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WO1992018508A1 - Nouveaux composes de cephem - Google Patents

Nouveaux composes de cephem Download PDF

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Publication number
WO1992018508A1
WO1992018508A1 PCT/JP1992/000472 JP9200472W WO9218508A1 WO 1992018508 A1 WO1992018508 A1 WO 1992018508A1 JP 9200472 W JP9200472 W JP 9200472W WO 9218508 A1 WO9218508 A1 WO 9218508A1
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WO
WIPO (PCT)
Prior art keywords
carboxy
compound
salt
alkyl
formula
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.)
Ceased
Application number
PCT/JP1992/000472
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English (en)
Inventor
Kazuo Sakane
Hideaki Yamanaka
Minoru Sakurai
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
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Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to JP4508083A priority Critical patent/JPH06509550A/ja
Publication of WO1992018508A1 publication Critical patent/WO1992018508A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates to new cephem compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • 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 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
  • R 1 is amino or protected amino
  • Z is N or CH
  • R 2 is hydrogen or an organic group
  • R 3 is lower alkyl
  • R 4 is lower alkyl
  • A is lower alkylene
  • R 5 is hydroxy or protected hydroxy
  • R 6 is carboxy, protected carboxy, carbamoyl
  • the object compound (I) of the present invention can be prepared by the following processes.
  • Process (1) (1)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z and A are each as defined above.
  • R a 2 is protected carboxy(lower)alkyl
  • R 2 b is carboxy(lower)alkyl
  • R 5 a is protected hydroxy
  • R 6 a is protected carboxy
  • Y is a leaving group
  • the starting compounds (II) and (V) or salts thereof can be prepared by the following Processes.
  • R 7 is hydrogen or lower alkyl
  • R 8 is hydrogen or lower alkyl
  • R 9 is amino or protected amino
  • R a 9 is protected ammo.
  • 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 :
  • Suitable “lower alkyl” may include straight or
  • branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
  • 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. benzyl, trityl, 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.
  • 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.
  • acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chlorine, bromine, iodine or fluorine) or the like.
  • Suitable “organic group” may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), mono(or di or tri)halo(lower)alkyl (e.g.
  • lower alkenyl e.g., vinyl, 1-propenyl, allyl,
  • lower alkynyl e.g., ethynyl, 1-propynyl, propargyl, 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.
  • aryl e.g., phenyl, naphthyl, etc.
  • ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.),
  • Suitable "protected carboxy” and “protected carboxy moiety" in the term “protected carboxy(lower)alkyl” may include esterified carboxy and the like. And suitable examples of said ester 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.
  • 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,
  • lower alkynyl ester e.g., ethynyl ester, propynyl ester, etc.
  • lower alkoxyalkyl ester e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester
  • lower alkylthioalkyl ester e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester,
  • mono(or di or tri)halo(lower)alkyl ester e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.
  • lower alkanoyloxy(lower)alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
  • 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,
  • substituent(s) such as substituted or unsubstituted phenyl ester (e . g. , phenyl ester, tolyl ester , t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,
  • lower alkylthioester e.g. methylthioester, ethylthioester, etc.
  • Suitable "lower alkylene” may include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • Suitable "protective group” in the “protected hydroxy group” may include acyl as mentioned above,
  • phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g. benzyl, 4-methoxybenzyl, etc.), tetrahydropyranyl and the like.
  • Suitable mono or di substituted carbamoyl may be mono or di(lower)alkylcarbamoyl (e.g. methylcarbamoyl,
  • dipropylcarbamoyl dipropylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, etc.), and the like.
  • Suitable “leaving group” may be halogen [e.g. chlorine, bromine, iodine, etc.], acyloxy such as
  • sulfonyloxy e.g. benzenesulfonyloxy, tosyloxy, mesyloxy, etc.
  • lower alkanoyloxy e.g. acetyloxy, propionyloxy, 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.
  • 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'-dibenzy
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g.
  • 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 o the compound (II) with a carbonyl 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
  • Suitable reactive derivative at the carboxy group of the compound (III) may include a conventional one used in a ⁇ -lactam chemistry, 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.
  • halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylie 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;
  • phenylazophenyl ester phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • 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,
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide
  • N,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide
  • polyphosphate 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-sulfophenyl)isoxazolium hydroxide
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, 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 (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the carboxy protective group in R a 2 .
  • 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. 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, etc.].
  • organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • the eliminatio 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.].
  • 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, ethanol, 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.
  • 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. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (I) or a salt thereof can be prepared by reaction the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • the present reaction may be carried out in a solvent such as acetone, chloroform, acetonitrile, methylene chloride, ethylene chloride, formamide,
  • reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the reaction may also be carried out in the presence of 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,
  • tri(lower)alkylamine e.g. trimethylamine, triethylamine, diisopropylethylamine etc.
  • picoline alkali metal alkanoate [e.g. sodium 2-ethylhexanoate, etc.]
  • N-(lower)alkylmorpholine N,N-di(lower)alkyIbenzylamine, or the like.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the carboxy protective group in R a 6 .
  • 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 hydroxy group in R 5 is transformed into a
  • the compound (If) or a salt thereof can be prepared by subjecting the compound (Ie) or a salt thereof to
  • 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 reaction is usually carried out in a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • hydrophilic solvents may be used in a mixture with water.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (V) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Vb) or a salt thereof can be prepared by subjecting the compound (Va) or a salt thereof to introduction reaction of the carboxy protective group.
  • the introducing agent of a carboxy protective group to be used in this reaction may include a conventional esterifying agent such as an alcohol or its reactive derivative (e.g. halide, sulfonate, sulfate, diazo
  • This reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, tri(lower) alkylamine, pyridine, or the like.
  • an inorganic or organic base such as an alkali metal carbonate, tri(lower) alkylamine, pyridine, or the like.
  • This reaction is usually carried out in a
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the reaction can be carried out in the presence of a condensing agent as
  • Process (D) is illustrated in Process (1).
  • the compound (IIa) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (V) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent such as alcohols (e.g., methanol, ethanol,
  • reaction temperature is not critical and the
  • reaction is usually carried out under cooling to warming.
  • This reaction may also be carried out in the presence of an inorganic or an organic base as defined in Process
  • the compound (IIe) or a salt thereof can be prepared by subjecting the compound (IIb) or a salt thereof to
  • the present invention includes, within the scope of the invention, the case that the protected hydroxy group in R 5 is transformed into a hydroxy group during the reaction.
  • the compound (IIe) or a salt thereof can be prepared by subjecting the compound (IId) or a salt thereof to elimination reaction of the hydroxy protective group in R a 5 .
  • 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 compound (II) or a salt thereof can be prepared by subjecting the compound (Ilf) or a salt thereof to elimination reaction of the amino protective group in R a 9 .
  • 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.
  • 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.
  • test data on MIC minimum inhibitory concentration
  • the object compound 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.
  • 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
  • Preferred embodiments of the object compound (I) are as follows.
  • R 1 is amino or acylamino
  • Z is N or CH
  • R 2 is hydrogen, lower alkyl.
  • R 3 is lower alkyl.
  • R 4 is lower alkyl
  • A is lower alkylene
  • R 5 is hydroxy, acyloxy, or phenyl(lower)alkoxy which may have one or more suitable substituent(s) [more preferably lower
  • R 6 is carboxy, esterified carboxy [more preferably phenyl(lower)alkyloxycarbonyl which may have one or more suitable substituent(s); most preferably benzhydryloxycarbonyl], carbamoyl, or mono or di(lower)alkylcarbamoyl.
  • Trifluoroacetic acid (10 ml) was dropwise added to the above suspension under ice-cooling. The mixture was stirred at 5°C for an hour and poured into isopropyl ether (100 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to give 7 ⁇ -formamido-3-[N,N-dimethyl-N- ⁇ 2-(2-carboxy-4- oxo-5-hydroxy-1,4-dihydropyridin-1-yl)ethyl ⁇ - ammoniomethyl]-3-cephem-4-carboxylate trifluoroacetate (1.44 g).
  • reaction mixture was kept between 5.0 and 5.5 with an aqueous solution saturated with sodium
  • reaction mixture was diluted with water (30 ml) and ethyl acetate (30 ml) and adjusted to pH 7.0 with an aqueous solution saturated with sodium bicarbonate.
  • the separated aqueous layer was washed with ethyl acetate (30 ml) three times. After adjusted to pH 1.0 with 6N hydrochloric acid, the aqueous layer was subjected to column

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

Abstract

On décrit de nouveaux composés de céphem de la formule (I) où R1 représente amino ou amino protégé, Z représente N ou CH, R2 représente hydrogène ou un groupe organique, R3 représente alkyle inférieur, R4 représente alkyle inférieur, A représente alkylène inférieur, R5 représente hydroxy ou hydroxy protégé et R6 représente carboxy, carboxy protégé etc., et des sels pharmaceutiquement acceptables de ces composés, lesquels peuvent être utilisés comme un médicament.
PCT/JP1992/000472 1991-04-15 1992-04-14 Nouveaux composes de cephem Ceased WO1992018508A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4508083A JPH06509550A (ja) 1991-04-15 1992-04-14 新規なセフェム化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9107973.1 1991-04-15
GB919107973A GB9107973D0 (en) 1991-04-15 1991-04-15 New cephem compounds and process for preparation thereof

Publications (1)

Publication Number Publication Date
WO1992018508A1 true WO1992018508A1 (fr) 1992-10-29

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WO (1) WO1992018508A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096740A3 (fr) * 2006-02-20 2007-10-18 Orchid Res Lab Ltd Nouvelles céphalosporines
WO2011014008A3 (fr) * 2009-07-28 2011-06-30 한국과학기술연구원 Nouveaux dérivés de 3-phénoxy-4-pyrone, de 3-phénoxy-4-pyridone, ou de 4-pyridone, procédé d'élaboration correspondant, et composition antimicrobienne contenant de tels dérivés comme principes actifs

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TWI547496B (zh) * 2011-10-04 2016-09-01 葛蘭素集團公司 抗菌化合物

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GB2117770A (en) * 1982-03-29 1983-10-19 Bristol Myers Co Cephalosporin derivatives
EP0345671A2 (fr) * 1988-06-06 1989-12-13 Fujisawa Pharmaceutical Co., Ltd. Composés céphem et procédés pour leur préparation
JPH06230778A (ja) * 1993-01-29 1994-08-19 Kawai Musical Instr Mfg Co Ltd 音響効果付加装置
JPH06310792A (ja) * 1993-04-22 1994-11-04 Nec Corp 光増幅器

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Publication number Priority date Publication date Assignee Title
GB2117770A (en) * 1982-03-29 1983-10-19 Bristol Myers Co Cephalosporin derivatives
EP0345671A2 (fr) * 1988-06-06 1989-12-13 Fujisawa Pharmaceutical Co., Ltd. Composés céphem et procédés pour leur préparation
JPH06230778A (ja) * 1993-01-29 1994-08-19 Kawai Musical Instr Mfg Co Ltd 音響効果付加装置
JPH06310792A (ja) * 1993-04-22 1994-11-04 Nec Corp 光増幅器

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Title
Chemical Abstracts, vol. 107, no. 13, 28 September 1987, (Columbus, Ohio, US), see page 612, column 2, abstract no. 115433p, & JP,A,6230778 (BANYU PHARMACEUTICAL) 9 February 1987 *
Patent Abstracts of Japan, vol. 12, no. 213 (C-505)[3060], 17 June 1988, & JP,A,6310792 (TAKEDA) 18 January 1988 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007096740A3 (fr) * 2006-02-20 2007-10-18 Orchid Res Lab Ltd Nouvelles céphalosporines
WO2011014008A3 (fr) * 2009-07-28 2011-06-30 한국과학기술연구원 Nouveaux dérivés de 3-phénoxy-4-pyrone, de 3-phénoxy-4-pyridone, ou de 4-pyridone, procédé d'élaboration correspondant, et composition antimicrobienne contenant de tels dérivés comme principes actifs

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JPH06509550A (ja) 1994-10-27

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