WO1992006978A1 - 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
WO1992006978A1
WO1992006978A1 PCT/JP1991/001394 JP9101394W WO9206978A1 WO 1992006978 A1 WO1992006978 A1 WO 1992006978A1 JP 9101394 W JP9101394 W JP 9101394W WO 9206978 A1 WO9206978 A1 WO 9206978A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydroxy
optionally substituted
compound
mono
Prior art date
Application number
PCT/JP1991/001394
Other languages
English (en)
Inventor
Masayoshi Murata
Toshiyuki Chiba
Hideo Tsutsumi
Kohji Hattori
Satoru Kuroda
Hiroaki Ohtaka
Fumiyuki Shirai
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
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to US07/853,746 priority Critical patent/US5286721A/en
Publication of WO1992006978A1 publication Critical patent/WO1992006978A1/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 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.
  • R 1 is carboxy, COO- or protected carboxy
  • R 2 is hydroxy(lower)alkyl or protected
  • R 8 is hydrogen or lower alkyl
  • Z is a group of the formula
  • R 3 is hydrogen; lower alkyl or lower alkenyl, each of which is
  • cyclic-aminocarbonyl acylamino, ureido, optionally substituted heterocyclic-carbonylamino, carbamoyloxy, mono(or di)(lower)- alkylcarbamoyloxy, lower
  • alkylthio halo(lower)alkylthio, optionally substituted
  • heterocyclicthio optionally substituted heterocyclic group, optionally substituted aryl, and acyl;
  • R 9 is hydrogen or lower alkyl
  • R 10 is lower alkyl
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include;
  • a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g.
  • a salt with an acid such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate,
  • inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate
  • a salt with a basic or acidic amino acid e.g.
  • Such intermolecular quaternary salt can be prepared when R 3 is, for example, pyridyl( lower)alkyl (e.g.
  • the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
  • R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and Z are each as defined above,
  • R 4 is lower alkyl or ar(lower)alkyl.
  • the starting compounds used in the above Processes may be new and can be prepared, for example, by the methods as shown in the following.
  • R 5 and R 6 are each hydrogen or amino-protective group
  • R 7 is lower alkoxy or aryl
  • L is a leaving group
  • X is halogen
  • Suitable “protected carboxy” may include esterified carboxy wherein “esterified carboxy” can be referred to the ones as mentioned below.
  • ester moiety of an 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, for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl 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.
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); 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 having hydroxy group such as hydroxymethyl, hydroxyethyl, hydroxypropyl,
  • hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like in which more preferable example may be hydroxy(C 1 -C 4 )- alkyl and the most preferable one may be 1-hydroxyethyl.
  • Suitable "protected hydroxy(lower)alkyl” means aforementioned hydroxy(lower)alkyl, in which the hydroxy group is protected by a conventional hydroxy-protective group such as those mentioned in the explanation of imino-protective group as mentioned below; and further ar(lower)alkyl such as mono- or di- or
  • triphenyl(lower)alkyl e.g. benzyl, benzhydryl, trityl, etc.
  • trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, diisopropylmethylsilyl, etc.), triarylsilyl (e.g. triphenylsilyl, etc.),
  • triar(lower)alkylsilyl e.g. tribenzylsilyl, etc.
  • tribenzylsilyl e.g. tribenzylsilyl, etc.
  • hydroxy( lower)alkyl thus defined may be ⁇ phenyl(or nitrophenyl) (C 1 -C 4 )alkoxy ⁇ carbonyloxy(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-trimethylsilyloxyethyl and
  • 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 preferable one may be methyl.
  • Suitable “amino-protective group” may include acyl such as carbamoyl, aliphatic acyl, aromatic acyl,
  • 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-alkylcarbamoyl e.g. methylcarbamoyl, ethylcarbamoyl, etc.
  • alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),
  • cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl,
  • the aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as
  • phenyl(lower) alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • phenyl(lower) alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • acyl groups may be further substituted with one or more suitable substituent(s) such as nitro,
  • nitroaralkoxycarbonyl e.g. nitrobenzyloxycarbonyl, etc.
  • lower alkoxy(lower)alkanoyl e.g. methoxyacetyl, etc.
  • 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 and benzyloxycarbonyl.
  • Suitable "lower alkoxy” may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, etc., in which more preferable example may be C 1 -C 4 alkoxy and the most preferable one may be methoxy for the
  • Suitable "aryl” may include C 6 -C 10 aryl such as phenyl, tolyl, xylyl, cumenyl, mesithyl, naphthyl, and the like, in which more preferable example may be phenyl.
  • Suitable “leaving group” may include an inorganic acid residue such as azido, halogen (e.g. chlorine, bromine, fluorine or iodine), and the like, an organic acid residue such as acyloxy, for example, lower alkanoyloxy (e.g.
  • sulfonyloxy e.g. benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, etc.
  • more preferable example may be C 1 -C 4 alkanoyloxy and the most preferable one may be acetoxy.
  • Suitable "halogen” may include chlorine, bromine, iodine and fluorine, in which more preferable example may be chlorine.
  • Suitable "lower alkenyl” may include C 2 -C 6 alkenyl such as vinyl, allyl, butenyl, hexenyl, etc., in which the most preferable example may be vinyl and 2-butenyl.
  • Suitable “mono(or di) (lower) alkylcarbamoyl” means carbamoyl which is mono(or di) substituted by
  • aforementioned lower alkyl wherein the most preferable example may be methylcarbamoyl and dimethylcarbamoyl.
  • Suitable "mono(or di) (lower)alkenylcarbamoyl” means carbamoyl which is mono(or di) substituted by aforementioned lower alkenyl, wherein more preferable example may be mono(lower)alkenylcarbamoyl, and the most preferable one may be allylcarbamoyl.
  • Suitable "mono(or bis) [hydroxy(lower)alkyl]carbamoyl” means carbamoyl, which is mono(or di)substituted by aforementioned hydroxy(lower) alkyl, wherein more
  • preferable example may be mono[hydroxy(lower) alkyl]- carbamoyl, and the most preferable one may be
  • cyclic-aminocarbonyl may include cyclic-aminocarbonyl such as C 2 -C 7 , preferably C 3 -C 6 alkyleneaminocarbonyl, which may be substituted by one or more, preferably one or two suitable substituent(s) such as lower alkyl as
  • acylamino means amino group substituted by aforementioned acyl, wherein more preferable example may be lower alkanoylamino, lower alkylsulfonylamino, lower alkoxycarbonylamino and lower alkoxy(lower)alkanoylamino, and the most preferable one may be acetylamino,
  • substituted heterocyclic-carbonylamino means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • More preferable heterocyclic group may be any organic compound.
  • heterocyclic group such as : -unsaturated 3 to 8-membered, preferably 5 or
  • 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 may be substituted by one or more, preferably one or two suitable substituent(s) such as :
  • -lower alkoxy which may be straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc., more preferably C 1 -C 4 alkoxy;
  • C 1 -C 4 alkyl e.g. methyl, etc.
  • lower alkoxy and lower alkyl moieties may respectively be the same as those for lower alkoxy and lower alkyl as mentioned above, more preferably C 1 -C 4 alkoxy(C 1 -C 4 )alkyl;
  • lower alkyl moiety may be the same as those for lower alkyl as mentioned above, more preferably C 1 -C 4 alkylthio (e.g. methylthio, etc.); and the like.
  • the imino-moiety(ies) in its ring, may be substituted by imino-protective group, which may be the same as those for amino-protective group as mentioned above, more preferably C 2 -C 4 alkenyloxycarbonyl.
  • substituted heterocyclic-carbonylamino may be unsaturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) optionally substituted by lower
  • alkylthio in which more preferable example may be pyridyl optionally substituted by lower alkylthio.
  • heterocyclic-carbonylamino thus defined may be pyridyl- carbonylamino optionally substituted by lower alkylthio and the most preferable one may be pyridin-3-ylcarbonyl- amino and 2-methylthiopyridin-3-ylcarbonylamino.
  • substituted heterocyclicthio may be unsaturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), or containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), each of which is optionally substituted by lower alkyl, in which more preferable example may be imidazolyl, tetrazolyl and thiadiazolyl, and each of which is oprionally substituted by lower alkyl.
  • heterocyclicthio thus defined may be imidazolylthio, tetrazolylthio and thiadiazolylthio, and each of which is optionally substituted by lower alkyl, and the most preferable one may be 1-methyltetrazol-5-ylthio,
  • optionally substituted heterocyclic group may be unsaturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), or containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), each of which is optionally substituted by lower alkyl, in which more preferable example may be pyridyl, imidazolyl and thiazolyl, each of which is optionally substituted by lower alkyl.
  • optionally substituted may be unsaturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), or containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), each of which is optionally substituted by lower alkyl, in which more preferable example may be pyridyl, imidazolyl and thiazolyl, each of which is optionally substituted by lower alkyl.
  • heterocyclic group thus defined may be pyridyl
  • imidazolyl and thiazolyl each of which is optionally substituted by lower alkyl, in which the most preferable one may be pyridin-2(or 3)-yl, 2-methylpyridin-3-yl, imidazol-1(or 2 or 4)-yl and 2-methylthiazol-4-yl.
  • Suitable "mono(or di) (lower)alkylcarbamoyl" moiety of “mono(or di)(lower)alkylcarbamoyloxy" may be the same as mentioned above, in which more preferable example of
  • mono(lower)alkylcarbamoyloxy and the most preferable one may be methylcarbamoyloxy and ethylcarbamoyloxy.
  • Suitable "lower alkylthio" may include straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio, hexylthio, and the like, in which more preferable example may be C 1 -C 4 alkylthio, and the most preferable one may be methylthio.
  • halo(lower)alkylthio means aforementioned lower alkylthio substituted by aforementioned halogen, in which more preferable example may be mono(or
  • di)halo(lower) alkylthio and the most preferable one may be difluoromethylthio.
  • Suitable "optionally substituted aryl” may include aforementioned aryl, which is optionally substituted by suitable group(s) as mentioned in the explanation of aforementioned heterocyclic group, in which more
  • preferable example may be halophenyl, and the most
  • preferable one may be 4-fluorophenyl.
  • Suitable "acyl” may be the same as those mentioned in the explanation of amino-protective group, in which more preferable example may be lower alkoxycarbonyl and the most preferable one may be ethoxycarbonyl.
  • R 3 may be :
  • hydroxy(lower)alkyl e.g. hydroxymethyl
  • hydroxy e.g. 3-hydroxyazetidin-1- ylcarbonylmethyl, etc.
  • ureido(lower)alkyl e.g. ureidomethyl, etc.
  • heterocyclic-carbonylamino(lower)alkyl wherein the heterocyclic moiety is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrimidyl,
  • dihydrotriazinyl and is optionally substituted by lower alkylthio (e.g. pyridin-3-ylcarbonylaminomethyl,
  • heterocyclicthio(lower) alkyl wherein the heterocyclic moiety is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrimidyl, pyrazinyl,
  • pyridazinyl triazolyl, tetrazolyl, dihydrotriazinyl, thiazolyl, 1,2-thiazolyl, thiazolinyl or thiadiazolyl, and is optionally substituted by lower alkyl [e.g.
  • pyrrolyl pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrimidyl, pyrazinyl,
  • pyridazinyl triazolyl, tetrazolyl, dihydrotriazinyl, thiazolyl, 1,2-thiazolyl, thiazolinyl or thiadiazolyl, and is optionally substituted by lower alkyl [e.g.
  • R 10 are as follows : R 1 is carboxy or protected carboxy (e.g. allyloxycarbonyl, etc.) R 2 is hydroxy(lower)alkyl (e.g. 1-hydroxyethyl, etc.) or protected hydroxy(lower)alkyl [e.g.
  • Z is a group of the formula :
  • R 3 is hydrogen, lower alkyl (e.g. methyl,
  • lower alkoxy(lower)alkyl e.g.
  • R 1 is carboxy, COO- or lower alkenyloxycarbonyl (e.g.
  • R 2 is hydroxy(lower)alkyl (e.g. 1-hydroxyethyl, etc.) or tri(lower)alkylsilyloxy(lower)alkyl [e.g.
  • R 8 is hydrogen or lower alkyl (e.g. methyl, etc.),
  • Z is a group of the formula :
  • R 3 is hydrogen
  • lower alkyl e.g. methyl, etc.
  • lower alkenyl e.g. vinyl, 2-butenyl, etc.
  • lower alkoxy(lower)alkyl e.g.
  • carbamoyl(lower)alkyl e.g. carbamoylmethyl, etc.
  • hydroxy(lower) alkyl e.g. hydroxymethyl, 2-hydroxyethyl, etc.
  • halo(lower)alkyl e.g. chloromethyl, etc.
  • mono(or di)(lower)alkylcarbamoyl(lower)alkyl e.g. methylcarbamoylmethyl
  • lower alkyleneaminocarbonyl(lower)alkyl preferably C 3 -C 6 alkyleneaminocarbonyl(lower)- alkyl optionally substituted by hydroxy (e.g. 3-hydroxyazetidin-1-ylcarbonylmethyl, etc.), lower alkanoylamino(lower)alkyl (e.g.
  • lower alkylsulfonylamino(lower)alkyl e.g. methylsulfonylaminomethyl, etc.
  • lower alkoxycarbonylamino(lower)alkyl e.g. methoxycarbonylaminomethyl, etc.
  • lower alkoxy(lower)alkanoylamino(lower)alkyl e.g. methoxyacetylaminomethyl, etc.
  • ureido(lower)alkyl e.g. ureidomethyl, etc.
  • pyridylcarbonylamino(lower)alkyl optionally substituted by lower alkylthio (e.g.
  • lower alkylthio(lower)alkyl e.g. methylthiomethyl, etc.
  • mono(or di)halo- (lower)alkylthio(lower)alkyl e.g.
  • tetrazolylthio(lower)alkyl or thiadiazolylthio(lower)alkyl each of which is optionally substituted by lower alkyl [e.g. (1-methyltetrazol-5-ylthio)methyl, imidazol-2-ylthiomethyl,
  • R 9 is hydrogen or lower alkyl (e.g. methyl, etc.), and
  • R 10 is lower alkyl (e.g. methyl, etc.).
  • Suitable "ar(lower)alkyl” means aforementioned lower alkyl, which is substituted by aryl as mentioned above, in which more preferable example may be phenyl(C 1 -C 4 )alkyl and the most preferable one may be benzyl.
  • the compound (I-e) or salts thereof can be prepared by reacting the compound (Il-a) or salts thereof with the compound (III) or salts thereof.
  • Suitable salts of the compounds (I-e) and (Il-a) may be the same as those for the compound (I).
  • Suitable salts of the compound (III) may be the same acid addition salts as those given for the compound (I).
  • This reaction is usually carried out in a
  • This reaction can be carried out in the presence of an organic or inorganic base such as those given in the explanation of Process 2.
  • the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
  • the compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to removal reaction of the carboxy-protective group on
  • 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. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.).
  • organic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • cation trapping agent e.g.
  • This reaction is usually carried out in a
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
  • the reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride,
  • chromous acetate, etc. an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), and the like.
  • a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate,
  • the reaction is preferably carried out around neutral
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • dioxane e.g. methanol, ethanol, propanol, etc.
  • acetic acid e.g. phosphate buffer, acetate buffer, etc.
  • buffer solution e.g. phosphate buffer, acetate buffer, etc.
  • the carboxy-protective group is allyl group, it can be deprotected by hydrogenolysis using a palladium compound.
  • Suitable palladium compound used in this reaction may be palladium on carbon, palladium hydroxide on carbon, palladium chloride, a palladium-ligand complex such as tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)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.),
  • 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
  • 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 conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc., or a mixture thereof.
  • the removal reaction can be selected according to the kind of carboxy-protective group to be removed.
  • the present process includes within the scope thereof a case that the hydroxy-protective group on R 2 and/or amino-protective group(s) of R 5 and/or R 6 are removed at the same time during the reaction.
  • the compound (I-d) or salts thereof can be prepared by subjecting the compound (I-c) or salts thereof to removal reaction of the hydroxy-protective group on
  • 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. tetrabutylammonium fluoride, etc.
  • the present process includes within the scope thereof a case that the carboxy-protective group on R 1 and/or amino-protective group(s) on R 5 and/or R 6 are removed at the same time during the reaction.
  • Process 4
  • the compound (I-f) or salts thereof can be prepared by reacting the compound (XI) or salts thereof with the compound (III) or salts thereof.
  • Suitable salts of the compound (I-f) may be the same as those for the compound (I).
  • Suitable salts of the compound (XI) may be the same as those for the compound (Il-a).
  • This reaction is usually carried out in a
  • This reaction can be carried out in the presence of an organic or inorganic base such as those given in the explanation of Process 2.
  • the compound (I-e) or salts thereof can be prepared by reacting the compound (XII) or salts thereof with a base.
  • Suitable salts of the compound (XII) may be the same as those for the compound (XI).
  • This reaction is usually carried out in a
  • This reaction can be carried out in the presence of an organic or inorganic base such as those given in the explanation of Process 2.
  • the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
  • the object compound (I) obtained according to the above Processes can be isolated and purified in a
  • the compound (VI) or salts thereof can be prepared by reacting the compound (IV) with the compound (V) or salts thereof.
  • Suitable salts of the compounds (V) and (VI) may be the same acid addition salts as those for the compound (I).
  • the compound (V) 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 alkali metal hydroxide (e.g. sodium bicarbonate), sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
  • 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
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • 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
  • a liquid base can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (VIII) or salts thereof can be prepared by reacting the compound (VI) or salts thereof with the compound (VII) or salts thereof.
  • Suitable salts of the compound (VIII) may be the same as those for the compound (I).
  • Suitable salts of the compound (VII) may be salts with bases such as those given for the compound (I).
  • Suitable example of the compound (VII) may be oxalyl halide, in which the carboxy group may be protected by a conventional carboxy-protective group as mentioned above.
  • This reaction can be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium
  • tri(lower)alkylamine e.g.
  • N,N-di(lower)alkylaminopyridine such as N,N-dimethylaminopyridine, etc.] quinoline, imidazole, N-lower alkylmorphorine (e.g. N-methylmorphorine, etc.), N-lower alkylpiperidine (e.g. N-ethylpiperidine, etc.), N,N-di(lower)alkylbenzylamine (e.g. N,N-dimethyl- benzylamine, etc.), and the like.
  • N-lower alkylmorphorine e.g. N-methylmorphorine, etc.
  • N-lower alkylpiperidine e.g. N-ethylpiperidine, etc.
  • N,N-di(lower)alkylbenzylamine e.g. N,N-dimethyl- benzylamine, etc.
  • This reaction is usually carried out in a
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (X) or salts thereof can be prepared by reacting the compound (VIII) or salts thereof with the compound (IX).
  • This reaction is usually carried out in a
  • N,N-dimethylformamide N,N-dimethylformamide, pyridine, benzene, toluene, xylene, etc., or a mixture thereof.
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under from warming to heating.
  • the compound (II) or salts thereof can be prepared by cyclizing the compound (X) or salts thereof.
  • Suitable salts of the compounds (X) and (II) may be the same as those for the compound (I).
  • This reaction is usually carried out in a
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under from warming to heating.
  • the compound (II-c) or salts thereof can be prepared by subjecting the compound (Il-b) or salts thereof to a removal reaction of the carboxy-protective group on
  • Suitable salts of the compound (Il-b) may be salts with acids such as those given for the compound (I).
  • Suitable salts of the compound (II-c) may be the same as those for the compound (II).
  • the present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the present process includes within the scope thereof a case that the hydroxy-protective group on R 2 and/or amino-protective group(s) on R 5 and/or R 6 is removed at the same time during the reaction.
  • the compound (Il-e) or salts thereof can be prepared by subjecting the compound (Il-d) or salts thereof to removal reaction of the hydroxy-protective group on
  • Suitable salts of the compounds (Il-d) and (Il-e) may be the same as those for the compound (II).
  • This reaction is usually carried out by a
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • tetra(lower)alkylammonium fluoride e.g. tetrabutylammonium fluoride, etc.
  • the present process includes within the scope thereof a case that the carboxy-protective group on R 1 and/or amino-protective group(s) on R 5 and/or R 6 are removed at the same time during the reaction.
  • the compound (Il-g) or salts thereof can be prepared by subjecting the compound (Il-f) or salts thereof to removal reaction of the amino-protective group(s) on
  • Suitable salts of the compounds (Il-f) and (Il-g) may be the same as those for the compound (II).
  • This reaction is usually carried out by a
  • the present process includes within the scope thereof a case that the carboxy- and/or hydroxy-protective
  • the compound (XIV) or salts thereof can be prepared by reacting the compound (IV) with the compound (XIII) or salts thereof.
  • Suitable salts of the compounds (XIII) and (XIV) may be the same acid addition salts as those for the compound (I).
  • the compound (XIII) 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 alkali metal hydroxide (e.g. sodium bicarbonate), sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
  • 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
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • Suitable enolizating agent may include tri(lower)alkylsilyl
  • tri(C 1 -C 4 )alkylsilyl trihalo(C 1 -C 4 )alkanesulfonate e.g. trimethylsilyl trifluoromethanesulfonate, etc.
  • tin compound such as stannous (lower)alkylsulfonate which may have halogen(s), preferably stannous
  • polyhalo(C 1 -C 4 )alkylsulfonate e.g. stannous
  • This reaction is usually carried out in a
  • a liquid base can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (XV) or salts thereof can be prepared by subjecting the compound (XlV-a) or salts thereof to removal reaction of the amino-protective group(s) on and/or
  • Suitable salts of the compounds (XlV-a) and (XV) may be the same as those for the compound (XIV).
  • This reaction is usually carried out by a
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the present process includes within the scope thereof a case that the carboxy- and/or hydroxy-protective group(s) on R 1 and/or R 2 are removed at the same time during the reaction.
  • the compound (VI-a) or salts thereof can be prepared by subjecting the compound (XV) or salts thereof to a reductive cleavage reaction.
  • Suitable salts of the compound (VI-a) may be the same as those for the compound (VI).
  • the method applicable for this reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and 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.
  • 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.
  • 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 compound (Vl-b) or salts thereof can be prepared by introducing an amino-protective group into the compound (Vl-a) or salts thereof.
  • Suitable salts of the compound (Vl-b) may be the same as those for the compound (VI-a).
  • Suitable introducing agent of the amino-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.
  • 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. sodium methoxide, sodium ethoxide, potassium
  • 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
  • alkali metal alkanoic acid e.g.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine
  • 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, ⁇ -chlorovinylethyl ether
  • 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 trichloride, 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
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
  • the compound (XII) or salts thereof can be prepared by reacting the compound (Il-a) or salts thereof with the compound (III) or salts thereof.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as tetrahydrofuran, dioxane, water, methanol,
  • buffer solution e.g. phosphate buffer, etc.
  • This reaction can be carried out in the presence of an organic or inorganic base such as those given in the explanation of Process 2.
  • the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
  • the compound (III) or salts thereof can be prepared by reacting the compound (XVI) or salts thereof with the compound (XVII).
  • Suitable salts of the compound (XVI) may be the same acid addition salts as those given for the compound (I).
  • This reaction is usually carried out in a
  • This reaction can be carried out in the presence of an organic or inorganic acid such as those given in the explanation of Process 2.
  • the reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming.
  • acceptable salts thereof of the present invention are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as antimicrobial agents.
  • in vitro Antimicrobial Activity 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.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution,
  • auxiliary substances such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be 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.
  • chloroformate was added dropwise to the solution, while the pH was kept constant at 8.0-8.5 by dropping 4N sodium hydroxide solution. After dropping, the reaction mixture was stirred until the pH became unchanged.
  • reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 40.8 g of 2-(N-allyloxycarbonylaminomethyl)-3-t- butyldimethylsilyloxybutan-1-ol.
  • N,N-dimethylformamide was added 1.73 g of sodium azide at 0°C.
  • the mixture was stirred at 50°C for 7 hours. After the starting material disappeared, 350 ml of ethyl acetate and 350 ml of water were added to the reaction mixture.
  • the organic layer was washed in turn with water three times and brine. The half amount of solvent was evaporated and then 5.11 g of triphenylphosphine was added thereto
  • dichloromethane was added. After stirring for 30 minutes, 2.43 ml of triethylamine was added to the mixture and then the temperature of the mixture was raised to room temperature. The mixture was extracted with chloroform and the organic layer was washed in turn with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate.
  • dichloromethane was added dropwise dimethyl sulfoxide (374 ml) while keeping the temperature below -50°C. After the mixture was stirred for 30 minutes at -50°C ⁇ -60°C,
  • 1,2-bis(benzyloxycarbonyl)-4-(1-hydroxyethyl)pyrazolidine (675 g) was added dropwise below -50°C. After the mixture was stirred for 45 minutes at -50°C ⁇ -60°C, triethylamine (122 ml) was added dropwise below -50°C. The reaction mixture was allowed to warm to 0°C and quenched with water (500 ml). The aqueous layer was separated and extracted twice with dichloromethane (200 ml x 2).
  • the pH was adjusted to 8.0 with 4N aqueous sodium hydaroxide in an ice-bath and allyl chloroformate (29 ml) was added keeping pH at 8.0-8.5. After stirring for an hour at pH 8.0-8.5, the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated under reduced
  • phosphite (595 ⁇ l)in xylene (11 ml) was heated at 90°C for 2 hours and then hydroquinone (64 mg) was added. The mixture was heated at 130°C ⁇ 135°C for 2 hours, cooled to room temperature, and then diluted with ethyl acetate.
  • 1,2-Bis(benzyloxycarbonyl)-4-(1-hydroxyethyl)- pyrazolidine 100 g was treated with activated charcoal at room temperatures for 30 minutes.
  • (2S,3R)-1-(N-Allyloxycarbonyl-N-methylamino)-2- allyloxycarbonylaminomethyl-3-t-butyldimethylsilyloxybutane (28.2 g) was obtained from (2R,3R)-2-(N-allyloxycarbonyl-N- methylaminomethyl)-3-t-butyldimethylsilyloxy-1- methanesulfonyloxybutane (59 g) in substantially the same method as those of Preparations 4 and 5.
  • N,N-dimethylformamide 600 ml. After stirring at the same temperature for 30 minutes, to the mixture were added n-hexane (2 I ), ethyl acetate (1 l), and water (5 I ) . The organic layer was separated, washed successively with water (1l x 3) and brine (1 l), and dried over magnesium sulfate. Removal of the solvents gave 1-(N-allyloxycarbonyl-N- methylamino)-2-(N-allyloxycarbonyl-N-methylaminomethyl)-3- (t-butyldimethylsilyloxy)butane (123 g).
  • triphenylphosphine 870 mg of dimedone, 0.089 ml of acetic acid and 143 mg of tetrakis(triphenylphosphine)palladium at room temperature under nitrogen.
  • the mixture was stirred at 30°C for a few minutes, and then stirring was continued at room temperature for 30 minutes. After a pale yellow precipitate was deposited, 2.2 ml of ethyl acetate was added. The precipitate was filtrated and washed with ethyl acetate and dichloromethane under nitrogen, and dissolved in pH 6.86 buffer solution. 399 mg of Benzyl formimidate hydrochloride was added to the solution at 0°C, while the pH was kept at 8.5. After stirring for 1.5 hours at pH 7.0, the reaction mixture was washed five times with 30% tetrahydrofuran in ethyl acetate while the pH was kept at pH 7. Purification was carried out by a column
  • triphenylphosphine (0.17 g) in a mixture of tetrahydrofuran (25 ml) and ethanol (8.3 ml) were added successively acetic acid (0.56 ml), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and tributyltin hydride (1.75 ml) at 30°C under nitrogen atmosphere. After stirring for 15 minutes, the resulting precipitates were collected by filtration, washed with ethyl acetate and dissolved in phosphate buffer (pH 6.86, 50 ml).

Landscapes

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

Abstract

Composés d'acide 1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique répondant à la formule (a), dans laquelle R1 représente carboxy, COO- ou carboxy protégé; R2 représente hydroxyalkyle(inférieur) ou hydroxyalkyle(inférieur) protégé; R8 représente hydrogène ou alkyle inférieur; Z représente un groupe répondant aux formules (b) ou (c), dans lesquelles R3 représente hydrogène; alkyle inférieur ou alcényle inférieur, dont chacun est éventuellement substitué par le groupe constitué d'alcoxy inférieur, carbamoyle, hydroxy, halogène, mono(ou di)alkylcarbamoyle(inférieur), mono(ou di) alcénylcarbamoyle(inférieur), mono(ou bis)[hydroxyalkyle(inférieur)]carbamoyle, aminocarbonyle cyclique éventuellement substitué, acylamino, uréido, carbonylamino hétérocyclique éventuellement substitué, carbamoyloxy, mono(ou di) alkylcarbamoyloxy(inférieur), alkylthio inférieur, haloalkylthio(inférieur), thio hétérocyclique éventuellement substitué, groupe hétérocyclique éventuellement substitué, aryle éventuellement substitué, et acyle; R9 représente hydrogène ou alkyle inférieur; et R10 représente alkyle inférieur. Ces composés ou leurs sels pharmaceutiquement acceptables sont utiles en tant qu'agents antimicrobiens.
PCT/JP1991/001394 1990-10-15 1991-10-14 Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique WO1992006978A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US07/853,746 US5286721A (en) 1990-10-15 1991-10-14 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909022309A GB9022309D0 (en) 1990-10-15 1990-10-15 1-azabicyclo(3.2.0.)hept-2-ene-2-carboxylic acid compounds
GB9022309.0 1990-10-15

Publications (1)

Publication Number Publication Date
WO1992006978A1 true WO1992006978A1 (fr) 1992-04-30

Family

ID=10683704

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/001394 WO1992006978A1 (fr) 1990-10-15 1991-10-14 Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique

Country Status (5)

Country Link
EP (1) EP0506982A1 (fr)
JP (1) JPH05502898A (fr)
AU (1) AU8660891A (fr)
GB (1) GB9022309D0 (fr)
WO (1) WO1992006978A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5319122A (en) * 1992-11-12 1994-06-07 Merck & Co., Inc. Process for the preparation of benzylformimidate
US7241776B2 (en) 2004-08-02 2007-07-10 Abbott Laboratories Cyanoamidine P2X7 antagonists for the treatment of pain

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
EP0111286A1 (fr) * 1982-12-10 1984-06-20 Sanraku Incorporated Dérivés du bêta-lactame et leur procédé de préparation
EP0184843A1 (fr) * 1984-12-13 1986-06-18 Merck & Co. Inc. Carbapénèmes et 1-méthylcarbapénèmes ayant un substituant mono ou bicyclo-hétéroarylalkyle quaternaire en position 2
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
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
EP0111286A1 (fr) * 1982-12-10 1984-06-20 Sanraku Incorporated Dérivés du bêta-lactame et leur procédé de préparation
EP0184843A1 (fr) * 1984-12-13 1986-06-18 Merck & Co. Inc. Carbapénèmes et 1-méthylcarbapénèmes ayant un substituant mono ou bicyclo-hétéroarylalkyle quaternaire en position 2
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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5319122A (en) * 1992-11-12 1994-06-07 Merck & Co., Inc. Process for the preparation of benzylformimidate
US7241776B2 (en) 2004-08-02 2007-07-10 Abbott Laboratories Cyanoamidine P2X7 antagonists for the treatment of pain

Also Published As

Publication number Publication date
AU8660891A (en) 1992-05-20
JPH05502898A (ja) 1993-05-20
EP0506982A1 (fr) 1992-10-07
GB9022309D0 (en) 1990-11-28

Similar Documents

Publication Publication Date Title
EP0343499B1 (fr) Dérivés de l'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ène-2-carboxylique
US4923857A (en) 3-Alkenyl-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid compounds
EP0272456B1 (fr) Dérivés d'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique et procédé de préparation
US4925838A (en) 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds
EP0394991B1 (fr) Composés de l'acide 1-azabicyclo(3.2.0)hept-2-ène-2-carboxylique
EP0272455B1 (fr) Dérivés de l'acide 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ène-2-carboxylique
FI83419B (fi) Foerfarande foer framstaellning av som laekemedel anvaendbara 1,2,6-substituerad karbapen-2-em-3-karboxylsyra.
EP0090366B1 (fr) Dérivés d'acide 1-azabicyclo(3.2.0)hept-2-ène-2-carboxylique, procédés pour leur préparation et compositions pharmaceutiques les contenant
US4536335A (en) Carbapenem antibiotics
US5215983A (en) Carbapenem compounds
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
WO1992006978A1 (fr) Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique
WO1992002521A1 (fr) Composes d'acide 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylique
US4983596A (en) 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid derivatives and their preparation
WO1993023402A1 (fr) Derives de 3-azetidinylthio-carbapeneme, preparation et utilisation de ces derives en tant qu'agents antimicrobiens
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
US5306816A (en) Processes for preparing carbapenem derivatives
US5202437A (en) 3-pyrrolidinylthio-1-azabicyclo(3.2.0)-hept-2-ene-2-carboxylic acid compounds
EP0722447A1 (fr) Derives de 3-pyrrolidinylthio-carbapenem et leur activite antimicrobienne
CA1263117A (fr) Carbapenemes, production et utilisation
JPH04321688A (ja) ２−（置換ピロリジニルチオ）カルバペネム誘導体
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
JPH0912577A (ja) カルバペネム化合物、その製造法および剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA FI HU JP KR NO SU 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

WWE Wipo information: entry into national phase

Ref document number: 1991919287

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1991919287

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1991919287

Country of ref document: EP