WO1997033888A1 - Composes de carbapenem, leur production et leur utilisation - Google Patents

Composes de carbapenem, leur production et leur utilisation Download PDF

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Publication number
WO1997033888A1
WO1997033888A1 PCT/JP1997/000756 JP9700756W WO9733888A1 WO 1997033888 A1 WO1997033888 A1 WO 1997033888A1 JP 9700756 W JP9700756 W JP 9700756W WO 9733888 A1 WO9733888 A1 WO 9733888A1
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group
compound
dihydro
diastereomer
methyl
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PCT/JP1997/000756
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English (en)
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Tetsuo Miwa
Seizo Soejima
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Takeda Chemical Industries, Ltd.
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Priority to AU22337/97A priority Critical patent/AU2233797A/en
Publication of WO1997033888A1 publication Critical patent/WO1997033888A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms

Definitions

  • TECHNICAL FIELD This invention relates to a novel carbapenem compound having excellent antibacterial activities and administrable not only parenterally but also orally, a method of producing the compound and an antibacterial agent.
  • R stands for hydrogen atom or -CR 4 R 5 R 6 group (wherein R stands for H, hydroxyl group or a protected hydroxyl group; R and R 6 stand for H, alkyl group, alkenyl group, alkynyl group, aralkyl group or aryl group; or R and R form, taken together with the adjacent carbon atom, a ring) ;
  • R stands for H or carboxyl-protective group;
  • R stands for H, alkyl group, alkenyl group, alkynyl, aralkyl group, aryl group or -S0 2 R group (wherein R stands for hydroxyl group, alkyl group, alkenyl group alkynyl group, aralkyl group or aryl group) ;
  • Z stands for 0, S or - N(R )- group (wherein R is of the same meaning as R ) ;
  • m denotes 0 or 1;
  • n denotes 0, 1, 2 or 3, and
  • carbapenem compounds show, in general, excellent antibacterial activities against gram-positive and gram-negative bacteria, the antibacterial activities are insufficient and the physico-chemical properties or the stability in a living body, especially the stability to renal dehydropeptidase-1 (DHP-1), are unsatisfactory.
  • DHP-1 renal dehydropeptidase-1
  • the present invention relates to
  • R is an optionally substituted lower alkyl group
  • R is hydrogen or a lower alkyl group
  • Y is a bond or an optionally substituted lower alkylene group
  • R is an optionally hydrogenated condensed oxazine or thiazine ring group, which may optionally be substituted, or its ester, or salt thereof
  • (2) a method of producing the compound described in (1) above which comprises reacting a compound of the formula: wherein L is a leaving group, and other symbols are of the same meaning as defined above, or its ester, or a salt thereof with a compound represented by the formula: H-S-Y-R wherein symbols are of the same meaning as defined above, or a salt thereof, and
  • the compound (I) of this invention shows excellent antibacterial activities against a broad spectrum of pathogenic bacteria ranging from gram-positive to gram- negative ones. Besides, it is excellent in chemical stability and the stability to DHP-1, and it shows antibacterial activities by injection or oral administration.
  • lower alkyl group of the optionally substituted lower alkyl group shown by R use is made of, for example, straight- chain or branched C ⁇ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl) .
  • substituents include cyano group, amino group, mono- or di- C ⁇ . 4 alkylamino group (e.g. methylamino and dimethylamino) , hydroxyl group, C w alkyloxy group (e.g.
  • methoxy and ethoxy , carbamoyloxy group, C U4 alkylthio group (methylthio and ethylthio), C ⁇ _ 4 alkyl ⁇ sulfonyl group (e.g. methylsulfonyl and ethylsulfonyl), halogen (e.g. fluorine, chlorine and bromine), sulfamoyl group and C 4 alkoxy-carbonyl group (e.g. ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl) .
  • C U4 alkylthio group methylthio and ethylthio
  • C ⁇ _ 4 alkyl ⁇ sulfonyl group e.g. methylsulfonyl and ethylsulfonyl
  • halogen e.g. fluorine, chlorine and bromine
  • Number of these substituents ranges preferably from 1 to 3, and, when the number of these substituents is 2 or more, they may be the same as or different from one another.
  • these substituents may optionally be protected with a readily removable protective group, preferably exemplified by a silyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl, allyloxycarbonyl, t- butoxycarbonyl, benzyloxycarbonyl or p- nitrobenzyloxycarbonyl.
  • R More preferable examples of R include groups representable by the formula:
  • R stands for H, halogen, or, respectively optionally substituted hydroxyl group or amino group.
  • substituents of the hydroxyl group or amino group shown by R use is made of, for example, removable protective groups mentioned as above. More preferable examples of R include hydroxyl group. Especially preferable examples of R 1 include (IR)-hydroxyethyl group.
  • esterified carboxyl group is shown by COOR .
  • ester residual group of carboxyl group i.e. R
  • ester residual groups as used in the field of ⁇ -lactam antibiotics such as cephalosporin, more specifically, ester residual groups usually employed as the group forming readily removable ester (ester convertible to so-called prodrug) at 4-position of the cephalosporin skeleton and groups commonly used as ester residual groups of carboxylic acid in the field of pharmaceuticals.
  • C 7 alkyl groups C 2 _ 6 alkenyl groups, C 6 _ ⁇ 0 aryl groups or C 7 . 20 aralkyl group.
  • C 7 alkyl groups use is made of, for example, methyl, ethyl, propyl, isopropyl, butyl and t-butyl, as C 2 _ 6 alkenyl groups, use is made of, for example, vinyl, aryl and crotyl, as C 6 . 10 aryl groups, use is made of, for example, phenyl and naphthyl, and as C 7 . 20 aralkyl groups, use is made of, for example, benzyl, phenethyl, benzhydryl and trityl.
  • R 5 stands for H or respectively optionally substituted alkyl groups or C 3 . 6 cycloalkyl groups
  • R stands for respectively optionally substituted C J . JQ alkyl groups
  • C 3 _ 10 cycloalkyl groups alkyloxy groups
  • C 3 _ 10 cycloalkyloxy groups C 3 _ 10 cycloalkyl C 1-6 alkyl groups
  • C ⁇ _ 6 alkyloxy groups C 2 . 6 alkenyl groups, C 6 . 10 aryl groups or C 7 . 12 aralkyl groups.
  • C ⁇ _ 6 alkyl groups shown by R use is made of, for example, methyl, ethyl, propyl, isopropyl, butyl and 2,2-dimethylpropyl, and, as the C 3 . 6 cycloalkyl groups, use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkyl groups of the C 1 _ 10 alkyl groups and Cu o alkyloxy groups shown by R use is made of, for example, methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, pentyl, 2,2- dimethylpropyl, hexyl, heptyl and decyl; as cycloalkyl groups of the C 3 . 10 cycloalkyl groups, C 3 . 10 cycloalkyloxy groups, C 3 . 10 cycloalkyl C ⁇ alkyl groups and C 3 .
  • 10 cycloalkyl C j . ⁇ alkyloxy groups use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl; and, as C ⁇ g alkyl groups of the C 3 . 10 cycloalkyl C ⁇ alkyl groups and C 3 . 10 cycloalkyl C ⁇ alkyloxy groups, use is made of, for example, methyl, ethyl, propyl, butyl, pentyl and hexyl. As C 2 .
  • alkenyl groups use is made of, for example, vinyl, allyl and crotyl; as C 6 . 10 aryl groups, use is made of, for example, phenyl and naphthyl; and, as C 7 _ 12 aralkyl groups, use is made of, for example benzyl and phenethyl.
  • substituents in the respectively optionally substituted Cj_ 7 alkyl groups C 2 . 6 alkenyl groups, C 6 . 10 aryl groups or C 7 . 20 aralkyl groups shown by R , in the respectively optionally substituted C ⁇ g alkyl groups or 3 - 6 cycloalkyl groups shown by R , and in the respectively optionally substituted alkyl group, C 3 . 10 cycloalkyl group, C ⁇ o alkyloxy groups, C 3 . 10 cycloalkyloxy groups, C 3 . 10 cycloalkyl C j . ⁇ alkyl groups, c 3 - ⁇ o cycloalkyl C 6 alkyloxy groups, C 2 .
  • ester residual groups shown by R include groups often used in the process of preparing pharmaceuticals [e.g. methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tertiary butyl group, 2,2,2-trichloroethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group, phenethyl group, bis(methoxyphenyl)methyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, benzhydryl group, trityl group, trimethylsilyl group, 2-trimethylsilylethyl group or allyl group], or groups giving readily removable ester derivatives in a living body suitable for oral administration [e.g.
  • acetoxymethyl group 1- acetoxyethyl group, 1-acetoxypropyl group, pivaloyloxyraethyl group, isopropyloxycarbonyloxymethyl group, l-(isopropyloxycarbonyloxy)ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy)ethyl group, ethoxycarbonyloxymethyl group, 1-
  • R of the above formulae use is made of H or a lower alkyl group.
  • the lower alkyl group use is preferably made of, for example, Cj_ alkyl groups.
  • Examples of the C ⁇ . 3 alkyl groups include methyl, ethyl, propyl or isopropyl, especially methyl being preferable.
  • Y in the above formulae use is made of a bond or an optionally substituted lower alkylene group.
  • the lower alkylene group use is preferably made of C,.-, alkylene groups.
  • C ⁇ alkylene groups mention is made of, for example, methylene, ethylene and propylene.
  • substituent in the lower alkylene group mention is made of, for example, halogen (e.g. fluorine, chlorine and bromine) , hydroxy group, C ⁇ alkyloxy groups (e.g. methoxy and ethoxy), amino group, and mono- or di-C ⁇ alkylamino groups (e.g. dimethylamino) . Number of such substituents is preferably 1 or 2.
  • R in the above formula is an optionally hydrogenated condensed oxazine or thiazine ring group, which may optionally have substituents.
  • the R is preferably exemplified by a group represented by the formula:
  • ring A is optionally hydrogenated oxazine or thiazine ring, which may optionally have substituents
  • ring B stands for an optionally substituted heterocyclic ring, which may optionally be oniumized.
  • Preferable examples of ring A include dihydro-1,3- oxazine, perhydro-1,3-oxazine, dihydro-l,3-thiazine or perhydro-1,3-thiazine.
  • heterocyclic ring shown by ring B include 5- to 6-membered N-containing heterocyclic ring containing 1 to 4 hetero-atoms such as N, 0 and S, which is preferably condensed with the linkage bonding 2-position to 3-position of ring A.
  • heterocyclic ring shown by ring B include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, variously condensed thiadiazole, variously condensed oxadiazole and their structurally possible hydrogenated groups.
  • examples of the 6-membered N-containing heterocyclic group include pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, variously condensed oxazine, variously condensed thiazine, variously condensed oxadiazine, variously condensed thiadiazine and their structually possible hydrogenated groups.
  • Preferable examples of ring B include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole and tetrazole.
  • the condensed heterocyclic group form by ring A and ring B may optionally be oniumized by quaternizing the nitrogen atom therein.
  • the oniumized condensed heterocyclic group includes groups in the following cases, namely, the case where cationic charge is localized at the bridge-head nitrogen atom of the condensed heterocyclic group, non-localized at the whole ring A, non-localized at the whole ring B or non- localized at the whole heterocyclic group formed by ring A and ring B, as shown by the following formulae:
  • the condensed heterocyclic ring formed by ring A and ring B may optionally have, other than the substituent Y, substituents on a ring-forming carbon atom and substituents on a ring-forming nitrogen atom.
  • substituents on ring A include C_ 6 alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), C 2 . fl alkenyl groups (e.g. vinyl, allyl and crotyl), C 2 . 6 alkynyl groups (e.g. 2-propinyl), C 6 . 10 aryl groups (e.g. phenyl, tolyl and naphthyl), C 7 .
  • C_ 6 alkyl groups e.g. methyl, ethyl, propyl and isopropyl
  • C 2 . fl alkenyl groups e.g. vinyl, allyl and crotyl
  • aralkyl groups e.g. benzyl
  • 5- to 6-membered nitrogen-containing heterocyclic groups each containing 1 to 4 hetero-atoms such as N, 0 and S e.g. 2-pyridyl
  • substituents may optionally be further substituted with 1 to 3 substituents exemplified by halogen (e.g. fluorine, chlorine and bromine), hydroxy group, C 6 alkyloxy groups (e.g. methoxy and ethoxy), amino group, mono- or di-C ⁇ alkylamino groups (e.g.
  • substituents on ring B include, in addition to the same ones as those on ring A, hydroxyl group, amino group, mono- or di-C ⁇ g alkylamino groups (e.g. methylamino and dimethylamino) , mercapto group, C ⁇ e alkyloxy groups (e.g. methoxy and ethoxy), C y . 6 alkylthio groups (e.g.
  • the ring B may have 1 to 3 substituents.
  • the optionally hydrogenated condensed oxazine or thiazine cyclic groups shown by R may optionally be further substituted with 1 to 4 substituents exemplified above as those on ring B. When the number of those substituents is two or more, those substituents may optionally be the same as or different from one another.
  • R is 6,7-dihydro- 5H-imidazo[2,1-b] [1,3]thiazin-6-yl, 6,7-dihydro-5H- l,2,3-triazolo[5,l-b] [1,3]thiazin-6-yl and 2-amino-6,7- dihydro-5H-l,2,4-triazolo[5,1-b] [1,3]thiazin-6-yl.
  • salts of the compounds represented by the above formulae or their esters use is preferably made of pharmacologically or synthetically acceptable ones.
  • use is made of, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acid amino acid.
  • inorganic bases capable of producing these salts use is made of, for example, alkali metals (e.g. sodium and potassium) and alkaline earth metals (e.g.
  • organic bases use is made of, for example, trimethylamine, triethylamine, pyridine, picoline, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, tris(hydroxymethylamino)methane and dicyclohexylamine
  • inorganic acids use is made of, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid
  • organic acids use is made of, for example, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzensulfonic acid and p-toluenesulfonic acid
  • basic or acid amino acid use is made of, for example, arginine, lysine, ornithine, aspartic acid and glutamic acid
  • salts with acids include those in which the carboxyl group at 3-position of the compound (I) takes the form of carboxylate anion: (COO ⁇ ) and those forming intramolecular salt as a pair with the cationic charge in the case where R is an oniumized condensed heterocyclic group, and salts formed when R is, for example, a group:
  • Y ⁇ stands for anion formed by removing proton H from an inorganic acid or an organic acid. (e.g. chloride ion, bromide ion, sulfate ion, p-toluene sulfonate ion, methanesulfonate ion and trifluoroacetate ion) ] .
  • the compound of the formula (I) and an ester or salt thereof may either be hydrate or a non-hydrate.
  • the compound (I) of this invention can be produced by, for example, allowing a compound represented by the formula (II) :
  • L stands for a leaving group, and other symbols are of the same meaning as defined above or an ester thereof or a salt thereof [as the ester or salt, substantially the same one as in (I) can be used] to react with a compound represented by the formula (III): H-S-Y-R wherein symbols are of the same meaning as defined above or a salt thereof.
  • L in the compound (II) use is made of a leaving group commonly employed in the field of organic synthetic chemistry [leaving groups described in, for example, Compendium of Organic Synthetic Methods, Vol.1 to Vol.7, John Wely & Sons Inc., New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)].
  • Practical examples of L include C 1-6 alkanesulfonyloxy groups optionally substituted with, e.g. 1 to 3 halogen atoms (e.g. methanesulfonyloxy and trifluoromethanesulfonyloxy) , C 6 .
  • allene sulfonyloxy groups optionally substituted with e.g. C ⁇ alkyl groups (e.g. benzenesulfonyloxy or toluenesulfonyloxy) , di-Ci. 6 alkylphosphonoxy groups (e.g. dimethylphosphonoxy) , di-C 6 . 10 arylphosphonoxy group (e.g. diphenylphosphonoxy) ] , halogen (e.g. chlorine, bromine) or C ⁇ alkanesulfinyl groups (e.g. methanesulfinyl) , or C 6 . 10 allene sulfinyl groups (e.g. benzenesulfinyl) . More preferable L is diphenylphosphonoxy group.
  • C ⁇ alkyl groups e.g. benzenesulfonyloxy or toluenesulfonyloxy
  • salts of the compound (III) use is made of, for example, alkali metal (e.g. sodium and potassium) salts, alkaline earth metal (e.g. calcium and magnesium) salts and ammonium salt.
  • alkali metal e.g. sodium and potassium
  • alkaline earth metal e.g. calcium and magnesium
  • ammonium salt When reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formulae of the compounds (II) and (III), these groups may optionally be protected, in accordance with a conventional method, with the protective groups mentioned below. After completion of the reaction, these protective groups can be removed in accordance with a conventional method.
  • the reaction between the compound (II) and the compound (III) proceeds advantageously usually in the presence of a base.
  • a base examples include organic amine such as triethylamine and diisopropylethylamine and basic inorganic salts such as sodium hydrogencarbonate and potassium carbonate.
  • the reaction can be conducted usually by stirring in an inert solvent.
  • any one can be used so long as it does not hamper the reaction, which is preferably exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and chloroform, alkyl nitriles such as acetonitrile and propionitrile, nitroalkanes such as nitromethane and nitroethane and amides such as dimethylformamide and dimethylacetamide.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane, diethoxyethane and tetrahydrofuran
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • alkyl nitriles such as acetonitrile and propionitrile
  • nitroalkanes such
  • reaction temperature varies with, among others, the starting compounds (II) and (III), kinds of bases then added and kinds of solvents then employed, it ranges usually from -40°C to 100°C, preferably from -30°C to 50°C.
  • the reaction time ranges usually from one minute to 48 hours, preferably from about 15 minutes to about 24 hours.
  • the compounds represented by the formula (III) can be produced by the methods described in literature references or methods analogous thereto. These methods are exemplified by those described in, for example, M. R. Grimmet et al. , Aust. J. Chem, Vol.38, p.1873 (1985), Compendium of Organic Synthetic Methods, Vol .1 to Vol.7, John Wely & Sons Inc., New York (1971-1992), Comprehensive Organic Synthesis, Vol.l-Vol.9, Pergamon Press, Oxford (1991) and R. C Larock, Comprehensive Organic Transformation, VCH, New York (1989), or analogous methods thereto.
  • the compound represented by the formula (III) can be produced, practically, by converting X of the compound represented by the formula (III'):
  • X stands for an optionally protected hydroxyl group or mercapto group, and other symbols are of the same meaning as defined above, when X is not mercapto group, to mercapto group by a method described in literature reference, e.g. R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989).
  • the compound represented by the formula (III') can be produced by, for example, subjecting alcohol or a mercaptan derivative represented by formula (IV):
  • the compound represented by the formula (III') can be produced by, for example, allowing alcohol or a mercaptan derivative represented by the formula (VI):
  • L stands for a leavable group, and other symbols are of the same meaning as defined above, which can be synthesized by a reaction described in a known literature reference or an analogous reaction thereto, to react with a compound represented by the formula (VIII) :
  • L stands for a leavable group, and other symbols are of the same meaning as defined above.
  • the hydroxyl group or mercapto group shown by H-Q of the compound represented by the formula (VI) or the amino group shown by H-N of the compound represented by the formula (VII) may optionally be protected, and, in that case, the addition elimination reactions of both compounds can be allowed to proceed stepwise, while conducting deprotection of the protective group in the course of the reactions.
  • alkyl- type protective groups e.g. benzyl such as benzyl, p- methoxybenzyl and p-nitrobenzyl; substituted methyl such as diphenyl methyl, triphenyl methyl and methoxy methyl; 2-tetrahydropyranyl
  • acyl-type protective groups e.g. alkyloyl such as acetyl; aroyl such as benzoyl; t-butoxycarbonyl
  • silyl-type protective groups e.g.
  • L 6 alkanesulfonyloxy (e.g. trifluoromethanesulfonyloxy) , C 6 _ 10 allene sulfonyloxy groups (e.g. benzenesulfonyloxy and p- toluenesulfonyloxy) and hydroxyl group.
  • practical examples of L include halogen (e.g. fluorine, chlorine and bromine), substituted hydroxyl group [e.g. C L _ 6 alkyloxy (e.g. methoxy) or C 6 . 10 aryloxy (e.g. phenoxy) or Cj. 6 alkyloyloxy (e.g. acetoxy) or C 6 .
  • aroyloxy e.g. benzoyloxy
  • substituted mercapto groups e.g. Cj. 6 alkylthio (e.g. methylthio) or C 6 . 10 arylthio (e.g. phenylthio) or C (t alkyloylthio (e.g. acetylthio) or C 6 _ 10 aroylthio (e.g. benzoylthio) ] .
  • the N-containing heterocyclic group B shown by the formulae (V) and (VII) include 5- to 6-membered N- containing heterocyclic groups containing 1 to 4 hetero-atoms, which can be produced by a conventional method. These N-containing heterocyclic groups can be described, when structually possible, as known in the field of organic chemistry, in different chemical structures as described below in accordance with chemical equilibrium of keto-enol type or imine-enamine type.
  • N-containing heterocyclic groups shown by Bl, B2 and B3 are of tautomeric structure of ring B.
  • the compound (I) of this invention can also be produced by subjecting a compound (VIII) of the formula
  • M and G stand for groups which form double bond by reacting with each other, in other words, M reacts with G to form double bond by elimination, and, other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, use can be made of similar ones as those of (I)] to ring-closure reaction.
  • R 7 and R7' stand for a lower alkoxy group, a lower alkyl group or aryl group, is mentioned.
  • the compound (I) can also be produced by allowing a compound represented by the formula (VIII-1):
  • G 1 stands for 0 or S, and other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, use can also be made of similar ones to those of (I)] to react with a compound represented by the formulae: P(R 7 ) 3 (IX),
  • reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIII-1), these groups may optionally be protected with the protective groups described below in accordance with a conventional method. After completion of the reaction, these protective groups can be removed by a conventional method.
  • R or R use is made of, for example, C ⁇ g alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; as the lower alkyl group, use is made of, for example, C ⁇ alkyl groups such as methyl, ethyl, propyl, butyl and pentyl; and, as the aryl group, use is made of C 6 . 10 aryl groups such as phenyl.
  • reaction are conducted usually under heating in the absence of solvent or in an inert solvent.
  • inert solvent any one can be used so long as it does not hamper the reaction, preferable examples of such solvents include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, or halogenated hydrocarbons such as dichloromethane and chloroform.
  • the amount of the compound (IX) or (IX') to be employed is 2 molar equivalents or more, preferably 2 to 10 molar equivalents, relative to the compound (VIII-1).
  • reaction temperature varies with the starting compounds (VIII-1), (IX), (IX') and kinds of the solvent, it ranges usually from about 20 to 160°C, preferably from about 80 to 140°C.
  • the reaction time ranges usually from 30 minutes to 100 hours, preferably from 1 to 72 hours.
  • Production Method 2-2 The compound (I) can be produced by subjecting a compound represented by the formula (VIII-2): wherein symbols are of the same meaning as defined above, or its ester or salt as the ester or salt, use can also be made of ones similar to those of (I), to ring-closure reaction, followed by, depending on necessity, removing the protecting groups.
  • the ring-closure reaction is conducted in an inert solvent.
  • the inert solvent include aromatic hydrocarbons, ethers and halogenated hydrocarbons as employed in the above Production Method 2-1.
  • the reaction is conducted under heating at temperatures ranging from about 0 to 160°C, preferably from about 30 to 140°C. While the reaction time depends on the kinds of the compound (VIII-2) and the reaction temperature then employed, it ranges usually from about 30 minutes to 100 hours, preferably from one hour to 72 hours.
  • the starting materials employed in Production Method 2, 2-1 and 2-2 i.e. the compounds represented by the formulae (VIII), (VIII-1) and (VIII-2), use is made of, for example, compounds represented by the formula (III), which can be produced by conventional methods [for example, methods disclosed in JPA
  • the amino group when an amino group is contained in the structures of the compounds represented by (II), (VIII), (VIII-1) and (VIII-2) or esters of salts thereof [as the ester or salt, use can also be made of ones similar those of (I)], or in the structures of the compounds represented by the formulae (III) and (III'), the amino group may optionally be protected with a protecting group.
  • a protecting group use is conveniently made of, for example, such ones as employed in the fields of ⁇ - lactam type antibiotics and peptides.
  • hydroxyl-protecting group use is conveniently made of, for example, such one as employed in the fields of ⁇ - lactam type antibiotics and peptides. Among them, use is made of, for example, chloroacetyl, benzyl, p- nitrobenzyl, o-nitrobenzyl, methylthiomethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, 2-tetrahydropyranyl, 4-methoxy-4- tetrahydropyranyl, p-nitrobenzyloxycarbonyl, o- nitrobenzyloxycarbonyl and allyloxycarbonyl.
  • carboxyl group when a carboxyl group is contained in the structures of similar compounds, the carboxyl group may optionally be protected.
  • carboxyl-protecting group use is made of, for example, such ones as employed in the fields of ⁇ -lactam type antibiotics and peptides.
  • benzyl benzhydryl, trityl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, phenethyl, 2-trimethylsilylethyl, bis(p- methoxyphenyl)methyl, tertiary butyl and allyl.
  • the substituent R i.e. the heterocyclic group formed by condensation of ring A with ring B, may optionally be converted to a chemically different group represented by R at the step of producing the compound represented by the formula (I) or (III), or at the stage of the compound represented by the formula (I) or (III).
  • the substituent on the substituent R may optionally be converted to a chemically different group at the step of producing the compound represented by the formula (I) or (III), or at the stage of the compound represented by the formula (I) or (III), by conducting, depending on necessity, adequate functional group conversion.
  • a conventional reaction can be employed [e.g. R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)].
  • the carboxyl group shown by COOH of the object compound (I) may, as described above, optionally be esterified.
  • R of the esterified carboxyl group shown by COOR* may, when desired, optionally be converted to different R* at the step of producing the compound represented by the formula (I) or (II) or at the stage of the compound represented by the formula (I) or (II).
  • R* for this conversion, use can be made of a reaction commonly employed for a similar purpose in the field of ⁇ -lactam type antibiotics.
  • the object compound (I) thus produced can be isolated and purified by conventional means, for example, solvent-extraction, pH change, phasic transfer, salting out, crystallization, recrystallization and chromatography. And, when a protecting group is contained in the reaction product, the compound (I) is produced by, when so desired, removing the protective group by a conventional method. So far, in the fields of ⁇ -lactam and peptide synthesis, protective groups of amino, hydroxyl or carboxyl are sufficiently studied, and the methods of protection and deprotection have been established. These methods can be utilized in the method of producing the object compound of this invention and in the method of producing intermediates for its synthesis.
  • the compound (I) shows excellent antibacterial activities against gram-positive and gram-negative bacteria including clinically separated strains, which is remarkably less toxic, showing, depending on cases, excellent oral absorbability and is stable physico- chemically and biochemically (especially against DHP- I), thus being a valuable antibiotic substance.
  • the compound (I) is, therefore, utilized as drugs for man and domestic animals, which can be safely used as an antibacterial agent for the treatment and prevention of infectious diseases caused by various bacteria.
  • the compound (I) of this invention can, for example, be added to animal feed as bactericidal agent for preservation of the feed. And, it can also be used as bactericidal agent for clearing harmful bacteria on medical and dental appliances .
  • the compound (I) of this invention can be used, singly or in combination with any other active components (for example, any other antibacterial agents, anti-inflammatory agents, antipyretics and analgesics), and, depending on necessity, adding, besides pharmaceutically acceptable carriers, adjuvants e.g. a stabilizer and dispersant, as pharmaceutical preparations such as injections, capsules, tablets, liquid medicines (e.g. suspensions and emulsions) formulated by conventional methods. These preparations can be administered parenterally (e.g. intravenous or intramuscular injection) or orally. Injectable preparations can be provided in a dosage form of ampoules of vials supplemented with a preservative.
  • active components for example, any other antibacterial agents, anti-inflammatory agents, antipyretics and analgesics
  • adjuvants e.g. a stabilizer and dispersant
  • pharmaceutical preparations such as injections, capsules, tablets, liquid medicines (e.g. suspensions and emulsions)
  • preparations may optionally be suspensions, solutions or emulsions in an oleaginous or aqueous medium, which may contain an adequate amount of conventional adjuvants such as a suspending agent, stabilizer and (or) powdery agent.
  • the compound (I) of this invention can also be provided in a form of a pulverized or powdery agent, which can be used, by dissolving in sterilized water containing no pyrogenic substance.
  • the compound (I) can be formulated into tablets, capsules, powdery preparations or pulverized preparations for oral administrtion by adequately mixing with a binder (e.g. syrup, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinyl pyrrolidone and methyl cellulose), a filler (e.g. lactose, sugars, corn starch, calcium phosphate, sorbitol and glycine) , a lubricant (e.g. magnesium stearate, talc, polyethylene glycol and silica), a disintegrator (e.g. potato starch) or a wetting agent (e.g. sodium lauryl sulfate) .
  • a binder e.g. syrup, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinyl pyrrolidone and methyl cellulose
  • a filler e.g. lactose, sugars
  • Tablets and powdery preparations can be film-coated by a per se known method.
  • Orally administrable preparations may also be used as liquid preparations e.g. aqueous or oily suspensions, solutions, emulsions, syrups and elixir.
  • these preparations may be mixed with other components, for example, a known antioxidant, preservative, binder, wetting agent, lubricant, sticking agent or flavoring agent.
  • these preparations may further be mixed with any other active components (e.g. any other ⁇ -lactam type antibiotic substances) to give those showing a broader spectrum of antibacterial activities.
  • the ratio of the compound (I) in the pharmaceutical composition containing the compound (I), though variable with forms of the composition, may be that commonly employed in general antibacterial preparations. For example, in a solid preparations such as capsules, tablets and granules, the ratio of the compound (I) ranges from about 30 to 95 weight %.
  • the compound (I) can be used for the treatment and prevention of infectious diseases from bacteria in man and any other mammalian animals (e.g.
  • the dosage of the compound (I) per day ranges, in non-oral administration, from about 0.5 to 80 mg, preferably from about 2 to 40 mg of the active component [i.e. the compound (I)] per kg of the body weight of adult patients.
  • the administration is preferably conducted intravenously or intramuscularly divided into 1 to 4 doses daily.
  • the daily dose of oral administration ranges from about 1 to 500 mg, preferably about 5 to 100 mg, in terms of the active component, per kg of the body weight of adult patients, divided into 1 to 3 doses.
  • novel carbapenem compounds (I) producecd by the method of this invention have excellent properties, for example, having antibacterial activities of a broad spectrum, the present invention provides a novel antibacterial agent useful clinically.
  • IR spectrum was measured by using IR-810 manufactured by Nihon Bunkosha or FT-200 manufactured by Horiba, Ltd.
  • NMR spectrum was measured, using, as internal or external standard, tetramethyl silane or sodium 3-(trimethylsilyl)propionate, by means of GEMINI 200 (200MHz) spectrometer manufactured by Varian Co., and all the delta values were shown by ppm.
  • the numerical values shown in parenthesis ( ) are mixture ratios of each solvent by volume. Percent (%) in the mixed solvents means volume %. Symbols in Reference Examples and Working Examples have the following meanings.
  • PNB p-nitrobenzyl (or 4-nitrobenzyl) hexetil: l-(cyclohexyloxycarbonyloxy)ethyl pivoxil: pivaloyloxymethyl
  • 6-Benzoylthio-6,7-dihydro-5H-imidazo[2,1- b] [ 1, 3]thiazine To a solution of triphenyl phosphine (4.26 g) in anhydrous THF (35 ml) was added, at -15°C, diisopropyl azodicarboxylate (3.20 ml). The mixture was stirred for 30 minutes at -15°C. To the reaction mixture was then added a hexamethyl phosphoramide solution (20 ml) of 6-hydroxy-6,7-dihydro-5H-imidazo[2, 1-b] [ 1, 3]thiazine (1.30 g) and thiobenzoic acid (1.90 ml).
  • reaction mixture was washed with water and a saturated aqueous saline solution, which was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off, and the residue was purified by means of a column chromatography (carrier: silica gel, 250 g, developing solvent: ethyl acetate - hexane, 2:3 ⁇ 3:2) to afford the title compound (13.0 g) as a colorless solid product.
  • the extract solution was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure.
  • the residue was purified by means of a column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate - ethanol, 9:1 -» 4:1).
  • the eluate was concentrated, and the resulting precipitate was washed with ethyl acetate to afford the title compound (6.04 g) as a colorless solid product.
  • 6-Hydroxy-2-methyl-6,7-dihydro-5H-l,2,4-triazolo[5,1-b] [l,3]thiazine To a solution of 2-methyl-6-(tetrahydropyran-2- yloxy)-6,7-dihydro-5H-l,2,4-triazolo[5,1- b] [l,3]thiazine (2.64 g) in ethanol (50 ml) was added pyridinium p-toluene sulfonate (520 mg), and the mixture was stirred for 18 hours at 70 °C. The solvent was distilled off under reduced pressure, and to the residue was added methylene chloride.
  • 2-Mercapto-4,5-dimethylimidazole (6.41g) was suspended in ethanol (100ml), and to the suspension were added sodium hydrogencarbonate (5.04g) and epichlorohydrin (4.00ml) in the order mentioned at room temperature. The mixture was stirred for 18 hours at the same temperature. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. To the residue were added water and diethyl ether. Insolubles were collected by filtration and dried to obtain the title compound (lO.Og).
  • 6-Benzoylthio-2,3-dimethyl-6,7-dihydro-5H- imidazo[2,1-b] [1,3]thiazine To a solution of triphenylphosphine (7.87g) in anhydrous tetrahydrofuran (100ml) was added diisopropyl azodicarboxylate (6.07g) at 0 °C. The mixture was stirred for 15 minutes at the same temperature.
  • the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual solid substance was collected by filtration, and washed with ethyl acetate-ether (1 : 1 ; 150 ml) to. give the title compound (10.8 g) as a pale yellow solid product. The filtrate was concentrated and the residue was filtered off, and washed with ethyl acetate.
  • Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (192 mg) was dissolved in a mixture of THF (8 ml) and a pH 7 phosphate buffer solution (0.2M, 8 ml). To the solution was added 10% palladium- carbon (200 mg), which was subjected to hydrogenation for one hour at room temperature under atmospheric pressure. The catalyst was filtered off and washed with water sufficiently.
  • Diastereomer-1 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- 1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate 40 mg was dissolved in dry N,N- dimethylacetamide (2 ml) at -15°C. To the solution was added ( 1-iodoethyl)cyclohexyl carbonate (45 mg) . The mixture was stirred for one hour at -15°C.
  • Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2,1-b]1,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (46 mg) was dissolved in acetonitrile (2 ml). To the solution was added methyl iodide (0.28 mg), and the mixture was stirred for 8 hours at room temperature. The reaction mixture was concentrated, which was dissolved in a mixture of THF (2 ml) and a pH 7 phosphate buffer solution (0.2M, 2 ml).
  • Diastereomer-2 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- 1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (43 mg) was subjected to the same reaction as in Working Example 6 to afford the title compound (20 rag) as a colorless solid product.
  • Diastereomer-1) Diastereomer-1 of sodium (4R,5S,6S)-(6,7-dihydro-
  • Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-tetrazolo[5,1-b] [1,3]thiazin-6-ylthio)-6- [ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (263 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (163 mg) as a colorless solid product.
  • Diastereomer-1 (350 mg) of 4-nitrobenzyl (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H-l,2,4- triazolo[5,l-b] [1,3]thiazin-6-ylthio)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate obtained in Working Example 12a was subjected to same reaction procedure as in Working Example 2 to give diastereomer-1 (208 mg) of the title compound as a colorless solid product.
  • Diastereomer-2 (350 mg) of 4-nitrobenzyl (4R,5S,6S)-3-(2-amino-6 ,7- dihydro-5H-1,2,4-triazolo[5, 1-b] [1,3]thiazin-6-ylthio)- 6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclof3.2.0]hept-2-ene-2-carboxylate obtained in Working Example 12a was subjected to same reaction procedure as in Working Example 2 to give diastereomer- 2 (207 mg) of the title compound as a colorless solid product.
  • Diastereomer-1 (53 mg) of Sodium (4R,5S,6S)-3-(2- amino-6,7-dihydro-5H-l,2,4-triazolo[5,1-b] [1,3]thiazin-
  • Diastereomer-1 (37mg) of sodium (4R,5S,6S)-3-(2- amino-6,7-dihydro-5H-1,2,4-triazolo[5,1-b] [1,3]thiazin- 6-ylthio)-6-[(R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in Working Example 12b was dissolved in dried dimethylacetamide (1 ml) at -15 °C. To the solution was added iodomethyl pivalate (32 mg), and the mixture was stirred for 1 hour at -15 °C.
  • Diastereomer-1 (260 mg) obtained in Working Example 13a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-1 (I89mg) of the title compound.
  • Diastereomer-2 (300 mg) obtained in Working Example 13a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-2 (211 mg) of the title compound.
  • Diastereomer-1 (39 mg) obtained in Working Example 13b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-1 (29 rag) of the title compound.
  • Diastereomer-2 (45 mg) obtained in Working Example 13b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-2 (13 mg) of the title compound.
  • Diastereomer 1 Diastereomer-1 (300 mg) of 4-nitrobenzyl
  • Example 15a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-1 (319 mg) .
  • Diastereomer-2 (600 mg) obtained in Working Example 15a was subjected to the same reaction and purification procedures as in Working Example 2
  • Diastereomer-1 (63 mg) obtained in Working Example 15b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-1 (63 mg) .
  • Diastereomer-2 (80 mg) obtained in Working Example 15b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-2 (91 mg) .
  • Example 16a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-1 (279 mg) of the title compound.
  • Diastereomer-2 (420 mg) obtained in Working Example 16a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-2 (162 mg) of the title compound.
  • Diastereomer-1 (530 mg) obtained in Example 17a was subjected to the same reaction and purification procedures as in Example 2 to give diastereomer-1 (226 mg) of the title compound.
  • Diastereomer-2 (346 mg) obtained in Example 17a was subjected to the same procedures to give diastereomer-2 (162 mg) of the title compound.
  • Diastereomer-1 (81 mg) obtained in Example 17b was subjected to the same reaction and purification procedures as in Example 3 to give diastereomer-1 (61 mg) of the title compound.
  • Diastereomer-2 (67 mg) obtained in Example 17a was subjected to the same procedures to give diastereomer-2 (66 mg) of the title compound.
  • (Diastereomer-1) IR (KBr) : 1759 cm “1 . : H-NMR (CDC1 3 ) ⁇ : 1.1-2.1 (19H, m) , 2.19 (3H, d,
  • Tetrahydrofuran was distilled off under reduced pressure. To the residue was added ethyl acetate (300 ml), and insolubles were filtered off. The aqueous layer was concentrated under reduced pressure. The residue was purified by column chromatography (carrier:SP-207, 800 ml;developing solvent:water - 15% ethanol) and freeze-dried to give the title compound (4.79 g) as a colorless solid product. IR (KBr): 3300, 1748, 1597, 1545, 1362 cm "1 .
  • the compound (I) of this invention has antibacterial activities of a broad spectrum, and they can be used for the treatment and prevention of various diseases of man and other animals caused by pathogenic bacteria.
  • Test Example Minimum Inhibitory Concentration (MIC) Minimum Inhibitory Concentration (MIC)
  • the minimum inhibitory concentration [MIC (unit: ( ⁇ /ml)] of the test compound was determined by an agar dilution method. More specifically, 0.25 ml of an aqueous solution of the test compound diluted stepwise was put into a Petri dish, which was then mixed with 9.75 ml of Muller-Hinton agar containing fildis enrichment [F-MH medium, fildis enrichment (5%)]). On thus-prepared mixed agar plate, a suspension of the test bacteria (about 10 CFU/ml) was spread, which was incubated at 37°C overnight. The minimum concentration of the test compound to completely inhibit the growth of the test bacteria was expressed as MIC. [Table 1J

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Abstract

Composés de carbapenem répondant à la formule (1), dans laquelle R1 représente un groupe alkyle inférieur éventuellement substitué, R2 représente un groupe alkyle inférieur, Y représente une liaison ou un groupe alkylène inférieur éventuellement substitué, et R représente un groupe à noyaux oxazine ou thiazine condensés éventuellement hydrogéné et éventuellement substitué; ou leurs esters ou sels. Ces composés présentent des activités antibactériennes, une stabilité et une absorbabilité par voie orale excellentes.
PCT/JP1997/000756 1996-03-11 1997-03-11 Composes de carbapenem, leur production et leur utilisation WO1997033888A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019072A1 (fr) * 1992-03-17 1993-09-30 Yamanouchi Pharmaceutical Co., Ltd. Derive de carbapenem
WO1995025108A1 (fr) * 1994-03-14 1995-09-21 Merck & Co., Inc. Composes de carbapeneme, compositions les contenant, et methodes de traitement associees
WO1996026939A1 (fr) * 1995-03-02 1996-09-06 Takeda Chemical Industries, Ltd. Composes de carbapenem, leur production et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019072A1 (fr) * 1992-03-17 1993-09-30 Yamanouchi Pharmaceutical Co., Ltd. Derive de carbapenem
WO1995025108A1 (fr) * 1994-03-14 1995-09-21 Merck & Co., Inc. Composes de carbapeneme, compositions les contenant, et methodes de traitement associees
WO1996026939A1 (fr) * 1995-03-02 1996-09-06 Takeda Chemical Industries, Ltd. Composes de carbapenem, leur production et leur utilisation

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