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GB2048241A - Novel 7???-methoxycephalosporins and process for producing the same - Google Patents

Novel 7???-methoxycephalosporins and process for producing the same Download PDF

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GB2048241A
GB2048241A GB7933266A GB7933266A GB2048241A GB 2048241 A GB2048241 A GB 2048241A GB 7933266 A GB7933266 A GB 7933266A GB 7933266 A GB7933266 A GB 7933266A GB 2048241 A GB2048241 A GB 2048241A
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alpha
group
cephem
methyl
methoxy
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Toyama Chemical Co Ltd
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Toyama Chemical Co Ltd
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Priority claimed from JP9991779A external-priority patent/JPS5625188A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • 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

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

Abstract

A 7???-methoxycephalosporin represented by the following general formula and a salt thereof: <IMAGE> wherein R<1> represents a hydrogen atom or a carboxyl-protecting group; R<2> represents an organic group linked to the carbon atom through an oxygen or sulfur atom; R<3> represents a lower alkyl group; n is 0, 1 or 2; A represents a substituted or unsubstituted alkyl group; R<4> represents a lower alkyl group; and R<5> represents a hydrogen atom or a hydroxyl-protecting group, have a broad antibacterial spectrum and high resistance to ???-lactamase produced from bacteria, and are well absorbed in a living body. They can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Novel 7a-methoxycephalosporins and process for producing the same This invention relates to novel 7-methoxycephalosporins and methods for producing these compounds.
The compounds of this invention are characterized by having a broad antibacterial spectrum against Gram-positive and -negative bacteria, particularly having an excellent antibacterial activity against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Proteus species, Serratia marcesens, Alkaligenes faecalis, etc. and being stable to p-lactamase produced from bacteria.
They are, therefore, very useful in treating various infectious diseases.
Although conventional 7a-methoxycephalosporins are known to have an antibacterial activity against Gram-positive bacteria, they have a relatively weak antibacterial activity against Gram-negative bacteria as mentioned above which causes clinically serious infectious diseases.
The present inventors have conducted extensive research on 7a-methoxycephalosporins. As a result, it has been found that novel compounds represented by the general formula (I) described hereinafter, in which the cephem ring bears an organic-group-substituted oxy- or thio-methyl group at the 3-position and a methoxy group at the 7a-position, and the amino group at the 7p-position is linked to the group:
wherein R3, R4, R5, A and n have the meanings described hereinafter, and salts of the compounds have effective antibacterial activity, and low toxity, and are well absorbed in a living body.
It is an object of this invention to provide novel 7a-methoxycephalosporins having in their molecule a 2,3-dioxo-1-piperazinecarbonylamido group and a group
It is another object of this invention to provide novel 7a-methoxycephalosporins having a broad antibacterial spectrum.
It is a further object of this invention to provide novel 7cz-methoxycephalosporins having high resistance to p-lactamase produced from bacteria.
It is a still further object of this invention to provide novel 7a-methoxycephalosporins having an effective antibacteriai activity against clinical isolates of bacteria.
It is a still further object of this invention to provide a process for producing the novel 7a-methoxycephalosporins.
It is a still further object of this invention to provide a pharmaceutical composition comprising the novel 7a-methoxycephalosporins or its salt as active ingredient.
Other objects and advantages of this invention will become apparent from the following description.
According to the present invention, there can be obtained the novel compound which includes 7a- methoxycephalosporins represented by the general formula (I), and salts thereof.
wherein R1 represents a hydrogen atom or a carboxyl-protecting group; R2 represents an organic group linked through an oxygen or sulfur atom; R3 represents a lower alkyl group; n is O, 1 or 2; A represents a substituted or unsubstituted alkyl group; R4 represents a lower alkyl group; and R5 represents a hydrogen atom or a hydroxyl-protecting group.
The term "alkyl" used herein means a straight or branched chain alkyl having 1 to 14 carbon atoms, such as methyl, ethyl propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl or the like; the term "lower alkyl" used herein means a straight chain alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl or butyl; the term "lower alkoxy" used herein means a monovalent -0-lower alkyl in which the lower alkyl defined above is bonded to oxygen, namely a straight chain alkoxy having 1 to 4 carbon atoms; the term "acyl" used herein means an acyl having 1 to 10 carbon atoms, such as formyl, acetyl, propionyl; butyryl, benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl, thenoyl or the like; and the term "acyloxy" used herein means a monovalent -O-acyl in which the acyl defined above is bonded to oxygen, namely an acyloxy having 1 to 10 carbon atoms. When the terms "acyl" and "acyloxy" mean those formed from a heterocyclic ring containing N, 0 and/or S in any number in any position of the ring, the hetero atom or atoms are calculated as the number of carbon atoms.
In the general formulas described herein, R1 is a hydrogen atom or a carboxyl-protecting group.
The carboxyl-protecting groups in this invention are those which have conventionally been used in the penicillin and cephalosporin fields and include ester-forming groups which can be removed by catalytic reduction, chemical reduction or other treatments under mild conditions; ester-forming groups which can easily be removed in living bodies; and other known ester-forming groups which can easily be removed by treatment with water or an alcohol, such as organic silyl groups, organic phosphoruscontaining groups, organic tin-containing groups, or the like.
Examples of suitable carboxyl-protecting groups are: (a) Alkyl groups, especially, a straight or branched chain alkyl having 1 to 14 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, pentyl and the like; (b) Substituted lower alkyl groups at least one of the substituents of which is chloro, bromo, fluoro, nitro, carboalkoxy, acyl, lower alkoxy, oxo, cyano, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, 1 -indanyl, 2-indanyi, furyl, pyridyl, 4-imidazolyl, phthalimido, acetidino, aziridino, pyrrolidinyl, piperidino, morpholino, thiomorpholino, N-lower-alkylpiperazino, 2,5-dimethylpyrrolidinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino, lower alkylamino, di-iower-alkylamino, acyloxy, acylamino, di-lower-alkylaminocarbonyl, lower alkoxycarbonylamino, lower alkoxycarbonyloxy, or lower alkylanilino or lower alkylanilino substituted by chloro, bromo, lower alkyl, or lower alkoxy; (c) Cycloalkyl groups containing 3 to 7 carbon atoms, lower-alkyl-substituted C37cycloalkyl groups, or [2,2-di(lower alkyi)-1 ,3-dioxolan-4-yl)methyl groups; (d) Alkenyl groups containing up to 10 carbon atoms; (e) Alkinyl groups containing up to 10 carbon atoms; (f) Phenyl group, susbstituted phenyl groups, at least one of the substituents of which is one selected from the substituents examplified in above (b); or aryl groups represented by the formula:
wherein X is -CH=CH-O-, --CH=CHH--S-, --CH,CH,SS-, --CH=NN-CH==N-, -CH=CH-CH=CH-, -CO-CH=CH-CO-, or - CO - CO - CH=CH-, or substituted derivatives thereof, the substituents of which are ones selected from those exemplified in above (b), or the formula:
wherein Y is a lower alkylene group such as CH and CH, or substituted derivatives thereof, the substituents of which are ones selected from those exemplified in above (b):: (g) Aralkyl groups such as benzyl group or substituted benzyl groups, at least one of the substituents of which is one selected from those exemplified in above (b); (h) Heterocyclic groups such as furyl, quinolyl, methyl-substituted quinolyl, phenazinyl, 13-benzodioxolanyl, 3-(2-methyl-4-pyrroiinyl), 3-(4-pyrrolinyl), and N-(methylpyridyl), or substituted heterocyclic groups, at least one of the substituents of which is one selected from those exemplified in above (b); (i) Aiicyclic indanyl or phthalidyl groups or substituted derivatives thereof, the substituent of which is methyl, chloro, bromo or fluoro, alicyclic tetrahydronaphthyl group or its substituted derivative, the substituent of which is methyl, chloro, bromo or fluoro, trityl group, cholesteryl group, and bicyclo-[4,4,Oj-decyl group.
The carboxyl protecting groups listed above are typical examples, and there may be used any groups selected from those disclosed in U.S. Patents 3,499,909; 3,573,296; and 3,641,018, West German Offenlegungsschrift 2,301,014; 2,253,287; and 2,337,105.
In the general formulas R2 is "an organic group linked through an oxygen or sulfur atom". Examples of R2 are lower alkoxy groups; lower alkylthio groups; acyloxy groups; carbamoyloxy group; and heterocyclic thio groups containing 0, S and N alone or in any combination in any position, such as oxazolylthio, thiazolylthio, isoxazolylthio, isothiazolylthio, imidazolylthio, pyrazolylthio, pyridylthio, pyrazinylthio, pyrimidinylthio, pyridazinylthio, quinolythio, isoquinolylthio, quinazolylthio, indolylthio, indazolylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, triazinylthio, benzimidazolylthio, benzoxazolylthio, benzthiazolylthio, triazolopyridylthio, purinylthio, pyridine-1 -oxide-2-ylthio, and the like.
Further, the above-mentioned R2 groups may be substituted by a halogen atom or a lower alkyl, phenyl, C25alkenyl, hydroxyl, lower alkoxy, lower alkylthio, nitro, cyano, lower alkylamino, di-lower alkylamino, acylamino, acyl, acyloxy, acyl-lower alkyl, carboxyl, carbamoyl, amino-lower alkyl, Nlower-alkylamino-lower alkyl, N,N-di-lower-alkylamino-lower-alkyl, hydroxy-lower-alkyl, hydrooxyimino-lower-alkyl, lower-alkoxy-lower-alkyl, carboxy-lower-alkyl, sulfo-lower-alkyl, sulfo, sulfamoyllower-alkyl, sulfamoyl, carbamoyl-lower-alkyl, carbamoyl-C25alkenyl, N-hydroxycarbamoyl-lower-alkyl or the like.
In the general formulas, A is a substituted or unsubstituted alkyl group. Examples of the said alkyl group are as exemplified in the definition of alkyl hereinbefore. Examples of substituents of the substituted alkyl groups for group A are halogen atoms, lower alkoxy groups, cyano group, nitro group, carboxyl group, lower alkoxycarbonyl groups, hydroxyl group, lower alkylthio groups, acyl groups, N,Ndisubstituted amino groups, and the like.
In the general formulas, R4 is a lower alkyl group. Examples of the said lower alkyl group are as exemplified in the definition of alkyl hereinbefore.
In the general formulas, R5 is a hydrogen atom or a hydroxyl-protecting group. The hydroxyl-protecting group include all groups which can usually be used as hydroxyl-protecting groups, such as lower alkyl, a-ethoxyethyl, benzyl, benzhydryl, trityl, tetrahydrofuryl, tetrahydropyranyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyi, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, obromobenzyloxycarbonyl, o-nitrophenylsulfenyl, acetyl, chloroacetyl, trifluoroacetyl, formyl, tert.-butoxycarbonyl, p-methoxybenzyloxyca rbonyl, 3 ,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxy- carbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridine- 1 -oxide-2-yl-methoxycarbonyl, 2- pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1 -cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1 -adamantyloxycarbonyl, 8- quinolyloxycarbonyl and the like and organic silyl group, such as di- or tri-lower alkylsilyl, di- or tri-lower alkoxysilyl, diphenylmethylsilyl and the like.
The salt of the 7a-methoxycephalosporin of this invention represented by the general formula (I) includes those formed at the acidic group and those formed at the basic group, which are well known in the penicillin and cephalosporin fields. Of the salts, pharmaceutically acceptable salts are preferred. The salts formed at the acidic group include salts with alkali metals such as sodium, potassium and the like; alkaline earth metals such as calcium, magnesium and the like; ammonium; and nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-P-phenethylamine, l-ephenamine, N,N-dibenzylethylenediamine, trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, and dicyclohexylamine.
The salts formed at the basic group include salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; and organic sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like.
All optical isomers and racemic compounds, and all crystal forms and hydrates of the 7 a-methoxy- cephalosporin represented by the general formula (I) and salt thereof are included within the scope of this invention.
Among various 7a-methoxycephalosporins according to this invention, those represented by the following formula (la) and salts thereof are preferred:
wherein A represents a lower alkyl group; R4 represents a methyl group; and R1, R2 and R5 have the same meanings as defined above. Of the 7cL-methoxycephalosporins represented by the above formula (la) and salts thereof, most preferred are those in which R5 is a hydrogen atom, particularly those in which R5 is a hydrogen atom and R2 is an acetoxy group, substituted 5-(1 ,2,3,4-tetrazolyl)thio group or 2-( 1 ,3,4-thiadiazolyl)thio group.
As the preferable compounds of this invention there are exemplified the following compounds though this invention is not restricted thereto: 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1 -piperazinecarboxam ido)- -(S or R)-hydroxybutanamido]-7n- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxyllc acid or a pharmaceutically acceptabls salt thereof.
7ss-(D-&alpha;-[4-(n- or iso-)propyl-2,3-dioxo- 1 -piperazinecarboxamido]--(S or R) hydroxybutanamido]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4- carboxylic acid or a pharmaceutically acceptable salt thereof.
7ss-[D-&alpha;-[4-(n-or lso)butyl-2,3-dioxo-1-plperazinecerboxamldol/ss-(S or R)-hydroxybutanamido) 7&alpha;-methoxy-3-[6-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acid or a phermaceutlcally acceptsble salt thereof.
7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1 -piperazinecarboxam ido)-p-(S or R)-hydroxybutana mido]-7 a- methoxy-3-acetoxymethyl-A3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7ss-[D-&alpha;-(4-methyl-2,3-dioxo-1-piperazinecarboxamldo)-ss-(S sor R)-hydroxybutanamido]-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazlnscarboxamido)-ss-(S or R)-hydroxybutanamldo)-7&alpha;- methoxy-3-(2-1,3,4-thladlazolyl)thlomethyl]-# -cephem-4-carboxylic acld or a pharmaceutlcally acceptable salt thereof.
7ss-[D-&alpha;(4-ethyl-2,3-dioxo-1-plperazlnecarboxamido)-ss-(S or R)-hydroxybutanamldo]-7&alpha;- methoxy-3-( 5-[ 1 -(2-hydroxysthyl)-1,2,3,4-tetrazolylthiomethyl i-A3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7ss-[D-&alpha;-(4-noctyl-2,3-dioxo- 1 - piperazinecarboxamido)-P-(S or R)-hydroxybutanamido-]7 a- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7,B-[D.--(4-ethyl-2,3-dioxo-1- piperazinecarboxamido)-23-(S or R)-methoxybutanamindo]-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -ceph4-carboxylic acld or a pharmaceutically acceptable salt thereof.
7P-[D-a-(4-ethyl-2,3-dioxo- 1- piperazinecarboxamido)-p-(S or R)-ethoxybutanemido]-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4- acid or a pharmaceutically acceptable salt thereof.
7ss-[D-&alpha;-(4-ethyl-2,3-dloxo- 1 - piperazinecarboxamido)-P-(S or R)-tert.-butoxybutana mido]-7a- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomelthyl]-# -cephem-4-carbvoxylic acld or a pharmaceutically acceptable salt thereof.
7P-[D-a-(4-ethyl-2,3-dioxo- 1 - piperazinecarboxamido)-ss-(S or R)-formyloxybutanamido]-7 a- methoxy-3-[5-(1 1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephmem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazlnacarboxamldo)-ss-(S or R)-acetoxybutamido]-7&alpha;- methoxy-3-[5-(1 1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7P-[D-a-(4-n-ethyl-2,3-dioxo-l -piperazinecarboxa mido)-p-(S or R)-(2-tetrahydropyranyloxy) butanemido]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-# -cephem-4-carboxylic acld or a pharmaceutically acceptable salt thereof.
The compounds represented by the general formula (I) or salts thereof are produced by the known methods such as, for example, those described below.
Production method (1): A method by which a compound of the general formula (II) :
wherein R represents a hydrogen stom, an organio silyl group or organlc phosphorus-contalning group ; and R, R, R4 and R6 have the same msanings as deflned above, is reacted with a resctlve derlvativa in the carboxyl group of a compound represented by the general formula (III):
wherein R3, n and A have the same meanings as defined above.
Production method (2): A method by which a compound of the general formula (IV):
wherein R1, R2 and R6 have the same meanings as defined above, is reacted with a compound represented by the general formula (V):
wherein R3, R4, R5, n and A have the same meanings as defined above or a reactive derivative in the carboxyl group of said compound (V).
Production method (3): A method by which a cephalosporin of the general formula (VI):
wherein R', R2, R3, R4, R5, n and A have the same meanings as defined above, is reacted, in the presence of methanol, with an alkali metal or alkaline earth metal methylate represented by the general formula (VII): M1(OCH3)ml (all) wherein M' represents an alkali metal or an alkaline earth metal; m' is 1 or 2, and then reacted with a halogenating agent.
Production method (4): A method by which a 7-methoxycephalosporin of the general formula (Vlil):
wherein R7 represents a group easily replaceable by a nucleophilic reagent; and R1, R3 R4, R5, n and A have the same meanings as defined above, is reacted with a compound represented by the general formula (IX): (R2)m2M2 (IX) wherein M2 represents a hydrogen atom, an alkali metal or an alkaline earth metal; m2 is 1 or 2; and R2 has the same meaning as defined above.
The organic silyl groups and the organic phosphorus-containing groups represented by P6 in the above-mentioned general formulas include those groups which are conventionally used as amino- or carboxyl-protecting group in the penicillin and cephalosporin synthesis fields, such as
(C2HsO)2P-, and (C2H5)2P-, which are easily removed by treatment with, for example, water or an alcohol.
The groups represented by R7, which are easily replaceable by a nucleophilic reagent, include halogen atoms such as chlorine, bromine and the like; lower alkanoyloxy groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy and the like; arylcarbonyloxy groups such as benzoyloxy, naphthoyloxy and the like; arylthiocarbonyloxy groups such as thiobenzoyloxy, thionaphthoyloxy and the like; arylcarbonylthio groups such as benzoylthio, naphthoylthio and the like; arylthiocarbonylthio groups such as thiobenzoylthio, thionaphthoylthio and the like; carbamoyloxy group; thiocarbamoyloxy group; pyridine-N-oxide-2-yl group; and pyridazine-N-oxide-6-yl group.These groups represented by R7 may further contain substituents such as, for example, a halogen atom, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, acyl group and the like.
The compound represented by the general formula (V) is easily obtained by the reaction between an alkali metal salt, an alkaline earth metal salt or an organic base salt of a compound represented by the general formula (X):
wherein R4 and R5 have the same meanings as defined above, and a reactive derivative in the carboxyl group of a compound represented by the general formula (III) in the presence of an acid-binding agent in an inert solvent.
The compounds represented by the general formulas (II) and (1V) may be synthesized in a manner known per se, for example, the manner described in the Journal of Synthetic Organic Chemistry, Japan, Vol.35,568-574(1977).
The modes of practice of the production methods (1), (2), (3) and (4) are described below.
The methods (1) and (2) can be carried out under nearly the same conditions. The compound (II) or (IV) is dissolved or suspended in an inert solvent such as, for example, water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, methoxyethanol, diethyl ether, diisopropyl ether, benzene, toluene, methylene chloride, chloroform, ethyl acetate, or methyl isobutyl ketone, each alone or in admixture of two or more. To the resulting solution or suspension is added a reactive derivative in the carboxyl group of the compound (III), or the compound (V) or a reactive derivative in the carboxyl group of the compound (V). The mixture is allowed to react in the presence or absence of a base at 600 to 800 C, preferably --400 to 300C.A reaction time of 5 minutes to 5 hours is generally sufficient.
The bases used in the above reaction include inorganic bases such as alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates and alkali metal acetates; tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine and the like; and secondary amines such as dicyclohexylamine, diethylamine and the like.
When the compound (V) or a salt thereof is used in the method (2) as the starting material, the reaction can be carried-out in the presence of a dehydrating-condensing agent such as, for example, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N,N'-diethylcarbodiimide, N,N'-carbonyl bis(2-methylim idazole), trial kyl phosphites, ethyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, 2-chloro-1 ,3,2-dioxaphospholane, oxazolyl chloride, dimethylchloroforminium chloride, and dimethylethoxyforminium chloride.
The method (3) is carried out in the following way: A cephaloshorin of the formula (VI) obtained in a known manner [Japanese Patent Application Kokai (Laid-Open) Nos. 70,788/76 and 113,890/76] is dissolved or suspended in an inert solvent such as, for example, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, acetonitrile, methanol or the like or a mixture of two or more of these solvents. To the resulting solution or suspension is added an alkali metal or an alkaline earth metal methylate (VII) together with methanol.
The resulting mixture is subjected to reaction, and the reaction mixture is then reacted with a halogenating agent. In this reaction, methanol is used in excess and the amount of the alkali metal or an alkaline earth metal methylate (VII) used is preferably 2 to 6 equivalents per equivalent of the cephalosporin (Vi! used. The term "in excess" means an amount of more than one equivalent per equivalent of the cephalosporin (Vl). All of the above reactions are carried out at 1200 to -1 OOC, preferably100 to -500C. A reaction time of to 30 minutes is sufficient and the reaction is terminated by acidifying the reaction system.
The halogenating agent used in this method is generally known to be a source for supplying a positive halogen atom such as Cl+, Br+ or l+. Examples of such halogenating agents include halogens such as chlorine, bromine and the like; N-haloimides such as N-chlorosuccinimide, N-bromosuccinimide and the like; N-haloamides such as N-chloroacetamide, N-bromacetamide and the like; N halosulfonamides such as N-chlorobenzenesulfonamide, N-chloro-p-toluenesulfonamide and the like: 1 halobenzotriazoles; 1-halotriazines; organic hypohalogenite such as tert.-butyl hypochlorite, tert.-butyl hypoidide and the like; halohydantoins such as N,N-dibromohydantoin, and the like. Of these halgenating agents, tert.-butyl hypochlorite is preferred.The halogenating agent is used in an amount sufficient for supplying a positive halogen in an amount equivalent to that of the cephalosporin of the general formula (VI).
Suitable acids for the termination of reaction are those which, when added to a cold reaction mixture, will not cause solidification of the reaction mixture or freezing of the reaction mixture into a heavy viscous mixture. Examples of the suitable acids are 98% formic acid, glacial acetic acid, trichloroacetic acid and methanesulfonic acid.
After the termination of the reaction, the excess halgenating agent can be removed by treating with a reducing agent such as trialkyl phosphite, sodium thiosulfate, or the like.
In carrying out the production method (4), when a compound of the formula (VIII) is used other than the compound in which the group R7 is a heterocyclic aromatic amine-N-oxide thio group having a thio group on the carbon atom adjacent to the N-oxide group, said compound is reacted with a compound of the formula (IX) in an inert solvent such as, for example, water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, 2-methoxyethanol, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, dichloroethane, chloroform, dichloromethane, and the like alone or in admixture of two or more.
The above reaction is carried out preferably in a strongly polar solvent such as water. It is advantageous to maintain the pH of the reaction solvent at 2 to 10, preferably 4 to 8. The reaction is effected after the addition of a buffer such as sodium phosphate to adjust the pH to a desired value.
Although the reaction conditions are not critical, the reaction is generally carried out at 0 to 1 000C for several hours to several tens of hours.
When a compound of the general formula (VIII) in which the group R7 is a heterocyclic aromatic amine-N-oxide thio group having a thio group on the carbon atom adjacent to the N-oxide group is used, the compound of the general formula (VIII) and a compound of the general formula (IX) are reacted with each other in the inert solvent listed above in the presence of a divalent copper compound. This procedure is particularly useful when the compound of the general formula (IX) is an alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, benzyl alcohol, ethylene glycol or the like. In this case, the reaction proceeds smoothly by the use of an excess of the alcohol to serve as a solvent.The divalent copper compounds used in this procedure are inorganic or organic divalent copper compounds such as, for example, cupric chloride, cupric bromide, cupric fluoride, cupric nitrate, cupric sulfate, cupric borate, cupric phosphate, cupric cyanide, cupric formate, cupric acetate, cupric propionate, cupric citrate, cupric tartrate, cupric benzoate, and cupric salicylate. The amount of the divalent copper compound used is preferable 0.5 mole or more per mole of the compound represented by the general formula (VIII). Although depending on the types of the compound of the general formula (VII I), divalent copper compound, and compound of the general formula (IX) used, generally the reaction temperature is 0 to 100 C, and the reaction time is several minutes to several days.
Conversion from a compond of the general formula (I) in which R1 is a carboxyl-protecting group to a compound of the general formula (I) in which R1 is a hydrogen atom or a salt of the latter compound, conversion from a compound of the general formula (I) in which R1 is a hydrogen atom to a salt or to a compound of the general formula (I) in which R1 is a carboxyl-protecting group, or conversion from a salt of a compound of the general formula (I) to its free acid can be carried out in a conventional manner.
When the starting materials have active groups, the active groups may be protected, during the reaction, with a group which is usually used as a protecting group for carboxyl amino or hydroxyl group.
After the completion of the reaction, the protecting group may be removed to obtain the compound of this invention represented by the formula (I). As the protecting group for amino group, there may be exemplified trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesuifonyl, pnitrobenzyloxycarbonyl, O-bromobenzyloxycarbonyi, o-nitrophenylsulfenyl, acetyl, chloroacetyl, trifl uoroacetyl, formyl, tert.-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-di methoxybenzyloxy- carbonyl, 4-(phenylazo)benzyloxycarbonyi, 4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridine- 1 - oxide-2-yl-methoxycarbonyl, 2-pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1 -dimethypropoxycarbonyl, isopropoxycarbonyl, 1 -cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1 - adamantyloxycarbonyl, 8-quinolyloxycarbonyl, and the like; and other easily removable aminoprotecting groups, for example, trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidine, 2- hydroxy-5-chlorobenylidene, 2-hydroxy- 1 -naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1- methoxycarbonyl-2-propylidene, 1 -ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1 - acetyl-2-propylidene, 1 -benzoyl-2-propylidene, 1 -[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, 1 - [N-(4-methoxyphenyl)carba moyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonyl- cyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, di- or tri-alkylsilyl, and the like.
As the protecting group for hydroxyl group, there may be examplified a-ethoxyethyl, benzyl, trityl, benzhydryl, tetrahydrofuryl, tetrahydropyranyl and the substituted or unsubstituted acyl, alkoxycarbonyl and aralkoxycarbonyl groups mentioned above as the aminoprotecting groups.
As the protecting group for carboxyl group, there may be used the same carboxyl-protecting groups as for R1.
The conditions for the production are not limited to those described above, but suitably modified in accordance with the particular type of reagent used.
Isolation of a 7a-methoxycephalosporin (I) or a salt thereof from the reaction mixture can be carried out in a conventional manner.
The method for the production of 7a-methoxycephalosporin represented by the general formula (I) and a salt thereof is not limited to those described above. These compounds can be produced also by other known methods.
The 7cg-methoxycephalosporin represented by the general formula (I) and the salt thereof thus obtained are very useful for the therapy of man and mammals diseases because of their broad antibacterial spectrum against Gram-positive bacteria and Gram-negative bacteria, their excellent antibacterial activity to Gram-negative bacteria such as Esherichia coli, Klebsiella pneumoniae, Protius species, Serratia marcescens, Alkaligenes faecalis, etc. and their stability to p-lactamase.
The pharmacological effect of typical compounds among the compounds of the present invention are shown below.
(1) The minimum inhibitory concentration (MIC in mcg/ml).
The figures given in Table 1 represent the minimum inhibitory concentration (MIC in mcg/ml) of each compound, which was determined according to the method described in "Chemotherapy (Society of Chemotherapy, Japan), Vol. 16, 98-99 (1968)": A culture obtained by cultivating the test bacterium in a Heart Infusion broth (Eiken Kagaku Co.) was inoculated into a Heart Infusion agar medium (Eiken Kagaku Co.). After 20 hours of the incubation at 370C, the growth of the bacterium was inspected to determine the minimum inhibitory concentration (MIC in mcg/ml). The inoculation rate of the bacterium was 104 cells/plate.
TABLE 1
Compound CS-1170 Bacteria (control) A B C D E F G H E. coli NlHJ 0.39 #0.1 #0.1 #0.1 0.2 #0.1 #0.1 #0.1 0.2 Kl. pneumoniae Y-50 0.39 #0.1 0.2 0.2 0.2 0.2 0.2 0.2 #0.1 Ser. marcescens W-35 100 6.25 6.25 6.25 50 6.25 6.25 3.13 3.13 Ser. marcescens IlD620 3.13 0.2 0.2 0.2 1.56 0.39 0.78 0.39 30.1 Pro. morganii T-216 12.5 1.56 3.13 3.13 12.5 3.13 3.13 12.5 1.56 Aci. calcoacaticus A-6 50 12.5 50 50 50 25 12.5 50 50 E. coll TK-3 (Penicillinase-producing bacterium) 1.56 #0.1 0.2 0.2 0.39 #0.1 0.39 #0.1 #0.1 Kl : pneumonie Y-4 (Panicillinase-producing bacterium) 1.56 0.39 0.39 0.78 0.78 0.78 - 0.78 0.39 Klebslella spp. Y-72 12.5 0.39 0.78 1.56 12.5 3.13 0.78 0.78 1.56 Pro. vulgeris GN-76 (Cephalosoprolnase-producing bacterium) 3.13 1.58 1.58 3.13 3.13 3.13 6.25 3.13 1.56 Ser. marcescens W-S (Cephalosporinase-producing bacterium) > 200 50 50 100 200 12.5 100 25 25 Ent. cloacae IlD977 > 200 50 50 100 200 50 50 25 25 E. coli GN-5482 (Cephalosporinase-producing bacterlum) 50 6.25 6.25 12.5 12.5 3.13 - 6.25 6.25 Note: (1) CS-i 170:
(2) Compound A:Sodium salt of 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazlnecarboxamldo)-ss-(S)hydroxy- butanamldo]-7&alpha;-methoxy-3-[6-(-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxyllc acid represented by the formula:
(hereinafter referred to as T-1 982.) (3) Compound B: Sodium salt of 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazinecarboxamldo)-ss-(S)hydroxy- butanamido2-7a-methoxy-3-I 5-[1 -(2-hydroxyethyl)-1,2,3,4-tetrazolylithiomethyl {-A3-cephem-4 carboxylic acid represented by the formula:
(4) Compound C:Sodium salt of 7ss-(D-&alpha;-(4-ethyl-2,3-dioxo-1-plperazlnecarboxamido)-ss-(S)hydroxy- buta namido]-7 a-methoxy-3-[2-( 1,3 ,4-thiadiazolyl)thiomethyl]-A3-cephem-4-carboxylic acid represented by the formula:
(5 Compound D: Sodium salt of 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazinecarboxamldo)-ss-(S)hydroxy- butanemido]-7&alpha;-methoxy-3-acetoxymethyl-# -cephem-4-carboxylic acid represented by the formula:
(6) Compound E: Sodium salt of 7ss-[D-&alpha;-(4-n-butyl-2,3-dioxo- -piperazinecarboxamido)-,- (S)hydroxybutanam ido]-7a-methoxy-3-[5-( 1-methyl-i 1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4- carboxylic acid represented by the formula:
(7) Compound F: Sodium salt of 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1 -piperazinecarboxamido)-ss-(R)hydroxy- butanamldo]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thlomethyl]-# cemphem-4-carboxylio acid represented by the formula:
(8) Compound G: Sodium salt of 7,B-[D-zg-(4-ethyl-2,3-dioxo-1 -piperazinecarboxamido)-,B- (S)methoxybutanamido]-7a-methoxy-3-[5-methyl-i ,2,3 A-tetrazolyl)thiomethyl]-A3-cephem-4- carboxylic acid represented by the formula:
(9) Compound H:Sodium salt of 7P-[D-a-(4-ethyl-2,3-dioxo-l -piperazinecarboxamido)-p-(S)- formyloxybutanemldo]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4- carboxylic acid represented by the formula:
(2) Stability to p-lactamase.
The stability to p-lactamase was examined by iodometry at 300 C. by the method of Perret [Perret, C.J., "lodometric assay of penlollllnase", Nature, 174, 1012-1013 (1954)], except that a 0.1 M phosphate buffer solution (pH 7.0) was used in place of the 0.2 M phosphate buffer solution (pH 6.5).
The stability of each compound was shwon in Table 2 in terms of realative degree of hydrolysis, assuming the stability of Cephaloridin (CER) to cephalosporinase as 100 and the stability of Penicillin G (PC-G) to penicillinase as 100.
TABLE 2 Stabllty to ss-lactamase
Cephalosporinase- or penicillinase producing bacteria PC-G CER CEZ T-1982 E. coil GN-5482 22 100 130 < 0.1 Cephalosporinase Ser. marcescens W-8 21 100 94 0.04 E.coilTK-3 100 115 21 Penlolillnase Ki. pneumoniae Y-4 100 1 41 4 < v0.55 Note: CEZ means Cefazolin T-1982 is the same as defined in Table 1 as compound A.
(3) Infection-protective activity.
Four-week old ICR-strain mice (male) in groups, each group consisting of five mice, were inoculated intraperitoneally with a presecribed quantity of a pathogenic bacterium suspended in 5% mucin. After one hour from the inoculation, the mice were subcutaneously administered with the test preparation to determine the infection-protective activity. The results obtained were shown in Table 3.
The figures in Table 3 represented the protective activity in terms of EDng.
TABLE 3 infection-protective activity
EDso (subcutaneous) MIC (mcg/ml) (mg/mouse) Challenge Inoculated dose bacteria (cells/ quantity Strain mouse) (cells/ml) T-1982 CS-1170 T-1982 CS-1170 Pro. vulgaris 108 0.78 1.56 GN-3027 8.0 > < x 106 1o6 0.78 0.067 0.82 Ser. marcescens 100 < 0.1 3.13 llD260 1.0 x107 0.088 0.71 106 < 0.1 0.78 Ki. pneumoniae 108 < 0.1 0.78 Y-50 1.9 x 10 106 # 0.1 0.39 0.10 0.73 Note: T-1982 is the same as defined in Table 1.
CS-1170 is the same as defined in Table 1.
The 7a-methoxycephalosporins of this invention are low toxic. For instance, T-i 982 showed a LD50 of 5 g/kg or more (ICR-strain mice; intraveous).
The 7a-methoxycephalosporins of this invention represented by the general formula (I) and salts thereof are administered to man and mammals in the form of free acid or pharmaceutically acceptable salt or ester. The compound is formulated into various dosage forms which are customary in penicillin or cephalosporin preparations such as, for example, capsules, syrups and injections, and administered either orally or parenterally.
When the compound is administered to man, intravenous injection (including drip infusion) or intramuscular injection is particularly suitable. Furthermore, the antibacterial compound of this invention may be used in admixture with a solid or liquid carrier or a diluent which is usually used in a known antibiotic injection and the like.
The form of injection includes powder which is dissolved, before use, in a suitable vehicle, for example, sterilized water, saline solution or the like. Moreover, when the antibacterial compound of this invention is used in the form of an injection, it may be used along with a local anesthetic, for example, lidocaine hydrochloride, or other drugs.
The dosage of the antibacterial compound of this invention may be varied depending upon man or mammal, and when it is administered to man, an appropriate dosage may be selected depending on the age, the kind of infectious disease and the symptom of the disease. For example, in the case of injection, it is suitable to administer to adult 0.5 to 10 g, in terms of potency, of the compound per day in several portions.
This invention is illustrated below in detail with reference to Examples which, however, are merely illustrative and not limitative. in the Examples, all percentages are by weight unless otherwise specified.
EXAMPLE 1 (1) in 50 ml of methylene chloride was suspended 2.0 g of D-threonine, and 6.85 ml of trimethylchlorosilane was added to the resulting suspension, after which 7.01 ml of triethylamine was added dropwise thereto at 0 to 50C. The temperature of the suspension was gradually elevated, and reaction was effected at 200C for 1.5 hrs, after which 5.9 g of a mixture of 4-ethyl-2,3-dioxo-piperazinecarbonyl chloride and triethylamine hydrochloride (the content of 4-ethyl-2,3-dioxo-1 -piper- azinecarbonyl chloride was 58.55% by weight) was added to the reaction mixture. The resulting mixture was subjected to reaction at 200C for 1 hr and then distilled under reduced pressure to remove the solvent. To the residue was added 30 ml of water, and the pH of the resulting solution was adjusted to 7.5 with sodium hydrogen carbonate, after which the solution was washed with 50 ml of ethyl acetate and then 50 ml of acetonitrile was added to the solution. The pH of the resulting mixture was adjusted to 1.5 with 2 N hydrochloric acid. Sodium chloride was added to the mixture to saturate the same and the acetonitrile layer was thereafter separated.
The aqueous layer was subjected to extraction with four 50-ml portions of acetonitrile, and the four extract acetonitrile layers were combined with the above-mentioned acetonitrile layer, and the combined acetonitrile layer was washed with saturated sodium chloride solution, after which the acetonitrile layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was recrystallized from n-butanol to obtain 3.6 g (yield 75%) of D-&alpha;-(4-ethyl-2,3-dioxo-1-plperazinecarboxamldo)-ss-(S)-hydroxybutyric acid having a melting point of 1640 to 1 660C.
IR(KBr)cm-1 : # 1740, 1710, 1870 NMR (CD3SOCD3) ppm values 1.11 (3H, t, CH3), 1.13 (3H, d, CH3), 3.28-3.75 (4H, m, CH2 x 3.78-4.30 (4H, m, CH2, CH x 2).
(2) In 15 ml of methylene chloride was suspended 1.0 g of D-a-(4-ethyl-2,3-dioxo-1 - plperazlnecarboxamldo)-ss-(S)-hydroxybutyric acid, and 0.38 ml of 1-methylmorpholine was added thereto to convert the suspension to a solution. To the solution was added 0.35 ml of ethyl chlorocarbonate at 150 to-20 C, and the solution was subjected to reaction at the same temperature for 1.5 hrs.Thereafter, 1.67 g of diphenyl methyl 7ss-amlno-3-[5-(1-methyl-1,2,3,4- tetrazolyl)thiomethyl]-A3-cephem-4-carboxylate was added to the reaction mixture, and the resulting mixture was subjected to reaction at the same temperature for 1 hr, and then at 100 to 05C for 1.5 hrs.The reaction mixture was distilled under reduced pressure to remove the solvent, and to the residue were added 30 ml of water and 30 ml of ethyl acetate, after which the resulting solution was stirred.
The thus precipitated while crystals were collected by filtration to obtain 2.5 g (yield 95%) of diphenylmethyl 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-piperazinecarboxamido)-ss-(S)-hydroxybutanamldo]-3-(5-1-methyl 1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-carboxylate having a melting point of 1210 to 1 250C (decomp.).
IR(KBr) om-1 : # 1785, 1720, 1880 NMR (CD3SOCD3) ppm values: 1.00 (3H, t, CH3), (1.16 (3H, d, CH3), 3.4.O (1 OH, m, CH2 x 4, CH x 2), 3.85 (3H, s, CH3), 4.25 (2H, q, CH2), 5.10 (1 H, d, CH), 5.8 (1 H, m, CH), 6.85 (1 H, s, CH), 7.2-7.45 (10H, s, C6H5 x 2), 8.91 (1H, s, NH), 9.28 (1H, a, NH).
(3) In a mixture of 30 ml of dried methylene chloride and 2 ml of dried tetrahydrofuran was dissolved 1.0 g of diphenylmethyl 725-[D--(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-,B-(S)- hydroxybutanamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylate, and the resulting solution was cooled to -700C. To the cooled solution was added 3.55 ml (1.66 mM/ml) of a methanol solution of lithium methoxide at the same temperature, and the resulting mixture was stirred for 3 min, after which 0.18 ml of tert-butyl hypochlorite was added thereto. The resulting mixture was stirred at the same temperature for 15 min, after which 0.39 ml of acetic acid was added to the resulting solution, and the temperature of the solution was elevated to room temperature.The solution was distilled under reduced pressure to remove the solvent, and to the residue were added 20 ml of ethyl acetate and 20 ml of water to dissolve the residue, after which the pH of the resulting solution was adjusted to 6.5 with aqueous sodium bicarbonate solution. The organic layer was separted, washed with water, and dried over anhydrous magnesium sulfate,and thereafter distilled under reduced pressure TO remove the solvent.The residue was purified by a column chromatography [Wako silica gel C-200; eluted with a mixture of benzene and ethyl acetate (1 :2 by volume )1, upon which 0.6 g (yield 40.8%) of dlphenylmethyl 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazinecarboxamlde)-ss-(S)-hydroxybutanamido]-7&alpha;- methoxy-3-[5-(-(methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylate.
IR (KBr) om-1 : Vc=o 1780, 1710, 1870 NMR (CDCl3) ppm values: 1.20 (3H, t, CH3), 1.25 (3H, d, CH3) 3.5 (3H, s, CH3), 3.79 (3H, s, CH3), 3.2-4.0 (8H, m, CH2 x 4), 4.3-4.6 (4H, m, CH2, CH x 2), 5.02 (1H, s, CH), 6.85 [1h, s, NH), 7.2-7.4 (10H, s, C6H5 x 2) 8.5 (iH, s, NH), 9.55 (1H,d, NH).
(4) In 5 ml of anisole was dissolved 0.5 g of diphenylmethyl 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1- piperazinecarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;-methoxy-3-[6-(1-methyl-1,2,3,4- tetrazolyl)thiomethyl]-A3-cephem-4-carboxylate, and 5 ml of trifluoracetic acid was added to the resulting solution with ice-cooling, after which the resulting solution was stirred at the same temperature for 30 min. The reaction mixture was distilled under reduced pressure to remove the solvent, and to the residue were added 10 ml of ethyl acetate and 10 ml of water, after which saturated, sodium hydrogen carbonate solution was added thereto with stirring to adjust the pH thereof to 6.5, thereby dissolving the residue. The aqueous layer was separated, to which 10 ml of methyl acetate was then added.The pH of the resulting mixture was adjusted to 2.0 with 2 N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with two 10 ml portions of methyl acetate, and the two extracts were combined with the above-mentioned organic layer, and the combined organic layer was washed with saturated aqueous sodium chloride solution.
After drying over anhydrous magnesium sulfate, the organic layer was distilled under reduced pressure to remove the solvent, and the residue was treated with diethyl ether to obtain 1.25 g (yield 63.3%) of 7,B-[D-cz-(4-ethyl-2,3-dioxo- 1 -piperazinecerboxamido)-ss-(S)-hydroxybutanamido]-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxylic acld having amelting point of 11 80 to 1 200C (decomp.).
IR (KBr) cm-1 : Vo=o 1770,1705,1675 NMR (CD2SOCD3) ppm values: 1.10 (3H, t, CH3), 1.15 (3H, d, CH3), 3.40 (3H, s, CH3), 3.93 (3H, s, CH3), 3.5-4.0 (8H, m, CH2 x 4), 4.1-4.4 (4H, m, CH2, CH x 2), 5.03 (1 H, s, CH), 9.2 (2H, d, NH x 2).
In the same manner as above, the following compounds were obtained: 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1-piperazlnecarboxmldo)-ss-(S)-hydroxybutamamido]-7&alpha;- methoxy-3-[2-(1,3,4-thiadlazolyl)thiomethyl]-# -cephem-4-oarboxylic acid, m.p. 1080 to 112 0C (decomp.).
IR (KBr) cm-': vc=O 1780, 1720,1680 NMR (CD2SOCD3 + D20) ppm values: 1.02-1.39 (6H, m, CH3 x 2), 3.50 (3H, s, CH3), 3.3-4.5 (12H, m, CH2 x 5, CH x 2), 5.05 (1H, s, ch), 9.42 (1H, s, CH), 7ss-[D-&alpha;-(4-octyl-2,3-dioxo-1-piperazlnecarboxamido)-ss-(S)-hyclroxybutanamido)-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl)-# -cephem-4-carboxylic acld, m.p. 113 to 115 C (decomp.).
IR (KBr) cm-1: vc=O 1780, 1 660-1720 NMR (CD2SOCD3) ppm values: 0.80-1.60b(1 (18H, m, CH2 x 6, CH3 x 2). 3.30-4.50 (12H, m, CH2 m, CH2 CH x 2), 3.48 (3H, s, CH3), 3.95 (3H, s, CH3), 5.00 (1 H, s, CH), 8.37 (1 H, s, NH), 9.40 (1 H, d, NH).
7ss-[D-&alpha;-(4-n-butyl-2,3-dloxo-1-piperazinecarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;- methoxy-3-[5-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxylic acid, m.p. 125 -133 C (decomp.).
IR (KBr) cm-': Vco 1785,1710,1680 NMR(CD2SOCD3) ppm values : 0.80-1.60 (10H, m, CH2 x 2, CH3 x 2), 3.20-4.40 (12H, m, CH2 x 5, CH x 2), 3.41 (3H, s, CH3), 3.94 (3H, s, CH3), 5.08 (1 H, s, CH), 9.27 (1 H, s, NH), 9.30 (1 H, d, NH).
7ss-[D-&alpha;-(4-sthyl-2,3-dloxo-1-plperazinecarboxemldo)-ss-(R)-hydroxybutansmldo]-7-&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acid, m.p. 1440 to 1 500C (decomp.).
IR (KBr) cm-1: Vc=o 1780, 1735-i 660 NMR(CD3COCD3 : CD3SOCD3 = 4:1 by volume) ppm values: 0.96-1.37 (6H, m, CH3 x 2), 3.30-4.92 (12H, m, CH2 x 5, CH x 2), 3.54 (3H, s, CH3), 4.04 (3H, s, CH3), 5.10 (1H, s, CH), 9.23 (1 H, bs, NH), 9.46 (1H, d, NH).
EXAMPLE 2 (1) In 45 ml of methylene chloride was suspended 4.5 g of D-a-(4-ethyl-2,3-dioxo-i plperazinecarboxamldo)-ss-(S)-hydroxybutyrlo acid, and 1.60 g of N-methylmorpholine was added to the resulting suspension to convert the suspension to a solution. The solution was cooled to -20 C, and 1.78 g of ethyl chlorocarbonate was added thereto, after which the resulting solution was subjected to reaction st-13' to -1 60C for 1.5 hrs. Subsequently, 6.50 g of diphenylmentyl 7ss-amino-3-acetoxy- methyl-A3-hem-4-carboxylate was added to the reaction mixture at-30 C. Reaction was effected at -10 to -1 50C for 30 min and then at 100 to 0 C for 30 min, after which the reaction mixture was distilled under reduced pressure toremove the solvent.To the residue were added 50 ml of ethyl acetate, 50 ml of methyl acetete and 40 ml of water to dissolve the residue. The organic layer was separated, dried over anhydrous magnesium sulfate, and thereafter distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography [Wako silica gel C-200; eluted with a mixture of chloroform and ethanol (60:1 by volume)] to obtain 8.2 g (yield 78.2%) of white powder of diphenyl methyl 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1 -piperazinecarboxamido)-B-(S)- hydroxybutana m ido]-3-acetoxymethyl-A3-cephem-4-carboxylate.
IR(KBr) cm-1 : Vc=D 1780, 1760, 1870 (2) In 80 ml of methylene chloride was dissolved 8.0 g of the diphenylmethyl 7ss-[D-&alpha;-(4-sthyl- 2,3-dioxo-1-plperazlnacarboxamldo)-ss-(S)-hydroxybutanamldo]-3-acetoxymethyl-# -cephem-4- carboxylate obtained in above (1), and to the solution was added 26 ml of a methanol solution of lithium methoxide (the lithium methoxide content, 1.51 mM/ml) at -700C. The solution was stirred at-85 to -700C for 3 min, and 1.60 g of tert-buthyl hypochlorite was thereafter added to the solution, after which reaction was effected at the same temperature for 1 5 min.To the reaction mixture was added 3 ml of acetic acid, and the temperature of the mixture was gradually elevated to OOC, after which the mixture was distilled under reduced pressure to remove the solvent. To the residue was added 100 ml of ethyl acetate and 50 ml of water to dissolve the residue, and the organic layer was separated, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (Wako silica gel C-200; eluted with ethyl acetate) to obtain 2.65 g (yield 31.8%) of white powder of dlphenylmethyl 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1- plperazlnecarboxamldo)-ss-(S)-hydroxybutenamldo]-7&alpha;-methoxy-3-acetoxymethyl-# -cephem-4- carboxylate.
IR (KBr) cm-': Vo=o 1780, 1740, 1710, 1680 (3) To 2.65 g of the diphenylmethyl 7p-[D-ct-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-,B-(S)- hydroxybutanamldo]-7&alpha;-methoxy-3-acetoxymethyl-# -cephem-4-carboxylate obtained in above (2) were added 26 ml of aniosole and 26 ml of trifluoroacetic acid with ice-cooiing, and the resulting mixture was subjected to reaction at the same temperature for 30 min, after which the reaction mixture was distilled under reduced pressure to remove the solvent. Diethyl ether was added to residue to wash the latter, thereby obtaining 2.0 g (yield 97.6%) of white powder of 7B-[D-(u-(4-ethyl-2,3-dioxo-l - plperazinecarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;-methoxy-3-acetoxymethyl-# -cephem-4- carboxylic acid having a melting point of 1420 to 1 450C (decomp.).
IR (KBr) cm-1: Pc=o 1780, 1805, 1670 NMR (CD3COCD3 : CD3SOCD3 = 4 : 1 by volume) ppm values: 0.85-1.45 (6H, m, CH3 x 2), 2.03 (3H, s,CH3),3.15-4.95(12H,m, CH2 x 5, CH x 2), 3.48 (3H, s, CH3), 5.06 (1 H, s, CH), .84(1 H, s, NH), 9.34 (1 H, d, NH).
EXAMPLE 3 In 24 ml of nitromethane were dissolved 0.71 g of 7ss-[&alpha;-&alpha;-(4-ethyl-2,3-dloxo-1 plperazinecarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;-methoxy-3-acetoxymethyl-# -cephem-4- carboxylic acid and 0.22 g of 1 -(2-hydroxyethyl)-5-mercapto-1 H-tetrazole, and the resulting solution was subjected to reaction at 800C for 5 hrs, after which the reaction mixture was distilled under reduced pressure to remove the solvent. To the resulting residue were added 20 ml of ethyl acetate and 20 ml of acetone to dissolve the residue. To the resulting solution was then added diphenyl diazomethane until the redish violet color remained without vanishing, and the resulting mixture was thereafter distilled under reduced pressure to remove the solvent.The resulting residue was purified by a column chromatography [Wako silic gel C-200, eluted with a mixture of chloroform and ethanol (20:1 by volume)] to obtain a pale yellow powder. To the powder were added 3.5 mi of anisole and 3.5 ml of trifluoroacetic acid with ice-cooling, and the resulting mixture was subjected to reaction at the same temperature for 30 min, after which the reaction mixture was distilled under reduced pressure to remove the solvent.Ethyl acetate was added to the resulting residue to wash the latter, upon which there was obtained 0.28 g (yield 34%) of a pale yellow powder of 7,8-[D--(4-ethyl-2,3-dioxo-1- plperazlnecarboxamido)-ss-(S)-hydroxybutanamido]-7&alpha;-methoxy-3-[5-[1-(2-hydroxyethyl)-1,2,3,4- tetrazolyl)thiomethyl]-thiomethyliA3-cephem-4-carboxylic acid having a melting point of 1280 to 1350C (decomp.).
IR(KBr) cm-1 : Vc=D 1780, 1710, 1675 NMR (CD3COCD3 : CD3SOCD3 = 4:1 (by volume)) ppm values: 0.9-1.4 (6H, m, CH3 x 2), 3.47 (3H, s, CH3), 3,20-4,60 (18H, m, CH2 x 7, CM x 2), 5.03 (1H, s, CH), 9.01 (1H, s, NH), 9.31 (1H, d, NH), The same procedure as above was repeated, except that 1 -methyl-5-mercapto-i H-tetazole was substituted for the 1 -(2-hyd roxyethyl)-5-mercapto- 1 H-tetrazole, to obtain 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo- 1-plperazlnecarboxamldo)-ss-(S)-hydroxybutanamldo)-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4- tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid.
The melting point, IR spectrum and NMR spectrum of this product were idential with those of the product in Example 1.
EXAMPLE 4 In 7 ml of anhydrous methylene chloride was dissolved 0.20 g of D-a-(4-ethyl-2,3-dioxo-1 - plperazinecarboxamldo)-ss -(S)-tert.- butoxybutyric acid, after which 0.10 g of oxalyl chloride and one drop of dimethylformamide were added to the resulting solution in this order with ice-cooling, and the resulting mixture was subjected to reaction at room temperature for 30 min. The reaction mixture was distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in 8 ml of anhydrous methylene chloride, and the resulting solution was cooled to-50 C.To the solution were added 0.3 g of diphenylmethyl 7ss-amlno-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl)- A3-cephem-4-carboxylate and 0.1 of dimethylaniline in this order, after which the resulting mixture was subjected to reaction at -200C overnight. The reaction mixture was distilled under reduced pressure to remove the solvent, and the resulting residue was dissolved in a mixture of 10 ml of water and 15 ml of ethyl acetate, after which the ethyl acetate layer was separated, washed thoroughly with water, and then distilled to remove the solvent.The resulting residue was purified by a column chromatography [Wako silica gel C-200; eluted with a mixture of benzene and ethyl acetate (2 1 by volume)] to obtain 0.31 g (yield 63%) of diphenylmethyl 7A-[D-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamidoj-p-(S)- tert-butoxybutanamido]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4- carboxylate having a melting point of 1090 to 11 50C (decomp.).
IR (KBr) cm-': vc=O 1780, 1720-1680 NMR (CDCI3) ppm values: 1.30 (9H, s, CH3 x 3), 1.03-1.55 (6H, m, CH3 x 2), 3.51 (3H, s, CH3), 3.72 (3H, s CH3), 3.18-4.68 (12H, m, CH2 x 5, CH x 2), 4.98 (1H, s, CH), 6.76 (1H, s, CH), 7.22 (10H, bs, C8H5 x 2), 8.04 (1H, bs, NH), 9.50 (1H, d, NH).
The above product was dissolved in a mixture of 2 ml of anisole and 2 ml of trifluoroacetic acid, and the resulting solution was subjected to reaction at room temperature for 30 min. The reaction mixture was dried under reduced pressure to dryness, after which 10 ml of ethyl acetate was added to the residue, and the resulting mixture was stirred for one hour. The crystals thus precipitated were collected by filtration and dried to obtain 0.21 g (yield 55.7%) of 7-[D-a-(4-ethyl-2,3-dioxo-1- piperazinecarboxa mido)-ss-(S)-hydroxybutanam ido]-7 methoxy -3-[5-methyl- 1,2,3,4 tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid. The melting point (decomp.), IR spectrum and NMR spectrum of this product were identical with those of the product obtained in Example 1.
EXAMPLE 5 In a mixture of 40 ml of anhydrous methylene chloride and 20 ml of anhydrous methanol was dissolved 1 g of 7p-| D-(E-(4-ethyl-2,3-dioxo- 1 -piperazinecarboxam ido)-,B-( S) -hydroxybuta na m ido]- 3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxyllc acid, and the resulting solution was cooled to-75 C.To the solution was added dropwise 3.7 ml of lithium methoxide solution in methanol (9.2 mM lithium methoxide was contained therein) and the solution was subjected to reaction at 750 to -700C for 3 min, after which 0.22 ml of tert butyl hydrochlorite was added thereto, and the resulting mixture was subjecteds to reaction for 1 5 min. 1 o the reaction mixture was added 0.28 ml of formic acid, and the temperature of the mixture was elevated to room temperature. The mixture was distilled under reduced pressure to remove the solvent, and 4 ml of water, 4 ml of saturated aqueous sodium chloride solution and 20 ml of acetonitrile were added to the resulting residue to dissolve the residue.To the resulting solution was added dropwise 6 N hydrochloric acid to adjust the pH of the solution to 1.2. The organic layer was separated and then dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. To the resulting residue was added 14 ml of acetone and the resulting mixture was stirred. The crystals thus precipitated were collected by filtration, to obtain 0.71 g of the acetone adduct of 7,5-[D--(4-methyl-2,3-dioxo-1 plperazinacarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;-methoxy-3-[5-(1-msthyl-1,2,3,4- tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acld.
The said adduct was suspended in 4.3 ml of 20% hydrous acetone, and sodium hydrogen carbonate was added to the suspension to adjust the pH thereof to 5.0. To the suspension was added 70 mg of active carbon, and the mixture was stirred for 3 to 4 min, and then filtered through celite tc remove the active carbon.The pH of the filtrate was adjusted to 1.5 with 6 N hydrochloric acid., The filtrate was then stirred at room temperature for 30 min and then with ice-cooling for 3 hrs, after which the crystals thus precipitated were collected by filtration and then dried to obtain 0.5 g (yield 45%) of 7ss- [D-a-(4-ethyl-2,3-dioxo- 1 -piperazinecarboxam (ldo)-ss-(S)-hydroxybutena m ido]-7 &alpha;-methoxy -3-[5-( 1 methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxylle acid dihydrate having a melting point of 1730 to 1 750C (decomp.).
IR (KBr) cm~1: v,=, 1775,1710,1657,1660 The NMR spectrum of the product was identical with that of the product in Example 1.
EXAMPLE 6 In 20 ml of anhydrous methylene chloride was suspended 1 g of 7P-[D-a-(4-ethyl-2,3-dioxo- 1 piperazinecsrboxamido)-ss-(S)-hydroxybutaenamldo]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl] A3-cephem-4-carboxylic acid, and to the suspension were added 0.8 ml of vinyl ethyl ether and 42 mg of pyridinium-p-toluenesulfonate, and the resulting mixture was subjected to reaction under reflux for 50 min to produce 7-{ D-a-(4-ethyl-2,3-dioxo- 1 -piperazinecarboxamido)-,3- (S)-[1-(1-ethoxyethyl)oxy]-butamamldo]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]=# -cephem-4- carboxylic acid.The reaction mixture was cooled to -750C, and 0.5 ml of anhydrous methanol was added thereto, after which 2.87 ml of lithium methoxide solution in methanol (7.52 mM of lithium methoxide was contained therein) was dripped thereinto. the resulting mixture was subjected to reaction at 750 to -700C for 3 min, after which 3 ml of anhydrous methylene chloride containing 0.25 ml of tert.-butyl hypochlorite was added dropwise thereto over 10 min.The resulting mixture was subjected to reaction at the same temperature for a further 5 min, after which 0.34 ml of acetic acid was added thereto, and the temperature of the resulting mixture was elevated to OOC. To the reaction mixture was added 5 ml of water, and the resulting mixture was stirred, after which the organic layer was separated and distilled under reduced pressure to remove the solvent.The resulting residue (7ss-[D- a-(4-ethyl-2,3-dioxo-i -piperazinecarboxamido)-p-(S)-[1 -(1 -ethoxyethyl)oxy]butanamido)-7- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid was contained therein) was dissolved in 15 ml of acetone, and 30 mxg of p-toluenesulfonic acid monohydrate was added to the solution, and the solution was stirred at room temperature for 2 hrs and then allowed to stand at 50C overnight.The crystals thus precipitated were collected by filtration and then washed with water to obtain 0.85 g of the acetone adduct of 783-[D-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)- -(S)-hydroxybutanam ido]-7 a-methoxy-3-[5-( methyl ,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4- carboxylic acid.
This adduct was suspended in 5 ml of 20 hydrous acetone, and the pH thereof was adjusted to 5.0 by adding thereto sodium hydrogen carbonate, after which 85 mg of active carbon was added thereto, and the resulting mixture was stirred for 3 to 4 min, and then filtered through celite to remove the active carbon. To the filtrate was added 6 N hydrochloric acid to adjust the pH of the filtrate to 1.5, after which the filtrate was stirred at.room temperature for 30 min and then with ice-cooling for 3 hrs. The crystals thus precipitated were collected by filtration to obtain 0.66 g (yield 60%) of 7-ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-ss-(S)-hydroxybutanamido]-7&alpha;-methoxy- 3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxylic acid dihydrate having a melting point of 1730 to 1 750C (decomp.).
IR (KBr) cm~1: vc=O 1775,1710,1675,1660 The NMR spectrum of the product was identical with that of the product in Example 1.
EXAMPLE 7 (1) In 50 ml of anhydrous methylene chloride was dissolved 2.5 g of diphenylmethyl D-(t-(4-ethyl- 2,3-dioxo-1-piperazlnecarboxamido)-ss-(S)-hydroxybutyrate, and to the solution were added at -400C boron trifluoridediethyl ether complex (BF3 content: 47% by weight) and 50 ml of diethyl ether solution of diazomethane (the diazomethane content: about 1.4 g) in this order. The mixture was subjected to reaction. The temperature of the reaction mixture was thereafter elevated gradually to room temperature, and 20 ml of water was added to the mixture, after which the organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent.The resulting residue was purified by a column chromatography [Wako silica gel C-200; eluted with a mixture of benzene and ethyl acetate (5:1 by volume)] to obtain 0.68 g (yield 26.4%) of diphenylmethyl D-&alpha;-(4-ethyl-2,3-dloxo-1- plperazinecarboxamido)-ss-(S)-methoxybutyrate.
(2) In a mixture of 5 ml of anisole and 5 ml of trifluoroacetic acid was dissolved 0.6 g of the diphenylmethyl D-&alpha;-(4-sthyl-2,3-dioxo-1-plperazinecarboxamldo)-ss-(S)-methoxybutyrate obtained in above (1), and the resulting solution was subjected to reaction with ice-cooling for 30 min. The reaction mixture was distilled under reduced pressure to remove the solvent, and to the residue were added 10 ml of diethyl ether and 10 ml of diisopropyl ether, and the resulting mixture was stirred for one hour. The crystals thus precipitated were collected by filtration to obtain 0.37 g (yield 95.8%) of D-a-(4-ethyl-2,3- dioxo-1-piperazinecarboxamido)--(S)-methoxybutyricacid having a melting point of 1320 to 1330C.
(3) In 3 ml of anhydrous methylene chloride was suspended 0.1 8 g of the D-a-(4-ethyl-2,3-dioxo- 1-piperazinecarboxamido)-ss-(S)-methoxybutyric acid obtained in above (2), and thereto was added 0.1 g of oxalyl chloride. One drop of N,N-dimethylformamide was added to the suspension, and the temperature of the suspension was elevated to room temperature, after which the suspension was subjected to reaction for one hour. The reaction mixture was distilled under reduced pressure to remove the solvent, and the resulting residue was dissolved in 5 ml of anhydrous methylene chloride, after which to the resulting solution were added 0.28 g of diphenylmethyl 7P-amino-7a-methoxy-3-[5-(1- methyl-1,2,3,4-tetrazolyl)thiomethyl)-# -cephem-4-carboxylate at-30 to-40 C, and then 0.086 g of dimethylaniline.The resulting mixture was subjected to reaction at 200 to -1 00C for 12 hrs, and then distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in a mixture of 5 ml of water and 10 ml of ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate.The organic layer was distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a column chromatography [Wako silica gel C-200; eluted with a mixture of benzene and ethyl acetate (1:1 by volume)], to obtain 0.28 g (yield 57.8%) if diphenylmethyl 7ss-[D-&alpha;-(4-ethyl-2,3- dioxo- 1 -piperazinecarboxam ido)-,-(S)-methoxybutanamido]-7-methoxy -3-[5-( 1-methyl- 1,2,3,4 tetrazolyl)thlomethyl]-# -cephem-4-carboxylate.
(4) In a mixture of 2 ml of anisole and 2 ml of trifluoroacetic acid was dissolved 0.18 g of the dlphenylmethyl 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazinecarboxamido)-ss-(S)-methoxybutanamido]-7&alpha;- methoxy -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylate, and the solution was subjected to reaction for 30 min with ice-cooling. The reaction mixture was distilled under reduced pressure to remove the solvent, and to the resulting residue was added 10 ml of ethyl acetate, after which the mixture was stirred for 30 min.The crystals thus precipitated were collected by filtration to obtain 0.1 g (yield 70%) of 7p-[D-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-/3-(S)- methoxybutanamldo]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl-# -cephyem-4- carboxylic acid having a melting point of 1300 to 1 360C (decomp.).
IR (KBr) cm-': Pc=o 1790, 1720-1680 NMR (CD3COCD3 : CD3SOCD3 = 4:1 by volume) ppm values: 1.17 (3H, t, CH3), 1.23 (3H, d, CH3), 3.33 (3H, s, CH3), 3.45 (3H, s, CH3), 3.96 (3H, S, CH3), 3.25-4.60 (12H, m, CH2 x 5, CH x2), 5.08 (1H, s, CH), 8.97 (1H, s, NH), 9.31 (1H, d, NH).
In the same manner as above, the following compounds were obtained: 7ss-[D-&alpha;-(4-athyl-2,3-dioxo1-piperazinecarboxamido)-ss-(S)-hydroxybutanamido]-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxylic acid, m.p., 1100 to 11 90C (decomp.).
IR (KBr) cm-1: Vc=D 1780, 1720-1 670 NMR (CD3COCD3: CD3SOCD3 = 4:1 by volume) ppm values: 1.10-1.35 (9H, m, CH3 x 3), 3.50 (3H, s,CH3),3.98 (3H, s, CH3), 3.30-4.70 (14H,m,CH2 x 6, CH x 2), 5.03 (1H, s, CH), 8.96 (1H,s,NH), 9.40(1 H, d, NH).
7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazlnecarboxamldo)-ss-(S)-tert-butoxybutanamido]-7&alpha;- methoxy -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl-# -cephem-4-carboxylic acid, m.p., 11 00 to 11 50C (decomp.) IR (KBr) cm-1: vc=O 1780, 1730-1680 NMR (CD3COCD3) ppm values: 0.82-1.42 (1 (15H, m, CH3 x 5), 3.50 (3H, s, CH3), 3.94 (3H, s, CH3), 3.22-4.58 (12H, m, CH2 x 5, CH x 2), 5.04 (1H, s, CH), 8.48 (1H, s, NH), 9.40 (1H, d, NH) EXAMPLE 8 (1) to 0.5 g of D-&alpha;-(4-ethyl-2,3-dioxo-1 -plperazlnecarboxamldo)-ss-(S)-hydroxybutyrlc acid was added 5 ml of formic acid, and the resulting mixture was subjected to reaction at 500C for 2 hrs, after which the reaction mixture was distilled under reduced pressure to remove the solvent.To the resulting residue was added 5 ml of ethyl acetate, and the crystals thus precipitated were collected by filtration to obtain 0.45 g (yield 82%) of D-&alpha;-(4-ethyl-2,3-dioxo-1-piperazinecerboxamldo)-ss-(S)-formyloxybutrio acid having a melting point of 1 700 to 1 750C.
IR(KBr) cm-1 : Vc=D 1740-1710, 1660 NMR(CD3SOCD3) ppm values : 1.15 (3H, t, CH3), 1.35 (3H, d, CH3), 3.10-3.72 (4H, m, CH2 x 2), 3.72--4.10 (2H, m, CH,), 4.40--4.70 (1H, m, CH), 5.28--5.64 (1H, m, CH), 8.15(1H, s.
9.41 (1H,d,NH).
(2) In 5 ml of anhydrous methylene chloride was suspended 0.3 g of D-a-(4-ethyl-2,3-dioxo-1 - piperazlnecarboxamido)-ss-(S)-formyloxybutyric acid, and 0.14 g of oxalyl chloride was added to the suspension with ice-cooling, after which one drop of dimethylformanide was added thereto. The temperature of the suspension was elevated to room temperature, and the suspension was subjected to reaction for 30 min. The reaction mixture thus obtained was distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in 5 ml of anhydrous methylene chloride, and the solution was cooled to-40 C.To the solution was added 0.45 g of diphenylmethyl 7ss-amlno-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylate, after which 0.12 ml of N,N-dimethylaniline was added thereto. The resulting mixture was subjected to reaction at -200C overnight. The reaction mixture was distilled under reduced pressure to remove the solvent, and 10 ml of water and 20 ml of ethyl acetate were added to the resulting residue to dissolve the latter, after which the organic layer was separated, washed with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, and thereafter distilled under reduced pressure to remove the solvent.The resulting residue was purified by a column chromatography [Wako silica gel C-200; eluted with a mixture of chloroform and acetone (10:1 by volume)] to obtain 0.5 g (yield 64%) of diphenylmethyl 7-[D-a-(4-ethyl-2,3-dioxo- 1 -piperazinecarboxamido)-p-(S)-formyloxybutanamido]- 7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylate.
(3) in a mixture of 2 ml of anisole and 2 ml of trifluoroacetic acid was dissolved 0.2 g of diphenyl methyl 7P-[D-a-(4-ethyl-2,3-dioxo-l -plperazinecarboxamido)-ss-(S)-form7yloxybutanam ido] 7a-methoxy -3-[S-( 1 -methy- 1 ,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylate, and the resulting solution was subjected to reaction for 15 min with ice-cooling. The reaction mixture was distilled under reduced pressure to remove the solvent, and 10 ml of ethyl acetate was added to the resulting residue, after which the resulting mixture was stirred for 30 min.The crystals thus precipitated were collected by filtration to obtain 0.15 g (yield 94%) of 7-[D-a-(4-ethyl-2,3-dioxo-1 -piperazinecarboxamido)-p-(S)- formyloxybutanamldo]-7&alpha;-methoxy-3-[5-(1-methylo-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4- carboxylic acid having a melting point of 1 470 to 1550C (decomp.).
IR (KBr) cm-': Vc=o 1 780,1720-1680 NMR (CD3SOCD3) ppm values: 0.90-1.35 (6H, m, CH3 x 2), 3.20-3.80 (6H, m, CH2 x 3), 3.40 (3H, s, CH3), 3.80-4.10 (2H, m, CH2), 3.94 (3H, s, CH3), 4.20-4.40 (2H, m, CH2), 4.50-4.90 (1 H, m, CH), 5.07 (1 H, s, CH), 5.20-5.50 (1 H, m, CH), 8.20 (1 H, s,
9.43 (1 H, s, NH), 9.54 (1H, d, NH) In the same manner as above the following compound was obtained:: 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1-piperazlnecarboxamido]-ss-(S)-acetoxybutanamido]-7&alpha;- methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid, m.p., 1360 to 1420C (decomp.).
NMR (CD3COCD3 : CD3SOCD3 =4:1 by volume) ppm values: 1.06-1.35 (6H, m, CH3 x 2), 2.01 (3H, s, CH3), 3.45 (3H, s, CH3), 3.98 (3H, s, CH3), 3.35-5.00 (12H, m, CH2 x 5, CHx2), 5.02 (1H, s, CH), 9.37 (1H, s, NH), 9.45 (1H, d, NH).
EXAMPLE 9 (1) In 20 ml of anhydrous methylene chloride was suspended 0.5 g of 7ss-[D-&alpha;-4-ethyl-2,3- dloxo-1-plperazlnecerboxamido)-ss-(S)-hydroxybuteamido]-3-[6-(1-methyl-1,2,3,4tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid, after which 0.76 ml of 2,3-dihydropyran and 0.021 g of pyridinium p-toluenesulfonate were added to the suspension. The resulting mixture was refluxed for 2 hrs. After the completion of the reaction, the reaction mixture was cooled to 750 C, and 1.5 ml of a lithium methoxide solution in methanol (3.725 mM of lithium methoxide was contained therein), after which the resulting mixture was subjected to reaction for 3 min. To the reaction mixture was added 0.123 ml of tert.-butyl hypochlorite, and the mixture was subjected to reaction for 15 min.To the reaction mixture was added 0.12 ml of formic acid, and the temperature of the mixture was elevated to room temperature, after which the mixture was distilled under reduced pressure to remove the solvent.
The resulting residue was dissolved in a mixture of 10 ml of water and 10 ml of ethyl acetate, after which the pH of the solution was adjusted to 7.5 with a dilute aqueous sodium hydrogen carbonate solution. the aqueous layer was separated, and 10 ml of ethyl acetate was added thereto, after which the pH thereof was adjusted to 1.5 with 2 N hydroxhloric acid with ice-cooling. The organic layer was separated therefrom, washed wilth water and saturated aqueous sodium chloride solution in this order, and then dried over anhydrous sodium sulfate.The organic layer was distilled under reduced pressure to remove the solvent, and diethyl ether was added to the residue, after which the crystals thus precipitated were collected by filtration to obtain 0.42 g (yield 70.6%) of 7-[D-a-(4-ethyl-2,3 dioxo-1 piperazinecarboxa mldo)-ss-(S)-tetrahydropyranyloxy)-butanamldo]-7 st-methoxy -3-[5-( 1 methyl 1.2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acid having a melting point of 1 320C (decomp.).
IR (KBr) cm-': vc=O 1770, 1710-1670 NMR (CDCI3 + D20) ppm values: 1.20 (3H, t, CH3), 1.25 (3H, d, CH3), 1.4-1.9 (6H, m, CH2 x 3), 3.52 (3H, s, CH3), 3,89(3H, s, CH3), 3.5-4.9 (15H, m, CH2 x 6, CH x 3), 4.98 (1 H, s, CH).
(2) In 10 ml of 20% hydrous acetone was dissolved 0.5 g of 7ss-[D-&alpha;-(4-sthyl-2,3-dioxo-1 piperazinecarboxamido)-p-(S)-tetrahydropyranyloxy)butana mido]-7-methoxy -3-[5-( 1 methyl 1,2,3,4tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid, after which the pH of the solution was adjusted to 0.5 with 6 N hydrochloric acid. The solution was subjected to reaction at room temperature for 2 hrs with stirring, after which the reaction mixture was distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in a mixture of 8 ml of acetonitrile and 2 ml of saturated aqueous sodium chloride solution, and the organic layer was then separated.The aqueous layer was extracted with two 4-ml portions of acetonitrile, and the two extract acetonitrile layers were combined with the above organic layer. the combined organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. To the resulting residue was added 7 ml of acetone, and the resulting mixture was stirred sufficiently, after which the crystals thus precipitated were collected by filtration, to obtain 0.4 g of the acetone adduct of 7ss-[D-&alpha;-(4-athyl-2,3-dioxo-1 piperazinecarboxamido)--(S)-hydrnxybutanamido]-7a-methoxy -3-[5-(1 -methyl- ,2,3,4- tetrazolyl)thiomethyl]-# -cephem-4-carboxyllc acid.This was suspended in 2.4 ml of 20% hydrous acetone, and the pH thereof was adjusted to 5.0 with sodium hydrogen carbonate, after which 40 mg of active carbon was added thereto. The resulting mixture was stirred for 3 to 4 min, and then filtered through celite to remove the active carbon. The pH of the filtrate was then adjusted to 1.5 with 6 N hydrochloric acid, and the filtrate was stirred for 30 min at room temperature, and thereafter stirred for 3 hrs with ice-cooling. The crystals thus precipitated were collected by filtration to obtain 0.32 g (yield 68.7%) of 7ss-[D-&alpha;-(4-athyl-2,3-dloxo-1-plperazinecarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;- methoxy -3-[5-(1-methyl-1,2,3,4-tatrazolyl)thiomethyl]-# -cephem-4-carboxylic acid dihydrate having a melting point of 1730 to 1 750C (decomp.).
IR(KBr) cm-1 : Vc=o 1775, 1710, 1675, 1660 NMR (CD3SOCD3) ppm values: 1.10 (3H, t, CH3), 1.15 (3H, d, CH3), 3.40 (3H, s, CH3), 3.93 (3H, s, CH3), 3.5.0 (8H, m, CH2 x 4), 4.1-4.4 (4H, m, CH2, CH x 2)5.03 (1 H, s, CH), 9.2 (2H, d, NH x 2).
EXAMPLE 10 In 10 ml of 80% hydrous tetrahydrofuran was suspended 0.58 g of 7ss-(D-&alpha;-amlno-ss-(S)- hydroxybutana mido]-7 methoxy -3-[5-( 1-methyl- 1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4- carboxylic acid, after which triethylamine was added to the suspension to adjust the pH of 7.0 to 7.5. To the resulting solution was added 0.48 g of a mixture of 4-ethyl-2,3-dioxo-1 -piperazinecarbonyl chloride and triethylamine hydrochloride (58% by weight of 4-ethyl-2,3-dioxo-1 -piperazinecarbonyl chloride was contained therein) at 30 to 50C while adding triethylamine to adjust the pH to 7.0 to 7.5. At the same temperature, reaction was effected to 1 hr, after which the pH was adjusted to 5.5 with 6 N hydrchloric acid.The reaction mixture was distilled under reduced pressure to remove the solvent, and 4 ml of 20% hydrous acetone was added to the residue to dissolve the residue, after which the pH of the solution was adjusted to 1.5 with 6 N hydrochloric acid at 30 to 50C. The solution was then stirred for 5 hrs, and the crystals thus precipitated were collected by filtration, to obtain 0.54 g (yield 65.1%) of 7p-[D-x-(4- ethyl-2,3-dioxo- 1 -piperazinecarboxamido)-p-( S)-hydroxybutanamidoj-7a-methoxy -3-[5-( 1 methyl 1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxylic acid dihydrate having a melting point of 1 730 to 1 750C (decomp.).
IR(KBr) cm-1 : Vo=o 1775, 1710, 1657, 1860 The NMR spectrum of the product was identical with that of the product of Example 1.
PHARMACEUTICAL PREPARATION EXAMPLE 1 Sodlum blcarbonate was added to 7ss-[D&alpha;-(4-ethylo-2,3-dioxo-1-plperazlnecarboxamldo)-ss-(S)- hydroxybutanemldo]-7&alpha;-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4- carboxylic acid, and the resulting mixture was treated in the conventional manner to obtain sodium salt which had been freeze-dried and sterilized. In 20 ml of saline solution was dissolved 1 g of said sodium salt in terms of potency to obtain an injection.
PHARMACEUTICAL PREPARATION EXAMPLE 2 In 3 ml of 0.5% (W/V) aqueous lidocaine hydrochloride solution was dissolved 1 g, in terms of potency, of the same compound as in Pharmaceutical Preparation Example 1 to obtain an injection.
PHARMACEUTICAL PREPARATION EXAMPLE 3 In 20 ml of 5% aqueous glucose solution was dissolved 1 g, in terms of potency, of the same compound as in Pharmaceutical Preparation Example 1 to obtain an injection.
In the same manner as in Pharmaceutical Preparation Example 1, freeze-dried sodium salts of other compounds could be obtained, and injections could by obtained from the salts.

Claims (17)

1. A 7a-methoxycephalosporin or a salt thereof, said 7a-methoxycephalosporin being represented by the general formula:
wherein R' represents a hydrogen atom or a carboxyl-protecting group; R2 represents an organic group linked through an oxygen or sulfur atom; R3 represents a lower alkyl group; n is 0, 1 or 2; A represents a substituted or unsubstituted alkyl group; R4 represents a lower alkyl group; and R5 represents a hydrogen atom or a hydroxyl-protecting group.
2. A 7a-methoxycephalosporin or a salt thereof according to Claim 1, wherein R4 represents a methyl group.
3. A 7a-methoxycephalosporin or a salt thereof according to Claim 1, wherein R5 represents a hydrogen atom.
4. A 7a-methoxycephalosporin or a salt thereof according to Claim 1, wherein R5 represents a hydroxyl-protecting group.
5. A 7a-methoxycephalosporin or a salt thereof according to Claim 3, wherein A represents a lower alkyl group.
6. A 7a-methoxycephalosporin or a salt thereof according to Claim 5, wherein R2 represents a acetoxy group or a substituted or unsubstituted 5-(1,2,3,4-tetrazolyl)thlo or 2-( 1 ,3,4-thidiazolyl)thio group.
7. 7-[D-a-(4-ethyl-2 3-dioxo- 1 -piperazinecarboxamido)-,B-(S)-hydroxybutanamido]-7 methoxy -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomathyl]-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
8.7ss-[D-&alpha;-(4-athyl-2,3-dloxo-1-plperazinecarboxamldo)-ss-(R)-hydroxybutanamldo)-7&alpha;-methoxy -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
9.7ss-[D-&alpha;-(4-athyl-2,3-dloxo-1-plperazlnecarboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;-methoxy -3-f S-[ 1 -(2-hydroxyethyl)-1,2,3,4-tgetrazolyl)thlomethyl]-# -cephem-4-carboxyllc acid or a pharmaceutically acceptable salt thereof.
10. 7ss-[D-&alpha;-(4-ethyl-2,3-dloxo-1-plperazinecèrboxamldo)-ss-(S)-hydroxybutanamldo]-7&alpha;- methoxy -3-acetoxymethyl-A3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
11.7p-[D--(4-ethyl-2,3-dioxo- 1 -piperazinecarboxa mido)--( S)-hydroxybutanamidoj-7a-methoxy -3-[2-(1,3,4-thiadlazolyl)thlomethyl]-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
12.7ss-[D-&alpha;-(4-n-butyl-2,3-dloxo- 1 -piperazinecarboxam ido)-P-(S )-hydroxybutana mido]-7 amethoxy -3-[5-(1 -methyl- 2,3,4-tetrazolyl)thlomethyl]-# -cephem-4-carboxyllc acid or a pharmaceutically acceptable salt thereof.
13,7ss-[D-&alpha;-(4-ethyl-2,3-dioxo-1-plperazinecarboxamldo)-ss-(S)-methoxybutanamido]-7&alpha;- methoxy -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-# -cephem-4-carboxyllc acid or a pharmaceutically acceptable salt thereof:
14. 7ss-[D-&alpha;-(4-ethyl-2,3-dioxo- 1 -piperazinecarboxam ido)-B-(S)-formyloxybutana m ido]-7a- methoxy 3-[5-(1-methyl-1,2,3,4-tetrazoyl)thiomethyl]-# -cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
1 S. A method for producing a 7a-methoxycephalosporin represented by the general formula,
wherein R1 represents a hydrogen atom or a carboxylprotecting group; R2 represents an organic group linked through an oxygen or sulfur atom; R2 represents a lower alkyl group; n is 0, 1 or 2; A represents a substituted or unsubstituted alkyl group; R4 represents a lower alkyl group; and R5 represents a hydrogen atom or a hydroxy-protecting group, or salt thereof, which comprises [A] reacting a compound of the general formula,
wherein R' represents a hydrogen atom or a carboxylprotecting group;R2 represents an organic group and R', R2, R4 and R5 have the same meanings as defined above, with a reactive derivative in the carboxyl group of a compound represented by the general formula,
wherein A, R3 and n have the same meanings as defined above, or [B] reacting a compound of the general formula,
wherein R1, R2 and R5 have the same meanings as defined above, with a compound represented by the general formula,
wherein A, R3, R4, R5 and n have the same meanings as defined above or a reactive derivate in the carboxyl group of said compound, or [C] reacting a compound of the general formula,
wherein R1, R2, R3, R4, R5, A and n have the same meanings as defined above, in the presence of methanol, with an alkali metal alkaline earth metal methylate represented by the general formula, M1(OCH3)m1 wherein M1 represents an alkali metal or an alkaline earth metal; m' is 1 or 2; and then reacting the reaction product with a halogenating agent, or [D] reacting a 7a-methoxycephalosporin of the general formula,
wherein R7 repsents a group easily replaceable by a nucleophilic reagent; and R', R3, R4, R5, A and n have the same meanings as defined above, with a compound represented by the general formula, (R2) M2 m2 wherein M2 represents a hydrgen atom, an alkali metal or an alkaline earth metal; m2 is 1 or 2; and R2 has the same meaning as defined above.
16. A pharmaceutical composition useful for treating bacteria infections in man and mammals which comprises an antibacterially effective amount of a 7a-methoxycephalosporin or its pharmaeutically acceptable salt as claimed in Claim 1, 2, 3 or 5, in combination with a pharmaceutically acceptable inert diluent or carrier.
17. A pharmaceutical composition according to Claim 16, wherein the 7a-methoxycephalosporin or its pharmaceutically acceptable salt is 7p-[D-cr-(4-ethyl-2,3-dioxo-1 -piperazinecarboxamido)-p-(S or R)-hydroxybutanamldo]-7&alpha;-methoxy-3-[5-[1-methyl-1,2,3,4-tetrazolyl)thlomethyl]-# -cephem-4- carboxylic acid or a pharmaceutically acceptable salt thereof.
GB7933266A 1979-04-23 1979-09-26 7a-methoxycenphalosporins and process for producing the same Expired GB2048241B (en)

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JP4900179A JPS55141491A (en) 1979-04-23 1979-04-23 7alpha-methoxycephalosporin and antibacterial
JP9991779A JPS5625188A (en) 1979-08-07 1979-08-07 7alpha-methoxycephalosporin

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AU5129079A (en) 1980-10-30
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