WO1996023798A1 - Composes cephem, production et utilisation desdits composes - Google Patents

Composes cephem, production et utilisation desdits composes Download PDF

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Publication number
WO1996023798A1
WO1996023798A1 PCT/JP1996/000166 JP9600166W WO9623798A1 WO 1996023798 A1 WO1996023798 A1 WO 1996023798A1 JP 9600166 W JP9600166 W JP 9600166W WO 9623798 A1 WO9623798 A1 WO 9623798A1
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group
amino
alkyl
compound according
compound
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PCT/JP1996/000166
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English (en)
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Akio Miyake
Kenji Okonogi
Tomoyasu Ishikawa
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Takeda Chemical Industries, Ltd.
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Priority to AU44968/96A priority Critical patent/AU4496896A/en
Publication of WO1996023798A1 publication Critical patent/WO1996023798A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • This invention relates to a novel cephem compound having excellent antibacterial activities on a broad range of Gram-positive and Gram-negative bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA) and bacteria belonging to the genus Pseudomonas, to a method of producing the compound and to an
  • antibacterial composition containing the compound.
  • cephem compounds are not sufficiently satisfactory in the range and strength of antibacterial activities, especially antibacterial activities against bacterial belonging to the genus Pseudomonas resistant to conventional cephalosporin compounds, Staphylococcus aureus and methicillin resistant Staphylococcus aureus (MRSA). Circumstances being such, creation of novel compounds overcoming this point has been desired.
  • A is an optionally substituted group of the formula
  • B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms, and R 3 is an
  • R 1 is an optionally protected amino group
  • R 2 is H or a group bonded through a carbon atom, or an ester or salt thereof
  • the present invention relates to
  • R 1 is an optionally protected amino group
  • R 2 is H or a group bonded through a carbon atom
  • A is an optionally substituted group of the formula
  • B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms and R 3 is an optionally substituted hydrocarbon group, or an ester or salt thereof,
  • R 1 is an amino group optionally protected with C 1-6 alkanoyl, C 3-5 alkenoyl, C 6-10 aryl-carbonyl, phthaloyl, heterocyclic-carbonyl, C 1-6 alkylsulfonyl,
  • camphorsulfonyl C 6-10 arylsulfonyl, substituted
  • thiocarbamoyl C 6-10 aryl-methyl, di-C 6-10 aryl-methyl, tri-C 6-10 aryl-methyl, C 6-10 arylmethylene, C 6-10 arylthio group, substituted silyl, 2-C 1- 10 alkoxy-carbonyl-1-methyl-1-ethenyl or a group of the formula M'OCO- (wherein M' is an alkali metal),
  • R 2 is H, an optionally substituted hydrocarbon group or an optionally substituted non-aromatic heterocyclic group
  • R 2 is a C 1-6 alkyl, C 2-6 alkenyl or 3- to 7-membered non- aromatic cyclic hydrocarbon group each of which may be substituted with 1 to 4 substituent (s) selected from the group consisting of heterocyclic group, C 1-6 alkoxy, C 3-7 cycloalkyloxy, C 6-10 aryloxy, C 7-19 aralkyloxy, heterocyclic-oxy, mercapto, C 1-6 alkylthio, C 3-10
  • heterocyclic-thio amino, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, tri-C 1-6 alkylammonium, C 3-10
  • cycloalkylamino C 6-10 arylamino, C 7-19 aralkylamino, heterocyclic-amino, cyclic-amino, azido, nitro,
  • halogen cyano, carboxyl, C 1-10 alkoxy-carbonyl, C 6-10 aryloxy-carbonyl, C 7-19 aralkyloxy-carbonyl, C 6-10 aryl- acyl, C 1-6 alkanoyl, C 3-5 alkenoyl, C 6-10 aryl-acyloxy, C 2-6 alkanoyloxy, C 3-5 alkenoyloxy, carbamoyl, thiocarbamoyl, carbamoyloxy, phthalimido, C 1-6 alkanoylamino, C 6-10 aryl-acylamino, C 1-10 alkoxy-carboxamido, C 6-10 aryloxycarboxamido and C 7-19 aralkyloxy-carboxamido,
  • R 2 is a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, amino, tri-C 1-6 alkylammonium, halogen, carboxyl, C 1-10 alkoxy-carbonyl, carbamoyl, cyano, azido, and a group formed by removing one hydrogen atom bonded to a carbon atom of 5- to 8-membered heterocyclic ring having 1 to 4 hetero-atoms selected from N (which may be oxidized), O and S or a condensed ring thereof,
  • R 2 is (1) a C 1-3 alkyl group, (2) a C 1-3 alkyl group substituted with halogen, hydroxyl, C 1-6 alkoxy,
  • B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms;
  • R 3 is a C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl group each of which may be substituted with 1 to 4 substituents selected from the group consisting of heterocyclic group, hydroxyl, C 1-6 alkoxy, C 3-7 cycloalkyloxy, C 6-10 aryloxy, C 7-19
  • cycloalkylamino C 6-10 arylamino, C 7-19 aralkylamino, heterocyclic-amino, cyclic-amino, azido, nitro, halogen, cyano, carboxyl, C 1-6 alkoxy-carbonyl, C 6-10 aryloxy-carbonyl, C 7-19 aralkyloxy-carbonyl, C 6-10 arylacyl, C 2-6 alkanoyloxy, C 2-5 alkenoyloxy, cabamoyl, thiocarbamoyl, carbamoyloxy, phthalimido, C 1-6
  • alkanoylamino C 6-10 aryl-acylamino, C 1-10 alkoxy-carboxamido, C 6-10 aryloxy-carboxamido and C 7-19
  • the imidazole ring and/or ring B in the group of the formula [A 1 ] or [A 2 ] may have 1 or 2 substituents selected from the group consisting of hydroxyl, hydroxy-C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 5-6
  • cycloalkenyl C 3-10 cycloalkyl-C 1-6 alkyl, C 6-10 aryl, C 7-12 aralkyl, heterocyclic group, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, amino-C 1-6 alkoxy, C 3-10 cycloalkyloxy, C 6-10 aryloxy, C 7-19 aralkyloxy, mercapto, mercapto-C 1-6 alkyl, sulfo, sulfo-C 1-6 alkyl, C 1-6 alkylthio, C 1-6 alkylthio-C 1- 6 alkyl, C 3-10 cycloalkylthio, C 6-10 arylthio, C 7-19
  • aralkylthio amino-C 1-6 alkylthio, amino, amino-C 1-6 alkyl, mono-C 1-6 alkylamino, di-C 1-6 alkylamino, mono-C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylamino-C 1-6 alkyl, C 3-10 cycloalkylamino, C 6-10 arylamino, C 7-19 aralkylamino, cyclic amino, cyclic-amino-C 1-6 alkyl, cyclic-amino-C 1-6 alkylamino, acylamino, ureido, C 1-6 alkylureido, azido, nitro, halogen, halogeno-C 1-6 alkyl, cyano, cyano-C 1-6 alkyl, carboxyl, carboxy-C 1-6 alkyl, C 1-6 alkoxy-carbonyl, C 1-6 alkoxy-carbonyl-C
  • R 3 is a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, amino, halogen, carboxyl, C 1-10 alkoxy-carbonyl,
  • A' ® is a group of the formula or
  • R 3' is a C 2-4 alkenyl group or a C 1-4 alkyl group which may be substituted with hydroxyl, carboxyl or carbamoyl
  • R 3" is H, amino or carbamoyl, or an ester or salt thereof
  • R 1 is an optionally protected amino group
  • R 2 is H, a C 2-4 alkenyl group, cyclopentyl or a C 1-4 alkyl group which may be substituted with halogen
  • R 3'" is a
  • (31) a method for producing the compound described in the above (1), which comprises deoxidizing a compound of the formula
  • An antibacterial composition which comprises an effective amount of the compound described in above (1) and a pharmaceutically acceptable carrier, diluent or excipient, and the like.
  • the cephem compound in the present specification includes a group of compounds named on the basis of "chepham” disclosed in "The Journal of The American Chemical Society” Vol. 84, p.3400 (1962), which means a compound, among the cepham compounds, having a double bond at the 3,4-positions.
  • the compounds of this invention include the compound of the formula [I] showing the free form or an ester or salt thereof (a salt of the compound [I] or a salt of the ester of the compound [I]).
  • the compound of the formula [I] shown in the free form or an ester or salt thereof is simply referred to as the compound [I], the antibacterial compound [I] or the compound of the formula [I].
  • the compound [I] in the present specification include, usually, not only the free form but also an ester or salt thereof. This is applicable as well to the starting compounds, for example, compounds [II], [III], [V] and [VI] described in the following.
  • R stands for an optionally protected amino group.
  • amino-protective groups In the fields of ⁇ -lactam and peptide, amino-protective groups have been sufficiently studied, and the method of protecting amino group has been established. In the present invention, as amino-protective groups, those conventional ones can be adequately employed. Examples of amino-protective groups to be employed include optionally substituted C 1-6 alkanoyl groups, optionally substituted C 3-5 alkenoyl groups, optionally substituted C 6-10 aryl-carbonyl groups, phthaloyl group,
  • heterocyclic-carbonyl groups optionally substituted C 1-6 alkylsulfonyl groups, camphorsulfonyl group, optionally substituted C 6-10 arylsulfonyl groups, substituted oxycarbonyl groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted C 6-10 aryl-methyl groups, optionally substituted di-C 6-10 aryl-methyl groups, optionally substituted tri-C 6-10 aryl-methyl groups, optionally substituted C 6-10 aryl-methylene groups, optionally substituted C 6-10 arylthio group, substituted silyl groups, 2-C 1-10 alkoxy-carbonyl-1-methyl-1-ethenyl groups and groups represented by the formula M'OCO- (wherein M' is an alkali metal).
  • C 1-6 alkanoyl groups As “optionally substituted C 1-6 alkanoyl groups”, use is made of, for example, C 1-6 alkanoyl groups which may optionally be substituted with 1 to 3 substituents selected from halogen, oxo, C 1-6 alkoxy, C j-6 alkanoyl,
  • C 6-10 aryl halogeno-C 6-10 aryl, C 6-10 aryloxy, halogeno-C 6- 10 aryloxy and C 6-10 arylthio. More specifically, use is made of, for example, formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl, 4-chloro-3-oxobutyryl, phenylacetyl, p-chlorophenylacetyl, phenoxyacetyl and p-chlorophenoxyacetyl.
  • C 3-5 alkenoyl groups use is made of, for example, C 3-5 alkenoyl groups optionally substituted with 1 to 3 substituents
  • halogen and C 6-10 aryl more specifically, for example, acryloyl, crotonoyl, maleoyl, cinnamoyl, p-chlorocinnamoyl and ⁇ -phenylcinnamoyl.
  • C 6-10 aryl-carbonyl groups use is made of, for example, C 6-10 arylcarbonyl groups optionally substituted with 1 to 3 substituents selected from halogen, nitro, hydroxy, C 1-6 alkyl and C 1-6 alkoxy, more specifically, for example, benzoyl, naphthoyl, p-toluoyl, p-tert-butylbenzoyl, p-hydroxybenzoyl, p-methoxybenzoyl, p-tert-butoxybenzoyl, p-chlorobenzoyl and p-nitrobenzoyl.
  • substituents selected from halogen, nitro, hydroxy, C 1-6 alkyl and C 1-6 alkoxy
  • Heterocyclic group in “heterocyclic-carbonyl group” means a group formed by removing one hydrogen atom bonded to carbon atom of the heterocyclic ring.
  • the heterocyclic ring means a 5- to 8-membered ring containing 1 to several numbers, preferably 1 to 4 hetero-atoms such as nitrogen atom (which may be oxidized), oxygen atom and sulfur atom, or a condensed ring thereof.
  • heterocyclic group use is practically made of, for example, 2- or 3-pyrrolyl; 4-or 5-pyrazolyl; 2-, 4- or 5-imidazolyl; 1,2,3- or
  • 1,2,4-triazolyl 1H- or 2H-tetrazolyl; 2- or 3-furyl; 2- or 3-thienyl; 2-, 4- or 5-oxazolyl; 3, 4- or 5- isoxazolyl; 1, 2 , 3-oxadiazol-4-yl or 1, 2 , 3-oxadiazol-5- yl; 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl;
  • benzopyranyl ; quinolyl; pyrido[ 2 , 3-d]pyrimidyl; 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2 , 7-naphthyridyl; thieno[2,3- d]pyridyl; pyrimidopyridyl; pyrazinoquinolyl; and benzopyranyl.
  • C 1-6 alkylsulfonyl group use is made of a C 1-6 alkylsulfonyl group optionally substituted with 1 to 3 substituents
  • halogen selected from, for example, halogen, C 6-10 aryl and C 6-10 aryloxy. More specifically, use is made of, for example, methanesulfonyl and ethanesulfonyl.
  • C 6-10 arylsulfonyl group a C 6-10 arylsulfonyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C 1-6 alkyl and C 1-6 alkoxy. More specifically, for example, benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p-tert-butylbenzenesulfonyl, p-methoxybenzenesulfonyl, p-chlorobenzensulfonyl and p-nitrobenzenesulfonyl.
  • substituents selected from, for example, halogen, nitro, C 1-6 alkyl and C 1-6 alkoxy. More specifically, for example, benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p
  • substituted oxycarbonyl group examples include, in addition to a C 1-10 alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, cyclopropyloxycarbonyl,
  • cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and norbornyloxycarbonyl a C 6-10 aryloxycarbonyl group (e.g. phenoxycarbonyl and naphthyloxycarbonyl) or a C 7- 19 aralkyloxy-carbonyl group (e.g. benzyloxycarbonyl and benzhydryloxycarbonyl), those further having 1 to 3 substituents selected from a C 1-4 alkoxy group (e.g. methoxy and ethoxy), a C 1-4 acyl group (e.g. acetyl and propionyl), a substituted silyl group (the substituted silyl group described later, e.g.
  • a C 1-4 alkylsulfonyl group e.g. methanesulfonyl and ethanesulfonyl
  • halogen e.g. fluorine, chlorine and bromine
  • cyano e.g. a C 1-4 alkyl group (e.g. methyl and ethyl) and nitro.
  • methoxymethyloxycarbonyl methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl, p-methylbenzyloxycarbonyl, p- methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl.
  • a C 1-4 alkyl group e.g. methyl and ethyl
  • phenyl group e.g. phenyl group
  • a C 1-7 acyl group e.g. acetyl, propionyl and benzoyl
  • a C 1-4 alkoxy-phenyl group e.g- methoxyphenyl
  • halogen selected from, for example, halogen, nitro, C 1-6 alkyl and C 1-6 alkoxy. More specifically, for example, benzyl, naphthylmethyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl and p-nitrobenzyl are used.
  • di-C 6-10 aryl-methyl group use is made of a di-C 6-10 aryl-methyl group optionally substituted with 1 to 3 substituents
  • halogen selected from, for example, halogen, nitro, C 1-6 alkyl and C 1-6 alkoxy. More specifically, for example, benzhydryl and di(p-tolyl)methyl are used.
  • tri-C 6-10 aryl-methyl group use is made of a tri-C 6-10 aryl-methyl group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C 1-6 alkyl and C 1-6 alkoxy. More specifically, for example, trityl and tri(p-tolyl)methyl are used.
  • C 6-10 aryl-methylene group As optionally substituted C 6-10 aryl-methylene group", use is made of, a C 6-10 aryl-methylene group optionally substituted with 1 to 3 substituents selected from, for example, halogen, nitro, C 1-6 alkyl and C 1-6 alkoxy. More specifically, for example, benzylidene, p-methylbenzylidene and p-chlorobenzylidene are used-
  • o-nitrophenylthio is used.
  • Substituted silyl group forms, together with the amino group to be protected, a group represented by the formula R 6 R 7 R 8 SiNH-, (R 6 R 7 R 8 Si) 2 N- or
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 9a and R 10a each stand for a C 1-6 alkyl group or a C 6-10 aryl group
  • Z a stands for a Cj . , 3 alkylene group
  • C 1-6 alkyl group use is made of, for example, a straight-chain or branched C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and n-pentyl.
  • C 6-10 aryl group use is made of, for example, phenyl and
  • C 1-3 alkylene group use is made of, for example, methylene, ethylene and propylene.
  • substituted silyl group include trimethylsilyl, tert-butyl dimethylsilyl and -Si(CH 3 ) 2 CH 2 CH 2 Si(CH 3 ) 2 -.
  • C 1-10 alkoxy of "2-C 1-10 alkoxy-carbonyl-1-methyl-1-ethenyl group” use is made of straight-chain, branched or cyclic C 1-10 alkoxy such as methoxy, ethoxy, tert-butoxy or cyclohexyloxy.
  • 2-C 1-10 alkoxy-carbonyl-1-methyl-1-ethenyl group examples include 2-methoxycarbonyl-1-methyl-1-ethenyl, 2-ethoxycarbonyl-1-methyl-1-ethenyl, 2-tert-butoxycarbonyl-1-methyl-1-ethenyl, 2-cyclohexyloxycarbonyl-1-methyl-1-ethenyl and 2-norbornyloxycarbonyl-1-methyl-1-ethenyl.
  • alkali metal shown by M' include sodium and potassium, sodium being especially preferable.
  • R 1 is preferably amino group, when the
  • R 2 stands for H or a group bonded through a carbon atom.
  • group bonded through a carbon atom include an optionally substituted
  • hydrocarbon group e.g. an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aralkyl group or an optionally substituted cyclic hydrocarbon group
  • an optionally substituted non-aromatic heterocyclic group having a bond at the carbon atom e.g. an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aralkyl group or an optionally substituted cyclic hydrocarbon group
  • alkyl group of “optionally substituted alkyl group” include C 1-6 alkyl groups such as methyl, ethyl, n-propyl,
  • alkenyl group of "optionally substituted alkenyl group” include C 2-6 alkenyl groups such as vinyl, allyl, isopropenyl, methallyl, 1,1-dimethylallyl, 2-butenyl and 3-butenyl.
  • alkynyl group of “alkynyl group”
  • optionally substituted alkynyl group include C 2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
  • aralkyl group of “optionally substituted aralkyl group” include C 7-19 aralkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, naphthylmethyl and benzhydryl.
  • C 3-7 cycloalkyl groups such as cyclobutyl and cyclopentyl are
  • non-aromatic heterocyclic group of “optionally substituted non- aromatic heterocyclic group” include 3- to 6-membered non-aromatic heterocyclic groups containing, other than carbon atoms, one or two hetero-atoms such as N, O and S; specifically, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl and
  • Examples of the substituents which the above-mentioned "hydrocarbon group” has include heterocyclic groups, hydroxyl group, C 1-6 alkoxy groups, C 3-7
  • alkylamino groups di-C 1-6 alkylamino groups, tri-C 1-6 alkylammonium groups, C 3-10 cycloalkylamino groups, C 6-10 arylamino groups, C 7-19 aralkylamino groups,
  • heterocyclic amino groups cyclic-amino groups, azido group, nitro group, halogen atoms, cyano group, carboxyl group, C 1-10 alkoxy-carbonyl groups, C 6-10 aryloxy-carbonyl groups, C 7-19 aralkyloxy-carbonyl groups, C 6-10 aryl-acyl groups, C 1-6 alkanoyl groups, C 3-5 alkenoyl groups, C 6-10 aryl-acyloxy groups, C 2-6
  • alkanoyloxy groups C 3-5 alkenoyloxy groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted
  • alkanoylamino groups C 6-10 aryl-acylamino groups, C 1-10 alkoxy-carboxamido groups, C 6-10 aryloxy-carboxamido groups and C 7-19 aralkyloxy-carboxamido groups.
  • the number of these substituents which may be the same as or different from one another, ranges from 1 to 4.
  • C 1-6 alkoxy group includes e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert- butoxy, n-pentyloxy and n-hexyloxy;
  • C 3-10 cycloalkyloxy group includes e.g. cyclopropyloxy and cyclohexyloxy;
  • C 6-10 aryloxy group includes e.g. phenoxy and
  • C 7-19 aralkyloxy group includes e.g.
  • C 1-6 alkylthio group includes e.g.
  • C 3-10 cycloalkylthio group includes cyclopropylthio and cyclohexylthio
  • C 6-10 arylthio includes e.g.
  • C 7-19 aralkylthio group includes e.g. benzylthio, phenylthio and
  • benzhydrylthio includes e.g. methylamino, ethylamino, n-propylamino and n-butylamino;
  • di-C 1-6 alkylamino group includes e.g.
  • tri-C 1-6 alkyl ammonium group includes e.g. trimethyl ammonium
  • C 3-10 cycloalkylamino group includes e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino
  • C 6-10 arylamino group includes e.g. anilino and N-methylanilino
  • C 7-19 aralkylamino group includes e.g- benzylamino, 1-phenylethylamino, 2-phenylethylamino and
  • cyclic amino group includes e.g. pyrrolidino, piperidino, piperazino, morpholino and 1-pyrrolyl;
  • halogen atom includes fluorine, chlorine, bromine and iodine;
  • C 1-10 alkoxy-carbonyl group includes e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,
  • C 6-10 aryloxy-carbonyl group includes e.g. phenoxycarbonyl and naphthyloxycarbonyl;
  • C 7-19 aralkyloxy-carbonyl group includes e.g.
  • C 6-10 aryl-acyl group includes e.g. C 6-10 aryl-carbonyl group such as benzoyl, naphthoyl, phthaloyl and phenylacetyl;
  • C, -6 alkanoyl group includes e.g.
  • C 3-5 alkenoyl group includes e.g- acryloyl, crotonoyl and maleoyl
  • C 6-10 aryl-acyloxy group includes e.g- C 6-10 aryl-carbonyloxy group such as benzoyloxy, naphthoyloxy and phenylacetoxy
  • C 2-6 alkanoyloxy group includes e.g.
  • C 3-5 alkenoyloxy group includes e.g. acryloyloxy and crotonoyl.
  • carbamoyl group optionally substituted with one or two substituents selected from, for example, C 1-4 alkyl group (e.g- methyl and ethyl), phenyl group, C 1-7 acyl group (e.g- acetyl, propionyl and benzoyl) and C 1-4 alkoxy-phenyl group (e.g.
  • methoxyphenyl and cyclic aminocarbonyl group, more specifically, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, pyrrolidinocarbonyl, piperidionocarbonyl,
  • thiocarbamoyl group use is made of thiocarbamoyl group optionally substituted with one or two substituents selected from, for example, C 1-4 alkyl group (e.g. methyl and ethyl) and phenyl group, for example, thiocarbamoyl, N-methylthiocarbamoyl and N-phenylthiocarbamoyl.
  • C 1-4 alkyl group e.g. methyl and ethyl
  • phenyl group for example, thiocarbamoyl, N-methylthiocarbamoyl and N-phenylthiocarbamoyl.
  • optionally substituted carbamoyloxy group use is made of carbamoyloxy group optionally substituted with one or two substituents selected from, for example, C 1-4 alkyl group (e.g.
  • C 1-6 alkanoylamino mention is made of, for example, acetamido, propionamido,
  • C 6-10 arylacylamino group mention is made of, for example, C 6-10 aryl-carbonylamino group such as benzamido,
  • C 1-10 alkoxycarboxamido group mention is made of, for example, methoxycarboxamido (CH 3 OCONH-), ethoxycarboxamido and tert-butoxycarboxamido; as "C 6-10 aryloxy-carboxamido group”, mention is made of, for example,
  • aralkyloxy-carboxamido group mention is made of, for example, benzyloxycarboxamido (C 6 H 5 CH 2 OCONH-) and benzhydryloxycarboxamido.
  • hydrocarbon group means a group formed by removing one hydrogen atom bonded to the carbon atom of
  • heterocyclic ring and the heterocyclic ring includes 5- to 8-membered ring containing one to several heteroatoms, preferably 1 to 4 hetero-atoms, e.g. nitrogen atom (which may be oxidized), oxygen atom and sulfur atom.
  • heteroatoms e.g. nitrogen atom (which may be oxidized), oxygen atom and sulfur atom.
  • heterocyclic groups include 2- or 3-pyrrolyl; 3-, 4- or 5-pyrazolyl; 2-, 4- or 5- imidazolyl; 1,2,3- or 1,2,4-triazolyl; 1H- or 2H-tetrazolyl; 2- or 3-furyl; 2- or 3-thienyl; 2-, 4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 1, 2 , 3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl; 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl; 1,2,4- or 1,3,4-oxadiazolyl; 2-, 4- or 5-thiazolyl; 3-, 4- or 5-isothiazolyl; 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazol-5-yl; 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; 1,2,5- or 1, 3,4-thiadiazoly
  • pyrazinyl 2-, 3- or 4-piperidinyl; piperazinyl; 3H- indol-2-yl or 3H-indol-3-yl ; 2-, 3- or 4-pyranyl; 2-, 3- or 4-thiopyranyl; benzopyranyl; quinolyl;
  • pyrido[2,3-d]pyrimidinyl 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthylidyl; thieno[2,3-d]pyridyl;
  • Preferable examples of the said "optionally substituted hydrocarbon group” include C 1-6 alkyl groups (e.g. methyl, ethyl, n-propyl and isopropyl) optionally substituted with one to three substituents selected from, for example, hydroxyl group, C 3-7 cycloalkyl group (e.g. similar ones to those described above), C 1-6 alkoxy group (e.g. similar ones to those described above), C 1-6 alkylthio group (e.g. similar ones to those described above), amino group, tri-C 1-6 alkylammonium group (e.g. similar ones to those described above), halogen atom (e.g.
  • carboxyl group C 1-10 alkoxycarbonyl group (e.g. similar ones to those described above), optionally substituted carbamoyl group, cyano group, azido group and heterocyclic group (e.g.
  • optionally substituted hydrocarbon group examples include straight-chain and branched C 1-3 alkyl groups such as methyl, ethyl, n-propyl and isopropyl;
  • C 1-3 alkyl groups substituted with, for example, halogen atom, hydroxyl group, C 1-6 alkoxy group, carboxyl group, C 1-10 alkoxycarbonyl group or cyano group, as exemplified by fluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, tert-butoxycarbonylmethyl, 1-carboxy-1-methylethyl, 1-tert- butoxycarbonyl-1-methylethyl; and allyl group.
  • fluoromethyl 2-fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, tert-butoxycarbonylmethyl, 1-carboxy-1-methylethyl, 1-tert- butoxycarbonyl-1-methylethyl; and allyl group.
  • heterocyclic groups containing, other than carbon atoms, one or two hetero-atoms such as nitrogen atom, oxygen atom or sulfur atom, as exemplified by oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,
  • R 2 As preferable groups of R 2 , mention is made of, for example, hydrogen atom or optionally substituted hydrocarbon groups, especially, for example, C 1-6 alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), and C 3-7 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).
  • R 2 is preferably H, a C 2-4 alkeny group (e.g.
  • allyl cyclopentyl or a C 1-4 alkyl group (e.g. methyl, ethyl, propyl, isopropyl) which may be substituted with 1 to 3 halogen atoms (e.g. fluorine, chlorine,
  • bromine more preferably a fluoro-C 1-4 alkyl group (e.g. fluoromethyl, 2-fluoroethyl).
  • the substituent A ⁇ is an optionally substituted group of the formula
  • B is a 6-membered aromatic heterocyclic ring having, other than carbon atoms, one or two nitrogen atoms as ring-constituent atoms, and R is an
  • the 6-membered aromatic heterocyclic ring for B means a 6-membered aromatic heterocyclic ring whose hetero atom(s) is/are one or two nitrogen atoms.
  • the present invention includes all the cases where the positive charge is localized on the nitrogen atom and where the nitrogen atom is non-localized on the imidazole ring or the whole condensed ring.
  • substituted hydrocarbon group shown by R 3 include C 1-6 alkyl groups (C 1-6 alkyl group means methyl, ethyl, n-propyl, isopropyl, etc.) optionally substituted with one to three substituents selected from, for example, hydroxyl group, C 3-7 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkylthio groups, amino group, halogen atom, carboxyl group, C 1-10 alkoxycarbonyl group, optionally substituted carbamoyl group, cyano group, azido group and heterocyclic group, which are more specifically exemplified by cyclopropylmethyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-hydroxyethyl, ethylthiomethyl, 2-aminoethyl, 2-fluoroethyl, 2,2-difluoroethyl
  • hydrocarbon group include straight-chain and branched C 1-3 alkyl groups such as methyl, ethyl, n-propyl and isopropyl, and straight-chain C 1-6 alkyl groups
  • halogen atom selected from halogen atom, hydroxyl group, C 1-6 alkoxy group, carboxyl group, C 1-10 alkoxycarbonyl group, cyano group and carbamoyl group, which are exemplified by 2-fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl,
  • C 1-3 alkyl groups e.g. methyl and ethyl are preferable.
  • the group represented by the formula [A 1 ] or [A 2 ], may have, preferably, one or two substituents at its imidazole ring or/and ring B.
  • substituents include hydroxyl group, hydroxy-C 1-6 alkyl group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 cycloalkyl group, C 5-6 cycloalkenyl group, C 3-10 cycloalkyl-C 1-6 alkyl group, C 6-10 aryl group, C 7-12 aralkyl group, heterocyclic group, C 1-6 alkoxy group, C 1- 6 alkoxy-C 1-6 alkyl group, amino-C 1-6 alkoxy group, C 3-10 cycloalkyloxy group, C 6-10 aryloxy group, C 7-19 aralkyloxy group, mercapto group, mercapto-C 1-6 alkyl group, sulfo group, sulfo-
  • C 1-6 alkyl group straight-chain or branched C 1-6 alkyl groups, for example, are preferable, and use is made of, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • C 2-6 alkenyl group straight-chain or branched C 2-6 alkenyl groups, for example, are preferable, and use is made of, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl and 1,1-dimethylallyl.
  • C 2-6 alkynyl group straight-chain or branched C 2-6 alkynyl groups, for example, are preferable, and use is made of, for example, thienyl, 1-propynyl and propargyl.
  • C 3-10 cycloalkyl group C 3-10 3- to 7-membered alicyclic hydrocarbon groups, for example, are
  • C 5-6 cycloalkenyl group 5- to 6-membered cyclic hydrocarbon groups having double bond, for example, are preferable, and use is made of, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl.
  • C 6-10 aryl group use is made of, for example, phenyl, ⁇ -naphthyl, ⁇ -naphthyl and biphenylyl .
  • C 7-12 aralkyl group use is made of, for example, 1-phenylethyl, 2-phenylethyl, phenylpropyl and naphthylmethyl.
  • C 3-10 cycloalkyloxy group use is made of, for example, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and norbornyloxy.
  • amino-C 1-6 alkoxy group use is made of, for example, aminomethoxy, 2-aminoethoxy and 3-aminopropoxy.
  • C 6-10 aryloxy group use is made of, for example, phenoxy and naphthyloxy.
  • C 7-19 aralkyloxy group use is made of, for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, naphthylmethyloxy, benzhydryloxy and trityloxy.
  • C 1 . 6 alkylthio group use is made of, for example, methylthio, ethylthio, n-propylthio and n-butylthio.
  • amino-C 1-6 alkylthio group use is made of, for example, aminomethylthio, 2-aminoethylthio and 3- aminopropylthio.
  • C 3-10 cycloalkylthio group use is made of, for example, cyclopropylthio and cyclohexylthio.
  • C 6-10 arylthio group use is made of, for example, phenylthio and naphthylthio.
  • C 7-19 aralkylthio group use is made of, for example, benzylthio, phenylethylthio, benzhydrylthio and tritylthio.
  • hydroxy-C 1-6 alkyl group use is made of, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl.
  • C 3-10 cycloalkyl-C 1-6 alkyl group use is made of, for example, cyclopropylmethyl, cyclopropylethyl and cyclobutylmethyl.
  • mercapto-C 1-6 alkyl group use is made of, for example, mercaptomethyl, 1-mereaptoethyl and 2-mercaptoethyl.
  • C 1-6 alkoxy-C 1-6 alkyl group use is made of, for example, methoxymethyl, ethoxymethyl and 2-methoxyethyl.
  • C 1-6 alkylthio-C 1-6 alkyl group use is made of, for example, methylthiomethyl and 2-methylthioethyl.
  • amino-C 1-6 alkyl group use is made of, for example, aminomethyl, 2-aminoethyl and 3-aminopropyl.
  • di-C 1-6 alkylamino-C 1-6 alkyl group use is made of, for example, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N- diethylamino)ethyl and 3-(N,N-dimethylamino)propyl.
  • cyclic-amino groups of "cyclic-amino- C 1-6 alkyl group” are cyclic-amino groups described in the following.
  • cyclic-amino-C 1-6 alkyl group use is made of, for example, pyrrolidinomethyl,
  • cyclic-amino-C 1-6 alkylamino group are cyclic-amino-C 1- 6 alkyl groups described above, and, as "cyclic-amino-
  • C, -6 alkylamino group use is made of, for example, pyrrolidinoethylamino, piperidinoethylamino,
  • halogeno-C 1-6 alkyl group use is made of, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
  • cyano-C 1-6 alkyl group use is made of, for example, cyanomethyl and 2-cyanoethyl.
  • Carboxy-C 1-6 alkyl group use is made of, for example, carboxymethyl, 1-carboxyethyl and 2-carboxyethyl.
  • sulfo-C 1-6 alkyl group use is made of, for example, sulfomethyl and 2-sulfoethyl.
  • C 2-6 alkanoyl-C 1-6 alkyl group C 1-6 alkanoyl groups to be described later are preferable.
  • C 2-6 alkanoyl-C 1-6 alkyl group use is made of, for example, acetylmethyl, 1-acetylethyl and
  • alkanoyloxy group of "C 2-6 alkanoyloxy-C 1-6 alkyl group” C 2-6 alkanoyloxy groups to be described later are preferable.
  • C 2-6 alkanoyloxy-C 1-6 alkyl group use is made of, for example, acetoxymethyl, 1- acetoxyethyl and 2-acetoxyethyl.
  • alkoxycarbonyl group of "C 1-10 alkoxy-carbonyl-C 1-6 alkyl group” C 1-10 alkoxy-carbonyl groups to be described later are preferable.
  • C 1-10 alkoxy-carbonyl C 1-6 alkyl group use is made of, for example, methoxycarbonyl, ethoxycarbonyl and tert- butoxycarbonylmethyl.
  • carbamoyloxy-C 1-6 alkyl group use is made of, for example, carbamoyloxymethyl.
  • mono-C 1-6 alkylamino group use is made of, for example, methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n-pentylamino and n-hexylamino.
  • di-C 1-6 alkylamino group use is made of, for example, dimethylamino, diethylamino, methylethylamino, di-(n-propyl) amino and di-(n-butyl)amino.
  • C 3-10 cycloalkylamino group use is made of, for example, cyclopropylamino, cyclopentylamino and cyclohexylamino.
  • C 6-10 arylamino group use is made of, for example, anilino and N-methylanilino.
  • C 7-19 aralkylamino group use is made of, for example, benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino and tritylamino.
  • Cyclic-amino group means a group formed by removing one hydrogen atom bonding to the ring-forming nitrogen atom of the N-containing heterocyclic ring or of the group formed by saturating the double bond of the N-containing heterocyclic ring, and, as the cyclic amino group, use is made of, for example, 1H-tetrazol-1-yl, 1H-pyrrol-1-yl, pyrrolino, pyrrolidino, 1H-imidazol-1-yl, imidazolino, imidazolidino, 1H-pyrazol- 1-yl, pyrazolino, pyrazolidino, piperidino, piperazino and morpholino.
  • the alkyl group of "C 1-10 alkoxy-carbonyl group” includes, besides C 1-6 alkyl groups (e.g. similar ones to those mentioned above), C 3-10 cycloalkyl groups (e.g- similar ones to those mentioned above.
  • C 1-10 alkoxy-carbonyl group use is made of, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
  • C 6-10 aryloxy-carbonyl group use is made of, for example, phenoxycarbonyl and naphthyloxycarbonyl.
  • C 7-19 aralkyloxy-carbonyl group use is made of, for example, benzyloxycarbonyl,
  • substituted sulfonyl group of "sulfonamido group” use is made of "C 1-6 alkylsulfonyl group", for example, methanesulfonyl and ethanesulfonyl.
  • halogen atom use is made of, for example, fluorine, chlorine and bromine.
  • C 1-6 alkylureido group use is made of, for example, methylureido, ethylureido and n-propylureido.
  • C 6-10 aryl-acyl group use is made of, for example, phenylacetyl.
  • C 1-6 alkanoyl group use is made of, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl.
  • C 3-5 alkenoyl group use is made of, for example, acryloyl, crotonoyl and maleoyl.
  • C 6-10 aryl-acyloxy group use is made of, for example, phenylacetyloxy.
  • C 3-5 alkenoyloxy group use is made of, for example, acryloyloxy, crotonoyloxy and maleoyloxy.
  • carbamoyl-C 1-6 alkyl group use is made of, for example, carbamoylmethyl and 2-carbamoylethyl.
  • C 1-6 alkanoylamino group use is made of, for example, formylamino and acetylamino.
  • C 6-10 aryl-acylamino group use is made of, for example, phenylacetylamino.
  • C 1-10 alkoxy-carboxamido group use is made of, for example, methoxycarboxamido and
  • C 6-10 aryloxy-carboxamido group use is made of, for example, phenyloxycarboxamido.
  • C 7-19 aralkyloxy-carboxamido group use is made of, for example, benzyloxycarboxamido.
  • Heterocyclic group means a group formed by removing one hydrogen atom bonded to the carbon atom of the heterocyclic ring.
  • heterocyclic ring include a 5- to 8-membered ring containing one to several number, preferably 1 to 4, of hetero-atoms, e.g. nitrogen atom (which may be oxidized), oxygen atom and sulfur atom. Practical examples of such
  • heterocyclic group to be used include 2- or 3-pyrrolyl; 3-, 4- or 5-pyrazolyl; 2-, 4- or 5-imidazolyl; 1,2,3-or 1,2,4-triazolyl; 1H- or 2H-tetrazolyl; 2- or 3- furyl; 2- or 3-thienyl; 2-, 4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl; 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl;
  • the compound [I] include a compound of the formula [I-a]
  • R 1 is amino group
  • R 2 is a C 1-6 alkyl group (e.g. methyl, ethyl, propyl and isopropyl) and R 3 is a C 1-6 alkyl group (e.g. methyl, ethyl, propyl and isopropyl) or (2) R 1 is amino group, R 2 is a C 3-6
  • cycloalkyl group e.g. cyclopentyl
  • R 3 is a C 1-6 alkyl group (e.g. methyl, ethyl, propyl and isopropyl).
  • More preferable examples of the compound [I] include a compound of the formula
  • R 1 is an optionally protected amino group
  • R 2' is H, a C 2-4 alkenyl group, cyclopentyl or a C 1-4 alkyl group which may be substituted with halogen
  • A' ⁇ is a group of the formula or wherein R 3' is a C 2-4 alkenyl group or a C 1-4 alkyl group which may be substituted with hydroxyl, carboxyl or carbamoyl, R 3" is H, amino or carbamoyl, or an ester or salt thereof.
  • R 1 is an optionally protected amino group
  • R 2 ' is H, a C 2-4 alkenyl group, cyclopentyl or a C 1-4 alkyl group which may be substituted with halogen
  • R 3' is a C 2-4 , alkenyl group or a C 1-4 alkyl group which may be substituted with carbamoyl, or an ester or salt
  • R 2' is preferably cyclopentyl or a C 1-4 alkyl group which may be substituted with halogen and R 3''' is preferably a C 1-4 alkyl group which may be substituted with carbamoyl.
  • the mark ⁇ attached on the right shoulder of -COO at the 4-position shows that the carboxyl group is carboxylate anion and forms, making a pair with the positive charge on the substituent A, an internal salt.
  • the compound [I] may optionally form a
  • the pharmaceutically acceptable salt use is made of, for example, inorganic basic salts, ammonium salts, organic basic salts, inorganic acid addition salts, organic acid addition salts and basic amino acid salts.
  • inorganic base capable of forming an inorganic basic salt use is made of, for example, alkali metal salts (e.g. sodium and potassium) and alkaline earth metals (e.g- calcium);
  • organic base capable of forming an organic basic salt use is made of, for example, procaine, 2-phenylethylbenzylamine,
  • salts use is made of, for example, p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid and maleic acid; and, as a basic amino acid capable of forming a basic amino acid salt, use is made of, for example, lysine, arginine, ornithine and histidine.
  • basic salts i.e.
  • inorganic basic salts, ammonium salts, organic basic salts and basic amino acid salts mean those capable of being formed in the case where an acid group such as carboxyl group and sulfo group exists in the substituents R 1 , R 2 , R 3 or A ⁇ of the compound [I] or where carboxyl group exists at the 4-position; and acid addition salts (i.e.
  • inorganic acid addition salts and organic acid addition salts mean those capable of being formed in the case where a basic group such as amino group, monoalkylamino group, dialkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, cyclic amino group and N-containing heterocyclic group exists in the substituents R 1 , R 2 , R 3 or A ⁇ of the compound [I].
  • the acid addition salts include salts in which one mol. of acid is added to the moiety forming the internal salt of the compound [I], i.e.
  • Ester derivatives of the compound [I] mean esters producible by esterifying the carboxyl group in the molecule which are utilizable as intermediate of the synthesis and are metabolically unstable and non-toxic esters. Examples of the ester utilizable as intermediate include
  • C 1-6 alkyl ester optionally substituted C 2-6 alkenyl ester, C 3-10 cycloalkyl ester, C 3-10 cycloalkyl-C 1-6 alkyl ester, optionally substituted C 6-10 aryl ester,
  • C 1-6 alkyl ester use is made of, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl and n-hexyl, which may be substituted with one to three of, for example, benzyloxy, C 1-4 alkyl sulfonyl (e.g. methyl sulfonyl), trimethyl silyl, halogen (e.g- fluorine, chlorine and bromine), acetyl, nitrobenzoyl, mesylbenzoyl, phthalimido, succinimide,
  • benzenesulfonyl phenylthio, di-C 1-4 alkylamino (e.g- dimethylamino), pyridyl, C 1-4 alkyl sulfinyl (e.g.
  • methyl sulfinyl and cyano.
  • groups include benzyloxymethyl, 2-methylsulfonylethyl, 2-trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, phthalimidomethyl,
  • phenylthiomethyl dimethylaminoethyl, pyridine-oxido-2- methyl, methylsulfinylmethyl and 2-cyano-1,1- dimethylethyl.
  • C 2-6 alkenyl group forming "C 2-6 alkenyl ester” use is made of, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl, 1,1-dimethylallyl and 3-methyl-3-butenyl.
  • cycloalkylester use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl.
  • C 3-10 cycloalkyl-C 1-6 alkyl group forming "C 3- 10 cycloalkyl-C 1-6 alkyl ester” use is made of, for example, cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • substituted C 6-10 aryl ester use is made of, for example, phenyl, ⁇ -naphthyl, ⁇ -naphthyl and biphenylyl, which may optionally be substituted with one to three of, for example, nitro and halogen (e.g. fluorine, chlorine and bromine).
  • nitro and halogen e.g. fluorine, chlorine and bromine.
  • substituted C 7-12 aralkyl ester use is made of, for example, benzyl, 1-phenylethyl, 2-phenylethyl,
  • phenylpropyl and naphthylmethyl which may optionally be substituted with one to three of, for example nitro, C 1-4 alkoxy (e.g. methoxy), C 1-4 alkyl (e.g. methyl and ethyl) and hydroxy.
  • C 1-4 alkoxy e.g. methoxy
  • C 1-4 alkyl e.g. methyl and ethyl
  • hydroxy e.g. methyl and ethyl
  • Specific examples of such groups include p-nitrobenzyl, p-methoxybenzyl and 3,5-di-tert-butyl-4-hydroxybenzyl.
  • di-C 6-10 aryl-methyl group forming "di-C 6-10 aryl-methyl ester” use is made of, among others, benzhydryl.
  • tri-C 6-10 aryl-methyl group forming tri C 6-10 aryl-methyl ester use is made of, among others, trityl.
  • substituted silyl group forming substituted silyl ester use is made of, for example, trimethylsilyl, tert-butyldimethylsilyl and - Si(CH 3 ) 2 CH 2 CH 2 Si(CH 3 ) 2 -.
  • the above-mentioned esters include ester at 4-position.
  • the present invention includes, besides the above- described ester derivatives, phamacologically
  • amino group may optionally be substituted.
  • substituents on the amino group use is made of, for example, protective groups of the optionally protected amino groups shown by R 1 .
  • the compound [I] of this invention includes a solvate thereof.
  • the solvent of the solvate use is made of, for example, water; alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone and the like; ethers such as
  • the compound [I] and starting compounds of this invention include cis-isomer (Z-compound), trans-isomer (E-compound) and a cis-trans mixture.
  • the compound [I] of this invention is preferably a trans-isomer (E-compound).
  • the cis-isomer (Z-compound), for example, means one of the geometrical isomers having the partial structure represented by the formula [VII], and the trans-isomer means a geometrical isomer having the partial structure represented by the formula [VIII].
  • the compound [I] can be synthesized by reacting, for example, a 7-amino compound of the formula [II]
  • This method comprises acylation of the 7-amino compound [II] with carboxylic acid R b OH or a salt or reactive derivative thereof.
  • carboxylic acid R b OH in the free state or in the form of a salt or reactive derivative thereof can be used as an agent for acylating the amino group at 7-position of the 7-amino compound [II]. More specifically,
  • carboxylic acid R b OH or its reactive derivatives such as inorganic basic salts, organic basic salts, acid halides, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active ester and active thioesters of carboxylic acid R b OH are used for the acylation.
  • inorganic basic salts include alkali metal salts (e.g. sodium salt and potassium salt) and alkaline earth metal salts (e.g.
  • examples of organic basic salts include trimethylamine salt, triethylamine salt, tert- butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt and quinoline salt;
  • examples of acid halides include acid chloride and acid bromide;
  • mixed acid anhydrides include mono C 1-6 alkyl carbonate mixed acid anhydride (e.g. mixed acid anhydride of carboxylic acid R b OH with, for example, monomethyl carbonate, monoethyl carbonate,
  • C 1-6 aliphatic carboxylic acid mixed anhydride e.g. mixed acid anhydride of carboxylic acid R b OH with, for example, acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid,
  • acetoacetic acid C 7-12 aromatic carboxylic acid mixed anhydride (e.g. mixed acid anhydride of carboxylic acid R b OH with, for example, benzoic acid, p-toluic acid or p-chlorobenzoic acid) and organic sulfonic acid mixed anhydride (e.g. mixed acid anhydride of carboxylic acid R b OH with, for example, methanesulfonic acid,
  • ethanesulfonic acid benzenesulfonic acid or p-toluenesulfonic acid
  • active amides include amide with an N-containing heterocyclic
  • compound e.g. acid amide of carboxylic acid R b OH with pyrazole, imidazole or benzotriazole, and these N-containing heterocyclic compounds may optionally be substituted with, for example, C 1-6 alkyl group (e.g. methyl and ethyl), C 1-6 alkoxy group (e.g. methoxy and ethoxy), halogen atom (e.g. fluorine, chlorine and bromine), oxo group, thioxo group, or C 1-6 alkylthio group (e.g. methylthio and ethylthio).
  • C 1-6 alkyl group e.g. methyl and ethyl
  • C 1-6 alkoxy group e.g. methoxy and ethoxy
  • halogen atom e.g. fluorine, chlorine and bromine
  • oxo group e.g. fluorine, chlorine and bromine
  • thioxo group e.g
  • any one usable for this purpose in the field of synthesizing ⁇ -lactam and peptide can be utilized, examples of which include, besides organic phosphoric acid ester (e.g. diethoxyphosphoric acid ester and diphenoxyphosphoric acid ester), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester,
  • ester with an aromatic heterocyclic thiol compound [e.g. 2-pyridylthiol ester or 2-benzothiazolylthiol ester, and these heterocyclic ring may optionally be substituted with a C 1-6 alkyl group (e.g.
  • the 7-amino compound [II] can be used in the free state, as a salt or ester thereof.
  • salts of the 7-amino compound [II] include inorganic basic salts, ammonium salts, organic basic salts, inorganic acid addition salts and organic acid addition salts.
  • inorganic basic salts examples include alkali metal salts (e.g. sodium salt and potassium salt) and
  • alkaline earth metal salts e.g. calcium salt
  • organic basic salts include trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt and quinoline salt;
  • examples of inorganic acid addition salts include hydrochloride, hydrobromide, sulfate, nitrate and phosphate; and examples of organic acid addition salts include formate, acetate, trifluoroacetate,
  • the starting compound R b OH, its salts and reactive derivatives can readily be produced by known methods (e.g. methods disclosed in JPA S60(1985)-231684 or JPA S62(1987)-149682) or methods analogous thereto.
  • the reactive derivative of carboxylic acid R b OH can be allowed, after isolating from the reaction mixture, to react with the 7-amino compound [II], or the reaction mixture containing the reactive derivative of
  • carboxylic acid R b OH can be allowed, as it is, to react with the 7-amino compound [II].
  • a proper condensing agent is employed.
  • the condensing agent use is made of N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide; azolides such as N,N'-carbonyldiimidazole and N,N'-thiocarbonyldiimidazole; a dehydrating agent such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene; and 2-halogenopyridinium salts such as 2-chloropyridinium methyliodide and 2-fluoropyridinium methyliodide.
  • the reaction is considered to proceed via a reactive derivative of carboxylic acid R b OH.
  • the reaction is conducted generally in a proper solvent which does not hamper the reaction.
  • the solvent use is made of ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated
  • hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane; hydrocarbons such as n-hexane, benzene and toluene; amides such as formamide, N,N-dimethyIformamide and N,N-dimethylacetamide; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; and, besides, dimethyl sulfoxide, sulfolane, hexamethyl phosphoramide and water, for example, are employed singly or as a mixture solvent.
  • the amount of an acylating agent (R b OH) to be used ranges usually from about 1 to 5 mol., preferably from about 1 to 2 mol., relative to one mol. of the 7-amino compound [II].
  • the reaction is conducted at temperatures ranging from about -80 to 80 °C, preferably from about -40 to 50 °C, most
  • reaction time depends on the kinds of 7-amino compound [II] and carboxylic acid R b OH, kinds of solvent (when a mixed solvent is employed, the mixing ratio) and reaction temperature, and ranges usually from about 1 minute to 72 hours, preferably from about 15 minutes to 3 hours.
  • acid halide employed as the acylating agent, the reaction can be conducted in the presence of a deacidifier for the purpose of eliminating liberated hydrogen halogenide from the reaction mixture.
  • the deacidifier examples include inorganic base such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogencarbonate; tertiary amine such as triethylamine, tri (n-propyl) amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyl
  • inorganic base such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogencarbonate
  • tertiary amine such as triethylamine, tri (n-propyl) amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyl
  • dimethylamine pyridine, lutidine, ⁇ -collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine; and alkylene oxide such as propylene oxide and epichlorohydrin.
  • reaction or an ester or salt thereof can be produced by, for example, the following steps:
  • R 4 is a protecting group of carboxyl group
  • R 5 is a protecting group of amino group
  • other symbols are of the same meaning as defined above, is allowed to react with an optionally substituted imidazole
  • carboxyl-protecting group shown by R mention is made of the above-mentioned ester- Especially, readily removable carboxyl-protecting groups, which are conventionally employed in this field, such as tri(lower)alkylsilyl group e.g.
  • trimethylsilyl group benzhydryl group, p-methoxybenzyl group, tert-butyl group, p-nitrobenzyl group and phenacyl group, are preferable.
  • amino-protecting group shown by R 5 mention is made of the above-mentioned amino-protecting group. Especially, tri(lower)alkylsilyl groups such as
  • acyl type protecting groups such as formyl group, trifluoroacetyl group, acetyl group, tert-butoxycarbonyl group, methoxy acetyl group, benzyloxy carbonyl group and p-nitrobenzyloxy carbonyl group
  • aralkyl type protecting group such as benzyl group, benzhydryl group and trityl group
  • X include halogen atoms such as chlorine, bromine and iodine; acyloxy groups such as acetoxy, propionyloxy, butyryloxy and 3-oxobutyryloxy; alkylsulfonyloxy groups such as
  • arylsulfonyloxy groups such as benzenesulfonyloxy, naphthalenesulfonyloxy, p-toluenesulfonyloxy, p-tert- butylbenzenesulfonyloxy, p-methoxybenzenesulfonyloxy, p-chlorobenzenesulfonyloxy and p-nitrobenzenesulfonyloxy.
  • benzenesulfonyloxy and p-toluenesulfonyloxy groups are preferable.
  • the imidazole compound [IV] is also used as a salt thereof.
  • the salt include alkali metal salts such as lithium salt, sodium salt and potassium salt; and addition salts with trialkylamine such as triethylamine and
  • the full nucleophilic substitution reaction between the compound [IX] and the compound [IV] is conducted, in general cases, preferably in an inactive solvent, as exemplified by ketones such as acetone; halogenated hydrocarbons such as chloroform,
  • dichloromethane and dichloroethane ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile; alcohols such as methanol, ethanol and n-propanol; amides such as
  • nucleophilic reagent [IV] to be used ranges usually from 1 to 5 mol., preferably from about 1 to 3 mol. relative to 1 mol. of the compound [IX].
  • the reaction temperature ranges from 0°C to 100 °C, preferably from 10°C to 50°C.
  • the reaction time ranges from 30 minutes to 24 hours, preferably from 1 to 10 hours. This reaction can be accelerated by the addition of a base or a salt.
  • base and the salt mention is made of, for example, inorganic bases such as sodium
  • hydroxide potassium hydroxide, sodium carbonate and potassium carbonate
  • organic amine including trialkylamine such as triethylamine and
  • diisopropylethylamine diisopropylethylamine.
  • salt use is made of, for example, quaternary ammonium salt such as tetrabutyl ammonium salt.
  • Examples of the halogen compound represented by R 3 X to be reacted with the compound (X) include C 1-6 lower alkyl halide, C 2-6 lower alkenyl halide, C 2-6 lower alkynyl halide, hydroxy lower alkyl halide, carboxy lower alkyl halide, carbamoyl lower alkyl halide and lower alkenoyl lower alkyl halide.
  • C 1-6 lower alkyl halide C 2-6 lower alkenyl halide, C 2-6 lower alkynyl halide, hydroxy lower alkyl halide, carboxy lower alkyl halide, carbamoyl lower alkyl halide and lower alkenoyl lower alkyl halide.
  • the reaction between the compound [X] and R 3 X is usually conducted preferably in an inactive solvent, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as
  • the amount of R 3 X to be employed ranges from 1 to 20 mol., preferably from 5 to 10 mol.
  • the reaction time ranges from 1 to 48 hours, preferably from 5 to 24 hours.
  • the protective group of the compound [XI] obtained as above, when the protecting group is tri ( lower) alkylsilyl group, can be removed by processing the compound with water.
  • protective group is, for example, benzhydryl group, trityl group, p-methoxybenzyl group, tert-butyl group, tert-butoxycarbonyl group or formyl group, it can be removed by processing the compound with, for example, formic acid, hydrochloric acid, trifluoroacetic acid, phenol or cresol.
  • Method (2) A method of producing the compound
  • n denotes 0 or 1
  • other symbols are of the same meaning as defined above, to react with an
  • Method (3) A method of producing the compound described in (1) above, which is characterized by allowing, for example, a compound represented by the formula [III]
  • the compound [III] can be produced by allowing a compound of the formula [XIII]
  • the compound [VII] in this production method can be produced by allowing the compound [IV] to react with a halogen compound represented by R 3 X under substantially the same conditions as those for leading the compound [XI] to the corresponding quaternary ammonium salt in Method (1).
  • monohalogenoacetyl group e.g. chloroacetyl and
  • bromoacetyl can be removed by using thiourea; an alkoxycarbonyl group (e.g. methoxycarbonyl,
  • ethoxycarbonyl and tert-butoxycarbonyl can be removed by using an acid (e.g. hydrochloric acid); an
  • aralkyloxycarbonyl group e.g. benzyloxycarbonyl, p-methylbenzyloxycarbonyl and p-nitrobenzyloxycarbonyl
  • 2,2,2-trichloroethoxycarbonyl can be removed by using zinc and an acid (e.g. acetic acid)-
  • the ester residual group can be removed by a per se known method or an analogous method thereto.
  • 2-methylsulfonylethyl ester can be removed by using alkali; aralkyl ester (e.g.
  • benzyl ester, benzhydryl ester, p-methoxybenzyl ester and p-nitrobenzyl ester can be removed by using an acid (e.g. trifluoroacetic acid) or by means of catalytic reduction; 2,2,2-trichloroethyl ester can be removed by using zinc and an acid (e.g. acetic acid); and silyl ester (e.g.
  • trimethylsilyl ester and tert-butyldimethylsilyl ester can be removed by using only water.
  • a method established in the field of ⁇ -lactam can be employed, and, in the present invention also, a conventional technique can be utilized as it is- For example, phosphorus trichloride and phosphorus tribromide can be employed.
  • the compound [I] of this invention has
  • antibacterial activities of a broad spectrum can be used safely for prophylaxis and therapy of various diseases, in man and mammals (e.g. mouse, rat, rabbit, dog, cat, cow and pig), caused by pathogenic bacteria, for example, respiratory infection and urinary tract infection.
  • man and mammals e.g. mouse, rat, rabbit, dog, cat, cow and pig
  • pathogenic bacteria for example, respiratory infection and urinary tract infection.
  • antibacterial spectrum of the antibacterial compound [I] are as follows, among others: (1) showing a
  • Gram-positive bacteria e.g. Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • ⁇ -lactamase-producing Gram-negative bacteria e.g. genera Escherichia, Enterobacter and Proteus.
  • the antibacterial compound [I] of this invention has such characteristic features as (1) having excellent stability, (2) showing high
  • the compound [I] of this invention can be administered, like known penicillin preparations or cephalosporin preparations, non-orally or orally as injectable preparations, capsules, tablets or granular preparations (injectable preparations are especially preferable).
  • the daily dose ranges from 0.5 to 80 mg, preferably from 1 to 40 rag relative to 1 Kg of the body weight of a man or an animal infected with pathogenic bacteria as described above, which may be administered in two to three divided doses.
  • injectable preparations are especially preferable.
  • the daily dose ranges from 0.5 to 80 mg, preferably from 1 to 40 rag relative to 1 Kg of the body weight of a man or an animal infected with pathogenic bacteria as described above, which may be administered in two to three divided doses.
  • injectable preparations use is made of, for example, distilled water and physiological saline solution, and, carriers for capsules, powdery preparations, granular preparations or tablets are used as a mixture with known pharmaceutically acceptable excipients (e.g.
  • starch maltose, sucrose, calcium carbonate or calcium phosphate
  • binders e.g. starch, gum arabic
  • carboxymethyl cellulose hydroxypropyl cellulose or crystalline cellulose
  • lubricants e.g. magnesium stearate or talc
  • disintegrants e.g. carboxymethyl calcium and talc
  • NMR spectra were measured using tetramethylsilane as an internal or external standard with a spectrometer Gemini 200 and all ⁇ values were expressed in ppm.
  • the value shown in ( ) for a mixed solvent is a mixing ratio in volume of constituent solvents.
  • the percent (%) for a solution indicates the number of grams in 100 ml of the
  • the mixture was extracted with 120 ml of water, and the aqueous layer was separated. The organic layer was again extracted with 60 ml of water, and the aqueous layers were combined. Further, the aqueous layer was washed with ethyl acetate. To the aqueous layer was added 6.7 g of O-cyclopentylhydroxylamine, and the pH of the mixture was adjusted to 5 with IN-NaOH, which was stirred overnight at room temperature (25°C, the same shall apply
  • IR(KBr,cm -1 ) 3300, 2950, 1720, 1640, 1520, 1400, 1180.
  • the concentrate was lyophilized to give 0.93 g of the titled compound.
  • the precipitate was dissolved in 40 ml of a mixture of water and tetrahydrofuran (1:1). To this solution, under ice-cooling, were added 0.52 ml of tri-n-butylamine and 0.23 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-trityloxyiminoacetyl chloride hydrochloride. The mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added 6 ml of a 90% aqueous solution of formic acid. The mixture was stirred for one hour at room temperature, which was concentrated under reduced pressure.
  • the precipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate.
  • To the solution was added, under ice-cooling, 150 mg of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyliminoacetylchloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate.
  • the mixture was stirred for 15 minutes at 0°C.
  • the reaction mixture was
  • reaction mixture was concentrated, which was subjected to an MCI gel CHP-20P column chromatography. Fractions eluted with a 30% aqueous solution of ethanol were collected, which was concentrated under reduced
  • the concentrate was lyophilized to give 77 mg of the titled compound.
  • the precipitate was collected by filtration.
  • the precipitate was dissolved in 20 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate.
  • To the solution was added, under ice-cooling, 61 mg of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride hydrochloride, while adjusting the pH to 8 with an aqueous solution of sodium hydrogen carbonate.
  • the mixture was stirred for 30 minutes at 0°C.
  • the reaction mixture was
  • This Trecipitate was dissolved in 40 ml of a mixture of tetrahydrofuran and water (1:1), whose pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. To the solution was added, under ice-cooling, 120 mg of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride, while the pH was adjusted to 8 with an aqueous solution of sodium hydrogen carbonate. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was
  • reaction mixture was concentrated, which was subjected to a MCI gel CHP-20P column chromatography. Fractions eluted with a 15% aqueous solution of ethanol were collected and concentrated. The concentrate was freeze-dried to give 113 mg of the titled compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé céphem de formule (1) dans laquelle R1 est un groupe amino éventuellement protégé, R2 est H ou un groupe relié par un atome de carbone, A+ est un groupe éventuellement substitué de formule (2) ou (3) (dans laquelle B est un anneau hétérocyclique aromatique à 6 éléments possédant, à part les atomes de carbone, un ou deux atomes d'azote en tant qu'atomes constituant l'anneau et R3 est un groupe hydrocarbure éventuellement substitué) ou ester ou sel dudit composé, qui est utile en tant qu'agent antibactérien.
PCT/JP1996/000166 1995-01-30 1996-01-29 Composes cephem, production et utilisation desdits composes WO1996023798A1 (fr)

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JP7/12739 1995-01-30
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JP8551795 1995-04-11
JP7/85517 1995-04-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5948774A (en) * 1995-05-29 1999-09-07 Takeda Chemical Industries, Ltd. Cephem compounds, their production and use
US6248740B1 (en) 1997-04-25 2001-06-19 Takeda Chemical Industries, Ltd. Condensed pyridazine derivatives, their production and use
US6610694B1 (en) 1998-10-06 2003-08-26 Takeda Chemical Industries, Ltd. Condensed pyridazine compounds, their production and use
WO2003072582A1 (fr) * 2002-02-28 2003-09-04 Lg Life Sciences Ltd. Nouveaux composes a base de cephalosporine et procede de fabrication correspondant
US6627630B1 (en) 1998-10-21 2003-09-30 Takeda Chemical Industries, Ltd. Condensed pyridazine derivatives, their production and use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0111281A2 (fr) * 1982-12-06 1984-06-20 Fujisawa Pharmaceutical Co., Ltd. Dérivés de céphalosporines et procédés pour leur préparation
WO1985004879A1 (fr) * 1984-04-23 1985-11-07 Takeda Chemical Industries, Ltd. Nouveaux composes de cephem
EP0229369A2 (fr) * 1985-12-26 1987-07-22 Takeda Chemical Industries, Ltd. Céphalosporines, procédé pour leur préparation et compositions pharmaceutiques les contenant
JPH01272590A (ja) * 1988-04-22 1989-10-31 Dai Ichi Seiyaku Co Ltd ３−セフェム−４−カルボン酸
EP0630899A1 (fr) * 1992-09-18 1994-12-28 Otsuka Kagaku Kabushiki Kaisha Compose de cepheme, son procede de production et medicament le contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0111281A2 (fr) * 1982-12-06 1984-06-20 Fujisawa Pharmaceutical Co., Ltd. Dérivés de céphalosporines et procédés pour leur préparation
WO1985004879A1 (fr) * 1984-04-23 1985-11-07 Takeda Chemical Industries, Ltd. Nouveaux composes de cephem
EP0229369A2 (fr) * 1985-12-26 1987-07-22 Takeda Chemical Industries, Ltd. Céphalosporines, procédé pour leur préparation et compositions pharmaceutiques les contenant
JPH01272590A (ja) * 1988-04-22 1989-10-31 Dai Ichi Seiyaku Co Ltd ３−セフェム−４−カルボン酸
EP0630899A1 (fr) * 1992-09-18 1994-12-28 Otsuka Kagaku Kabushiki Kaisha Compose de cepheme, son procede de production et medicament le contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 114, no. 23, 10 June 1991, Columbus, Ohio, US; abstract no. 228624q, page 808; column l; XP002000694 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5948774A (en) * 1995-05-29 1999-09-07 Takeda Chemical Industries, Ltd. Cephem compounds, their production and use
US6248740B1 (en) 1997-04-25 2001-06-19 Takeda Chemical Industries, Ltd. Condensed pyridazine derivatives, their production and use
US6610694B1 (en) 1998-10-06 2003-08-26 Takeda Chemical Industries, Ltd. Condensed pyridazine compounds, their production and use
US6627630B1 (en) 1998-10-21 2003-09-30 Takeda Chemical Industries, Ltd. Condensed pyridazine derivatives, their production and use
WO2003072582A1 (fr) * 2002-02-28 2003-09-04 Lg Life Sciences Ltd. Nouveaux composes a base de cephalosporine et procede de fabrication correspondant

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