+

WO1992002521A1 - Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique - Google Patents

Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique Download PDF

Info

Publication number
WO1992002521A1
WO1992002521A1 PCT/JP1991/000997 JP9100997W WO9202521A1 WO 1992002521 A1 WO1992002521 A1 WO 1992002521A1 JP 9100997 W JP9100997 W JP 9100997W WO 9202521 A1 WO9202521 A1 WO 9202521A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
imidazolinyl
compound
imidazolin
preparation
Prior art date
Application number
PCT/JP1991/000997
Other languages
English (en)
Inventor
Masayoshi Murata
Toshiyuki Chiba
Hideo Tsutsumi
Akira Yamada
Kohji Hattori
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB909016507A external-priority patent/GB9016507D0/en
Priority claimed from JP3196181A external-priority patent/JPH04234886A/ja
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP3512378A priority Critical patent/JPH06503803A/ja
Publication of WO1992002521A1 publication Critical patent/WO1992002521A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/14—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 hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
    • 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

Definitions

  • the present invention relates to novel
  • one object of the present invention is to provide novel 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof , which are highly active against a number of pathogenic microorganisms and are useful as antimicrobial agents.
  • 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 comprising, as an active ingredient, said 1-azabicyclot 3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically
  • Still further object of the present invention is to provide a use of said 1-azabicyclo[3.2.0]hept-2-ene- 2-carboxylic acid compounds and pharmaceutically
  • R 1 is carboxy, protected carboxy or carboxylato
  • R 2 is hydroxy(lower) alkyl or protected hydroxy ⁇
  • R 3 is azetidinyl, pyrrolidinyl, imidazolinyl,
  • each heterocyclic group may be substituted by one or more suitable amino acids
  • R 10 is hydrogen or lower alkyl
  • A is lower alkylene
  • R 3 is lower alkylpyrrolidinyl. then R 10 is hydrogen
  • salts 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,
  • a base salt 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,
  • an organic base salt for example, an organic amine salt (e.g. triethylamine salt,
  • dicyclohexylamine salt N,N'-dibenzylethylenediamine salt, etc.
  • a salt with an acid such as an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g.
  • formate acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • the object compound (I) and pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
  • R 1 , R 2 , R 3 , R 10 and A are each as defined above,
  • R a 1 is protected carboxy
  • R a 2 is protected hydroxy(lower)alkyl
  • R b 2 is hydroxy(lower)alkyl
  • R a 3 is azetidmyl, pyrrolidinyl, imidazolinyl, tetrahydropyrimidinyl or piperidyl; wherein the ring carbon atom(s) may be substituted by one or more suitable substituent(s), and the ring nitrogen atom(s) is(are)
  • R b 3 is azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydropyrimidinyl or piperidyl; wherein the ring carbon atom(s) may be substituted by one or more suitable substituent(s), R c 3 is azetidmyl, pyrrolidinyl, imidazolinyl, tetrahydropyrimidinyl or piperidyl; wherein the ring carbon atom(s) may be substituted by one or more suitable substituent(s), and the ring nitrogen atom(s) is(are)
  • R d 3 is azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydropyrimidinyl or piperidyl; wherein the ring carbon atom(s) may be substituted by one or more suitable substituent(s), and the ring nitrogen atom(s) is (are) mono- or disubstituted by lower alkyl,
  • R 4 is a suitable substituent(s)
  • R 5 is lower alkyl or ar(lower)alkyl
  • R 6 is hydrogen or lower alkyl
  • R 9 is hydrogen, lower alkyl or
  • R a 9 is lower alkyl or hydroxy(lower)alkyl, and n is an integer of 2 or 3.
  • R 1 , R 2 , R 3 , R 9 , R 10 , A and n are each as defined above,
  • R 7 and R 8 are each an amino-protective group, L is a leaving group, and
  • X is an acid residue
  • 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 alkanoyloxy(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 alkanoyloxy(lower)alkyl
  • 2-mesylethyl ester, etc. mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
  • alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester e.g.
  • 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) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl 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, and the most preferable one may be allyloxycarbonyl.
  • Suitable "hydroxy(lower)alkyl” may include straight or branched lower alkyl substituted by hydroxy group such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 1- (hydroxymethyl) ethyl, 1-hydroxy-1-methylethyl,
  • hydroxy(C 1 -C 4 ) alkyl and the most preferable one may be hydroxymethyl, 2-hydroxyethyl and 1-hydroxyethyl.
  • Suitable "protected hydroxy(lower)alkyl” may include 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 preferably, lower alkenyloxycarbonyl and phenyl(or nitrophenyl)- (lower)alkoxycarbonyl; and further C 6 -C 10 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,
  • hydroxy(lower)alkyl thus defined may be ⁇ phenyl(or nitrophenyl) (C 1 -C 4 )alkoxy ⁇ carbonyloxy(C 1 -C 4 ) alkyl, C 2 -C 4 alkenyloxycarbonyloxy(C 1 -C 4 ) alkyl and
  • ⁇ tri(C 1 -C 4 )alkylsilyl ⁇ oxy(C 1 -C 4 )alkyl and the most preferable one may be 1-t-butyldimethylsilyloxyethyl.
  • 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
  • Suitable "acid residue” may include an inorganic acid residue such as azide, halogen (e.g. chlorine, bromine, fluorine or iodine), and the like, an organic acid residue such as acyloxy (e.g. benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, acetoxy, etc.), and the like, in which more preferable example may be halogen and the most preferable one may be chlorine.
  • halogen e.g. chlorine, bromine, fluorine or iodine
  • organic acid residue such as acyloxy (e.g. benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, acetoxy, etc.), and the like, in which more preferable example may be halogen and the most preferable one may be chlorine.
  • Suitable “leaving group” may include acid residue as mentioned above, in which more preferable example may be lower alkanoyloxy and the most preferable one may be acetoxy.
  • Suitable "ar(lower)alkyl” may include C 6 -C 10
  • ar( lower)alkyl such as phenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.), tolyl(lower)alkyl, xylyl(lower)alkyl, naphthyl(lower)alkyl (e.g. naphthylmenthyl, etc.), and the like.
  • Suitable "imino-protective group” may include acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by 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,
  • N-(lower)alkylcarbamoyl e.g. methylcarbamoyl
  • alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), 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, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
  • the aromatic acyl may include aroyl (e.g. benzoyl, toluoyl, xyloyl, etc.), N-arylcarbamoyl (e.g.
  • the heterocyclic acyl may include heterocyclic-carbonyl (e.g. furoyl, thenoyl, nicotinoyl, isonicotmoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
  • heterocyclic-carbonyl e.g. furoyl, thenoyl, nicotinoyl, isonicotmoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.
  • the aliphatic acyl substituted by aromatic group(s) may include aralkanoyl such as phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.),
  • aralkanoyl such as phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.)
  • aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.)
  • aryloxyalkanoyl such as phenoxytlower alkanoyl
  • the aliphatic acyl substituted by heterocyclic group(s) may include heterocyclic-alkanoyl such as
  • heterocyclic(lower)alkanoyl e.g. thienylacetyl
  • acyl groups may be further substituted by one or more suitable substituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), halogen (e.g. chlorine, bromine, iodine, fluorine), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy. butoxy, pentyloxy, hexyloxy, etc.), lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio,
  • lower alkyl e.g. methyl, ethylthio, propylthio, isopropylthio
  • N-allyloxycarbonyl-N-methylamino, etc.), and the like, and preferable acyl having such substituent(s) may be mono(or di or tri)haloalkanoyl (e.g. chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc.), mono(or di or tri)haloalkoxycarbonyl (e.g. chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), nitro- (or halo- or lower alkoxy-)aralkoxycarbonyl (e.g.
  • mono(or di or tri)haloalkanoyl e.g. chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc.
  • mono(or di or tri)haloalkoxycarbonyl e.g. chlorometh
  • nitrobenzyloxycarbonyl chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl, etc.
  • mono(or di or tri)-halo(lower)alkylsulfonyl e.g. fluoromethylsulfonyl difluoromethylsulfonyl, trifluoromethylsulfonyl,
  • imino-protective group thus defined may be C 1 -C 4 alkanoyl
  • Suitable "amino-protective group” may be the same as those for "imino-protective group", in which more
  • amino-protective group thus defined may be (C 2 -C 4 )alkenyloxycarbonyl and phenyl(or
  • nitrophenyl) (C 1 -C 4 )alkoxycarbonyl and the most preferable one may be allyloxycarbonyl.
  • each heterocyclic group may be substituted by suitable substituent(s)" may include : azetidmyl, pyrrolidinyl, imidazolinyl, tetrahydropyrimidinyl, piperidyl, 1,1-di(lower)alkylpiperidinio,
  • ring carbon atom(s) may be substituted by one to three suitable substituent(s) selected from the group consisting of lower alkyl, pyridyl(lower)alkyl, carbamoyl, mono(or di) (lower)alkylcarbamoyl, carbamoyl(lower)alkyl, mono(or di) ( lower) alkylcarbamoyl(lower)alkyl,
  • alkylthio(lower)alkyl lower alkylsulfinyl(lower)alkyl, lower alkenylthio(lower)alkyl, lower alkoxy(lower)-alkylthio(lower)alkyl, carbamoyloxy(lower)alkylthio(lower)alkyl, mono(or di) (lower) alkylcarbamoyl(lower)-alkylthio(lower)alkyl, lower alkylsulfonyl(lower)alkyl, mono(or di or tri)halo(lower) alkylthio(lower) alkyl, lower alkoxy(lower)alkanoylamino(lower)alkyl, lower
  • alkanoylamino(lower)alkyl ureido(lower)alkyl, lower alkylsulfonylamino(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl, (1-pyridinio) (lower)alkyl, 1- (lower)alkylpyridinio(lower)alkyl and N-containing heterocyclicthio(lower)alkyl wherein said heterocyclic group may be substituted by lower alkyl, and the ring nitrogen atom(s) may be substituted by the group consisting of lower alkyl, lower alkanimidoyl, N- ( lower) alkyl(lower)alkanimidoyl and imino-protective group.
  • Suitable substituent(s) can be referred to the ones as mentioned in the above and subsequent descriptions.
  • Suitable "mono(or di) (lower)alkylcarbamoyl” means carbamoyl substituted by straight or branched lower alkyl as mentioned above, such as methylcarbamoyl,
  • dipropylcarbamoyl isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, and the like, in which more preferable example may be mono(or
  • Suitable “carbamoyl(lower)alkyl” may include lower alkyl as mentioned above, wherein the lower alkyl is substituted with carbamoyl, in which more preferable example may be carbamoyl(C 1 -C 4 )alkyl and the most
  • preferable one may be carbamoylmethyl.
  • Suitable "mono ( or di ) ( lower ) alkylcarbamoyl( lower) -alkyl” means aforementioned carbamoyl(lower)alkyl, wherein the nitrogen atom(s) is(are) substituted by lower alkyl as mentioned above, in which more preferable example may be di(C 1 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl and the most
  • pyridyl(lower)alkyl may include lower alkyl as mentioned above, wherein the lower alkyl is substituted with pyridine, in which more preferable example may be pyridyl(C 1 -C 4 )alkyl and the most preferable one may be pyridin-3-ylmethyl.
  • lower alkyl substituted by lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like, in which the most preferable example may be methoxymethyl and methoxyethyl.
  • Suitable carbamoyloxy(lower)alkyl means
  • Suitable "mono(or di) (lower) alkylcarbamoyloxy(lower)- alkyl” means aforementioned lower alkyl substituted by mono(or di) (lower)alkylcarbamoyloxy, wherein the mono(or di) ( lower) alkylcarbamoyl moiety may be the same as those mentioned above, in which the most preferable example may be N-ethylcarbamoyloxymethyl.
  • lower alkyl substituted by lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, and the like, in which the most preferable example may be methylthiomethyl and t-butylthiomethyl.
  • Suitable "lower alkylsulfinyl(lower)alkyl" means aforementioned.
  • alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,
  • pentylsulfinyl hexylsulfinyl, and the like, in which the most preferable example may be methylsulfinylmethyl.
  • Suitable "lower alkenylthio(lower) alkyl" means aforementioned lower alkyl substituted by lower
  • alkenylthio such as allylthio, vinylthio, and the like, in which the most preferable example may be allylthiomethyl.
  • Suitable "lower alkoxy( lower)alkylthio(lower)alkyl” means aforementioned lower alkyl substituted by lower alkoxy(lower)alkylthio wherein the lower
  • alkoxy(lower)alkyl moiety may be the same as mentioned above, in which the most preferable example may be methoxymethylthiomethyl and 2-methoxyethylthiomethyl.
  • Suitable "carbamoyloxy(lower)alkylthio(lower)alkyl” means aforementioned lower alkyl substituted by
  • carbamoyloxy(lower) alkyl moiety may be the same as those mentioned above, in which the most preferable example may be carbamoyloxymethylthiomethyl.
  • Suitable "mono(or di) (lower)alkylcarbamoyl(lower)-alkylthio(lower)alkyl” means aforementioned lower alkyl substituted by mono(or di) (lower)alkylcarbamoyl(lower)- alkylthio wherein the mono(or di) (lower)alkylcarbamoyl-(lower) alkyl moiety may be the same as those mentioned above, in which the most preferable example may be
  • Suitable "lower alkanoylamino(lower)alkyl" means aforementioned lower alkyl substituted by lower
  • alkanoylamino wherein the lower alkanoylamino moiety may be the same as mentioned in the explanation of the acyl group, in which the most preferable example may be
  • ureido(lower) alkyl means aforementioned lower alkyl substituted by ureido, in which the most preferable example may be ureidomethyl.
  • Suitable "lower alkylsulfonylamino(lower)alkyl” means aforementioned lower alkyl substituted by lower
  • alkylsulfonylamino such as mesylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,
  • hexylsulfonylamino and the like, in which the most preferable example may be mesylsulfonylaminomethyl.
  • Suitable "lower alkoxycarbonylamino(lower)alkyl” means aforementioned lower alkyl substituted by lower alkoxycarbonylamino wherein the lower alkoxycarbonyl moiety may be the same as those mentioned in the
  • 1-(lower)alkylpyridinio in which the most preferable example may be 3- (1-methyl-3-pyridinio)propyl.
  • Suitable "lower alkanimidoyl” may include straight or branched one such as formimidoyl, acetimidoyl,
  • N-(lower)alkyl(lower)alkanimidoyl means aforementioned lower alkanimidoyl substituted by lower alkyl at the nitrogen atom, in which the most preferable example may be N-methylformimidoyl.
  • N-containing heterocyclic group in the term of "optionally substituted N-containing
  • heterocyclicthio(lower)alkyl means saturated or
  • unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom and optionally other hetero-atom(s) such as an oxygen, sulfur, nitrogen atom and the like.
  • N-containing heterocyclic group moiety may be heterocyclic group such as :
  • pyrimidyl pyrazinyl
  • pyridazinyl triazolyl (e.g.,
  • tetrazolopyridyl tetrazolopyridazinyl
  • oxazolyl isoxazolyl, oxadiazolyl, (e.g.,
  • 1,3-thiazolyl 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
  • heterocyclic group is optionally
  • halogen e.g. chlorine, bromine, iodine or
  • N-containing heterocyclicthio(lower)alkyl thus defined may be lower alkyl substituted by unsaturated 5 or 6 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) such as pyrrolyl, pyrrolinyl, imidazolyl,
  • heterocyclic group is optionally substituted by lower alkyl, in which more preferable example may be lower alkylimidazolyl(lower)alkyl and lower
  • alkyltetrazolyl(lower)alkyl and the most preferable example may be 1-methylimidazol-2-yl and
  • Suitable "lower alkylsulfonyl(lower)alkyl" means aforementioned lower alkyl substituted by lower
  • alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl,
  • hexylsulfonyl and the like, in which the most preferable example may be methylsulfonylmethyl.
  • tri)halo(lower)alkylthio(lower)alkyl means aforementioned lower alkyl substituted by halo(lower)alkylthio, wherein the halo(lower)alkyl moiety may be straight or branched lower alkyl having one to three halogen (e.g.
  • chlorine, bromine, iodine, fluorine such as chloromethyl, fluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, difluoromethyl, trifluoromethyl, chloroethyl, chlorofluoroethyl, difluoroethyl, trifluoroethyl, chloropropyl, difluoropropyl, trichlorobutyl,
  • chloropentyl chlorohexyl, and the like, in which the most preferable example may be difluoromethylthiomethyl.
  • Suitable "lower alkoxy(lower)alkanoylamino- (lower)alkyl” means aforementioned lower alkyl substituted by lower alkoxy(lower)alkanoylamino wherein the lower alkoxy and lower alkanoyl moieties may be the same as those mentioned above, in which the most preferable example may be methoxyacetylaminomethyl.
  • Suitable "3-(lower)alkyl-1-(2-imidazolinio)" means 2-imidazolin-1-yl substituted by aforementioned lower alkyl at 3-position, in which the most preferable example may be 3-methyl-1-(2-imidazolinio).
  • Suitable "3-[hydroxy(lower)alkyl]-1-(2-imidazolinio)" means 2-imidazolin-1-yl substituted by aforementioned hydroxy(lower) alkyl at 3-position, in which the most preferable example may be 3-(2-hydroxyethyl)-1-(2-imidazolinio).
  • Suitable "3-(lower)alkyl-1,4,5,6-tetrahydro-1-pyrimidinio means 1,4,5,6-tetrahydropyrimidin-1-yl substituted by .aforementioned lower alkyl at 3-position, in which the most preferable example may be 3-methyl-1,4,5,6-tetrahydro-1-pyrimidinio.
  • R 3 may be :
  • alkylimidazolinyl such as 2-(C 1 -C 4 )alkyl-2-imidazolinyl [e.g. 2-methyl-2-imidazolin-1(or 4)-yl, etc.], etc.;
  • 2-carbamoyl(C 1 -C 4 )alkyl-2-imidazolinyl e.g. 2-carbamoylmethyl-2-imidazolin-1(or 4)-yl, etc.], etc.;
  • azetidinyl e.g. azetidin-3-yl, etc.
  • pyrrolidinyl e.g. pyrrolidin-2(or 3 )-y1, etc.
  • N-(lower)alkyl(lower)alkanimidoyl]pyrrolidinyl such as 1-[N-(C 1 -C 4 )alkyl(C 1 -C 4 )alkanimidoyl]pyrrolidinyl [e.g. 1-(N-methylformimidoyl)pyrrolidin-2-yl, etc.];
  • lower alkyl] [lower alkoxy(lower)alkyl]imidazolinyl such as N-[C 1 -C 4 alkyl]-[C 1 -C 4 alkoxy(C 1 -C 4 )alkyl]-2- imidazolinyl [e.g. 1-methyl-2-(methoxymethyl)-2- imidazolin-5-yl, etc. ];
  • - tetrahydropyrimidinyl such as 1,4,5,6-tetrahydropyrimidinyl (e.g. 1,4,5,6-tetrahydropyrimidin-1-yl, etc.);
  • 1, 1-di( C 1 -C 4 ) alkylpiperidinio e.g. 1, 1-di( C 1 -C 4 ) alkylpiperidinio (e.g.
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • the compound (I) or salts thereof can be prepared by cyclizing the compound (II) or its reactive derivative at the carbonyl group adjacent to R 1 or salts thereof.
  • Suitable salts of the compound (II) may be the same as those for the compound (I).
  • Suitable reactive derivative of the compound (II) may include tri(lower)alkoxyphosphoranylidene compound thereof (e.g. triethoxyphosphoranylidene compound, etc.),
  • triphenylphosphoranylidene compound, etc. each of which can be prepared by reacting the compound (II) with tri(lower)alkyl phosphite or triarylphosphine,
  • This reaction is preferably carried out by heating the compound (II) in a conventional solvent which does not adversely influence the reaction such as dioxane,
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under from warming to heating.
  • 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. Suitable salts of the compounds (I-a) and (I-b) may be the same as those for the compound (I) .
  • the present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
  • Suitable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. 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.
  • 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, zing 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 deprote ⁇ ted 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, benzoyl acetate, 2-methyl-3-oxovaleric acid, etc.), a cyanohydrin compound (e.g. ⁇ -tetrahydropyranyloxybenzyl cyanide, etc.), lower alkanoic acid or a salt thereof (e.g. formic acid, acetic acid, ammonium formate, sodium acetate, etc.), N-hydroxysuccinimide, and the like.
  • amine e.g. morpholine, N-methylaniline, etc.
  • an activated methylene compound e.g. dimedone, benzoyl acetate, 2-methyl-3-oxovaleric acid, etc.
  • a cyanohydrin compound e.g. ⁇
  • 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.
  • 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 imino-protective group.
  • Suitable salts of the compound (I-e) may be salts with bases such as those given for the compound (I).
  • Suitable salts of the compound (I-f) 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.
  • the compound (I-g) or salts thereof can be prepared by reacting the compound (I-f) or salts thereof with the compound (III) or salts thereof.
  • Suitable salts of the compound (I-g) may be the same as those for the compound (I) .
  • Suitable salts of the compound (III) may be the same acid addition salts as mentioned for the compound (I).
  • This reaction is usually carried out in a
  • This reaction can be carried out in the presence of an organic of inorganic base such as those given in the explanation of Process 2.
  • the compound (l-h) or salts thereof can be prepared by reacting the compound (Xl-a) or salts thereof with the compound (Ill-a) or salts thereof.
  • Suitable salts of the compound (Xl-a) may be the same as those for the compound (I).
  • Suitable salts of the compound (III-a) may be the same as those for the compound (III).
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the compound (I-i) or salts thereof can be prepared by reacting the compound (Xl-b) or salts thereof with the compound (III-a) or salts thereof.
  • Suitable salts of the compound (Xl-b) may be the same as those for the compound (I).
  • the method and the reaction conditions e.g. reaction temperature, solvent, etc.
  • the reaction conditions are substantially the same as those for the Process 5, and therefore are to be referred to said explanation.
  • the compound (I-e) or salts thereof can be prepared by introducing the imino-protective group into the
  • Suitable introducing agent of the imino-protective group used in this reaction may be a conventional
  • acylating agent which is capable of introducing the acyl group as mentioned before such as carboxylic acid, carbonic acid, sulfonic acid and their reactive
  • Such reactive derivative may include acid chloride, acid bromide, a mixed acid
  • anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,
  • halogenated phosphoric acid etc.
  • dialkylphosphorous acid sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,
  • heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole, an activated ester (e.g.
  • N-hydroxy compound such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,
  • This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.
  • alkali metal e.g. lithium, sodium, potassium, etc.
  • alkaline earth metal e.g. calcium, etc.
  • alkali metal hydride e.g. sodium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride,
  • the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound [e.g. N,N'-dicyclohexylcarbodiimide,
  • a ketenimine compound e.g. N,N' -carbonylbis(2- methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.
  • an olefinic or acetylenic ether compounds e.g. ethoxyacetylene,
  • N-hydroxybenzotriazole derivative e.g. 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.
  • diazenedicarboxylate e.g. diethyl diazenedicarboxylate, etc.
  • a phosphorus compound e.g. ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus tirchloride, etc.
  • thionyl chloride oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate
  • a reagent referred to a so-called "Vilsmeier reagent" formed by the reaction of an amide compound such as N,N-di ( lower)alkylformamide (e.g. dimethylformamide, etc. ), N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like.
  • 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 heating.
  • the compound (I-j) or salts thereof can be prepared by reacting the compound (I-f) or salts thereof with an alkylating agent.
  • Suitable salts of the compound (I-j) may be the same as those for the compound (I).
  • Suitable alkylating agent used in this reaction may include a conventional one which is capable of alkylating a hydroxy group to an alkoxy group such as dialkyl sulfate (e.g. dimethyl sulfate, diethyl sulfate, etc.), alkyl sulfonate (e.g. methyl sulfonate, etc.), alkyl halide (e.g. methyl iodide, ethyl iodide, propyl bromide, etc.), diazoalkanes (e.g. diazomethane, diazoethane, etc.), and the like.
  • dialkyl sulfate e.g. dimethyl sulfate, diethyl sulfate, etc.
  • alkyl sulfonate e.g. methyl sulfonate, etc.
  • alkyl halide e.g. methyl iodide, eth
  • This reaction is preferably carried out in the presence of an inorganic or organic base such as those given in the explanation of the Process 2.
  • this reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, methanol, ethanol, propanol, pyridine,
  • N,N-dimethylformamide or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (I-k) or salts thereof can be prepared by reacting the compound (XI-c) or salts thereof with the compound (Ill-a) or salts thereof.
  • Suitable salts of the compound (XI-c) may be the same as those for the compound (XI-a).
  • Suitable salts of the compound (I-k) may be the same as those for the compound (I).
  • the compound (VII) or salts thereof can be prepared by reacting the compound (V) with the compound (VI) or salts thereof.
  • Suitable salts of the compound (VI) and (VII) may be the same acid addition salts as those for the compound (I).
  • the compound (VI) or salts thereof can be prepared from the known compounds by a conventional manner or that described in the Preparations of the present
  • This reaction can be carried out in the presence of a base such as inorganic base, for example, alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), 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.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g.
  • a base such as inorganic base
  • alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • an organic base for example, an organic amine (e.g. triethylamine, pyridine, picoline, ethanolamine, triethanolamine,
  • Suitable enolizating agent may include tri(lower)alkylsilyl trihalo(lower)-alkanesulfonate, preferably tri(C 1 -C 4 )alkylsilyl trihalo(C 1 -C 4 )alkanesulfonate (e.g. trimethylsilyl trifluoro ⁇ methanesulfonate, etc.), tin compound such as stannous ( lower)alkylsulfonate which may have halogen(s),
  • stannous polyhalo(C 1 -C 4 )alkylsulfonate e.g. stannous trifluoromethanesulfonate, etc.
  • stannous polyhalo(C 1 -C 4 )alkylsulfonate e.g. stannous trifluoromethanesulfonate, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
  • a liquid base can be also used as the solvent.
  • the compound (II) or salts thereof can be prepared by reacting the compound (VII) or salts thereof with the compound (VIII).
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
  • the compound (X) or salts thereof can be prepared by reacting the compound (V) with the compound (IX).
  • Suitable salts of the compound (X) may be the same as those for the compound (VII).
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the compound (IV) or salts thereof can be prepared by reacting the compound (X) or salts thereof with the compound (VIII).
  • Suitable salts of the compound (IV) may be the same as those for the compound (IV-a).
  • the compound (IV-a) or salts thereof can be prepared by subjecting the compound (IV) or salts thereof to a removal reaction of the amino-protective group(s).
  • Suitable salts of the compound (IV-a) may be the same as those for the compound (IV).
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the compound (XI) or salts thereof can be prepared by cyclizing the compound (IV-a) or salts thereof.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the object compounds obtained according to the above Processes can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
  • 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 further, are very stable against dehydropeptidase and show high urinary excretion, therefore have high potential for the treatment of various infectious diseases.
  • Test Method in vitro Antimicrobial Activity was determined by the two-fold agar-plate dilution method as described below.
  • 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.
  • 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 depended upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between 1 mg and about 4,000 mg or even more per day may be administered to a patient.
  • An average single dose of about 1 mg, 10 mg, 50 mg, 100 mg, 250 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 microorganisms.
  • N-allyloxycarbonyl-L-aspartic acid (1690 g).
  • reaction mixture was diluted with ethyl acetate (300 ml), washed in turn with water, hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation gave a residue, which was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate
  • dichloromethane 750 ml were added successively Meldrum's acid (27.85 g) , dicyclohexylcarbodiimide (39.86 g) and 4-dimethylaminopyridine (25.18 g) at 5oC. After stirring at ambient temperature for 12 hours, the mixture was washed in turn with hydrochloric acid (1N, 220 ml), cold water (200 ml) and brine (200 ml), and evaporated. The residue was taken up into a mixture of acetic acid (250 ml) and water (250 ml) and the resulting mixture was heated to reflux for 1 hour.
  • the reaction mixture was diluted with a mixture of ethyl acetate (1.5 l) and water (1.5 l). After adjusting pH to 1 with hydrochloric acid (6N). The mixture was allowed to stir at ambient temperature for additional 1 hour. The separated organic layer was washed with water and diluted with water (1.5 l). After adjusting pH to 7 with aqueous sodium hydrogen carbonate, the organic layer was washed with brine and dried over magnesium sulfate.
  • N-Allyloxycarbonyl-D-aspartic acid was obtained in 82.0% yield in substantially the same manner as that of Preparation 1-1).
  • N-(2-aminoethyl)aminoacetic acid (9.33 g) in substantially the same method as that of Preparation 1-1).
  • the mixture was stirred for 30 minutes at -78°C, and allyl bromide (1.3 ml) was added to the reaction mixture at -78oC.
  • the reaction temperature was raised to -20oC over a period of 30 minutes, and the solution was poured into ice-water, and sodium chloride was added to saturate the aqueous phase.
  • the organic phase was separated and the aqueous phase was extracted with ethyl acetate.
  • the combined organic phase was dried over magnesium sulfate, and concentrated.
  • Methyl iodate (13.2 ml) was added to a acetone solution (20 ml) containing 3-pyridilacetonitrile (5.0 g) and the mixture was allowed to stand at ambient
  • reaction mixture was poured into water (2 l) and ethyl acetate (3 l), and the organic layer was separated. The organic layer was washed in turn with lN-aqueous
  • N-benzyloxycarbonylglycine 3-hydroxypropylamide (94.5 g) under 15oC for 15 minutes and the mixture was stirred for 1 day at ambient temperature.
  • concentrated hydrochloric acid 140 ml
  • carbobenzoxy chloride 40.5 ml
  • pH to 9.5-10.5 with IN aqueous sodium hydroxide pH to 9.5-10.5 with IN aqueous sodium hydroxide

Landscapes

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

Abstract

L'invention se rapporte à un composé représenté par la formule [I]; où: R1 représente un carboxy, un carboxy protégé ou un carboxylato; R2 représente un hydroxyalkyle(inférieur) ou un hydroxyalkyl(inférieur); R3 représente un azétidinyle, un pyrrolidinyle, un imidazolinyle, un tétrahydropyrimidinyle, un pipéridyle, un 1,1-dialkylepipéridinio(inférieur), un 3-alkyle(inférieur)-1-(2-imidazolinio), un 3-[hydroxyalkyle(inférieur)]-1-(2-imidazolinio) ou un 3-alkyle(inférieur)-1,4,5,6-tétrahydro-1-pyrimidinio, ou chaque groupe hétérocyclique peut être substitué par un ou plusieurs substituants appropriés; R10 représente hydrogène ou un alkyle inférieur; et A représente un alkylène inférieur; à condition que, lorsque R3 représente un alkylpyrrolidinyle inférieur, alors R10 représente hydrogène; ou à un sel pharmaceutiquement acceptable d'un tel composé, utilisable comme agent anti-microbien.
PCT/JP1991/000997 1990-07-27 1991-07-25 Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique WO1992002521A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP3512378A JPH06503803A (ja) 1990-07-27 1991-07-25 １―アザビシクロ［３．２．０］ヘプト―２―エン―２―カルボン酸化合物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB909016507A GB9016507D0 (en) 1990-07-27 1990-07-27 1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid compounds
GB9016507.7 1990-07-27
JP3/196181 1991-03-08
JP3196181A JPH04234886A (ja) 1990-03-08 1991-03-08 １−アザビシクロ［３．２．０］ヘプト−２−エン−２−カルボン酸化合物

Publications (1)

Publication Number Publication Date
WO1992002521A1 true WO1992002521A1 (fr) 1992-02-20

Family

ID=26297391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000997 WO1992002521A1 (fr) 1990-07-27 1991-07-25 Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique

Country Status (2)

Country Link
JP (1) JPH06503803A (fr)
WO (1) WO1992002521A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023402A1 (fr) * 1992-05-11 1993-11-25 Fujisawa Pharmaceutical Co., Ltd. Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens
EP0574940A1 (fr) * 1992-06-18 1993-12-22 Tanabe Seiyaku Co., Ltd. Procédé d'élimination du groupe protecteur de groupe carboxyle
WO2011160020A2 (fr) 2010-06-18 2011-12-22 Fob Synthesis Agents antibactériens de carbapénem avec activité anti-gram négatif
WO2017004077A1 (fr) * 2015-06-29 2017-01-05 Duke University Prochelateurs antimicrobiens pour cibler les bactéries résistant aux médicaments et leurs procédés de fabrication et d'utilisation
CN109053596A (zh) * 2018-09-11 2018-12-21 成都百事兴科技实业有限公司 一种乳清酸的合成新方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0010316A1 (fr) * 1978-10-24 1980-04-30 Merck & Co. Inc. Acides 1-carba-2-pénem-3-carboxyliques 1-, 6- et 2-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4348320A (en) * 1976-11-19 1982-09-07 Merck & Co., Inc. Substituted azetidiones
EP0330108A1 (fr) * 1988-02-22 1989-08-30 Fujisawa Pharmaceutical Co., Ltd. Composés dérivés d'acide 3-alkényl-1-aza-bicyclo(3.2.0)hept-2-ène-2-carboxylique
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4348320A (en) * 1976-11-19 1982-09-07 Merck & Co., Inc. Substituted azetidiones
EP0010316A1 (fr) * 1978-10-24 1980-04-30 Merck & Co. Inc. Acides 1-carba-2-pénem-3-carboxyliques 1-, 6- et 2-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0330108A1 (fr) * 1988-02-22 1989-08-30 Fujisawa Pharmaceutical Co., Ltd. Composés dérivés d'acide 3-alkényl-1-aza-bicyclo(3.2.0)hept-2-ène-2-carboxylique
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

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023402A1 (fr) * 1992-05-11 1993-11-25 Fujisawa Pharmaceutical Co., Ltd. Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens
EP0574940A1 (fr) * 1992-06-18 1993-12-22 Tanabe Seiyaku Co., Ltd. Procédé d'élimination du groupe protecteur de groupe carboxyle
US5587474A (en) * 1992-06-18 1996-12-24 Tanabe Seiyaku Co., Ltd. Method for removing the protecting group for carboxyl group
WO2011160020A2 (fr) 2010-06-18 2011-12-22 Fob Synthesis Agents antibactériens de carbapénem avec activité anti-gram négatif
WO2011160020A3 (fr) * 2010-06-18 2012-04-12 Fob Synthesis Agents antibactériens de carbapénem avec activité anti-gram négatif
US9149461B2 (en) 2010-06-18 2015-10-06 Fob Synthesis, Inc. Carbapenem antibacterials with gram-negative activity
US9937151B2 (en) 2010-06-18 2018-04-10 Fob Synthesis, Inc. Carbapenem antibacterials with gram-negative activity
KR101862041B1 (ko) 2010-06-18 2018-05-29 포브 신세시스 그람음성 활성을 갖는 카바페넴 항균제
WO2017004077A1 (fr) * 2015-06-29 2017-01-05 Duke University Prochelateurs antimicrobiens pour cibler les bactéries résistant aux médicaments et leurs procédés de fabrication et d'utilisation
US10533018B2 (en) 2015-06-29 2020-01-14 Duke University Antimicrobial prochelators to target drug-resistant bacteria and methods of making and using the same
CN109053596A (zh) * 2018-09-11 2018-12-21 成都百事兴科技实业有限公司 一种乳清酸的合成新方法

Also Published As

Publication number Publication date
JPH06503803A (ja) 1994-04-28

Similar Documents

Publication Publication Date Title
US4925838A (en) 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds
EP0343499B1 (fr) Dérivés de l'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ène-2-carboxylique
EP0272456B1 (fr) Dérivés d'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique et procédé de préparation
JP2748500B2 (ja) ３―アルケニル―１―アザビシクロ［３．２．０］ヘプト―２―エン―２―カルボン酸化合物
EP0394991B1 (fr) Composés de l'acide 1-azabicyclo(3.2.0)hept-2-ène-2-carboxylique
US5286721A (en) 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds
US5194624A (en) Intermediates for the preparation of compounds of antimicrobial activity
JPH05255250A (ja) 新規第四級アミンチオール化合物
WO1992002521A1 (fr) Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique
WO1993023402A1 (fr) Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens
US4983596A (en) 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid derivatives and their preparation
US5202437A (en) 3-pyrrolidinylthio-1-azabicyclo(3.2.0)-hept-2-ene-2-carboxylic acid compounds
JPH05239058A (ja) ３−ピロリジニルチオ−１−アザビシクロ［３．２．０ヘプト−２−エン−２−カルボン酸化合物
EP0506982A1 (fr) Composes d'acide 1-azabicyclo 3.2.0]hept-2-ene-2-carboxylique
JPH04234886A (ja) １−アザビシクロ［３．２．０］ヘプト−２−エン−２−カルボン酸化合物
WO1994005667A1 (fr) Derives de carbapenem et procedes pour leur preparation
JPH04321688A (ja) ２−（置換ピロリジニルチオ）カルバペネム誘導体
JPH06116268A (ja) ３−置換オキシ−１−アザビシクロ［３．２．０］ヘプト−２−エン−２−カルボン酸化合物
JPH08259566A (ja) 二環式化合物およびその製造方法並びに該化合物を含有する医薬組成物
HU197904B (en) Process for producing carbapenem antibiotics

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

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

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载