Cephalosporin compounds of formula (I): ##STR1## wherein: R.sup.1 is a hydrogen or an amino protecting group; PA0 R.sup.2 and R.sup.3 are, independently, a hydrogen or a hydroxy protecting group, or form together a cyclic diol protecting group; PA0 R.sup.4 and R.sup.5 are, independently, a hydrogen or a carboxyl protecting group; PA0 X and Y are a nitrogen and a carbon atom, respectively, or a carbon and a nitrogen atom, respectively; PA0 R.sup.6 and R.sup.7 are, independently, a hydrogen or an amino, substituted amino, hydroxy, alkoxy, C.sub.1-4 alkyl, carboxyl or alkoxy carbonyl group, or jointly form a C.sub.3-7 cycloalkyl group together with the carbon to which they are attached, when X and Y are a nitrogen and a carbon, respectively, or R.sup.7 is a hydrogen or an amino group when X and Y are a carbon and a nitrogen, respectively; and PA0 Q is .dbd.CH-- or .dbd.N--, or pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates and isomers thereof, and isomers thereof possess potent and broad antibacterial activities.

FIELD OF THE INVENTION 
The present invention relates to novel cephalosporin compounds and 
pharmacologically acceptable non-toxic salts, physiologically hydrolyzable 
esters, hydrates and solvates, and isomers thereof, which possess potent 
and a broad spectrum of antibacterial activities. The invention also 
relates to processes for preparing these compounds and to pharmaceutical 
compositions containing same as active ingredients. 
BACKGROUND OF THE INVENTION 
Antibiotics of cephalosporin series are widely used for the treatment of 
diseases which are caused by general pathogenic bacteria in human beings 
and animals. Particularly, such antibiotics have been found to be useful 
for the treatment of diseases caused by bacteria exhibiting resistance to 
other antibiotics, e.g., penicillin-resistant bacteria; and also for the 
treatment of penicillin-hypersensitive patients. 
In most circumstances, it is desirable to employ antibiotics possessed with 
broad antibacterial activities, e.g., against both Gram-positive and 
Gram-negative bacteria. It is well known that the activity of a 
cephalosporin compound generally depends upon the substituent on the 3- or 
7-position of the cephem ring. In this regard, there have been many 
studies made in developing a variety of cephalosporin antibiotics with 
such broad spectrum of antibiotic activities by introducing a 7-.beta. 
acylamido group and various substituents on the 3-position of the cephem 
ring. 
For example, GB Patent No. 1,399,086 discloses cephalosporin derivatives of 
formula (A): 
##STR2## 
wherein: R.sup.a represents a hydrogen or an organic group; 
R.sup.b represents an etherified mono-valent organic group; 
B represents S or S.fwdarw.O; and 
P represents an organic group. 
Stimulated by the discovery of these compounds, there have followed 
numerous antibiotic compounds having improved efficacy properties with 
respect to certain microorganisms, especially against Gram-negative 
bactetia, including those compounds disclosed in GB Patent No. 1,522,140 
which have the following formula (B) and exist as a syn isomer or as a 
mixture of syn and anti isomers wherein the syn isomer is present in an 
amount of at least 90%: 
##STR3## 
wherein: R.sup.c represents a furyl or thienyl group; 
R.sup.d represents a C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, furylmethyl or 
thienylmethyl group; and 
R.sup.e represents a hydrogen, or a carbamoyl, carboxymethyl, sulfonyl or 
methyl group. 
Thereafter, further efforts have been made to prepare new and improved 
cephalosporin compounds having antibiotic properties against both 
Gram-positive and Gram-negative bacteria and, as a result, cephalosporin 
compounds having a modified but similar structure to the formula (A) or 
(B) have been developed. 
For example, Belgian Patent No. 852,427 discloses a cephalosporin 
antibiotic of formula (A) in which R.sup.a is substituted with various 
organic groups including 2-aminothiazol-4-yl and the oxygen of oxyamino 
group is attached to an aliphatic carbon which itself can be substituted 
with a carboxyl group, and the substituent on the C-3 position is an 
acyloxymethyl, hydroxymethyl, formyl or optionally substituted 
heterocyclic thiomethyl group. 
Compounds having strong antibiotic activities against some of the 
Gram-negative bacteria producing .beta.-lactamase in addition to other 
pathogenic bacteria have been studied to develop certain cephalosporin 
compounds with .alpha.-carboxy-3,4-substituted benzyl group as the R.sup.b 
group has been known to show a strong activity against a wide range of 
pathogenic bacteria. 
PCT/JP86/00140 discloses cephem compounds of formula (C): 
##STR4## 
wherein: R.sup.f represents a hydrogen or an amino protecting group; 
R.sup.g and R.sup.h represent a hydrogen or oxygen, or a methyl, carboxyl 
or protected carboxyl group, respectively; 
R.sup.i and R.sup.j represent a hydrogen or oxygen, respectively; 
R.sup.k represents a hydrogen or a carboxyl protecting group; 
a, b and c are 0 or 1, independently; 
X is a hydrogen, a hydroxyl group or 
##STR5## 
Y represents a carbon or nitrogen; and Z represents a halogen, an acetoxy 
or heterocyclic group. 
European Patent Appl. No. 87308525.2 gives a cephem compound of formula 
(D): 
##STR6## 
wherein: R.sup.l represents a hydrogen or an amino protecting group; 
R.sup.m and R.sup.n represent a hydroxy or substituted hydroxy group 
independently, or they can link together to form a protected diol; 
R.sup.O and R.sup.p represent a hydrogen or a carboxyl protecting group, 
independently; 
R.sup.q represents a hydrogen or a C.sub.1-4 alkyl group substituted with 1 
to 3 halogens; and 
the dotted line represents a 2-cephem or 3-cephem compound. 
German Patent Application No. 2714880.7 discloses cephalosporin compounds 
of formula (E): 
##STR7## 
wherein: R.sup.r represents a hydrogen, or a substituted or unsubstituted 
alkyl, acyl, arylsulfonyl, alkylsulfonyl or amino protecting group; 
R.sup.s represents a hydrogen, or a substituted or unsubstituted alkyl, 
alkenyl, alkynyl, cycloalkyl, aralkyl, acyl, aryl, alkylsulfonyl, 
arylsulfonyl or heterocyclic group; 
R.sup.t represents a hydrogen, an ester group or anion; 
R.sup.u represents a hydrogen or a lower alkyloxy group; 
X represents S, O, CH.sub.2 or NH; and 
A represents a hydrogen or halogen, or a substituted or unsubstituted 
alkenyloxy or --CH.sub.2 Y wherein Y represents a hydrogen or halogen or a 
moiety of a cyclic compound. 
SUMMARY OF THE INVENTION 
Unexpectedly, it has been found that cephem compounds having an optionally 
substituted 4- and/or 6-aminopyrimidinylthiomethyl group on the C-3 
position and 
(Z)-2-(2-aminothiazol-4-yl)-2-(.alpha.-carboxyl-3,4-disubstituted 
benzyloxyimino)acetamide on the 7-.beta. position show superior antibiotic 
activities against various pathogenic bacteria. 
Accordingly, it is a primary object of the present invention to provide the 
novel cephalosporin compounds and their pharmacologically acceptable 
non-toxic salts, physiologically hydrolyzable esters, hydrates and 
solvates, and isomers thereof. 
It is another object of the present invention to provide processes for 
preparing such compounds. 
It is a further object of the present invention to provide pharmaceutical 
compositions containing same. 
In accordance with one aspect of the present invention, there are provided 
novel cephalosporin compounds of formula (I): 
##STR8## 
wherein: R.sup.1 is a hydrogen or an amino protecting group; 
R.sup.2 and R.sup.3 are, independently, a hydrogen or a hydroxy protecting 
group, or form together a cyclic diol protecting group; 
R.sup.4 and R.sup.5 are, independently, a hydrogen or a carboxyl protecting 
group; 
X and Y are a nitrogen and a carbon atom, respectively, or a carbon and a 
nitrogen atom, respectively; 
R.sup.6 and R.sup.7 are, independently, a hydrogen or an amino, substituted 
amino, hydroxy, alkoxy, C.sub.1-4 alkyl, carboxyl or alkoxy carbonyl 
group, or jointly form a C.sub.3-7 cycloalkyl group together with the 
carbon to which they are attached, when X and Y are a nitrogen and a 
carbon, respectively, or 
R.sup.7 is a hydrogen or an amino group when X and Y are a carbon and a 
nitrogen, respectively; and 
Q is .dbd.CH-- or .dbd.N--. 
In accordance with another aspect of the present invention, there are 
provided processes for preparing the cephalosporin compounds of formula 
(I). 
In accordance with a further aspect of the present invention, there are 
provided pharmacologically acceptable non-toxic salts, physiologically 
hydrolyzable esters, hydrates and solvates of the compounds of formula 
(I). 
In accordance with still another aspect of the present invention, there are 
provided pharmacological compositions comprising one or more of the 
cephalosporin compounds represented by formula (I) and their 
afore-mentioned derivatives as an active ingredient and their 
pharmaceutically acceptable carriers.

DETAILED DESCRIPTION OF THE INVENTION 
The novel cephalosporin compounds of formula (I) include both syn isomers 
and mixtures of syn and anti isomers, which mixtures contain at least 90% 
of the syn isomer, as well as their derivatives mentioned above. In 
formula (I), the carbon to which 3,4-substituted phenyl is attached is an 
asymmetric center to form diastereomers which are also included within the 
scope of the present invention, as well as mixtures thereof. 
In addition, the compounds of formula (I) in accordance with the present 
invention may exist in tautomeric forms and such tautomers are also 
included within the scope of the invention. Namely, when Q is CH, the 
aminothiazolyl group undergoes tautomerism to form an iminotiazolinyl 
group to yield its tautomers which may be represented as: 
##STR9## 
When Q is N, the aminothiadiazol group forms tautomers with the 
iminothiadiazoline group which are also included in the present invention, 
as follows: 
##STR10## 
Among the compounds of the present invention, preferred are those wherein: 
all of R.sup.1, R.sup.4 and R.sup.5 are a hydrogen; R.sup.2 and R.sup.3 
are independently a hydrogen or an acetyl group; R.sup.6 is a hydrogen or 
a methyl group and R.sup.7 is a hydrogen or an amino group, or they form a 
cyclopentane or cyclohexane ring when X and Y are a nitrogen and a carbon 
atom, respectively, or R.sup.7 is a hydrogen or an amino group when X and 
Y are a carbon and a nitrogen atom, respectively. 
Suitable pharmacologically acceptable salts of the cephalosporin compounds 
(I) are conventional non-toxic salts and may include: inorganic acid salts 
(e.g., hydrochloride, hydrobromide, sulfate, phosphate, et.); organic 
carboxylic and sulfonic acid salts (e.g., formate, trifluoroacetate, 
citrate, acetate, maleate, tartrate, oxalate, succinate, benzoate, 
fumarate, mandelate, ascorbate, malate, methanesulfonate, 
para-toluenesulfonate, etc.); and inorganic and organic base salts such as 
salts with alkali metal hydroxides (e.g., sodium hydroxide, potassium 
hydroxide, etc.), alkaline earth metal or alkali metal carbonates (e.g., 
sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium 
carbonate and calcium carbonate, etc.) and amino acid salts. 
The physiologically hydrolyzable esters of the compounds(I) may include, 
for example, indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, 
glycyloxymethyl, phenylglycyloxymethyl 
and-5-methyl-2-oxo-1,3-dioxolan-4-ylmethyl ester, and other 
physiologically hydrolyzable esters which have been widely used in the 
penicillin and cephalosporin antibiotic art. These salts and esters can be 
prepared in accordance with known methods in the art. 
A compound of formula (I) may be prepared by reacting a compound of formula 
(II) with a compound of formula (III) in the presence of a solvent, and, 
if necessary, removing the amino or carboxylic acid protecting group or 
reducing S.fwdarw.(O).sub.m : 
##STR11## 
wherein: R.sup.1 to R.sup.7 X Y and Q have the same meanings as defined 
above; 
L is a leaving group; and 
m is O or l. 
The amino protecting group in R.sup.1 above may be those groups which can 
be readily removed under the conventionally need mild conditions to form a 
free amino group and may include: acyl, substituted and unsubstituted 
aryl(lower)alkyl(e.g., benzyl, diphenylmethyl and triphenylmethyl), 
(lower) alkoxyaryl (e.g., 4-methoxybenzyl), halo(lower)alkyl(e.g., 
trichloromethyl and trichloroethyl), tetrahydropyranyl, substituted 
phenylthio, substituted alkylidene, substituted aralkylidene and 
substituted cycloalkylidene. The acyl group as an amino protecting group 
may include, for example, C.sub.1-5 alkanoyl (e.g., formyl and acetyl), 
and aryl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl), where the acyl 
group can be substituted with 1 to 3-substituents such as a halogen, a 
hydroxy, cyano and nitro group. In addition, the amino protecting group 
may include the reaction products obtained from reacting amino groups with 
silane, boron or phosphorous compounds. 
The hydroxy protecting group in R.sup.2 or R.sup.3 may include, for 
example, acyl [e.g. , formyl or --COR.sup.a, wherein R.sup.a is a 
C.sub.1-8 alkyl(e.g., acetyl)], alkoxycarbonyl [e g., --CO.sub.2 R.sup.a 
wherein R.sup.a is a C.sub.1-8 alkyl], silyl [e.g., (C.sub.1-4 
alkyl)silyl(e.g., trimethylsilyl and t-butyldimethylsilyl)], borate and 
phosphate [--B (OR.sup.b ) or --P(O)(OR.sub.b)2, wherein R.sup.b is a 
C.sub.1-4 alkyl]; and cyclic diol protecting group formed by both R.sup.2 
and R.sup.3 may include, for example, a C.sub.1-7 alkylidenedioxy(e.g., 
methylenedioxy, ethylenedioxy or isopropylidenedioxy), a substituted 
alkylidenedioxy(e.g., methoxymethylenedioxy, diphenylmethylenedioxy or 
carbonyldioxy), cyclic borate (e.g., --OB(OH)O--), cyclic phosphate (e.g., 
--OP(O)(OH)O-- or --OP(O)(OR.sup.b)O--wherein R.sup.b is a C.sub.1-4 
alkyl) and di (C.sub.1-4 alkyl)silyldioxy (e.g., dimethylalkyldioxy). 
The carboxyl protecting group in R.sup.4 or R.sup.5 may be any one of those 
which can be readily removed under the conventional mild conditions to 
form a free carboxyl group and may include, for example, 
(lower)alkylesters (e.g., methyl ester and tertbutyl ester) , 
(lower)alkenylesters (e.g., vinylester and allylester), 
(lower)alkoxy(lower)alkylesters (e.g., methoxymethylester), halo (lower) 
alkylesters (e.g., 2,2,2-trichloroethylester), substituted and 
unsubstituted aralkyl esters (e.g., benzylester and p-nitrobenzyl ester), 
(lower) aralkoxy esters (e.g., p-methoxybenzyl ester) and silyl esters. 
The amino, hydroxy, cyclic diol or carboxyl protecting group can be 
properly selected after considering the chemical property of the desired 
compound(I). 
The leaving group L in formula (II) may include, for example, a halogen 
such as chlorine, fluorine and iodine, a (lower) alkanoyloxy group such as 
acetoxy, a (lower)alkanesulfonyloxy group such as methanesulfonyloxy, an 
arenesulfonyloxy group such as p-toluenesulfonyloxy, an alkoxycarbonyloxy 
group and the like. 
The term "lower" as used hereinabove and elsewhere in this specification, 
for example, in reference to "lower alkyl", encompasses those compounds 
having 1 to 6 carbon atoms, more preferably, 1 to 4 carbon atoms. 
The dotted line of formula(II) which are starting materials for the of 
preparation cephalosporin compounds represents a single or double bond; 
and, therefore, the compounds of formula(II) may be the compounds of 
formula(II-a), or the compounds of formula(II-b), or mixtures thereof: 
##STR12## 
wherein R.sup.1 to R.sup.5, Q, m and L have the same meanings as defined 
before. 
The compounds of formula(II) may be prepared by activating a compound of 
formula(IV) or, salts thereof with an acylating agent and then reacting 
wit-h a compound of formula(V) in accordance with the following scheme(A). 
##STR13## 
wherein: R.sup.1 to R.sup.5, m and L have the same meanings as defined 
previously. The dotted line of formula(V) represents a single or double 
bond; and therefore, the compounds of formula(V) may be the compounds of 
formula(V-a) or the compounds of formula(V-b), or mixtures thereof: 
##STR14## 
wherein: R.sup.5, m and L have the same meanings as defined previously. 
The acylated derivative from the compound of formula(IV) may be an acid 
chloride, anhydrous acid, mixed anhydrous acid (preferably, anhydrous acid 
formed with methyl chloroformate, mesitylenesulfonyl chloride, 
p-toluenesulfonyl chloride or chlorophosphate) or activated ester 
(preferably an ester formed by reaction with N-hydroxy benzotriazole in 
the presence of a condensing agent, e.g., dicyclohexyl carbodiimide). The 
acylation may be conducted by using a free acid of the compound(IV) in the 
presence of a condensing agent, e.g., dicyclohexyl carbodiimide or 
carbonyl diimidazole. Further, the acylation may be conventionally 
conducted in the presence of an organic base, e.g., a tertiary 
amine(preferably, triethyl amine, diethylaniline and pyridine) or an 
inorganic base, e.g., sodium bicarbonate and sodium carbonate, and a 
solvent, e.g., a halogenated hydrocarbon (e.g., methylene chloride and 
chloroform), tetrahydrofuran, acetonitrile, dimethyl formamide, dimethyl 
acetamide and mixtures thereof and an aqueous mixture thereof. 
The acylation may be conducted at a temperature ranging from -50.degree. C. 
to 50.degree. C., preferably from -30.degree. C. to 20.degree. C., and the 
acylating agent may be used in a stoichiometric amount, or an excess(1.05 
to 1.2 equivalents) thereof, based on the compound of formula(V). 
In order to prepare the compound of formula(I), amino or carboxyl 
protecting groups of formula(II) can be readily removed by any of the 
conventional deprotecting methods which are well known in the field of 
cephalosporin antibiotics. For example, acid- or base-hydrolysis or 
reduction is generally applicable. For example, when the compound of 
formula(II) comprises an amido group as a protecting group, the compound 
may be subjected to an aminohalogenation, aminoetherification and 
hydrolysis procedure. The acid-hydrolysis is suitable for removing a 
tri(di)phenylmethyl or alkoxycarbonyl group; and may be conducted by 
employing an organic acid, e.g., formic acid, trifluoroacetic acid and 
p-toluenesulfonic acid, or an inorganic acid, e.g., hydrochloric acid. 
The reaction for introducing the compound(III) into the 3-position of the 
compound(II) to prepare the compound(I) is carried out in the presence of 
a solvent or mixtures thereof such as lower alkylnitrile, e.g., 
acetonitrile and propionitrile, lower halogenated alkane, e.g., 
chloromethane, dichloromethane and chloroform, ether, e.g., 
dimethylformamide, ester, e.g., ethylacetate, ketone, e.g., acetone, 
hydrocarbon, e.g., benzene, a cohol, e.g., methanol and ethanol, and 
sulfoxide, e.g., dimethylsulfoxide, wherein the temperature may range from 
-10 to 80.degree. C., more preferably from 20 to 40.degree. C.; and the 
compounds of the formula(III) are used in an amount of 0.5 to 2 molar 
equivalents, more preferably 1.0 to 1.1 molar equivalents, based on the 
compounds of formula(II). 
The separation and purification of the compounds(I) can be carried out by 
using a conventional method such as recrystallization, column 
chromatography over silica gel or ion-exchange chromatography. 
The compounds of formula(I) and non-toxic salts such as salts with alkali 
metal, alkaline earth metal, inorganic acid, organic acid or amino acid in 
accordance with the present invention, as described above, exhibit potent 
and broad antibacterial activities against Gram-positive bacteria and a 
variety of Gram-negative bacteria as well particularly against 
Pseudomonas. 
Also, these compounds have high stability to .beta. lactamases produced by 
a number of Gram-negative bacteria. 
The pharmaceutical compositions of the invention may be formulated for 
administration in unit dose or multi-dose containers. The compositions may 
take various forms such as solution, suspension or emulsion in an oily or 
aqueous vehicle, which can contain conventional additives such as a 
dispersant, suspending agent, stabilizer and the like. Alternatively, the 
active ingredient may be formulated into a dried powder that can be 
normally dissolved in an aqueous solution of sterile pyrogen-free water 
before use. The compositions may be also formulated into suppositories 
containing conventional suppository bases such as cocoa butter or other 
glycerides. 
The pharmaceutical compositions in a unit dose form may preferably comprise 
about 50 to 1,500mg of the active ingredient, depending on the age and 
body weight of the patient, the nature and severity of the illness, and so 
on. In general, it has been shown advantageous to administer the active 
compounds in an amount ranging from 500 to 5,000mg per day in order to 
achieve the desired results, depending on the routes and frequency of 
administration. In case of intramuscular or intravenous administration for 
adult human treatment, the dosage of about 150 to 3,000mg per day is 
thought to be sufficient, although it may vary in case of treatment for 
specific infections caused by certain strains. 
Exemplary compounds of formula(I) of the present invention are as follows: 
I-1: 7-[(Z)-2-(aminothiazol-4-yl) 
-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimino) 
acetamido]-3-(4,6-diaminopyrimidine-2-yl) 
thiomethyl-3-cephem-4-carboxylate 
##STR15## 
I-2: 7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4- 
dihydroxybenzyloxyimino) acetamido]-3-(4,6-diamino 
-5-methylpyrimidine-2-yl) thiomethyl-3-cephem-4-carboxylate 
##STR16## 
I-3 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o) acetamido]-3-(4-aminopyrimidine-2-yl) thiomethyl-3-cephem-4-carboxylate 
##STR17## 
I-4 : 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o) acetamido]-3-(4-amino-5,6-cyclopentapyrimidine-2-yl) 
thiomethyl-3-cephem-4-carboxylate 
##STR18## 
I-5 : 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o) acetamido]-3-(4,5,6-triaminopyrimidine-2-yl) 
thiomethyl-3-cephem-4-carboxylate 
##STR19## 
I-6 : 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o) acetamido]-3-(2,6-diaminopyrimidine-4-yl) 
thiomethyl-3-cephem-4-carboxylate 
##STR20## 
I-7: 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o) acetamido]-3-(6-aminopyrimidine-4-yl) thiomethyl-3-cephem-4-carboxylate 
##STR21## 
The following Preparation Examples and Examples illustrate how some of the 
starting materials of formulae(II) and (III) and of the compounds of 
formula(I) can be prepared. 
R- and S- diastereoisomers depending on the stereo configuration of the 
asymmetric carbon on which 7.beta.-dihydroxybenzyl group is attached were 
obtained in the Examples and they were determined by .mu.-Bondapak 
C.sub.18 Steel Column, using 25% methanol containing 0.5% acetic acid. 
PREATION EXAMPLE 1 
Synthesis of 2-bromo-2-(3,4-O-isopropylidenedioxyphenyl)acetic acid 
diphenylmethyl ester 
Step 1) Synthesis of 
2-(3,4-dihydroxyphenyl)-2-hydroxy-1,1,1-trichloroethane 
1036g of trichloroacetaldehyde monohydrate was added to a solution of 440g 
of 1,2-dihydroxybenzene dissolved in 1L of methylenechloride and the 
resultant solution was cooled to 0.degree. C. 102g of triethylamine was 
added dropwise to the solution and heated to room temperature. After 
stirring for about 20 min., the reaction solution was heated to 50.degree. 
C. and further stirred for 3 hours at that temperature. After the 
completion of the reaction, the solution was evaporated under reduced 
pressure to remove methylene chloride and the residue obtained was 
dissolved in 4L of ethyl acetate. The resultant solution was washed with 
2,400ml of 0.5N hydrochloric acid and 2L of saturated sodium chloride 
solution, subsequently. The resultant was dried on anhydrous magnesium 
sulfate and distilled under reduced pressure to obtain 540g of the title 
compound. 
NMR(.delta., acetone-d.sub.6): 5.2(d, 1H), 6.0(d, 1H), 6.8(d, 1H), 7.0(dd, 
1H), 7.2(d, 1H), 7.9(s, 1H), 8.0(s, 1H) 
Step 2) Synthesis of .alpha.-trichloromethyl-3,4-isopropylidenedioxy 
benzylalcohol 
515g of the compound obtained in step 1 was dissolved in 2.5L of benzene 
and thereto were added 305ml of 2,2-dimethoxypropane and 2.84g of 
phosphorous pentoxide. The reaction mixture was heated under reflux for 2 
hours. The reaction was carried out with a reactor equipped with a soxhlet 
extractor filled with 600g of calcium chloride to remove by-product 
methanol. After 2 hours, 77ml of 2,2-dimethoxypropane was added to the 
mixture, the resultant was further refluxed for 3 hours, cooled to room 
temperature, washed four times with 500ml of 1N aqueous sodium carbonate 
solution and 500ml of saturated sodium chloride solution, subsequently, 
dried on anhydrous magnesium sulfate and distilled under reduced pressure. 
The residue thus obtained was purified with silicagel column 
chromatography to obtain 220g of the title compound. 
NMR(.delta., CDCl.sub.3): 1.66(s, 6H), 3.61(d, 1H), 4.98(d, 1H), 
6.53-6.90(m, 3H) 
Step 3) Synthesis of 2-(3,4-O-isopropylidenedioxyphenyl)-2-hydroxyacetic 
acid 
119.4g of lithium hydroxide monohydrate was dissolved in 500ml of water and 
the resultant solution was cooled to 0.degree. C. Thereto were added 201g 
of the compound obtained in step 2 and 413ml of dioxane and the resultant 
mixture was stirred for 3 days at room temperature. 240g of ice was added 
thereto, the mixture was stirred for 30 min. with further adding 300ml of 
6N hydrochloric acid and 120g of ice. The resultant was filtered, washed 
with 1.8L of water and then 700ml of chloroform, and dried under nitrogen 
atomsphere to obtain 60g of the title compound. 
NMR(.delta., DMSO-d.sub.6): 1.61(s, 6H) -4.85(s, 1H), 6.60-6.83(m, 3H), 
8.2(bs, 2H) 
Step 4) Synthesis of 2-(3,4-O-isopropylidenedioxyphenyl)-2-hydroxyacetic 
acid diphenylmethyl ester 
50g of the compound obtained in step 3 was dissolved in 400ml of acetone 
and thereto was added dropwise 1M diphenyldiazo-methane dissolved in 
diethylether until nitrogen gas occurred no more. The reaction mixture was 
further stirred for 20 min., distilled under reduced pressure and purified 
with silicagel column chromatography to obtain 70g of the title compound. 
NMR(.delta., CDCl.sub.3): 1.69(s, 6H), 5.62(d, 1H), 6.20(d, 1H), 6.70(d, 
1H), 6.87(s, 1H), 6.89(d, 1H), 6.97(s, 1H), 7.26(b, 10H) 
Step 5) Synthesis of 2-bromo-2-(3,4-O-isopropylidene-dioxyphenyl)acetic 
acid diphenylmethyl ester 
108g of the compound obtained in step 4 was dissolved in 1.3L of 
dimethylformamide and the resultant solution was cooled to -60.degree. C. 
Thereto was added 187.4g of phosphorous tribromide and the resultant 
solution was warmed to -15.degree. C., stirred for 20 min. and distilled 
under reduced pressure. The residue thus obtained was dissolved in 1L of 
ethylacetate and the resultant solution was washed with 1L of saturated 
sodium chloride solution four times, dried on anhydrous magnesium sulfate 
and distilled under reduced pressure to obtain 115.96g of the title 
compound. 
NMR(.delta., CDCl.sub.3): 1.66(d, 6H), 5.41(s, 1H), 6.63(d, 1H), 6.84(s, 
1H), 6.86(d, 1H), 6.97(s, 1H), 7.25(d, 10H) 
PREATION EXAMPLE 2 
Synthesis of 2-(2-triphenylmethylamino 
thiazol-4-yl)-2-(.alpha.-diphenylmethyloxycarbonyl-3,4-O-isopropylidenedio 
xybenzyloxyimino)acetic acid 
Step 1) Synthesis of 2-(2-triphenylmethylaminothiazol-4-yl)-2- 
(.alpha.-diphenylmethyloxycarbonyl-3,4-O-isopropylidenedioxybenzyl-oxyimin 
o) acetic acid allylester 
61g of potassium carbonate and 29.4g of potassium iodide were added to a 
solution of 58.18g of 2-(2-triphenyamino-thiazol-4-yl) -2-hydroxyimino 
acetic acid-allylester dissolved in 140ml of dimethylformamide and the 
resultant solution was cooled to 0.degree. C. Thereto was added dropwise a 
solution of 80.16g of the compound obtained in Preparation Example 1 
dissolved in 60ml of dimethyl-formamide for 1 hour and further stirred for 
20 min. The resulting solution was distilled under reduced pressure to 
remove the solvent. The residue thus obtained was dissolved in 2L of ethyl 
acetate. The resulting solution was washed six times with 400ml of 
saturated sodium chloride solution, dried on anhydrous magnesium sulfate 
and distilled under reduced pressure to remove the solvent. The residue 
thus obtained was purified with silicagel column chromatography to obtain 
89g of the title compound. 
NMR(.delta., CDCl.sub.3): 1.69(s, 6H), 4.81(d, 2H), 5.27 (ABq, 2H), 5.79(s, 
1H), 5.80-5.99(m, 1H), 6.53(s, 1H), 6.64(d, 1H), 6.78(d, 1H), 6.87(s, 1H), 
7.13-7.36(m, 27H) 
Step 2) Synthesis of 2-(2-triphenylmethylaminothiazol4-yl)-2- 
(.alpha.-diphenylmethyloxycarbonyl-3,4-O-isopropylidenedioxybenzyloxyimino 
)acetic acid 
14.5g of potassium 2-ethylhexanoate, 3.75g of triphenylphosphine and 0.6g 
of tetrakis(triphenylphosphine)palladium were added to a solution of 60g 
of the compound obtained in step 1 dissolved in 500ml of methylene 
chloride and stirred for 1 hour at room temperature. The reaction mixture 
was washed three times with 500ml of saturated sodium chloride solution, 
dried on anhydrous magnesium sulfate, and distilled under reduced pressure 
to remove the solvent. The residue thus obtained was purified with 
silicagel column chromatography to obtain 50g of the title compound. 
NMR(.delta., CDCl.sub.3): 1.70(s, 6H), 5.68(s, 1H), 6.55(s, 1H), 6.66(d, 
1H), 6.80(d, 1H), 6.89(s, 1H), 7.04-7.27(m, 27H) 
PREATION EXAMPLE 3 
Synthesis of para-methoxybenzyl 3-chloromethyl-7- [(Z) -2- 
(.alpha.-diphenyloxycarbonyl-3,4-O-isopropylidenedioxybenzyloxyimino) -2- 
(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate 
28.1g of pyridine was added to a solution of 36g of paramethoxybenzyl 
7-amino-3-chloromethyl-3-cephem-4-carboxylate suspended in 950ml of 
methylene chloride. The resultant solution was stirred and cooled to 
-20.degree. C. Thereto was added 50.09g of the compound obtained in 
Preparation Example 1 and the reaction solution was stirred for 5 min. 
13.62g of phosphorous oxychloride was added to the reaction mixture and 
further stirred for 30 min. The reaction mixture was washed three times 
with 400ml of saturated sodium chloride solution and dried on anhydrous 
magnesium sulfate. The resultant thus obtained was distilled under reduced 
pressure to remove the solvent and purified with silicagel column 
chromatography to obtain 70g of the title compound of solid-foam. 
NMR(.delta.CDCl.sub.3): 1.59(d, 6H), 3.33(ABq, 2H), 3.83(s, 3H), 4.51(ABq, 
2H), 4.96(d, 1H), 6.27(s, 2H), 5.87(dd, 1H), 5.95(s, 1H), 6.6-7.45(m, 
35H), 8.21(d, 1H) 
Example 1 
Synthesis of 7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.- carboxy 
-3,4-dihydroxybenzyloxyimino) acetamido]-3-(4,6-diamino-pyrimidine-2-yl) 
thiomethyl-3-cephem-4-carboxylate(Compounds I-1S and I-1R) 
1.84g of 4,6-diaminopyrimidine-2-thiol was added to a solution of 5.0g of 
the compound obtained in Preparation Example 3 dissolved in 20ml of 
dimethylformamide and the resultant was stirred for 1 hour at room 
temperature. 200ml of distilled water and 200ml of ethyl acetate were 
added thereto and the resultant was shaken and separated to obtain an 
organic layer. The organic layer was washed with 200ml of saturated sodium 
chloride solution three times, dried on 50g of anhydrous magnesium sulfate 
and evaporated under reduced pressure to remove the solvent. The 
concentrate thus obtained was added dropwise to 300ml of diethyl ether 
with stirring to obtain precipitates, which was washed with 200ml. of 
diethyl ether and dried to obtain 4.62g of white powders. The powders were 
dissolved in 15ml of anisole and the resultant solution was cooled to 
0-4.degree. C. 30ml of trifluoroacetic acid was added dropwise thereto and 
the reaction mixture was stirred for 1 hour at room temperature and cooled 
to -10-15.degree. C. Thereto was added dropwise 180ml of diethyl ether and 
the resultant was filtered, washed with 50ml of acetone and 150ml of 
diethyl ether, subsequently, and dried to obtain 2.25g of an ivory solid. 
The solid was isolated by .mu.-Bondapak C.sub.18 Steel Column 19mm .times. 
30cm using 5% methanol as an eluent to obtain 460mg of I-1S and 457mg of 
I-1R of the title compounds as white powders. 
M.S (FAB. M+1): 690 
NMR (.delta., D.sub.2 O, .div.NaHCO.sub.3) 
I-1S:3.29(ABq, 2H), 4.07(ABq, 2H), 4.96(d, 1H), 5.37(s, 1H), 5.42(s,1H), 
5.62(d, 1H), 6.79.about.7.02(m,4H). 
I-1R:3.31(ABq, 2H), 4.11(ABq, 2H), 4.94(d, 1H), 5.38(s, 1H), 5.41(s, 1H), 
5.58(d, 1H), 6.80.about.7.03(m, 4H). 
IR(KBr, cm.sup.-1): 1770(.beta.-lactam), 1660, 1630, 1570 
Example 2 
Synthesis of 7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxyl 
-3,4-dihydroxybenzyloxyimino)acetamido]-3-(4,6-diamino-5-methylpyrimidine- 
2-yl)thiomethyl-3-cephem-4-carboxylate (Compounds I-2S and I-2R) 
The same procedures as described in Example 1 were repeated except that 
1.99g of 4,6-diamino-5-methylpyrimidine- 2-thiol was used as a starting 
material to obtain 445mg of I-2S and 443mg of I-2R of the title compounds. 
M.S (FAB, M+1): 704 
NMR (.delta., D.sub.2 O +NaHCO.sub.3) 
I -2S: 1.83 (s, 3H ), 3.33 (ABq, 2H), 4.11(ABq, 2H), 4.94(d, 1H), 
5.39(s,1H), 5.59(d, 1H), 6.80.about.7.03(m, 4H). 
I-2R:1.84(s,3H), 3.32(ABq, 2H), 4.09(ABq, 2H), 4.95(d, 1H), 5.39(s, 1H), 
5.62(d, 1H), 6.80.about.7.03(m, 4H). 
IR (KBr, cm.sup.-1): 1770(.beta.-lactam), 1665, 1630, 1580 
Example 3 
Synthesis of 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxyl-3,4-dihydroxybenzyloxyimi 
no) acetamido]-3-(4-amino-pyrimidine-2-yl) 
thiomethyl-3-cephem-4-carboxylate(Compounds I-3S and I-3R) 
The same procedures as described in Example 1 were repeated except that 
1.72g of 4-aminopyrimidine-2-thiol was used as a starting material to 
obtain 450mg of I-3S and 454mg of I-3R of the title compounds. 
M.S (FAB, M+1): 675 
NMR (.delta., D.sub.2 O +NaHCO.sub.3) 
I-3S:3.30(ABq, 2H), 4.09(ABq, 2H), 4.98(d, 1H), 5.36(s, 1H), 5.62(d, 1H), 
6.49(d, 1H), 6.81.about.7.02(m, 4H), 7.96(d, 1H). 
I-3R:3.31(ABq. 2H), 4.11(ABq, 2H), 4.96(d, 1H), 5.38(S, 1H), 5.63(d, 1H), 
6.49(d. 1H), 6.82.about.7.01(m, 4H), 7.98(d, 1H). 
IR(KBr, cm.sup.-1): 1770(.beta.-lactam), 1670, 1630, 1570 
Example 4: 
Synthesis of 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxyl-3,4-dihydroxybenzyioxyimi 
no)acetamido]-3-(4-amino-5,6-cyclopentapyrimidine-2-yl)thiomethyl-3-cephem- 
4-carboxylate (Compounds I-4S and I-4R) 
The same procedures as described in Example 1 were repeated except that 
2.23g of 4-amino-5,6-cyclopentapyrimidine-2-thiol was used as a starting 
material to obtain 438mg of I-4S and 441mg of I-4R of the title compounds. 
M.S (FAB. M+1): 715 
NMR (.delta., D.sub.2 O +NaHCO.sub.3) 
I-4S: 2.12(m, 2H), 2.68(t,2H), 2.95(t,2H), 3.34(ABq, 2H), 4.23(ABq, 2H), 
4.96(d, 1H), 5.38(s, 1H), 5.54(d, 1H), 6.81.about.7.02(m, 4H). 
I -4R: 2.11(m, 2H), 2.69(t,2H), 2.95(t,2H), 3.33(ABq, 2H), 4.22(ABq, 2H) 
4.97(d, 1H), 5.38(s, 1H), 5.59(d, 1H), 6.80.about.7.02(m, 4H). 
IR(KBr, cm.sup.-1): 1770(.beta.-lactam), 1665, 1635, 1580 
Example 5 
Synthesis of 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o)acetamido]-3-(4,5,6-triaminopyrimidine-2-yl)thiomethyl-3-cephem-4-carboxy 
late (Compounds I-5S and I-5R) 
The same procedures as described in Example 1 were repeated except that 2g 
of 4,5,6-triaminopyrimidine-2-thiol was used as a starting material to 
obtain 510mg of I-5S and 520mg of I-5R of the title compounds. 
M.S (FAB, M+1): 705 
NMR (.delta., D.sub.2 O +NaHCO.sub.3) 
I-5S: 3.31 (ABq, 2H), 4.07(ABq, 2H), 4.96(d, 1H), 5.40(s, 1H), 5.65(d, 1H), 
6.80.about.7.05(m, 4H). 
I-5R: 3.32(ABq, 2H), 4.11(ABq, 2H), 4.95(d, 1H), 5.41(s, 1H), 5.63(d, 1H), 
6.80.about.7.01 (m, 4H). 
IR(KBr, cm.sup.-1): 1770(.beta.-lactam), 1670, 1620, 1580 
Example 6 
Synthesis of 
7-[(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o)acetamido]-3-(2,6-diamino- 
pyrimidine-4-yl)thiomethyl-3-cephem-4-carboxylate (Compounds I-6S and 
I-6R) 
The same procedures as described in Example 1 were repeated except that 
1.84g of 2,6-diaminopyrimidine-2-thiol was used as a starting material to 
obtain 510mg of I-6S and 490mg of I-6R of the title compounds. 
MS(FAB, M+1): 690 
NMR (.delta., D.sub.2 O +NaHCO.sub.3) 
I-6S: 3.30(ABq, 2H), 4.05(ABq, 2H), 4.98(d, 1H). 5.41(s, 1H), 5.65(d. 1H), 
5.89(S, 1H), 6.79.about.7.02(m, 4H) 
I-6R : 3.31 (ABq. 2H). 4.10(ABq. 2H). 4.97(d. 1H), 5.39(S. 1H). 5.61(d. 
1H). 5.89(S. 1H). 6.80.about.7.03(m, 4H) 
IR(KBr, cm.sup.-1): 1770(.beta.-lactam), 1670, 1630, 1580 
Example 7 
Synthesis of 
7[-(Z)-2-(aminothiazol-4-yl)-2-(.alpha.-carboxy-3,4-dihydroxybenzyloxyimin 
o)acetamido]-3-(6-amino-pyrimidine-4-yl)thiomethyl-3cephem-4-carboxylate 
(Compounds I-7S and I-7R) 
The same procedures as described in Example 1 were repeated except that 
1.99g of 6-aminopyrimidine-4-thiol. was used as a starting material to 
obtain 420mg of I-7S and 410mg of I-7R of the title compounds. 
MS(FAB. M+1): 675 
NMR(.delta., D.sub.2 O +NaHCO.sub.3 ) 
I-7S: 3.33(ABq, 2H), 4.11(ABq, 2H), 4.94(d, 1H), 5.59(d, 1H). 5.89(s, 1H), 
6.80.about.7.03(m, 4H), 8.19(s, 1H) 
I-7R: 3.32(ABq, 2H), 4.09(ABq, 2H), 4.95(d,1H), 5.62(d, 1H), 5.91 (s, 1H), 
6.80.about.7.03(m, 4H), 8.20(s, 1H) 
IR(KBr, cm .sup.-1): 1770(.beta.-lactam), 1650, 1630, 1580 
ACTIVITY TEST 
In order to illustrate surprisingly superior antibacterial effectiveness of 
the compounds of the present invention, the minimal inhibitory 
concentrations(MIC) and the pharmakinetic variables of the compounds 
synthesized against standard strains were determined and compared with 
Ceftazidime, which was used as a control compound. 
These MIC values were taken by employing a two-fold dilution method: that 
is, two-fold serial dilutions of each of the test compounds were made and 
dispersed in a Muller-Hinton agar medium; 2.mu.l of the standard test 
strain which had the 10.sup.7 CFU(Colony Forming Unit) per ml was 
inoculated on the medium; and these were incubated at 37.degree. C. for 20 
hours. The results of the MIC tests are shown in Table 1. 
The pharmakinetic variables were determined using SD rats (.male.) of a 
body weight of 230.+-.10g as follows. The "S" compound of each of the 
Examples was injected to femoral vein of 4-5 rats by 20mg/Kg and then 
blood was collected from femoral artery in 1, 2.5, 5, 10, 20, 40, 60 and 
120 min. The pharmakinetic variables were determined from the 
concentration of the compound in blood by agar well method and the results 
are shown in Table 2. 
TABLE 1 
__________________________________________________________________________ 
Compounds 
Strains I-1S 
I-1R 
I-2S 
I-2R 
I-3S 
I-3R 
I-4S 
I-4R 
I-5S 
I-5R 
__________________________________________________________________________ 
Staphylococcus aureus 6538P 
2 2 1 2 2 2 1 2 2 2 
Staphylococcus aureus giorgio 
1 1 1 1 1 2 1 2 1 1 
Staphylococcus aureus 77 
8 32 4 32 4 16 8 32 8 32 
Staphylococcus aureus 241 
64 128 64 128 128 128 64 128 64 128 
Staphylococcus epidermidis 887E 
32 64 16 64 32 64 32 32 32 64 
Streptococcus laecalis 29212A 
4 16 4 32 4 32 4 16 4 16 
E. coli 10536 .ltoreq.0.008 
0.063 
.ltoreq.0.008 
0.063 
.ltoreq.0.008 
0.031 
.ltoreq.0.008 
0.063 
.ltoreq.0.008 
0.063 
E. coli 3190Y 0.031 
0.13 
0.063 
0.13 
0.031 
0.13 
0.031 
0.25 
0.031 
0.063 
E. coli 851E 0.031 
0.13 
0.031 
0.13 
0.063 
0.13 
0.031 
0.13 
0.031 
0.13 
E. coli TEM1 1193E 
0.031 
0.25 
0.031 
0.5 0.031 
0.5 0.063 
0.5 0.031 
0.25 
E. coli TEM3 3455E 
0.016 
0.25 
0.016 
0.25 
0.016 
0.25 
0.016 
0.25 
0.016 
0.25 
E. coli TEM5 3739E 
0.063 
0.25 
0.063 
0.25 
0.063 
0.25 
0.063 
0.25 
0.063 
0.25 
E. coli TEM7 3457E 
.ltoreq.0.008 
0.063 
.ltoreq.0.008 
0.016 
0.063 
0.016 
.ltoreq.0.008 
0.063 
.ltoreq.0.008 
0.063 
E. coli TEM9 2639E 
0.25 
0.5 0.25 
0.5 0.25 
0.5 0.25 
0.5 0.25 
0.5 
Pseudomonas aeruginosa 1912E 
0.25 
1 0.5 2 0.25 
1 0.25 
2 0.25 
1 
Pseudomonas aeruginosa 10145 
0.13 
2 0.13 
2 0.13 
2 0.13 
2 0.13 
2 
Pseudomonas aeruginosa 6065 
0.25 
8 0.25 
8 0.5 8 0.13 
8 0.25 
8 
Acinetobacter 15473A 
0.13 
1 0.25 
1 0.13 
1 0.13 
1 0.13 
1 
calcoaceticus 
Citrobacter diversus 2046E 
0.063 
1 0.016 
2 0.031 
2 0.063 
2 0.063 
1 
Enterobacter IND + VE 1194E 
2 32 4 32 2 32 2 32 2 32 
cloacae 
Enterobacter P99 
16 32 8 32 8 16 8 32 8 32 
cloacae 
Klebsiella SHV-1 1976E 
0.13 
0.5 0.13 
0.5 0.13 
1 0.13 
0.5 0.13 
0.25 
aerogenes 
Klebsiella K1 + 1082E 
0.031 
0.5 0.031 
1 0.031 
0.5 0.031 
1 0.031 
0.5 
aerogenes 
Proteus vularis 6059A 
0.13 
0.5 0.13 
0.5 0.13 
0.5 0.13 
0.5 0.13 
0.5 
Serratia marcescens 1826E 
0.25 
2 0.25 
2 0.25 
2 0.25 
2 0.25 
2 
Salmonella typhimurium 14028A 
0.016 
0.13 
0.016 
0.25 
0.016 
0.013 
0.016 
0.13 
0.016 
0.13 
__________________________________________________________________________ 
Compounds 
Strains I-6S 
I-6R 
I-7S 
I-7R 
Ceftazidime 
__________________________________________________________________________ 
Staphylococcus aureus 6538P 
1 1 2 2 16 
Staphylococcus aureus giorgio 
1 1 1 2 4 
Staphylococcus aureus 77 
8 16 4 8 32 
Staphylococcus aureus 241 
64 64 64 128 &gt;128 
Staphylococcus epidermidis 887E 
32 32 32 32 &gt;128 
Streptococcus laecalis 29212A 
2 4 2 4 &gt;128 
E. coli 10536 .ltoreq.0.008 
0.016 
.ltoreq.0.008 
0.016 
0.13 
E. coli 3190Y 0.031 
0.063 
0.031 
0.063 
0.063 
E. coli 851E 0.031 
0.063 
0.063 
0.13 
0.063 
E. coli TEM1 1193E 
0.031 
0.063 
0.063 
0.13 
0.25 
E. coli TEM3 3455E 
0.016 
0.031 
0.016 
0.031 
8 
E. coli TEM5 3739E 
0.063 
0.063 
0.063 
0.063 
8 
E. coli TEM7 3457E 
.ltoreq.0.008 
0.016 
0.016 
0.031 
16 
E. coli TEM9 2639E 
0.13 
0.25 
0.13 
0.25 
&gt;128 
Pseudomonas aeruginosa 1912E 
0.13 
0.25 
0.25 
0.25 
1 
Pseudomonas aeruginosa 10145 
0.25 
0.25 
0.25 
2 2 
Pseudomonas aeruginosa 6065 
0.25 
1 0.5 4 16 
Acinetobacter 5473A 
0.13 
0.25 
0.13 
0.25 
2 
calcoaceticus 
Citrobacter diversus 2046E 
0.063 
0.13 
0.063 
0.13 
0.5 
Enterobacter IND + VE 1194E 
2 4 2 4 128 
cloacae 
Enterobacter P99 
8 8 8 8 64 
cloacae 
Klebsiella SHV-1 1976E 
0.13 
0.25 
0.25 
0.25 
0.25 
aerogenes 
Klebsiella K1 + 1082 E 
0.031 
0.25 
0.063 
0.25 
0.25 
aerogenes 
Proteus vularis 6059A 
0.13 
0.25 
0.25 
0.25 
0.063 
Serratia marcescens 1826E 
0.13 
0.5 0.25 
0.5 0.25 
Salmonella typhimurium 14028A 
0.016 
0.13 
0.016 
0.13 
0.25 
__________________________________________________________________________ 
TABLE 2 
______________________________________ 
Compounds 
Cefta- 
Variables 
I-1S I-2S I-3S I-4S I-5S I-6S I-7S zidime 
______________________________________ 
T.sub.1/2 (min) 
62 55 58 57 59 62 59 20 
AUC(.mu.g. 
3694 3247 3472 3329 3571 3589 3601 1863 
min/ml) 
______________________________________