EP0665847A1 - Cephem compounds, and their pharmaceutical compositions - Google Patents

Cephem compounds, and their pharmaceutical compositions

Info

Publication number
EP0665847A1
EP0665847A1 EP93922658A EP93922658A EP0665847A1 EP 0665847 A1 EP0665847 A1 EP 0665847A1 EP 93922658 A EP93922658 A EP 93922658A EP 93922658 A EP93922658 A EP 93922658A EP 0665847 A1 EP0665847 A1 EP 0665847A1
Authority
EP
European Patent Office
Prior art keywords
cephem
vinyl
compound
pyridin
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP93922658A
Other languages
German (de)
French (fr)
Inventor
Kohji Kawabata
Takeshi Terasawa
Ayako Nakamura
Hideko Nakamura
Fumiyuki Shirai
Kazuo Sakane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB929222291A external-priority patent/GB9222291D0/en
Priority claimed from GB939314495A external-priority patent/GB9314495D0/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0665847A1 publication Critical patent/EP0665847A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—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, cefaclor, or cephalexine
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to new cephem compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • cephem compounds have been known as described, for example, in Japanese Kokai 62-36385.
  • the present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof , which have antimicrobial activities, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a method for treating infectious diseases in human being and animals.
  • one object of the present invention is to provide the cephem compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms.
  • Another object of the present invention is to provide processes for the preparation of the cephem compounds and salts thereof.
  • a further object of the present invention is to provide pharmaceutical composition comprising, as an active ingredient, said cephem compounds or their
  • Still further object of the present invention is to provide a method for treating infectious diseases caused by pathogenic microorganisms, which comprises
  • R 1 is amino or protected amino
  • R 2 is hydrogen, a hydroxy protective group
  • R 3 is carboxy or protected carboxy
  • R 4 is pyridylvinyl which may have suitable substituent(s),
  • R 3 is not carboxy
  • R 3 is not benzhydryloxycarbonyl.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 1 , R 2 , R 3 , and R 4 are each as defined above,
  • R 2 a is a hydroxy protective group and R 9 is ester moiety of esterified carboxy
  • the starting compound (II) can be prepared by the following processes.
  • R 3 , R 4 and R 9 are each as defined above,
  • R 3 a is protected carboxy
  • R 5 is ammo or protected amino
  • R 5 a is protected amino
  • R 6 is lower alkyl or aryl
  • R 7 is pyridyl which may have suitable
  • R 8 is lower alkyl
  • Y is a leaving group
  • syn isomer means one geometrical isomer having the partial structure represented by the following formula :
  • anti isomer means the other geometrical isomer having the partial structure represented by the following formula : (wherein R 1 and R 2 are each as defined above), and all of such geometrical isomers and mixture thereof are included within the scope of this invention.
  • the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atom(s), and all of such isomers and mixture thereof are included within the scope of this invention.
  • Suitable "lower alkyl” and “lower alkyl moiety" in the term “mono (or di or tri)halo(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 preferred one may be C 1 -C 4 alkyl and the most preferred one may be methyl, ethyl or propyl.
  • Suitable “protected amino” may include an acylamino or an amino group substituted by a conventional protecting group such as ar ( lower) alkyl which may have suitable substituent(s) [e.g. mono(or di or tri)phenyl(lower)alkyl (e.g. benzyl, trityl, etc.), etc.] or the like.
  • a conventional protecting group such as ar ( lower) alkyl which may have suitable substituent(s) [e.g. mono(or di or tri)phenyl(lower)alkyl (e.g. benzyl, trityl, etc.), etc.] or the like.
  • acyl moiety in the term “acylamino” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl,
  • benzenesulfonyl, tosyl, etc. aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl,
  • acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chlorine, bromine , iodine or fluorine ) or the like .
  • Suitable “protected carboxy” may include esterified carboxy and the like.
  • Suitable example of ester moiety of 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, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.);
  • lower alkoxyalkyl ester e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methox ⁇ ethyl ester, 1-ethoxyethyl ester, etc.
  • lower alkylthioalkyl ester e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.
  • mono(or di or tri)halo(lower)alkyl ester e.g.
  • alkanoyloxy( lower)alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
  • alkoxycarbonyloxy(lower)alkyl ester e.g.,
  • lower alkenyloxycarbonyloxy( lower)alkyl ester e.g., ethenyloxycarbonyloxymethyl ester, 1-(or
  • cycloalkylcarbonyloxy( lower)alkyl ester which may have lower alkyl (e.g., cyclopentylcarbonyloxymethyl ester, cyclohexylcarbonyloxymethyl ester,
  • cyclo( lower) alkyloxycarbonyloxy(lower)alkyl ester which may have one or two lower alkyl (e.g.,
  • cyclo( lower) alkyl(lower)alkcxycarbonyloxy( lower)alkyl ester e.g., 1-(or 2-) [cyclobutylmethoxycarbonyloxy]ethyl ester, 1-(or 2-) [cyclopentylmethoxycarbonyloxy]ethyl ester, 1-(or 2-) [cyclohexylmethoxycarbonyloxy]ethyl ester, 1-(or 2-)[[1-(or 2-)cyclobutylethoxy]carbonyloxy]ethyl ester, 1-(or 2-)[[1-(or 2-)cyclopentylethoxy]-carbonyloxy]ethyl ester, 1-(or 2-)[[1-(or 2-)[[1-(or 2-)[[1-(or 2-)cyclopentylethoxy]-carbonyloxy]ethyl ester, 1-(or 2-)[[1-(or 2-)[[1-(or 2-)[
  • lower alkanesulfonyl(lower)alkyl ester e.g. mesylmethyl ester, 2-mesylethyl ester/ etc.
  • ar( lower) alkyl ester for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3, 4-dimeth ⁇ xybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);
  • suitable substituent(s) e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3, 4-dimeth ⁇ xybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester,
  • substituent( s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,
  • Suitable "hydroxy protective group” may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more suitable substituent(s) [e.g., mono(or di or tri)phenyl (lower) alkyl (e.g., benzyl, trityl, etc.),
  • Suitable "aryl” may include phenyl, naphthyl and the like.
  • Suitable “leaving group” may include acid residue and the like .
  • Suitable "halogen moiety" in the term “mono(or di or tri)halo(lower)alkyl” may include fluorine, bromine, chlorine and iodine.
  • Suitable “acid residue” may include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), acyloxy [e.g., sulfonyloxy (e.g., benzenesulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
  • halogen e.g., fluorine, chlorine, bromine, iodine, etc.
  • acyloxy e.g., sulfonyloxy (e.g., benzenesulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.
  • Suitable "substituent” in the terms “pyridylvinyl which may have suitable substituent(s)” and “pyridyl which may have suitable substituent(s)” may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or
  • bromomethyl dibromomethyl, tribromomethyl, 1 or
  • phenyl ( lower) alkyl e.g., benzyl, phenethyl,
  • carboxy(lower)alkyl e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.
  • di(lower)alkylamino e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.
  • hydroxy(lower) alkyl protected hydroxy( lower) alkyl, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, echylrhio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.
  • lower alkylthio e.g., methylthio, echylrhio, propylthio, isopropylthio, butylthio, etc.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g.
  • trimethylamine salt triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt,
  • N,N'-dibenzylethylenediamine salt, etc. an organic acid salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate,
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group, or a salt thereof with the compound (III) or its reactive derivative at the carboxy group, or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a earbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide,
  • Suitable reactive derivative at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide;
  • a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid,
  • dibenzylphosphoric acid dibenzylphosphoric acid, halogenated phosphoric acid, etc.] dialkylphosphorous acid, sulfurous acid,
  • 1-hydroxy-1H-benzotriazole dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
  • phenylazophenyl ester phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-guinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydr ⁇ xylamine,
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivatives can optionally be selected from them according to the kind of the
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile,
  • a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,
  • trialkyl phosphite ethyl polyphosphate; isopropyl
  • oxalyl chloride lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.];
  • triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, diisopropylethylamine, etc.), pyridine,
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, diisopropylethylamine, etc.), pyridine,
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the hydroxy protective group.
  • Suitable method of this elimination reaction may include conventional one such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium,
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • the hydroxide or carbonate or bicarbonate thereof e.g. trimethylamine
  • Suitable acid may include an organic acid [e.g.
  • trihaloacetic acid e.g. trichloroacetic acid
  • trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethan ⁇ l, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • 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 cooling to warming.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid,
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black,
  • palladium oxide palladium on carbon
  • colloidal palladium palladium on barium sulfate
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. ieduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the present invention includes, within the scope of the invention, the case that the protected amino group in
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to esterification reaction..
  • reaction may include a conventional one such as an alcohol of the formula : HO-R 9 (IX) (wherein R 9 is as defined above) or its reactive equivalent (e.g., halide,
  • This reaction is usually carried out in the presence of a base.
  • Suitable base may include, for example, an inorganic 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 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 bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • alkaline earth metal hydroxide e.g., magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • alkaline earth metal carbonate e.g., magnesium carbonate, calcium carbonate, etc.
  • alkali metal bicarbonate e.g., sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal acetate e.g., sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphate e.g., magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as trialkylamine (e.g., trimethylamine,
  • This reaction is usually carried out in a solvent such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (VId) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not adversely affect the reaction.
  • solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene,
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium, potassium, etc.), sodium bicarbonate (e.
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri ( lower )alkylamine e.g.,
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal ( lower )alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine,
  • N,N-di(lower)alkylbenzylamine N,N-di(lower)alkylaniline or the like.
  • the base and/or the starting compound When the base and/or the starting compound are in liquid, they can be also used as a solvent.
  • the compound (II) or a salt thereof can be prepared by subjecting the compound (VIa) or a salt thereof to elimination reaction of the amino protective group.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (2), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (2).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the present invention includes, within the scope of the invention, the case that the protected carboxy group in R 3 is transformed into a carboxy group during this reaction.
  • the compound (VIc) or a salt thereof can be prepared by subjecting the compound (VIb) or a salt thereof to elimination reaction of the carboxy protective group.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (2), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (2).
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the present invention includes, within the scope of the invention, the case that the protected amino group in R is transformed into an amino group during this
  • the compound (VI) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (VIII) or a salt thereof.
  • This reaction can be carried out in the manner disclosed in Preparation 16 or similar manners thereto.
  • the compound (VIe) or a salt thereof can be prepared by subjecting the compound (VIc) or a salt thereof to esterification reaction.
  • This reaction can be carried out in a similar manner to that of the aforementioned Process (3), and therefore the reagent to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3) .
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1) ⁇ (3) and (A) ⁇ (E) can be referred to the ones as exemplified for the compound (I).
  • the object compound (I) and pharmaceutically acceptable salts thereof are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including
  • Gram-positive and Gram-negative microorganisms are useful as antimicrobial agents, especially oral
  • test data on MIC minimum inhibitory concentration
  • test data on urinary excretion of each representative compound of this invention are shown in the following.
  • Test compound One loopful of an overnight culture of each test strain in Trypticase-soy broth (10 viable cells per ml) was streaked on heart infusion agar (HI-agar)containing graded concentrations of test compound, and the minimal inhibitory concentration (MIC) was expressed in terms of yg/ml after incubation at 37°C for 20 hours.
  • Test compound :
  • Test compound was suspended in 0.5% methyl cellulose solution. The rats were starved overnight before dosing with 20 mg (*"free acid form of test compound” equivalent) /kg. Urine samples were collected at 0 to 6 and 6 to 24 hours after oral administration.
  • concentrations were measured by the disc-plate diffusion method using Bacillus subtilis ATCC 6633 as the test organism and sodium citrate agar (0.8% sodium citrate, 0.5% polypeptone, 0.3% beef extract and 1.0% agar) as the test medium.
  • the diluents of "free acid form of test compound" for the standard curves were prepared with 1/15 M phosphate buffer (pH 7.0). The plates were incubated at 37 °C for 18 hours and the zone of inhibition were
  • Test compound
  • the object compound (I) and 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.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
  • magnesium stearate magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, 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
  • an average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg of the object compound (I) of the present invention may be used in treating diseases
  • the object compound (I) wherein R 3 is esterified carboxy and a pharmaceutically acceptable salt thereof are useful as prodrug of the object compound (I) wherein R 3 is carboxy and a pharmaceutically acceptable salt thereof.
  • Preferred embodiments of the object compound (I) are as follows.
  • R 1 is amino, or protected amino [more preferably acylamino or mono(or di or tri)phenyl(lower)alkylamino]
  • R 2 is hydrogen, a hydroxy protective group [more
  • acyl more preferably lower alkanoyl] or phenyl (lower) alkyl which may have one or more suitable substituent(s) [more preferably mono(or di or tri)phenyl(lower)alkyl, most preferably trityl]], lower alkyl or mono(or di or tri)halo(lower) alkyl
  • R 3 is carboxy or esterified carboxy [more preferably
  • alkanoyloxy(lower)alkoxycarbonyl (more preferably
  • R 4 is pyridylvinyl which may have lower alkyl
  • R 3 is not carboxy
  • R 3 is not benzhydryloxycarbonyl.
  • 1,4-diazabicyclo[2,2,2]octane (1.29 g) was added dropwise propionaldehyde (12.47 ml). After stirring at room temperature for 2 weeks, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was distilled under vacuum to give n-hexyl
  • the precipitate containing 7 ⁇ -[2-(2-aminothiazol-4-yl)-2-acetoxyimino-acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) was collected by filtration, and dried in vacuo.
  • the precipitate was dissolved in 10% methanol aqueous solution (280 ml), and thereto was ammonium chloride (5.12 g) and the mixture was adjusted to pH 8 with a sodium carbonate aqueous solution. The solution was stirred at room temperature for 30 minutes maintaining pH 8 with a sodium carbonate aqueous solution.
  • the solution was adjusted to pH 6 with IN hydrochloric acid, and evaporated in vacuo to remove methanol.
  • the solution was subjected to column chromatography on HP-20 (Trademark : Mitsubishi Kasei Corporation) and eluted with 15% isopropyl alcohol aqueous solution.
  • Triethylamine (1.50 ml, 10.6 mmol) was added to a suspension of 7 ⁇ -amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid dihydrochloride (syn isomer) (1.00 g, 2.66 mmol) in tetrahydrofuran (20 ml).
  • Trimethylsilyl chloride (0.84 ml, 6.65 mmol) was added dropwise to the cold mixture (5°C) during a period of 5 minutes. The mixture was stirred for 30 minutes at room temperature and cooled again to ca. 5°C. To the mixture was added a solution of 1-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetyl]benz ⁇ triazole-3-oxide (syn isomer) (1.45 g, 2.66 mmol) in N,N-dimethylformamide (15 ml) over a period of 10 minutes. The mixture was stirred overnight at room temperature and concentrated under reduced
  • dichloromethane 150 ml were added triethylamine (5.02 ml) and phosphorus pentachloride (6.69 g) at 5°C. The mixture was stirred at 5°C for 1 hour. After a solution of 7 ⁇ -amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (10.9 g) in dichloromethane (218 ml) and bis(trimethylsilyl)acetamide (26.7 ml) was stirred at room temperature for 45 minutes, to the solution was added the activated solution obtained above. The mixture was stirred at 5°C for 2 hours, and then at room temperature for 15 hours.
  • the reaction mixture was poured into a mixture of ethyl acetate (600 ml), tetrahydrofuran (600 ml) and water (1.2 l). The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was
  • N,N-dimethylformamide (15 ml) was added cesium carbonate (255 mg) at 5°C. The mixture was stirred at 5°C for 15 minutes. To the mixture was added 1-bromoethyl pivalate (328 mg) . The mixture was stirred at 5°C for 7 hours.
  • Bondepak resin (Trademark : Waters Associates, Inc.) to afford 7 ⁇ -[2-(2-aminothiazol-4-yl)-2-difluoromethoxyimino-acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4- carboxylic acid (syn isomer) (748 mg).

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Abstract

New cephem compounds of formula (I), wherein R<1> is amino or protected amino, R<2> is hydrogen, a hydroxy protective group, lower alkyl or mono(or di or tri)halo(lower)alkyl, R<3> is carboxy or protected carboxy, and R<4> is pyridylvinyl which may have suitable substituent(s), with proviso that (i) when R<2> is hydrogen and R<4> is 3-pyridylvinyl, then R<3> is not carboxy, and (ii) when R<2> is tetrahydropyranyl and R<4> is 3-pyridylvinyl, then R<3> is not benzhydryloxycarbonyl, and pharmaceutical acceptable salts thereof which are useful as a medicament.

Description

DESCRIPTION CEPHEM COMPOUNDS, AND THEIR PHARMACEUTICAL COMPOSITIONS
TECHNICAL FIELD
This invention relates to new cephem compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some cephem compounds have been known as described, for example, in Japanese Kokai 62-36385.
DISCLOSURE OF INVENTION
The present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof , which have antimicrobial activities, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a method for treating infectious diseases in human being and animals.
Accordingly, one object of the present invention is to provide the cephem compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms.
Another object of the present invention is to provide processes for the preparation of the cephem compounds and salts thereof.
A further object of the present invention is to provide pharmaceutical composition comprising, as an active ingredient, said cephem compounds or their
pharmaceutically acceptable salts. Still further object of the present invention is to provide a method for treating infectious diseases caused by pathogenic microorganisms, which comprises
administering said cephem compounds to infected human being or animals.
The object cephem compounds of the present invention are novel and can be represented by the following general formula (I) :
wherein R1 is amino or protected amino,
R2 is hydrogen, a hydroxy protective group,
lower alkyl or mono ( or di or tri)halo(lower)alkyl,
R3 is carboxy or protected carboxy, and
R4 is pyridylvinyl which may have suitable substituent(s),
with proviso that
(i) when R2 is hydrogen and R4 is
3-pyridylvinyl, then
R3 is not carboxy, and
(ii) when R2 is tetrahydropyranyl and R4 is
3-pyridylvinyl, then
R3 is not benzhydryloxycarbonyl.
The object compound (I) of the present invention can be prepared by the following processes.
wherein R1, R2, R3, and R4 are each as defined above,
R2 a is a hydroxy protective group and R9 is ester moiety of esterified carboxy
represented by a group of the formula :
-COOR9.
The starting compound (II) can be prepared by the following processes.
wherein R3, R4 and R9 are each as defined above,
R3 a is protected carboxy,
R5 is ammo or protected amino,
R5 a is protected amino,
R6 is lower alkyl or aryl,
R7 is pyridyl which may have suitable
substituent(s),
R8 is lower alkyl,
X is acid residue and
Y is a leaving group.
Regarding the compounds (I), (Ia), (lb), (Ic), (Id) and (III), it is to be understood that said compounds include syn isomer, anti isomer and a mixture thereof.
For example, with regard to the object compound (I), syn isomer means one geometrical isomer having the partial structure represented by the following formula :
(wherein R1 and R2 are each as defined above), and anti isomer means the other geometrical isomer having the partial structure represented by the following formula : (wherein R1 and R2 are each as defined above), and all of such geometrical isomers and mixture thereof are included within the scope of this invention.
In the present specification and claim, the partial structure of these geometrical isomers and mixture thereof are represented for convenient sake by the following formula :
(wherein R1 and R2 are each as defined above)
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atom(s), and all of such isomers and mixture thereof are included within the scope of this invention.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.
Suitable "lower alkyl" and "lower alkyl moiety" in the term "mono (or di or tri)halo(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 preferred one may be C1-C4 alkyl and the most preferred one may be methyl, ethyl or propyl.
Suitable "protected amino" may include an acylamino or an amino group substituted by a conventional protecting group such as ar ( lower) alkyl which may have suitable substituent(s) [e.g. mono(or di or tri)phenyl(lower)alkyl (e.g. benzyl, trityl, etc.), etc.] or the like.
Suitable "acyl moiety" in the term "acylamino" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g.
benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl,
phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g.
benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like. The acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chlorine, bromine , iodine or fluorine ) or the like .
Suitable "protected carboxy" may include esterified carboxy and the like. Suitable example of ester moiety of 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, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.);
lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxγethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthioalkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g.
2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
alkanoyloxy( lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
valeryloxymethyl ester, pivaloyloxymethyl ester,
hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or
2-)valeryloxyethyl ester, 1-(or 2-)isovaleryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or 2-)-(3,3-dimethylbutyryloxy)ethyl ester, 1-(or 2-) [2- (or
3-)ethylbutyryloxy]ethyl ester, 1-(or 2-) [2- (or 3- or 4-)methylvaleryloxy]ethyl ester, 1-(or 2-)[2-(or 3- or 4-)propylvaleryloxy]ethyl ester, etc.);
alkoxycarbonyloxy(lower)alkyl ester (e.g.,
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)-[methoxycarbonyloxy]ethyl ester, 1-(or 2-)[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)[propoxycarbonyloxy]ethyl ester, 1-(or 2-)[isopropoxycarbonyloxy]ethyl ester, 1-(or
2-) [butoxycarbonyloxy]ethyl ester, 1-(or 2-)-[isobutoxycarbσnyloxy]ethyl ester, 1-(or 2-) [pentoxy- carbonyloxy]ethyl ester, 1-(or 2-) [isopentoxycarbonyloxy]- ethyl ester, 1-(or 2-)[1-(or 2-)ethylpropoxycarbonyloxy]- ethyl ester, 1-(or 2-) [neopentoxycarbonyloxy]ethyl ester, 1-(or 2-)[1-(or 2- or 3-)methylbutoxycarbonyloxy]ethyl ester, 1-(or 2- ) [hexyloxycarbonyloxy]ethyl ester, 1-(or 2-) [3,3-dimethylbutoxycarbonyloxy]ethyl ester, 1-(or 2-)[isohexyloxycarbonyloxy]ethyl ester, 1-(or 2- ) -[1-(or 2- or 3-)ethylbutoxycarbonyloxy]ethyl ester,
1-(or 2-)[1-(or 2- or 3-)propylbutoxycarbonyloxy]ethyl ester, etc.);
lower alkenyloxycarbonyloxy( lower)alkyl ester (e.g., ethenyloxycarbonyloxymethyl ester, 1-(or
2-)propenyloxycarbonyloxymethyl ester, 1-(or 2- or
3-)butenyloxycarbonyloxymethyl ester, 1-(or 2- or 3- or 4-)pentenyloxycarbonyloxymethyl ester, 1-(or
2-)ethenyloxycarbonyloxyethyl ester, 1-(or 2-)[1-(or
2-)propenyloxycarbonyloxy]ethyl ester, 1-(or 2-)[1-(or 2- or 3-)butenyloxycarbonyloxy]ethyl ester, 1-(or 2-)[1-(or
2- or 3- or 4-)pentenyloxycarbαnyloxy]ethyl ester, etc.); lower alkoxycarbonyl(lower)alkenyl ester [e.g., 1-(or 2- or 3-)methoxycarbonyl-1-(or 2-)propenyl ester, 1-(or 2- or 3-)ethoxycarbonyl-1-(or 2-)propenyl ester, 1-(or 2- or 3-)propoxycarbonyl-1- (or 2-)propenyl ester, 1-(or 2- or 3-)butoxycarbonyl-1-(or 2-)propenyl ester, 1-(or 2- or 3-)isobutoxycarbonyl-1-(or 2-)propenyl ester, 1-(or 2- or 3-)pentoxycarbonyl-1-( or 2-)propenyl ester, 1-(or 2- or
3-)isopentoxycarbonyl-1-(or 2-)propenyl ester, 1-(or 2- or 3-)hexyloxycarbonyl-1-(or 2-)propenyl ester, 1-(or 2- or
3- or 4-)methoxycarbonyl-1-(or 2- or 3-)butenyl ester, 1-(or 2- or 3- or 4-)ethoxycarbonyl-1-(or 2- or 3-)butenyl ester, 1-(or 2- or 3- or 4-)propoxycarbonyl-1- ( or 2- or 3-)butenyl ester, 1-(or 2- or 3- or
4-)butoxycarbonyl-1-(or 2- or 3-)butenyl ester, 1-(or 2- or 3- or 4-)isobutoxycarbonyl-1- ( or 2- or 3-)butenyl ester, 1-(or 2- or 3- or 4-)pentoxycarbonyl-1-(or 2- or 3-)butenyl ester, 1-(or 2- or 3- or
4-)isopentoxycarbonyl-1-(or 2- or 3-)butenyl ester, 1-(or 2- or 3- or 4-)hexyloxycarbonyl-1-(or 2- or 3-)butenyl ester, 1-(or 2- or 3- or 4- or 5-)methoxycarbonyl-1- (or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or
5-)ethoxycarbonyl-1-(or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or 5-)propoxycarbonyl-1- ( or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or
5-)butoxycarbonyl-1-(or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or 5-)isobutoxycarbonyl-1-(or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or
5-)pentoxycarbonyl-1-(or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or 5- )isopentoxycarbonyl-1- (or 2- or 3- or 4-)pentenyl ester, 1-(or 2- or 3- or 4- or
5-)hexyloxycarbonyl-1-(or 2- or 3- or 4-)pentenyl ester, etc.]; phthalidylidene( lower) alkyl ester;
( 5-(lower)alkyl-2-oxo-l,3-dioxol-4-yl) (lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-l,3-dioxol-4-yl)methyl ester,
(5-propyl-2-oxo-l,3-dioxol-4-yl)methyl ester, 1-(σr
2-) (5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-) (5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-) (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; cycloalkylcarbonyloxy(lower)alkyl ester which may have suitable substituent(s) [e.g.,
cycloalkylcarbonyloxy( lower)alkyl ester which may have lower alkyl (e.g., cyclopentylcarbonyloxymethyl ester, cyclohexylcarbonyloxymethyl ester,
cycloheptylcarbσnylσxymethyl ester,
1-methylcyclohexylcarbonyloxymethyl ester,
1-(or 2-) [cyclopentylcarbonyloxy]ethyl ester, 1-(or
2-) [cyclohexylcarbonyloxy]ethyl ester, 1-(or
2-) [cycloheptylcarbonyloxy]ethyl ester, etc.), etc.]; cyclo( lower)alkyloxycarbonyloxy( lower )alkyl ester which may have suitable substituent(s) [e.g.,
cyclo( lower) alkyloxycarbonyloxy(lower)alkyl ester which may have one or two lower alkyl (e.g.,
cyclopentyloxycarbonyloxymethyl ester,
cyclohexyloxycarbonylσxymethyl ester, 1-(or
2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or
2-)[cyclohexyloxycarbσnyloxy]ethyl ester, 1-(or 2-)[2-isopropyl-5-methylcyclohexyloxycarbonyloxy]ethyl ester, etc.), etc.];
cyclo( lower) alkyl(lower)alkcxycarbonyloxy( lower)alkyl ester (e.g., 1-(or 2-) [cyclobutylmethoxycarbonyloxy]ethyl ester, 1-(or 2-) [cyclopentylmethoxycarbonyloxy]ethyl ester, 1-(or 2-) [cyclohexylmethoxycarbonyloxy]ethyl ester, 1-(or 2-)[[1-(or 2-)cyclobutylethoxy]carbonyloxy]ethyl ester, 1-(or 2-)[[1-(or 2-)cyclopentylethoxy]-carbonyloxy]ethyl ester, 1-(or 2-)[[1-(or
2-)cyclohexylethoxy]carbonyloxy]ethyl ester, etc.);
lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester/ etc.);
ar( lower) alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3, 4-dimethσxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);
aryl ester which may have one or more suitable
substituent( s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,
4-chlorophenyl ester, 4-methoxyphenyl ester, etc.);
tri(lower)alkyl silyl ester; lower alkylthioester (e.g. methylthioester, ethylthiσester, etc.) and the like.
Suitable "hydroxy protective group" may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more suitable substituent(s) [e.g., mono(or di or tri)phenyl (lower) alkyl (e.g., benzyl, trityl, etc.),
4-methoxybenzyl, etc.], trisubstituted silyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.),
tetrahydropyranyl and the like.
Suitable "aryl" may include phenyl, naphthyl and the like.
Suitable "leaving group" may include acid residue and the like .
Suitable "halogen moiety" in the term "mono(or di or tri)halo(lower)alkyl" may include fluorine, bromine, chlorine and iodine.
Suitable "acid residue" may include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), acyloxy [e.g., sulfonyloxy (e.g., benzenesulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
Suitable "substituent" in the terms "pyridylvinyl which may have suitable substituent(s)" and "pyridyl which may have suitable substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl,
1-methylpropargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or tri)halo(lower)alkyl (e.g.,
fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl,
bromomethyl, dibromomethyl, tribromomethyl, 1 or
2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2, 2-difluoroethyl, etc.), halogen
(e.g., chlorine, bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc.), ar(lower)alkyl such as
phenyl ( lower) alkyl (e.g., benzyl, phenethyl,
phenylpropyl, etc.), carboxy(lower)alkyl, protected carboxy(lower) alkyl, nitro, amino, protected amino, di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.),
hydroxy(lower) alkyl, protected hydroxy( lower) alkyl, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, echylrhio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g.
trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, etc.], an organic acid salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate,
p-toluenesulfonate, etc.], an inorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], and. the like.
The processes for preparing the object and starting compounds of the present invention are explained in detail in the following.
Process (1)
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group, or a salt thereof with the compound (III) or its reactive derivative at the carboxy group, or a salt thereof.
Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a earbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide,
mono(trimethylsilyl)acetamide [e.g. N-(trimethylsilyl)-acetamide], bis(trimethylsilyl)urea or the like;
a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide;
a mixed acid anhydride with an acid such as 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, sulfonic acid [e.g.
methanesulfonic acid, etc.], aliphatic carboxylic acid
[e.g. acetic acid, propionic acid, butyric acid,
isobutyric acid, pivalic acid, pentanoic acid,
isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substitued imidazole,
1-hydroxy-1H-benzotriazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
pentachlorophenyl ester, mesylphenyl ester,
phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-guinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydrσxylamine,
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the
compound (III) to be used.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound (III) is used in a free acid form or its salt form, the reaction is
preferably carried out in the presence of a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,
N,N'-carbonyl-bis(2-methylimidazole); pentamethylene-ketene-N-cyclohexylimine, diphenylketnne-N-cyclohexyl¬imine; ethoxyacetylene; 1-alkoxy-1-chloroethylene;
trialkyl phosphite; ethyl polyphosphate; isopropyl
polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; thionyl chloride;
oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.];
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyDisoxazolium hydroxide
intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, diisopropylethylamine, etc.), pyridine,
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
Process (2)
The compound (lb) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the hydroxy protective group.
Suitable method of this elimination reaction may include conventional one such as hydrolysis, reduction and the like.
(i) For Hydrolysis :
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium,
potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine,
triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g.
formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, ammonium chloride, etc.]. The elimination using Lewis acid such as
trihaloacetic acid [e.g. trichloroacetic acid,
trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents
[e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanσl, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. 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 cooling to warming. (ii) For reduction :
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid,
trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black,
palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium
carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. ieduced copper, Raney copper, Ullman copper, etc.) and the like. The reduction is usually carried out in a
conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the
above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The present invention includes, within the scope of the invention, the case that the protected amino group in
RR iiss ttrra.nsformed into an amino group during this
reaction.
Process (3)
The compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to esterification reaction..
Suitable esterifying agent to be used in this
reaction may include a conventional one such as an alcohol of the formula : HO-R9 (IX) (wherein R9 is as defined above) or its reactive equivalent (e.g., halide,
sulfonate, sulfate, diazo compound, etc.) or a salt thereof, or the like.
This reaction is usually carried out in the presence of a base.
Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g., sodium
hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g., sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.) or the like, and an organic base such as trialkylamine (e.g., trimethylamine,
triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene,
1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[5.4.0]-undecene-5 or the like.
This reaction is usually carried out in a solvent such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,
chloroform or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The compound (IX) or its reactive equivalent, or a salt thereof can be prepared in the manner disclosed in Preparations, similar manners thereto or a conventional manner. Process (A)
The compound (VId) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not adversely affect the reaction. These conventional solvent may also be used in a mixture with water. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri ( lower )alkylamine (e.g.,
trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal ( lower )alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine,
N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
When the base and/or the starting compound are in liquid, they can be also used as a solvent.
Process (B)
The compound (II) or a salt thereof can be prepared by subjecting the compound (VIa) or a salt thereof to elimination reaction of the amino protective group.
This reaction can be carried out in a similar manner to that of the aforementioned Process (2), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (2).
The present invention includes, within the scope of the invention, the case that the protected carboxy group in R3 is transformed into a carboxy group during this reaction. Process ( C )
The compound (VIc) or a salt thereof can be prepared by subjecting the compound (VIb) or a salt thereof to elimination reaction of the carboxy protective group.
This reaction can be carried out in a similar manner to that of the aforementioned Process (2), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (2).
The present invention includes, within the scope of the invention, the case that the protected amino group in R is transformed into an amino group during this
reaction. Process (D)
The compound (VI) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (VIII) or a salt thereof.
This reaction can be carried out in the manner disclosed in Preparation 16 or similar manners thereto.
Process (E)
The compound (VIe) or a salt thereof can be prepared by subjecting the compound (VIc) or a salt thereof to esterification reaction.
This reaction can be carried out in a similar manner to that of the aforementioned Process (3), and therefore the reagent to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3) .
Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1) ~ (3) and (A) ~ (E) can be referred to the ones as exemplified for the compound (I).
The object compound (I) and pharmaceutically acceptable salts thereof 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, especially oral
antimicrobial agents.
Now in order to show the utility of the object compound (I), the test data on MIC (minimal inhibitory concentration) and the test data on urinary excretion of each representative compound of this invention are shown in the following.
(A) Minimal inhibitory concentration Test method :
In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (10 viable cells per ml) was streaked on heart infusion agar (HI-agar)containing graded concentrations of test compound, and the minimal inhibitory concentration (MIC) was expressed in terms of yg/ml after incubation at 37°C for 20 hours. Test compound :
(1) 7β-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-[(E)-2-(pyridin-4-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer)
(B) Urinary excretion
Test method :
Male JCL SD strain rats (age, 6-7 weeks) were used. Test compound was suspended in 0.5% methyl cellulose solution. The rats were starved overnight before dosing with 20 mg (*"free acid form of test compound" equivalent) /kg. Urine samples were collected at 0 to 6 and 6 to 24 hours after oral administration. Antibiotic
concentrations were measured by the disc-plate diffusion method using Bacillus subtilis ATCC 6633 as the test organism and sodium citrate agar (0.8% sodium citrate, 0.5% polypeptone, 0.3% beef extract and 1.0% agar) as the test medium. The diluents of "free acid form of test compound" for the standard curves were prepared with 1/15 M phosphate buffer (pH 7.0). The plates were incubated at 37 °C for 18 hours and the zone of inhibition were
measured. Test compound :
( 2) 1-(Cyclohexyloxycarbonyloxy)ethyl
7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate dihydrochloride (syn isomer)
7β-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
For therapeutic administration, the object compound (I) and pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
The pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
In needed, there may be included in the above
preparations, auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid,
magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
While 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, amounts 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 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg of the object compound (I) of the present invention may be used in treating diseases
infected by pathogenic microorganisms. Especially, the object compound (I) wherein R3 is esterified carboxy and a pharmaceutically acceptable salt thereof are useful as prodrug of the object compound (I) wherein R3 is carboxy and a pharmaceutically acceptable salt thereof. Preferred embodiments of the object compound (I) are as follows.
R1 is amino, or protected amino [more preferably acylamino or mono(or di or tri)phenyl(lower)alkylamino], R2 is hydrogen, a hydroxy protective group [more
preferably acyl [more preferably lower alkanoyl] or phenyl (lower) alkyl which may have one or more suitable substituent(s) [more preferably mono(or di or tri)phenyl(lower)alkyl, most preferably trityl]], lower alkyl or mono(or di or tri)halo(lower) alkyl, R3 is carboxy or esterified carboxy [more preferably
alkanoyloxy(lower)alkoxycarbonyl (more preferably
C1-C8 alkanoyloxy(lower)alkoxycarbonyl),
alkoxycarbonyloxy(lower)alkoxycarbonyl (more
preferably C1-C7 alkoxycarbonyloxy(lower)- alkoxycarbonyl), cycloalkylcarbonyloxy(lower)- alkoxycarbonyl which may have suitable
substituent(s) (more preferably
cyclo(C1-C8)alkylcarbonyloxy(lower)alkoxycarbonyl which may have lower alkyl),
cyclo(lower) alkyloxycarbonyloxy(lower)- alkoxycarbonyl which may have suitable
substituent(s) (more preferably cyclo(lower)- alkyloxycarbonyloxy(lower)alkoxycarbonyl
which may have one or two lower alkyl),
cyclo(lower)alkyl(lower)alkoxycarbonyloxy(lower)- alkoxycarbonyl, lower alkoxycarbonyl(lower)- alkenyloxycarbonyl, lower alkenyloxycarbonyloxy- (lower)alkoxycarbonyl or (5-(lower)alkyl-2-oxo-l,3- dioxol-4-yl)(lower)alkoxycarbonyl] and
R4 is pyridylvinyl which may have lower alkyl,
with proviso that
(i) when R2 is hydrogen and R4 is 3-pyridylvinyl, then
R3 is not carboxy, and
(ii) when R2 is tetrahydropyranyl and R4 is
3-pyridylvinyl, then
R3 is not benzhydryloxycarbonyl. The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.. Preparation 1
To a mixture of diphenylmethyl 7β-tert-butoxycarbonylamino-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate iodide (100 g), methylene chloride (1000 ml) and saturated sodium chloride (170 ml) was added 1N sodium hydroxide solution (173 ml) with stirring at room
temperature. After the mixture was stirred at the same temperature for 45 minutes, the separated organic layer was washed with brine, dried over magnesium sulfate. To this organic layer was added 3-pyridinecarbaldehyde (24.6 g) at room temperature, and the mixture was stirred at the same temperature for 20 hours. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel to give diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (21.03 g) (Compound A) and diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( 7.81 g) ( Compound B).
Compound A
IR (Nujol) : 1765, 1700 cm-1
NMR (DMSO-d6, δ) : 1.41 (9H, s), 3.30 and 3.56 (2H, ABq, J=17.5Hz), 5.21 (1H, d, J=4.8Hz), 5.56 (1H, dd, J=8.3Hz, 4.8Hz), 6.49 (1H, d, J=12.2Hz), 6.55 (1H, d, J=12.2Hz), 6.79 (1H, s), 7.27-7.65 (12H, m), 8.08 (1H, d, J=8.3Hz), 8.38 (1H, m),
8.43 (1H, m)
Compound B
IR (Nujol) : 1770, 1700 cm-1
NMR (DMSO-d6, 6) : 1.42 (9H, s), 3.75 and 4.05 (2H, ABq, J=17.5Hz), 5.21 (1H, d, J=4.8Hz), 5.58 (1H, dd, J=8.8Hz, 4.8Hz), 7.12 (1H, s), 7.18 (1H, d, J=16.2Hz), 7.27-7.58 (13H, m), 8.12 (1H, d, J=8.8Hz), 8.45 (2H, m)
Preparation 2
The following compounds were obtained according to a similar manner to that of Preparation 1. Diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(Z)-2-(pyridin-4-yl)vinyl]-3-cephem-4-carboxylate (Compound A) and
Diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E)-2-(pyridin-4-yl)vinyl]-3-cephem-4-carboxylate (Compound B)
Compound A :
IR (Nujol) : 1770, 1720, 1695 cm-1
NMR (DMSO-d6, δ) : 1.41 (9H, s), 3.28 and 3.59 (2H, ABq, J=17.9Hz), 5.23 (1H, d, J=4.8Hz ), 5.58 (1H, dd, J=4.8Hz, 9.0Hz), 6.46 (1H, d, J=12.1Hz),
6.60 (1H, d, J=12.1Hz), 6.80 (1H, s), 7.11-7.50 (12H, m), 8.07 (1H, d, J=9.0Hz), 8.48 (2H, m)
Compound B :
IR (Nujol) : 1775, 1705 cm-1
NMR (DMSO-d6, δ) : 1.42 (9H, s), 3.74 and 4.05 (2H, ABq, J=17.6Hz), 5.22 (1H, d, J=4.9Hz), 5.60 (1H, dd, J=8Hz, 9Hz), 7.01 (1H, d, J=16.6Hz), 7.04 (2H, m), 7.08 (1H, s), 7.25-7.67 (11H, m), 8.13 (1H, d, J=8.9Hz), 8.46 (2H, m)
Preparation 3
To a solution of diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (70.8 g) in formic acid (280 ml) was added dropwise cone, hydrochloric acid (54.8 ml) at room
temperature. After being stirred at room temperature for 2 hours, the mixture was added dropwise to a mixture of acetone (2.1 ℓ) and ethyl acetate (4.2 ℓ) under
ice-cooling. The resulting precipitate was collected by filtration to give 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid dihydrochloride (34.27 g).
IR (Nujol) : 1760, 1700 cm-1
NMR (DMSO-d6, δ) : 3.54 and 3.67 (2H, ABq,
J=17.3Hz), 5.17 (1H, d, J=5.0Hz), 5.36 (1H, d,
J=5.0Hz), 6.78 (2H, s), 7.93 (1H, m), 8.34 (1H, m), 8.77 (1H, m), 8.83 (1H, m)
Preparation 4
The following compound was obtained according to a similar manner to that of Preparation 3.
7β-Amino-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid dihydrochloride
IR (Nujol) : 1760, 1695 cm-1
NMR (DMSO-d6, δ) : 3.86 and 4.13 (2H, ABq,
J=17.2Hz), 5.18 (1H, d, J=5.2Hz), 5.24 (1H, d, J=5.2Hz), 7.30 (1H, d, J=16.5Hz), 7.72 (1H, d, J=l6.5Hz), 7.99 (1H, m), 8.57 (1H, m), 8.77 (1H, m), 8.99 (1H, m)
Preparation 5
To a solution of diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E)-2-(pyridin-4-yl)vinyl]-3-cephem-4yearboxylate (1.6 g) in methylene chloride (4.8 ml) and anisole (1.6 ml) was added trifluoroacetic acid (3.2 ml) under ice-cooling. After being stirred at room temperature for 2 hours, the mixture was poured into diisopropyl ether. The resulting precipitate was
collected by filtration to give 7β-amino-3-[(E)-2- (pyridin-4-yl)vinyl]-3-cephem-4-carboxylic acid
bis(trifluoroacetate) (1.49 g).
IR (Nujol) : 1780, 1660, 1600 cm-1
NMR (DMSO-d6, δ) : 3.86 and 4.15 (2H, ABq,
J=17.5Hz), 5.27 (1H, d, J=5.2Hz), 5.34 (1H, d,
J=5.2Hz), 7.09 (1H, d, J=16.6Hz), 7.27 (1H, d, J=16.6Hz), 7.78 (2H, d, J=6.4Hz), 8.73 (2H, d, J=6.4Hz) Preparation 6
To a solution of 3-pentanol (1.76 g) in
dichloromethane (18 ml) were added pyridine (1.62 ml) and 1-chloroethyl chloroformate (2.16 ml) at 5°C. The mixture was stirred at 5°C for 30 minutes and then at room
temperature for 3.5 hours. The reaction mixture was diluted with dichloromethane, washed with water, with IN hydrochloric acid, with aqueous sodium hydrogencarbonate solution and with brine, dried over magnesium sulfate, and evaporated in vacuo to give 1-chloroethyl 1-ethylpropyl carbonate (3.66 g) .
IR (Film) : 1750 cm-1
NMR (CDCl3, δ) : 0.93 and 0.94 (total 6H, t, J=7Hz), 1.5-1.7 (4H, m), 1.84 (3H, t, J=6Hz), 4.66 (1H, p, J=6Hz), 6.44 (1H, q, J=6Hz)
Preparation 7
The following compounds were obtained according to a similar manner to that of Preparation 6. (l) 1-Chloroethyl [(1R,2S,5R)-2-isopropyl-5- methylcyclohexyl]carbonate
IR (Film) : 1740 cm-1
NMR (CDCl3, δ) : 0.8-1.2 (11H, m), 1.3-2.2 (6H, m), 1.83 (3H, d, J=6Hz), 4.59 (1H, m), 6.43 (1H, g, J=6Hz) (2) 1-Chloroethyl 4-methylpentyl carbonate
IR (Film) : 1745 cm-1
NMR (CHCl3, δ) : 0.90 (6H, d, J=7Hz), 1.1-1.3 (2H, m), 1.4-1.8 (3H, m), 1.84 (3H, d, J=6Hz), 4.19 (2H, t, J=7Hz), 6.43 (1H, q, J=6Hz)
Preparation 8
To a solution of 1-chloroethyl 1-ethylpropyl
carbonate (3.60 g) in benzene (16.2 ml) were added
tetrabutylammonium bromide (119 mg) and
trimethylbromosilane (3.67 ml). The mixture was stirred at 80°C for 23 hours. After cooling to the room
temperature, the reaction mixture was evaporated in vacuo. The residue was dissolved in dichloromethane. The
solution was washed with water and with brine, dried over magnesium sulfate, and evaporated in vacuo to give
1-bromoethyl 1-ethylpropyl carbonate (3.42 g).
IR (Film) : 1745 cm-1
NMR ( CHCl3, δ) : 0.93 and 0.94 (total 6H, t, J=7Hz), 1.5-1.7 (4H, m), 2.04 (3H, d, J=6Hz), 4.67 (1H, p, J=6Hz), 6.62 (1H, q, J=6Hz)
Preparation 9
The following compounds were obtained according to a similar manner to that of Preparation 8.
(1) 1-Bromoethyl 3,3-dimethylbutyrate
IR (Film) : 1750 cm-1
NMR ( CHCl3, δ) : 1.06 (9H, s), 1.99 (3H, d, J=6Hz), 2.24 (2H, s), 6.72 (1H, q, J=6Hz)
(2) 1-Bromoethyl [(1R,2S,5R)-2-isopropyl-5- methylcyclohexyl]carbonate
IR (Film) : 1745 cm-1
NMR (CHCl3, δ) : 0.7-1.1 (11H, m), 1.4-2.2 (6H, m), 2 . 03 ( 3H, d, J=6Hz ) , 4 . 60 (1H, m) , 6 . 62 (1H, q, J=6Hz )
(3) 1-Bromoethyl 4-methylpentyl carbonate
IR (Film) : 1745 cm-1
NMR (CHCl3, δ) : 0.90 (6H, d, J=7Hz), 1.1-1.3 (2H, m), 1.4-1.8 (3H, m), 2.03 (3H, d, J=6Hz), 4.20 (2H, t, J=7Hz), 6.61 (1H, q, J=6Hz) Preparation 10
To a mixture of n-hexyl acrylate (18 g) and
1,4-diazabicyclo[2,2,2]octane (1.29 g) was added dropwise propionaldehyde (12.47 ml). After stirring at room temperature for 2 weeks, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was distilled under vacuum to give n-hexyl
2-(1-hydroxypropyl)-2-propenoate (10.38 g).
IR (Neat) : 3400, 1695 cm-1
NMR (DMSO-d6, δ) : 0.80-0.90 ( 6H, m), 1.28-1.36 (8H, m), 1.51-1.71 (2H, m), 4.09 (2H, t, J=6.3Hz), 4.25-4.33 (1H, m), 4.95 (1H, d, J=5.1Hz), 5.82 (1H, m), 6.09 (1H, m) Preparation 11
The following compounds were obtained according to a similar manner to that of Preparation 10.
(1) n-Butyl 2-(1-hydroxypropyl)-2-propenoate
IR (Neat) : 3400, 2920, 1700 cm-1
NMR (DMSO-d6, δ) : 0.69-0.93 (6H, m), 1.23-1.34 (3H, m), 1.51-1.71 (3H, m), 4.10 (2H, t, J=6.4Hz), 4.24-4.33 (1H, m), 4.96 (1H, d, J=5.0Hz),
5.81-5.83 (1H, m), 6.09-6.10 (1H, m) (2) 3-Methylbutyl 2-(1-hydroxypropyl)-2-propenoate
IR (Neat) : 2930, 1710 cm-1
NMR (DMSO-d6, δ) : 0.82 (3H, t, J=7.4Hz), 0.89 (6H, d, J=6.4Hz), 1.17-1.73 (5H, m), 4.13 (2H, t, J=6.7Hz), 4.25-4.33 (1H, m), 4.96 (1H, d,
J=5.1Hz), 5.82-5.83 (1H, m), 6.09 (1H, m)
(3) 3-Methylbutyl 2-(1-hydroxyethyl)-2-propenoate
IR (Neat) : 3350, 2900, 1690 cm-1
NMR (DMSO-d6, δ) : 0.90 (6H, d, J=6.4Hz), 1.18 (3H, d, J=6.4Hz), 1.46-1.74 (3H, m), 4.17 (2H, t, J=5.4Hz), 4.43-4.48 (1H, m), 5.03 (1H, d,
J=4.8Hz), 5.84-5.86 (1H, m), 6.05-6.06 (1H, m) Preparation 12
To a n-hexyl 2-(1-hydroxypropyl)-2-propenoate (6 g) was dropwise added 47% hydrobromic acid (8.21 ml) under ice-cooling. After a few minutes, cone, sulfuric acid (8.05 ml) was added thereto dropwise and the reaction mixture was allowed to reach room temperature. After stirring at ambient temperature overnight, the resulting reaction mixture was transferred into a separatory funnel, the lower layer was discarded and the upper layer was extracted twice with ether. The combined ether extracts were washed with saturated sodium bicarbonate solution, water and brine, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (Z)-2-(n-hexyloxycarbonyl)-2-pentenylbromide (4.05 g).
IR (Neat) : 2910, 1700, 1635 cm-1
NMR (CHCl3, δ) : 0.90 (3H, t, J=6.4Hz), 1.13 (3H, t,
J=7.5Hz), 1.34 (6H, m), 1.66-1.73 (2H, m),
2.24-2.39 (2H, m), 4.15-4.19 (2H, m), 4.23 (2H, s), 6.95 (1H, t, J=7.7Hz) Preparation 13
The following compounds were obtained according to a similar manner to that of Preparation 12. (1) (Z)-2-(n-Butoxycarbonyl)-2-pentenylbromide
IR (Neat) : 1700 cm-1
NMR (CHCl3, δ) : 0.96 (3H, t, J=7.2Hz), 1.13 (3H, t, J=7,5Hz), 1.34-1.49 (2H, m), 1.62-1.76 (2H, m), 2.24-2.39 (2H, m), 4.17-4.22 (2H, m), 4.23 (2H, s), 6.95 (1H, t, J=7.7Hz)
( 2 ) (Z)-2-(3-Methylbutyloxycarbonyl)-2-pentenylbromide IR (Neat) : 2910, 1700, 1630 cm-1
NMR (CHCl3, δ) : 0.95 (6H, d, J=6.4Hz), 1.13 (3H, t, J=7.5Hz), 1.55-1.81 (3H, m), 2.27-2.36 (2H, m),
4.19-4.26 (4H, m), 6.95 (1H, t, J=7.6Hz)
( 3 ) (Z)-2-(3-Methylbutyloxycarbonyl)-2-butenylbromide
IR (Neat) : 2920, 1700, 1635 cm-1
NMR (CDCl3, δ) : 0.94 (6H, d, J=6.4Hz), 1.54-1.81
(3H, m), 1.92 (3H, d, J=7.3Hz), 4.19-4.26 (4H, m), 7.06 (1H, q, J=7.3Hz)
Preparation 14
To 3,3-dimethylbutyryl chloride (24.225 g) was added dropwise paraldehyde (7.928 g). To the mixture was added zinc chloride (25 mg). The mixture was stirred at 90°C for 5 hours. The reaction mixture was distilled to give 1-chloroethyl 3,3-dimethylbutyrate (15.49 g) (55-57°C/14 mmHg).
NMR (CHCl3, δ) : 1.05 (9H, s), 1.79 (3H, d, J=6Hz), 2.24 (2H, s), 6.55 (1H, q, J=6Hz )
Preparation 15
To a solution of 3-ethynylpyridine (30.94 g) in benzene (300 ml) was 2,2'-azobisisobutylnitrile (493 mg) under reflux and to the mixture was added dropwise tributyltin hydride (87.32 g) over 50 minutes under nitrogen. The mixture was refluxed for 1 hour and evaporated in vacuo. The residue was chromatographed on silica gel to give 3-[(E)-2-tributylstannylvmyl]pyridine (55.91 g) as an oil.
IR (Film) : 2900, 1730, 1580 cm-1
NMR (CHCl3, δ) : 0.8-1.6 (27H, m), 6.85 (1H, d,
J=19.6Hz), 6.99 (1H, d, J=19.6Hz), 7.2-7.3 (1H, m), 7.7-7.8 (1H, m), 8.4-8.5 (1H, m), 8.6-8.65 (1H, m)
Preparation 16
To a cooled solution of diphenylmethyl
7β-formamido-3-methylsulfonyloxy-3-cephem-4-earboxylate (69.29 g) in N,N-dimethylformamide (690 ml) was added 3-[(E)-2-tributylstannylvinyl]pyridine (55.19 g) and lithium bromide (24.67 g) at 5°C. The mixture was degassed by nitrogen for 5 minutes. To the mixture was added bis( acetnitrile)palladium( II) chloride (737 mg) and the mixture was stirred at 5°C for 30 minutes and at room temperature for 20 hours. The mixture was poured into ice-water (4.5 ℓ) and the precipitates were collected by filtration and washed with cold water. The precipitates were dissolved in tetrahydrofuran and to the solution was added a mixture of ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was
dissolved in acetnitrile (300 ml) and the solution was washed with hexane (300 ml) twice. The acetnitrile layer was evaporated in vacuo and the residue was
chromatographed on silica gel to give diphenylmethyl 7β-formamido-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (54.89 g) . IR (Nujol) : 3200, 1760, 1670 cm-1
NMR (DMSO-d6, δ) : 3.79 and 4.10 (2H, ABq,
J=17.6Hz), 5.28 (1H, t, J=4.9Hz ), 5.89 (1H, dd, J=8.9 and 4.9Hz), 7.07 (1H, s), 7.16 (1H, d, J=16.3Hz), 7.3-7.5 (13H, m), 8.19 (1H, s),
8.45-8.55 (2H, m), 9.19 (1H, d, J=8.9Hz)
Preparation 17
To a solution of diphenylmethyl 7β-formamido-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (54.8 g) in methanol (550 ml) was added dropwise cone, hydrochloric acid (91.7 ml) at 5°C and the mixture was stirred at room temperature for 4 hours. The mixture was poured into a mixture of ethyl acetate ( 2 ℓ) and ice water ( 1 ℓ) and adjusted to pH 7 by addition of 5N aqueous sodium
hydroxide solution. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added ethyl acetate and the crystalline solid was collected by
filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo to give diphenylmethyl
7β-amino-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (22.56 g).
IR (Nujol) : 1750, 1700 cm-1
NMR (DMSO-d6, δ) : 2.43 (2H, br s), 3.71 and 4.04
(2H, ABq, J=17.7Hz), 4.88 (1H, d, J=5.1Hz), 5.12 (1H, d, J=5.1Hz), 7.01 (1H, d, J=15.6Hz), 7.17 (1H, d, J=15.6Hz), 7.05 (1H, s), 7.2-7.6 (12H, m), 8.4-8.5 (2H, m)
Preparation 18
To a suspension of diphenylmethyl 7β-amino-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (2.35 g) and anisole (2.4 ml) in dichloromethane (12 ml) was added trifluoroacetic acid (4.8 ml) at 5°C. The mixture was stirred at 5°C for 1.5 hours. The reaction mixture was poured into diisopropyl ether and the precipitates were collected by filtration, washed with diisopropyl ether, and dried in vacuo to give 7β-amino-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid
bis(trifluoroacetate) (2.79 g).
NMR (DMSO-d6, δ) : 3.87 and 4.11 (2H, ABq, J=17Hz), 5.24 (1H, d, J=5Hz), 5.32 (1H, d, J=5Hz), 7.19 (1H, d, J=16Hz), 7.63 (1H, t, J=7Hz), 7.67 (1H, d, J=16Hz), 8.15 (1H, dd-like), 8.61 (1H, dd,
J=1.5Hz, 5Hz), 8.78 (1H, d, J=1.5Hz)
Preparation 19
The following compounds were obtained according to a similar manner to that of Preparation 1.
(1) Diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(Z)-2- (6-methylpyridin-3-yl)vinyl]-3-cephem-4-earboxylate IR (Nujol) : 1765, 1705, 1670 cm-1
NMR (DMSO-d6, δ) : 1.41 (9H, s), 2.43 (3H, s), 3.30 and 3.53 (2H, ABq, J=17.7Hz), 5.21 (1H, d, J=4.8Hz), 5.24 (1H, dd, J=8.9Hz, 4.8Hz), 6.44 (1H, d, J=12.5Hz), 6.51 (1H, d, J=12.5Hz), 6.83 (1H, s), 7.20-7.49 (12H, m), 8.08 (1H, d,
J=8.9Hz), 8.26 (1H, s)
(2) Diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(Z)-2- (2-methylpyridin-3-yl)vinyl]-3-cephem-4-earboxylate IR (Nujol) : 1760, 1695, 1660 cm-1
NMR (DMSO-d6, δ) : 1.39 (9H, s), 2.40 (3H, s), 3.10 and 3.29 (2H, ABq, J=17.3Hz), 5.12 (1H, d,
J=4.7Hz), 5.50 (1H, dd, J=8.8Hz), 6.61 (1H, d, J=12.1Hz), 6.71 (1H, d, J=12.1Hz), 6.83 (1H, s), 7.14-7.49 (12H, m), 8.02 (1H, d, J=8.8Hz), 8.35 (1H, m) Preparation 20
The following compounds were obtained according to a similar manner to that of Preparation 3. (1) 7β-Amino-3-[(Z)-2-(e-methylpyridin-S-yl)vinyl]-3- cephem-4-carboxylic acid dihydrochloride
IR (Nujol) : 3320, 1760, 1690 cm-1
NMR (DMSO-d6, δ) : 2.75 (3H, s), 3.52 and 3.65 (2H, ABq, J=17.3Hz), 5.18 (1H, d, J=5.1Hz ), 5.34 (1H, d, J=5.1Hz), 6.75 (2H, s), 7.81 (1H, d,
J=8.4Hz), 8.38 (1H, d, J=8.4Hz), 8.67 (1H, s)
(2) 7β-Amino-3-[(Z)-2-(2-methylpyridin-3-yl)vinyl]-3- cephem-4-carboxylic acid dihydrochloride
IR (Nujol) : 3320, 1750, 1680 cm-1
NMR (DMSO-d6, δ) : 2.71 (3H, s), 3.50 and 3.60 (2H, ABq, J=17.2Hz), 5.14 (1H, d, J=5.0Hz), 5.26 (1H, d, J=5.0Hz), 6.74 (1H, d, J=12.0Hz), 6.83 (1H, d, J=l2.0Hz), 7.76 (1H, dd, J=7.8Hz, 5.8Hz), 8.21 (1H, d, J=7.8Hz), 8.64 (1H, d, J=5.8Hz)
Preparation 21
The following compounds were obtained according to a similar manner to that of Preparation 6.
(1) 1-Chloroethyl 1-propylbutyl carbonate
IR (Neat) : 1769, 663 cm-1
NMR (CHCl3, δ) : 0.92 (6H, t, J=7Hz), 1.2-1.7 (8H, m), 1.83 (3H, d, J=6Hz), 4.80 (1H, m), 6.43 (1H, q, J=6Hz)
(2) 1-Chloroethyl cyclobutylmethyl carbonate
IR (Neat) : 1767, 663 cm-1
NMR (CHCl3, δ) : 1.7-2.2 (6H, m), 1.84 (3H, d,
J=6Hz), 2.68 (1H, m), 4.18 (2H, d, J=7Hz), 6 . 43 (1H, q , J=6Hz )
Preparation 22
The following compounds were obtained according to a similar manner to that of Preparation 8.
(1) 1-Bromoethyl 1-propylbutyl carbonate
IR (Neat) : 1763, 590 cm-1
NMR (CHCl3, δ) : 0.92 ( 3H, t, J=7Hz), 1.2-1.7 (8H, m), 2.03 (3H, d, J=6Hz), 4.8-4.9 (1H, m), 6.61
(1H, q, J=6Hz)
(2) 1-Bromoethyl cyclobutylmethyl carbonate
IR (Neat) : 1764, 590 cm-1
NMR (CHCl3, δ) : 1.7-2.2 (6H, m), 2.03 (3H, d,
J=6Hz), 2.68 (1H, m), 4.19 (2H, d, J=7Hz), 6.61 (1H, q, J=6Hz)
(3) 1-Bromoethyl cyclohexyl carbonate
IR (Neat) : 1750 cm-1
NMR (CHCl3, δ) : 1.2-2.0 (10H, m), 2.03 (3H, d,
J=6Hz), 4.6-4.8 (1H, m), 6.62 (1H, g, J=6Hz)
Preparation 23
To a solution of diphenylmethyl
7β-(t-butoxycarbonylamino)-3-chloromethyl-3-cephem-4-carboxylate (1 kg) in acetone (20 ℓ) was added sodium iodide (291 g) and then triphenylphosphine (611 g) portionwise at ambient temperature. The reaction mixture was stirred for a day. The precipitate was filtered and washed twice with acetone (2 ℓ ) to give diphenylmethyl 7β-(t-butoxycarbonylamino)-3-[(triphenylphosphonio)methyl-3-cephem-4-earboxylate iodide. To a suspension of
diphenylmethyl 7β-(t-butoxycarbonylamino)-3-[(triphenylphosphonio)methyl]-3-cephem-4-earboxylate iodide obtained above in ethyl acetate (17 ℓ) and water (8.5 ℓ) was added potassium carbonate (1.1 kg) in water (4 ℓ) and pH was adjusted to 10-10.5. After stirring for 30 minutes at ambient temperature, the aqueous layer was separated and extracted twice with ethyl acetate (2 ℓ ×
2). The combined organic layer was washed with saturated sodium chloride solution (5 ℓ ) and evaporated under reduced pressure. To the residue in acetonitrile (8 ℓ) and water (1 ℓ) was added nicotinaldehyde (202 ml) dropwise under ice cooling. The mixture was stirred for 2.5 days at 3°C and then poured into ethyl acetate (15 ℓ) and 5% sodium hydrogensulfite. The organic layer was separated, washed with 5% sodium hydrogensulfite solution (3 ℓ) and saturated sodium chloride solution (5 ℓ), dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (5 kg) (dichloromethane:acetone = 19:1 (V/V)) and the fractions containing the object compound was evaporated. Acetone (1 ℓ) was added to the residue and the mixture was stirred for 6 hours and allowed to stand for 14 hours. The precipitate was filtered and dried under reduced pressure to give diphenylmethyl
7β-(t-butoxycarbonylamino)-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (300.7 g). The filtrate was evaporated and the residue was recrystallized in the same manner above to give the object compound (76 g).
IR (Nujol) : 1765, 1700 cm-1
NMR (DMSO-d6, δ) : 1.41 (9H, s), 3.30 and 3.56 (2H,
ABq, J=17.5Hz), 5.21 (1H, d, J=4.8Hz), 5.56 (1H, dd, J=8.3Hz, 4.8Hz), 6.49 (1H, d, J=12.2Hz),
6.55 (1H, d, J=12.2Hz), 6.79 (1H, s), 7.27-7.65 (12H, m), 8.08 (1H, d, J=8.3Hz), 8.38 (1H, m), 8.43 (1H, m) Preparation 24
To a suspension of 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (303 mg) in acetone (3 ml) and N,N-dimethylformamide (2 ml) was added dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (152 mg) in acetone (1 ml) at 5°C. After stirring for 30 minutes, i-bromoethyl-1-ethylpropylcarbonate (266 mg) was added at the same temperature. The reaction mixture was stirred for an hour, then was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water twice and brine, dried over magnesium sulfate. After addition of oxalic acid (90 mg), the solution was stirred for an hour. The precipitate was filtered and dried under reduced pressure to give
1-(1-ethylpropyloxycarbonyloxy)ethyl
7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate oxalate (195 mg).
IR (KBr) : 3429, 1790, 1755, 1628 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.34 (1.5H, d, J=5.4Hz), 1.45 (1.5H, d, J=5.4Hz), 1.3-1.6 (4H, m), 3.25 (0.5H, d, J=17.9Hz), 3.30 (0.5H, d, J=17.9Hz), 3.62 (1H, d, J=17.8Hz), 4.40-4.60 (1H, m), 4.95-5.00 (1H, m), 5.16 (1H, d,
J=5.1Hz), 6.4-6.75 (2H, m), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.6 (2H, m)
Preparation 25
The following compound was obtained according to a similar manner to that of Preparation 24.
1-Cyclohexyloxycarbonyloxyethyl 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate oxalate
IR (KBr) : 3429, 1790, 1755 cm-1
NMR (DMSO-d6, δ) : 1.0-2.0 (10H, m), 1.33 (1.5H, d, J=5.4Hz), 1.43 (1.5H, d, J=5.4Hz), 3.25 (0.5H, d, J=18.0Hz), 3.29 (0.5H, d, J=18.0Hz), 3.62 (1H, d, J=18.0Hz), 4.4-4.6 (1H, m), 4.9-5.0 (1H, m), 5.1-5.2 (1H, m), 6.4-6.8 (2H, m), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.48 (2H, br s)
Example 1
To a solution of 7β-amino-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylic acid dihydrochloride (12 g) and N-(trimethylsilyl)acetamide (49.9 g) in methylene chloride (240 ml) was added 2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl chloride hydrochloride (syn isomer) (10.9 g) under ice-cooling. After being stirred for 4 hours at the same temperature, the mixture was added dropwise to diisopropyl ether (1.5 ℓ). The precipitate containing 7β-[2-(2-aminothiazol-4-yl)-2-acetoxyimino-acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) was collected by filtration, and dried in vacuo. The precipitate was dissolved in 10% methanol aqueous solution (280 ml), and thereto was ammonium chloride (5.12 g) and the mixture was adjusted to pH 8 with a sodium carbonate aqueous solution. The solution was stirred at room temperature for 30 minutes maintaining pH 8 with a sodium carbonate aqueous solution. The solution was adjusted to pH 6 with IN hydrochloric acid, and evaporated in vacuo to remove methanol. The solution was subjected to column chromatography on HP-20 (Trademark : Mitsubishi Kasei Corporation) and eluted with 15% isopropyl alcohol aqueous solution. The
fractions containing the object compound were collected and lyophilized to give crude product, which was purified by preparative HPLC utilizing a C18 μ Bondapak resin
(Trademark : Waters Associates, Inc.) to afford 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (0.36 g). IR (Nujol) : 1750, 1650 cm-1
NMR (DMSO-d6, δ) : 3.19 and 3.54 (2H, ABq,
J=17.7Hz), 5.24 (1H, d, J=4.8Hz), 5.81 (1H, d, J=8.2Hz and 4.8Hz ), 6.54 (1H, d, J=12.2Hz), 6.61 (1H, d, J=12.2Hz), 6.65 (1H, s), 7.12 ( 2H , br s ) , 7. 34 ( 1H , m) , 7. 63 ( 1H , m) , 8. 43 (2H, m), 9.51 (1H, d, J=8.2Hz), 11.29 (1H, s)
Example 2
The following compounds were obtained according to a similar manner to that of Example 1.
(1) 7β-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-[(E)-2-(pyridin-4-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 1760, 1650 cm-1
NMR (DMSO-d6, δ) : 3.71 and 4.04 (2H, ABq,
J=l7.7Hz), 5.25 (1H, d, J=4.9Hz), 5.85 (1H, dd, J=4.9Hz, 8.2Hz), 6.68 (1H, s), 6.98 (1H, d, J=16.3Hz), 7.15 (2H, s), 7.39 (2H, d, J=5.8Hz),
7.61 (1H, d, J=16.3Hz), 8.54 (2H, d, J=5.8Hz), 9.53 (1H, d, J=8.2Hz), 11.33 (1H, s)
(2) 7β-[2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 3200, 1755, 1650 cm-1
NMR (DMSO-d6, δ) : 3.70 and 4.00 (2H, ABq,
J=17.5Hz), 5.23 (1H, d, J=4.6Hz), 5.83 (1H, d, J=8.1Hz), 6.69 (1H, s), 7.02 (1H, d, J=16.4Hz),
7.14 (2H, s), 7.39 (1H, s), 7.87 (1H, d,
J=16.4Hz), 7.87 (1H, m), 8.45 (1H, m), 8.63 (1H, s), 9.52 (1H, d, J=8.1Hz), 11.34 (1H, br s) Example 3
Triethylamine (1.50 ml, 10.6 mmol) was added to a suspension of 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid dihydrochloride (syn isomer) (1.00 g, 2.66 mmol) in tetrahydrofuran (20 ml).
Trimethylsilyl chloride (0.84 ml, 6.65 mmol) was added dropwise to the cold mixture (5°C) during a period of 5 minutes. The mixture was stirred for 30 minutes at room temperature and cooled again to ca. 5°C. To the mixture was added a solution of 1-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetyl]benzσtriazole-3-oxide (syn isomer) (1.45 g, 2.66 mmol) in N,N-dimethylformamide (15 ml) over a period of 10 minutes. The mixture was stirred overnight at room temperature and concentrated under reduced
pressure to remove most of the tetrahydrofuran. The concentrate was poured into ice water (100 ml) with vigorous stirring to give 7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (955 mg).
IR (Nujol) : 1725, 1650 cm-1
NMR (DMSO-d6, δ) : 2.95 and 3.34 (2H, ABq,
J=17.0Hz), 5.21 (1H, d, J=4.9Hz), 5.82 (1H, dd, J=8.2 and 4.9Hz), 6.43 (1H, d, J=12.2Hz), 6.58 (1H, s), 6.89 (1H, d, J=12.2Hz), 7.25-7.30 (18H, m), 7.65 (1H, d, J=8.3Hz), 8.42-8.46 (2H, m),
9.90 (1H, d, J=8.2Hz)
Example 4
To a cooled solution of 7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (1.39 g, 1.94 mmol) and potassium carbonate (147 mg, 1.07 mmol) in
N,N-dimethylformamide (14 ml) was added iodomethyl
pivalate (515 mg, 2.13 mmol) at 0°C. The mixture was stirred at about 5°C for 30 minutes. The reaction mixture was poured into a mixture of ice water (90 ml) and ethyl acetate (120 ml). The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration to give pivaloyloxymethyl
7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer) (283.7 mg).
NMR (DMSO-d6, δ) : 1.14 (9H, s), 3.32 and 3.65 (2H,
ABq, J=18.0Hz), 5.35 (1H, d, J=4.9Hz), 5.64 and 5.80 (2H, ABq, J=5.9Hz), 6.01 (1H, dd, J=8.2Hz and 4.9Hz), 6.51 (1H, d, J=12.1Hz), 6.59 (1H, s), 6.66 (1H, d, J=12.lHz), 7.23-7.39 (18H, m), 7.64-7.68 (1H, m), 8.46-8.47 (2H, m), 9.95 (1H,
J=8.2Hz)
Example 5
Pivaloyloxymethyl 7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer) (185 mg, 0.223 mmol) was stirred in 90% formic acid (0.69 ml) for 40 minutes at room temperature. The reaction mixture was filtered, and the filtrate was poured into a mixture of ice water (10 ml) and ethyl acetate (10 ml). The aqueous layer was adjusted to pH 5 with sodium hydrogencarbonate. The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration to give pivaloyloxymethyl 7β-[2-(2-amino-thiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer) (72.9 mg) .
IR (Nujol) : 1740, 1655 cm-1
NMR (DMSO-d6, δ) : 1.12 (9H, s), 3.29 and 3.65 (2H, ABq, J=17.9Hz), 5.28 (1H, d, J=4.8Hz), 5.60 and 5.76 (2H, ABq, J=5.9Hz), 5.86 (1H, dd, J=8.1Hz and 4.8Hz), 6.48 (1H, d, J=12.1Hz), 6.59 (1H, d, J=12.1Hz), 6.66 (1H, s), 7.17 (2H, br s), 7.35 (1H, dd, J=4.8Hz and 8.0Hz), 7.65 (1H, d,
J=8.0Hz), 8.45-8.47 (2H, m), 9.53 (1H, d,
J=8.1Hz), 11.32 (1H, s)
Example 6
To a solution of 7β-amino-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylic acid dihydrochloride (2 g) and N-( trimethylsilyl) acetamide (10.5 g) in methylene chloride (40 ml) was added 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochloride (syn isomer) (2.01 g) at -10 ~ -20°C. After being stirred for 1 hour under ice-cooling, the mixture was poured into a mixture of water (230 ml) and methylene chloride (150 ml) and adjusted to pH 6 with an aqueous sodium hydrogencarbonate solution. The separated aqueous layer was adjusted to pH 5 with IN hydrochloric acid, and evaporated to remove methylene chloride. The solution was adjusted to pH 5 with IN hydrochloric acid, subjected to column
chromatography on HP-20, and eluted with 15% isopropyl alcohol aqueous solution. The fractions containing the object compound was collected and lyophilized to give crude product, which was purified by preparative HPLC utilizing a C18 μ Bondapac resin (Trademark : Waters Associates, Inc.) to afford 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) .
IR (Nujol) : 3200, 1750, 1650 cm-1
NMR (DMSO-d6, δ) : 3.17 and 3.54 (2H, ABq,
J=17.6Hz), 3.83 (3H, s), 5.23 (1H, d, J=4.8Hz), 5.79 (1H, dd, J=8.1Hz, 4.8Hz), 6.52 (1H, d, J=12.2Hz), 6.64 (1H, d, J=12.2Hz), 6.73 (1H, s), 7 . 22 ( 2H , br s ) , 7 . 34 (1H, m ) , 7 . 65 (1H, m ) , 8 . 45 ( 2H, m) , 9 . 66 (1H, d , J=8 . 2Hz )
Example 7
The following compounds were obtained according to similar manners to those of Examples 1, 3 and 6.
(1) 7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-[(E)-2-(pyridin-4-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 3250, 1780, 1660 cm-1
NMR (DMSO-d6, δ) : 3.72 and 4.06 (2H, ABq,
J=17.7Hz), 3.86 (3H, s), 5.25 (1H, d, J=4.9Hz), 5.84 (1H, dd, J=8.1Hz, 4.9Hz ), 6.77 (1H, s), 7.00 (1H, d, J=16.3Hz), 7.24 (2H, br s), 7.40
(2H, d, J=5.9Hz), 7.61 (1H, d, J=16.3Hz), 8.55 (2H, d, J=5.9Hz), 9.68 (1H, d, J=8.1Hz)
(2) 7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 3250, 1750, 1650 cm-1
NMR (DMSO-d6, δ) : 3.72 and 4.02 (2H, ABq,
J=17.5Hz), 3.86 (3H, s), 5.23 (1H, d, J=4.8Hz), 5.80 (1H, dd, J=8.1Hz, 4.8Hz), 6.77 (1H, s),
7.02 (1H, d, J=16.4Hz), 7.24 (2H, s), 7.39 (1H, m), 7.54 (1H, d, J=16.4Hz), 7.87 (1H, m), 8.46 (1H, m), 8.63 (1H, s), 9.67 (1H, d, J=8.1Hz) Example 8
To a stirred solution of 7β-[2-(2-aminothiazol-4-yl)2-methoxyiminoacetamido]-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (500 mg, 1.03 mmol) in N,N-dimethyIformamide (10 ml) was added potassium carbonate (71.2 mg, 0.515 mmol) at 5°C. The mixture was stirred at 5°C for 30 minutes. To the solution was added iodomethyl pivalate (249 mg, 1.03 mmol). The mixture was stirred at 5°C for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration to give pivaloyloxymethyl 7β-[2-(2-amino-thiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) (368 mg, 0.613 mmol).
IR (Nujol) : 1765, 1740, 1665 cm-1
NMR (DMSO-d6, δ) : 1.16 (9H, s), 3.77 and 4.14 (2H, ABq, J=17.9Hz), 3.85 (3H, s), 5.29 (1H, d,
J=4.8Hz), 5.89 and 5.98 (2H, ABq, J=5.9Hz), 5.91 (1H, dd, J=4.8Hz and 8.1Hz), 6.78 (1H, s), 7.16 (1H, d, J=l6.2Hz), 7.25 (2H, br s), 7.42 (1H, m), 7.42 (1H, d, J=16.2Hz), 7.92 (1H, m), 8.49 (1H, m), 8.68 (1H, m), 9.69 (1H, d, J=8.1Hz)
Example 9
The following compounds were obtained according to similar manners to those of Examples 4 and 8.
(1) 1-Acetoxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- methoxyiminoacetamido]-3-[(E)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1760, 1665 cm-1
NMR (DMSO-d6, δ) : 1.50 and 1.51 (total 3H, two d,
J=5.4Hz), 2.06 and 2.08 (total 3H, two s), 3.75 and 4.13 (2H, ABq, J=17.8Hz), 3.86 (3H, s), 5.28 and 5.29 (total 1H, two d, J=4.8Hz), 5.83-5.92 (1H, m), 6.76 and 6.77 (total 1H, two s), 6.99 and 7.06 (total 1H, two d, J=5.4Hz), 7.13 (1H, d, J=16.5Hz), 7.24 (2H, br s), 7.36 (1H, d, J=16.5Hz), 7.40-7.47 (1H, m), 7.87-7.91 (1H, m), 8.48-8.50 (1H, m), 8.67 (1H, br s), 9.69 (1H, d, J=8.1Hz)
(2) 1-(Isopropyloxycarbonyloxy) ethyl 7β-[2-(2- aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-2- (pyridin-4-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1655 cm-1
NMR (DMSO-d6, δ) : 1.23-1.26 (6H, m), 1.53 and 1.54 (total 3H, two d, J=5.4Hz), 3.75 and 4.12 (2H, ABq, J=17.0Hz), 3.85 (3H, s), 4.76-4.83 (1H, m), 5.28 and 5.31 (total 1H, two d, J=4.9Hz),
5.85-5.93 (1H, m), 6.75 (1H, s), 6.91 and 6.96
(total 1H, two d, J=5.4Hz ), 7.08 (1H, d,
J=16.2Hz), 7.24 (2H, br s), 7.43-7.44 (2H, m), 7.47 (1H, d, J=l6.2Hz), 8.57 (2H, d, J=5.9Hz), 9.69 (1H, d, J=8.1Hz)
Example 10
To a solution of 2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (syn isomer) (20.2 g) in
dichloromethane (150 ml) were added triethylamine (5.02 ml) and phosphorus pentachloride (6.69 g) at 5°C. The mixture was stirred at 5°C for 1 hour. After a solution of 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (10.9 g) in dichloromethane (218 ml) and bis(trimethylsilyl)acetamide (26.7 ml) was stirred at room temperature for 45 minutes, to the solution was added the activated solution obtained above. The mixture was stirred at 5°C for 2 hours, and then at room temperature for 15 hours. The reaction mixture was poured into a mixture of ethyl acetate (600 ml), tetrahydrofuran (600 ml) and water (1.2 ℓ). The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was
triturated with diisopropyl ether. The precipitates were collected by filtration to give 7β-[2-{2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylic acid (syn isomer) (21.1 g).
IR (Nujol) : 1770, 1670 cm-1
NMR (DMSO-d6, δ) : 3.21 and 3.50 (2H, ABq, J=18Hz), 5.28 (1H, d, J=5Hz), 5.88 (1H, dd, J=5Hz, 8Hz ), 6.59 (1H, s), 6.61 (2H, s), 7.0-7.4 (31H, m),
7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 8.77 (1H, s), 9.94 (1H, d, J=8Hz)
Example 11
The following compounds were obtained according to similar manners to those of Examples 1, 3, 6 and 10.
( 1 ) 7β-[2-(2-Tritylaminothiazol-4-yl)-2-difluoromethoxy- iminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3- cephem-4-carboxylic acid (syn isomer)
NMR (DMSO-d6, δ) : 3.33 and 3.69 (2H, ABq,
J=17.9Hz), 5.28 (1H, d, J=4.8Hz), 5.73 (1H, dd, J=7.6Hz, 4.9Hz), 6.68 (2H, s), 6.97 (1H, s),
7.28 (2H, br s), 7.32-7.34 (15H, m), 7.81-7.88 (1H, m), 8.23-8.28 (1H, m), 8.72-8.78 (2H, m),
9.92 (1H, d, J=7.6Hz)
( 2) 7β-[2-(2-Amino-4-thiazolyl)-2-trityloxyimino- acetamido]-3-[(Z)-2-(2-methylpyridin-3-yl)vinyl]-3- cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 1755, 1640 cm-1
NMR (DMSO-d6, δ) : 2.44 (3H, s), 2.72 and 3.17 (2H, ABq, J=16.9Hz), 5.15 (1H, d, J=4.9Hz), 5.79 (1H, dd, J=8.2Hz, 4.9Hz), 6.49 (1H, d, J=12.1Hz),
8.33 (1H, m), 9.85 (1H, d, J=8.2Hz) ( 3) 7β-[2-(2-Amino-4-thiazolyl)-2-trityloxyimino- acetamido]-3-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-3- cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 1750, 1740, 1650 cm-1
NMR (DMSO-d6, δ) : 2.44 (3H, s), 3.01 and 3.35 (2H,
ABq, J=16.7Hz), 5.21 (1H, d, J=4.8Hz), 5.83 (1H, dd, J=8.4Hz, 4.8Hz), 6.42 (1H, d, J=12.1Hz), 6.59 (1H, s), 6.79 (1H, d, J=12.1Hz), 7.17-7.30 (18H, m), 7.51-7.56 (1H, m) , 8.34 (1H, m), 9.91 (1H, d, J=8.4Hz)
(4) 7β-[2-(2-Aminothiazol-4-yl)-2-trityloxyimino- acetamido]-3-[(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4- carboxylic acid (syn isomer)
IR (Nujol) : 1730, 1650 cm-1
NMR (DMSO-d6, δ) : 3.61 and 3.81 (2H, ABq, J=17Hz), 5.17 (1H, d, J=5Hz), 5.82 (1H, dd, J=5Hz, 8Hz), 6.62 (1H, s), 6.70 (1H, d, J=16Hz), 7.1-7.4 (18H, m), 7.77 (1H, d, J=16Hz), 7.8 (1H, m), 8.39 (1H, d, J=5Hz), 8.62 (1H, d-like), 9.91
(1H, d, J=8Hz)
( 5) 7β-[2-( 2-Amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-3- cephem-4-carboxylic acid (syn isomer)
IR (Nujol) : 3260, 1740, 1655 cm-1
NMR (DMSO-d6, δ) : 2.45 (3H, s), 3.19 and 3.51 (2H, ABq, J=17.7Hz), 5.23 (1H, d, J=4.8Hz), 5.81 (1H, dd, J=8.2Hz, 4.8Hz), 6.49 (1H, d, J=12.2Hz), 6.57 (1H, d, J=12.2Hz), 6.65 (1H, s), 7.11 (2H, br s), 7.20 (1H, d, J=8.1Hz), 7.54 (1H, d,
J=8.1Hz), 8.33 (1H, s), 9.50 (1H, d, J=8.2Hz), 11.28 (1H, s) (6) 7β-[2-(2-Amino-4-thiazolyl)-2-hydroxyiminoacetamido]- 3- 1(Z)-2-(2-methylpyridin-3-yl)vinyl]-3-cephem-4- carboxylic acid (syn isomer)
IR (Nujol) : 1750, 1660 cm-1
NMR (DMSO-d6, δ) : 2.43 (3H, s), 2.88 and 3.25 (2H, ABq, J=17.1Hz), 5.10 (1H, d, J=4.8Hz), 5.69 (1H, dd, J=8.2Hz, 4.8Hz), 6.54 (1H, d, J=12.1Hz), 6.62 (1H, s), 6.76 (1H, d, J=12.1Hz ), 7.12 (2H, br s), 7.16 (1H, m), 7.45 (1H, d, J=6.5Hz), 8.34 (1H, d, J=4.8Hz), 9.42 (1H, d, J=8.2Hz), 11.32 (1H, s)
Example 12
To a solution of 7β-[2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (1.5 g) in
N,N-dimethylformamide (15 ml) was added cesium carbonate (255 mg) at 5°C. The mixture was stirred at 5°C for 15 minutes. To the mixture was added 1-bromoethyl pivalate (328 mg) . The mixture was stirred at 5°C for 7 hours.
The reaction mixture was poured into a mixture of ethyl acetate (100 ml), tetrahydrofuran (100 ml) and ice-water (200 ml). The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel to give 1-pivaloyloxyethyl
7β-[2-(2-tritylaminothiazol-4-yl)-2-trityloxyimino-acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyi]-3-cephem-4-carboxylate (syn isomer) (665 mg).
IR (Nujol) : 1770, 1730, 1670 cm-1
NMR (DMSO-d6, δ) : 1.04 (9H, s), 1.31 and 1.45
(total 3H, d, J=5Hz), 3.30 and 3.61 (2H, ABq, J=18Hz), 5.3-5.4 (1H, m), 5.9-6.0 (1H, m),
6.4-6.8 (4H, m), 7.0-7.4 (31H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 8.77 (1H, br s), 9.9-10.0 (1H, m) Example 13
The following compounds were obtained according to similar manners to those of Examples 4, 8 and 12. (1) 1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3- [(E)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
(syn isomer)
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.56 (3H, d, J=5Hz), 3.79 and 4.13 (2H, ABq, J=17Hz), 4.5-4.
(1H, m), 5.35 and 5.38 (total 1H, d, J=5Hz), 5.76 (1H, s), 6.0-6.1 (1H, m), 6.63 (1H, s), 6.95 (1H, m), 7.15 (1H, d, J=16Hz), 7.2-7.5 (19H, m), 7.8-8.0 (1H, m), 8.49 (1H, d, J=5Hz), 8.68 (1H, m), 9.96 (1H, d, J=8Hz)
(2) Pivaloyloxymethyl 7β-[2-(2-aminothiazol-4-yl)-2- trityloxyiminoacetamido]-3-[(E)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1760, 1730, 1670 cm-1
NMR (DMSO-d6, δ) : 3.80 and 4.15 (2H, ABq, J=18Hz), 5.37 (1H, d, J=5Hz), 5.91 and 6.01 (2H, ABq, J=6Hz), 6.0-6.1 (1H, m), 6.63 (1H, s), 7.2-7.5 (20H, m), 7.93 (1H, d-like), 8.50 (1H, d,
J=4Hz), 8.69 (1H, br s), 9.96 (1H, d, J=8Hz)
(3) 1-(3-Methylbutyryloxy)ethyl 7β-[2-(2-tritylamino- thiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1770, 1730, 1670, 1510 cm-1
NMR (DMSO-d6, δ) : 0.8-0.9 (6H, m), 1.32 and 1.44
(total 3H, d, J=5Hz), 2.0-2.2 (3H, m), 3.3 and 3.6 (2H, m), 5.32 (1H, d, J=5Hz), 5.9-6.0 (1H, m), 6.4-6.9 (4H, m), 7.1-7.3 (31H, m), 7.4 (1H, m) , 8 . 4-8 . 5 ( 2H . m) , 8 .78 (1H, s )
(4) Pivaloyloxymethyl 7β-[2-(2-amino-4-thiazolyl)-2- trityloxyiminoacetamido]-3-[(Z)-2-(2-methylpyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3340, 1780, 1745, 1675, 1610 cm-1
NMR (DMSO-d6, δ) : 1.16 (9H, s), 2.44 (3H, s), 3.21 and 3.48 (2H, ABq, J=17.7Hz), 5.28 (1H, d, J=4.9Hz), 5.61 and 5.79 (2H, ABq, J=5.9Hz), 5.96 (1H, dd, J=8.2Hz, 4.9Hz), 6.57 (1H, d,
J=11.9Hz), 6.57 (1H, s), 6.75 (1H, d, J=11.9Hz), 7.15-7.29 (18H, m), 7.46 (1H, m), 8.36 (1H, m), 9.88 (1H, d, J=8.2Hz) (5) Pivaloyloxymethyl 7β-[2-(2-amino-4-thiazolyl)-2- trityloxyiminoacetamido]-3-[(Z)-2-(6-methylpyridin- 3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1750, 1665 cm-1
NMR (DMSO-d6, δ) : 1.14 (9H, s), 2.44 (3H, s), 3.22 and 3.51 (2H, ABq, J=17.5Hz), 5.35 (1H, d,
J=4.9Hz), 5.66 and 5.81 (2H, ABq, J=5.9Hz), 6.01 (1H, dd, J=8.3Hz), 6.46 (1H, d, J=12.0Hz), 6.60 (1H, s), 6.62 (1H, d, J=12.0Hz), 7.19-7.30 (18H, m), 7.52-7.56 (1H, m), 8.34-8.35 (1H, m), 9.95 (1H, d, J=8.3Hz)
(6) 1-(3-Methylbutoxycarbonyloxy)ethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate ( syn isomer)
IR (Nujol) : 1760, 1680 cm-1
NMR (DMSO-d6, δ) : 0.80 and 0.87 (total 6H, d,
J=7Hz), 1.3-1.7 (6H, m), 3.26 and 3.60 (2H, ABq, J=18Hz), 4.1-4.2 (2H, m), 5.32 and 5.33 (total 1H, d, J=5Hz), 5.9-6.0 (1H, m), 6.3-6.8 (4H, m)) 7.1-7.3 (31H, m), 7.6-7.7 (1H. m) , 8.4-8.5 (2H, m), 8.76 (1H, s), 9.94 (1H, d, J=8Hz)
(7) 1-(Isobutyloxycarbonyloxy)ethyl 7β-[2-(2- tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]- 3-[(Z)-2-(3-pyridyl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1670, 1580 cm-1
NMR (DMSO-d6, δ) : 0.8-0.9 (6H, m), 1.3-1.4 (3H, m), 1.8-2.0 (1H, m), 3.29 and 3.61 (2H, ABq,
J=17.6Hz), 4.24 (2H, d, J=7.0Hz), 5.32 (1H, d, J=4.9Hz), 5.91 (1H, dd, J=8.2Hz, 4.7Hz), 6.5-6.9 (4H, m), 7.2-7.4 (31H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 8.78 (1H, br s), 9.93 (1H, d, J=8.2Hz)
(8) 1-(3,3-Dimethylbutyryloxy)ethyl 78-[2-(2-tritylamino- thiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) IR (Nujol) : 1770, 1740, 1670, 1580 cm-1
NMR (DMSO-db-, δ) : 0.92 (9H, s), 0.98 (2H, s), 1.45
(3H, d, J=5.4Hz), 3.41 and 3.60 (2H, ABq,
J=18.1Hz), 5.32 (1H, d, J=4.2Hz), 5.9-6.0 (1H, m), 6.4-6.9 (4H, m), 7.1-7.4 (31H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m) , 8.78 (1H, s), 9.9-10.0
(1H, m)
(9) 1-(Hexyloxycarbonyloxy) ethyl 7β-[2-(2- tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]- 3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
(syn isomer)
IR (Nujol) : 1770, 1750, 1670 cm-1
NMR (DMSO-d6, δ) : 0.8-1.6 (14H, m), 3.30 and 3.60 (2H, ABq, J=18Hz), 4.0-4.1 (2H, m), 5.32 and 5.33 (total 1H, d, J=5Hz), 5.9-6.0 (1H, m), 6.5-5.8 (4H, m), 7.1-7.4 (31H, m), 7.6-7.7 (1H, m), δ.4-8.5 (2H, m) , 8.78 (1H, s), 9.94 and 9.95 (total 1H, d, J=8Hz) (10) 1-Isobutyryloxyethyl 7β-[2-(2-tritylaminothiazol-4- yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1720, 1670, 1510 cm-1
NMR (DMSO-d6, δ) : 1.0-1.1 (6H, m), 1.32 and 1.44 (total 3H, d, J=5Hz), 3.1-4.7 (2H, m), 5.32 and
5.33 (total 1H, d, J=5Hz), 5.9-6.0 (1H, m), 6.5-6.8 (4H, m), 7.2-7.3 (31H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 8.78 (1H, s), 9.93 and 9.95 (total 1H, d, J=8Hz)
(11) 1-(4-Methylpentoxycarbonyloxy)ethyl 7β-[2-(2- tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]- 3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1670 cm-1
NMR (DMSO-d6, δ) : 0.8-0.9 (6H, m), 1.1-1.3 (2H, m), 1.36 and 1.48 (total 3H, d, J=5Hz), 1.4-1.6 ( 3H, m), 3.29 and 3.60 (2H, ABq, J=18Hz), 4.0-4.1 (2H, m), 5.32 and 5.33 (total 1H, d, J=5Hz), 5.9-6.0 (1H, m), 6.5-6.8 (4H, m), 7.1-7.3 (31H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 8.78 (1H, s), 9.93 and 9.94 (total 1H, d, J=8Hz)
(12) 1-(1-Ethylpropoxycarbonyloxy)ethyl 7β-[2-(2- tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]- 3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1730, 1670 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.36 and 1.49 (total 3H, d, J=5Hz), 1.4-1.6 (4H, m), 3.2-3.7 (2H, m), 4.50 (1H, m) , 5.32 (1H, d, J=5Hz), 5.9-6.0 (1H, m), 6.4-6.8 (4H, m), 7.1-7.3 (31H, m), 7.1-7.8 (1H, m) , 8.5 (2H, m), 8.77 (1H, s),
9.95 (IK, d, J=7Hz)
(13) Cycloheptylearbonyloxymethyl 7β-[2-(2-aminothiazol- 4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
NMR (DMSO-d6, δ) : 1.3-1.9 (13H, m), 3.33 and 3.65 (2H, ABq, J=18Hz), 5.36 (1H, d, J=5Hz), 5.65 and
5.76 (2H, ABq, J=6Hz), 6.00 (1H, dd, J=5Hz, 8Hz), 6.51 (1H, d, J=12Hz), 6.59 (1H, s), 6.65 (1H, d, J=12Hz), 7.1-7.3 (18H, m), 7.6-7.7 (1H, m), 8.3-8.5 (2H, m), 9.95 (1H, d, J=8Hz)
(14) 1-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy- carbonyloxy]ethyl 7β-[2-(2-aminothiazol-4-yl)-2- trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1740 cm-1
NMR (DMSO-d6, δ) : 0.7-2.0 (18H, m), 1.37 and 1.49 (total 3H, d, J=5Hz), 3.28 and 3.62 (2H, ABq, J=18Hz), 4.45 (1H, m) , 5.36 (1H, d, J=5Hz), 5.9-6.1 (1H, m), 6.5-6.8 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.94 and
9.96 (total 1H, d, J=8Hz )
(15) 1-Methylcyclohexylcarbonyloxymethyl 7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1740 cm-1
NMR (DMSO-d6, δ) : 1.10 (3H, s), 1.2-1.5 (8H, m), 1.9-2.0 (2H, m), 3.30 and 3.62 (2H, ABq, J=18Hz), 5.36 (1H, d, J=5Hz), 5.69 and 5.81 (2H, ABq, J=6Hz), 6.01 (1H, dd, J=5Hz, 8Hz), 6.53 (1H, d, J=12Hz), 6.59 (1H, s), 6.67 (1H, d, J=12Hz), 7.1-7.9 (18H, m), 7.66 (1H, m), 8.47 (2H, m), 9.95 (1H, d, J=8Hz )
(16) (E)-2-(Isobutoxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1765, 1700, 1670 cm-1
NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6.7Hz), 1.00 (3H, t, J=7.4Hz), 1.87 (1H, m), 2.31 (2H, m), 3.26 and 3.61 (2H, ABq, J=18.0Hz), 3.87 (2H, d, J=6.5Hz), 4.84 and 4.92 (2H, ABq, J=11.9Hz), 5.33 (1H, d, J=4.9Hz), 5.96 (1H, dd, J=8.3Hz,
4.9Hz), 6.47 (1H, d, J=12.1Hz), 6.58 (1H, s), 6.59 (1H, d, J=12.1Hz), 6.98 (1H, t, J=7.8Hz), 7.30 (16H, m), 7.64 (1H, m), 8.44 (2H, m), 9.95 (1H, d, J=4.9Hz)
(17) (E)-2-(Isobutoxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(2- methylpyridin-3-yl)vinyl]-3-cephem-4-earboxylate ( syn isomer)
IR (Nujol) : 3400, 1770, 1695, 1670 cm-1
NMR (DMSO-de., δ) : 0.89 (6H, d, J=6.7Hz), 1.03 (3H, t, J=7.4Hz), 1.91 (1H, m), 2.26 (3H, m), 2.44 (3H, s), 3.10 and 3.42 (2H, ABq, J=17.5Hz), 3.89 (2H, d, J=6.4Hz), 4.85 and 4.96 (2H, ABq,
J=11.8Hz), 5.25 (1H, d, J=4.9Hz), 5.91 (1H, dd,
J=8.3Hz, 4.9Hz), 6.56 (1H, s), 6.57 (1H, d, J=12.0Hz), 6.70 (1H, d, J=12.0Hz), 7.01 (1H, t, J=7.7Hz), 7.12-7.28 (17H, m), 7.44 (1H, m), 8.35 (1H, m), 9.88 (1H, d, J=8.3Hz) (18) (E)-2-(Isobutoxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(6- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1765, 1700, 1680, 1665 cm-1
NMR (DMSO-d6, δ) : 0.92 (6H, d, J=7.0Hz ), 1.00 (3H, t, J=7.6Hz), 1.85-1.92 (1H, m), 2.26-2.44 (2H, m), 2.44 (3H, s), 3.25 and 3.58 (2H, ABq, J=17.6Hz), 3.87 (2H, d, J=7.0Hz), 4.85 and 4.93 (2H, ABq, J=12.0Hz), 5.33 (1H, d, J=4.9Hz), 5.96
(1H, dd, J=8.3Hz, 4.9Hz), 6.31 (1H, d, J=12.0Hz), 6.54 (1H, d, J=12.0Hz), 6.55 (1H, s), 6.98 (1H, t, J=7.6Hz), 7.05-7.29 (18H, m),
7.51-7.56 (1H, m), 8.32 (1H, m), 9.94 (1H, d, J=8.3Hz)
(19) (E) -2-(n-Hexyloxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1770, 1705, 1670, 1605 cm-1
NMR (DMSO-d6, δ) : 0.78-0.83 (3H, m), 0.99 (3H, t, J=7.4Hz), 1.24 (6H, m), 1.49-1.57 (2H, m),
2.21-2.36 (2H, m), 3.26 and 3.60 (2H, ABq,
J=17.7Hz), 4.07 (2H, t, J=6.6Hz), 4.82 and 4.92
(2H, ABq, J=11.9Hz), 5.33 (1H, d, J=4.9Hz), 5.98 (1H, dd, J=8.3Hz, 4.9Hz), 6.47 (1H, d, J=12.1Hz), 6.58 (1H, s), 6.59 (1H, d, J=12.1Hz), 6.96 (1H, t, J=7.7Hz), 7.23-7.37 (18H, m),
7.63-7.67 (1H, m), 8.43-8.46 (2H, m), 9.95 (1H, d, J=8.3Hz)
(20) (E)-2-(n-Butoxycarbonyl)-2-pentenyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoactamido]-3-[(Z)-2-(pyridin- 3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) IR (Nujol) : 1765, 1710, 1680 cm-1
NMR (DMSO-d6, δ) : 0.86 (3H, t, J=7.2Hz), 0.99 (3H, t, J=7.4Hz), 1.22-1.41 (2H, m), 1.49-1.63 (2H, m), 2.21-2.36 (2H, m), 3.26 and 3.61 (2H, ABq, J=17.9Hz), 4.08 (2H, t, J=6.4Hz), 4.82 and 4.91
(2H, ABq, J=11.8Hz), 5.33 (1H, d, J=4.9Hz), 5.97 (1H, dd, J=8.4Hz, 4.9Hz), 6.47 (1H, d,
J=12.lHz), 6.58 (1H, s), 6.59 (1H, d, J=12.1Hz), 6.96 (1H, t, J=7.7Hz), 7.23-7.36 (18H, m), 7.63-7.67 (1H, m), 8.43-8.46 (2H, m), 9.94 (1H, d, J=8.4Hz)
(21) (E)-2-(Isopentyloxycarbonyl)-2-butenyl 7β-[2-(2- amino-4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3410, 1770, 1680 cm-1
NMR (DMSO-d6, δ) : 0.86 (6H, d, J=6.1Hz), 1.42-1.67 (3H, m), 1.88 (3H, d, J=7.2Hz), 3.26 and 3.61 (2H, ABq, J=17.7Hz), 4.11 (2H, t, J=6.7Hz), 4.81 and 4.93 (2H, ABq, J=11.9Hz), 5.33 (1H, d, J=5.1Hz), 5.99 (1H, dd, J=8.4Hz, 5.1Hz), 6.47 (1H, d, J=l2.1Hz), 6.58 (1H, s), 6.59 (1H, d, J=12.lHz), 7.08 (1H, q, J=7.2Hz), 7.23-7.37 (18H, m 7.63-7.67 (1H, m), 8.43-8.46 (2H, m), 9.94 (1H, d,
J=8.4Hz)
(22) (E)-2-(Ethoxycarbonyl)-2-butenyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1765, 1700, 1665 cm-1
NMR (DMSO-d6, δ) : 1.19 (3H, t, J=7.1Hz), 1.88 (3H, d, J=7.2Hz), 3.27 and 3.62 (2H, ABq, J=17.7Hz), 4.12 (2H, q, J=7.1Hz), 4.81 and 4.93 (2H, ABq, J=11.9Hz), 5.34 (1H, d, J=4.9Hz), 5.79 (1H, dd, J=8.3Hz, 4.9Hz), 6.47 (1H, d, J=12.1Hz), 6.58 (1H, s), 6.59 (1H, d, J=12.1Hz), 7.08 (1H, q, J=7.2Hz), 7.23-7.37 (18H, m), 7.64-7.68 (1H, m), 8.43-8.46 (2H, m), 9.94 (1H, d, J=8.3Hz)
(23) (E)-2-(Isobutoxycarbonyl)-2-butenyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1775, 1700, 1600 cm-1
NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6.7Hz), 1.85-1.91 (4H, m), 3.27 and 3.61 (2H, ABq, J=17.9Hz), 3.87 (2H, d, J=6.7Hz), 4.84 and 4.94 (2H, ABq, J=11.9Hz), 5.33 (1H, d, J=5.0Hz), 6.47 (1H, d,
J=12.3Hz), 6.58 (1H, s), 6.59 (1H, d, J=12.3Hz), 7.09 (1H, q, J=7.2Hz), 7.30-7.36 (18H, m),
7.63-7.67 (1H, m), 8.43-8.46 (2H, m), 9.94 (1H, d, J=8.2Hz)
(24) (E)-2-(Isopentyloxycarbonyl)-2-pentenyl 7β-[2-(2- amino-4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1765, 1700, 1670, 1600 cm-1
NMR (DMSO-d6, δ) : 0.86 (6H, d, J=6.4Hz), 0.99 (3H, t, J=7.5Hz), 1.43-1.70 (3H, m), 2.22-2.48 (2H, m), 3.27 and 3.61 (2H, ABq, J=17.8Hz), 4.11 (2H, t, J=6.7Hz), 4.82 and 4.92 (2H, ABq, J=11.8Hz), 5.34 (1H, d, J=4.9Hz), 5.98 (1H, dd, J=8.4Hz,
4.9Hz), 6.47 (1H, d, J=12.1Hz), 6.58 (1H, s), 6.59 (1H, d, J=12.1Hz), 6.96 (1H, t, J=7.7Hz), 7.23-7.37 (18H, m), 7.63-7.67 (1H, m), 8.43-8.46 (2H, m), 9.95 (1H, d, J=8.4Hz) (25) (E)-2-(Ethoxycarbonyl)-2-pentenyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1765, 1700, 1665 cm-1
NMR (DMSO-d6, δ) : 0.99 (3H, t, J=7.1Hz), 1.20 (3H, t, J=6.8Hz), 2.23-2.33 (2H, m), 3.27 and 3.61 (2H, ABq, J=17.8Hz), 4.12 (2H, q, J=7.1Hz), 4.81 and 4.91 (2H, ABq, J=11.8Hz), 5.33 (1H, d, J=4.8Hz), 5.98 (1H, dd, J=8.4Hz, 4.8Hz), 6.47
(1H, d, J=12.0Hz), 6.58 (1H, s), 6.58 (1H, d, J=12.0Hz), 6.96 (1H, t, J=7.6Hz), 7.26-7.36 (18H, m), 7.63-7.67 (1H, m), 8.43-8.46 (2H, m), 9.94 (1H, d, J=8.4Hz)
(26) (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3- [(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1800, 1770, 1720 cm-1
NMR (DMSO-d6, δ) : 2.13 (3H, s), 3.37 and 3.70 (2H, ABq, J=18Hz), 4.89 and 5.04 (2H, ABq, J=14Hz), 5.36 (1H, d, J=5Hz), 6.02 (1H, dd, J=5Hz, 8Hz), 6.48 (1H, d, J=12Hz), 6.59 (1H, s), 6.63 (1H, d, J=12Hz), 7.2-7.4 (18H, m), 7.6-7.7 (1H, m),
8.4-8.5 (2H, m), 9.93 (1H, d, J=8Hz)
(27) 1-[3,3-Dimethylbutoxycarbonyloxy]ethyl 7β-[2-(2- tritylamino-4-thiazolyl)-2-trityloxyiminoacetamido]- 3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
(syn isomer)
IR (Nujol) : 1750, 1670 cm-1
NMR (DMSO-d6, δ) : 0.82 and 0.89 (9H, two s, 9H), 1.33-1.56 (5H, m), 3.26 and 3.60 (2H, ABq, J=l7.6Hz), 4.11-4.18 (2H, m), 5.31 and 5.32 (1H, two d, J=4.9Hz), 5.88-5.98 (1H, m), 6.44-6.77 (4H, m), 7.14-7.29 (31H, m), 7.63-7.67 (1H, m), 8.44-8.46 (2H, m), 8.78 (1H, m), 9.94 and 9.95 (1H, two d, J=8.2Hz)
(28) 1-(n-Pentyloxycarbonyloxy)ethyl 7β-[2-(2-tritylamino- 4-thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1755, 1740, 1640 cm-1
NMR (DMSO-d6, δ) : 0.80-0.86 (3H, m), 1.21-1.58 (9H, m), 3.26 and 3.65 (2H, ABq, J=17.7Hz), 4.05-4.12 (2H, m), 5.31 and 5.32 (1H, two d, J=4.9Hz), 5.89-5.96 (1H, m), 6.48-6.76 (4H, m), 7.14-7.29 (31H, m), 7.63 (1H, m), 8.44-8.47 (2H, m), 8.78
(1H, m), 9.94 and 9.95 (1H, two d, J=8.3Hz)
(29) 1-(1-Ethylpropoxycarbonyloxy)ethyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(2- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1660 cm-1
NMR (DMSO-d6, δ) : 0.73-0.89 (6H, m), 1.02-1.57 (7H, m), 2.44 (3H, m) , 3.08 and 3.49 (2H, ABq,
J=17.6Hz), 4.49-4.58 (1H, m), 5.28 (1H, d,
J=4.9Hz ), 5.92-6.02 (1H, m), 6.54-6.82 (4H, m), 7.13-7.31 (18H, m), 7.41-7.49 (1H, m), 8.36-8.37 (1H, m), 9.86 and 9.87 (1H, two d, J=8.3Hz) (30) 1-(Cyclohexyloxycarbonyloxy) ethyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(2- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1670 cm-1
NMR (DMSO-d6, δ) : 1.17-1.99 (10H, m), 1.38 and 1.52 (3H, two d, J=5.4Hz), 2.44 ( 3H, s), 3.09 and 3.29 (2H, ABq, J=17.7Hz), 4.59 (1H, m), 5.28 and 5.29 (1H, two d, J=4.9Hz), 5.98 (1H, m), 6.57 (1H, s), 6.58 (1H, d, J=12.1Hz), 6.71 (1H, d, J=12.1Hz), 6.76 (1H, m), 7.13-7.31 (18H, m),
7.45 (1H, m), 8.35 (1H, m), 9.88 and 9.89 (1H, each d, J=8.1Hz)
(31) 1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2-amino-4- thiazolyl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(6- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1750, 1660 cm-1
NMR (DMSO-d6, δ) : 1.09-1.94 (10H, m), 1.36 and 1.49 (3H, two d, J=5.4Hz), 2.44 (3H, s), 3.26 and
3.61 (2H, ABq, J=17.4Hz), 4.53 (1H, m), 5.34 and 5.35 (1H, two d, J=4.9Hz), 6.02 and 6.03 (1H, two dd, J=8.4Hz, 4.9Hz), 6.43-6.78 (3H, m), 6.60 (1H, s), 7.19-7.30 (18H, m), 7.53-7.57 (1H, m), 8.35 (1H, m), 9.95 and 9.96 (1H, each d,
J=8.4Hz)
(32) 1-(Ethoxycarbonyloxy) ethyl 7β-[2-(2-aminothiazol-4- yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1682 cm-1
NMR ( DMSO-d6 , δ ) : 1. 19 and 1. 21 ( total 3H , each t, J=7.1Hz), 1.36 and 1.49 (total 3H, each d,
J=5.4HZ), 3.29 and 3.65 (2H, ABq, J=18.9Hz), 4.14 (2H, m), 5.36 and 5.37 (total 1H, each d,
J=4.9Hz), 5.98-6.08 (1H, m), 6.48-6.77 (3H, m), 6.59 (1H, s), 7.26-7.30 (18H, m), 7.63-7.70 (1H, m), 8.45-8.47 (2H, m), 9.94 and 9.95 (total 1H, two d, J=8.4Hz) (33) 1-Acetoxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1735, 1660 cm-1
NMR (DMSO-d6, δ) : 1.33 and 1.44 (total 3H, each d, J=5.4Hz), 2.03 and 2.04 (total 3H, each s), 3.29 and 3.67 (2H, ABq, J=17.0Hz), 5.34-5.39 (1H, m), 5.97-6.09 (1H, m), 6.43-6.87 (3H, m), 6.59 (1H, s), 7.20-7.37 (18H, m), 7.65-7.69 (1H, m),
8.45-8.48 (2H, m), 9.92-9.96 (1H, m)
(34) 1-(Cyclopentyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3- [(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1745, 1665 cm-1
NMR (DMSO-d6, δ) : 1.35 and 1.48 (total 3H, two d, J=5.4Hz), 1.40-1.90 (8H, m), 3.28 and 3.64 (2H, ABq, J=18.0Hz), 4.95-5.06 (1H, m), 5.36 and 5.37 (total 1H, two d, J=4.9Hz), 5.98-6.08 (1H, m),
6.48-6.79 (3H, m), 6.59 (1H, s), 7.13-7.39 (18H, m), 7.62-7.70 (1H, m), 8.43-8.52 (2H, m),
9.93-9.97 (1H, m) (35) 1-(Isopropyloxycarbonyloxy) ethyl 7β-[2-(2-amino- thiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1735 cm-1
NMR (DMSO-d6, δ) : 1.18-1.24 (6H, m), 1.35 and 1.48
(total 3H, each d, J=5.4Hz), 3.28 and 3.64 (2H, ABq, J=17.8Hz), 4.76 and 4.78 (total 1H, each t, J=6.2Hz), 5.35 and 5.37 (1H, two d, J=4.9Hz), 5.98-6.08 (1H, m), 6.48-6.76 (3H, m), 6.59 (1H, s), 7.24-7.29 (18H, m), 7.62-7.70 (1H, m), 8 . 45-8 . 47 ( 2H, m) , 9. 94 and 9 . 96 (1H, two d , J=8 . 5Hz )
(36) 1-(Cyclohexyloxycarbonyloxy) ethyl 7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1665 cm-1
NMR (DMSO-d6, δ) : 1.09-1.90 (10H, m), 1.35 and 1.48 (total 3H, each d, J=5.4Hz), 3.28 and 3.64 (2H,
ABq, J=17.3Hz), 4.45-4.59 (1H, m), 5.34-5.37 (1H, m), 5.98-6.04 (1H, m), 6.48-6.78 (3H, m), 6.59 (1H, s), 7.18-7.39 (17H, m), 7.61-7.72 (1H, m), 8.43-8.52 (2H, m), 9.92-9.99 (1H, m)
Example 14
To a solution of 7β-[2-difluoromethoxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (6.05 g) in methanol (30 ml) was added cone.
hydrochloric acid (4.5 ml) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of water and ethyl acetate. The separated aqueous layer was adjusted to pH 5 with 1N sodium hydroxide solution, washed with ethyl acetate twice and evaporated to remove ethyl acetate. The solution was adjusted to pH 3 with aqueous sodium hydrogencarbonate solution, subjected to column chromatography on Diaion HP-20, and eluted with aqueous 20% isopropyl alcohol solution. The fractions containing the object compound was collected and lyophilized to give crude product, which was purified by preparative HPLC utilizing a C18 μ
Bondepak resin (Trademark : Waters Associates, Inc.) to afford 7β-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyimino-acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4- carboxylic acid (syn isomer) (748 mg).
IR (Nujol) : 1740 cm-1
NMR (DMSO-d6, δ) : 3.22 and 3.58 (2H, ABq, J=17.7Hz),
5.28 (1H, d, J=4.8Hz), 5.85 (1H, dd, J=4.8Hz, 8.0Hz), 6.55 (1H, d, J=12.2Hz), 6.62 (1H, d,
J=12.2Hz), 6.99 (1H, s), 7.12 (1H, t, J=71.1Hz), 7.32-7.38 (1H, m), 7.36 (2H, br s), 7.63-7.69 (1H, m), 8.43-8.47 (2H, m), 10.01 (1H, m) Example 15
A solution of 1-pivaloyloxyethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate
(syn isomer) (640 mg) in 90% formic acid aqueous solution (4.8 ml) was stirred at room temperature for 4.5 hours.
The insoluble material in the reaction mixture was
filtered off. The filtrate was poured into a mixture of ethyl acetate and water. The mixture was adjusted to pH 5. The organic layer was separated, washed with water and with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration and dried to give 1-pivaloyloxyethyl 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl-3-cephem-4-earboxylate (syn isomer) (219 mg).
IR (Nujol) : 1760, 1720, 1650, 1590, 1500 cm-1
NMR (DMSO-d6, δ) : 1.08 and 1.12 (total 9H, s), 1.29 and 1.42 (total 3H, d, J=5Hz), 3.29 and 3.65 (2H, ABq, J=18Hz), 5.28 and 5.30 (total 1H, d, J=5Hz), 5.87 and 5.89 (total 1H, dd, J=5Hz,
8Hz), 6.43 (1H, d, J=12Hz), 6.54 (1H, d, J=12Hz), 6.65 (1H, s), 6.6-6.8 (1H, m), 7.13 (2H, br s), 7.2-7.4 (1H, m) , 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.52 and 9.54 (total 1H, d, J=8Hz), 11.3 (1H, s) Example 16
The following compounds were obtained according to similar manners to those of Examples 5 and 15. (1) 1-Methylcyclohexylcarbonyloxymethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1660, 1600 cm-1
NMR (DMSO-d6, δ) : 1.08 (3H, s), 1.1-1.6 (8H, m),
1.8-2.0 (2H, m), 3.27 and 3.62 (2H, ABq,
J=18Hz), 5.28 (1H, d, J=5Hz), 5.66 and 5.78 (2H, ABq, J=6Hz), 5.86 (1H, dd, J=5Hz, 8Hz), 6.49 (1H, d, J=12Hz), 6.65 (1H, s), 6.64 (1H, d, J=12Hz), 7.14 (2H, br s), 7.3-7.4 (1H, m),
7.6-7.7 (1H, m), 8.45 (2H, m), 9.53 (1H, d, J=8Hz), 11.3 (1H, s)
(2) 1-(Cyclohexyloxycarbonyloxy) ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(E)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1630 cm-1
NMR (DMSO-d6, δ) : 1.1-2.0 (13H, m), 3.73 and 4.09 (2H, ABq, J=17Hz), 4.55 (1H, m), 5.27 and 5.30
(total 1H, d, J=5Hz), 5.8-6.0 (1H, m), 6.67 (1H, s), 6.92 (1H, m), 7.12 (1H, d, J=16Hz), 7.14 (2H, br s), 7.3-7.5 (2H, m), 7.8-8.0 (1H, m), 8.49 (1H, d, J=4Hz), 8.68 (1H, br s), 9.54 (1H, d, J=8Hz), 11.3 (1H, s)
(3) Pivaloyloxymethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-[(E)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1650 cm-1 NMR (DMSO-d6, δ) : 1.16 (9H, s), 3.76 and 4.12 (2H, ABq, J=18Hz), 5.28 (1H, d, J=5Hz), 5.8-5.9 (1H, m), 5.88 and 5.98 (2H, ABq, J=6Hz), 6.69 (1H, s), 7.14 (1H, s), 7.15 (1H, d, J=16Hz), 7.3-7.5 (3H, m), 7.92 (1H, d, J=8Hz), 8.49 (1H, d,
J=8Hz), 8.68 (1H, br s), 9.54 (1H, d, J=8Hz), 11.3 (1H, br s)
(4) 1-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxycarbonyloxy]ethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1730 cm-1
NMR (DMSO-d6, δ) : 0.74 (3H, d, J=7Hz), 0.8-2.1
(15H, m), 1.35 and 1.45 (1H, d, J=5Hz), 3.24 and
3.62 (2H, ABq, J=18Hz), 4.3-4.5 (1H, m), 5.27-5.28 (total 1H, d, J=5Hz ), 5.87 (1H, m), 6.4-6.7 (4H, m), 7.12 (2H, br s), 7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, br s), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
(5) Cycloheptylearbonyloxymethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1750, 1650 cm-1
NMR (DMSO-d6, δ) : 1.3-1.7 (10H, m), 1.7-2.0 (2H, m), 2.4-2.5 (1H, m), 3.29 and 3.64 (2H, ABq, J=18Hz), 5.28 (1H, d, J=5Hz), 5.62 and 5.73 (2H, ABq, J=6Hz), 5.86 (1H, dd, J=5Hz, 8Hz), 6.48 (1H, d, J=12Hz), 6.63 (1H, d, J=12Hz), 6.76 (1H, s), 7.12 (2H, br s), 7.34 (1H, dd, J=5Hz, 8Hz), 7.65 (1H, d, J=8Hz), 8.45 (2H, m), 9.52 (1H, d, J=8Hz), 11.3 (1H, s) (6) 1-(3-Methylbutoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1640, 1590, 1500 cm-1
NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6Hz), 1.3-1.7 (6H, m), 3.29 and 3.63 (2H, ABq, J=18Hz), 4.12 and 4.13 (total 2H, t, J=7Hz), 5.28 and 5.29 (total 1H, d, J=5Hz), 5.88 (1H, m), 6.3-6.8 (4H, m), 7.19 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.52 and 9.53 (total 1H, d,
J=8Hz), 11.3 (1H, s)
(7) 1-(3-Methylbutyryloxy) ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1750, 1660, 1600, 1510 cm-1
NMR (DMSO-d6, δ) : 0.87 and 0.88 (total 6H, d,
J=7Hz), 1.30 and 1.41 (total 3H, d, J=5Hz), 1.8-2.0 (1H, m), 2.15 and 2.17 (total 2H, d, J=7Hz), 3.30 and 3.64 (2H, ABq, J=17Hz), 5.28 and 5.29 (total 1H, d, J=5Hz), 5.87 (1H, m), 6.4-6.8 (4H, m), 7.13 (2H, br s), 7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
(8) 1-Isobutyryloxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido)-3-[(Z)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1670, 1520 cm-1
NMR (DMSO-d6, δ) : 1.0-1.1 (6H, m), 1.30 and 1.41
(total 3H, d, J=5Hz), 3.29 and 3.65 (2H, ABq, J=18Hz), 5.28 and 5.29 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.4-6.9 (4H, m), 7.13 (2H, br s), 7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.46 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3
(1H, s) (9) 1-Hexyloxycarbonyloxyethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1750, 1660, 1600, 1510 cm-1
NMR (DMSO-d6, δ) : 0.8-1.0 (3H, m), 1.1-1.7 (11H, m), 3.27 and 3.63 (2H, ABq, J=18Hz), 4.0-4.1 (2H, m), 5.2-5.3 (1H, m), 5.8-6.0 (1H, m),
6.4-6.8 (4H, m), 7.13 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.46 (2H, m), 9.52 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
(10) 1-(1-Ethylpropoxycarbonyloxy)ethyl 7β-[2-(2-amino- thiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-ceρhem-4-carboxylate ( syn isomer)
IR (Nujol) : 3300, 1770, 1740, 1650, 1600, 1510 cm-1 NMR (DMSO-d6, δ) : 0.7-0.9 ( 6H, m), 1.35 and 1.45
(total 3H, d, J=5Hz), 1.4-1.6 (4H, m), 3.24 and 3.28 (total 1H, d, J=18Hz), 3.62 (1H, d, J=18Hz), 4.51 (1H, m), 5.27 (1H, d, J=5Hz), 5.87
(1H, m), 6.4-6.7 (4H, m), 7.15 (2H, br s),
7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.52-9.54 (total 1H, d, J=8Hz), 11.3 (1H, s) (11) 1-(3,3-Dimethylbutyryloxy)ethyl 7β-[2-(2-aminothiazol- 4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)- vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1775, 1740, 1655, 1600, 1505 cm-1
NMR (DMSO-d6, δ) : 0.9-1.0 (11H, m), 1.30-1.42
(total 3H, d, J=5.4Hz), 3.25 and 3.64 (2H, ABq,
J=17.8Hz), 5.28-5.29 (total 1H, d, J=4.9Hz), 5.8-5.9 (1H, m), 6.5-6.9 ( 4H, m), 7.22 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (1H, m), 9.53 and 9.56 (total 1H, d, J=8.1Hz), 11.36 (1H, s) 2) 1-(Isobutyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)- 2-(3-pyridyl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1765, 1750, 1655, 1600, 1505 cm-1
NMR (DMSO-d6, δ) : 0.87 (6H, d, J=6.7Hz), 1.34 and 1.45 (3H, d, J=5.4Hz), 1.80-2.0 (1H, m), 3.25 and 3.64 (2H, ABq, J=17.9Hz), 3.89 (2H, d, J=6.6Hz), 5.27 and 5.28 (total 1H, d, J=4.8Hz), 5.8-5.95 (1H, m), 6.4-6.8 (4H, m), 7.20 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.52 and 9.55 (total 1H, d, J=8.2Hz), 11.34 (1H, s) (13) 1-(4-Methylpentoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3300, 1770, 1745, 1660, 1610, 1520 cm-1 NMR (DMSO-d6, δ) : 0.8-0.9 (6H, m), 1.2-1.7 (8H, m),
3.25 and 3.63 (2H, ABq, J=18Hz), 4.0-4.1 (2H, m), 5.27 and 5.29 (total 1H, d, J=5Hz), 5.8-6.0 (1H, m), 6.47 and 6.51 (total 1H, d, J=12Hz), 6.6-6.8 (3H, m), 7.13 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.46 (2H, m), 9.52 and 9.53
(total 1H, d, J=8Hz), 11.3 (1H, s)
(14) (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 3200, 1800, 1765, 1730, 1660 cm-1
NMR (DMSO-d6, δ) : 2.11 (3H, s), 3.34 and 3.68 (2H, ABq, J=18Hz), 4.86 and 5.00 (2H, ABq, J=14Hz), 5.28 (1H, d, J=5Hz), 5.86 (1H, d, J=5.8Hz), 6.44 and 6.60 (2H, ABq, J=12Hz), 6.65 (1H, s), 7.13 (2H, br s), 7.2-7.3 (1H, m), 7.6-7.7 (1H, m), 8.4 (2H, m), 9.50 (1H, d, J=8Hz), 11.3 (1H, s) (15) 1-[(3,3-Dimethylbutoxy)carbonyloxy]ethyl 7β-[2-(2- amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate ( syn isomer)
IR (Nujol) : 1755, 1730, 1650 cm-1
NMR (DMSO-d6, δ) : 0.89 (9H, s), 1.33 and 1.44 (3H, each d, J=5.5Hz), 1.48-1.57 (2H, m), 3.29 and 3.63 (2H, ABq, J=17.9Hz), 4.10-4.18 (2H, m), 5.27 and 5.28 (1H, each d, J=4.9Hz), 5.86 and 5.88 (1H, each dd, J=8.3Hz, 4.9Hz), 6.45-6.73 (4H, m), 7.13 (2H, br s), 7.32-7.37 (1H, m),
7.63-7.67 (1H, m), 8.46 (2H, m), 9.51 and 9.53 (1H, each d, J=8.3Hz), 11.30 (1H, s)
(16) 1-(n-Pentyloxycarbonyloxy)ethyl 7β-(2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1770, 1740, 1640 cm-1
NMR (DMSO-d6, δ) : 0.83-0.89 (3H, m), 1.26-1.58 (9H, m), 3.25 and 3.63 (2H, ABq, J=17.7Hz), 4.06-4.11
(2H, m), 5.27 and 5.28 (1H, two d, J=4.8Hz), 5.83-5.92 (1H, m), 6.44-6.73 (4H, m), 7.12 (2H, br s), 7.31-7.37 (1H, m), 7.63-7.67 (1H, m), 8.46 (2H, m), 9.51 and 9.53 (1H, two d, J=8.2Hz), 11.30 (1H, s)
(17) 1-(1-Ethylpropoxycarbonyloxy) ethyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(2- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( yn isomer) IR (Nujol) : 1760, 1750, 1640 cm-1
NMR (DMSO-d6, δ) : 0.80-0.88 (6H, m), 1.37 and 1.48
(3H, two d, J=5.4Hz), 1.46-1.55 (4H, m), 2.44 (3H, m), 3.04 and 3.45 (2H, ABq, J=17.9Hz), 4.49-4.54 (1H, m), 5.20 (1H, d, J=4.9Hz),
5.78-5.87 (1H, m), 6.51-6.80 (4H, m), 7.11 (2H, s), 7.12-7.28 (1H, m), 7.40-7.47 (1H, m),
8.35-8.37 (1H, m), 9.45-9.47 (1H, each d,
J=8.3Hz), 11.28 (1H, s)
(18) (E)-2-(Isobutoxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(2- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3250, 1765, 1695, 1655 cm-1
NMR (DMSO-d6, δ) : 0.89 (6H, d, J=6.7Hz), 1.01 (3H, t, J=7.7Hz), 1.90 (1H, m), 2.26 (2H, m), 2.38 (3H, s), 3.06 and 3.40 (2H, ABq, J=17.6Hz), 3.88 (2H, d, J=6.4Hz), 4.82 and 4.92 (2H, ABq,
J=11.9Hz), 5.17 (1H, d, J=4.9Hz), 5.76 (1H, dd,
J=8.2Hz, 4.9Hz), 6.53 (1H, d, J=12.0Hz), 6.62 (1H, s), 6.68 (1H, d, J=12.0HZ), 6.98 (1H, t, J=7.7Hz), 7.12-7.16 (3H, m), 7.43 (1H, m), 8.35 (1H, m), 9.46 (1H, d, J=8.2Hz), 11.29 (1H, s)
(19) Pivaloyloxymethyl 7β-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(2-methylpyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3270, 1770, 1740, 1655 cm-1
NMR (DMSO-d6, δ) : 1.14 (9H, s), 2.43 (3H, s), 3.18 and 3.49 (2H, ABq, J=17.8Hz), 5.20 (1H, d, J=4.8Hz), 5.56 and 5.74 (2H, ABq, J=5.9Hz), 5.81 (1H, d, J=8.2Hz, 4.8Hz), 6.53 (1H, d, J=11.9Hz), 6.63 (1H, s), 6.73 (1H, d, J=11.9Hz), 7.13 (2H, br s), 7.17 (1H, m), 7.44 (1H, m), 8.36 (1H, m), 9 . 46 (1H, d , J=8 . 2Hz ) , 11 . 29 (1H, s )
(20) 1-(Cyclohexyloxycarbonyloxy) ethyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(2- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1775, 1750, 1660, 1605 cm-1
NMR (DMSO-d6, δ) : 1.12-1.98 (10H, m), 1.35 and 1.47 (3H, each d, J=5.4Hz), 2.44 (3H, s), 3.06 and 3.38 (2H, ABq, J=18.2Hz), 4.55 (1H, m), 5.19 and
5.21 (1H, each d, J=4.9Hz), 5.83 (1H, m), 6.55 (1H, d, J=12.2Hz), 6.61 (1H, s), 6.62 (1H, m), 6.77 (1H, d, J=12.2Hz), 7.12 (2H, br s), 7.16 (1H, m), 7.44 (1H, m), 8.36 (1H, m), 9.45 and 9.47 (1H, d, J=8.2Hz), 11.28 (1H, s)
(21) 1-(Cyclohsxyloxycarbonyloxy)ethyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(6- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1770, 1745, 1650 cm-1
NMR (DMSO-d6, δ) : 1.05-1.96 (10H, m), 1.35 and
1.45 (3H, each d, J=5.4Hz), 2.45 (3H, s), 3.24 and 3.60 (2H, ABq, J=18.0Hz), 4.52 (1H, m), 5.27 and 5.28 (1H, each d, J=4.9Hz), 5.83-5.92 (1H, m), 6.39-6.74 (3H, m) , 6.64 and 6.65 (1H, two s), 7.13 (2H, br s), 7.20 (1H, m), 7.50-7.55 (1H, m), 8.33 (1H, s), 9.52 and 9.53 (1H, each d, J=8.2Hz), 11.30 (1H, s)
(22) Pivaloyloxymethyl 7β-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(6-methylpyridin-3- yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 1750, 1650, 1590 cm-1
NMR (DMSO-d6, δ) : 1.12 (9H, s), 2.45 (3H, s), 3.28 and 3.62 (2H, ABq, J=18.2Hz), 5.27 (1H, d, J=4.9Hz), 5.62 and 5.77 (2H, ABq, J=5.9Hz), 5.86 (1H, dd, J=8.2Hz, 4.9Hz), 6.42 (1H, d, J=12.0Hz), 6.60 (1H, d, J=12.0Hz), 6.66 (1H, s), 7.13 (2H, br s), 7.19-7.23 (1H, m), 7.50-7.56
(1H, m), 8.32-8.33 (1H, m), 9.53 (1H, d,
J=4.9Hz), 11.31 (1H, s)
(23) (E)-2-(Isobutoxycarbonyl)-2-p2entenyl 7β-[2-(2-amino- 4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(6- methylpyridin-3-yl)vinyl]-3-cephem-4-carboxylate ( syn isomer)
IR (Nujol) : 1760, 1700, 1660 cm-1
NMR (DMSO-d6, δ) : 0.87 (6H, d, J=6.7Hz), 0.98 (3H, t, J=7.5Hz), 1.81-1.95 (1H, m), 2.19-2.34 (2H, m), 2.44 (3H, s), 3.23 and 3.58 (2H, ABq,
J=18.0Hz), 3.85 (2H, d, J=6.7Hz), 4.82 and 4.89 (2H, ABq, J=11.8Hz), 5.25 (1H, d, J=4.9Hz), 5.81 (1H, dd, J=8.2Hz, 4.9Hz), 6.37 (1H, d, J=12.0Hz), 6.53 (1H, d, J=12.0Hz), 6.65 (1H, s),
6.95 (1H, t, J=7.5Hz), 7.13 (2H, br s), 7.13-7.16 (1H, m), 7.49-7.54 (1H, m), 8.30-8.31 (1H, m), 9.52 (1H, d, J=8.2Hz), 11.30 (1H, s) (24) (E)-2-(Isobutoxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1760, 1710, 1690, 1640 cm-1
NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6.7Hz), 0.98 (3H, t, J=7.6Hz), 1.88 (1H, m), 2.26 (2H, m), 3.22 and 3.60 (2H, ABq, J=17.9Hz), 3.86 (2H, d,
J=6.5Hz), 4.81 and 4.89 (2H, ABq, J=11.9Hz), 5.25 (1H, d, J=4.9Hz), 5.81 (1H, dd, J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.1Hz), 6.56 (1H, d, J=12.1Hz), 6.64 (1H, s), 6.95 (1H, t, J=7.7Hz), 7.12 (2H, br s), 7.32 (1H, m), 7.63 (1H, m), 8.44 (2H, m), 9.52 (1H, d, J=8.2Hz), 11.30 (1H, s)
(25) (E)-2-(n-Hexyloxycarbonyl)-2-pentenyl 7β-[2-(2-amino- 4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3280, 1775, 1705, 1645 cm-1
NMR (DMSO-d6, δ) : 0.82-0.87 (3H, m), 0.94-1.00 (3H, m), 1.25 (6H, m), 1.49-1.57 (2H, m), 2.18-2.33 (2H, m), 3.21 and 3.59 (2H, ABq, J=17.9Hz), 4.06 (2H, m, J=6.5Hz), 4.79 and 4.88 (2H, ABq,
J=11.8Hz), 5.25 (1H, d, J=4.9Hz), 5.82 (1H, dd,
J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.0Hz), 6.56 (1H, d, J=12.0Hz), 6.64 (1H, s), 6.94 (1H, t, J=7.7Hz), 7.13 (2H, br s), 7.30-7.36 (1H, m), 7.62-7.66 (1H, m), 8.44-8.45 (2H, m), 9.51 (1H, d, J=8.2Hz), 11.30 (1H, s)
(26) (E)-2-(n-Butoxycarbonyl)-2-pentenyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 3300, 1780, 1710, 1650 cm-1
NMR (DMSO-d6, δ) : 0.87 (3H, t, J=7.2Hz ), 0.98 (3H, t, J=7.5Hz), 1.23-1.41 (2H, m), 1.49-1.63 (2H, m), 2.18-2.33 (2H, m), 3.23 and 3.66 (2H, ABq, J=17.9Hz), 4.07 (2H, t, J=6.4Hz), 4.79 and 4.88
(2H, ABq, J=11.8Hz), 5.26 (1H, d, J=4.9Hz), 5.82 (1H, dd, J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.1Hz), 6.56 (1H, d, J=12.1Hz), 6.64 (1H, s), 6.94 (1H, t, J=7.7Hz), 7.12 (2H, br s), 7.30-7.36 (1H, m), 7.62-7.66 (1H, m), 8.43-8.45 ( 2H, m) , 9. 51 (1H, d, J=8. 2Hz ) , 11. 30 (1H, s )
(27) (E)-2-(3-Methylbutoxycarbonyl)-2-butenyl 7β-[2-(2- amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 3310, 1780, 1710, 1655, 1610 cm-1
NMR (DMSO-d6, δ) : 0.87 (6H, d, J=6.5Hz), 1.42-1.52 (2H, m), 1.58-1.69 (1H, m), 1.85 (3H, d, J=7.2Hz), 3.23 and 3.60 (2H, ABq, J=17.8Hz),
4.09 (2H, t, J=6.6Hz), 4.79 and 4.88 (2H, ABq, J=11.8Hz), 5.25 (1H, d, J=4.9Hz), 5.83 (1H, dd, J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.1Hz), 6.57 (1H, d, J=12.1Hz), 6.64 (1H, s), 6.64-6.99 (3H, m), 6.99-7.13 (1H, m), 7.62-7.66 (1H, m), 8.45
(2H, m), 9.51 (1H, d, J=8.2Hz), 11.30 (1H, m)
(28) (E)-2-(Ethoxycarbonyl)-2-butenyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1700, 1650 cm-1
NMR (DMSO-d6, δ) : 1.20 (3H, t, J=7.1Hz), 1.85 (3H, d, J=7.2Hz), 3.24 and 3.61 (2H, ABq, J=17.9Hz), 4.11 (2H, q, J=7.1Hz), 4.78 and 4.89 (2H, ABq,
J=11.8Hz), 5.26 (1H, d, J=4.9Hz), 5.84 (1H, dd, J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.1Hz), 6.57 (1H, d, J=12.1Hz), 6.65 (1H, s), 7.04 (1H, g, J=7.2Hz), 7.13 (2H, s), 7.30-7.36 (1H, s),
7.62-7.66 (1H, m), 8.45 (2H, m), 9.51 (1H, d,
J=8.2Hz), 11.31 (1H, s)
(29) (E)-2-(Isobutoxycarbonyl)-2-butenyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin- 3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) IR (Nujol) : 3280, 1765, 1700, 1650 cm-1
NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6.7Hz), 1.84-1.91 (4H, m), 3.23 and 3.60 (2H, ABq, J=18.0Hz), 3.85 (2H, d, J=6.7Hz ), 4.81 and 4.90 (2H, ABq,
J=11.9Hz), 5.25 (1H, d, J=4.8Hz), 5.82 (1H, dd,
J*=8.1Hz, 4.8Hz), 6.43 (1H, d, J=12.1Hz), 6.56 (1H, d, J=l2.1Hz), 6.64 (1H, s), 7.07 (1H, q, J=7.2Hz), 7.12 (2H, br s), 7.30-7.36 (1H, m), 7.62-7.66 (1H, m), 8.43-8.45 (2H, m), 9.52 (1H, d, J=8.1Hz), 11.32 (1H, s)
(30) (E)-2-(3-Methylbutoxycarbonyl)-2-pentenyl 7β-[2-(2- amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate ( syn isomer)
IR (Nujol) : 3280, 1770, 1700, 1640 cm-1
NMR (DMSO-d6, δ) : 0.87 (6H, d, J=6.5Hz), 0.97 (3H, t, J=7.5Hz), 1.43-1.71 (3H, m), 2.18-2.33 (2H, m), 3.23 and 3.60 (2H, ABq, J=17.9Hz), 4.10 (2H, t, J=6.7Hz), 4.79 and 4.87 (2H, ABq, J=11.8Hz),
5.26 (1H, d, J=4.9Hz), 5.82 (1H, dd, J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.1Hz), 6.56 (1H, d, J=12.1Hz), 6.64 (1H, s), 6.93 (1H, t, J=7.7Hz), 7.13 (2H, s), 7.30-7.36 (1H, m), 7.62-7.66 ( 1H , m ) , 8. 43 -8. 45 ( 2H, m ) , 9. 52 ( 1H , d, J=8 . 2Hz),
11.30 (1H, s)
(31) (E)-2-(Ethoxycarbonyl)-2-pentenyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (Nujol) : 3280, 1770, 1705, 1640 cm-1
NMR (DMSO-d6, δ) : 0.97 (3H, t, J=7.5Hz), 1.20 (3H, t, J=7.1Hz), 2.17-2.32 (2H, m), 3.23 and 3.61 (2H, ABq, J=17.7Hz), 4.11 (2H, q, J=7.0Hz), 4.77 and 4.87 (2H, ABq, J=11.8Hz), 5.26 (1H, d,
J=4.8Hz), 5.82 (1H, dd, J=8.2Hz, 4.8Hz), 6.43 (1H, d, J=12.1Hz), 6.57 (1H, d, J=12.1Hz), 6.65 (1H, s), 6.93 (1H, t, J=7.7Hz), 7.12 (2H, br s), 7.29-7.36 (1H, m) , 7.62-7.66 (1H, m), 8.46 (2H, m), 9.51 (1H, d, J=8.2Hz), 11.30 (1H, s)
(32) 1-(Ethoxycarbonyloxy) ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl) vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1650 cm-1
NMR (DMSO-d6, δ) : 1.16 and 1.22 (total 3H, each t, J=7.1Hz), 1.33 and 1.44 (total 3H, each d,
J=5.4Hz), 3.25 and 3.64 (2H, ABq, J=17.8Hz), 4.13 and 4.14 (total 2H, each q, J=7.1Hz ), 5.28 and 5.29 (total 1H, each d, J=4.8Hz), 5.83-5.92 (1H, m), 6.45-6.74 (3H, m), 6.65 (1H, s), 7.12 (2H, br s), 7.31-7.37 (1H, m), 7.64-7.67 (1H, m), 8.44-8.52 (2H, m), 9.51 and 9.53 (total 1H, each d, J=8.2Hz), 11.30 (1H, s)
(33) 1-Acetoxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1650 cm-1
NMR (DMSO-d6, δ) : 1.30 and 1.40 (total 3H, each d, J=5.5Hz), 2.01 and 2.02 (total 3H, each s), 3.27 and 3.64 (2H, ABq, J=16.9Hz), 5.27 and 5.28 (total 1H, each d, J=8.6Hz), 5.83-5.92 (1H, m), 6.42-6.84 (3H, m), 6.65 (1H, s), 7.12 (2H, br s), 7.31-7.38 (1H, m), 7.64-7.68 (1H, m),
8.45-8.46 (2H, m), 9.51 and 9.52 (total 1H, each d, J=8.2Hz), 11.30 (1H, s) (34) 1-(Cyclopentyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1660 cm-1
NMR (DMSO-d6, δ) : 1.33 and 1.44 (total 3H, each d,
J=5,4Hz), 1.50-1.80 (10H, m), 3.25 and 3.63 (2H, ABq, J=18.0Hz), 4.97-5.03 (1H, m), 5.27 and 5.29 (total 1H, each d, J=4.9Hz), 5.83-5.92 (1H, m), 6.45-6.73 (3H, m) , 6.64 (1H, s), 7.13 (2H, br s), 7.36-7.38 (1H, m), 7.64-7.67 (1H, m),
8.44-8.50 (2H, m), 9.52 and 9.54 (total 1H, two d, J=8.2Hz), 11.31 (1H, s)
(35) 1-(Isopropyloxycarbonyloxy)ethyl 7β-[2-(2-amino- thiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1660 cm-1
NMR (DMSO-d6, δ) : 1.21-1.26 (6H, m), 1.33 and 1.44 (total 3H, two d, J=5.4Hz), 3.25 and 3.63 (2H,
ABq, J=18.0Hz), 4.72-4.81 (1H, m), 5.27 and 5.29 (total 1H, two d, J=4.9Hz), 5.83-5.92 (1H, m), 6.45-6.57 (3H, m), 6.65 (1H, s), 7.12 (2H, br s), 7.31-7.37 (1H, m), 7.63-7.66 (1H, m),
8.43-8.50 (2H, m), 9.51 and 9.53 (total 1H, two d, J=8.2Hz), 11.30 (1H, s)
(36) 1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydrσxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1740, 1655 cm-1
NMR (DMSO-d6, δ) : 1.14-1.87 (10H, m), 1.34 and 1.45 (total 3H, each d, J=5.2Hz), 3.25 and 3.63 (2H, ABq, J=18.1Hz), 4.48-4.59 (1H, m), 5.24-5.30 (1H, m), 5.83-5.92 (1H, m), 6.48-6.74 (3H, m), 6.64 (1H, s), 7.12 (2H, br s), 7.29-7.38 (1H, m), 7.63-7.67 (1H, m), 8.42-8.48 (2H, m), 9.51 and 9.53 (total 1H, each d, J=8.2Hz), 11.30 (1H, s)
Example 17
The following compounds were obtained according to similar manners to those of Examples 4, 8 and 12.
(1) 1-(2-Ethylbutyryloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1792, 1757, 1697 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.3-1.6 (7H, m),
2.1-2.2 (1H, m), 3.40 and 3.65 (2H, ABq,
J=18Hz), 5.36 (1H, d, J=5Hz ), 6.0-6.1 (1H, m), 6.4-6.9 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.9-10.0 (1H, m)
(2) 1-Cyclopentylcarbonyloxyethyl 7β-[2-(2-tritylamino- thiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1770, 1725, 1665 cm-1
NMR (DMSO-d6, δ) : 1.32 and 1.44 (total 3H, d,
J=5Hz), 1.4-1.9 (8H, m), 2.7-2.8 (1H, m), 3.30 and 3.61 (2H, ABq, J=18Hz), 5.32 (1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.5-6.9 (4H, m), 7.1-7.3 (31H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 8.78 (1H, br s), 9.9-10.0 (1H, m)
(3) 1-Cyclohexylcarbonyloxyethyl 7β-[2-(2-aminothiazol-4- yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer) IR (KBr) : 1790, 1751, 1683, 1620 cm-1
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.32 and 1.44 (total 3H, d, J=5Hz), 2.1-2.3 (1H, m), 3.2-3.4 (1H, m), 3.6-3.8 (1H, m), 5.36 and 5.37 (total 1H, d, J=5Hz), 6.0-6.1 (1H, m), 6.4-6.9 (4H, m),
7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.94 and 9.96 (total 1H, d, J=8Hz)
(4) 1-Propionyloxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1788, 1755, 1682, 1618 cm-1
NMR (DMSO-d6, δ) : 0.9-1.1 (3H, m), 1.32 and 1.44 (total 3H, d, J=5Hz), 3.2-3.3 (1H, m), 3.6-3.7 (1H, m), 5.3-5.4 (1H, m), 6.0-6.1 (1H, m),
6.5-6.9 (4H, m), 7.1-7.3 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.9-10.0 (1H, m)
(5) 1-Valeryloxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- trytyloxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1790, 1755, 1684, 1618 cm-1
NMR (DMSO-d6, δ) : 0.8-0.9 (3H, m), 1.2-1.6 (7H, m), 2.2-2.3 (2H, m), 3.2-3.4 (1H, m), 3.66 (1H, d, J=18Hz), 5.3-5.4 (1H, m), 6.0-6.1 (1H, m),
6.4-6.9 (4H, m), 7.1-7.4 (18H, m), 7,6-7.7 (1H, m) , 8.4-8.5 (2H, m), 9.9-10.0 (1H, m)
(6) 1-(1-Propylbutoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.1-1.6 (11H, m), 3.2-3.4 (1H, m), 3.5-3.7 (1H, m), 4.65 (1H, m), 5.36 (1H, d, J=5Hz), 6.0-6.1 (1H, m), 6 . 5-6 .7 ( 4H , m) , 7 . 2-7 . 4 ( 18H, m) , 7 . 6-7 . 7 (1H, m) , 8. 4-8 . 5 ( 2H, m) , 9. 94 and 9. 96 ( total 1H, d, J=8Hz ) (7) 1-Butyloxycarbonyloxyethyl 7β-[2-(2-aminothiazol-4- yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1788, 1765, 1684, 1620 cm-1
NMR (DMSO-d6, δ) : 0.82 and 0.88 (total 3H, t,
J=7Hz), 1.2-1.7 (4H, m), 1.36 and 1.49 (total
3H, d, J=5Hz), 3.2-3.4 (1H, m), 3.65 (1H, d, J=18Hz), 4.0-4.1 (2H, m), 5.35 and 5.37 (total 1H, d, J=5Hz), 6.0-6.1 (1H, m), 6.5-6.8 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.94 and 9.95 (total 1H, d, J=8Hz )
(8) 1-(2,2-Dimethylpropoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1790, 1763, 1684, 1618 cm-1
NMR (DMSO-d6, δ) : 0.87 and 0.90 (total 9H, s), 1.38 and 1.50 (total 3H, d, J=5Hz), 3.2-3.4 (1H, m), 3.65 (1H, d, J=18Hz), 3.82 (2H, s), 5.35 (1H, d, J=5Hz), 6.0-6.1 (1H, m), 6.4-6.8 (4H, m),
7.1-7.3 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.94 and 9.95 (total 1H, d, J=8Hz)
(9) 1-(1-Methylbutoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-carbσxylate (syn isomer)
IR (KBr) : 1790, 1759, 1684, 1618 cm-1
NMR (DMSO-d6, δ) : 0.7-1.5 (13H, m), 3.2-3.3 (1H, m), 3.64 (1H, d, J=18Hz), 4.6-4.8 (1H, m), 5.36 (1H, d, J=5Hz), 6.0-6.1 (1H, m) , 6.4-6.8 (4H, m), 7.2-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.9-10.0 (1H, m) (10) 1-(4-MethyIpentancyloxy)ethyl 7β-[2-(2-aminothiazol- 4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin- 3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1791, 1751, 1683, 1618 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.2-1.6 (6H, m), 2.2-2.4 (2H, m), 3.2-3.4 (1H, m), 3.65 (1H, d,
J=18.1Hz), 5.2-5.4 (1H, m), 5.9-6.1 (1H, m), 6.4-6.9 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.8-10.0 (1H, m) (11) 1-(Butyryloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2- trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1787, 1758, 1681, 1619 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (3H, m), 1.32 and 1.44 (3H, d, J=5.4Hz), 1.4-1.6 (2H, m), 2.2-2.3 ( 2H m), 3.2-3.4 (2H m), 3.66 (1H, d, J=18.5Hz), 5.3-5.4 (1H, m), 5.9-6.1 (1H, m), 6.4-6.8 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.9-10.1 (1H, m)
(12) 1-(2-Ethylbutoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1789, 1764, 1681, 1619 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.1-1.6 (8H, m), 3.2-3.4 (1H, m), 3.65 (1H, d, J=18.1Hz), 3.9-4.1 (2H, m), 5.2-5.4 (1H, m), 5.9-6.1 (1H, m),
6.4-6.8 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.9-10.1 (1H, m) (13) 1-(Propoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1791, 1762, 1983, 1616, 1540 cm-1
NMR (DMSO-d6, δ) : 0.83, 0.88 (3H, t, J=7.4Hz),
1.36, 1.49 (3H, d, J=5.4Hz), 3.2-3.4 (1H, m), 3.65 (1H, d, J=17.8Hz), 4.05 (2H, m), 5.34-5.38 (1H, m), 5.95-6.10 (1H, m) , 6.40-6.80 (4H, m), 7.1-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.85-10.0 (1H, m)
(14) 1-(Cyclobutylmethylσxycarbonyloxy) ethyl 7β-[2-(2- aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3- [(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1786, 1763, 1684, 1618 cm-1
NMR (DMSO-d6, δ) : 1.36 and 1.49 (total 3H, d,
J=5Hz), 1.6-2.1 (6H, m), 2.5-2.6 (1H, m),
3.2-3.4 (1H, m), 3.65 (1H, d, J=18Hz), 5.36 and 5.37 (total 1H, d, J=5Hz), 6.0-6.1 (1H, m),
6.5-6.8 (4H, m), 7.2-7.4 (18H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.95 (1H, d, J=8Hz)
(15) 1-(1-Ethylpropoxycarbonyloxy)ethyl 7β-[2- acetoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- [(Z)-2-pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1766.5, 1762.6, 1718.6, 1683.6 cm-1
NMR (DMSO-d6, δ) : 0.83 ( 6H, t, J=7.4Hz ), 1.34 and 1.46 (3H, two d, J=5.4Hz), 1.45-1.56 (4H, m),
2.14 (3H, s), 3.27 and 3.68 (2H, ABq, J=18.3Hz), 4.49 (1H, m), 5.32 and 5.33 (1H, two d, J=4.9Hz), 5.90 and 5.91 (1H, two dd, J=8.1Hz, 4.9Hz), 6.45-6.72 (3H, m), 7.04 and 7.07 (1H, two s), 7.32-7.36 (3H, m), 7.63-7.72 (1H, m), 8 . 45-8 . 47 ( 2H , m) , 9 . 93 and 9 . 95 (1H, two d , J=8 . 1Hz )
Example 18
The following compounds were obtained according to similar manners to those of Examples 5 and 15.
(1) 1-(2-Ethylbutyryloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1786, 1776, 1749, 1670 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.3-1.7 (7H, m), 2.15 (1H, m), 3.2-3.7 (2H, m), 5.29 (1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.4-6.9 (4H, m), 7.12 (2H, s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m),
8.4-8.5 (2H, m), 9.52 and 9.54 (total 1H, d, J=8Hz), 11.3 (1H, s)
(2) 1-Cyclopentylcarbonyloxyethyl 7β-[2-(2-aminothiazol- 4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1784, 1753, 1678, 1620 cm-1
NMR (DMSO-d6, δ) : 1.30 and 1.41 (total 3H, d,
J=5Hz), 1.4-1.9 (8H, m), 2.6-2.8 (1H, m), 3.28 and 3.65 (2H, ABq, J=18Hz), 5.28 and 5.29 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.4-6.9 (4H, m), 7.13 (2H, br s), 7.2-7.3 (1H, m), 7.6-7.7 (1H, m), 8.3-8.4 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
(3) 1-Cyclohexylcarbonyloxyethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate (syn isomer)
IR (KBr) : 1782, 1751, 1674, 1616 cm-1
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.30 and 1.40 (total 3H, d, J=5Hz), 2.1-2.3 (1H, m), 3.24 and 3.65 (2H, ABq, J=18Hz), 5.28 and 5.29 (total 1H, d, J=5Hz), 5.8-6.0 (1H, m), 6.4-6.8 (4H, m), 7.13 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (1H, m), 9.52 and 9.53 (total 1H, d,
J=8Hz), 11.3 (1H, s)
(4) 1-Propionyloxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-carboxylate (syn isomer)
IR (Nujol) : 1778, 1757, 1678, 1620 cm-1
NMR (DMSO-d6, δ) : 1.0-1.1 (3H, m), 1.3 and 1.40
(total 3H, d, J=5Hz), 2.30 (2H, q, J=7Hz),
3.2-3.3 (1H, m), 3.6-3.7 (1H, m), 5.2-5.3 (1H, m), 5.8-5.9 (1H, m), 6.4-6.9 (4H, m), 7.12 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.52 (total 1H, d, J=8Hz), 11.3 (1H, s) (5) 1-Valeryloxyethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1782, 1759, 1670, 1618 cm-1
NMR (DMSO-d6, δ) : 0.84 (3H, t, J=7Hz), 1.2-1.6 (4H, m), 1.30 and 1.40 (total 3H, d, J=5Hz), 2.28
(2H, t, J=6Hz), 3.2-3.3 (1H, m), 3.64 (1H, d, J=18Hz), 5.28 and 5.29 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.4-6.9 (4H, m), 7.13 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz),
11.3 (1H, s)
(6) 1-(1-Propylbutyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer )
IR (KBr) : 1784, 1759, 1674, 1618 cm-1
NMR (DMSO-d6, δ) : 0.8-0.9 (6H, m), 1.2-1.6 (11H, m), 3.2-3.3 (1H, m), 3.6-3.7 (1H, m), 4.6-4.7 (1H, m), 5.27 (1H, d, J=5Hz), 5.8-5.9 (1H, m),
6.4-6.7 (4H, m), 7.14 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s) (7) 1-Butyloxycarbonyloxyethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1767, 1678, 1620 cm-1
NMR (DMSO-d6, δ) : 0.87 (3H, t, J=7Hz), 1.2-1.7 (7H, m), 3.2-3.4 (1H, m), 3.64 (1H, d, J=18Hz), 4.09 and 4.10 (total 2H, t, J=6Hz), 5.27 and 5.29 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.4-6.8 (4H, m), 7.13 (2H, br s), 7.2-7.4 (1H, m),
7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
(8) 1-(2,2-Dimethylpropoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1767, 1674, 1616 cm-1
NMR (DMSO-d6, δ) : 0.89 (9H, s), 1.36 and 1.46
(total 3H, d, J=5Hz), 3.2-3.3 (1H, m), 3.63 (1H, d, J=18Hz), 3.81 and 3.82 (total 2H, s), 5.27 and 5.29 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m),
6.4-6.8 (4H, m), 7.12 (2H, br s), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.52 (total 1H, d, J=8Hz), 11.3 (1H, s) (9) 1-(1-Methylbutoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate ( syn isomer)
IR (KBr) : 1780, 1759, 1673, 1616 cm-1
NMR (DMSO-d6, δ) : 0.8-0.9 (3H, m), 1.1-1.6 (10H, m), 3.2-3.3 (1H, d, J=18Hz), 4.6-4.8 (1H, m), 5.2-5.3 (1H, m), 5.8-5.9 (1H, m), 6.4-6.8 (4H, m), 7.13 (2H, br s), 7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
(10) 1-(4-Methylpentanoyloxy)ethyl 7β-[2-(2-aminothiazol- 4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 3338, 1789, 1751, 1670, 1616 cm-1
NMR (DMSO-d6, δ) : 0.83 (6H, d, J=6.3Hz), 1.3-1.6
(6H, m), 2.28 (2H, t, J=7.6Hz), 3.2-3.4 (1H, m), 3.64 (1H, d, J=17.9Hz), 5.2-5.3 (1H, m), 5.8-6.0 (1H, m), 6.4-6.8 (4H, m), 7.12 (2H, br s), 7.2-7.4 (2H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.4-9.6 (1H, m)
(11) 1-(Butyryloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]- 3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 3411, 1780, 1758, 1670, 1618 cm-1
NMR (DMSO-d6, δ) : 0.7-1.0 (3H, m), 1.30 and 1.40
(3H, d, J=5.5Hz), 1.2-1.6 (2H, m), 2.2-2.4 (2H, m), 3.2-3.4 (1H, m), 3.65 (1H, d, J=18.0Hz), 5.2-5.4 (1H, m), 5.8-6.0 (1H, m), 6.4-6.9 (4H, m), 7.13 (2H, br s), 7.1-7.4 (2H, m), 7.6-7.7 (1H, m), 8.4-8.6 (2H, m), 9.4-9.6 (1H, m), 11.3 (1H, s) (12) 1-(2-Ethylbutoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1762, 1683, 1616 cm-1
NMR (DMSO-d6, δ) : 0.84 (6H, t, J=7.4Hz), 1.1-1.6
(8H, m), 3.2-3.4 (1H, m), 3.63 (1H, d, J=17.9Hz), 4.02 (2H, d, J=5.6Hz), 5.2-5.3 (1H, m), 5.8-5.9 (1H, m), 6.4-6.8 (4H, m), 7.12 (2H, br s), 7.2-7.4 (2H, m) , 7.6-7.7 (1H, m), 8.4-8.6 (2H, m), 9.51 and 9.53 (1H, d, J=8.3Hz), 11.29
(1H, s)
(13) 1-(Propoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1762, 1675, 1616, 1533 cm-1
NMR (DMSO-d6, δ) : 0.87 (3H, t, J=7.4Hz), 1.34 and 1.45 (3H, d, J=5.4Hz), 1.4-1.7 (2H, m), 3.2-3.3 (1H, m), 3.64 (1H, d, J=17.9Hz), 4.05 (2H, m), 5.26-5.30 (1H, m), 5.8-6.0 (1H, m), 6.4-6.8 (4H, m), 7.13 (2H, br s), 7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.51 and 9.53 (1H, d, J=8.3Hz), 11.30 (1H, s) (14) 1-(Cyclobutylmethyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)- 2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate ( syn isomer)
IR (KBr) : 1762, 1674, 1620 cm-1
NMR (DMSO-d6, δ) : 1.34 and 1.44 (total 3H, d,
J=5Hz), 1.6-2.1 (6H, m), 2.5-2.7 (1H, m),
3.2-3.7 (2H, m), 4.07 and 4.08 (2H, d, J=7Hz), 5.27 and 5.29 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.4-6.8 (4H, m) , 7.15 (2H, br s), 7.2-7.4 (1H, m), 7.6-7.7 (1H, m) , 8.4-8.5 (2H, m), 9.52 and 9.53 (total 1H, d, J=8Hz), 11.3 (1H, s)
Example 19
To a solution of 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid dihydrochloride
(2 g) and N-(trimethylsilyl)acetamide (6.98 g) in
dichloromethane (40 ml) was added 2-acetoxyimino-2-(2-aminothiazol-4-yl)acetylchloride hydrochloride (syn isomer) (1.81 g) under ice-cooling. After being stirred for 1 hour at the same temperature, the mixture was poured into diisopropyl ether. The resulting precipitate was collected by filtration, dissolved in water, and adjusted to pH 4 with an aqueous sodium bicarbonate solution. The solution was subjected to Diaion HP-20, and the desired compound was eluted with 20% isopropyl alcohol aqueous solution. The fractions containing the object compound were collected, evaporated in vacuo to remove isopropyl alcohol, and lyophilized to give 7β-[2-acetoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylic acid (syn isomer).
IR (KBr) : 1772.3, 1683.6 cm-1
NMR (DMSO-d6, δ) : 2.14 ( 3H, m), 3.22 and 3.60 (2H, ABq, J=17.7Hz), 5.29 (1H, d, J=4.8Hz), 5.85 (1H, dd, J=8.0Hz, 4.8Hz), 6.55 (1H, d, J=11.6Hz), 6.62 (1H, d, J=11.6Hz), 7.07 (1H, s), 7.31-7.35
(3H, m), 7.63-7.72 (1H, m), 8.43-8.46 (2H, m), 9.93 (1H, d, J=8.0Hz)
Example 20
To a solution of 1-(1-ethylpropoxycarbonyloxy)ethyl
7β-[2-acetoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) (100 mg) in methanol (1 ml) was added concentrated hydrochloric acid (32.8 yl) at room temperature. After being stirred for 1 hour at the same temperature. The mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 1-(1-ethylpropoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) (62.9 mg).
IR (Nujol) : 3300, 1770, 1740, 1650, 1600, 1510 cm-1 NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.35 and 1.45 (total 3H, d, J=5Hz), 1.4-1.6 (4H, m), 3.24 and
3.28 (total 1H, d, J=18Hz), 3.62 (1H, d,
J=18Hz), 4.51 (1H, m), 5.27 (1H, d, J=5Hz), 5.87 (1H, m), 6.4-6.7 (4H, m), 7.15 (2H, br s),
7.2-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.5 (2H, m), 9.52-9.54 (total 1H, d, J=8Hz), 11.3 (1H, s)
Example 21
To a solution of 2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acid (syn isomer) (1.14 g) in
N,N-dimethylacetamide (20 ml) was added portionwise potassium carbonate (367 mg) under ice-cooling. After stirring for one hour at the same temperature, at 3-10°C, the mixture was added to the solution prepared by adding dropwise bis ( trimethylsilyl) acetamide (4.62 ml) to a suspension of 7β-amino-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid dihydrochloride (1.0 g) in dichloromethane (30 ml) at ambient temperature, stirring for 30 minutes and then cooling to 3-5°C with ice cooling. After stirring for 3 hours, the mixture was evaporated and the residue was added dropwise to water. The precipitate was filtered, washed with water and solved in
tetrahydrofuran. The solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel
(dichloromethane:methanol = (4:1 - 3:1)) to give 7β-[2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido)-3-[(Z)-2-pyridin-3-yl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (12.6 g).
IR (Nujol) : 1725, 1650 cm-1
NMR (DMSO-d6, δ) : 2.95 and 3.34 (2H, ABq,
J=17.0Hz), 5.21 (1H, d, J=4.9Hz), 5.82 (1H, dd, J=8.2 and 4.9Hz), 6.43 (1H, d, J=12.2Hz), 6.58 (1H, s), 6.89 (1H, d, J=12.2Hz), 7.25-7.30 (18H, m), 7.65 (1H, d, J=8.3Hz), 8.42-8.46 (2H, m), 9.90 (1H, d, J=8.2Hz)
Example 22
To a solution of 1-(1-ethylpropoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) (150 mg) in ethyl acetate (4.5 ml) was added 4N hydrochloric acid in ethyl acetate (0.119 ml) at 5°C. The mixture was stirred at 5°C for 1 hour. The precipitate in the reaction mixture was collected by filtration, washed with ethyl acetate and with diisopropyl ether, and dried in vacuo to give 1-(1-ethylpropoxycarbonyloxy)ethyl
7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
dihydrochloride (syn isomer) (110 mg).
IR (KBr) : 1782, 1759, 1672, 1632 cm-1
NMR (DMSO-d6, δ) : 0.7-1.0 (6H, m), 1.3-1.7 (7H, m), 3.41 and 3.77 (2H, ABq, J=18Hz), 4.4-4.6 (1H, m), 5.3-5.4 (1H, m), 5.8-6.0 (1H, m), 6.6-6.9 (4H, m), 7.31 (1H, s), 7.8-7.9 (1H, m), 8.2-8.3 (1H, m), 8.6-8.8 (2H, m), 9.77 (1H, d, J=8Hz),
12.4 (1H, br s)
Example 23
The following compounds were obtained according to a similar manner to that of Example 22. (1) (E)-2-(n-Butyloxycarbonyl)-2-pentenyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate
dihydrochloride (syn isomer)
IR (KBr) : 1781.9, 1716.3, 1700.9, 1683.6 cm-1
NMR (DMSO-d6, δ) : 0.89 (3H, t, J=7.1Hz ), 0.98 (3H, t, J=7.6Hz), 1.28-1.39 (2H, m), 1.54-1.62 (2H, m), 2.22-2.29 (2H, m) , 3.36 and 3.75 (2H, ABq, J=17.8Hz), 4.09 (2H, t, J=6.1Hz), 4.77 and 4.84 (2H, ABq, J=11.6Hz), 5.34 (1H, d, J=4.4Hz), 5.85
(1H, dd, J=7.7Hz, 4.4Hz), 6.59 (1H, d, J=11.8Hz), 6.67 (1H, d, J=11.8Hz), 6.82 (1H, s), 6.95 (1H, t, J=7.6Hz), 7.75-7.82 (1H, m),
8.15-8.19 (1H, m), 8.69-8.74 (2H, m), 9.74 (1H, d, J=7.7Hz), 12.32 (1H, s)
(2) 1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
dihydrochloride (syn isomer)
IR (KBr) : 1782, 1757, 1670, 1632 cm-1
NMR (DMSO-d6, δ) : 1.1-2.0 (13H, m), 3.40 and 3.78 (2H, ABq, J=18Hz), 5.36 and 5.40 (total 1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.8-6.9 ( 4H, m),
7.8-7.9 (1H, m), 8.2-8.3 (1H, m), 8.7-8.8 (2H, m), 9.76 (1H, d, J=8Hz), 12.4 (1H, s)
(3) 1-(2-Ethylbutyryloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate dihydrochloride (syn isomer)
IR (KBr) : 1782, 1749, 1670, 1630 cm-1
NMR (DMSO-d6, δ) : 0.7-0.9 (6H, m), 1.3-1.6 (7H, m), 2.0-2.2 (1H, m), 3.41 and 3.79 (2H, ABq, J=18Hz), 5.38 (1H, d, J=5Hz), 5.8-5.9 (1H, m), 6.7-6.8 (3H, m), 6.84 (1H, s), 7.8-7.9 (1H, m), 8.2-8.3 (1H, m), 8.7-8.9 (2H, m), 9.77 (1H, d, J=8Hz), 12.41 (1H, s) (4) 1-(3-Methylbutyryloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)- vinyl]-3-cephem-4-carboxylate dihydrochloride (syn isomer)
IR (KBr) : 1784, 1753, 1676, 1632 cm-1
NMR (DMSO-d6, δ) : 0.89 (6H, m), 1.32 and 1.40
(total 3H, d, J=5Hz), 1.8-2.1 (1H, m), 2.17 and 2.20 (total 2H, d, J=6Hz), 3.41 and 3.80 (2H, ABq, J=18Hz), 5.37 and 5.39 (1H, m), 6.5-6.9 (4H, m), 7.8-7.9 (1H, m), 8.2-8.3 (1H, m), 8.7-8.8 (2H, m), 9.77 (1H, d, J=8Hz), 12.4 (1H, s)
Example 24
[(RS)-(1-Ethylpropoxycarbonyloxy)ethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) (590 mg) was dissolved in acetonitrile:pH 3 phosphate buffer (37:63) (120 ml). The mixture was subjected to preparative HPLC utilizing a C18 μ Bondapac resin
(Trademark : Waters Associates, Inc.) and eluted with a solvent system comprised acetonitrile:pH 3 phosphate buffer (37:63) at a flow rate of 80 ml/minute using LC-8A pump (Trademark: Shimadzu Corporation). The fractions containing the more polar compound at retention time of 27.3 minutes were combined and evaporated in vacuo to remove acetonitrile. The residue was adjusted to pH 7 with sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and evaporated in vacuo to give the more polar one (.Compound A) (134 mg) of two diastereomers [i.e.. [(R)-1-(1-ethylpropoxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) and [(S)-1-(1-ethylpropoxycarbonyloxy)ethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer)]. The less polar one (Compound B) (121 mg) of the above diastereomers at retention time of 31.2 minutes was obtained according to a similar manner to that as
described for Compound A.
Compound A :
IR (KBr) : 1783.8, 1758.8, 1675.8, 1618.0 cm-1
NMR (DMSO-d6, δ) : 0.83 (6H, t, J=7.5Hz), 1.35 (3H, d, J=5.4Hz), 1.52-1.60 (4H, m), 3.27 and 3.62
(2H, ABq, J=18.1Hz), 4.48-4.54 (1H, m), 5.27 (1H, d, J=4.9Hz), 5.85 (1H, dd, J=8.3Hz, 4.9Hz), 6.46 (1H, d, J=12.1Hz), 6.59 (1H, d, J=12.1Hz), 6.63 (1H, s), 6.64-6.72 (1H, m), 7.12 (2H, br s), 7.32-7.38 (1H, m), 7.63-7.68 (1H, m) , 8.46
(2H, m), 9.51 (1H, d, J=8.3Hz), 11.3 (1H, s)
[α]D 23 : -436.2° (C=0.5, CHCl3)
Compound B :
IR (KBr) : 1783.8, 1758.8, 1675.8, 1654.6, 1618 cm-1
NMR (DMSO-d6, δ) : 0.83 (6H, t, J=7.3Hz), 1.45 (3H, d, J^5.4Hz), 1.47-1.59 (4H, m), 3.23 and 3.61 (2H, ABq, J=18.0Hz), 4.45-4.52 (1H, m), 5.27 (1H, d, J=4.9Hz), 5.88 (1H, dd, J=8.2Hz, 4.9Hz), 6.52 (1H, d, J=12.1Hz), 6.63-6.68 (1H, m), 6.64
(1H, m), 6.67 (1H, d, J=12.lHz), 7.11 (2H, s), 7.31-7.37 (1H, m), 7.61-7.65 (1H, m), 8.44-8.46 (2H, m), 9.52 (1H, d, J=8.2Hz), 11.3 (1H, s)
[α]D 23 : -546.6° (C=0.5, CHCl3 ) Example 25
Two diastereomers [i.e.,
[(R)-1-(isovaleryloxy)ethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylate (syn isomer)
and
[(S)-1-(isovaleryloxy)ethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-carboxylate (syn isomer)] were obtained according to a similar manner to that of Example 24.
The more polar one (Compound C) of the above
diastereomers
IR (KRr) : 1789.6, 1751.0, 1733.7, 1683.6 cm-1
NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6.6Hz), 1.30 (3H, d, J=5.5Hz), 1.89-2.02 (1H, m), 2.17 (2H, d, J=6.6Hz), 3.30 and 3.65 (2H, ABq, J=17.9Hz), 5.28 (1H, d, J=4.9Hz), 5.86 (1H, dd, J=8.2Hz, 4.9Hz), 6.43 (1H, d, J=12.1Hz), 7.14 (2H, s), 7.32-7.38 (1H, s), 7.64-7.68 (1H, m), 8.45-8.47
(2H, m), 9.42 (1H, d, J=8.2Hz), 11.3 (1H, s)
[α]D 23 : -457.0° (C=0.5, CHCl3)
The less polar one (Compound D) of the above
diastereomers
IR (KBr) : 1781.9, 1749.1, 1683.6, 1670.1 cm-1
NMR (DMSO-d6, δ) : 0.87 (6H, d, J=7.1Hz), 1.41 (3H, d, J=5.3Hz), 1.89-1.96 (1H, m), 2.16 (2H, d, J=6.9Hz), 3.27 and 3.65 (2H, ABq, J=17.8Hz), 5.29 (1H, d, J=4.8Hz), 5.90 (1H, dd, J=8.3Hz,
4.8Hz), 6.49 .(1H, d, J=12.1Hz), 6.65 (1H, s), 6.65 (1H, d, J=12.1Hz), 6.76-6.80 (1H, m), 7.13 (2H, s), 7.31-7.38 (1H, m), 7.63-7.67 (1H, m), 8.46 (2H, m), 9.53 (1H, d, J=8.3Hz), 11.3 (1H, s) [α]D 23 : -545.4° (C=0.5, CHCl3)
Example 26
Two diastereomers [i.e.
[(R)-1-(2-Ethylbutyryloxy)ethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) and
[(S)-1-(2-Ethylbutyryloxy)ethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer) were obtained according to a similar manner to that of Example 24. . The more polar one of the above diastereomers
IR (KBr) : 1786, 1749, 1676, 1620 cm-1
NMR (DMSO-d6, δ) : 0.80 (6H, t, J=7Hz), 1.30 (3H, d, J=5Hz), 1.4-1.6 (4H, m), 2.15 (1H, m), 3.31 and 3.65 (2H, ABq, J=18Hz), 5.29 (1H, d, J=5Hz), 5.86 (1H, dd, J=5Hz, 8Hz), 6.43 (1H, d, J=12Hz),
6.60 (1H, d, J=12Hz), 6.65 (1H, s), 6.76 (1H, q, J=5Hz), 7.16 (2H, br s), 7.36 (1H, dd, J=5Hz, 8Hz), 7.67 (1H, d, J=8Hz), 8.4-8.5 (2H, m), 9.53 (1H, d, J=8Hz), 11.3 (1H, s) . The less polar one of the above diastereomers
IR (KBr) : 1782, 1749, 1676, 1616 cm-1
NMR (DMSO-d6, δ) : 0.79 (6H, t, J=7Hz), 1.42 (3H, d, J=5Hz), 2.15 (1H, m), 3.26 and 3.64 (2H, ABq, J=18Hz), 5.29 (1H, d, J=5Hz), 5.87 (1H, dd,
J=5Hz, 8Hz), 6.50 (1H, d, J=12Hz), 6.65 (1H, s), 6.65 (1H, d, J=12Hz), 6.79 (1H, q, J=5Hz), 7.13 (2H, br s), 7.35 (1H, dd, J=5Hz, 8Hz), 7.65 (1H, d, J=8Hz), 8.4-8.5 (2H, m), 9.54 (1H, d, J=8Hz), 11.3 (1H, s) Example 27
The hydrochloric acid salts of the compounds A and B obtained in Example 24 were obtained according to a similar manner to that of Example 22.
Bis (hydrochloric acid) salt of the compound A.
IR (KBr) : 1781.9, 1772.3, 1756.8, 1683.6,
1670.1 cm-1 Bis (hydrochloric acid) salt of the compound B.
IR (KBr) : 1789.6, 1772.3, 1751.0, 1683.6,
1670.1 cm-1
Example 28
The hydrochloric acid salts of the compounds C and D obtained in Example 25 were obtained according to a similar manner to that of Example 22.
Bis (hydrochloric acid) salt of the compound C
IR (KBr) : 1781.9, 1772.3, 1756.8, 1683.6,
1670.1 cm-1
Bis (hydrochloric acid) salt of the compound D
IR (KBr) : 1789.6, 1772.3, 1751.0, 1683.6,
1670.1 cm-1
Example 29
Two diastereomers [i.e.,
[(R)-1-Cyclohexyloxycarbonyloxyethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) and
[(S)S1-Cyclohexyloxycarbonyloxyethyl] 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)] were obtained according to a similar manner to that of Example 24.
The more polar one (Compound E) of the above
diastereomers
IR (KBr) : 1782, 1759, 1674, 1618 cm-1
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.33 (3H, d, J=5Hz), 3.28 and 3.63 (2H, ABq, J=18Hz), 4.54 (1H, m), 5.27 (1H, d, J=5Hz), 5.86 (1H, dd, J=5Hz, 8Hz), 6.48 (1H, d, J=12Hz), 6.60 (1H, d,
J=12Hz), 6.73 (1H, q, J=5Hz ) 7.13 (2H, br s), 7.35 (1H, dd, J=5Hz, 8Hz), 7.66 (1H, d, J=8Hz), 8.47 (2H, m), 9.52 (1H, d, J=8Hz), 11.3 (1H, s) The less polar one (Compound F) of the above
diastereomers
IR (KBr) : 1782, 1757, 1674, 1618 cm-1
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.44 (3H, d, J=5Hz), 3.25 and 3.63 (2H, ABq, J=18Hz), 4.51 (1H, m), 5.29 (1H, d, J=5Hz), 5.89 (1H, dd,
J=5Hz, 8Hz), 6.51 (1H, d, J=12Hz), 6.65 (1H, s), 6.6-6.7 (2H, m), 7.13 (2H, br s), 7.3-7.4 (1H, m), 7.64 (1H, d, J=8Hz), 8.3-8.6 (2H, m), 9.53 (1H, d, J=8Hz), 11.3 (1H, s)
Example 30
The hydrochloric acid salts of the compounds E and F obtained in Example 29 were obtained according to a similar manner to that of Example 22.
Bis (hydrochloric acid) salt of the compound E
IR (KBr) : 1782, 1757, 1674, 1632 cm-1
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.35 (3H, d, J=5Hz), 3.38 and 3.74 (2H, ABq, J=18Hz), 4.55 (1H, m), 5.34 (1H, d, J=5Hz), 5.86 (1H, dd, J=5.8Hz), 6.6-6.7 (3H. m),6.82 (1H, s), 7.77 (1H, dd, J=5Hz, 8Hz), 8.13 (1H, d, J=8Hz), 8.72 (2H, m), 9.74 (1H, d, J=8Hz), 12.3 (1H, s) Bis (hydrochloric acid) salt of the compound F
IR (KBr) : 1782, 1757, 1668, 1633 cm-1
NMR (DMSO-d6, δ) : 1.1-1.9 (10H, m), 1.42 (3H, d,
J=5Hz), 3.39 and 3.78 (2H, ABq, J=18Hz), 4.4-4.6 (1H, m), 5.38 (1H, d, J=5Hz), 5.90 (1H, dd, J=5Hz, 8Hz), 6.62 (1H, q, J=5Hz), 6.67 (1H, d,
J=12Hz), 6.76 (1H, d, J=12Hz), 6.83 (1H, s), 7.84 (1H, m), 8.19 (1H, d, J=8Hz), 8.6-8.8 (2H, m), 9.76 (1H, d, J=8Hz), 12.3 (1H, s) Example 31
To a suspension of 1-(1-ethylpropyloxycarbonyloxy)-ethyl 7β-amino-3-[(Z)-2-(pyridm-3-yl)vinyl]-3-cephem-4-carboxylate oxalate (250 mg) in dichloromethane (20 ml) was added dropwise bis (trimethylsilyl) acetamide (558 ml) at an ambient temperature. The reaction mixture was stirred for 30 minutes and cooled to 5°C with ice-water bath. 2-acetoxyimino-2-(2-aminothiazol-4-yl)acetyl chloride hydrochloride (syn isomer) (141 mg) was added portionwise to the solution at the same temperature.
After stirring for 30 minutes, the mixture was poured into a mixture of water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over
magnesium sulfate and evaporated under reduced pressure to give 1-(1-ethylpropyloxycarbonyloxy)ethyl 7β-[2-acetoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) (187 mg).
IR (KBr) : 1766.5, 1762.6, 1718.6, 1683.6 cm-1
NMR (DMSO-d6, δ) : 0.83 (6H, t, J=7.4Hz), 1.34 and 1.46 (3H, two d, J=5.4Hz), 1.45-1.56 (4H, m), 2.14 (3H, s), 3.27 and 3.68 (2H, ABq, J=18.3Hz), 4.49 (1H, m), 5.32 and 5.33 (1H, two d, J=4.9Hz), 5.90 and 5.91 (1H, two dd, J=8.1Hz, 4.9Hz), 6.45-6.72 (3H, m), 7.04 and 7.07 (1H, two s), 7.32-7.36 (3H, m), 7.63-7.72 (1H, m), 8.45-8.47 (2H, m), 9.93 and 9.95 (1H, two d, J=8.1Hz) Example 32
The following compound was obtained according to a similar manner to that of Example 31.
1-Cyclohexyloxycarbonyloxyethyl 7β-[2-acetoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-[(Z)-2-(pyridin-3-yl)-vinyl]-3-cephem-4-earboxylate (syn isomer)
IR (KBr) : 1759, 1670, 1619, 1537 cm-1
NMR (DMSO-d6, δ) : 1.0-2.2 (13H, m), 3.0-3.8 (2H, m), 4.4-4.65 (1H, m), 5.2-5.4 (1H, m), 5.9-6.0 (1H, m), 6.4-6.8 (3H, m), 7.06 (1H, d,
J=4.17Hz), 7.2-7.6 (3H, m), 7.6-7.8 (1H, m),
8.47 (2H, br s), 9.9-10.0 (1H, m)
Example 33
The following compound was obtained according to a similar manner to that of Example 20. 1-(Cyclohexyloxycarbonyloxy) ethyl 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4-earboxylate (syn isomer) IR (Nujol) : 1740, 1655 cm-1
NMR (DMSO-d6, δ) : 1.14-1.87 (10H, m), 1.34 and 1.45 (total 3H, each d, J=5.2Hz), 3.25 and 3.63 (2H, ABq, J=18.1Hz), 4.48-4.59 (1H, m), 5.24-5.30 (1H, m), 5.83-5.92 (1H, m), 6.48-6.74 (3H, m), 6.64 (1H, s), 7.12 (2H, br s), 7.29-7.38 (1H, m), 7.63-7.67 (1H, m), 8.42-8.48 (2H, m), 9.51 and 9.53 (total 1H, each d, J=8.2Hz), 11.30 (1H, s)
The following compounds can be obtained according to similar manners to those of Examples mentioned above.
(1) Cyclohexyloxycarbonyloxymethyl 7β-[2-(2-aminothiazol- 4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3- yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
(2) 1-(4-pentenyloxycarbonyloxy)ethyl
7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-[(Z)-2-(pyridin-3-yl)vinyl]-3-cephem-4- carboxylate (syn isomer)
(3) 1-(2-propylvaleryloxy)ethyl 7β-[2-(2-aminothiazol- 4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin- 3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer)
(4) 1-(1-Ethylpropoxycarbonyloxy) ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate sulfate
(syn isomer)
(5) 1-(1-Ethylpropoxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
p-toluenesulfonate (syn isomer)
(6) 1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate sulfate (syn isomer)
(7) 1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate
p-toluenesulfonate (syn isomer)

Claims

C L A I M S
A compound of the formula
wherein R1 is amino or protected amino,
R2 is hydrogen, a hydroxy protective group, lower alkyl or mono (or di or tri)halo(lower)alkyl,
R3 is carboxy or protected carboxy, and
R4 is pyridylvinyl which may have suitable substituent(s),
with proviso that
(i) when R2 ls hydrogen and R4 is
3-pyridylvinyl, then
R1 is not carboxy, and
(ii) when R2 is tetrahydropyranyl and R4 is
3-pyridylvinyl, then
R3 is not benzhydryloxycarbonyl, or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein
R1 is amino, acylamino or mono (or di or tri)phenyl(lower)alkylamino,
R2 is hydrogen, acyl, phenyl(lower)alkyl which may have one or more suitable substituent(s), lower alkyl or mono (or di or tri)halo(lower)alkyl,
R3 is carboxy or esterified carboxy and
R4 is pyridylvinyl which may have lower alkyl.
3. A compound of claim 2, wherein
R2 is hydrogen, lower alkanoyl, mono(or di or tri)phenyl(lower)alkyl, lower alkyl or mono(or di or tri)halo(lower)alkyl,
R3 is carboxy, alkanoyloxy(lower)alkoxycarbonyl,
alkoxycarbonyloxy(lower)alkoxycarbonyl, cycloalkylcarbonyloxy(lower)alkoxycarbonyl which may have suitable substituent(s), cyclo(lower)alkyloxycarbonyloxy(lower)alkoxycarbonyl which may have suitable substituent(s),
cyclo(lower)alkyl(lower)alkoxycarbonyloxy¬
(lower)alkoxycarbonyl,
lower alkoxycarbonyl(lower)alkenyloxyearbonyl, lower alkenyloxycarbonyloxy(lower)alkoxycarbonyl or
(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkoxycarbonyl. 4. A compound of claim 3, wherein
R2 is hydrogen, lower alkanoyl, trityl, lower alkyl or mono(or di or tri)halo(lower)alkyl, R3 is carboxy, C1-C8 alkanoyloxy(lower)alkoxycarbonyl, C1-C7 alkoxycarbonyloxy(lower)alkoxycarbonyl, cyclo(C5-C7)alkylcarbonyloxy¬
(lower)alkoxycarbonyl which may have lower alkyl, cyclo(lower)alkyloxycarbonyloxy¬
(lower)alkoxycarbonyl which may have one or two lower alkyl, cyclo(lower)alkyl(lower)alkoxycarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl, lower alkenyloxycarbonyloxy(lower)alkoxycarbonyl or
(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkoxycarbonyl.
5. A compound of claim 4, wherein
R1 is amino,
R2 is hydrogen,
R3 is lower alkanoyloxy(lower)alkoxycarbonyl,
lower alkoxycarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl or cyclo(lower)alkyloxycarbonyloxy(lower)alkoxycarbonyl, and
R4 is pyridylvinyl.
6. A compound of claim 5, which is selected from the group consisting of :
1-(3-Methylbutyryloxy)ethyl 7β-[2-(2-aminothiazol-4- yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(pyridin-3-yl) vinyl]-3-cephem-4-carboxylate (syn isomer) or its hydrochloride,
1-(1-Ethylpropoxycarbonyloxy)ethyl 7β-[2-(2-amino- thiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) or its hydrochloride,
(E)-2-(n-Butoxycarbonyl)-2-pentenyl 7β-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) or its hydrochloride, and
1-(Cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2- aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2- (pyridin-3-yl)vinyl]-3-cephem-4-carboxylate (syn isomer) or its hydrochloride. 7. A process for preparing a compound of the formula
wherein R1 is ammo or protected ammo,
R2 is hydrogen, a hydroxy protective group, lower alkyl or mono(or di or tri)halo- dower)alkyl,
R3 is carboxy or protected carboxy, and R4 is pyridylvinyl which may have suitable substituent(s),
with proviso that
(i) when R2 is hydrogen and R4 is
3-pyridylvinyl, then
R3 i.s not carboxy, and
(ii) when R2 is tetrahydropy anyl and R4 is
3-pyridylvinyl, then
R3 is not benzhydryloxycarbonyl, or a salt thereof,
which comprises
(1) reacting a compound of the formula :
wherein R3 and R4 are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula wherein R1 and R2 are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof to give a compound of the
formula :
wherein R1, R2, R3 and R4 are each as defined above, or a salt thereof, or
(2) subjecting a compound of the formula
wherein R1, R3 and R4 are each as defined above and
R2 a is a hydroxy protective group, or a salt thereof to elimination reaction of the hydroxy protective group to give a compound of the formula : wherein R1, R3 and R4 are each as defined above, or a salt thereof, or
(3) subjecting a compound of the formula
wherein R1, R2 and R4 are each as defined above, or a salt thereof to esterification reaction
to give a compound of the formula :
wherein R1, R2 and R4 are each as defined above and
R9 is ester moiety of esteri.fi.ed carboxy
represented by a group of the formula -COOR9,
or a salt thereof.
8 . A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a
pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
9. A method for the treatment of infectious diseases which comprises administering a compound of claim 1 of a pharmaceutically acceptable salt thereof to human or animals.
10. A compound of claim 1 or a pharmaceutically
acceptable salt thereof for use as an antimicrobial agent.
EP93922658A 1992-10-23 1993-10-19 Cephem compounds, and their pharmaceutical compositions Withdrawn EP0665847A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9222291 1992-10-23
GB929222291A GB9222291D0 (en) 1992-10-23 1992-10-23 New cephem compounds
GB939314495A GB9314495D0 (en) 1993-07-12 1993-07-12 New cephem compounds
GB9314495 1993-07-12
PCT/JP1993/001505 WO1994010177A1 (en) 1992-10-23 1993-10-19 Cephem compounds, and their pharmaceutical compositions

Publications (1)

Publication Number Publication Date
EP0665847A1 true EP0665847A1 (en) 1995-08-09

Family

ID=26301852

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93922658A Withdrawn EP0665847A1 (en) 1992-10-23 1993-10-19 Cephem compounds, and their pharmaceutical compositions

Country Status (9)

Country Link
EP (1) EP0665847A1 (en)
JP (1) JPH08502513A (en)
KR (1) KR950704331A (en)
CN (1) CN1144222A (en)
CA (1) CA2147609A1 (en)
IL (1) IL107359A0 (en)
MX (1) MX9306572A (en)
TW (1) TW255894B (en)
WO (1) WO1994010177A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69737382T2 (en) 1996-11-06 2007-10-31 Basilea Pharmaceutica Ag Vinyl-pyrrolidinone cephalosporin derivatives
TW415949B (en) * 1996-12-19 2000-12-21 Hoffmann La Roche Vinyl pyrrolidine cephalosporin derivatives with basic substituents
JP4100908B2 (en) 1999-07-30 2008-06-11 エーザイ・アール・アンド・ディー・マネジメント株式会社 Production method of basic antibiotics and inorganic acid salts and oxalate intermediates

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4546101A (en) * 1982-09-10 1985-10-08 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds useful for treating infectious diseases in human being and animals and processes for preparation thereof
GB8519606D0 (en) * 1985-08-05 1985-09-11 Fujisawa Pharmaceutical Co 3 7-d substituted-3-cephem compounds
JPH0686463B2 (en) * 1988-07-01 1994-11-02 明治製菓株式会社 Novel cephem compound, its production method and antibacterial agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9410177A1 *

Also Published As

Publication number Publication date
MX9306572A (en) 1994-04-29
CA2147609A1 (en) 1994-05-11
JPH08502513A (en) 1996-03-19
TW255894B (en) 1995-09-01
KR950704331A (en) 1995-11-17
IL107359A0 (en) 1994-01-25
WO1994010177A1 (en) 1994-05-11
CN1144222A (en) 1997-03-05

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