hours at a temperature within a range of from 0° to 40°C under a hydrogen gas stream of from 1 to 3 atm.
  • a solvent useful for the reaction includes, for example, acetone, diethyl ether, tetrahydrofuran, dioxane, ethylacetate, acetonitrile, methylenechloride, chloroform and the solvent mixture thereof.
  • the allyl group- capturing agent may be, for example, sodium 2-ethylhexanoate, potassium 2 -ethylhexanoate, pyridine, piperidine.
  • the reaction is conducted usually within a temperature range of from -10° to 50°C, preferably from 0° to 30 C° using from 0.01 to 0.5 mol of the palladium ligand complex catalyst and from 0.5 to 5 mol of the nucleophilic agent relative to 1 mol of the compound of the formula (IV), and the reaction is completed usually in from 0.5 to 5 hours.
  • the compound of the formula (I) can be isolated by column chromatography loading on silica gel, adsorptive resin such as Diaion HP-29, or freeze drying or crystallization.
  • the compound of the formula (II) as the starting material can be obtained by the Salzmann method (J. Am. Chem. Soc. Vol 102, 6161-6163, 1980) which is incorporated herein by reference in the case that R 1 is a hydrogen atom, and by Shih method (Heterocycles, Vol. 21, 29-40, 1984 or EP No. 272,455) which are incorporated herein by reference in the case where R 1 is a methyl group.
  • the compound of the formula (III) as the starting material can be obtained by the following scheme 1 or scheme 2.
  • Imipenem was used as internal standard material. After 10 ml of Mueller Hinton Broth was poured into the sterilized test tubes, one platinum loop of each test microorganism was inoculated and incubated overnight at 37°C. Staphylococcus aureus was cultured in Trypticase Soy Broth instead of Mueller Hinton Broth.
  • the antibacterial agent solutions were prepared by dissolving 5 mg of each antibacterial agent in sterilized distilled water to give the concentration of 1 mg/ml, and by preparing a two-fold dilution series to concentration of 0.25 ⁇ g/ml.
  • MIC Minimal Inhibitory Concentration Test. 0.11 ml of bacterial culture was poured into a sterilized test tube containing 10 ml of buffered saline gelatin (BSG) solution and thoroughly mixed. The agar plate containing the antibacterial agent was then inoculated with a bacterial suspension using a stamp, and cultured at 37°C for 18 hours. After observing the growth of bacteria, MIC was considered to be the lowest drug concentration at which there is no growth. The results are shown in table 1.
  • the above precipitates were dissolved in a Tris buffer, and loaded on DEAE-Sepharose fast flow, and anion exchange chromatography was carried out to give the swine DHP-I.
  • the above DHP-I was divided into 1ml portion of the concentration of 1 unit/ml and stored at 0°-70°C.
  • Glycyldehydrophenylalanie GDP
  • imipenem Glycyldehydrophenylalanie
  • Campbell's method Method of Engymol. 19:722-729, 1970 incorporated herein by reference, the decrease in absorbence due to enzyme reaction is observed, and can be used to determine the maximum hydrolysis velocity.
  • the stability to DHP-I is represented as the comparative hydrolysis velocity to that of GDP.
  • the antibacterial agent solution was prepared by a four-fold dilution series to 0.781 mg/ml using the sterilized test tube. After 0.2 ml of the antibacterial solution was administered to the tail vein of a 4-5 weeks old aged ICR mouse with 20 + 1g weight and observed for 2 weeks. The LD 50 was determined by probit analysis. The numbers of both male and female are five, respectively.
  • the compounds of the present invention have excellent antibacterial activities against various gram positive bacteria and gram negative bacteria and are useful as antibacterial agents for treatment and prevention of human infectious diseases caused by such bacteria. Because of the broad antibacterial spectrum the compounds of the present invention may be used in the form of additives for animal food, preserving agents, and other sterilization and disinfection agents for industrial use as well as medical use.
  • the compound of the present invention may be used in the form of drug formulation suitable for nonoral administration, oral administration, external administration; liquid formulation such as injection solutions, syrups or emulsions; solid formulation such as tablets, capsules or granules; and external application formulations such as ointments or suppositions.
  • Dosage varies depending upon the condition of the patient, the weight, age, sex, type of formulation, and how the dose is to be administered. Usually, however, a preferred daily dose of the active ingredient to an adult is from about 5 to 50 mg/kg, and a preferred daily dose to a child is within a range of from about 5 to 25 mg/kg, which is preferably administered once a day or several times a day.
  • the compound of the present invention may be administered in combination with a DHP-I inhibiting agent such as cilastatin.
  • a DHP-I inhibiting agent such as cilastatin.
  • silica gel 60 F 254 (Merck) was used as the plate, and an ultraviolet detector or ninhydrin color development method KM n O 4 was used as a detecting means.
  • silica gel for a column silicagel 60 (Merck) was used, and UV spectrophotometer DMS 100S (Varian) was used for detecting the UV absorbency.
  • UV spectrophotometer DMS 100S Varian
  • M-352 (ACS) model was used for high speed liquid chromatography.
  • TMS tetramethylsiland
  • DSS 2,2-dimethyl-2-silapentane-5-sulfonate
  • Rhodium (II) acetate dimer as a catalyst, and the solution was refluxed for 2.5 hours. After the reaction, the mixture solution was concentrated under reduced pressure to evaporate the organic solvent, and the produced material in the form of a syrup was dried in a vacuum to give 0.632 g (87.3%) of ( 4R,5R,6S,8R)-allyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-3,7-dione-2-carboxylate. This compound is also unstable so it must be used immediately after preparation.
  • the extract was washed successively with water and saturated aqueous sodium chloride, and the organic layer dried over anhydrous magnesium sulfate. After the filtration, the filtrate was concentrated under reduced pressure and the solvent evaporated to obtain 2.2 g of crude material.
  • EXAMPLE 1-2 To the mixture of 10 ml of tetrahydrofuran and 10 ml of 0.1 M 4 -morpholinepropanesulfonic acid buffer(pH 7.0) was added 0.316 g (0.462 mmol) of the (E)-(4R,5S,6S,8R,2'S,4'S) -p-nitrobenzyl-3-[ 1- (p-nitrobenzyloxycarbonyl)-2-methoxyiminopyrrolidin-4-yl-thio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylate obtained in EXAMPLE 1-1 and stirred to dissolve.
  • the extract was washed successively with water and saturated aqueous sodium chloride, and the organic layer dried over anhydrous magnesium sulfate. After the filtration, the filtrate was concentrated under reduced pressure and the solvent evaporated to obtain 2.55 g of crude material.
  • the resin was washed first with water to remove 4 -morpholinepropanesulfonic acid and then eluted with 5% aqueous acetone solution to collect the fractions containing the desired product.
  • the fractions were combined and concentrated at 10° - 20°C under reduced pressure.
  • EXAMPLE 8-3 To the mixture of 12 ml of tetrahydrofuran and 12 ml of 0.1 M morpholinepropanesulfonic acid buffer (pH 7.0) was added 0.37 g (0.486 mmol) of (E)-(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[1-(p-nitrobenzyloxycarbonyl)-2-(N-methanesulfonyl-N-methylhydrazonomethyl)pyrrolidin-4-yl-thio]-4-methyl-6-(1-hydroxyethyl)-1-azabicycl o [3,2,0]-hept-2-ene-7-one-2-carboxylate obtained in EXAMPLE 8-2 and stirred to dissolve.
  • EXAMPLE 16-1 1.520 g (4.19 mmol) of (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclof3,2,0]-hept-3,7-dione-2-carboxylate obtained in REFERENCE EXAMPLE 1 was added to 180 ml anhydrous acetonitrile, stirred at room temperature and cooled to 0°C using an ice bath.
  • the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to evaporate the organic solvent. After the residue was washed with ethylacetate, separated, and the water layer was concentraed under reduced pressure at 20°C, then the extracted impurity was removed by filtration.
  • the mixture solution was concentrated under reduced pressure to evaporate the solvent, and then extracted with ethylacetate. After the extracted solution was washed several times with water and saturated with sodium chloride, the organic layer was dried over anhydrous magnesium sulfate, filtered and then the filtrate was concentrated under reduced pressure to give 11.5 g of the residue.
  • EXAMPLE 18-2 To 100 ml of tetrahydrofuran was added 4.85 g ( 11.09 mmo l ) o f ( E ) - ( 2 S , 4R ) - 1 - ( p -nitrobenzyloxycarbonyl) -2-methoxyimino-4-tert-butyldimethylsilyloxypyrrolidine obtained in EXAMPLE 18-1 and stirred at room temperature to dissolve. Then 13.2 ml (13.2 mmol) 1 M tetrabutylammonium fluoride(tetrahydrofuran solution) was added dropwise and stirred at room temperature for 30 minutes.
  • the mixture solution was concentrated under reduced pressure to evaporate the solvent, and the residue was dissolved in ethylacetate and washed successively with water and sodium chloride. After the separation of the organic layer, it was dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated to give 5.5 g of the residue.
  • reaction solution A After 1.97 g (18.58 mmol) of sodium bicarbonate and 2.46 g (34.4 mmol) of hydroxylamine hydrochloride salt were added to 380 ml of water and stirred to dissolve (the reaction solution A).
  • the mixture solution was concentrated under reduced pressure to evaporate the solvent, and the residue was extracted with ethylacetate and dried over anhydrous magnesium sulfate.
  • the reaction solution were added dropwise 5.27 ml (39.65 mmol) of triethylamine and 1.85 ml (23.9 mmol) of methanesulfonyl chloride, and after the removal of the ice bath, stirred at room temperature for 1 hour. After the reaction, the mixture solution was concentrated under reduced pressure to evaporate the solvent, and the residue was extracted with ethylacetate.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3.29 g of the crude material.
  • the crude material was dissolved in 70 ml of methylenechloride. After the temperature of the reaction solution was adjusted to 0°C using an ice bath, 2.9 ml (21.02 mmol) of triethylamine and 0.98 ml (12.66 mmol) of methanesulfonyl chloride was added dropwise, and raised the temperature up to room temperature by removal of the ice bath. At the same temperature, after stirring for 1 hour, the reaction mixture was concentrated under reduced pressure and extracted with ethylacetate. The orgainc layer was washed successively with water and saturated aqueous sodium chloride.
  • (2S,4R) -1- (p-nitrobenzyloxycarbonyl) -2- (p-methoxybenzyloxycarbonylmethoxyimino) - 4-tert-butyldimethylsilyloxypyrrolidine obtained in EXAMPLE 21-1 was treated with the same operation as EXAMPLE 20 to give the desired product of (2S,4S)-1-(p-n i t r o b e n z y l o x y c a r b o n y l ) - 2 - ( p -methoxybenzyloxyca rbonylmethoxyimino ) - 4 -mercaptopyrrolidine.
  • the residue was dissolved in ethylacetate and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
  • the residue was dissolved in 80 ml of methylenechloride and cooled to 0°C using an ice bath 1.46 ml (10.84 mmol) of triethylamine and 0.53 ml (6.81 mmol) of methanesulfonylchloride which was added dropwise, removed from the ice bath, and stirred at room temperature for 1 hour. After the reaction, the mixture solution was concentrated under reduced pressure, extracted with ethylacetate and washed successively with water and brine.
  • (2S,4R) -1- (p-nitrobenzyloxycarbonyl)-2-(N-methylaminocarbonylme thoxyimino ) - 4 - tert -butyldimethylsilyloxypyrrolidine obtained in EXAMPLE 23-1 was treated, as discribed in EXAMPLE 20, to give ( 2S , 4R) - 1 - ( p-nitrobenzyloxycarbonyl ) -2 - (N-methylaminocarbonylmethoxyimino)-4-mercaptopyrrolidine.
  • EXAMPLE 26-5 In 100 ml of methylalcohol cooled to 0°C using an ice bath, was added 2.8 g (6.31 mmol) of (2S,4S)-1-(p-ni t r o b en z y l o xy c a r b ony l ) - 2 - N - ( 2 -pyridinylhydrazono)methyl-4-acetylthiopyrrolidine obtained in EXAMPLE 26-4 and stirred to dissolve. 6.31 ml of 2 N sodium hydroxide was added dropwise and stirred for 3 minutes.
  • ester compound obtained in EXAMPLE 27-2 was treated, as discribed in EXAMPLE 25, to give the desired product of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-N-(4-methoxybenzyloxyearbonylphenylhydrazono(methyl-4-mercaptopyrrolidine.
  • EXAMPLE 25-1 was added to 200 ml of methylenechloride and 4.72g(21.89 mmol) of 4 -nitrobenzylchlorof ormate sequentially, 3.9 ml (27.96 mmol) of triethylamine was added and stirred at room temperature for 24 hours. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure.
  • the crude material was dissolved in 100 ml of anhydrous acetonitrile and 0.732g(6.43 mmol) of potassium thioacetate was added and refluxed for 5 hours. After the reaction, the mixture solution was concentrated under reduced pressure, and 100 ml of methylenechloride was added and dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated to give 2.6 g of crude material.
  • reaction mixture solution was washed with satusatedcitric acid and saturated aqueous sodium chloride.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and 100 ml of tetrahydrofuran was added to the residue and stirred to dissolve.
  • 18 ml (18 mmol) of 1 M-tetrabutylammonium fluoride (tetrahydrofuran solution) was added dropwise and stirred at room temperature for 30 minutes.
  • the mixture solution was concentrated under reduced pressure, the residue was dissolved in ethylacetate and washed successively with water and saturated aqueous sodium chloride.
  • EXAMPLE 32-3 To 70 ml of methylenechloride was added 4.5 g (10.86 mmol) of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-(N-methanesulfonyl-N-methylhydrazono(methyl-4-hydroxypyrrolidine obtained in EXAMPLE 32-2 and stirred to dissolve. The reaction mixture solution was cooled to 0°C using an ice bath, and 2.23 ml (16.0 mmol) of triethyamine and 0.95 ml (12.3 mmol) of methanesulfonylchloride was added and stirred at the same temperature for 30 minutes.
  • reaction solution was concentrated under reduced pressure and 200 ml of ethylacetate was added, washed successively with water and saturated aqueous sodium chloride, and the separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 5.7 g of crude material.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (I) dans laquelle R1 est choisi dans le groupe composé d'un atome d'hydrogène ou d'un groupe méthyle, R2 est choisi dans le groupe composé d'un atome d'hydrogène, d'un groupe sel métallique ou non métallique, ou bien d'un groupe protecteur carboxy, R3 est choisi dans le groupe composé d'un atome d'hydrogène ou d'un groupe protecteur imino, R4 est choisi dans le groupe composé d'un atome d'hydrogène, d'un groupe alkyle inférieur, d'un groupe hydroxy, d'un groupe cyano ou bien d'un atome d'halogène, et R5 est tel que défini dans la revendication 1; ou bien un sel ou un ester pharmaceutiquement acceptables de celui-ci. Les composés de la présente invention possèdent une excellente activité antibactérienne contre diverses bactéries Gram positif et Gram négatif et sont utiles comme agents antibactériens pour le traitement et la prévention des maladies infectieuses humaines causées par de telles bactéries.
PCT/KR1993/000079 1992-09-02 1993-09-02 Derives de carbapenem et procedes pour leur preparation WO1994005667A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6507064A JPH08502732A (ja) 1992-09-02 1993-09-02 カルバペネム誘導体及びその製造方法
EP93919700A EP0658162A1 (fr) 1992-09-02 1993-09-02 Derives de carbapenem et procedes pour leur preparation
KR1019950700834A KR950702989A (ko) 1992-09-02 1995-03-02 새로운 카바페넴 유도체 및 그의 제조방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1992-15910 1992-09-02
KR1019920015910A KR940007029A (ko) 1992-09-02 1992-09-02 새로운 카바페넴 유도체 및 그의 제조방법

Publications (1)

Publication Number Publication Date
WO1994005667A1 true WO1994005667A1 (fr) 1994-03-17

Family

ID=19338915

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR1993/000079 WO1994005667A1 (fr) 1992-09-02 1993-09-02 Derives de carbapenem et procedes pour leur preparation

Country Status (6)

Country Link
EP (1) EP0658162A1 (fr)
JP (1) JPH08502732A (fr)
KR (2) KR940007029A (fr)
CN (1) CN1090283A (fr)
TW (1) TW255892B (fr)
WO (1) WO1994005667A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101367809B (zh) * 2007-06-28 2011-04-27 山东轩竹医药科技有限公司 含有巯基吡咯烷甲酰肼的培南衍生物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5913757A (ja) * 1982-07-14 1984-01-24 Sankyo Co Ltd ３−メルカプトピロリジン誘導体及びその製法
EP0160391A1 (fr) * 1984-03-27 1985-11-06 Sankyo Company Limited Dérivés de carbapénème et compositions les contenant
EP0182213A1 (fr) * 1984-11-08 1986-05-28 Sumitomo Pharmaceuticals Company, Limited Dérivés de carbapénème et leur préparatIon
EP0243686A2 (fr) * 1986-03-27 1987-11-04 Sumitomo Pharmaceuticals Company, Limited Dérivés de bêta-lactame et leur préparation
EP0272455A1 (fr) * 1986-11-24 1988-06-29 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5913757A (ja) * 1982-07-14 1984-01-24 Sankyo Co Ltd ３−メルカプトピロリジン誘導体及びその製法
EP0160391A1 (fr) * 1984-03-27 1985-11-06 Sankyo Company Limited Dérivés de carbapénème et compositions les contenant
EP0182213A1 (fr) * 1984-11-08 1986-05-28 Sumitomo Pharmaceuticals Company, Limited Dérivés de carbapénème et leur préparatIon
EP0243686A2 (fr) * 1986-03-27 1987-11-04 Sumitomo Pharmaceuticals Company, Limited Dérivés de bêta-lactame et leur préparation
EP0272455A1 (fr) * 1986-11-24 1988-06-29 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique

Also Published As

Publication number Publication date
JPH08502732A (ja) 1996-03-26
EP0658162A1 (fr) 1995-06-21
KR950702989A (ko) 1995-08-23
CN1090283A (zh) 1994-08-03
TW255892B (fr) 1995-09-01
KR940007029A (ko) 1994-04-26

Similar Documents

Publication Publication Date Title
US4963543A (en) 3-pyrolidinylthio-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid derivatives and processes for the preparation thereof
EP0343499B1 (fr) Dérivés de l'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ène-2-carboxylique
HU196800B (en) Process for producing carbepeneme derivatives and pharmaceutical compositions containing them as active component
NO890723L (no) Fremgangsmaate for fremstilling av terapeutisk aktive 3-alkenyl-1-azabicyklo 3.2.0 hept-2-en-2-karboksylsyrederivater
EP0474243B1 (fr) Dérivés de 1-méthylcarbapénèmes et procédé de leur préparation
GB2122196A (en) Carbapenem antibiotics
IE53047B1 (en) 2-carbamimidoyl-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, a process for preparing and an antibiotic composition comprising the same
CA2028176A1 (fr) Composes de carbapenem
KR880001069B1 (ko) 카르바페넴 유도체및 그의 제조방법
KR100589030B1 (ko) 카르바페넴 유도체, 그 사용 방법 및 그 중간체 화합물
KR890002228B1 (ko) 카르바페넴 유도체 및 그의 제조방법
KR970007946B1 (ko) 2-(2-치환된 피롤리딘-4-일)티오-카바페넴 유도체
HU193895B (en) Process for preparing carbapenem derivatives
RU2162088C2 (ru) 1-метилкарбапенем или его фармакологически приемлемые соли, композиция, способ предупреждения или лечения бактериальных инфекций
IE910978A1 (en) 2-(substituted pyrrolidinylthio)carbapenem derivatives
AU651505B2 (en) Aminoalkylpyrrolidinylthiocarbapenem derivatives
WO1994005667A1 (fr) Derives de carbapenem et procedes pour leur preparation
FI96311C (fi) Menetelmä farmaseuttisesti käyttökelpoisten 6-(1-hydroksietyyli)-3-(substituoitu tio)-7-okso-1-atsabisyklo/3.2.0/hept-2-eeni-2-karboksyylihappojohdannaisten valmistamiseksi
WO1995014692A1 (fr) Derives de carbapenem et leurs procedes de preparation
WO1992002521A1 (fr) Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique
AU636249B2 (en) Antibiotic c-3 dithioacetal-substituted carbapenem compounds, compositions, and methods of use thereof
HU198491B (en) Process for producing carbapenem antibiotics
JP2003183282A (ja) カルバペネム化合物
JP2832742B2 (ja) カルバペネム誘導体
JPH08134075A (ja) 新規なカルバペネム誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP KR RU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: US

Ref document number: 1995 392812

Date of ref document: 19950227

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1993919700

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1993919700

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1993919700

Country of ref document: EP