Antibacterial 1-oxadethiacephalosporins of the formula: ##STR1## [wherein Ar is ##STR2## (in which Acyl is organic or inorganic acyl); COB.sup.1 and COB.sup.2 each is carboxy or protected carboxy; PA1 Het is ##STR3## (in which COB.sup.3 is carboxy or protected carboxy); AND Y is hydrogen or methoxy; And when COB.sup.1, COB.sub.2, and/or COB.sup.3 is carboxy, pharmaceutically acceptable salts thereof are included, But with a proviso that when Y is methoxy, Het is ##STR4## a pharmaceutical or veterinary composition comprising the said 1-oxadethiacephalosporins and pharmaceutical carrier, and a method for treating or preventing human or veterinary infectious diseases comprising administering the said 1-oxadethiacephalosporin.

This invention relates to arylmalonamido-1-oxadethiacephalosporins. More 
specifically, it relates to compounds of the following formula: 
##STR5## 
[wherein Ar is 
##STR6## 
(in which Acyl is organic or inorganic acyl); COB.sup.1 and COB.sup.2 each 
is carboxy or protected carboxy; 
Het is 
##STR7## 
(in which COB.sup.3 is carboxy or protected carboxy); and 
Y is hydrogen or methoxy; 
and when COB.sup.1, COB.sup.2, and/or COB.sup.3 is carboxy, 
pharmaceutically acceptable salts thereof; 
with a proviso that when Y is methoxy, Het is 
##STR8## 
Cephalosporin analogs having oxygen in place of sulfur atom in the nucleus 
have been described in the Journal of Heterocyclic Chemistry, Volume 5, 
page 779 (1968) by J. C. Sheehan and M. Dadic; German Patent Application 
(OLS) No. 2,219,601 (1972); the Canadian Journal of Chemistry, Volume 52, 
page 3996 (1974 by S. Wolfe et al.; the Journal of American Chemical 
Society, Volume 96, page 7582 (1974) by B. G. Christensen et al.; and 
Japanese Patent Application (OPI No. 49-133594) claiming priorities based 
on U.S. Pat. application Nos. 303,905 and 395,662. 
The present inventors have now prepared various 1-oxadethiacephalosporins 
closely related to known (1-thia)cephalosporins. Contrary to the reports 
of B. G. Christensen et al., suggesting their racemic 1-oxadephalosporins 
showed about a half the potency of (1-thia)cephalosporins, the optically 
active products prepared by the present inventors were more active as the 
corresponding (1-thia)cephalosporins in their antibacterial property. 
However, the .beta.-lactam ring of the prior art 1-oxadethiacephalosporins 
was less stable to be clinical drugs, than that of (1-thia)cephalosporins. 
Compounds (I) selected from the optically active compounds prepared by the 
present inventors overcome the said deficiency of 
1-oxadethiacephalosporins. 
Furthermore, Compounds (I) showed the following characteristics when 
compared with other types of 1-oxadethiacephalosporins: 
(1) more potent antibacterial activity against gram negative b bacteria; 
(2) higher stability of the .beta.-lactam ring; 
(3) closer minimal inhibitory concentration between the bacteria producing 
and non-producing .beta.-lactamase; 
(4) less dependency on inoculum size; 
(5) higher effectiveness against bacteria resistant to certain other 
cephalosporins (e.g. Enterobacteria, Serratia, indole positive Proteus); 
(6) higher contribution of bactericidal character; and 
(7) higher blood level. 
Additionally, Compounds (I) where Y is methoxy have the following 
superiorities: 
(a) broader antibacterial spectra (e.g. 3.6 .mu.g/ml or more against 
Pseudomonas sp.), and anaerobic bacteria (Bacteroid fragilis); 
(b) higher potency against bacteria producing .beta.-lactamase; 
(c) higher stability in blood; and 
(d) lower binding with serum proteins. 
In the formula (I), preferably Ar is 3-thienyl, p-hydroxyphenyl, and 
p-acyloxyphenyl in which the acyl is 1-5C alkanoyl, carbamoyl, 2-6C 
N-alkylcarbamoyl, or ureidocarbonyl. 
The group Acyl in the definition of Ar can be inorganic or organic acyls 
containing up to 20 carbon atoms especially 1-5C alkanoyl, 2-5C 
alkoxycarbonyl, 8-20C aralkoxycarbonyl, carbamoyl, 2-6C N-alkylcarbamoyl, 
and ureidocarbonyl. 
Specific examples of the acyls include formyl, acetyl, propionyl, butyryl, 
isobutyryl, carbethoxycarbonyl, benzyloxycarbonyl, carbamoyl, 
N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, 
N-isobutylcarbamoyl, N,N-dimethylcarbamoyl, carbamoylcarbamoyl, 
N.sup..alpha. -methylureidocarbonyl, and like acyls. 
The group COB.sup.1, COB.sup.2, and COB.sup.3 can be carboxy or protected 
carboxy conventional in the chemistry of penicillins and cephalosporins, 
usually containing up to 20 carbon atoms. The protective groups can be the 
same or different for each carboxy in the molecule. Usually, the 
protective groups are removed to give free carboxy or salts, at any stage 
of synthesis of Compounds (I). Therefore, the structures of the 
carboxyprotective groups can vary widely without changing the gist of this 
invention. In other words, their structures have no specific significance 
other than protection, deprotection, and when included, salt formation. 
Specific examples of said protective groups are esters (including 
optionally substituted 1-5C alkyl esters e.g. methyl, ethyl, isopropyl, 
n-butyl, t-butyl, pentyl, cyclopropylmethyl, monohydroxy-t-butyl, 
2,2,2-trichloroethyl, chloromethyl, cyanomethyl, methanesulfonylethyl, 
acetylmethyl, acetoxymethyl, propionyloxymethyl, benzoyloxymethyl, 
methoxymethyl, phenoxymethyl, methylthiomethyl, phenylthiomethyl, 
tetrahydropyranyl, phthalimidomethyl, .alpha.,.alpha.-dimethylpropargyl, 
ethoxycarbonyloxyethyl, methoxycarbonyloxypropyl, and allyl esters; 
aralkyl esters e.g. benzyl, phenethyl, tolylmethyl, dimethylbenzyl, 
nitrobenzyl, halobenzyl, methoxybenzyl, phthalidyl, 
p-hydroxy-di-t-butylbenzyl, diphenylmethyl, trityl, phenacyl, 
chlorophenacyl, bromophenacyl, nitrophenacyl, and methylphenacyl esters; 
and another easily removable aliphatic esters; metal esters e.g. 
trimethylsilyl, dimethylmethoxysilyl, trimethylstannyl esters; and 
aromatic esters e.g. phenyl, naphthyl, tolyl, dimethylphenyl, nitrophenyl, 
methanesulfonylphenyl, chlorophenyl, pentachlorophenyl, indanyl, and 
pyridyl esters); or pharmaceutically acceptable salts (including alkali 
metal salts e.g. sodium and potassium salts; alkaline earth metal salts 
e.g. magnesium, calcium, and acyloxycalcium salts; and salts with organic 
bases e.g. procain, triethylamine, and dicyclohexylamine). Each carboxy in 
the molecule can be free or protected by the same or different groups. 
Preferably COB.sup.1, COB.sup.2, and/or COB.sup.3 can be free carboxy or 
its pharmaceutically acceptable salts (e.g. sodium and potassium salts). 
Some carboxy protective groups are, however, useful for changing the 
character of the products as drugs. In such cases, they can be 
specifically known groups for drugs conventional in the art. These groups 
include those forming the following pharmaceutically acceptable esters for 
enhancing the absorption through digestive organs: e.g. phthalidyl, 
acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, propionyloxyethyl, 
indanyl, phenyl, tolyl, dimethylphenyl, methoxyphenyl, 
methoxycarbonyloxyethyl, ethoxycarbonylmethyl, phenacyl, and like esters. 
Preferably Y is methoxy, although Y being hydrogen is also important. 
Usually, Compounds (I) are administered as salts for the parenteral 
administration to human or veterinary subjects. Most preferable salts are 
sodium or potassium salts, or salts with pharmaceutically acceptable 
organic bases e.g. procain or xylocain. The salt functions are selected 
from the view point of safety, solubility, stability, etc. 
Specific examples of Compounds (I) include the following ones: 
7.beta.-[.alpha.-(2-thienyl)-.alpha.-carboxyacetamido]-3-(1-methyltetrazol- 
5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(2-thienyl)-.alpha.-carboxyacetamido]-3-(1-carboxymethylte 
trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(2-thienyl)-.alpha.-carboxyactamido]-3-(2-methyl-1,3,4-thi 
adiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-3-(1-methyltetrazol- 
5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-3-(1-carboxymethylte 
trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-3-(2-methyl-1,3,4-th 
iadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-phenyl-.alpha.-carboxyacetamido)-3-(1-methyltetrazol-5-yl) 
thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-phenyl-.alpha.-carboxyacetamido)-3-(1-carboxymethyltetrazo 
l-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-phenyl-.alpha.-carboxyacetamido)-3-(2-methyl-1,3,4-thiadia 
zol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-3-(1-methyltetra 
zol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-3-(1-carboxymeth 
yltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-3-(2-methyl-1,3, 
4-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-acetoxyphenyl-.alpha.-carboxyacetamido)-3-(1-methyltetra 
zol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-acetoxyphenyl-.alpha.-carboxyacetamido)-3-(1-carboxymeth 
yltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-acetoxyphenyl-.alpha.-carboxyacetamido)-3-(2-methyl-1,3, 
4-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-propionyloxyphenyl-.alpha.-carboxyacetamido)-3-(1-methyl 
tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-pentanoyloxyphenyl-.alpha.-carboxyacetamido)-3-(2-methyl 
-1,3,4-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-carbamoyloxyphenyl-.alpha.-carboxyacetamido)-3-(1-methylte 
trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-N-methylcarbamoyloxyphenyl-.alpha.-carboxyacetamido)-3-( 
1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-N-pentylcarbamoyloxyphenyl-.alpha.-carboxyacetamido)-3-( 
2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-(.alpha.-p-ureidocarbonyloxyphenyl-.alpha.-carboxyacetamido)-3-(1-m 
ethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(2-thienyl)-.alpha.-carboxyacetamido]-7.alpha.-methoxy-3-( 
1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-7.alpha.-methoxy-3-( 
1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-phenyl-.alpha.-carboxyacetamido)-7.alpha.-methoxy-3-(1-met 
hyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-(.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-methoxy 
-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-(.alpha.-p-acetoxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-methoxy 
-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-(.alpha.-p-propionyloxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-me 
thoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-(.alpha.-p-benzoyloxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-meth 
oxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-(.alpha.-p-carbamoyloxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-me 
thoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-(.alpha.-p-N-methylcarbamoyloxyphenyl-.alpha.-carboxyacetamido)-7.a 
lpha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-ca 
rboxylic acid, 
7.beta.-(.alpha.-p-N-propylcarbamoyloxyphenyl-.alpha.-carboxyacetamido)-7.a 
lpha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-ca 
rboxylic acid, 
7.beta.-(.alpha.-p-ureidocarbonyloxyphenyl-.alpha.-carboxyacetamido)-7.alph 
a.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carbo 
xylic acid, 
7.beta.-(.alpha.-p-N.sup..alpha. 
-methylureidocarbonyloxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-methoxy- 
3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-phenyl-.alpha.-(5-indanyloxy)carbonylacetamido]-3-(1-methy 
ltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
7.beta.-[.alpha.-phenyl-.alpha.-(5-indanyloxy)carbonylacetamido]-7.alpha.-m 
ethoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxyli 
c acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-(5-indanyloxy)carbonylacetamido]-7.alp 
ha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carb 
oxylic acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-phenoxycarbonylacetamido]-7.alpha.-met 
hoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-(3,4-dimethylphenoxy)carbonylacetamido 
]-7.alpha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem 
-4-carboxylic acid, 
7.beta.-[.alpha.-p-hydroxyphenyl-.alpha.-(5-indanyloxy)carbonylacetamido]-7 
.alpha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4- 
carboxylic acid, 
Pivaloyloxymethyl 
7.beta.-[.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-methox 
y-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate, 
and their pharmaceutically acceptable salts (especially sodium and 
potassium salts). As intermediates for these free acids and salts, esters 
of the said compounds with ester groupings are also important. These 
include t-butyl, t-amyl, 2,2,2-trichloroethyl, acyloxymethyl, 
diphenylmethyl, trityl, benzyl, nitrobenzyl, methoxybenzyl, phenacyl, 
phenyl, indanyl, trimethylsilyl, trimethylstannyl, methoxydimethylsilyl 
esters, and like esters. 
Compounds (I) having 1-methyltetrazol-5-ylthiomethyl at position 3 are 
strongest antibacterial drugs against gram negative bacteria accompanied 
with less drop of the activity at higher inoculum size. 
Compounds (I) having 1-carboxymethyltetrazol-5-ylthiomethyl at position 3 
show stronger antiinfection effect in vivo than expected from in vitro 
data, because of their capability of achieving a high blood level. 
Compounds (I) having phenylmalonamido, (2-thienyl)malonamido, or 
(3-thienyl)malonamido at position 7 show potent antibacterial activity 
particularly against gram negative bacteria. 
Compounds (I) having p-hydroxyphenylmalonamido, p-acetoxyphenylmalonamido, 
p-carbamoyloxyphenylmalonamido, p-N-methylcarbamoyloxyphenylmalonamido, or 
p-ureidocarbonyloxyphenylmalonamido at position 7 are potent 
antibacterials less deactivated in living animals because of their lower 
protein binding and of their higher blood level than those of the 
corresponding unsubstituted arylmalonamido compounds. They also show 
highly intensified activity against some Pseudomonas strains including 
those resistant to carbenicillin. 
Compounds (I) having methoxy for Y at position 7.alpha. are more stable 
against .beta.-lactamase, more broadly effective (e.g. improved activity 
against Pseudomonas bacteria and other gram negative bacteria), and more 
potent than those having hydrogen for Y. 
All Compounds (I) are novel substances showing potent antibacterial 
activity and useful medicines, veterinary drugs, and disinfectants. For 
example, they are conventionally given orally or parenterally to men or 
animals at a daily dose of e.g. 0.05 to 200 mg/kg body weight. 
They are valuable antibiotics against various gram positive and negative 
bacteria, and useful as drugs for human and veterinary uses. They can be 
used for treating or preventing infections caused by gram positive 
bacteria (e.g. Staphylococcus aureus, Streptococcus pyogenes, Bacillus 
subtilis, Bacillus cereus, Diplococcus pneumoniae, Corynebacterium 
diphtheriae) and gram negative bacteria (e.g. Escherichia coli, Klebsiella 
pneumoniae, Proteus mirabilis, Proteus vulgaris, Proteus rettgeri, Proteus 
morganii, Enterobacter cloacae, Shigella sonnei, Salmonella paratyphi, 
Salmonella typhi, Serratia marsescens), and some are active even against 
Pseudomonas aeruginosa and anaerobic bacteria (e.g. Bacteroid fragilis). 
The compounds can be used also as disinfectants for preventing decay of 
perishables, additives to feedstuffs, or preventing bacterial growth of 
hygenical materials. 
Further, Compounds (I) are also useful intermediates for preparing useful 
antibiotics within or beyond the scope of Compounds (I). 
In order to show superior high activity of Compounds (I), minimal 
inhibitory concentrations of some Compounds (I) as sodium salts at an 
inoculum size of 10.sup.8 of gram negative bacteria on a nutrient agar 
plate of pH 7.0 are shown in Table I (Y=H), Table II (Y= OCH.sub.3), in 
comparison to the other types of stereochemically pure 
1-oxadethiacephalosporins in Table III. 
The compounds (I) can be used in a wide variety of oral or parenteral 
dosage forms solely or in admixture with other coacting substances. The 
pharmaceutical compositions may be a mixture of 0.01 to 99% of Compound 
(I) with a pharmaceutical carrier which can be a solid material or liquid 
material in which the compounds are dissolved, dispersed, or suspended. 
They can be in a unit dosage form. The solid compositions can take the 
form of tablets, powder, dry syrups, troches, granules, capsules, pills, 
suppositories, or like solid preparations. The liquid compositions can 
take the forms of injections, ointments, dispersions, inhalent, 
suspensions, solutions, emulsions, syrups, or elixirs. They may be 
flavored, colored, and tablets, granules, and capsules may be coated. 
All of diluents (e.g. starch, sucrose, lactose, calcium carbonate, kaolin); 
bulking agents (e.g. lactose, sugar, salt, glycine, starch, calcium 
carbonate, calcium phosphate, kaolin, bentonite, talc, sorbitol); binders 
(e.g. starch, acacia, gelatin, glucose, sodium alginate, tragacanth, 
carboxymethylcellulose, syrup, sorbitol, polyvinylpyrrolidone); 
disintegrators (e.g. starch, agar, carbonates, sodium laurylsulfate); 
lubricant (e.g. stearic acid, talc, paraffin, boric acid, silica, sodium 
benzoate, polyethylene glycol, cacao oil, magnesium stearate, emulsifying 
agents (e.g. lecithin, sorbitan monooleate, acacia); suspending agents 
(e.g. sorbitol, methyl cellulose, glucose, or sugar syrup, gelatin, 
hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, 
hydrogenated fats); solvents (e.g. water, buffer, peanut oil, sesame oil, 
methyl oleate); preservatives (e.g. methyl or ethyl p-hydroxybenzoate, 
sorbic acid); edible coloring agents, aromatic substances, solubilizing 
agents, buffers, stabilizing agents, analgesics, dispersing agents, 
wetting agents, antioxidants, and the like can be used if the agents to 
not exert adverse effect on the compounds, according to the methods 
conventional in the art. 
As members of .beta.-lactam antibiotics, Compounds (I) are not so stable 
enough to mix with various substances for a long time. Practically pure 
compounds and some inert additives are more preferable to make a drug for 
distribution (e.g. vials, capsules). 
Compounds (I) having one or more carboxylic acid salt groups are soluble in 
water, and conveniently used as solution for intravenus, intramuscular, or 
subcutaneous injection according to a conventional method. The compounds 
can be dissolved in aqueous or oily solvents for injection to give a 
solution in an ampoule, but generally, more prolonged storage are possible 
by making a vial preparation containing crystals, powder, microcrystals, 
or lyophilizate of Compound (I), and dissolving or suspending the drug 
before use with the said solvents for injection. The preparation may 
contain preferably said preservative. The vial preparation or injection 
can be given to a patient at a daily dose of e.g. 0.05 to 50 mg/kg body 
weight depending on the infected bacteria, condition of the patient, and 
interval of the administration. 
Compounds (I), especially those having COB.sup.1 being a pharmaceutically 
acceptable ester groupsing (e.g. indanyl, acetoxymethyl, 
pivaloyloxymethyl, ethoxycarbonyloxyethyl, phenacyl, phthalidyl, phenyl, 
tolyl, xylyl, methoxyphenyl esters), can be absorbed through the digestive 
organ to some extent, and can be administered to human or veterinary 
subjects as powder, tablets, granules, capsules, dry syrup, emulsions, 
solution, suspension, and like oral preparations. They may be pure 
compounds or a composition comprising Compounds (I) and said 
pharmaceutical carriers. The preparation can be made according to the 
methods conventional in the art, and can be administered to a patient at a 
daily dose of e.g. 0.5 to 200 mg/kg body weight depending on the condition 
of patient and the diseases. 
Further, Compounds (I) can be used as suppositories, ointments for topical 
or ocular use, powders for topical use, and like preparations preparable 
according to methods well known to those skilled in the art. The 
preparation can contain 0.01 to 99% of the Compound (I) together with a 
necessary amount of pharmaceutical carrier given above. A necessary amount 
e.g. 1 .mu.g to 1 mg of the preparation can be applied to the affected 
part. 
This invention also provides a method for treating or preventing human or 
veterinary bacterial infections by administering to the human or animal 
subject an effective amount of Compound (I) at a daily dose of e.g. 0.05 
to 50 mg/kg body weight for injection or e.g. 0.5 to 200 mg/kg body weight 
for oral administration, or 1 .mu.g to 1 mg for topical application, at an 
interval of e.g. 3 to 12 hours. 
The method is applicable for treating or preventing some diseases caused by 
bacteria sensitive to Compounds (I) e.g. pneumonia, bronchitis, 
pneumonitis, empyema, nasopharyngitis, tonsillitis, rhinitis, dermatitis, 
pustulosis, ulceration, abses, wound and soft tissue infections, ear 
infections, osteomyelitis, septicemia, gastroenteritis, enteritis, urinary 
tract infections, and pyelonephritis when caused by bacteria sensitive to 
Compound (I). 
Preferably the Compounds (I) are given to a patient in forms of 
pharmaceutical preparations e.g. powder, dry syrup, tablets, troches, 
granules, capsules, pills, suppositories, injections, ointments, 
dispersions, inhalent, suspensions, solutions, emulsions, syrups, and 
elixirs. They may be in a unit dosage form e.g. tablets, troches, 
capsules, injections, vials, granules or powder in a separate container or 
package. 
Preferble compounds (I) for the methods and preparations are those where Ar 
is 3-thienyl, p-hydroxyphenyl, or p-carbamoyloxyphenyl; COB.sup.1 is 
carboxy or its pharmaceutically acceptable salt groups, 
5-indanyloxycarbonyl, phenoxycarbonyl, dimethylphenoxycarbonyl, 
acetoxymethylcarbonyl, or pivaloyloxymethoxycarbonyl; COB.sup.2 is carboxy 
or its pharmaceutically acceptable salt group; Het is 
1-methyltetrazol-5-yl; and Y is hydrogen or methoxy. 
Most preferable ones for the methods and preparations are following 
compounds: 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-3-(1-methyltetrazol- 
5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, its sodium salt, 
and its potassium salt; 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-7.alpha.-methoxy-3-( 
1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, 
its sodium salt and its potassium salt; 
7.beta.-(.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-3-(1-methyltetra 
zol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, its sodium 
salt, and its potassium salt; 
7.beta.-(.alpha.-p-hydroxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-methoxy 
-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, its sodium salt, and its potassium salt; 
7.beta.-(.alpha.-p-carbamoyloxyphenyl-.alpha.-carboxyacetamido)-3-(1-methyl 
tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, its sodium 
salt, and its potassium salt; 
7.beta.-(.alpha.-p-carbamoyloxyphenyl-.alpha.-carboxyacetamido)-7.alpha.-me 
thoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid, its sodium salt, and its potassium salt; 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-(5-indanyloxy)carbonylacetamido]-7.alp 
ha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carb 
oxylic acid and its sodium salt, 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-phenoxycarbonylacetamido]-7.alpha.-met 
hoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylic 
acid and its sodium salt, 
7.beta.-[ 
.alpha.-(3-thienyl)-.alpha.-(3,4-dimethylphenoxy)carbonylacetamido]-7.alph 
a.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carbo 
xylic acid and its sodium salt, and 
7.beta.-[.alpha.-p-hydroxyphenyl-.alpha.-(5-indanyloxy)carbonylacetamido]-7 
.alpha.-methoxy-3-(1-methyltetrazol-5yl)thiomethyl-1-oxadethia-3-cephem-4-c 
arboxylic acid and its sodium salt. 
Compounds (I) can, for example, be prepared by treating an Amine (II) with 
an Arylmalonic acid (III) or reactive derivatives thereof. 
##STR9## 
(wherein Ar, COB.sup.1, COB.sup.2, Het, and Y are as defined above) 
The Compounds (II) are prepared in a manner analogus to the methods 
disclosed by German Patent Application (OLS) No. 2,355,209 (1974); 
Christensen et al., the Journal of American Chemical Society, Volume 96, 
page 7582; and U.S. Pat. No. 3,278,531 issued Oct. 11, 1966. 
Compounds (III) or the derivatives thereof can be prepared in a manner 
analogous to the methods disclosed by Japanese Patent Application (OPI) 
No. 51-1489; German Patent Application (OLS) No. 2,451,931; and Journal of 
the American Chemical Society, Volume 59, page 1901 (1937) and Volume 
91:8, page 2127, (1969). 
When Arylmalonic acid (III) is used as free acid, the acylation is carried 
out in a solvent (particularly nitriles, ethers, amides, and 
halohydrocarbons for solvent or mixtures thereof) in the presence of a 
condensing reagent [e.g. N,N'-dialkylcarbodiimides (e.g. 
N,N'-diethylcarbodiimide, N,N'-dicyclohexylcarbodiimide); carbonyl 
compounds (e.g. carbonyldiimidazole); acylamines (e.g. 
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline); isoxazolinium salts (e.g. 
N-ethyl-5-phenylisoxazolinium-3-sulfonate, N-t-butyl-5-methylisoxazolinium 
perchlorate); and other condensing reagents] at about -10.degree. C to 
about 70.degree. C. 
When Arylmalonic acid (III) is used in the forms of reactive derivatives 
for the acylation, it can be anhydrides [e.g. mixed anhydrides with 
alkylcarbonic acid, aralkylcarbonic acids, hydrohalogenic acids (acid 
halides), hydrogen azide (acid azide), phosphoric acid, phosphorous acid, 
sulfuric acid, sulfurous acid, hydrogen cyanide (acid cyanide); 
symmetrical intermolecular anhydrides; mixed anhydrides with aliphatic or 
aromatic sulfonic or carboxylic acids; special intramolecular anhydrides 
as ketene, isocyanate, and like reactive anhydrides]; reactive esters 
[e.g. enol ester; aryl ester (e.g. pentachlorophenyl, p-nitrophenyl, 
2,4-dinitrophenyl, benzotriazole esters)]; diacylimino esters; reactive 
amides [e.g. amides with imidazole or triazole; reactive amides e.g. 
2-ethoxy-1,2-dihydroquinolin-1-amide], and formimino derivatives (e.g. 
N,N-dialkyliminomethyl esters, N,N-diacylanilines). 
If required, these acylating reagents can be used in the presence of an 
acid receptor [e.g. inorganic bases (e.g. hydroxides, carbonates, or 
bicarbonates of alkali metals or alkaline earth metals), organic bases 
(e.g. tertiary amines, aromatic bases), alkylene oxides (e.g. ethylene 
oxide, proypylene oxide), amides (e.g. N,N-dimethylformamide, 
hexamethylphosphorotriamide), and other acid receptors] or molecular 
sieves, preferably in a solvent (particularly ketone, ester, ether, 
nitrile, amide, halohydrocarbon solvents, or their mixtures). 
The reaction is preferably carried out by contacting Amine (II) with 
Arylmalonic acid (III) or its reactive derivatives if required in the 
presence of a condensing reagent, acid receptor, dehydrating reagent, 
etc., preferably in a solvent at -50.degree. C to +70.degree. C for 10 
minutes to 10 hours as is exemplified in the working examples. 
The molar ratio of Amine (II) to Arylmalonic acid (III) or its derivative 
is about from 1 to 10, and more preferably from 1.0 to 2.0. 
The mixture can be stirred, kept dry by exclusion of moisture with 
dehydrating materials (e.g. sodium hydroxide, soda lime), and can be kept 
under inert gas (e.g. nitrogen, argon). 
The said solvents can be hydrocarbon (e.g. pentane, hexane, petroleum 
ether, benzene, toluene, xylene), halohydrocarbon (e.g. dichloromethane, 
chloroform, dichloroethane, chlorobenzene), ether (e.g. diethyl ether, 
methyl isobutyl ether, dioxane, tetrahydrofuran), ester (e.g. methyl 
acetate, ethyl acetate), ketone (e.g. acetone, methyl ethyl ketone, 
cyclohexanone), amide (e.g. dimethylformamide, 
hexamethylphosphorotriamide), sulfoxide (e.g. dimethylsulfoxide, 
diethylsulfoxide), nitrile (e.g. acetonitrile, benzonitrile), or 
nitroalkane (e.g. nitromethane, nitroethane, nitrobenzene), solvents or 
mixtures thereof. When so-called Schotten Bauman condition is applied for 
the acylation, alcohol (e.g. methanol, ethanol, isopropanol, t-butanol) or 
water can also be present in the reaction medium. 
Alternatively, Compounds (I) can be prepared from the corresponding 
non-fused ring azetidinones by cyclization by e.g. Wittig reaction. For 
example, Azetidinone (IV) is heated in an inert solvent (e.g. ether, 
aromatic hydrocarbon, halohydrocarbon, amide, sulfoxide, and anhydride 
solvents) to give Compounds (I) in high yield. 
##STR10## 
(wherein Ar, COB.sup.1, COB.sup.2, Het, and Y are defined above; and each 
of three R is equal or different, showing alkyl or aryl). 
Compounds (IV) can, for example, be prepared from known substances by the 
method described below and in Preparations 3 through 5: 
##STR11## 
(wherein Ar, COB.sup.1, COB.sup.2, Het and Y are as defined above and Hal 
is halogen). The positions of acylation and introduction of methoxy can be 
changed so far as the substance is not suffered from the reaction. 
When Ar is p-hydroxyphenyl, Compounds (I) can be treated with an inorganic 
or organic acylating reagent to give Compounds (I) where Ar is 
acyloxyphenyl. The acylating reagent and reaction condition are 
conventional in the art as is shown in Examples. 
When Ar is p-hydroxyphenyl, Compounds (I) can at first be protected at its 
hydroxy with an easily removable protecting group and afterwards 
deprotected to give the desired hydroxyphenyl compounds. Representative 
protective groups can be those which form esters [including C.sub.1 
-C.sub.6 .alpha.-haloalkanoyl (e.g. trifluoroacetyl, trichloroacetyl), 
C.sub.1 -C.sub.6 alkanoyl (e.g. formyl, acetyl), C.sub.4 -C.sub.8 
.beta.-ketocarboxylic acyl (e.g. acetoacetyl), C.sub.2 -C.sub.12 
alkoxycarbonyl (e.g. t-butoxycarbonyl, cyclopropylmethoxycarbonyl, 
norbornyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl), C.sub.8 -C.sub.15 
aralkoxycarbonyl (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 
p-nitro- or p-methylbenzyloxycarbonyl, diphenylmethoxycarbonyl), and the 
like acyls] and ethers [including C.sub.1 -C.sub.6 alkyl (e.g. methyl, 
t-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl), 
C.sub.7 -C.sub.15 aralkyl (e.g. benzyl, p-methoxy,- p-methyl- or 
p-nitrobenzyl, diphenylmethyl, trityl), and like groups]. The protecting 
group can preferably be introduced at the stage of Arylmalonic acid (III) 
or reactive derivatives thereof. The deprotection is carried out by e.g. 
1) cleavage of acylates or ethers with an acid (e.g. mineral acid, Lewis 
acid, strong carboxylic acid, sulfonic acid), or base (e.g. sodium or 
potassium carbonate, hydroxide, organic base) at room temperature or 
elevated temperature if required in the presence of cation scavenger, or 
2) hydrogenation of p-nitrobenzyloxycarbonyl or benzyl-oxycarbonyl with 
hydrogen and platinum or palladium by conventional manner. 
When the carboxy at position 4 or of the side chain at position 7 or in Het 
is protected, the protecting group may be deprotected to give desired 
Compounds (I) in conventional manners for removing the protective groups. 
For example, 1) highly reactive esters, amides, and anhydrides are readily 
hydrolyzed with an acid or base; 2) 2-haloethyl, benzyl, methylbenzyl, 
nitrobenzyl, and diarylmethyl esters are cleaved by mild reduction (e.g. 
with tin, zinc, or divalent chromium salts in the presence of acids; 
sodium dithionite; catalytic hydrogenation with hydrogen over catalyst 
e.g. platinum, palladium, nickel); 3) benzyl, methoxybenzyl, methylbenzyl, 
dimethoxybenzyl, t-alkyl, trityl, diarylmethyl, and cyclopropylmethyl, 
esters are cleaved by the action of acids or by solvolysis [e.g. with 
mineral acids (e.g. hydrochloric acid), Lewis acids (e.g. aluminum 
chloride) sulfonic acids (e.g. toluene-p-sulfonic acid), strongly acidic 
carboxylic acids (e.g. trifluoroacetic acid, formic acid) if required in 
the presence of a cation acceptor e.g. anisole]; 4) phenacyl, ethynyl, 
p-hydroxy-3,5-di-t-butylbenzyl esters are cleaved by the action of base 
(e.g. alkali metal thiophenoxides, inorganic base, basic salts), and like 
methods. 
Compounds (I) having one or more free carboxy can be converted into 
corresponding derivatives at the carboxy by introducing protective groups 
or substituents, by conventional methods (e.g. for esters, by the action 
of the corresponding alcohols with said condensing reagents, diazo 
compounds, haloformates, etc.; for salts, the action of alkali metal 
hydroxides, carbonates, or alkanoate salts, or the action of organic 
bases, ion-exchange resins). 
Following preparations 1 through 5 are methods for making the starting 
materials of some examples. The nomenclature in each description is in 
accordance with that described in Japanese Patent Application (Open to 
Public Inspection No. 49-133,594) filed by Merck Inc., U.S.A. 
Preparation 1(Preparation of 7.alpha.-amino compounds) 
(1) To a solution of diphenylmethyl 
7.beta.-phenylacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3- 
cephem-4-carboxylate (955 mg) in methylene chloride (24 ml) are added 
phosphorous pentachloride (666 mg) and pyridine (0.258 ml) in nitrogen gas 
at -20.degree. C. After stirring at -20.degree. C for 30 minutes and at 
room temperature for 30 minutes, the mixture is mixed with methanol (12 
ml) at -20.degree. C and stirred at room temperature for 30 minutes. The 
reaction mixture is diluted with water (6 ml), stirred for 30 minutes and 
concentrated under reduced pressure. The residue is dissolved in 5% 
aqueous solution of sodium hydrogencarbonate under ice cooling, and 
extracted with ethyl acetate. The extract is washed with water, dried on 
sodium sulfate, and concentrated by filtration and washed with ether to 
yield diphenylmethyl 
7.beta.-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-c 
arboxylate (661 mg). mp. 151-156.degree. C. Yield: 86.5%. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 3420, 3345, 1790, 1718, 1630 cm.sup.-1. 
.delta..sup.CDCl.sbsp.3 1.75brs2H, 3.81s3H, 4.28brs2H, 4.50d(4Hz)1H, 
4.64brs2H, 4.98d(4Hz), 1H, 6.90s1H, 7.20-7.70mlOH. 
UV: .lambda..sub.max.sup.(CH.sbsp.3.sup.).sbsp.2.sup.SO 286 nm 
(.epsilon.=8695). [.alpha.].sub.D.sup.22.5 - 232.8 .+-. 7.6.degree. 
(c=0.360, (CH 3).sub.2 SO). 
2) In a procedure similar to that of above (1), diphenylmethyl 
7.beta.-phenylacetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-1-oxa 
dethia-3-cephem-4-carboxylate (381.5 mg) in methylene chloride (8 ml) is 
treated with phosphorous pentachloride (259 mg) and pyridine (0.1 ml) at 
-20.degree. C, with methanol (8 ml), and with water (4 ml) to give 
diphenylmethyl 
7.beta.-amino-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-c 
ephem-4-carboxylate (273.3 mg). Yield: 88.8%. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 3420, 3350, 1794, 1723 cm.sup.-. 
NMR: .delta..sup.CDCl.sbsp.3 1.88s2H, 2.67s3H, 4.25+4.55ABq(14Hz)2H, 4.52 
d(4Hz)1H, 4.68s2H, 5.00d(4Hz)1H, 7.07s1H. 
(3) In a procedure similar to that of above (1), diphenylmethyl 
7.beta.-phenylacetamido-3-(1-t-butoxycarbonylmethyltetrazol-5-yl)thiomethy 
l-1-oxadethia-3-cephem-4-carboxylate (300 mg) in methylene chloride (10 ml) 
is treated with phosphorus pentachloride (180 mg) and pyridine (0.07 ml) 
at -20.degree. C, with methanol (4 ml), and with water (4 ml) to give 
diphenylmethyl 
7.beta.-amino-3-(1-t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-1-oxadet 
hia-3-cephem-4-carboxylate (189 mg). Yield: 76%. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1795, 1753, 1722 cm.sup.-1. 
NMR: .delta..sup.CDCl.sbsp.3 1.45s9H, 1.60-2.00m2H, 4.30s2H, 4.40-4.60mlH, 
4.65brs2H, 4.86s2H, 5.00d(4Hz)1H, 6.95s1H. 
Preparation 2 (Introduction of 7.alpha.-methoxy) 
(1) A solution of diphenylmethyl 
7.beta.-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-c 
arboxylate (600 mg) and 3,5-di-t-butyl-4-hydroxybenzaldehyde (353 mg) in a 
mixture of benzene (15 ml) and methylene chloride (5 ml) is refluxed for 1 
hour while removing water by means of molecular sieve in a Dean Stark 
water-separator. The resulting solution of diphenylmethyl 
7.beta.-(3,5-di-t-butyl-4-hydroxybenzal)amino-3-(1-methyltetrazol-5-yl)thi 
omethyl-1-oxadethia-3-cephem-4-carboxylate is cooled at -10.degree. C to 
-15.degree. C, mixed with anhydrous magnesium sulfate (1 g) and then 
nickel peroxide (0.69 g) with stirring, and stirred at -10.degree. C to 
-15.degree. C for 30 minutes and at room temperature for 15 minutes. The 
reaction mixture is filtered, and the solid is washed with benzene. To the 
resulting solution of diphenylmethyl 
7-(3,5-di-t-butyl-4-oxo-2,5-cyclohexadienylidenemethyl)imino-3-(1-methylte 
trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate is added methanol 
(10 ml), and the solution is allowed to stand at room temperature for 1 
hour, and concentrated to dryness under reduced pressure. The residue is 
chromatographed on silica gel (30 g) containing 10% water and eluted with 
a mixture of benzene and ethyl acetate (4:1) to give diphenylmethyl 
7.beta.-(3,5-di-t-butyl-4-hydroxybenzal)amino-7.alpha.-methoxy-3-(1-methyl 
tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylate (906 mg) as 
practically pure yellow foam. Yield: 99.7%. 
(2) To a solution of the produce of above (1) in a mixture of methanol (10 
ml) and tetrahydrofuran (5 ml) is added sodium salt of 
N-chloro-p-toluenesulfonamide (315 mg), and the mixture is stirred at room 
temperature for 1 hour, diluted with water, and extracted with methylene 
chloride. The extract is washed with water, dried or sodium sulfate, and 
evaporated to dryness under reduced pressure. The residue is purified by 
chromatography on silica gel (30 g) containing 10% water and eluted with a 
mixture of ethyl acetate: benzene;methylene chloride (1:1:1) to give 
diphenylmethyl 
7.beta.-amino-7.alpha.-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxade 
thia-3-cephem-4-carboxylate (469 mg). Over-all yield: 73.6%. mp. 
160.degree. - 162.degree. C (decomposition). 
IR: .nu..sub.max.sup.CHCl.sbsp.3 3425, 3350, 1792, 1724 cm.sup.-1. 
NMR: .delta..sup.CDCl.sbsp.3 2.00brs2H, 3.38s3H, 3.87s3H, 4.32s2H, 4.73s2H, 
4.92s1H, 7.00s1H. 
As is seen in above (1), nickel peroxide worked well for the oxidation of 
the phenolic intermediate to give the 4-oxocyclohexadienylidene compound. 
Preparation 3 (Preparation of Compound IV) 
(1) To a solution of crude diphenylmethyl 
.alpha.-(4.beta.-methylthio-3.beta.-amino-2-oxoazetidin-1-yl)-.alpha.-isop 
ropylideneacetate toluene-p-sulfonate salt (13.48 g) in methylene chloride 
(100 ml) is added a solution of chlorine in carbon tetrachloride (1.34 
Mole/liter; 19.4 ml) at -78.degree. C. The mixture is stirred at 
-78.degree. C for 20 minutes and at 0.degree. C for 20 minutes, and 
evaporated under reduced pressure. The residue is triturated thrice in a 
mixture of ether and petroleum ether, and evaporated to give crude 
diphenylmethyl .alpha.-[4.beta.- and 
4.alpha.-chloro-3.beta.-amino-4-oxoazetidin-1-yl]-.alpha.-isopropylideneac 
etate toluene-p-sulfonate salt. 
The product is treated with aqueous solution of sodium hydrogencarbonate 
and extracted with dichloromethane to give crude diphenylmethyl 
.alpha.-[4.beta.- and 
4.alpha.-chloro-3.beta.-amino-2-oxoazetidin-1-yl]-.alpha.-isopropylideneac 
etate. 
(2) To a solution of the product of above (1) (0.95 g) in a mixture of 
propargyl alcohol (3 ml) and tetrahydrofuran (2 ml) is added silver 
tetrafluoroborate (0.79 g), and the mixture is stirred at room temperature 
for 3 hours. The reaction mixture is diluted with benzene (50 ml), cooled 
to 0.degree. C, and stirred with a mixture of 5% aqueous solution of 
sodium hydrogencarbonate (10 ml) and saturated saline (5 ml). The mixture 
is filtrated through a layer of Celite, and filtrate is separated. The 
benzene layer is dried over sodium sulfate, concentrated under reduced 
pressure to give brown heavy oil, and purified by chromatography on silica 
gel to give diphenylmethyl .alpha.-[4.alpha.- and 
4.beta.-propargyloxy-3.beta.-amino-2-oxoazetidin-1-yl]-.alpha.-isopropylid 
eneacetate in a ratio of about 1:1. The product is treated with 
.alpha.-diphenylmethoxycarbonyl-.alpha.-phenylacetyl chloride (1 mole 
equivalent) in methylene chloride in the presence of 2 mole equivalents of 
triethylamine and 1 mole equivalent of N,N-dimethylformamide to give 
diphenylmethyl 
.alpha.-[4.beta.-propargyloxy-3.beta.-(.alpha.-phenyl-.alpha.-diphenylmeth 
oxycarbonylacetamido)-2oxoazetidin-1-yl]-.alpha.-isopropylideneacetate. 
(3) To a solution of the product of above (2) (18.2g) in methanol (40 ml) 
is added a suspension of pre-reduced 5% palladium on calcium carbonate (3 
g) in methanol (70 ml), and the mixture is hydrogenated under hydrogen 
atmosphere for 1 hour. After removing the catalyst by filtration, the 
reaction mixture is evaporated to give diphenylmethyl 
.alpha.-[4.beta.-allyloxy-3.beta.-(.alpha.-phenyl-.alpha.-diphenylmethoxyc 
arbonylacetamido)-2-oxoazetidin-1-yl]-.alpha.-isopropylideneacetate. 
(4) To a solution of the product obtained above (3) (8.6 g) in chloroform 
(70 ml) is gradually added a solution of m-chloroperbenzoic acid (2.8 g), 
and the mixture is kept at room temperature for 1 day. The reaction 
mixture is concentrated under reduced pressure. The obtained residue is 
dissolved in ethyl acetate, washed with 50% sodium sulfite, 5% sodium 
hydrogencarbonate in water, and saline, dried, and concentrated. The 
residue is purified by chromatography over silica gel to give 
diphenylmethyl 
.alpha.-[4.beta.-(2,3-epoxypropoxy)-3.beta.-(.alpha.-diphenylmethoxycarbon 
yl-.alpha.-phenylacetamido)-2-oxazetidin-1-yl]-.alpha.-isopropylideneacetat 
e. 
(5) A solution containing lithium 1-methyl-1H-tetrazol-5-yl-mercaptide is 
prepared by mixing 1-methyl-5-mercapto-1H-tetrazole (2.8 g) in 
tetrahydrofuran (70 ml) with n-butyllithium (2.0 ml; 1.80 mole per liter 
hexane) under ice cooling and nitrogen atmosphere with stirring for 40 
minutes. To this solution is added dropwise a solution of diphenylmethyl 
.alpha.-[4.beta.-(2,3-epoxypropoxy)-3.beta.-(.alpha.-phenyl-.alpha.-diphen 
ylmethoxycarbonylacetamido)-2-oxoazetidin-1-yl]-.alpha.-isopropylideneaceta 
te (15.8 g) in tetrahydrofuran (50 ml), and stirred for 5 hours at room 
temperature. The reaction mixture is diluted with methylene chloride, 
washed with ice cold hydrochloric acid and water, dried over sodium 
sulfate, and evaporated under reduced pressure. Purification of the 
residue by chromatography over silica gel gives diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-ylthio)-2-hydroxypropoxy]-3.beta.- 
(.alpha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido]-2-oxoazetidin-1-y 
l}-.alpha.-isopropylideneacetate. 
(6) To a solution of the product of above (5) (21.0 g) in acetone (150 ml) 
is added Jone's reagent (13 ml), and the mixture is stirred for 0.5 hours 
at room temperature. After adding methanol at 0.degree. C, the reaction 
mixture is diluted with ethyl acetate to separate inorganic solid which is 
filtered off, and washed with water. Combined filtrate and washings are 
washed with water, dried over sodium sulfate, and evaporated under reduced 
pressure. Purification of the residue by chromatography on silica gel 
gives diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl}-. 
alpha.-isopropylideneacetate. 
(7) To a solution of the product of above (6) (7.5 g) in methylene chloride 
(95 ml) is bubbled ozone at -78.degree. C until the mixture shows blue 
color. To the solution is added dimethyl sulfide (7 ml), warmed to room 
temperature, washed with water, dried over sodium sulfate, and evaporated 
to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.(.alp 
ha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl}-.a 
lpha.-isopropylideneacetate. 
(8) To a solution of the product of above (7) (3.10 g) in methylene 
chloride (10 ml) is added acetic acid (10 ml), water (15 ml), and zinc 
powder (4.0 g) under ice cooling, and the mixture is stirred for 1 hour at 
the same temperature. The solid material is filtrated off from the 
reaction mixture which is washed with water, dried over sodium sulfate, 
and evaporated to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl}-. 
alpha.-hydroxyacetate. 
(9) To a solution of the product of above (8) (2.4 g) in methylene chloride 
(30 ml) is added thionyl chloride (0.3 ml) and pyridine (0.20 ml) under 
nitrogen and ice cooling. After stirring for 30 minutes at the same 
temperature, the mixture is poured into ice water, and extracted with 
ethyl acetate. The extract solution is washed with water, dried over 
sodium sulfate, and evaporated to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl}-. 
alpha.-chloroacetate. 
(10) To a solution of the product of above (9) (4.8 g) in methylene 
chloride (40 ml) is added triphenylphosphine (4.0 g), and the mixture is 
refluxed under nitrogen atmosphere for 2 hours. After cooling, the 
reaction mixture is poured into aqueous 2% sodium hydrogencarbonate 
solution, and is extracted with methylene chloride. The extract solution 
is dried over sodium sulfate, and evaporated under reduced pressure. 
Purification of the residue by silica gel chromatography gives 
diphenylmethyl 
.alpha.{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.alp 
ha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-2-oxoazetidin-1-yl}-.a 
lpha.-triphenylphosphoranylideneacetate, the starting material of Example 
I-1. 
Preparation 4 
(1) A solution of the product of Preparation 3 (4) (5.8 g) in methylene 
chloride (70 ml) cooled at -30.degree. C are added t-butyl hypochlorite (2 
ml) and a solution of lithium methoxide in methanol over a period of 10 
minutes, and the mixture is stirred for 2 minutes. The mixture is then 
mixed with 0.5 ml of acetic acid, poured into ice water, 5% sodium 
thiosulfate, water, and aqueous sodium chloride, dried, and evaporated to 
give diphenylmethyl 
.alpha.-[4.beta.-(2,3-epoxypropoxy)-3.beta.-(.alpha.-diphenylmethoxycarbon 
yl-.alpha.-phenylacetamido)-3.alpha.-methoxy-2-oxoazetidin-1-yl]-.alpha.-is 
opropylideneacetate. 
(2) The product of above (1) is treated with lithium 
1-methyl-1H-tetrazol-5-ylmercaptide (1.2 mole equivalents) in 
tetrahydrofuran at room temperature for 3 hours to give diphenylmethyl 
.alpha.-{.beta.-[3-(1-methyltetrazol-5-yl)thio-2-hydroxypropoxy]-3.beta.-( 
.alpha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-3.alpha.-methoxy-2 
-oxoazetidin-1-yl}-.alpha.-isopropylideneacetate. 
(3) The product of above (2) is treated with 2.2 mole equivalent of Jones 
reagent in acetone at room temperature for 60 minutes to give 
diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-3.alpha.-methoxy-2-ox 
oazetidin-1-yl}-.alpha.-isopropylideneacetate. 
(4) The product of above (3) is dissolved in methylene chloride, and ozone 
is bubbled therein at -78.degree. C. The mixture is mixed with acetic and 
and 5 weights of zinc at 0.degree. C and stirred for 2 hours to give 
diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-3.alpha.-methoxy-2-ox 
oazetidin-1-yl}-.alpha.-hydroxyacetate. 
(5) The product of above (4) is treated with thionyl chloride (1.2 mole 
equivalents) and pyridine (1.2 mole equivalents) in methylene chloride at 
0.degree. C for 20 minutes to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thioacetonyloxy]-3.beta.-(.alph 
a.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-3.alpha.-methoxy-2-oxoa 
zetidin-1-yl}-.alpha.-chloroacetate. 
(6) The product of above (5) is treated with triphenylphosphine (1.5 mole 
equivalents) in methylene chloride at refluxing temperature under nitrogen 
for 2 hours to give the starting material of Example I-2, diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thioacetonyl]oxy-3.beta.-(.alph 
a.-diphenylmethoxycarbonyl-.alpha.-phenylacetamido)-3.alpha.-methoxy-2-oxoa 
zetidin-1-yl}-.alpha.-triphenylphosphoranylideneacetate. 
Preparation 5 
(1) To a solution of diphenylmethyl .alpha.-[4.alpha.- and 
4.beta.-propargylpoxy-3.beta.-amino-2-oxoazetidin-1-yl]-.alpha.-isopropyli 
deneacetate, prepared by the method of Preparation 3 (1 and (2), in 
methylene chloride is added 1.1 mole equivalent of 
.alpha.-p-benzyloxyphenyl-.alpha.-diphenylmethoxycarbonylacetyl chloride 
in the presence of 1.1 mole equilvant of pyridine to give diphenylmethyl 
.alpha.-[4.alpha.- and 
4.beta.-propargyloxy-3.beta.-(.alpha.-p-benzyloxyphenyl-.alpha.-diphenylme 
thoxycarbonylacetamido)2-oxoazetidin-1-yl]-.alpha.-isopropylideneacetate, 
which is separated to give 4.beta.-propargyloxy isomer. 
(2) The product of above (1) is hydrogenated over palladium on calcium 
carbonate in ethanol at room temperature over 2 hours to give 
diphenylmethyl 
.alpha.-[4.beta.-allyloxy-3.beta.-(.alpha.-p-benzyloxyphenyl-.alpha.-diphe 
nylmethoxycarbonylacetamido)-2-oxoazetidin-1-yl]-.alpha.-isopropylideneacet 
ate. 
(3) The product of above (2) in methylene chloride is mixed with t-butyl 
hypochlorite and lithium methoxide in methanol, and the mixture stirred at 
-30.degree. C for 15 minutes to give diphenylmethyl 
.alpha.-[4.beta.-allyloxy-3.beta. 
(.alpha.-p-benzyloxyphenyl-.alpha.-diphenylmethoxycarbonylacetamido)- 
3.alpha.-methoxy-2-oxoazetidin-1-yl]-.alpha.-isopropylideneacetate. 
(4) The product of above (3) is epoxidized with 1.1 mole equivalent of 
m-chloroperbenzoic acid in methylene chloride at room temperature for 2 
days to give diphenylmethyl .alpha.-[4.beta.-(2,3-epoxypropoxy)-3.beta. 
-(.alpha.-p-benzyloxyphenyl-.alpha.-diphenylmethoxycarbonylacetamido)- 
3.alpha.-methoxy-2-oxoaxetidin-1-yl]-.alpha.-isopropylideneacetate. 
(5) The product of above (4) is treated with lithium 
1-methyl-1H-tetrazol-5-ylmercaptide (1.2 mole equivalents) in 
tetrahydrofuran at room temperature for 2 hours to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-p-benzyloxyphenyl-.alpha.-diphenylmethyoxycarbonylacetamido)-3.alpha.- 
methoxy-2-oxoazetidin-1-yl}-.alpha.-isopropylideneacetate. 
(6) The product of above (5) is oxidized with 3 mole equivalents of Jones 
reagent at room temperature for 30 minutes to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-p-benzyloxyphenyl-.alpha.-diphenylmethoxycarbonylacetamido)-3.alpha.-m 
ethoxy-2-oxoazetidin-1-yl}-.alpha.-ispropylideneacetate. 
(7) The product of above (6) is treated with ozone in methylene chloride at 
-78.degree. C, followed by acetic acid and zinc (5 weights) to give 
diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-p-benzxyloxyphenyl-.alpha.-diphenylmethoxycarbonylacetamido)-3.alpha.- 
methoxy-2-oxoazetidin-1-yl}-.alpha.-hydroxyacetate. 
(8) The product of above (7) is treated with thionyl chloride (1.2 mole 
equivalents) and pyridine (1.2 mole equivalents) in methylene chloride at 
0.degree. C for 30 minutes to give diphenylmethyl 
.alpha.-{4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopropoxy]-3.beta.-(.al 
pha.-p-benzyloxyphenyl-.alpha.-diphenylmethoxycarbonylacetamido)-3.alpha.-m 
ethoxy-2-oxoazetidin-1-yl{-.alpha.-chloroacetate. 
(9) The product of above (8) is refluxed in methylene chloride in the 
presence of triphenylphosphine (1.5 mole equivalents) under nitrogen for 5 
hours to give the starting material of Example I-3, diphenylmethyl 
.alpha.-{3.beta.-(.alpha.-p-benzyloxyphenyl-.alpha.-diphenylmethoxycarbony 
lacetamido)-3.alpha.-methoxy-4.beta.-[3-(1-methyltetrazol-5-yl)thio-2-oxopr 
opoxy]-2-oxoazetidin-1-yl}-.alpha.-triphenylphosphoranylideneacetate. 
TABLE I 
__________________________________________________________________________ 
##STR12## 
Example No. III-8 III-11 
III-9 III-1 
III-2 
III-12 
III-10 
III-6 
Ar 
##STR13## 
##STR14## 
##STR15## 
C.sub.6 H.sub.5 
C.sub.6 H.sub.5 
C.sub.6 H.sub.5 
C.sub.6 H.sub.5 
##STR16## 
Het T A T T T Z A T 
B OH OH OH OH 5-indanyl 
OH OH OH 
__________________________________________________________________________ 
Escherichia coli H 
0.1 0.78 0.1 0.1 0.1 0.2 0.78 
0.2 
E. coli JC-2 0.1 12.5 0.1 0.2 0.2 0.39 
3.13 
0.39 
E. coli 377 0.2 6.25 0.2 0.2 0.2 0.78 
0.25 
0.39 
E. coli 73 &gt; &gt; &gt; &gt; &gt; &gt; &gt; &gt; 
Serratia marsescens 13880 
0.78 25 0.78 0.78 
0.78 
1.56 
50 0.78 
Klebsiella pneumoniae 
0.1 3.13 0.2 0.2 0.2 0.78 
3.13 
0.78 
K. 363 &gt; &gt; &gt; -- &gt; &gt; &gt; &gt; 
Enterobacter cloacae 233 
0.2 25 0.39 0.39 
0.39 
1.56 
12.5 0.78 
Proteus mirabilis PR-4 
0.2 1.56 0.39 0.39 
0.39 
0.39 
0.78 
0.78 
P. morganii No. 9 
0.39 1.56 0.39 0.39 
0.39 
0.39 
0.78 
0.78 
P. vulgaris No. 3 
-- -- -- -- -- -- -- &gt; 
P. vulgaris CN-329 
50 &gt; 100 100 50 100 &gt; &gt; 
Pseudomonas aeruginosa 
Denken &gt; &gt; &gt; &gt; &gt; &gt; &gt; &gt; 
Ps. aeruginosa 25619 
3.13 &gt; 6.25 3.13 
6.25 
3.13 
100 6.25 
Ps. aeruginosa 24 
&gt; -- -- &gt; &gt; &gt; &gt; &gt; 
__________________________________________________________________________ 
(Abbreviations) 
T: 1-methyltetrazol-5-yl; 
A: 1-carboxymethyltetrazol-5-yl; 
Z: 2-methyl-1,3,4-thiadiazol-5-yl. 
&gt;: higher than 100 .mu.g/ml. 
TABLE II 
__________________________________________________________________________ 
Minimal inhibitory concentration of (.mu.g/ml) 
##STR17## as sodium salt at an inoculum size 
of 10.sup.8 (ph 7.0) (The esters 
are assayed in the presence of 5% 
horse serum) 
__________________________________________________________________________ 
Example No. III-23 
III-19 
III-13 
III-24 
III-15 III-16 III-14 
III-25 
III-27 
Ar 
##STR18## 
##STR19## 
##STR20## 
##STR21## 
##STR22## 
##STR23## 
##STR24## 
##STR25## 
##STR26## 
Het T T T T T T T T T 
B OH OH OH 5-indanyl 
OH OH OH 
__________________________________________________________________________ 
Escherichia coli H 
0.025 
0.025 
0.025 
0.025 
0.1 0.1 0.2 0.1 0.05 
E. coli JC-2 
0.05 0.05 0.1 0.1 0.2 0.2 0.39 0.39 0.2 
E. coli 377 0.39 0.1 0.02 0.78 0.39 0.2 1.56 0.78 0.78 
E. coli 73 0.2 0.2 0.39 0.39 0.78 0.78 1.56 1.56 0.78 
Serratia marsescense 13880 
0.39 0.39 0.39 0.78 1.56 0.39 -- 1.56 3.13 
Klebsiella Pneumoniae 
0.05 0.2 0.1 0.1 0.2 0.2 0.39 0.39 0.39 
Klebsiella sp. 363 
0.1 0.05 0.05 0.05 0.1 0.2 0.78 0.39 0.2 
Enterobacter cloacea 233 
0.2 0.1 0.2 0.2 -- 0.39 0.78 0.78 0.78 
Proteus mirarbilis PR-4 
0.1 0.2 0.2 0.2 0.1 0.39 0.39 0.2 0.39 
P. Morganii No. 9 
0.1 0.1 0.1 0.2 0.39 0.2 0.39 0.39 0.39 
P vulgaris No. 3 
-- 0.2 0.2 0.39 0.39 0.39 0.39 0.39 0.39 
P. vulgaris CN-329 
0.1 0.1 0.1 0.1 0.39 0.78 0.2 0.2 0.2 
Pseudomonas aeruginosa 
Denken 100 100 100 100 100 100 &gt; &gt; &gt; 
Ps. aeruginosa 25619 
12.5 12.5 12.5 12.5 6.25 12.5 25 25 12.5 
Ps. aeruginosa 24 
50 50 50 50 50 25 100 100 50 
__________________________________________________________________________ 
(Abbreviations) 
T: 1-methyltetrazol-5-yl; 
&gt;: higher than 100 .mu.g/ml. 
TABLE III 
__________________________________________________________________________ 
Minimal inhibitory concentrating of the reference compounds as sodium 
salts at an inoculum size of 10.sup.8 (pH 7.0) 
(.mu.g/ml) 
__________________________________________________________________________ 
Compound No. (Optically pure) 
(1) 
(2) 
(3) 
(4) 
Cefalotin 
Cefazolin 
__________________________________________________________________________ 
Escherichia coli H 
&gt; 0.39 
1.56 
0.1 
3.2 1.6 
E. coli JC-2 &gt; 6.25 
1.56 
0.2 
12.5 3.2 
E. coli 377 &gt; &gt; 25 50 &gt; 100 
E. coli 73 &gt; &gt; &gt; &gt; &gt; &gt; 
Serratia marsescens 13880 
&gt; &gt; &gt; 100 
&gt; &gt; 
Klebsiella pneumoniae 
&gt; 1.56 
3.13 
0.2 
1.6 3.2 
Klebsiella 363 &gt; &gt; &gt; &gt; &gt; &gt; 
Enterobactor cloacea 233 
&gt; &gt; &gt; &gt; &gt; &gt; 
Proteus mirabilis PR-4 
&gt; 1.56 
1.56 
0.2 
3.2 6.2 
P. morganii No. 9 
&gt; &gt; 50 100 
&gt; &gt; 
P. vulgaris No. 3 
-- 
-- -- -- &gt; &gt; 
P. vulgaris CN-329 
&gt; &gt; &gt; &gt; &gt; &gt; 
Pseudomonas aeruginosa Denken 
&gt; &gt; &gt; &gt; &gt; &gt; 
Ps. aeruginosa 25619 
&gt; &gt; &gt; &gt; &gt; &gt; 
Ps. aeruginosa 24 
&gt; &gt; &gt; &gt; &gt; &gt; 
__________________________________________________________________________ 
*) Compound No. 
(1): 
7.beta.-(.alpha.-phenylglycinamido)-3-methyl-1-oxadethia-3-cephem-4-carbo 
ylic acid. 
(2): 7.beta.-(2-thienylacetamido)-1-oxadethiacephalosporanic acid. 
(3): 
7.beta.(1-tetrazolyl)acetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiometh 
l-1-oxadethia-3-cephem-4-carboxylic acid. 
(4): 
7.beta.-mandelamido-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cep 
em-4-carboxylic acid. 
&gt;: higher than 100 .mu.g/ml.