WO1993023402A1 - Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens - Google Patents

Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens Download PDF

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Publication number
WO1993023402A1
WO1993023402A1 PCT/JP1993/000598 JP9300598W WO9323402A1 WO 1993023402 A1 WO1993023402 A1 WO 1993023402A1 JP 9300598 W JP9300598 W JP 9300598W WO 9323402 A1 WO9323402 A1 WO 9323402A1
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alkyl
methyl
amino
carbamoyl
hydroxy
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PCT/JP1993/000598
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English (en)
Inventor
Hidenori Azami
Keiji Matsuda
Toshiyuki Chiba
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to JP5520047A priority Critical patent/JPH07500354A/ja
Publication of WO1993023402A1 publication Critical patent/WO1993023402A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms

Definitions

  • the present invention relates to novel
  • one object of the present invention is to provide novel 3-a2etidinylthio-1-azabicyclo- [3.2.0]hept-2-ene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic
  • Another object of the present invention is to provide processes for the preparation of novel
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said 3-azetidinylthio-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof.
  • Still further object of the present invention is to provide a use of said 3-azetidinylthio-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof as a medicament, or a method for the treatment of infectious diseases by pathogenic microorganisms in human being or animal.
  • R 1 is carboxy, COO- or protected carboxy
  • R 2 is hydroxy(lower)alkyl or protected
  • R 3 is hydrogen or lower alkyl
  • R 4 is substituted lower alkyl or substituted
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate,
  • a base salt such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium
  • trifluoroacetate maleate, tartrate, methanesulfonate, benzenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g. arginine, aspartic acid , glutamic acid, etc.
  • an intermolecular or intramolecular quaternary salt e.g. arginine, aspartic acid , glutamic acid, etc.
  • the said intermolecular quaternary salt can be formed, for example, when R 4 is N-(lower)alkyl-N-carbamoyKlower)alkylamino (e.g. N-methyl-N-carbamoylmethylamino, etc.), or di ( lower)alkylamino (e.g. N,N-dimethylamino, etc.) and said amino is substituted by suitable substituent(s) such as lower alkyl (e.g. methyl, etc.), carbamoyl(lower)alkyl (e.g. carbamoylmethyl, etc.), etc.; and the like.
  • suitable substituent(s) such as lower alkyl (e.g. methyl, etc.), carbamoyl(lower)alkyl (e.g. carbamoylmethyl, etc.), etc.; and the like.
  • Suitable intermolecular quaternary salt may include N,N-di(lower)alkyl-N-carbamoylammonio halide (e.g. N,N-dimethyl-N-carbamoylammonio iodide,
  • intramolecular quaternary salt can be regarded as
  • intermolecular quaternary salt can be expressed as corresponding acid addition salt of intramolecular quaternary salt.
  • the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
  • R 1 , R 2 , R 3 , and R 4 and R 5 are each as defined above,
  • R 1 a is protected carboxy
  • R a 2 is protected hydroxy(lower)alkyl
  • R 2 b is hydroxy(lower)alkyl
  • R a 4 is substituted lower alkyl or substituted
  • R 5 is hydrogen
  • R 4 b is substituted lower alkyl or substituted
  • R 6 is lower alkyl.
  • the compound (III) used in the Process 1 can be prepared, for example, by the following method or a conventional manner.
  • R 4 , R 5 and R 6 are each as defined above.
  • Suitable “protected carboxy” may include esterified carboxy wherein “esterified carboxy” can be referred to the ones as mentioned below.
  • esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxyI lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
  • lower alkyl ester e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.
  • suitable substituent(s) for example, lower alkanoyloxyI lower alkyl este
  • 2-mesylethyl ester, etc. mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
  • lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
  • ar(lower)alkyl ester which may have at least one suitable substituent(s) such as mono- or di- or
  • triphenyl(lower)alkyl ester which may have halogen or lower alkoxy (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenz ⁇ l ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester,
  • aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
  • More preferable example of the protected carboxy thus defined may be C 2 -C 4 alkenyloxycarbonyl and phenyl(or nitrophenyl) (C 1 -C 4 )alkoxycarbonyl.
  • Suitable "hydroxy(lower)alkyl” may include straight or branched lower alkyl having hydroxy group such as hydroxymethyl, hydroxyethyl, hydroxypropyl,
  • hydroxy(C 1 -C 4 )alkyl and the most preferable one may be 1-hydroxyethyl.
  • Suitable "protected hydroxy(lower)alkyl” means aforementioned hydroxy(lower)alkyl, in which the hydroxy group is protected by a conventional hydroxy-protective group such as those mentioned in the explanation of imino-protective group as mentioned below; ar(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl (e.g.
  • trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, diisopropylmethylsilyl, etc.), triarylsilyl (e.g. triphenylsilyl, etc.), triar(lower)alkylsilyl (e.g.
  • hydroxy(lower) alkyl thus defined may be [phenyl(or
  • Suitable "lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferable example may be C 1 -C 4 alkyl and the most
  • one may be methyl for R 3 and ethyl for R 5 .
  • N-(or N,N-di)(lower)alkylcarbamoyl means carbamoyl group mono- or disubstituted by above-mentioned lower alkyl such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl,
  • dipropylcarbamoyl isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and the like, in which more preferable example may be di(C 1 -C 4 )alkylcarbamoyl. and the most preferable one may be dimethylcarbamoyl.
  • N-[N-hydroxy(lower)alkyl-N-(lower)-alkylamino(lower)alkyl]carbamoyl means aforementioned N-(lower)alkylcarbamoyl group, wherein said lower alkyl group is further substituted by
  • N-(lower)alkyl-N-hydroxy(lower)alkylamino group Said lower alkyl and hydroxy(lower)alkyl moieties are the same ones as mentioned above.
  • N-[N-hydroxy(lower)-alkyl-N-(lower)alkylamino(lower)alkyl]carbamoyl thus defined may be N-[N-hydroxy(C 1 -C 4 )alkyl-N-(C 1 -C 4 )-alkylamino(C 1 -C 4 )alkyl]carbamoyl, and the most preferable one may be N-[2-[N-(2-hydroxyethyl)-N-methylamino]ethyl]-carbamoyl.
  • N-[N-hydroxy(lower)alkyl-N,N-di(lower)alkylammonio(lower)alkyl]carbamoyl means aforementioned N-[N-hydroxy(lower)alkyl-N-(lower)alkylamino(lower)alkyl]carbamoyl group, wherein said amino group is further substituted by lower alkyl.
  • N-[N-hydroxy(lower)-alkyl-N,N-di(lower)alkylammonio(lower)alkyl]carbamoyl thus defined may be N-[N-hydroxy(C 1 -C 4 )alkyl-N,N-di(C 1 -C 4 )alkylammonio(C 1 -C 4 )alkyl]carbamoyl, and the most preferable one may be N-[2-[N-(2-hydroxyethyl)-N,N-dimethylammonio]ethyl]carbamoyl.
  • Suitable "N-[amino(lower)alkyl]carbamoyl” means aforementioned carbamoyl(lower)alkyl group, wherein said lower alkyl group is further substituted by amino, in which more preferable example may be
  • N-[amino[ C 1 -C 4 )alkyl]carbamoyl and the most preferable one may be 4-aminobutylcarbamoyl.
  • Suitable "N-[protected amino(lower)alkyl]carbamoyl” means N-[amino(lower)alkyl]carbamoyl group, wherein said amino group is further substituted by suitable
  • amino-protective group such as acyl as mentioned below, in which preferable examples may be N-[lower
  • Suitable optionally substituted heterocyclic moiety of "optionally substituted heterocyclic-thio" may be heterocyclic group as mentioned below, in which preferable examples of said heterocyclic group may be unsaturated 3 to 8-membered, preferably 5 or 6 membered heteromonocyclic group containing 1 to 4 nitrogen atom, optionally
  • optionally substituted heterocyclic-thio may be lower alkyl-tetrazolylthio, and the most preferable one may be
  • Suitable "lower alkylthio" means thio group
  • Suitable "di(lower)alkylsulfonio" means
  • di(C 1 -C 4 )alkylsulfonio and the most preferable one may be dimethylsulfonio.
  • halo(lower)alkylthio means aforementioned lower alkylthio, wherein said lower alkyl is further substituted by halogen such as chloro, fluoro, bromo and iodo, in which more preferable example may be
  • dihalo(C 1 -C 4 )alkylthio and the most preferable one may be difluoromethylthio.
  • Suitable "lower alkoxy” may include straight of branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, etc., in which more preferable example may be
  • (C 1 -C 4 )alkoxy and the most preferable one may be methoxy.
  • acylamino means amino substituted by acyl group as mentioned below, in which preferable example may be lower alkanoylamino, halo(lower)alkanoylamino, lower alkoxycarbonylamino, lower alkoxy(lower)alkanoylamino, lower alkylsulfonylamino, carbamoylamino, and C 6 -C 10 ar(lower)alkoxycarbonylamino, and the most preferable one may be acetylamino, trifluoroacetylamino,
  • Suitable "protected amino” may include acylamino as mentioned above, wherein said acyl group can be removed by a conventional method, in which preferable example may be lower alkenyloxycarbonylamino and
  • nitro(C 6 -C 10 )ar(lower)alkoxycarbonylamino and the most preferable one may be allyloxycarbonylamino and
  • N-protected-N-(lower)alkylamino may include N-acyl-N-(lower)alkylamino, wherein said acyl group may be the same one as mentioned in protected amino, in which more preferable example may be N-(lower
  • alkenyloxycarbonyl)-N-(lower)alkylamino and the most preferable one may be N-allyloxycarbonyl-N-methylamino.
  • lower alkylamino group wherein said lower alkyl is further substituted by carbamoyl, in which more preferable example may be carbamoyl(C 1 -C 4 )alkylamino, and the most preferable one may be carbamoylmethylamino.
  • Suitable "N-protected-N-[carbamoyl(lower)alkyl]amino" means aforementioned carbamoyl(lower)alkylamino group, wherein said amino group is further substituted by amino-protective group such as acyl as mentioned below.
  • N-protected-N-[carbamoyl(lower)alkyl]amino thus defined may be N-(lower alkenyloxycarbonyl)-N-[carbamoyl(lower)alkyl]amino, and the most preferable one may be N-allyloxycarbonyl-N- (carbamoylmethyl)amino.
  • N-carbamoyl(lower)alkyl-N-(lower)-alkylamino means aforementioned
  • carbamoyl(lower)alkylamino group wherein said amino group is further substituted by lower alkyl, in which most preferable example may be N-carbamoylmethyl-N-methylamino.
  • N-carbamoyl(lower)alkyl-N,N-di(lower)alkyl-ammonio means aforementioned N-carbamoyl(lower)alkyl-N- (lower)alkylamino group, wherein said amino group is further substituted by lower alkyl, in which most
  • preferable example may be N-carbamoylmethyl-N,N-dimethylammonio.
  • Suitable "N-(lower alkylcarbamoyl)(lower)alkyl-N-(lower)alkylamino" means aforementioned N-carbamoyl(lower)alkyl-N-(lower)alkylamino group, wherein said carbamoyl group is further substituted by lower alkyl as mentioned above, in which more preferable example may be N-[(C 1 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl-N-(C 1 -C 4 )alkyl-amino, and the most preferable one may be
  • N-(methylcarbamoyl)methyl-N-methylamino N-(methylcarbamoyl)methyl-N-methylamino.
  • Suitable "N-(lower alkylcarbamoyl) (lower)alkyl-N,N-di(lower)alkylammonio" means aforementioned N-(lower alkylcarbamoyl) (lower)alkyl-N-(lower)alkylamino group, wherein said amino group is further substituted by lower alkyl as mentioned above, in which more preferable example may be N-[(C 1 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl-N,N-di(C 1 -C 4 )-alkylammonio, and the most preferable one may be
  • Suitable optionally substituted heterocyclic moiety of "optionally substituted heterocyclic-carbonyl” may be heterocyclic group as mentioned below, wherein preferable heterocyclic group may be saturated or unsaturated
  • alkenyloxycarbonylamino(lower)alkanoyl and the most preferable one may be 4-hydroxyazetidin-1-yl-carbonyl, 4-(5-aminopentanoyl)piperazin-1-yl and 4-(5-allyloxycarbonylaminopentanoyl)piperazin-1-yl.
  • Suitable "optionally substituted heterocyclic group” may be heterocyclic group as mentioned below, in which more preferable example may be saturated or unsaturated 3 to 8-membered, preferably 5 or 6 membered heteromonocyclic group containing 1 to 4 nitrogen atom, and saturated of unsaturated (preferably unsaturated) 3 to 8-membered, preferably 5 or 6 membered heteromonocyclic group
  • optionally substituted heterocyclic group thus defined may be saturated or unsaturated 5 or 6 membered heteromonocyclic group
  • containing 1 to 4 nitrogen atom optionally substituted by the group consisting of lower alkyl, hydroxy(lower)alkyl and carbamoyl(lower)alkyl, and unsaturated 5 or 6 membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom, in which more preferable example may be pyridyl, imidazolyl, pyrazolyl, pyrrolidinyl, each of which being optionally substituted by (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl and carbamoyl(C 1 -C 4 )alkyl, and
  • Suitable "[hydroxy(lower)alkyl]amino" means amino group substituted by aforementioned hydroxy(lower)alkyl, in which more preferable example may be hydroxy(C 1 -C 4 )- alkyl and the most preferable one may be 2-hydroxyethylamino.
  • N-protected-N-[protected hydroxy(lower)-alkyl]amino means aforementioned hydroxy(lower)alkyl, wherein said hydroxy and amino groups are protected by suitable protective groups such as acyl as mentioned below, in which preferable example may be N-(lower
  • alkenyloxycarbonyl)-N-[lower alkenyloxycarbonyloxy-(lower)alkyl]amino and the most preferable one may be N-allyloxycarbonyl-N-[2-(allyloxycarbonyloxy)ethyl]amino.
  • Suitable "N-(lower)alkyl-N-[hydroxy(lower)alkyl]-amino" means aforementioned [hydroxy(lower)alkyl]amino group, wherein said amino group is further substituted by lower alkyl, in which more preferable example may be
  • N-(C 1 -C 4 )alkyl-N-[hydroxy(C 1 -C 4 )alkyl]amino and the most preferable one may be N-methyl-N-(2-hydroxyethyl)amino.
  • N,N-di(lower)alkyl-N-[hydroxy(lower)-alkyl]ammonio means aforementioned N-(lower)alkyl-N- [hydroxy(lower)alkyl]amino group, wherein said amino group is further substituted by lower alkyl, in which more preferable example may be N,N-di(C 1 -C 4 )alkyl-N-[hydroxy- (C 1 -C 4 )alkyl]ammonio, and the most preferable one may be N,N-dimethyl-N-(2-hydroxyethyl)ammonio.
  • N-(lower)alkyl-N-[N-[hydroxy(lower)alkyl]-carbamoyl(lower)alkyl]amino means aforementioned
  • N-carbamoyl(lower)alkyl-N-(lower) alkylamino group wherein said carbamoyl group is further substituted by
  • hydroxy(lower)alkyl as mentioned above, in which most preferable example may be N-methyl-N-[N-(2-hydroxyethyl)-carbamoylmethyl]amino.
  • Suitable "N-[N-[hydroxy(lower)alkyl]carbamoyl- (lower)alkyl]-N,N-di(lower)alkylammonio" means
  • N-(lower)alkyl-N-[N-[hydroxy(lower)alkyl]-carbamoyl(lower)alkyl)amino group wherein said amino group is further substituted by lower alkyl, in which most preferable example may be N-[N-(2-hydroxyethyl)carbamoylmethyl]-N,N-dimethylammonio.
  • Suitable "N-(lower)alkyl-N-[carbamoyloxy(lower)-alkyl]amino” means aforementioned "N-(lower)alkyl-N-[hydroxy(lower)alkyl]amino group, wherein said hydroxy group is further substituted by carbamoyl, in which more preferable example may be N-(C 1 -C 4 )alkyl-N-[carbamoyloxy(C 1 -C 4 )alkyl]amino, and the most preferable one may be N-methyl-N-[2-(carbamoyloxy)ethyl]amino.
  • Suitable "N,N-di(lower)alkyl-N-[carbamoyloxy(lower)-alkyl]ammonio" means aforementioned "N-(lower)alkyl-N-[carbamoyloxy(lower)alkyl]amino group, wherein said amino group is further substituted by lower alkyl, in which more preferable example may be N,N-di(C 1 -C 4 )alkyl-N- [carbamoyloxy(C 1 -C 4 )alkyl]ammonio, and the most preferable one may be N,N-dimethyl-N-[2-(carbamoyloxy)ethyl]ammonio.
  • Suitable "aryl” may include C 8 -C 10 aryl such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like, in which most preferable example may be phenyl.
  • acyl may include aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.
  • the aliphatic acyl may include saturated or
  • alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl. hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl,
  • alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl. hexanoyl, etc.)
  • alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl,
  • N-alkylcarbamoyl e.g. methylcarbamoyl, ethylcarbamoyl, etc.
  • alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)-alkanecarbonyl (e.g. cyclopropanecarbonyl,
  • the aliphatic acyl substituted with aromatic group(s) may include ar(lower)alkoxycarbonyl such as
  • phenyl(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • phenyl(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • acyl groups may be further substituted with one or more suitable substituent(s) such as nitro, and the like, and preferable acyl having such substituent(s) may be nitroar(lower)alkoxycarbonyl (e.g.
  • Suitable "optionally substituted imino-containing heterocyclic group” may be heterocyclic group as mentioned below, wherein said heterocyclic group contains imino moiety, in which preferable example may be unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing an imino moiety, optionally substituted by lower alkyl, more preferable one may be 2H-pyrrolyl, 1-pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, each of which being substituted by lower alkyl, and the most preferable one may be 1-methyl-2-pyrrolinio.
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexam
  • methylmethylene, ethylethylene, propylene, and the like in which more preferable example may be C 1 -C 4 alkylene and the most preferable one may be trimethylene.
  • Suitable "carbamoyl(lower)alkyl” means aforementioned lower alkyl substituted by carbamoyl, in which most preferable example may be carbamoylmethyl.
  • heterocyclic group means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • More preferable heterocyclic group may be any organic compound.
  • heterocyclic group such as ;
  • N-oxide pyrimidyl, pyrazinyl, pyridazinyl, triasolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
  • tetrazolopyridyl e.g., tetrazolo[1,5-b]pyridazinyl, etc.
  • tetrazolopyridazinyl e.g., tetrazolo[1,5-b]pyridazinyl, etc.
  • oxazolyl isoxazolyl, oxadiazolyl (e.g., isoxazolyl, oxadiazolyl (e.g., isoxazolyl, oxadiazolyl (e.g., isoxazolyl, oxadiazolyl (e.g., isoxazolyl, oxadiazolyl (e.g., isoxazolyl, oxadiazolyl (e.g.,
  • 1,3-thiazolyl 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
  • 6-membered heteromonocyclic group containing a sulfur atom for example, tetrahydrothienyl, etc.
  • heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like; wherein said heterocyclic group may be substituted by one or more, preferably one or two suitable substituent(s) such as :
  • hydroxy(lower)alkyl or protected hydroxy(lower)alkyl as mentioned above, more preferably hydroxy(C 1 -C 4 )alkyl [e.g. hydroxymethyl, etc.) or tri[C 1 -C 4 )alkylsilyloxy-(C 1 -C 4 )alkyl (e.g. hydroxymethyl, 2-hydroxyethyl, etc.);
  • -lower alkoxy which may be straight or branched one alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc., more preferably C 1 -C 4 alkoxy;
  • lower alkoxy and lower alkyl moieties may respectively be the same as those for lower alkoxy and lower alkyl as mentioned above, more preferably C 1 -C 4 alkoxy(C 1 -C 4 )alkyl;
  • lower alkyl moiety may be the same as those for lower alkyl as mentioned above, more preferably C 1 -C 4 alkylamino(C 1 -C 4 )-alkyl;
  • lower alkylamino(lower)alkyl which is the lower alkylamino(lower)alkyl as mentioned above, in which the amino group is protected by a conventional
  • amino-protective group such as acyl as mentioned above, more preferably N-(C 1 -C 4 )alkyl-N-(C 2 -C 4 )alkenyloxy-carbonylamino(C 1 -C 4 )alkyl;
  • acyl mentioned above, more preferably C 2 -C 4 alkenyloxy-carbonylimino;
  • lower alkyl moiety may be the same as those for lower alkyl as mentioned above, more preferably C 1 -C 4 alkylamino;
  • lower alkylamino which is the lower alkylamino group as mentioned above, in which the amino group is protected by a conventional amino-protective group such as acyl mentioned above, more preferably C 1 -C 4 alkylamino;
  • aminovaleryl aminoisovaleryl, aminohexanoyl, and the like (e.g. 5-aminovaleryl, etc.);
  • amino(lower)alkanoyl group and amino protective group may be the same as mentioned above, in which preferable example may be lower alkenyloxycarbonylamino(lower)-alkanoyl [e.g. 5-(allyloxycarbonylamino)valeryl, etc.]; and the like.
  • Preferred embodiments of R 1 , R 2 , R 3 , R 4 and R 5 are as follows.
  • R 1 is carboxy or esterified carboxy
  • R 2 is hydroxy(lower)alkyl, acyloxy(lower)alkyl, mono- (or di or tri)phenyl(lower)alkoxy(lower)alkyl. tri(lower)alk ⁇ lsilyloxy(lower)alkyl, triphenylsilyloxy(lower)alkyl or
  • R 3 is hydrogen or lower alkyl
  • R 4 is carbamoyl(lower)alkyl; lower alkylthio(lower)alkyl;
  • amino(lower)alkyl mono(or di) (lower)alkylamino- (lower)alkyl; lower alkoxy(lower)alkyl;
  • acylamino(lower)alkyl mono(or di)(lower)alkyl- carbamoyl(lower)alkyl;
  • azetidinylcarbonyl(lower)alkyl azetidinylcarbonyl(lower)alkyl, pyrrolidinyl- carbonyl(lower)alkyl, imidazolidinylcarbonyl(lower)- alkyl, piperidinylcarbonyl(lower)alkyl,
  • R 5 is hydrogen, or
  • R 1 is carboxy, COO- or esterified carboxy
  • R 2 is hydroxy(lower)alkyl, aryloxy(lower)alkyl, mono(or di or tri)phenyl(lower)alkoxy ⁇ lower)alkyl,
  • R 3 is hydrogen or lower alkyl.
  • R 4 is carbamoyl(lower)alkyl,
  • N-(or N,N-di) (lower)alkylcarbamoyl(lower)alkyl N-[N-hydroxy(lower)alkyl-N-(lower)alkylamino- (lower)alkyl)carbamoyl(lower)alkyl,
  • heterocyclic-thio(lower)alkyl optionally substituted by lower alkyl, lower alkylthio(lower)alkyl,
  • lower alkoxy(lower)alkyl carbamoyloxy(lower)alkyl, acylamino(lower)alkyl, amino(or protected amino)- (lower)alkyl, lower alkylamino(lower)alkyl,
  • heterocyclic-carbonyl(lower)alkyl optionally
  • heterocyclic(lower)alkyl optionally substituted by the group consisting of lower alkyl and
  • R 5 is hydrogen
  • R 4 is hydrogen and R 5 is heterocyclic group or
  • R 4 and R 5 are combined together to form optionally
  • R 1 , R 2 , R 3 , R 4 and R 5 are as follows.
  • R 1 is carboxy
  • R 2 is hydroxy(lower)alkyl
  • R 3 is lower alkyl
  • R 4 is carbamoyl(lower)alkyl, lower alkylthio(lower)alkyl, di(lower)alkylamino(lower)alkyl,
  • azetidinylcarbonyl(lower)alkyl optionally
  • R 5 is hydrogen, or R 1 is carboxy or COO-,
  • R 2 is hydroxy(lower)alkyl (e.g. 1-hydroxyethyl, etc.), R 3 is lower alkyl (e.g. methyl, etc.),
  • R 4 is carbamoyl(lower)alkyl (e.g. carbamoylmethyl, etc.),
  • N-(or N,N-di) (lower)alkylcarbamoyl(lower)alkyl e.g.
  • lower alkylthio(lower)alkyl e.g. methylthiomethyl, etc.
  • di(lower)alkylsulfonio(lower)alkyl e.g.
  • halo(lower)alkylthio(lower)alkyl e.g.
  • lower alkoxy(lower)alkyl e.g. methoxymethyl, etc.
  • carbamoyloxy(lower)alkyl e.g. carbamoyloxymethyl, etc.
  • lower alkanoylamino(lower)alkyl e.g.
  • halo(lower)alkanoylamino(lower)alkyl e.g.
  • lower alkoxy(lower)alkanoylamino(lower)alkyl e.g. methoxyacetylaminomethyl, etc.
  • lower alkylsulfonylaminof lower alkyl e.g. methylsulfonylaminomethyl, etc.
  • phenyl(lower)alkoxycarbonylamino(lower)alkyl e.g. 2-(benzyloxycarbonylamino)ethyl, etc.
  • nitro(C 6 -C 10 )ar(lower)alkoxycarbonylamino]- (lower)alkyl e.g. aminomethyl, 2-aminoethyl, allyloxycarbonylaminomethyl, 2-(p-nitrobenzyloxy-carbonylamino)ethyl, etc.
  • alkylamino(lower)alkyl or N-(lower)alkenyloxycarbonyl-N-(lower)alkylamino(lower)alkyl e.g.
  • N-(lower)alkenyloxycarbonyl-N-[carbamoyl(lower)-alkyl]amino(lower)alkyl e.g.
  • N-carbamoyl(lower)alkyl-N-(lower)alkylamino(lower)-alkyl e.g. 2-(N-carbamoylmethyl-N-methylamino)ethyl., etc.]
  • N-carbamoyl(lower)alkyl-N,N-di(lower)alkylammonio- (lower)alkyl e.g. 3-(N-carbamoylmethyl- N,N-dimethylammonio)propyl, etc.
  • N-(lower alkylcarbamoyl) (lower)alkyl-N-(lower)alkyl-amino(lower)alkyl e.g. 3-[N-(methylcarbamoyl)-methyl-N-methylamino]propyl, etc.]
  • N-(lower alkylcarbamoyl) (lower)alkyl-N,N-di(lower)-alkylammonio(lower)alkyl e.g.
  • lower alkylpyridyl(lower)alkyl e.g. (1-methyl-3-pyridinio)methyl, 2-(1-methyl-3-pyridinio)ethyl, etc.] imidazolyl(lower)alkyl [e.g.
  • alkylimidazolyl(lower)alkyl e.g.
  • pyrazolyl(lower)alkyl e.g. (1,2-dimethyl-4-pyrazolio)methyl, etc.
  • pyrrolidinyl(lower)alkyl e.g.
  • pyridyl(lower)alkenyl e.g. 2-(3-pyridyl)ethenyl, etc.
  • lower alkylpyridyl(lower)alkenyl e.g.
  • N-(lower)alkenyloxycarbonyl-N-[lower alkenyl-oxycarbonyloxy(lower)alkyl]amino(lower)alkyl e.g. [N-allyloxycarbonyl-N-[2-(allyloxycarbonyloxy)-ethyl]amino]methyl, etc.]
  • N-(lower)alkyl-N-[hydroxy(lower)alkyl]amino(lower)-alkyl e.g. 2-[N-methyl-N-(2-hydroxyethyl)amino]-ethyl, 3-[N-methyl-N-(2-hydroxyethyl)amino]-propyl, etc.]
  • N,N-di(lower)alkyl-N-[hydroxy-(lower)alkyl]ammonio(lower)alkyl e.g.
  • N-(lower)alkyl-N-[carbamoyloxy(lower)alkyl]amino- (lower)alkyl e.g. 3-[N-methyl-N-[2-(carbamoyloxy)-ethyl]amino]propyl, etc.]
  • N,N-di(lower)alkyl-N-[carbamoyloxy(lower)alkyl]-ammonio(lower)alkyl e.g. 3-[N,N-dimethyl-N-[2- (carbamoyloxy)ethyl)ammonio]propyl, etc.]
  • R 5 is hydrogen
  • R 5 is thiadiazolyl (e.g.
  • N-R 5 N,N-di(lower)- alkyliminio (e.g. N,N-dimethyliminio, etc.), or
  • R 4 and R 5 are combined together to form 1-pyrrolinyl ring optionally substituted by lower alkyl (e.g.
  • the compound (I) or salts thereof can be prepared by reacting the compound (II) or salts thereof with the compound (III) or salts thereof.
  • Suitable salts of the compound (II) may be the same as those for the compound (I).
  • Suitable salts of the compound (III) may be the same acid addition salts and/or intermolecular quaternary salt as exemplified for the compound (I).
  • This reaction is usually carried out in a
  • This reaction can be carried out in the presence of an organic or inorganic base such as those given in the explanation of Process 2 .
  • the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
  • the compound (I-b) or salts thereof can be prepared by subjecting the compound (i-a) or salts thereof to removal reaction of the carboxy-protective group on R a 1 .
  • Suitable, salts of the compounds (I-a) and (I-b) may be the same as those for the compound (I).
  • the present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
  • Hydorlysis is preferably carried out in the presence of a base or an acid.
  • Suitable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • Suitable acid may include an organic acid (e.g.
  • cation trapping agent e.g. phenol, anisole, etc.
  • the hydrolysis can be carried out in the presence of tri(lower)alkylammonium halide (e.g.
  • This reaction is usually carried out in a
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
  • the reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride,
  • chromous acetate, etc. an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), and the like.
  • a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate,
  • the reaction is preferably carried out around neutral
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the carboxy-protective group is allyl group, it can be deprotected by hydrogenolysis using a palladium compound.
  • Suitable palladium compound used in this reaction may be palladium on carbon, palladium hydroxide on carbon, palladium chloride, a palladium-ligand complex such as tetrakis(triphenylphosphine)palladium(0),
  • the reaction can preferably be carried out in the presence of a scavenger of allyl group generated in situ, such as amine (e.g. morpholine, N-methylaniline, etc.), an activated methylene compound (e.g. dimedone,
  • a scavenger of allyl group generated in situ such as amine (e.g. morpholine, N-methylaniline, etc.), an activated methylene compound (e.g. dimedone,
  • This reaction can be carried out in the presence of a base such as lower alkylamine (e.g. butylamine,
  • reaction can preferably be carried out in the presence of the corresponding ligand (e.g.
  • triphenylphosphine triphenyl phosphite, triethyl
  • This reaction is usually carried out in a
  • the removal reaction can be selected according to the kind of carboxy-protective group to be removed.
  • the compound (I-d) or salts thereof can be prepared by subjecting the compound (I-c) or salts thereof to removal reaction of the hydroxy-protective group on R a 2 .
  • Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I).
  • This reaction is usually carried out by a
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • tetra(lower)alkylammonium fluoride e.g.
  • the compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to removal reaction of the amino- and/or hydroxy-protective group on R a 4 .
  • Suitable salts of the compounds (I-e) and (I-f) may be the same as those for the compound (I).
  • This reaction is usually carried out by a
  • tetra(lower)alkylammonium fluoride e.g.
  • Processes can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
  • the compound (III) or salts thereof can be prepared by reacting the compound (IV) with the compound (V).
  • Suitable salts of the compound (IV) may be the same as those for the compound (III).
  • the starting compound (IV) can be prepared by a conventional process.
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, allyl alcohol, etc.), pyridine, N,N-dimethylformamide, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • alcohol e.g. methanol, ethanol, propanol, allyl alcohol, etc.
  • pyridine e.g. methanol, ethanol, propanol, allyl alcohol, etc.
  • N,N-dimethylformamide etc.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the object compound (I) and pharmaceutically are not critical and the reaction is usually carried out under from cooling to warming.
  • acceptable salts thereof of the present invention are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as antimicrobial agents.
  • the object compound (I) possessing more potent antimicrobial activity can be represented by the following formula :
  • R b 2 , R 4 and R 5 are each as defined above, and
  • R a 3 is lower alkyl
  • the compound (I) possessing the most potent antimicrobial activity can be represented by the following formula :
  • R a 3 , R 4 and R 5 are each as defined above,
  • quaternary salts of the compound (I) having di( lower)alkylamino or N-(lower)alkyl-N-carbamoyl- (lower)alkylamino as R 4 show fairly low toxicity.
  • Test Method in vitro Antimicrobial Activity was determined by the two-fold agar-plate dilution method as described blow.
  • Test compound One loopful of an overnight culture of a test strain in Trypticase-soy broth (10 viable cells per ml) was streaked on heart infusion agar (HI-agar) containing graded concentrations of the test compound, and the minimal inhibitory concentration (MIC) was expressed in terms of ⁇ g/ml after incubation at 37°C for 20 hours.
  • HI-agar heart infusion agar
  • the object compound (I) and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like.
  • auxiliary substances such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be
  • amount between 1 mg and about 4,000 mg or even more per day may be administered to a patient.
  • An average single dose of about 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg, of the object compound (I) of the present invention may be used in treating diseases infected by pathogenic
  • N-carbamoylmethyl-N-(3-cyanopropyl)-N,N-dimethylammonium bromide (3.55 g).
  • N-carbamoylmethyl-N-(3-cyanopropyl)-N,N-dimethylammonium bromide (3.54 g) in substantially the same manner as that of Preparation 1.
  • tert-butyldimethylsilyl chloride (15.83 g) by portions at 0°C. After two hours, the precipitate was filtered off, and the filtrate was washed in turn with 1N-hydrochloric acid, brine, saturated sodium hydrogen carbonate in water and brine. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (9:1 to 4:1, V/V) to give 2-tert-butyldimethylsilyloxy-1-iodoethane (26.93 g).
  • N-(4-(t-butoxycarbonylamino)butyl)amine (21.1 g) and triethylamine (23 ml) in methanol (60 ml) was allowed to stand at ambient temperature for 15 hours. Evaporation of the mixture gave a residue which was chromatographed on silica gel (800 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3) to give N-(4-(t-butoxycarbonylamino)-butyl)-2-cyanoacetamide (17.3 g).
  • tetra-n-butylammonium fluoride 70%, 12.5 g
  • the reaction mixture was taken up into a mixture of water (200 ml), ethyl acetate (100 ml) and hexane (100 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate.
  • N-(3-Cyanopropyl)-N-(N-(2-hydroxyethyl)carbamoylmethyl)-N,N-dimethylammonium bromide (5.74 g) was obtained in substantially the same manner as that of Preparation 8-1).
  • N-(2-Hydroxymethyl)-N-(3-cyanopropyl)-N,N-dimethyl-ammonium bromide (6.86 g) was obtained in substantially the same method as that of Preparation 8-1).
  • N-(2-Carbamoyloxyethyl)-N-(3-cyanopropyl)-N,N-dimethylammonium bromide was obtained in substantially the same manner as that of Preparation 8-1).
  • N-(2-Cyanoacetamidoethyl)-N,N-dimethyl-N-(2-hydroxyethyl)ammonium iodide (2.15 g) was obtained from N-cyanoacetyl-N',N'-dimethylethylenediamine (2.0 g) and iodoethanol (1.3 ml) in substantially the same method as that of Preparation 8-1).
  • 3-(2-Cyanoethyl)-1-methylpyridinium iodide (22.81 g) was obtained from 3-(2-cyanoethyl)pyridine (11.98 g) and iodomethane (20 ml) in substantially the same manner as that of Preparation 26-1).
  • triflate (3.2 ml) at 0°C.
  • N-methylpyrrolidine (1.25 ml) in benzene (5 ml) was heated to 70°C for 5 hours. After cooling, the resulting

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Abstract

Composé de la formule (I) dans laquelle R1 est carboxy, COO- ou un carboxy protégé; R2 est un hydroxyalkyle (inférieur) ou un hydroxyalkyle (inférieur) protégé; R3 est un hydrogène ou un alkyle inférieur; et R4 est un alkyle inférieur substitué ou un alcényle inférieur substitué et R5 est un hydrogène, ou R4 est un hydrogène et R5 est un groupe hétérocyclique ou un alkyle inférieur ou R4 est un hydrogène et la formule: =N-R5 est N,N-dialkylimino (inférieur), ou R4 et R5 sont combinés pour former facultativement un groupe hétérocyclique éventuellement substitué contenant un imino; ou sels pharmaceutiquement acceptables de ce composé, ayant une activité antimicrobienne.
PCT/JP1993/000598 1992-05-11 1993-05-07 Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens WO1993023402A1 (fr)

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EP0632039A1 (fr) * 1993-07-01 1995-01-04 LEDERLE (JAPAN), Ltd. Dérivés de 2-(1-(1,3-thiazolin-2-yl)azétidin-3-yl)thio-carbapéneme
US5783703A (en) * 1993-07-01 1998-07-21 Lederle (Japan), Ltd. Sulfur-containing compounds method for their use and prodction
EP1303501A1 (fr) * 2000-07-13 2003-04-23 Alteon, Inc. Thiazoliums et imidazoliums substitues par le cyanomethyle et traitements de troubles associes au vieillissement proteique
EP1340757A1 (fr) * 2000-11-16 2003-09-03 Sankyo Company, Limited D riv s 1-m thylcarbapenem
WO2005019185A1 (fr) * 2003-08-26 2005-03-03 Ecole Polytechnique Federale De Lausanne (Epfl) Liquides ioniques a base de sels d'imidazolium incorporant une fonctionnalite nitrile
EP1681287A1 (fr) 2000-07-04 2006-07-19 Ube Industries, Ltd. Composes de benzoxazole, procede d'elaboration de ceux-ci et herbicides

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EP0186525A1 (fr) * 1984-12-25 1986-07-02 Sankyo Company Limited Dérivés de carbapénème, leur préparation et application
EP0394991A1 (fr) * 1989-04-28 1990-10-31 Fujisawa Pharmaceutical Co., Ltd. Composés de l'acide 1-azabicyclo(3.2.0)hept-2-ène-2-carboxylique
WO1992002521A1 (fr) * 1990-07-27 1992-02-20 Fujisawa Pharmaceutical Co., Ltd. Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique

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EP0072710B1 (fr) * 1981-08-19 1986-02-19 Sankyo Company Limited Dérivés de Carbapénème, leur préparation et compositions les contenant
EP0186525A1 (fr) * 1984-12-25 1986-07-02 Sankyo Company Limited Dérivés de carbapénème, leur préparation et application
EP0394991A1 (fr) * 1989-04-28 1990-10-31 Fujisawa Pharmaceutical Co., Ltd. Composés de l'acide 1-azabicyclo(3.2.0)hept-2-ène-2-carboxylique
WO1992002521A1 (fr) * 1990-07-27 1992-02-20 Fujisawa Pharmaceutical Co., Ltd. Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique

Cited By (16)

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Publication number Priority date Publication date Assignee Title
US5534510A (en) * 1993-07-01 1996-07-09 Lederle (Japan), Ltd. 2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-carbapenem derivatives
US5679790A (en) * 1993-07-01 1997-10-21 Lederle (Japan), Ltd. 2- 1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-carbapenem derivatives
US5783703A (en) * 1993-07-01 1998-07-21 Lederle (Japan), Ltd. Sulfur-containing compounds method for their use and prodction
EP0632039A1 (fr) * 1993-07-01 1995-01-04 LEDERLE (JAPAN), Ltd. Dérivés de 2-(1-(1,3-thiazolin-2-yl)azétidin-3-yl)thio-carbapéneme
EP1681287A1 (fr) 2000-07-04 2006-07-19 Ube Industries, Ltd. Composes de benzoxazole, procede d'elaboration de ceux-ci et herbicides
EP1681286A1 (fr) 2000-07-04 2006-07-19 Ube Industries, Ltd. Composes de benzoxazole, procede d'elaboration de ceux-ci et herbicides
EP1303501A1 (fr) * 2000-07-13 2003-04-23 Alteon, Inc. Thiazoliums et imidazoliums substitues par le cyanomethyle et traitements de troubles associes au vieillissement proteique
EP1303501A4 (fr) * 2000-07-13 2004-03-03 Alteon Inc Thiazoliums et imidazoliums substitues par le cyanomethyle et traitements de troubles associes au vieillissement proteique
CZ300137B6 (cs) * 2000-11-16 2009-02-18 Sankyo Company Limited Deriváty 1-methylkarbapenemu
EP1340757A1 (fr) * 2000-11-16 2003-09-03 Sankyo Company, Limited D riv s 1-m thylcarbapenem
EP1340757A4 (fr) * 2000-11-16 2005-01-26 Sankyo Co D riv s 1-m thylcarbapenem
US7001897B2 (en) 2000-11-16 2006-02-21 Sankyo Company, Limited 1-methylcarbapenem derivatives
WO2005019185A1 (fr) * 2003-08-26 2005-03-03 Ecole Polytechnique Federale De Lausanne (Epfl) Liquides ioniques a base de sels d'imidazolium incorporant une fonctionnalite nitrile
AU2004266847B2 (en) * 2003-08-26 2008-08-07 Ecole Polytechnique Federale De Lausanne (Epfl) Ionic liquids based on imidazolium salts incorporating a nitrile functionality
JP4791361B2 (ja) * 2003-08-26 2011-10-12 エコール・ポリテクニーク・フェデラル・ドゥ・ローザンヌ（ウペエフエル） ニトリル官能基が組み込まれているイミダゾリウム塩に基づくイオン性液体
US8101777B2 (en) 2003-08-26 2012-01-24 Ecole Polytechnique Federale De Lausanne Ionic liquids based on imidazolium salts incorporating a nitrile functionality

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CN1084173A (zh) 1994-03-23
JPH07500354A (ja) 1995-01-12
GB9210096D0 (en) 1992-06-24
AU4272093A (en) 1993-12-13

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