WO1994010177A1 - Cephem compounds, and their pharmaceutical compositions - Google Patents

Cephem compounds, and their pharmaceutical compositions Download PDF

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Publication number
WO1994010177A1
WO1994010177A1 PCT/JP1993/001505 JP9301505W WO9410177A1 WO 1994010177 A1 WO1994010177 A1 WO 1994010177A1 JP 9301505 W JP9301505 W JP 9301505W WO 9410177 A1 WO9410177 A1 WO 9410177A1
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WIPO (PCT)
Prior art keywords
cephem
vinyl
compound
pyridin
alkyl
Prior art date
Application number
PCT/JP1993/001505
Other languages
English (en)
French (fr)
Inventor
Kohji Kawabata
Takeshi Terasawa
Ayako Nakamura
Hideko Nakamura
Fumiyuki Shirai
Kazuo Sakane
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.
Priority to EP93922658A priority Critical patent/EP0665847A1/en
Priority to KR1019950701518A priority patent/KR950704331A/ko
Priority to JP6510881A priority patent/JPH08502513A/ja
Priority to AU51575/93A priority patent/AU5157593A/en
Publication of WO1994010177A1 publication Critical patent/WO1994010177A1/en

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
PCT/JP1993/001505 1992-07-12 1993-10-19 Cephem compounds, and their pharmaceutical compositions WO1994010177A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93922658A EP0665847A1 (en) 1992-10-23 1993-10-19 Cephem compounds, and their pharmaceutical compositions
KR1019950701518A KR950704331A (ko) 1992-07-12 1993-10-19 세펨 화합물 및 그의 약제학적 조성물(cephem compounds and their pharmaceutical compositions)
JP6510881A JPH08502513A (ja) 1992-10-23 1993-10-19 セフェム化合物、およびそれらの医薬組成物
AU51575/93A AU5157593A (en) 1992-10-23 1993-10-19 Cephem compounds, and their pharmaceutical compositions

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GB929222291A GB9222291D0 (en) 1992-10-23 1992-10-23 New cephem compounds
GB9222291.8 1993-07-12
GB939314495A GB9314495D0 (en) 1993-07-12 1993-07-12 New cephem compounds
GB9314495.4 1993-07-12

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CN (1) CN1144222A (en, 2012)
CA (1) CA2147609A1 (en, 2012)
IL (1) IL107359A0 (en, 2012)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0849269A1 (en) * 1996-12-19 1998-06-24 F. Hoffmann-La Roche Ag Vinyl pyrrolidine cephalosporins with basic substituents
WO2001009135A1 (fr) * 1999-07-30 2001-02-08 Eisai Co., Ltd. Procede de preparation de sels d'addition acides inorganiques d'antibiotiques de base et oxalates intermediaires
US6294668B1 (en) 1996-11-06 2001-09-25 Hoffman-La Roche Inc. Vinylpyrrolidinone cephalosporin derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103264A2 (en) * 1982-09-10 1984-03-21 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds and processes for preparation thereof
JPS6236385A (ja) * 1985-08-05 1987-02-17 Fujisawa Pharmaceut Co Ltd ３，７−ジ置換−３−セフエム化合物およびその製造法
EP0349340A2 (en) * 1988-07-01 1990-01-03 Meiji Seika Kabushiki Kaisha Novel cephem compound, method for producing the same and anti-bacterial agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103264A2 (en) * 1982-09-10 1984-03-21 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds and processes for preparation thereof
JPS6236385A (ja) * 1985-08-05 1987-02-17 Fujisawa Pharmaceut Co Ltd ３，７−ジ置換−３−セフエム化合物およびその製造法
EP0349340A2 (en) * 1988-07-01 1990-01-03 Meiji Seika Kabushiki Kaisha Novel cephem compound, method for producing the same and anti-bacterial agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 107, no. 15, 12 October 1987, Columbus, Ohio, US; abstract no. 134126g, page 703; column R; *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294668B1 (en) 1996-11-06 2001-09-25 Hoffman-La Roche Inc. Vinylpyrrolidinone cephalosporin derivatives
EP0849269A1 (en) * 1996-12-19 1998-06-24 F. Hoffmann-La Roche Ag Vinyl pyrrolidine cephalosporins with basic substituents
US5981519A (en) * 1996-12-19 1999-11-09 Hoffman-La Roche Inc. Vinyl-pyrrolidinone cephalosporins
CN1104436C (zh) * 1996-12-19 2003-04-02 巴斯利尔药物股份公司 带有碱性取代基的乙烯基－吡咯烷酮头孢菌素
WO2001009135A1 (fr) * 1999-07-30 2001-02-08 Eisai Co., Ltd. Procede de preparation de sels d'addition acides inorganiques d'antibiotiques de base et oxalates intermediaires
US6642377B1 (en) 1999-07-30 2003-11-04 Eisai Co., Ltd. Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates

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KR950704331A (ko) 1995-11-17
CN1144222A (zh) 1997-03-05
CA2147609A1 (en) 1994-05-11
TW255894B (en, 2012) 1995-09-01
MX9306572A (es) 1994-04-29
EP0665847A1 (en) 1995-08-09
IL107359A0 (en) 1994-01-25
JPH08502513A (ja) 1996-03-19

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