IE44794B1 - Arylmalonamido-1-oxadethiacephalosporins - Google Patents

Abstract

New 1-oxa-dethia-cephalosporins are of formula (I) (where Ar is 2- or 3-thienyl phenyl, p-hydroxyphenyl or p-acyloxyphenyl; COB, and COB2 are COOH or protected carboxy; Het is u-methyltetrazol-5-yl (MT), opt. protected 1-carboxymethyltetrazol-5-yl (CMT) or 2-methyl-1, 3, 4-thiadiazol-5-yl (MTD); Y is H or MeO; with the provido that Het must be MT when Y is MeO). (I) have 4-8 times the antibacterial activity of the corresp. true cephalosporins, esp. against Gram. neg. bacteria (including resistant Pseudomonas strains), and have better stability than known 1-oxa-dethiacephalosporins. A typical cpd. is diphenylmethyl 7 beta-(beta-phenyl-alpha-diphenylmethoxycarbonylacetamido)-3-(-1-t- hiomethyl)-1-oxadethia-3-cephem-4-carboxylate. In an example, this is prepd. by reacting the corresp. 7-amino cpd. with monodiphenylmethyl phenylmalonate.

Description

This invention relates to certain 1-oxaaethia-cephalosporins.’ The invention provides a1compound of the formula: ArCHCQNII.; ΟΙ ι τ—1 f τ COB1b1 ο C0§2 CHjjSHet (I) wherein Ar is , , or Acyl-O—, COB and COB are each independently carboxy or protected carboxy; N-Ν N——N Het 1, J.J , JL8 CH„ CH„COBJ Ν—N or 3, COB·5 being carboxy or protected carboxy.* and N—N Ύ is hydrogen or methoxy) X3 provided that when Y is methoxy,. Het is ch^ .

The invention includes salts, e.g. pharmaceutically acceptable salts, of the above compounds (I).

Cephalosporin analogs having oxygen in place of a 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; .Dadicj, German Patent Application (01S) No. 2,219,601 (1972); the Canadian Journal of Chemistry, - 2 Volume 52, page 3996 (1974) hy Saul Wolfe et al.; and the Journal of American Chemical Society, Volume 96, page 7582 (1974) hy B.G. Christensen et al.

In contrast to the reports of B.G. Christensen et al. suggesting that their racemic 1-oxacephalosporins showed about half the potency of (1-thia)cephalosporins, the optically active products prepared by the present inventors were about 4 to 8 times as antibacterially active as the corresponding (1-thia)cephalosporins. However, the β-lactam .ring of the 1-oxadethiacephalosporins tends to be less stable with respect to their possible utility as clinical drugs than that of (l-thia)cephalosporins.

Compounds (I) (defined above) selected from the optically active compounds prepared by the present inventors overcome the above-mentioned deficiency of 1-oxadethiacephalosporins.

Furthermore, compounds (I) show the following characteristics: 1) more potent antibacterial activity against gram negative bacteria; 2) higher stability of the β-lactam ring; 3) closer minimal inhibitory concentration values between the bacteria producing and non-producing β-lactamase; 4) less dependency on inoculum size; ) higher effectiveness against bacteria resistant to certain other cephalosporins (e.g. Enterobacteria, Serratia or indole positive Proteus); 6) higher contribution of bactericidal character; and 7) higher blood level.

Additionally, compounds (I) wherein Y is methoxy have the following properties: - 3 .«ί·”4 , j . ! ·- . . a) broader antibacterial spectra jje.g. 3.6 γ/ml of more against Pseudomonas sp., anaerobic bacteria (Bacteroid fragilis)J ; b) higher potency against bacteria producing β-lactamase; c) higher stability in blood; .and d) lower binding with serum proteins.

- In formula (I), preferred groups Ar are 3-thienyl, p-hydroxyphe’nyl, and p-aeyloxyphenyl, in which the acyl moiety is 1-5C alkanoyl, carbamoyl, 2-6C N-alkylcarbamoyl or ureidocarbonyl.

' The group Acyl in the definition of Ar can be acyl containing up to 8 carbon atoms, especially 1-5C alkanoyl, 8-12C aralkanoyl, 7-90 aroyl, 2-50 alkoxycarbonyl, 8-20C aralkoxycarbonyl, carbamoyl, 2-6C Ν-alkylcarbamoyl or ureidocarbonyl. 1 - . - - · - » Specific examples of groups Acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, enanthoyl, phenylacetyl, phenylpropionyl, benzoyl, toluoyl, carbethoxycarbonyl, benzyloxycarbonyl, carbamoyl, ΪΓ-methylcarbamoyl, Nethylcarbamoyl, N-propylcarbamoyl, N-isobutylcarbamoyl, Ν,Ν-dimethylcarbamoyl, carbamoyloarbamoyi or NamethylureidocarbOhyl. 2 Ί Groups COB , COB and COB7 can be carboxy groups or protected carboxy groups conventional in the chemistry of penicillins and cephalosporins (usually.containing Up to - 15 carbon atoms). Protective groups can be the same or different·,for.each carboxy group in the molecule. Usually, such protective-groups are removed to give free carboxy compounds or salts thereof at any'stage of synthesis of compounds (I). The structure of the carboxy-protective 3Q group(s) can vary widely and generally has no special - 4 significance other than protection, deprotection, and, when included, salt formation.

Specific examples of the above-mentioned protective groups are esters (including optionally substituted alkyl esters, e.g. t-butyl, mono-hydroxy-t-butyl, 2,2,2trichloroethyl and acyloxymethyl esters; aralkyl esterst e.g. benzyl, p-tolylmethyl, p-nitrobenzyl, p-methoxybenzyl, phthalidyl, diphenylmethyl, trityl and phenacyl esters; metal esters, e.g. trimethylsilyl, dimethylmethoxysilyl and trimethylstannyl esters; and other easily removable aliphatic esters; and aromatic esters, e.g. phenyl, tolyl, 3,4-dimethylphenyl and 5-indanyl esters) and 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. procaine, triethylamine and dicyclohexylamine).

Each carboxy group in the molecule can be free or protected by the same or different groups. 2 X Preferably COB , COB and COBy are each, independently, free carboxy or pharmaceutically acceptable salts. Other preferred groups COB^ are 5-indanyloxycarbonyl, phenoxycarbonyl and dimethylphenoxycarbonyl.

Some carboxy protective groups are useful for changing the character of the products as drugs. Thus, some groups are known for use with drugs which are known in the art. These groups include the following pharmaceutically acceptable groups: phthalidyl, acyloxymethyl, indanyl, phenyl, tolyl, dimethylphenyl, and carbethoxymethyl esters. Preferably Y is methoxy, although compounds (I) wherein Y is hydrogen are also important.

Usually, compounds (I) are employed as salts for administration to human or veterinary subjects. Most preferred salts are sodium or potassium salts, and salts with certain organic bases. Salts are selected from the viewpoints of safety, solubility, stability, etc. -.5 - Compounds of particular interest within the scope of formula (I) are: (a) compounds of the formula:' ,SHeT 2' (IX) wherein Ar is phenyl, p-hydroxyphenyl, 2-thienyl, or 3-thienyl; Het is'l-methyltetrazol-5-yl, l-cartoxymethylt£trazol-5~yl, or 2-methy L-i,3,4-thiadiazol-5-yl, and derivatives thereof at the carboxy. (b) compounds of the formula: It (XIII) wherein Ar is phenyl, p-hydroxyphenyl, p-aoyloxyphenyl, 2-thienyl, or· 3-thienyl, and derivatives thereof at the carboxy Specific examples of compounds (I) include the following: 4 7 9 .J 7P-[a-(2-thienyl)-a_carboxyacetamido]-3-(l-methyltetrazol-5-yl)tliiomethyl-l-oxadethia-3-cephcm-4-carboxylie acid) 7β-[a-(2-thienyl)-a-carboxyacctamido]-3-(l-carboxymethyltetraZol-5-yl)thiomethyl-l-oxadetliia-3-cephem-4-carboxylic acid, 7β-[α-(2-thienyl)-α-oarboxyacetamido]-3-(2-methyl-l,3,4thiadiazol-5-yl)thiomothyl-l-oxadethia-3-cephem-4-carboxylic acid, 7β_[α_(3-thienyl)-a-carboxyacetamido]-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4- carboxylic acid, 7P-[a-(3~thienyl)- 7(3- [«-(3 -thi enyl) -a-e arb oxyac etam.ido]-3-(2-methyl-l,3>4thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid, 7β-(oc-phenyl-a-earboxyacetamido)-3-(1-methyltetrazol-5yl)thiomethyl-l-oxadethia-3-cophem-4-carboxylic acid, 7P-(a-phenyl-a-carboxyacetamido)-3-(l-carboxymethyltetrazol-5-yl)thiomothyl-l-oxadetliia-3-cephom-4-carboxylic acid, 7(3-( α-phenyl-oc-carboxyac etamido )-3-( 2-methyl-l, J, It— thiadiazol-5-yl)thiomethvl-l-oxadethia-3-cephem-4-carboxylic acid, 7j3-( 7β_(α..p_hydχ<oxyphenyl-α-caϊ,boxyacctamido)~3-(l-caϊ'boxymethyltetrazol-5-yl)thicmethyl-l-oxadethia-3-cephem-4-carboxylic acid, 7β- (α-ρ-hydroxyphenyl-a-carboxyac etamido ) -3-( 2-me thyl1,3,4-thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-cafboxylic acid, • 7P~(ot-p-acetoxyphenyl-a:-carbcxyacetai«ido)~3-(l-inethyltctrazol-5-yl) thiomethyl-l-oxadethia-3-cephem-4-cai,boxylic acid., - 7 , ' 7g-(arpr-aoetoxyphenyl-a-carboxyacetamido)-3-(l-oarboxymethyltetrazol-b-yl)thiomethyl-l-oxadethia- ’ -3-cephem-4carboxylic acid, 7β-(ά -p-abetoxyphenyl-α -carboxyacetamido)-3-(2-methy1-1,3,45 thiadiazol-5-yl)thiomethyl-l-oxadethia'~3-cephem-4-carboxylic acid, 7g- (a -p-propionyloxypheny1-a -carboxyacetamido)-3-1l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-oephem-4-oarboxylic acid, -(α-p-pentanoyloxyphenyl-α -carboxyacetamido)-3-(2-methy1-1,3, 4-thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid,. 7g-(a-p-oarbamoyloxyphenyl-a-oarboxyacetamido)-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid, 7g-(a-p-carbamoyloxyphenyl-a-carboxyacetamido)-3-(2-methyl1,3,4-thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephern-4-carboxylic acid, 7g-f«-p-N-methylcarbamoyi0xyphenyl-a-carboxyacetamido)-3(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid, 7g-foi -p-N-pentyloarbamoyloxyphenyl-α -carboxyacetamido)-3-(2methyl-1,3,4-thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-420 carboxylic aoid, 7|3-fci-p-ureidocarbotiyloxyphenyl-a-carboxyacetamido)-3-(l“ methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-oephem-4-carboxylic acid, 7β-{ά -(2-thienyl)-a-carboxyacetamido]-7o;-methoxy-3-(l-methyltetrazol-S-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid, 7g - [«-(3-thienyl)-a-carboxyaoetamido2j-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid, - 8 44794 7P-(a-phcnyl-a-carbo.\yacctainido)-7a-mctlioxy-3-(l-iiicthyltotrazol-5-yl)thiomethyl-l-oxadethia-3-ccphem-4-carboxylie acid, 7P-(a-p-hydroxyphcnyl-a-carboxyacetaniido)-7tt-Hietlioxy3-(l-moihyltetrazol-5-yl) thiometliyl-l-oxadothia-3-ccphcni-4carboxylic acid, 7p-(a-p-acetoxyphenyl-a-carboxyacetamido)-7“-methoxy3- (l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-ccpheni-4carboxylic acid) 7p-(a-p-propionyloxyphenyl~a-carboxyacetamido)~7amethoxy-3~(l-niethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem4- carboxylic acid, 7β - (α-ρ-benzoyl oxyphenyl-a-carboxyac e tamido) -7 7p-(a-p-carbamoyloxyphenyl-a-carhoxyacetamido)-7dmethoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia~3-cephem4-carboxylic acid, 7p-(a-p-N-inethylcarbamoyloxyphehyl-a-earboxyaeetaniido )7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3cephcm-4-carboxylic acid, 7p-(“-r> -N-propylearbamoyloxyphenyl-a-carboxyaeetamido)7a-methoxy-3-(l-methyltctrazol-5-yl)thiomethyl-1-oxadethia3-cephem-4-carboxylic acid, 7p~(a-p-ureidocarbonylGxyphenyl-a-carboxyacetainido)~7ttinethoxy-3-(l-methyitotrazol-5~yl)thiomethyl-l-oxadethia-3-cephem4»carboxylic acid, ahd 7{5-(a-me thyltireidocarbonyloxyphertyl-a-carboxyacotamido)-7“-methoxy-3-(l-methyltetrazol-5-yl)thiomothyl-l-OXadethia-S-c ephem-4—carboxylic acid; and derivatives thereof protected at the carboxy group with pharmaceutically - 9 <47?4 .., k .- - - . . I - , .acceptable groups or conventional protective groups e.g. the derivatives being salts (e.g. salts with inorganic or * - organic bases e.g. sodium, potassium, magnesium·, calcium, and other alkali metal or alkaline earth metal salts, or triethylamine, ' igicyclohexylamine, morpholine, or If-, methylmorpholine salts), and esters (e.g, t-butyl, t-amyl-, 2,2,2-trichloroethyl,' acyloxymethyl, phthalidyl, diphenylmethyl, trityl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenacyl,, phenyl or indanyl esters),.

Compounds (I) having a 1-methyltetrazol-5-ylthiomethyl group at position'3 are the strongest antibacterial drugs against gram negative bacteria accompanied with.a smaller drop in activity at higher inoculum sizes. - Compounds (I) having a l-carboxymethyltetrazol-515 ylthiomethyl group at position 3 show stronger antiinfection effects in vivo than would be expected from in vitro data.

This is due to their ability in achieving high blood levels.

Compounds (I) having a phenylmalonamido, (2-thienyl)malonamido or (3-thienyl)malonamido group at position 7 show .. potent antibacterial activity, particularly against gram negative bacteria.

Compounds (I) having aρ-hydroxyphenylmalonamido, pacetoxyphenylmalonamido, p-carbamoyloxyphenylmalonamido, p-®ffiethylcarbamoyloxyphenylmalonamido or p-ureidocarbonyl25 oxyphenylmalonamido group at position 7 are potent antibacterials showing.less deactivation ih living animals because of their lower protein binding and higher blood levels than are exhibited by the corresponding unsubstituted arylmalonamido compounds. They also show highly intensified -30 · activity against Pseudomonas strains, including those strains -,10 44794 resistant to carbenicillin.

Compounds (I) having a methoxy group for Y at position 7a are more stable against β-lactamase, more broadly effective (e.g. have improved activity against Pseudomonas bacteria and other gram negative bacteria), and are more potent than those having hydrogen for Y.

All compounds (I) are novel substances which show potent antibacterial activity and are useful medicines, veterinary drugs and disinfectants. For example, the compounds (I) may be administered orally or parenterally to humans or other animals at daily doses of e.g. from 0.05 to 50 tig/kg body weight.

The compounds (I) are usually used as vials containing sterilized microcryst'als or lyophilizate and administered as solutions made up before use. Furthermore, an effective amount of a compound (I) may be administered orally or parenterally with one or more pharmaceutically acceptable carriers, additives, diluents or stabilizers, in various preparation forms, e.g. vials, injections, salves, solutions, tablets, powders and capsules. · Thus, the invention provides a pharmaceutical or veterinary formulation'which comprises a compound of the invention or a salt of the invention., The invention further provides a pharmaceutical or veterinary composition which comprises a compound of the invention or a salt of the invention together with a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient, The above compositions or formulations may be in unit dosage form. - 11 44^94 The salts of compounds (I), including alkali metal salts, are used mainly for parenteral adjiinistration. The acyloxy» ’ - I methyl, indanyl, phenyl, phthalidyl·, and like esters are also suitable for oral application.

Compounds (I) are also useful intermediates for preparing useful compounds within or beyond the scope of the formula Also included within the scope of the invention is - - a method for inhibiting the growth of bacteria in an .10 environment, which method comprises administering to the environment an effective amount of.a compound of the invention or a salt of the invention, or a formulation of the invention, or of a composition of the invention.

Such a method can be employed in the prevention or cure of disease in a non-human animal, in the prevention of decay in a perishable substance or material, or in disinfecting a substance, material, article or building structure.

Compounds (I) can, for example, be prepared by treating an amine of formula (II) with an arylmalonic acid of formula (HI) or reactive derivatives thereof. . ι ο wherein Ar, COB , COB , Het- and Y arc as defined above. The amino group at position 7 of amine (II) may be activated by a silyl or stannyl group, or protected or activated by a-group, chosen from, 1-haloalkylidine, 125 alkoxyalkylidene, alkylene, carbonyl, readily removable acyl, and like groups, for the acylation. Removal of - 12 1 44?S4 these groups gives the objective compounds (l).

When the arylmalonic acid (ΠΤ) in used as the fret4 acid, the acylation io preferably curried out in a solvent (particularly-nitriles, ethers, amides, halohydrocarbons, or mixtures thereof) and in the presence of a condensing reagent [e.g. Ν,Ν'-dialkylcarbodiimides (e.g. Ν,Ν'-dicyclohexylcarbodiimide); carbonyl compounds (e.g. carbonyldiimidazole); acylaraines (e.g. 2-ethoxy-1-ethoxycarbonyi-1,2-dihydroquinoline); isoxazolinium salts (e.g. N-ethyl-5-phenylisoxazolinium-3sulfonate or N-t-butyl-5-methylisoxazolium perchlorate); and other condensing reagents] at -1O°C to 70°C.

When the arylmalonic acid (III) is used in the form of a reactive derivative, it can, for example, be an anhydride * [e.g. a mixed anhydride with an alkylcarbonic acid, an aralkylcarbonic acid, a hydrohalogenic acid (an acid halide), hydrogen azide (acid azide), phosphoric acid, phosphorous acid, sulfuric acid, sulfurous acid, hydrogen cyanide (acid cyanide); a symmetrical intermolecular anhydride; a mixed anhydride with an aliphatic or aromatic sulfonic or carboxylic acid; or a special intramolecular anhydride such as ketene, isocyanate and like reactive anhydrides] ; a reactive ester [e.g. an enol ester; an aryl ester (e.g. a pentachlorophc-nyl, p-nitrophenyl, 2,4-dinitrophenyl or benzotriazo.le esterfj ; a diacylimino ester; a reactive amide [e.g. amides with imidazole or triazole; or reactive amides, e.g. 2-ethoxy-1,2-dihydroquinolin-1-amide] or a formimino derivative (e.g. a N,N-dialkyliminomethyl ester or a Ν,Ν-diacylaniline).

If required, the above-mentioned acylating reagents can be used in the presence of an acid receptor [e.g. an - 13 447 9 inorganic base (e.g. a hydroxide, carbonate or bicarbonate of. an alkali metal or alkaline earth metal), an organic base (e.g. a tertiary amine Or an aromatic base), an alkylene oxide (e.g. ethylene oxide or propylene oxide), an amide (e.g, Ν,Ν-dimethylformamxde or hexamsthyl5 phosphorotriamide) and other acid receptors or a molecular sieve, preferably in a solvent (particularly a ketone, an . ester, an ether; a nitrile, an amide, a halohydrocarbon, or a mixture thereof).

Similarly, compounds of formula (IX) can be prepared by reacting an amine of the formula: (X) wherein Het is as defined above in connection with formula (IX), or a derivative thereof at the carboxy with a malonic acid derivative of the formula: i ArCHCOQH wherein Ar is as defined above in connection with formula (IX), or with a reactive derivative thereof in which one of the carboxy groups may be protected.

Similarly, compounds of formula (XIII, can be prepared by reacting an amine of the formula: (XIV) - 14 or a derivative thereof at the carboxy with a malonic acid derivative of the formula: ArCHCOOH I (XV) COOH wherein Ar ie as defined above in connection with formula (XIII), or with a reactive derivative thereof in which one of the carboxy groups may be protected.

Alternatively, compounds (I) can be prepared from the corresponding non-fused ring azetidinones by cyclization e.g by a . Wittig reaction. Thus, for example, an azetidinone of formula (IV) may be heated in an inert solvent (e.g. an ether, an aromatic hydrocarbon, a halohydrocarbon, an amide, a sulfoxide, or an anhydride) to give a compound (I) in high yield.

OCH2c!cH2SHet ArCHCONH/; ' „1 COB 'OPR, (IV) I 2 DOB 2 wherein Ar, COB , COB , Het and Y are as defined above; and each of the three 9 roups R is the same or different being optionally substituted alkyl or aryl.

Similarly, compounds of formula (IX) can be prepared by heating an azetidinone of the formula: ArCHCONH x COOH QCH2CCH2 SHet (XII) OPRu wherein Ar and Het are each as defined above in connection wih formula (IX), and each of the three groups R is the same or different and is optionally substituted alkyl or aryl, or a derivative thereof at the carboxy.

Similarly, compounds of formula (XIII) can be prepared by heating an azetidone of the formula: COOH ’ wherein Ar ds as defined above in connection with formula (XIII), and each of the three groups R is the same or different and is optionally substituted alkyl or aryl, or a derivative thereof at the carboxy.

.When Ar is p-hydroxyphenyl, compounds (I) can be treated with an acylating reagent to give compounds (I) wherein Ar is acyloxyphsnyl. The acylating reagent and reaction conditions employed are conventional in the art.

When Ar is p-hydroxyphenyl, the compounds can at first be protected at the hydroxy group with an easily removable 4 794 protective group and afterwards deprotected to give the desired hydroxyphenyl compounds. Representative protective groups include those which form esters ^including 0^-Cg a-haloalkanoyl (e.g. trifluoroacetyl or trichloroacetyl), ~0g alkanoyl (e.g. acetyl or formyl), C^-Οθ β-ketocarboxylic acyl (e.g. acetoacetyl), O2”C12 (θ-g· t-butoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl or 2,2,2trichloroethoxyearbonyl), Οθ-C^ aralkoxycarbonyl (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro-or p-methylbenzyloxycarbonyl or diphenylmethoxycarbonyl), and like acyls] and ethers ^including 0.,-Cg alkyl (e.g. methyl, t-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl or methoxymethyl), Cy-C^ aralkyl (benzyl, p-methoxy, p-methylor p-nitrobenzyl or diphenylmethyl, trityl), and like groupsj , The protective group is preferably introduced at the stage of use of the arylmalonic acid (III) or reactive derivatives thereof. The deprotection may, for example, be carried out by 1) cleavage of acylates or ethers with an acid (e.g. a mineral acid, a lewis acid, a strong carboxylic acid or a sulfonic acid) or a base (e.g. sodium or potassium carbonate, hydroxide or an organic base) at room temperature or, if required, at elevated temperature in the presence of a cation scavenger, or 2) hydrogenation of p-nitrobenzyloxycarbonyl or benzyl-oxycarbonyl with hydrogen and platinum or palladium in a conventional manner.

When the carboxy group at position. 4-, or in the side chain at position 7 and/or in group Het is protected, the protective group(s) may be removed to give the desired compound (I) by conventional methods for removing protective groups. Thus, for example: 1) highly reactive esters,, amides - 17 and anhydrides are readily hydrolyzed with an acid or a base; 2) 2-haloethyl, benzyl, methylbenzyl, nitrobenzyl and diarylmethyl esters are cleaved by mild reduction (e.g. with tin, zine or divalent chromium salts in the presence of an acid; with sodium dithionite; or with catalytic hydrogenation with hydrogen over, a catalyst, e.g. platinum, palladium or nickel); 3) benzyl, methoxybenzyl,'methylbenzyl, dimethoxybenzyl, t-alkyl, trityl, diarylmethyl and cyclopropylmethyl esters are cleaved by the action of an acid or by solvolysis (e.g. with a mineral aoid e.g. hydrochloric acid, a lewis acid e.g. aluminum chloride, a sulfonic acid e.g. toluene-psulfonic acid, a’strongly acidic carboxylic acid e.g. trifluoroacetic acid or formic aoid, if necessary in the presence of a cation acceptor e.g, anisole); 4) phenacyl, - ethynyl or p-hydroxy-3,5’4i-t-butylbenzyl esters are cleaved by the action of a base (e.g. an alkali metal thiophenoxide, an inorganic base or a basic salt), and like methods* Compounds (I) having one or more free carboxy groups can be converted into corresponding derivatives by introducing protective groups or substitutents into the carboxy group(s) by conventional methods (e.g. for esters, by the action of the corresponding alcohols with said condensing reagents, diazo compounds, or haloformates, for salts, the action of alkali metal hydroxides, carbonates or alkanoate salts, or the-action of organic bases or ion-exchange resins)..

The following detailed examples are provided to -. further illustrate and describe the invention. The elemental analyses and physical constants of the products . in each. Example are consistent with the given structures.

In the Examples, the products usually contain almost - 18 44 784 equal amounts of the isomers at. the α-asymmetric carbon atom in the amide side chain. Both of the isomers are, of Course, included in the scope of this invention, and, if necessary, such isomers are separable by chromatographic techniques or by other conventional methods. The nomenclature adopced is in accordance with that used in a Japanese Patent Application (open to Public Inspection No 49-153594) filed by Merck Inc., U.S.A.

Preparation 1 (Preparation of 7a-amino compounds) (1) To a solution of diphenylmethyl 7p-phenylacetamido-3(1-mbthyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4carboxylate (955 mg) in methylene chloride (24 ml) are added phosphorus pentachloride (666 mg) and pyridine (0.258 ml) in nitrogen gas at -20°C. After stirring at -20°C for 30 minutes and at room temperature for 30 minutes, the mixture is Mixed with methanol (12 ml) at -20°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 hydrogen carbonate under ice cooling, and extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate, and concentrated under reduced pressure. The separated crystals are collected by filtration and washed with ether to yield diphenylmethyl 7p-amino-3~(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3cephem-4-carboxylate (661 mg), mp. 151 - 156°C. Yield: 86.5?6. IR: •'SS 3420 , 3345, 1790, 1718, 1630 cm“1.

NMRf5CDC13 1.75brs2H, 3-Sls3H, 4.28brs2H, 4.50d(4Hz)lH, - 19 _ , v - .. --. - · . · -· ' ' ί f ] 4.64brs2H, 4.98d(4lIz)iH, 6.9OS1H, 7·20 - 7.70ml0H.

OT: X^KI3^2SO 286 nm (ε=8695)· E«]n2'5 -232.8 ±7.6° (0=0.360, (cn3)2so) (2) In a procedure similar to that of above (l) , diphenyl5 methyl 7P-phenyla'cetainido-3-(2-methyl-l,3,4-thiadiazol-5-yl)thiomethyi-l-oxade1;hia-3-cephem-4-carboxylate (381.5 mg) in methylene chloride (8 ml) is treated with phosphoius pentachloride (259 nig) and pyridine (O.l ml) at -20°C, with methanol (8 ml), and with water (4 ml) to give diphenylmethyl 7β-amino-3-(210. metbyl-l,3,4-thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4carboxyiate (273.3 mg)· Yield: 88.8 #.

IR: 3420, 3350, 1794, 1723 cm1.

NMR: 0CDC13 1.88S2H, 2.6?s3H, 4.25 + 4.55ABq(l4Hz)2H, 4.52d(4Hz)lH, ' 4.68s2H, 5.00d(4Hz)lH, 7-07slH. 3,5 (3) In a procedure similar to that of above (l), diphenylmethyl 7p-phenylacetamido-3-(l-t-butoxycarbonylmethyltetrazol5-yl)thi0methyl-l-oxa<3ethia-3-cephem-4-carboxylate (300 mg) in methylene chloride(lO ml) is treated with phosphorus pentachloride (l80 mg) and pyridine (o.O7 ml) at -20°C, with methanol (4 ml), and with water'(4 ml) to give diphenylmethyl 7P-anino-3(l-t-butoxycarbonylmethyltetrazol-5ryi)thiomethyl-l-oxadethia3-cephem-4-carboxylate (189 mg). Yields 76 $>· IB: 17?5, 1753, 1722 cm”1. .

NMR: 6CDCl3 1.45s9H, 1.60 - 2.00m2H, 4.30s2H, 4.40 4.60miH, 4.65brs2H, 4.86s2H, 5.o0d(4Hz)lH, 6.95slH. . -. 20 r ί Preparation 2 -(introduction, of 7a-mcthoxy) (1) A solution of diphenylmethyl 7?-amino-3-(l-methyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (600 ing) and 3,5-di-t-butyi-4-hydroxybenzaldehyae (353 mg) in a mixture of g 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-separater. The resulting solution of diphenylmethyl 7P-(3>5-di~t-butyl-4-hydroxyben2al)amino-3-(l-methyltetrazol-5-yl)thioraethyl-l-oxadothia-3-cephom-4-carboxylate is cooled at -10°C to -15 °C, mixed with anhydrous magnesium sulfate (l g) and then nickel peroxide (0.69 g) with stirring, and stirred at -10 °C to -15 °C for 30 minutes and at room temperature for 15 minutes. The reaction mixture is filtered, and the solid ie washed with benzene. To the resulting solution of diphenyl15 methyl 7-(3,5-di-t-butyl-4-oxo-2,5-cyclohexadienylidenemethyl)imino-3-(l-methyltetrazol-5-yl)thiomethyl-l-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 ji 20 on silica gel (30 g) containing 10 % water and eluted with a 1 mixture of benzene and ethyl acetate (4 : l) to give diphenylΐ methyl 7P-(3»5-di-t-butyl-4-hydroxybenzal)amino-7a-methoxy-3(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4carboxylate (906 mg) as practically pure yellow foam. Yields 99·7 ¢• 25 (2) To a solution of the abpve product in a mixture of methanol (lO ml) and tetrahydrofuran (5 ml) is added Girard T reagent (315 mg), and the mixture is stirred for 1 hour at room temperature, diluted with water, and extracted with methylene Chloride. The extract is washed with water, dried on sodium sulfate, and evaporated to dryness under reduced pressure. - 21 L.

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 (l : 1 : l) to give diphenylmethyl 7p-amino-7“-methoxy—3-(l-methyltetrazol-5-yl)thiomethyl-l5 oxadethia-3-cephem-4-carboxyiate (469 mg). Over-all yield throughout this example : 73*6 ¢. mp. l6o - l62°C (decomposition). IR: vJ®X3 3425, 3350, 1792, 1724 cm-1.

NMR: 6CDCl3 2.00brs2H, 3.38S3H, 3.87S3H, 4,,32s2H, 4.73S2H, 4.92slH, 7-OOslH.

Iq As is apparent from above preparation, nickel peroxide is found to be one of the best oxidizing reagents of the phenolic intermediate to introduce a methoxy at position 7a of 1-oxa and also 1-thia cephem rings.

I. Ring Formation ♦ Example 1-1 A solution of diphenylmethyl a-[4p-(l-methyltetrazol5-yl)thioaeetonyloxy-3P-(α-phenyi-a-diphenylmethoxyoarbonylac etamido)-2-oxoazetidin-l-yl]-a-triphenylphosphoranylideneacetate (650 mg) in dioxane (5 ml) is refluxed in nitrogen atmosphere for 16 hours. The reaction mixture is concentrate/! under reduced pressure. The residue is purified by chromatography on silica gel (20 g) containing 10 % water, and eluted with a mixture of benzene and ethyl acetate (4 : l) to give diphenylmethyl 7β(ec-phenyl-a-diphenylmethoxycarbonylacetamido)-3-(l-methyl25 tetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-earboxylate (432 mg), mp. 107 - 109°C. Yield: 80 IR: 3410 , 1793, 1719, 1694, 1630, 1600 cm1.

Examplo 1-2 In a procedure similar to that described in Example 1-1, diphenylmethyl a-[4j3-(l-meihyltetrazol-5-yl)thioacetonyloxy-3p-22 «4794 (a-phenyl-oc-diphenylmethoxycai’'bouylacetamido)-3“-mothoxy~2-oxoazctidin-l-yl]-a-tx’iphenylpho.sphoranylideneacetato (543 nlG') is refluxed in dioxane (5 ml) for 15 hours in nitrogen gas, and purified by chromatography on silica gel (l5 g) to give diphenylmethyl 73-( • Example 1-3 In a procedure similar to that of Example 1-2, diphenylmethyl 10 a-f3p-(“-p-benzyloxyphenyl-a-diphenylniethoxycarbonylacetamido)-3“raethoxy-40-|3-(l-raethyltetrazol-5-yl)thiomethyl-2-oxopropoxyj—2oxoazetidln-l-yl]-“-triphenylphosphoranilideneacetate is refluxed in dioxane for 10 hours under nitrogen and purified by chromatography .on silica gel to give diphenylmethyl 7P-(“-diphenylmethoxycarbonyl15 a-p-benzyloxyphenylacetamido)-7a-methoxy-3-(l-mothyltetrazol-5-yl) thiomethyl-l-oxadethia-3-cephem-4-carboxylate.

The starting material of this process is prepared from diphenylmethyl a-(3P-benzamido-4p-allyloxy-2-oxoaze.tidin-l-yl)d-isopropylideneacetate by the alignment of reactions comprising with l) peracid, 2) t-butyl hypochlorite, 3) lithium methoxide, 4) lithium 1- methyltetrazol-5-ylmercaptide, and 5) chromium trioxide to give diphenylmethyl oc-[3j3-benzamido-3“-methoxy-4p-[3-(l-methyltetrazol5-yl)thiomethyl-2-oxopropoxy]-2-oxoazetidin-l-yl]-a-isopropylideneacetate, which is treated with 6) phosphorus pentachloride, 7) methanol, and 8) triethylamine to give diphenylmethyl a-[3J3-amino3“-methoxy-4p-{3-(l-methyltetrazol-5-yl)thiomethyl-S-oxopropoxy}2- oxoazetidin-l-yl]-a-isopropylideneacetate, which is treated with 9) a-p-benzyloxyphenyl-oc-benzyloxycarbonylacetyl chloride and triethylamine, 10) ozone, ll) zinc and acetic acid, 12) thionyl chloride and pyridine, and 13) triphenylphosphine. - 23 44794 ' II. Amide formation · · Example H-l To a stirred solution of diphenylniethyl7P-amino-3-(lmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate g (192 mg) in tetrahydrofuran (2 ml) and acetone (l ini) are added . mono-diphenylmethyl phenylmalonate (208 mg) and N-ethoxycarbonyl2-ethoxy-l,2-dihydroquinoline (l48 mg) at O°Cj and then tho mixture is allowed to stand at room temperature overnight. The reaction mixture is diluted with ethyl acetate , washed with 2N-hydrochloric acid, water, 5 % aqueous solution of sodium hydrogencarbonate, and then water, dried on sodium sulfate, and evaporated to dryness.

The residue is purified by chromatography on silica gel (20 g) containing 10 % water and eluted with a mixture of benzene and ethyl acetate (4 : l). The crystals obtained from the fraction are washed with a mixture of ether and' n-pentano to give diphenylmethyl 7β(a-phenyl-a-diphen.ylmethoxycarbonylacetamido)-3-(l-inethyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carfaoxylate, mp. 100 - 105°CYield: 40 $.

IR: vCHC13 1800, 1720, 1680 cm-1, max .

NMR: 6CDC13 7-00slH, 6.95slH, 5*80dd(4;9Hz)lH, 5-06d(4Hz)lH, 4*75slH, 4.65'brshl, 4.33d2H, 3-86s3H.

By using a-(diphonylmethoxycarbonyl-a-phonyl)acetyl Chloride, triethylamine hydrofchloride, and pyridine instead of mono-diphenylmethyl phenylmalonate and N-ethoxyc^rbcnyl-2-ethoxy25 1,2-dihydroquinoline, the reaction is analogously carried out for 25 minutes to give the same- product as mentioned above in 99 % yield* mp. 107 - 109°C.

IR: vKRr 3410, 1793, 1719· 1094, 1630, 1000 cm-1, max *· UV:X^CH3^2S0 281 nm (ε = IOI36). mar ' NMR: 6^CD3^2SO 3.84s3H, 2)-30brs2H, 4*58brs.2H, 4.69slH/2, - 24 ν. $4 4.71slH/2, 5.02d(4lIz)lII, 5-70dd(4;9H'z)lH, 6.86brslH, 6.90brslH, 7-0 - 7.5m2OH, 7-76d(9Hz)lH, [a]p3 - 144.2 ± 8.1° (c = 0.226, (CH3)gS0) Example II-2 To a stirred solution of diphenylmethyl 7P-an'ino-3-(lmethyltetrazol-5-yl)thioinethyl-l-oxadethia-3-cephem-4-carboxylate (500 mg) in methylene chloride (20 ml) are added pyridine (o.l nil) and a solution of a-(p-nitrobonzyloxycarbonyl)-a-phenylacetyl ί • chloride (510 mg) in methylene chloride (2 ml) under ice - cooling 10 in nitrogen atmosphere, and the mixture is stirred for 25 minutes. lhe reaction mixture is poured into water, and extracted with methylene chloride. The extract is dried on sodium sulfate and evaporated to dryness to yield residue (l-04 g) which is chromatographed on silica gel (40 g) containing 10 fii water, eluted with a mixture of benzene and ethyl acetate (4 : l), and crystallized from a mixture of ethyl acetate and ether to give diphenylmethyl 7p-( UV: ^®3^2S0 278 nm (ε = 18490).

IR: vK®r 3400, 3340, 1792, 1742, 1718, 1680, 1631, l6o4, 1520, fltQX 1345 cm1.

NMR: 6^CD3^2S0 3-88s3H/2, 3‘89s3*I/2, 4.24brs2H, 4.65brs2H, -05slH, 5-20d(4Hz)lH, 5.32brs2H, 5-75mlH, 6.86slH, 7-20 - 7·70πι15Η, 7-50 - 8.0A2X24H. [α]22.5 _ 15θ-6 + 5Λ0 (c = O.35O) (CH3)2SO).

Example II-3 To a stirred solution of diphenylmethyl 7P-an>ino-3-(l.methyltetrazol-5-yl)thiomethyl-l-oxadothia-3-cophem-4-carboxylate (lOO mg) in methylene chloride (ll ml) are added pyridine (21 mg) - 25 ¢¢794 and a solution of a-(indaii-5-Yl)oxycarbonyl-a-phenylacetyl chloride (prepared from the corresponding acid (77 mg)) in methylene chloride (2 ml) under ice cooling, and the mixture is stirred for 30 minutes. · The reaction mixture is poured into a mixture of ethyl acetate and. t water, and the organic layei· is taken up. This is washed with diluted hydrochloric acid, aqueous solution of sodium hydrogencarbonate, water, and aqueous solution of sodium chloride, dried -. Cn magnesium sulfate, and evaporated to dryness. The residue is purified by chromatography on silica gel (5· 5 g) containing 10 % .10 water, and eluted with a mixture of benzene and ethyl acetate (4 s l) to give diphenylmethyl 7p-[“-'(5-indanyl)oxycarbonyl-aphenylacetamido]-3-(l-me_thyltotrazol-5-yl)thiomethyl-l-oxadethia3-ce.pheitt-4-carboxylate (3 44 mg) as pale yellow foam. Yield: 95.4 #. IR: 1800, 1735, 1685 cm1.

Example II-4 To a solution of diphenylmethyl 7P-amino-3-(l-methyltetrazol-5-yl)thioraethyl-l-oxadethia-3-cephem-4-carboxylate (l44 mg) in methylene chloride (4 ml) are added pyridine (θ.θ48 ml) and a solution of phenyImalonyl he'michloride in methylene chloride (2 ml) (prepared by reacting phehylmalonic acid (l08 mg) with thionyl chloride (o.048'ml) in a mixture of ether (l ml) and dimethylformamide (2 drops) at room temperature for 20 hours) and the mixture is kept at 0°C for 20 minutes. The reaction, mixture is diluted with ethyl acotate, washed with dilute hydrochloric acid and water, dried on sodium sulfate, and concentrated. Tho residue is purified by chromatography on silica gel containing 10 $ water, and eluted with a mixture of ethyl acetate and benzene (l : 1 to 1 : 0) to give diphenylme thyl 7p-( Yield: 6l ¢. - 26 Example ΤΙ-5 To a solution, of 7p-nmino-3-(l-motliyltetrazol-5-yl)thio-mcthyl-l-oxadcthia-3-eophoin~J|-carboxyl.i.c acid (78 mg) and triethylamine (Ο.Ο36 ml) in methylene chloride (l ml) is added a solution 5 of phenylmalonyl nionochloride monobenzhydryl estor in methylene chloride (2 ml) [prepared by reacting monobenzhydryl phenyiinalonate (60 mg) with thionyl chloride (0.04 ml) in a mixture of ether (l ml) arid dimethylformamide (l drop) at room temperature for 10 hours), and the mixture is kept at 0°C for 1 hour. The reaction mixture is diluted with a mixture of ethyl acetate and acetic aoid (9 : l) to give 7P-(a-diphenylrnethoxycarbonyl-a-phenylacetamido)-3-(lmethyltetrazol-5-yl)thiomethyl-l~oxadethia-3-cephem-4-carboxyiic acid (60 mg). .

Example 11-6 lg To a solution of 7P-umino-3-(l-methyltetrazol-5-yl)thioraethyl~l-oxadethia-3-eephem-4-carboxylio acid (78 mg) and triethylamine (0.036 ml) in methylene chloride (l ml) is added a solution of phenylchloroformylketene (45 mg) in methylene chloride (0.5 ml), and the mixture is kept at 0°C for 2 hours, .The reaction mixture 2o is washed with water, dried, and evaporated. The'residue is dissolved in ethyl acetate, purified by chromatography on silica gel (lO g) containing 10 $ water, and eluted with a mixture of ethyl acetate and acetic acid (9 : l) to yield 73-(«-phenyl-occarboxyacetamido)-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia25 3-cephem-4-earbexylic acid (88 mg). Yield: 74 ¢, Example 11-7 A solution of diphenylmethyl 7P-amino-3-(l-methyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (96 mg) in methylene chloride (3 ml) is added to a solution of a mixed anhydride [prepared by reacting mono-t-butyl p-hydroxyphenylmalonate (76 mg) - 27 Λ· 9 4 with i-butyl chloroformate (-0.037 ml) in the presence of triethylamine (O.o4l6 ml) in methylene chloride (4 ml) at -30 °C for 30 minutes and at 0°C for 10 minutes], and the mixture is stirred at -30°C for 30 minutes, at 0°C for 2 hours, and at room temperature for • 5 30 minutes. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in a mixture (2 ml) of pyridine and water (7 : 3)> and stirred at room temperature for 1 hour.

• The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is washed with water, 2N-hydrochlorio acid, water, 5 aqueous solution of sodium hydrogen carbonate, and water, dried on sodium sulfate, and concentrated under reduced pressure. The residue (l48 mg) is purified by chromatography on silica gel (l5 g) containing 10 % water and eluted with a mixture of benzene and ethyl acetate (4 : l). The eluate is triturated in a mixture of ether and pentane to give diphenylmethyl 7β-(α-ρhydroxyphenyl-a_t-butoxycarbonylacetamido)-3-(l-methyltetrazol-5yl)thiomethyl-l-oxadethia-3-cephem-4-carboxy'late (66 mg), mp. 124 - 126°C. Yield: 46 %.

IR: 34io, 3320, 1800, 1717, 1679, 1510 cm1.

.NMR; 6CDC13 1.40s9H, 3-80s3H, 4.27brs2H, 4.38SIH/2, 4.42slH/2, • 4.62brs2H, 5.04d(4Hz)lH, 5-70dd(4;10ffiz)lH, ’· 6.46 - 8.3iml7H.

Example II-8 To a suspension of α-ρ-hydroxyphenylmalonic acid monobenzhydryl ester (507 mg) in methylene chloride (3 ml) are added triethylamine (139 μΐ) and oxalyl chloride (85 μΐ) at 0°C.

After stirring for 45 minutes at 0°C, the mixture is added to a solution of diphenylmethyl 7p-amino-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (l91 mg) in methylene chloride (3 ml) and pyridine (80 μΐ) at 0°C. After stirring for - 28 30 minutes at 0°C, the reaction mixture is diluted with ethyl acetate, washed with 2N-hydrochloric acid, water, 5 sodium hydrogenoarbonate aqueous solution, and water, dried on sodium sulfate, and concentrated under reduced pressure. The residue is chromatographed on silica gel (15 g) containing 10 % water, and eluted with a mixture of benzene and ethyl acetate (9 : l) to give diphenylmethyl 7p-[a-p-hydroxyphenyl-a-diphenylmethoxycarbonylacetamido]-3-(1-methyltetrazol-5-yl)-thiomethyl-l-oxadethia-3cephem-4-carboxylate as colorless foam (137 mg). Yield: 41.6 ¢.

IR: 3325, 1798, 1722, 1679 cm1.

NMR. 6CDC13 3.73s3H, 4.20brs2H, 4.53brs2H, (4.6os + 4.63s)lH, 4.93brd(4Hz)lH, 5-47 - 5·77«1Η· Example 11-9 To a solution of diphenylmethyl 7P-amino-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (96 mg) in a mixture of tetrahydrofuran (l ml) and acetone (θ·5 ml) are added mono-t-butyl a-(2-thienyl)malonate (129 mg) and 1-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (l32 mg) in four equal portions at 1 hour intervals with stirring at room temperature in nitrogen gas, and the mixture is stirred for Γ hour. The reaction mixture is diluted with ethyl acetate, washed with 2Nhydrochloric acid, water, 5 $ aqueous sodium hydrogencarbonate, and water, dried on sodium sulfate, and concentrated under reduced pressure. The residue (z51 mg) is purified by chromatography on silica gel (lO g) containing 10 $ water, and eluted with a mixture of benzene and ethyl acetate (4 : l). The eluate is triturated with a mixture of ether and pentane to give diphenylmethyl 7β-[α(2-thienyl)-a-t-butoxycarbonylacetamido]-3-(l-methyltetrazol-5-yl) thioniethyl-l-oxadethia-3-cephem-4-carboxylate as amorphous powder (49 mg), mp. 97 - 99°C. Yield: 34.8 ¢. - 29 v <4794 IR: vCHC13 3400,-1800, 1720!, 1690, 1511 cm-1.

Max NMR: 6CDC13 1.47s9H, 3-93s3H, 4.32s2H, 4.69brs2H, 4.80brslH, .09d{4Hz)lH, 5.75dd(lO;4Hz)lH, 6.90 - 7-73ml5H.

* ( Example II-10 »1 To a solution of diphenylmethyl 7β-amino-3-(1-methyl10 tetrazol-5-yl)thioraethyl1-l-oxadethia-3-cephcm-4-carboxylate (96 mg) in a mixture' of tetrahydrofuran (l ml) and acetone (θ·5 al) are added mono-t-butyl a-(3-thienyl)malonate (132 mg) and 1-ethoxyoarbonyl-2-ethoxy-l,2-dihydroquinoline (l32 mg) under ice-cooling, and. the mixture is stirred .at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with water, IN-hydrochloric acid, water, 5 dp aqueous solution of sodium - hydrogen carbonate, and saturated solution of sodium chloride, dried on magnesium sulfa»te, and concentrated. The residue (l98 mg) is purified by chromatography on silica gel (lO g) containing 10 $ 2θ water, and eluted with a mixture of benzene and ethyl acetate (l : l) to yield diphenylmethyl 7P-[“-(3-thienyl)-oc-t-butoxycarbonyl acetamido]-3-(l-methyltetrazol-5-yl)thi omethyl-l-oxadethia-3-c ephem4-carboxyiate (56 mg) as colorless powder, mp. 85 - 90°C. ’ Yield: 39-7 #· IR: 1798, 1720, 1685, 1630 cm-1, max • NMR: 5CDC13 1.45s9H, 3.85s3H, 4·32ε2Η, 4.67Π13Η, 5.06d(4Hz)lH, 5.86dd(lOi4Hz)lH, 7.00slH, .7.1 - 7.65ml4H.

Example U-ll To a solution of diphenylmethyl 7P-amino-3~(l-t-butoxy30 carboxylmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4carboxylate (l02 mg) in a mixture of tetrahydrofuran (2 ml) and acetone (l ml) are added monobenzhydryl α-phenylmalonate (186 mg) « and N-ethoxycarbonyl-2~ethoxy-l,2-dihydroquinoline (88 mg) in two portions, and the mixture is stirred at room temperature for 3.5 - 30 1 hours. The reaction mixture is mixed, with ethyl acetate, washed With 2N-hydrochloric acid, water, 5 % sodium hydrogencarbonate aqueous solution and water, dried on sodium sulfate, and concentrated under reduced pressure. The residue is chromatographed on silica ® gel (lO g) containing 10 5½ water, eluted with a mixture of benzene and ethyl acetate (9 : l), and concentrated to give diphenylmethyl 7P-(a-diphenylmethoxycarbonyl-a-phenylacetamido)-3-(l“t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-l~oxadethia-3-cephem-4carboxylate (63 mg) as colorless foam. Yield: 39 $>· .10 IR: v™C13 1800, 1750, 1725, 1680 cm-1.

NMR: 6GDC13 6.96s1H, 6.93slH, 5-75dd(4;9Hz)lH, 5-O3d(4Hz)lH, 4.90s2H, 4.73slH/2, 4..71s1H/2, 4.60brs2H, 4.30s2H, . 1.40s9H· Example 11-12 To a solution of diphenylmethyl 7P-amino-3-(l-t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4carboxylate (87 mg) in acetonitrile (2 ml) are added N-[a-tbutoxycarbonyl-a-(2-thienyi)acetoxy]succinimide (76 mg) and Nmethylmorpholine (0.0l6 ml) in nitrogen atmosphere, and the mixture is stirred for 90 minutes. The reaction mixture-is mixed with ethyl acetate, washed with dilute hydrochloric acid, water, 5 $ sodium hydrogencarbonate aqueous solution, and water, dried or. sodium sulfate, and concentrated. The residue is chromatographed on silica gel (lO g) containing 10 % water, and eluted with a mixture of benzene and ethyl acetate (9 : l) to give diphenylmethyl 7p[a-t-butoxycarbonyl-oc-(2-thienyl)-acetamido]-3-(l-t-butoxyearbonylmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-earboxylate (96 mg) as colorless foam. Yield: 80 IR: vG®G13 1802, 1750, 1722, 1690 cm1, max NMR: 6CDC13 6.93slH, 5-72dd(4;9Hz)lH, 5-O6d(4Hz)lII, 4.83s2H, - [ 4.75brslH, 4.60brs2H, 4-30s2H, 1.45sl8H.

//:/-- Example ΪΙ-13 To a solution of diphenylmethyl 7P-amino-3-(2-methyli»3ι4-thiadiaj5ol-5-yl)thiometh.yl-l-oxadetfaia-3-cephem-4-caboxyiate g (213 mg) ih a mixture of tetrahydrofuran (4 ml) and acetone (2 ml) are added three lots of hemidiphenylmethyl a-phenylmalonate ‘ (13I itig. X 3) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroq.uinoline (107 nig X 3) at room temperature in 1.5 hours interval. After -· 2 hours, the reaction mixture is diluted with ethyl acetate, washed with water, diluted hydrochloric acid. Water, aqueous sodium hydrogenoarbonate, and water, dried on sodium sulfate, and eoneen- trated. The residue is purified by chromatography on silica gel (30 g) containing 10 $ water, eluted with a mixture of benzene and ethyl acetate (4 : l), and the eluate is triturated With a mixture bf ether and n-penfane to give diphenylmethyl 7p-(a-phenyl-a•;diphenylmothoxyearbonylaeetamide5-3-(2-methyl-l,3,4-thiadiazol3»yl)thiomethyl-l-oxadethia-3-cephom-4-carboxylate (l?0 mg) as colorless foam. Yields 47-5 IR: 3350, 1799, 1715, l690sh cm1.

.W: 0CI)C13 2.67s3H, 4.22 + 4.53ABq(l4Hz)2H, 4.57s2H, 4.75slH, .00d(4Hz)lH, 5.73dd(4;9.5Hz)lH, 6.92slH, 6.97slH. Example 11-14 To a solution of a-diphenylmethoxycarbonyl-e-phenyiaeetie acid (1Ο3.9 mg) in methylene chloride (2 ml) cooled at 0°C are added triethylamine (θ.θ42 ml) and oxalyl chloride (0.0256 ml). After stirring for 10 minutes at 0°0, the. mixture is poured into a solution of diphenylmethyl 7p-amino-7a-methoxy-3-(l-methyltetrazol-5-yl)th±omethyl-l-oxadethia-3-cephem-4-carboxyiate (101.7 mg) and pyridine (0.0594 ml) in methylene chloride (5 ml) - at 0°C, stirred for 1 hour at 0°G, diluted with ethyl acetate, *4 L. washed with dilute hydrochloric acid, water, aqueous sodium hydrogencarbonate, and watoi·, dried on sodium sulfate, and concentrated under reduced pressure. The obtained residue is chromatographed on silica gel (20 g) containing 10 fi water, and eluted with a mixture of benzene and ethyl acetate (4 : l) to give diphenylmethyl 7P-(K-dip]ionylniothoxycarbonyl-a-phenyiaeetamido)7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3cephem-4-carboxylate (121.2 mg) as colorless foam. Yield: 72-4 fi.

IR: v®?3 3320, 1792, 1725, 1700 cm-1.

NMR: 6CDC13 (3-40s + 3.42s)3H, 3.6953«, 4.22s2H, 4.45s2H, 4-75slH, 5-OOslH, 6.92s2H. 7-85slH.

Example 11-15 A mixture of a-(indan-5-yl)oxycarbonyl~a-phenylacetic acid (l48 mg) and thionyl* chloride (0.25 ml) is heated at 70°C for 1 hour, and evaporated under reduced pressure. The residue is dissolved in benzene (2 ml) and evaporated again to dryness.

The residue is dissolved in methylene chloride (2 ml), and poured into a solution of diphenylmethyl 7f3-amino-7a_meth.oxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (101.7 mg) and pyridine (0.0l6 ml) in methylene chloride (4 ml) at 0°C.

After stirring for 30 minutes at 0°C, the mixture is diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate, water, diluted hydrochloric acid, and water, dried on sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (20 g) containing 10 fi water to give diphenylmethyl 7β-[α_(indan-5-yl)oxycarbonyl-α-phenylacetamido]-7α- me thoxy-3-(l‘methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (II6.I mg) as colorless foam. Yield: 73-8 fi.

IR: v^X3 3390, 3320, 1780, 1727, 1700 cm1.

NMR: 6CDC13 2.05quintct(7Kz)2H, 2.87t(7Hz)4H, 3-48s3H, 3·77β3Η> - 33 4470 4 . 4.23S2H, 4.53S2H, 4.87sin, 5-02slII.

Example II-16 To a solution of a-diphenylmethoxycarbonyl-a-p-acetoxyphenylacetic acid (l42 mg) in methylene chloride (2 ml) cooled at 0°C are added triethylamine (O.O4l6 ml) and oxalyl chloride (0.0256 ml). After stirring for 15 minutes at 0°C, the mixture • is mixed gradually with a solution of diphenylmethyl 7β-amino7a-methoxy-3-(l-methyitetrazol-5-yl)thiomethyl-l-oxadethia-3cephem-4-carboxylate (101.7 mg) and pyridine (0.024 ml) ih methylene chloride (4 ml) at 0QC, stirred for 15 minutes, diluted with ethyl acetate, washed with aqueous sodium hydrogettcarbonate, water, diluted hydrochloric acid, and wafer, dried on sodium sulfate, and concentrated under reduced pressure. The obtained residue is chromatographed on silica gel (2Q g) containing 10 % water to give diphenylmethyl 7P-(d-diphenylmethoxycarbonyl-a-p-acetoxyphenylacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)-thiomethyl-1oxadethia-3-cephem-4-carboxylate (133.4 mg) as colorless foam from fractions eluted with a mixture of benzene and ethyl acetate (2 ί l). Yield: 74.5 ¢.

XR: vjojb 3325, 1792, 1730, 1700sh cm1.

NMR: 6CDC13 2.40s3H, 3.40s3H, 3.67S3H, 4.17s2H,'4.42s2H, 4.73S1H, • 4.98sih. ; Example, 11-17 To a solution of tx-diphenylmethoxycarbonyl-a-p-hydroxyphenylaoetic acid (254 mg) in methylene chloride (3 ml) are added triethylamine (o.083 ml) and oxalyl chloride (0.051 ml) at 0°G.

After stirring for 15 minutes, the mixture is added to a solution of diphenylmethyl 7P“amino-7a-metho:cy-3-(l-niethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-eephem-4-carboxyiate (l01,7 mg) and pyridine (O.o48 ml) in methylene chloride (4 ml) at Q°C. After -34-. 44794 I stirring for 30 minutes at 0°C', the mixture is diluted with ethyl acetate, washed with aqueous sodium hydrogcncarbonate, water, hydrochloric acid, and water, dried on sodium sulfate, and evaporated under reduced pressure. The obtained residue is chromatographed • 5 on silica gel (20 g) containing 10 $ water and eluted with a mixture of benzene and ethyl acetate (2 : l) to give diphenylmethyl 7β-(αdiphenylmethoxycarbonyl-a-p-hydroxyphenylacetamido)-7a-methoxy_3(l-tnethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cepheni-4-carboxylate (86.4 mg) as colorless foam. Yield: 49*6 ¢.

IR: vmaxl3 35S5> 3315, 179°’ 1722’ 1700sh cm-1· NMR: 5CDCl3 (3.45s + 3.48s)3H, (3.72s + 3.75s)3H, 4.38s2H, 4.45s2H, (4.67s + 4.70s)lH, 5.02slH.

Example 11-18 To a suspension of a-(5-indanyl)oxycarbonyl-a-p~ hydroxyphenylaeetio acid (370 mg) in methylene chloride (4 ml) are added triethylamine (139 μΐ) and oxalyl chloride (85 μΐ) at 0°C in nitrogen to give clear solution. After stirring for 20 miljutes at 0°C, the mixture is added to a solution of diphenylmethyl 7P-amino-7a-methoxy-3-(l-methyltetrazol-5-yl)-thiomethyl-120 oxadethia-3-cephem-4-carboxylate (203 mg) in methylene chloride (5 ml) and pyridine (80 μΐ), and the mixture is stirred for 10 minutes. The reaction mixture is diluted with .ethyl acetate, washed with 2N-hydrochloric acid, water, 5 $ sodium hydrogenearbonate aqueous solution, and water, dried over sodium sulfate, and concen25 trated under reduced pressure to give pale yellow foam, which is Chromatographed on silica gel (50 g) containing 10 $ water, and eluted with a mixture of benzene and acetic acid (l ; l) to give diphenylmethyl 7P-L“_P“hYtiroxyphonyl-a-(5-indanyl)-oxycarbenylacetamido]-7a-methoxy-3-(l-methyitetrazol-5-yl)-thiomethyl-130 oxadethia-3-cephem-4-carboxylate as crystalline residue (230 mg); -35'< ' 4479 4’ . . .

Yield: 71 · which is recrystallized from a mixture of chloroform and ether to give pure crystals melting at 114 - 116°C.

DV: 272 (ε = 9500), .· . ·',.· .·· vyju, ), 284. (ε = 9200) nm.

NMR: 6Cr)3C°CD3 2.1m2H, 2:87t(7Hz)4H, 3.43s3H, 3-91s3H, - ' ' 4.31S2H, 4.65s2H, 5.07slH, 5-13S1H, 6.92brs3H.

IR: 3590, 3335, 1789, 1736, 1722, 1700, l601 cm-1. flla j£ Example 11-19 To a solution of a-t-butoxycarbonyl-a-(3-thienyl)acetic 'acid (97 mg) in methylene chloride (l ml) are added triethylamine (0.042 ml) and oxalyl· chloride (0.026 ml) at 0°C in nitrogen atmosphere. After stirring for 30 minutes at 0°C, the mixture is poured-into a solution of diphenylmethyl 7p-amino-7®-methoxy-3“ (l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-eephem-4-cayboxylate (lOl mg) and pyridine (Q.024 ml) in methylene chloride (3 ml) at 0°C in nitrogen atmosphere. After stirring at 0°C for 90 minutes, the mixture is diluted with methylene chloride, Washed With 5 % sodium hydrogencarbonate in water, water, 2N-hydroehlor±c acid, and water, dried on sodium sulfate, concentrated under reduced ί pressure, chromatographed on silica gel (5 g) containing 10 % water, and eluted, with a mixture of benzene and ethyl acetate (2 : l) to give diphenylmethyl 7p-[*-t-butoxyearbonyl-a-(3-thienyl)acetamido]7o-methosy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadsthia-3-cephem- . 4-carboxylate (l44 mg) as colorless foam. Yield: quantitative.

IR: 1795, 1720, ca. 1700 cm1. nmR: 8CDC13 6.e>6slH, ('5.07a + 5.05s)lH, 4.6obrs3H, 4.30brs2R, 3.83S3H, (3.53s + 3>50s)3H, 1.41s9H.

Example 11-20 To a solution of 3-thienylrtlalonic acid indanyl ester (120 mg) in methylene chloride (1,5 ml) are added triethylamine (4z gl) and oxalyl chloride (26 [il) under ice cooling. After - ' · - _.,36_ I ι ι. stirring for 15 minutes, the mixture is added to a solution of diphenylmethyl 7P-amino-7a-mothoxy-3-(l-„iethyltotrnzol-5--yl)thiomethyl-l-oxadethia-3-ceplieni-4-carboxylate (ll6 mg) in methylene chloride (3 ml) and pyridine (24 μΐ) , and the mixture is stirred at 0°C for 1 hour. Tlio reaction mixture is poured into ethyl acetate, washed with 2N-hydrochloric acid, water, 5 % sodium hydrogencarbonate aqueous solution, and water, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel (lO g) containing 10 % water, and eluted with a mixture of benzene and .10 ethyl acetate (lO : l) to give diphenylmethyl 7β-[«-(3-thienyl)a-(indan-5-yl)oxyoarbonylacetamido]-7a-methoxy-3-(1-mcthyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (l40 mg).

Yield: 78 $· IR: v^3 3400, 3327. 1789, 1736. 1712 cm-1.

NMR: SCDC13 2.07m2H, 2.87br-t(7Hz)4H, 3-50s3H, 3-77s3H, 4.24s2H, 4.56s2H, 4.973IH, (5.02s+5.o4s)lH, 6.8Sbrs3H. [ot]^2··5 - 68.2 ± 1.1° (c = 1.023, CHCl^).

Example 11-21 To a solution of 3-thienylmalonic acid monobenzhydryl ester (710 mg) in methylene chloride (5 ml) are added triethylamine (210 μΐ) and oxalyl chloride (l30 μΐ) under ice cooling. After stirring for 15 minutes at the same temperature, the mixture is added to a solution of diphenylmethyl 7β-αηιίηο-7ζ-ιηβΐ1ιθχχ·-3·-(ΐmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (510 mg) in methylene chloride (15 ml) and pyridine (120 μΐ) Under ice cooling. After stirring for 30 minutes, the mixture is poured into ethyl acetate, washed with 2N-hydrochloric acid, Water, 5 $ sodium hydrogencarbonate and water, dried on magnesium sulfate, and concentrated. The residue is chromatographed on silica gel (lOO g) containing 10 fi Water, and eluted with a mixture of benzene - 37 _ k. 44*79<' and ethyl acetate (10:1- 4:l)· to give diphenylmethyl 7β-[α-(3thienyl) -α-diph enyl methoxye arbonyl ace tamido ] - 7«-nie thoxy-3- (1methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephcm-4-carboxyiate as colorless foam (834 mg). . .

- IR; v2HC13 1790, 1728, 1710sh cm1, o niax - - .

NMR; 6CDC13 3.30s3H, 3.60s3«, 4.09s2H/4,37s2H, 4.79slH, • 4.90slH, 6.d7s2H.

Example 11-22 (phenyl ester) To a suspension of 3-thienylmalonic acid monophenyl ester (105 mg) in methylene chloride (1.5 ml) are added triethylamine (42 μΐ) and oxalyl chloride (26 jil) under ice cooling. .

After stirring for 15 minutes, the mixture is added to a solution of diphenylmethyl 7p-amino-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-.l-oxadethia-3-cephem-4-carboxylate (116 mg) in methylene chloride (.3 ml) and pyridine (24 μΐ) at 0°C, and the mixture is stirred at 0°C for 1 hour. The reaction mixture is poured into ethyl acetate, washed with 2N-hydrochloric acid, water, 5 fi> sodium hydrogencarbonate aqueous solution, and { . water, dried over magnesium sulfate, and concentrated. The residue • 20 ' is chromatographed on silica gel'(lO g) containing 10 fi> water, and eluted with a mixture of benzene and ethyl acetate (8 : l) to give diphenylmethyl 7p-(u-(3-thienyi)-a-phenoxycarbonylacetamido]-7umethoxy-3-(l“methyitetrazol-5-‘yi)ih.iomethyl-l-oxhdethia-3“cephem4-carboxyiate as colorless foam (125 mg). Yield; 76 fi· IR: 34o6, 3341, 1789, 1740, 1711 cm1. . max NMR: 5CDCl3 3.49s3H; 3,783311, 4.24s2H„ 4.55s2H, 4.97slH, .O3SIH, 6.88slH, . [a]®2’5 -74.8 + 1.1° (c = 1,005 CHC13), Example 11-23 ‘ ¢0 a solution of 3-thienylaeetic acid mono-3,4-dimethyl-38 phenyl ester (l20 mg) in methylene chloride(l.5 ml) are added triethylamine (42 μΐ) and oxalyl chloride (26 μΐ) under ice cooling. After stirring for 15 minutes, the mixture is added to a solution of diphenylmethyl 7P-amino-7“-methoxy-3-(l-methyltetrazol-5-yi)5 thiomethyl-l-oxadethia-3-cephem-4-carboxylate (ll6 mg) in methylene chloride (3 ml) and pyridine (24 μΐ), and the mixture is stirred at 0°C for 1 hour. Ihe reaction mixture is poured into ethyl acetate, washed with 2N-hydrochloric acid, water, 5 % sodium hydrogencarbonate aqueous solution, and water, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel (lO g) containing 10 $ water, and eluted with a mixture of benzene and ethyl acetate (lO : l) to give diphenylmethyl 7P. [a-(3-thienyl)-a-(3,4-dimethylphenyl)oxycarbonylacetamido]-7amethO3;y-3-(l-methyltetrazol-5“yl)thiomethyl-l-oxadethia-3-cephem15 4-carboxylate (128 mg). Yield: 72 ¢.

' HR: 3405, 3340, 1790, 1737, 1712 cm1.

NMR: 6CDC13 2.22s6h, 3.50s3H, 3-76s3H, 4.24s2H, 4.56s2H, 4.95S1H, (5.00s + 5-02s)lH, 6.8 [α]22·5 _g8tl + iao (c _ 1.002, CHC13).

Example 11-24 To a solution of amino-7a-methoxy-3-(lmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-car.boxyiate (lOl mg) and pyridine in methylene chloride (3 ml) at 0°C. The mixture is stirred for 30 minutes, diluted with ethyl acetate, washed with 5 # sodium hydrogencarbonate aqueous solution, water, 2N-hydrochloric acid, and water, dried on sodium sulfate, and - 39 DD ·. . 447.9-4 ·· ·?''···' '-···.· · ·-· ' · · · · - L concentrated under reduced pressure- The obtained residue is chromatographed on silica gol (lO g) containing 10 $ water, and eluted with a mixture of benzene and ethyl acetate (4 s l) to give diphenylme thyl 70-[a-diphenylmethoxycarbonyl-α-(2-thionyl)ace tamido]5 7ffi-methoxy-3-(1-methyltetrazol-5-yl)—tliiomethyl-l-oxadethia-3-cephem-4carboxylate (l4o mg) as colorless foam. Yield: 85 ¢.

IR: ν^Χ3 .1785, 1720, ca, 1700 cm1.

NMR: 6CDC13 6.93S2H, 5.00s2H, 4.50brs2H, 4.15brs2H, 3.8OS3H, 3.40brs3H.

. Example 11-25 .

To a solution of a-(p-benzyloxyphenyl)malonic acid mono. benzyl ester (376 mg) in methylene chloride (4 ml) are added triethylamine (105 gl) and oxalyl chloride (65 gl) under ice cooling.

After stirring for 15 minutes under ice-cooling, mixture is added to a solution of diphenylmethyl 7p-smino-7a-methoxy-3-(l' methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxyiate (254 mg) and pyridine (60 pi) in. methylene chloride (7 ml) under ice cooling. After stirring for 30 minutes at the same temperature, ί the mixture is poured into ethyl acetate, washed with 2N-hydrochlorie 20 acid, water, 5. % sodium hydrogencarbonate aqueous,solution, and water, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica geL(20 g) containing 10 $ water, and eluted: with a mixture of benzene and ethyl acetate (id : l) to give diphenylmethyl 7P-[a-(p-benzyloxyphenyl)-a-benzyloxycarbonylacetamido]25 7ffi-methoxy-3-(l-methyitetrazoi-5-yl)thiortethyl-l-oxadethia-3-cephem4-carboxylate as colorless foam (390 mg)'.

NMR: 6CDC13 3.38S3H, 3-62s3H, 4.13s2H, 4.45s2R, 4.56s1H, 4.96s3H, 5^O9s2H, 6,82d(9Rz)2II, 6.84alH.

V—C/S 3411, 3326, 1789, 1722, 1700sh cm-1.

Mp3 -72.0 ± 2° (c = 0.553, CHC13). - 40 4 4 Example 11-26 To a solution of a-diphenylmethoxycarbonyl-p-(p-methoxybenzyl) oxyphenylacotie acid (l93 nig) in methylene chloride (2 ml) are added triethylamine (0.04l6 ml) and oxalyl chloride (0.0256 ml) .at 0°C, and tho mixture is stirred for 30 minutes. The resulting solution is added to a solution of diphenylmethyl 7β-ηπιίηο-7“methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem4-carboxylate (101-7 mg) and pyridine (0.024 ml) in methylene chloride (4 ml) at 0°C. After stirring for 30 minutes at 0°C, the mixture is diluted with ethyl acetate, washed with water, dried on sodium sulfate, and concentrated. The residue is chromatographed on silica gel (20 g) containing 10 $ water, and eluted with a mixture of benzene and othyl acetate (4 : l) to give diphenylmethyl 7β-[αp-(p-mo thoxyb enzyl)oxyphenyi-α-diplienylme thoxyc arbonylacetamido]7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia_3-cephem15 4-earboxylate (190-7 mg) as colorless foam. Yields 98 $· IR: 3420, 3325, 1792, 1730, 1700 sh cm-1.

NMR: 6CDC13 (3.38s + 3.40s)3H, 3-70s3H, 3-77s3H, 4.20s2H, 4.47s2H, 4.68slH, 4.95S2H, 5-OOslH.

Example 11-27 In a procedure similar to that of Example ΙΪ-26, diphenylmethyl zp-amino-7“-methoxy-3-(l_methyltetrazol-5-yl)thiomethyl-l-oxadethia~3-cephem-4_carboxylate (800 mg) is treated with a-p-(p-methoxybenzyl)oxyphenyl-a-p-methoxybenzyloxycarbonylacetyl chloride prepared from the corresponding free acid (1370 mg) 2§ and oxalyl chloride in the presence of pyridine (190 mg) and triethylamine (0.33 ml) in methylene chloride (42 ml) to give diphenylmethyl 73-[α-p-(p-methoxybenzyl)oxyphenyl-a-p-methoxyben2yloxycarbonylacetamido]-7<*-methoxy-3~(l-mothyltetrazol-5-yl)thiomethyl-l-oxadethia-3-csphem-4-carboxylate (l.45 g)» - 41 . L.

Yields nearly quantitative.

IR: vC^Cl3 1792, 1725, 1700sh cm-1. max J , · NMR: 6CDC13 3.45s3H/2, 3·4'8ξ3Η/2, 3-78s6H, 3-82s3H, 4.27brs2H, 4.57brs3H, 4.98s2H, 5.03slH. 5.13s2II.

Example 11-28 To a stirred suspension of p-(p-methoxybtnzyloxy)phenylmalonic acid (125 mg) in. methylene chloride (3 ml) are added triethylamine (55 μΐ) and oxalyl chloride (26 μΐ) at -15°C, and the suspension is stirred, for 40 minutes at 0°C. The mixture is added to a solution of diphenylmethyl 7p-amino-7a10 methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem4-carboxylate (lOO mg) in methylene chloride (3. ml) and pyridine (63 μΐ), and the mixture is stirred for 30 minutes at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2N-hydrochlorio acid and water, dried over sodium sulfate, and concentrated to give crude product (212 mg), which is chromatographed on silica gel (20 g) and eluted with a mixture of ethyl acetate and acetic acid (99:1^° give diphenylmethyl 7β-[α-Ρ~(ρmethoxybenzyloxy)phenyl -α-o arb oxyac etamido]-7 IR: vCRC13 3385. 3300-2400br, 1790, 1762, 1714, l6l2 cm-1. Πΐ3Χ NMR: 5CDC13 3.Zf3s3H/2, 3-46s3H/2, 3>74s3H, 3-78s6H, 4.22brs2H, 4.56brs3H, 4.96s2H, 5,O5slH.

The product obtained above (40 mg) gives 7p-(°c-p-bydroxy25 phenyl-a-carboxyacetamido)-7<*-methoxy-3- (l-mefhyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid by the action Of trifluoroacetic acid (0.2 ml) and anisole (0.4 ml) at 0°C for 20 minutes. - 42 « · · ί - - .. .·...... · · . **704 . L.

! III. Deprotection Example ΠΙ-1 To a solution of diphenylmethyl 7p-(a-phenyl-a-diphcnylmethoxycarbonylacetamido)-3-(l-mothyltetrazol-5-yl)thiomethyl-1— ' 5 oxadethia-3-cephem-4-carboxylate (120 mg) in methylene chloride (3 ml) are added anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) in nitrogen atmosphere, at 0°C, and the mixture is stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue· is purified by chromatography on silica eel (10 g) containing 10 <$> water, and eluted with a mixture of ethyl acetate and acetic acid ( IR: vNujo1 1778, 1670, 1606 cm-1, max IR: vKBr 3420, 2520br, 1775, 1674, 1606, 1528.5, 1376 cm-1, max OT: λ1 NaIiC03 265.5 nm (6=9442). max NMR: 61 NaHC°3 in D2° 4.02s3H, 4.05 + 4.32ABq(l3.5Hz)2H, 4.55brs2H, 5.l6d(4Hz)lH/2, 5.21d(4Hz)lH/2, .48d(4Hz)lH, 7.37s5H, 5.‘O8brslH (the last peak gradually diminished). [«3p3 “ 90:3 ± ^-2° (e = 0.310, 1 NaHttbj).

CD: i(0) (0.155 % NaHC03) 305(0), 285(- 2500), 276-5(0), 258(+ II700), 249.5(0), 232(- 59100), 25 210(- 3500).

Example III-2 To a solution, of diphenylmethyl 7p-[cc-(5-indanyl)oxycarbonyl-a-phenylacetpmido]-3-(l-methyltetrazol-5-yl)thiomethyll-oxadethia-3-cophcm-4-carboxylate (l44 mg) in methylene chloride (3 ml) are added anisole (0.2 ml) and trifluoroacetic acid , -(.0,4 ml) under ice cooling,’ and the mixture is stirred for 2 hours, c The reaction mixture is c}ilut;ed with ethyl acetate, washed with water and aqueous sodium hydrogencarbohato, dried, and evaporated. To the residue is triturated with ether, and the resulting powder is collected by filtration to give sodium 7p-ia-(5-ihdanyl)oxy5 - . oarboiiyl-a-phenylacetamido]-3-(l-methyltetrazol-5-yl)thiomethyl— T-oxadethia-3-cephem-4-carboiylate (60 mg).

IR; vNudoi 1760, l690sh, 167Ό cai1- max ..Example XII-3 To a solution of diphenylmethyl 7p-(a-carboxy-a~phenyiacetamido)-3-(l-methyltetraaol-5-yl)thiomethyl-l-oxadethia-3cephem-4-carboxylate (576 mg) in methylene chloride (lO ml) are addod anisole (l ml) and trifluoroacetic acid (l ml) in nitrogen atmosphere under ice cooling, and tlio mixture is stirred for 70 minutes. The reaction mixture is concentrated Under reduced pressure to give 7p-(oc-phenyl-ci-carboxyacetainido)-3-(l-tnethyitetrazol-5-yl)thiomethyl-ri-oxadethia“3“Cephem-4-carboxylic acid. . t Yield; nearly quantitative. Crude product.

Hl; vN^01 1778, 1670, l604 cm-1.

HiaX Example III-4 To a solution of 7p-(a-diphenylmethoxycarbonyl-aphenyiacetamid0)-3-(l-methyitetrazol-5-yl)thiomethyl-l-oxadethia3-cephem-4-carboxylic acid (72 mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) at 0°C. After 50 minutes under ice-cooling, the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (5 g) containing 10 fi water, and eluted with a mixture of acetic acid and ethyl acetate (l·i 9) to give 7p-(a-carboxy-a-phenylacetamido)-330 (l-methyltetrazOl-5-yl)thiomethyl-l-oxadethia-3-cophem- 44 h - PHl'IiMV J 1 11« hi i ι i ('ll llif;) . llip« ΗΛ l/UnG (ιΙιμμιιιιικιηΙ I inn) , Yliildi 75 $, IR: v^oi 1778, 1670, 1605 cm’'1.

Example III-5 A solution'of diphenylmethyl 7p-(a-p-nitrohenzyioxycarbonyl-a-phenylacetamido )-3-(l-methyltetrazol-5-yl) thiomethyll-oxadethia-3-cephem-4-carboxylate (715 mg) in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) is shaken in the presence of pre-reduced 5 % palladium on carbon (700 mg) and 1° 10 56 hydrochloric acid (2 ml) under hydrogen at 1 atm. and at room temperature for 70 minutes. The reaction mixture is filtered to remove the catalyst, diluted -with water (l20 ml) containing 10 hydrochloric acid (2 ml), concentrated to remove the organic solvent, and extracted with ethyl acetate. ' 15 The extract is washed with water, dried on magnesium sulfate, and evaporated under reduced pressure to'give diphenylmethyl 70-(a-carboxy-a-phenylacetamido)-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem~4-carboxylate (576 mg). Yield: 97.6 $ • (crude).

. Example ill-6 A mixture of diphenylmethyl 7p-(a-p-hydroxypkenyl-at-butoxycarbonylacetamido)-3-(1- -methyltetrazol-5-yl)thiomethyll-OXadethia-3-cephdm-4--carboxylate (74 mg), thiophenol (0.075 ml), and trifluoroacetic acid (0.75 ml) is stirred for 1,5 hours under ice-cooling. The reaction mixture is evaporated under reduced pressure. The residue is purified by chromatography on silica gel containing 10 56 water, and eluted with a mixture of acetic acid and ethyl acetate (l : 9). The eluate is triturated with a mixture of ether and pentane to give 7p-(a-p-hydroxyphenyl-«30 carboxyacetamido)-3-(1-mothyltetrazol-5-yl)thiomethyl-l-oXadefchia- 45 kz 3-cephem-4-carboxylic acid (30 mg). Yield: 58.9 ¢. mp. 130 - 142° (decomposition).

IR: 34θΟ, 1787, 1720 cm-1. ' ‘ max OT: λθ^3°Η 273 nm (6=7850).

Example III-7 To a solution of diphenylmethyl 70-(a-p-hydroxyphenyl-a-diphenylmethoxycarbonylacetamido)-3-(l-methyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (l37 mg) in methylene chloride (3 ml) are added anisole (0.3 ml) and trifluoroacetic acid (o.3,ml) at 0°C under nitrogen. After stirring for 1'hour at 0°C, the mixture is concentrated under reduced pressure, triturated with ether, and washed with ether to give 70-(α-ρ-hydroxyphenyl-cc-carboxyacetamido)-3-(1-methyltetrpzol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid I5 as colorless powder (8l mg) decomposing at 130 - l42°C.

Yield: 59.6 ¢.,,.

IR: 3400, 1787, 1720 cm-1.

OT: λ^3θΗ 273 nm (e=7850).

Example III-8 ‘ To a solution of diphenylmethyl 70-[a-('2-thienyl)-a-tbutoxycarbonylaoetamido']-3-(l-methyltetrazol-5-yl)thiomethyl-loxadethia-3-cephem-4-carboxylate (49 mg) in methylene chloride (l ml) are added anisole (0.4 ml) and trifluoroacetic acid (l ml) at 0°C, and the mixture is stirred under ice-cooling for 4 hours and at room temperature for 40 minutes. The reaction mixture is concentrated under reduced pressure. Th’e residue is purified by chromatography on silica gel (5 g) containing 10 $ water, and eluted with a mixture of ethyl acetate and acetic acid (9:l).

The eluate is triturated in ether to give 7β-[α-(2-thienyl)-a30 earboxyacotamido]-3-(l-methyltetrazol-5-yl)thiomothyl-l-oxadethia- 46 44794 3-cephem-4-carboxylic acid (23 mg) as amorphous powder. mp. 156 - l60°C (decomposition with foaming). Yield: 33.5 fi· IR: vKBr 3390, 1765, 1670, 1608, 1520 cm1, max [a·]23 - 62.0 ± 3.7° (0=0.279, 1 fi RaRCOf.

CDs λ(θ) (0.279, 1 fi NaHCO3) 3Οθ(θ), 282(- 2600), 276(0), 259(+ 11100), 249(0), 231.5(- 47400), 210(- 9700).

Example II1-9 A mixture of diphenylmethyl 7β-[a-(3-thienyl)-a-t10 butoxycarbonylacetamido]-3-(1-methyltetrazol-5-yl)thiomethyl-1oxadethia-3-cephem-4-carboxylate (56 mg), anisole (0,35 ml), and trifluoroacetic acid (0.35 ml) is stirred at 0°C for 2 hours.

The reaction mixture is evaporated under reduced pressure.

The residue is purified by chromatography on silica gel (5 g) containing 10 fi water, eluted with a mixture of ethyl acetate and acetic acid (9:l) and triturated in a mixture of n-pentane and ether (2:l) to give 7P-'[a-(3-thienyl)-a-carboxyacetamido]-3-(lmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid (37 mg) as colorless powder, mp. 155 - l60°C.

Yield: 96.8 fi.

IR; vNujol 3Zt0Q 17?0 l692 l6l0 cjn-l. max Example III-10 To a solution of diphenylmethyl 73-(a-diphenyimethoxycarbonyl-a-phenyiacetamido )-3-(1-t-butoxycarbonylmcthyltetrazol25 5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (60 mg) in anisole (0.5 ml) is added trifluoroacetic acid (l ml) under icecooling in nitrogen, and the mixture is kept at 0°C overnight.

The reaction mixture is concentrated under reduced pressure, and the residue is triturated with ethyl acetate to give crude 7β~(α-carboxy-a-phenylacetamido )-3-(l-carboxymethyltetrazol-5-yi)- 47 τ ·4ί^ thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid (22 rag) as powder. Yield: 64 • ®: νΞ*. 1775, 1725 cm1. . max Example III-ll · . : ‘5 ·/ To a solution of diphenylmethyl 7p-[10 overnight under ice-cooling. The reaction mixture is concentrated under reduced pressure. The residue is triturated with a mixture of ether and ethyl aoefate to give crude 7P“[a-(2-thienyl)-acarboxyacetamidoj-S-^l-carboxymethyltetrazol-S-ylJthiomethyl-lOxadethia-3-cephem-4-carfooxylio acid (30 mg), mp. decomposition from l60°C, Yield: 48 ¢. .

IR: ^80, 1725' cm1. · Example 'III-‘12 . .

To a solution of diphenylmethyl 7p-(a-phenyl-a-diphenylmethoxycarbonylaeetamldo)-3-(2-methyl-l,3,4-thiadiazol-5-yl)thio20 methyl-l-oxadethila-3'Lcephem-4-carboxylate (170 mg) in methylene chloride (3 ml) are. added anisole (0.2 ml) and trifluoroacetic acid (0.4 ml) at O'°C, ahd the mixture is stirred at 0°C for 1.5 hotirs. The reaction' mixture is concentrated under reduced pressure. The residue is purified on silica gel (lO g) containing 10 $ water, eluted with a mixture of ethyl acetate and acetic acid (9sl), and triturated with a mixture of ethyl acetate and ether to give 7p-(a-phenyl-a-carboxyacetamido)-3-(2-methyl-l,3,4thiadiazol-5-yl)thiomethyl-l-oXadethia-3-cephem-4-carboxylic acid ' (45.8 mg) as colorless powder. Yield; 45.1 mp. 130 - 132°C.

IR: vKRf 3410, 1772, l600 cm1, m ax * · - ί · . . . . L 4794 Example III-13 To a solution of diphenylmethyl 7p-(a-diphenylmethoxycarbonyl-α-phenylacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (121.2 mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and trifluoroacetic acid (θ.4 ml) at 0°C. After stirring at 0°C for 1 hour, the reaction mixture is concentrated under reduced pressure and triturated with ether to give 7p-(a-carboxy-cc-phenylacetamido)7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3cephem-4-carboxylic acid (46.5 mg) as colorless powder.

Yield: 59.8 . mp. 110 - ll6°C.

UV: λ^°Η 275.5 nm (e=9400). [a]^5 - 19.4 ± 2.8° (c=0.211, CH^OH) .

IR! v™* 1780, 1717, 1631 cm-1. Π13Χ NMR: 6D2° + NaHC°3 (3.46s + 3.53s)3H, (3.99s + 4.02s)3H, 4.0 - 4.2m2H, 4.48S2H, 4.53slH, 5.13slH, 7.38s5H.

Example III-14 To a solution of diphenylmethyl 7P-(a-diphenylmethoxyoarbonyl-a-p-acetoxyphenylacet amfido)-7a-methoxy-3-( 1-methyltetr azol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carbQxylate (133.4 mg) in methylehe chlorine (2 ml) are added anisole (0.2 ml) “ I and trifluoroacetic,acid (0.4 ml) at 0°C. The mixture is stirred for 45 minutes, evaporated, and triturated with a mixture of ether and pentane, and ether to give 73-(a-carboxy-a-p-acetoxyphenylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyll-oxadethia-3-cephem-4-carboxylic acid (77 mg) as colorless foam, mp. 110 - 115°C. Yield: 91.9 ¢.

UV: λ^30Η 275 nm (ε=93Οθ). [a]p5 - 27.5 ± 2.6° (0=0.258, CH OH). - 49 .. · XR:vR^ 1782, 1728, 1635 cm-1.

NMR: .δ°2° + NaHC03 9.33s3H, (3.47s + 3.53s)3H, (3.99s + 4.02s)3H, ’ I ca. 4.13brs2H, 4.46brs2H, 5.13slH, 7.12 + 7.47ABq(8Hz)4H.

' Exantple 1111-115 To a solution of diphenylmethyl 7p-(a-diphenylmethoxycarbonyl-a-p-hydroxyphenylacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-axadethia-3-cephem-4-oarboxylate (84:6 mg) in methylene chloride (2 ml) are added anisole (0.1 ml) and trifluoroacetic acid (0.3 ml) at 0°C. After stirring for 45 minutes at 0°C, the mixture is evaporated under reduced pressure and triturated with a mixture of ether and n-pehtane, and ether to yield 7P-(a-carboxy-oc-p-hydroxyphenylacetamido)-7affiethoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-315 ceph.em-4-carboxylic acid (46.4 mg) as colorless powder.

Yield: 89.9 ¢. mp. 117 - 122°C (decomposition).

OT: -\nax°H 276 nm (6=10200). [α]β5 - 15.3 ± 2.6° (0=0.216, CH^OH). 3»i 1780, 1719, 1632 cm-1.

!JMR: 6D2° + NaEC03 ' (3.45s + 3.53s)3H, (4.00s + 4.02s)3H, (4.08s + 4.13m)2H, (4,45s + 4.48s)2-3H, 5.‘l2slH, 6.87 + 7.28ABq(8Hz)4H.

Example III-16 To a solution of diphenylmethyl 7β-[α-p-hydroxyphenyl» 1 a-(5-indanyl)oxycarbonylacetamido)-7α-methoxy-3-(l-methyltetrazol5-yl)thiomethyi-l-oxadethia-3-cephem-4_carboxylate (l50 mg) in methylene chloride (l2‘ml) are added anisole (0.4 ml) and trifluoroacetic acid (0.4 ml) at 0°G in nitrogen. After stirring for 20 minutes at 0°C,.the reaction mixture is concentrated under reduced pressure, diluted with, benzene, and concentrated.

The residue is triturated with ether to give ?,>-[n-p-hydroxyphenyl -a- (5-indanyl)oxycarbonyIacet ami do]~?a - mo t hex y-3-(1mothylt etr azol-5-yl) t hi omethyl-1 -ox ad et hi a-3-ci'phi'm- 'l-earboxyl i c acid as powder (hl mg) melting at 123 - 12(»*'C with doeumpuaition.

Yield: 76.5 ¢.

IR: 3385, 1785, 1727, 1705, 1631, 1613, 1595 cm-1, max UV! (ε=12950), 276.5 (ε=12700) nm. ΖΠαΧ [α]22 + lt3 ± o.8°, [a]g6 _ 25.1 ± 1.2°, [a]g6 - 5.2 ± 1.2° (e=O.54l, CILjOH).

Example III-17 To a solution of diphenylmethyl 7p-[a-(p-henzyloxyphenyl)-a-benzyloxycarbonylacet amido]-7a-methoxy-3-(1-methyltetrazol-5-yl)thioinethyl-l-oxadethia-3-cephem-4-carboxylate (lOO mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and a solution of aluminum chloride (250 mg) in nitromethane (l,2 ml) under ice cooling. After stirring for 2 hours under ice cooling and for 1 hour at room temperature, the mixture is poured into a mixture of ethyl acetate and methanol (5:l), washed with 2N-hydrochloric acid and saturated saline, dried over sodium · sulfate, and concentrated.. The residue is washed, with ether to give 7p-(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3(1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4carboxylic acid (35 mg).

IR! 178°, 1-719, 1632 cm-1, max Example III-18 To a solution of diphenylmethyl 7β-[α-t-butoxyearbonyla-(3-thienyl)acetamido]-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (l44 mg) in anisole (0.3 ml) is added trifluoroacetic acid (l.7 ml) at 0°C in nitrogen gas. After stirring for 3 hours, the mixture is concentrated - 51 to dryness under reduced pressure, triturated with ether, and washed with ethyl acetate and ether to give 7p-[a-carboxy-a(3-thienyl)acetamido]-7a-metJioxy-3-(1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid (6l mg) as light yellow powder. Yield: 6l fi. mp. 118 - 125°θ (decomposition) from acetone. [a]*5 - 12.8 ± 2.5° (c=0.211, CB^OH), UV: λ°Η3θΗ 276 nm (ε=10200). max .

XR: 1780, 1705 cm-1.

NMR: 6D2° + yaHC03 4.03s3H, (4.lls +4.21m)2H, (4.51s + 4.53s)2-3H, 5.15slH, 7.05-7.25mlH, 7.27-7.52m2H.

Example XU-19 To a solution of diphenylmethyl 7p-[a-(3-thienyl)-adiphenylmethoxycarbopylaeet amido]-7a-methoxy-3-(1-methylt etrazol15 5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (830 mg) in methylane chloride (15 ml) are added anisole (2 ml) and trifluoroacetic acid (2 ml) under ice cooling. After stirring for 1'hour at the same temperature, the mixture is concentrated under reduced pressure. The residue is washed with ether to give 7p-{oc-(3-thienyl)-a-carboxyaeetamido]-7a-methoxy-3-(lmethyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid as powder (383 rag) melting at 110-13.4°C, identified with an authentic specimen by comparison of IR’ spectra in KBr disc and thin layer chromatograms.

Example 111-20 To a solution of diphenylmethyl-7P-[a-(3-thienyl)a-phenoxycarbonylacetamido]-7g-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-S-cepfiem^-carboxylate (100 mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) under ice cooling. After stirring for 1 hour, - 52 the mixture is concentrated, and triturated in ether to give 70- [a - ( 3-1 hl enyl)-a -phenoxyenvbo ny l ace 1 am ide]· 7a - met he \ y-1- flee thyl tetrazo 1-5-yl) thiomethyl- l-oxadelhi a- '-cephem· 4-carboxyl γ e acid as powder ('$ mg) melting at IOS-ΠΙ'V Yield; '0 IR: vC,lC13 3400sh,. 3325, 1788, 1745, 1705 em l. max [a]23 - 61.3 ± 2.0° (c=0.517, CHC13).

Example III-21 To a solution of 70-[a-(3-thienyl)-a-(3,4-dimethylphenyl)oxycarbonylacetamido]-7a-methoxy-3-(l-metbyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (l05 mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) under ice cooling. After stirring for 1 hour, the mixture is concentrated under reduced pressure, triturated with ether, and filtered The solid is washed with ether and dried to give 7p-[a-(3-thienyl)-a-(3,4-dimethylphenyl)oxycarbonylacetamido]-7a- methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3~cephem-4-carboxylic acid as powder (64 mg) melting at 110-113°C. Yield: 77 ¢.

IR: 34OOsh, 3325, 1787, 1737, 1704 cm-1, max [a]23 - 53.4 + l.9°,(c=O.5O4, CHC1 ).

Example III-22 To a solution of diphenylmethyl 7p-[a-(3-thienyl)-a(indan-5-yl)oxycarbonylaeetamido]-7<χ-methoxy-3-(l-methyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (97 mg) in methylene chloride (2 ml) are added anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) under ice cooling. After stirring for 1 hour, the mixture is concentrated under reduced pressure and the residue is triturated with ether to give 7β-[α-(3thienyl)-a-(5-indanyl)okycarbonylacetamidoJ-7a-methoxy-3(1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4- 53 carboxylic acfd as powder (34 mg) melting at 111-113°C, Yield: 45 #, TR: v™3 34o6sh, 3335,-1789, 1744, 1704 cm1,· max [23 - 57.5 ± 2.4° (c=0.402, CHC13).

Example III-23 To a solution of diphenylmethyl 7p-[a-diphenylmcthoxy' carbony 1-ά-('2-thienyl) acetamido]-7a-methoxy-3-(l-i“Cthyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-earboxylate (l40 mg) in methylene chloride are added anisole (0.2 ml) and trifluoroacetic acid (0.4 ml) at 0¾ in nitrogen gas. After stirring for 1 hour at 0°C, the mixture is evaporated tinder reduced pressure, triturated with ether, and washed with ether to give 7P-[a-oarboxy-a(2-thienyl)acetamido]-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3tcephem-4-oarboxylic acid (60 mg) as colorless powder. Yield: 70 fi. mp. 104 - 109°C (decomposition).

UV: λ2Η5011 275 nm (e=8800). max . [a]^ - 15.0 ± 1.5° (0=0,374, CH^H).

IRs-v??/ 1785,1715 cm-1. max NMR: SD2° + NaHc03 7.00 - 7.5m3H, 5.15slH, 4.04s3H, 20 ,(3.54s + 3.48s)3H.

Example XIX-24 To a solution of diphonylmethyl 7P-[a-(5-indanyl)oxyearbonyl-ΛL 7a-methoxy-3-( 1-methyl t e tr azol-5-yl) thiometXiyl-l-oxadethi a-3cepliem-4-carboxylic acid (74.5 mg) as colorless crystals.

Yield: 81.4 mp. 123 - 125°C (decomposition).

El: « 1770, 1702 cm1, max [a]p5 θ·2* * 1·4° (c=0.286, CH^OH) .

NMR: 6CDC13 2.07s2H, 2.85s4h, (3.32s + 3.43s)3H, 3.79s3H, 4.25s2H, 4.50s2H, 4.69s1H, 4.97slH.

Example III-25 To a solution of diphenylmethyl 7p-(a-p-carbamoyloxyphenyl-a-diphenylmethoxycarbonylacetamido)-7a-methoxy-3-(lmethyltetrazol-5-yl)thiomethyl-l-oxad ethi a-3-cephem-4-carboxylat e (17O.I mg) in methylene, chloride (2 ml) are added anisole (0.4 ml) and trifluoroacetic acid (0,4 ml) at 0°C, and the mixture is stirred for 45 minutes, evaporated to dryness under reduced pressure, and triturated with ether to yield 7P-(a-p-earbamoyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid (98.2 mg) as colorless powder, mp. 128 - 132°C.

IR: vKB5 1784, 1724(sh), 1710 cm1, max UV: λ°Β3°Η 273 nm (e=95OO). ' . [α]ρ5 23.1 ± 0.7° (c=0.900, CH3OH).

Example 111-26 In a procedure similar to that of Example III-25, diphenylmethyl 7p-(a-p-N-methylcarbomoyloxyphenyl-a-diphenylmethoxycarbonylacet amido )-7oc-methoxy-3-( l-methyltetrazol-5-yl )thiomethyl-l-oxadethia-3-cephem-4-carboxylate (lOO mg) is treated with anisole (O.l ml) and trifluoroacetic acid (0.1 ml) in methylene chloride (l ml) at 0°C for 1 hour to give 7p-(a-p-N-mcthylcarbomoylOxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-Carboxylic acid (52 mg) 49 % - 55 5 yield, mp. U> - Ϊ25°0.

IR: vi(B5 3385, 1786', 1725 cni1. , max OT: λί5°Η 271 «Μ, (ε=9532).

Example ΪΙΙ-27 In a procedure similar to that of Example 111-25 , diphenylmethyl 7β-(α-ρ-ureidocarbonyloxyphenyl-a-diphenylmethoxycarbonyl.acetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)tbiomethyll-Oxadethia-3-ceph‘em-4>-carboxylate (213 mg) is treated with anisole (0.4 ml) and1trifluoroacetic acid (0.4 ml) in methylene 10 chloride (3 ml) for 1 hour at 0°C to give 7p-(a-p-ureidocarbonyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyl tetr azol-5-yl)thiomethyi-l-oxadethia-3-cephem-4-carboXylic acid (125 mg) 91 $ yield, mp. 137- l42°C. .

IR: . 3440, 3330, 1780, 1712 cm-1.

NMR: 6^3^250 ( 3.25s + 3.4ls)jH, (3.90s + 3.93s)3H, 4.21brs2H, • 4.98brs2H, 4.85brslH, 5.05slH, 7.20 - 7.15m2H, 7.13d(8Hz)2H, 7A2d(8Hz)2H, (9.l5brs + 9.27brs)lH, .25brslH. .

UV: λ®*30Η 276 nm (ε=91Ο5). max Example 111-28 t , To a solution Cf diphenylmethyl 7P-[a-p-(p-methoxybenzyl)oxyphenyl-a-diphenylmethoxycarbonylacetamido]-7a-methoxy3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4Carboxylate (170 mg) in methylene chloride (3.5 m3) are added anisole (0.35 ml) and trifluoroacetic acid (0.35 ml) at 0°C, and the mixture is stirred for 45 minutes at 0°C, After evaporation of the solvent, the product is triturated with . ether to give 7p-(a-p-hydroxyphenyl- - 56 • ««».·/ Yield: nearly quantitative. mp. 125 - 132°C (decomposition).

Example XII-29 In a procedure similar to that of Example 111-28, diphenylmethyl 7p-[a-p-(p-methoxybenzyl)oxyphenyl-a-p-methoxybenzyloxycarbonylacetamido]-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (1.45 g) is treated with anisole (4 ml) and trifluoroacetic acid (4 ir.2 ) in methylene chloride (8 ml) at 0°C for 4o minutes to give 7P-(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-meth.yltetrazol-5-yl)thiomethyl-l-oxadethia-3 -cephein-4-carboxylic acid. rap. 125 - 132°C (decomposition). Yield: quantitative.

. Example III-30 1) To a solution of diphenylmethyl7p-[«-p-(p-methoxybenzyl)oxy-phenyl-oc-p-methoxybenzyloxyearbonyl-acetamido ]-7a-tnethoXy-3» {1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (1.20 g) in methylene chloride (24 ml) are added anisole (2.4 ml) and a solution of aluminum chloride (2.58 g) in nitromethane (12 ml) at 0eC under nitrogen. After stirring for 15 minutes at 0°G, the mixture is poured into cold 5 fi sodium hydrogencarbonate aqueous solution (100 ml) and filtered to remove the formpd precipitate.

The filtrate is washed twice with methylene chloride (2 x 100 ml), acidified with 2N-hydrochleric acid to pH 2.60, and poured in a column of high porous polymer HP-20 (60 ml) sold by Mitsubishi Chemical Industries Ltd. The column is washed with water (300 ml), and eluted with methanol. The eluate is concentrated under reduced pressure at room temperature. The residue is dissolved in methailol, treated with active carbon, and concentrated under reduced pressure to give 7p-(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3(l-methyl-tetrazol-5-yl)thiemethyl-l-oxadethia-3-cephem-4-earboxyiic acid as powder (595 mg) decomposing at 125 - 132°C. Yield: 88.5 fi. 2) The same product can be prepared in a method similar - 57 44794 to that of above l), wherein ' a) p-methoxy-benzyl ether is substituted by benzyl ether h) p-methoxybenzyloxycarbonyl group is substituted by benzyloxycarbonyl group, and/or · c) diphenylmethyl ester is substituted by benzyl ester.

IV. 0-Acylation Emample IV-1 ·' To a solution of diphenylmethyl 7P-(a-p-hydroxyphenyloc-diphenylmethoxycarbonylacet amido)-7a-methoxy-3-(1-methylt etrazol•10 5~yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (286 mg) in methylene chloride (2 ml) is added trichloroacetyl isocyanide (0.5 ml) while cooling at -78°C, After stirring at -78°C for 30 minutes and at 0°C for 1 hour,, the mixture is diluted with benzene (20 ml) and ethyl acetate (20 ml), washed, with water, 15 dried, and concentrated. The obtained residue is chromatographed on silica gel (30 g) containing 10 $ water and eluted with a mixture of benzene and ethyl acetate (l:l) to give diphenylmethyl 7P“(a-p-carbomoyioxyphenyi-a-diphenylmethoxycarbonylacetamido)7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-320 .cephem-4-carboxylate (179.9 mg) ascolorless foam.. Yield: 59.5 ¢. IRs 3530, 3425, 3325, 1790, 1750, 1728, l700sh cm1.

NMR: 6CDC13 (3.42s + 3.45s)3B, 3.73s3H, 4.22s2H, 4.42s2H, 4.80slH, .03slH, 5.33/®·· Example IV-2 In a procedure similar to that described above in Example IV-1, diphenylmethyl 7p-( 30presence of l,5-diazabicycloi3,5,03undecene at 0°C for 4.5 hours - 58 to give diphenylmethyl 7p-(a-p-N-iuethylcarbomoyloxyphonyl-adiphcnylmct hoxy carbonyl acet amido )-7 Yield; 49 ¢.

B IR: vCHC13 3460, 1785, 1725, 1700 cm1.

NMR: 2.87d(5Hz)3H, 3.45brs3H, 3.80s3H, 4.23brs2H, 4.47brS2H, 4.77brslH, 5.00slH, 4.95 - 5.40mlH, 6.97s2H.

Example IV-3 In a procedure similar to that described above in jq Example IV-1, diphenylmethyl 7P-(a-p-carbomoyloxyphenyl-adiphenylmethoxycarboxylacetamido)~715 trlchloroacetylureidocarbonyloxyphenyl derivative, which is hydrolyzed with wet silica gel (10 g) for 1 hour in methylene Chloride at room temperature to give diphenylmethyl 7β-(α-ρUreidocarbonyloxyphenyl-a-diphenylmethoxyearbonylacetamido)-7awethoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem20 4-earboxylate (l45 mg). Colorless foam. Yield: 79 ¢.

IR: vG^13 3500, 1790,'1758, 1725, 1700eh cm1.

NMR: 6CDC13 3.43s3H, 3.68s3H, 4.21brs2H, 4.43brs2H, 4.83brslH, .03slH, 5:80 - 6.70m2H, 6.95s2H, 8.23brslH, 9.20brslH, 6.95S2H. , V. Protection Example V-l To a suspension of 7p-(a-uarboxy-a-phenylacetaraido)-3(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid (400 mg) in methylene chloride (20 ml) is added diphenyldiazo20methane (700 mg), and the mixture is stirred at room temperature - 59 «47 9 4 for 30 minutes. The residue obtained by concentration under reduced pressure is chromatographed on silica gel (40 g) containing 10 water, and eluted with a mixture of benzene and ethyl acetate (l:l) to give diphenylmethyl 7p-(a-diphenyl5 methoxycarbonyl-a-phenylaeet amido)-3-(l-methylt etr azo1-5-yl)thiomethyl-l-oxadethia-3-cephom-4-carb0xylate (322 mg), mp, IO7 - 109°C. Yield: 47-4 ¢. (in another experiment, 95 % yield of the product was obtained).--Example V-2 To a suspension of 7p-(a-carboxy-a-phenylacetamido)-3(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4Carboxylic acid (50 mg) in a mixture of acetone (30 ml) and methanol (5 ml) is added a; solution of sodium acetate (17.6 mg) in methanol (2 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated under reduced pressure, and the residue is washed with acetone to give disodium 7β- ( IR: 3425, 1746, l660br, l6l0br, l4l0 cm1.

Example V-3 The products of above Examples having free carboxy are dissolved in aqueous sodium hydrogencarbonate to give the corresponding sodium salts, of which the antibacterial activity is examined. These compounds are more active than the correspond25 iiig compounds having sulfur atom instead of oxygen atom at position 1 of the ring system. Those having 7a-methoxy are stronger antibiotics against gram negative bacteria resistant to common cephalosporins and also strongly active against Pseudomonas aeruginosa strains.

Example V-4 > - 60 44 7Q4 To a solution of 7p--[a-(3-thienyl)-;x-carboxyacetamido]7a-methoxy-3-(l-methyltetrazoi-5-yl)thiomethyi-l-oxadethia-3cephom-4-carboxylic acid (2.04 g) in methanol (20 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mole/liter; 10 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate (lOO ml), stirred for 5 minutes, and filtered to collect separated solid, which are washed with ethyl acetate, and dried to give disodium salt of 7p-[a-(3-thienyl)-a-carboxyacetamido]-7a-methoxy-310 (l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cepheM-4carboxylic acid (l.9O g) . Yield: 86,7 fi. Colorless powder mp. decomposition from 150°C.

XR: 1768, 1680, 1012 cm1.

UV: λθ^°Η 271 nm (ε=942ρ).

Example V-5 To a solution of 7β-(a-p-hydroxyphenyl-a-carboxyacetamido)7oc-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia3-cephem-4-oarboxylic acid (359 mg) in methanol (7 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mole/liter; 2Q 1.73 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate, and dried to give disodium salt of 7p—(ot— p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyl25 tetrazol-5-yl)thiometliyl-l-oxadethia-3-cephem-4-carboxylie acid (342 mg). Yield: 88.8 fi. Colorless powder, mp. decomposition from 170°C. 1768, 1675, 1608 cm-1. 273 nm (s=11100).

Example V-6 - 61 '4'4·7-9 4 To a solution of 7p-[a-p-hydroxyphenyl-a-carboxyacetamido 3-7a-methoxy-3~(l-methyltetrazol-5-yl) thiomethyl-1oxudethia-3-copfieni-4-carboxylic acid (836 mg) in a mixture of methylene chloride (15 ml), ethyl acetate (l5 ml) and g methanol (lO ml) is added diphenyldiazomethane (950 mg).

After stirring for 3θ minutes at room temperature, the mixture is concentrated under reduced pressure, and washed, with n-hexane. The product is chromatographed on silica gel (9θ g) containing 10 XOacetate (l:l) to give diphenylmethyl 7p-(a-p-hydroxyphenyla-diphenyimethoxycarbonylacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylate (I.27O g). Yield: 95 <$,.

IH: 3585 , 3315, 1790, 1722, 1700sh cm-1. - 62 * 4 *9 4 VI. COMPOSITIONS AND THEIR USE Example VI-1 Disodium salt of 7p-(a-p-hydroxyplienyl-a-carboxyacet- . amido)-7a-methoxy-3-(l-methyltetrazol-5-yl) thiomethyl-l-oxadethia5 3-cephem-4-carboxylic acid (lOO mg) in a 5 ml vial is dissolved in sterilized water for injection (l ml) before use, and given to an adult patient suffering from pyelitis by way of intravenus injection.

Example VI-2 ‘t Lyophilizate from a solution of 7p-[a-(3-thienyl)-acarboxyacetamido ]-7tx-methoxy-3-(l-methylt etrazol-5-yl) thiomethyll-oxadethia-3-cephem-4-oarboxylic acid (l g) neutralized to pH 7.0 with sodium hydrogen carbonate is placed in a 150 ml vial. The lyophilizate is dissolved in sterilized water for injection (lOO ml) and dripped intravenously to an adult patient immediately after or during a surgical operation of cancer for preventing and treating post operative bacterial infection.

Example VI-3 Mycroorystalline. 7p-[ Bxampi e VI-4 Crystalline 7p-[ - 63 upper respiratory tract infection caused by Streptococcus pyogenes.

Example VI-5 Powdered- 7β-(α-ρ-hydroxyphenyl-a-(5-indanyl)oxycarbonylacet amido ]-7c®phem-4-rCarboxylic acid (100 mg) is mixed well with corn starch (150 mg) and talc (10 mg), powdered, and encapsulated in a hard gelatin capsule (250 mg volume). Each one capsule j.s administered orally at 3 hour intervals to an adult patient suffering from urinary tract infection caused by Escherichia coli.

Example VI-6 Mixed powder’of 7P-[ The granule is mixed with water before use to obtain a suspension, and one tea spoonful amount of the suspension is given orally to an infant suffering from pneumonia caused by Klebsiella pneumoniae.

Claims (94)

1. CLAIMS:1. A compound of the formula: (I) wherein Ar is or Acyl-O- 1 2 COB and COB are each independently carboxy or protected carboxy; N--N ·' *· X 8 JLJ ° r 3 ch 2 cob 3 COB 3 being carboxy or protected carboxy; and Y is hydrogen or methoxy; provided that when Y is methoxy, Het is AJ Jo

2. A compound as- claimed in claim 1, wherein Acyl is alkanoyl containing from 1 to 5 carbon atoms, carbamoyl, N-alkylcarbamoyl containing from 2 to 6 carbon atoms or ureidocarbonyl.

3. A compound as claimed in claim 1, wherein Acyl is 1-5C alkanoyl, 8-12C aralkanoyl, 7-9C aroyl, 2-5C alkoxycarbonyl,8-20G aralkoxycarbonyl, carbamoyl, 2-6C N-alkylcarbamoyl or ureidocarbonyl.

4. A compound as claimed in claim 1, wherein Acyl is formyl, acetyl, 5. Propionyl, butyryl, isobutyryl, enanthoyl, phenylacetyl, phenylpropionyl, benzoyl, toluoyl, carbethoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isObutylcarbamoyl, Ν,Ν-dimethylcarbamoyl, carbamoylcarbamoyl or l^-methylureidooarbonyl.

5. A compound as claimed in any one Of claims 1 to 4, wherein COB 1 2-3 10 COB , and COS , if present, are each independently carboxy or protected carboxy in the form of a pharmaceutically acceptable salt, 1 T

6. A compound as claimed in any one of claims 1 to 4, wherein COB 1 is 5-indanyloxycarbonyl, phenoxycarbonyl, tolyloxycarbonyl or dimethylphenQxycarbonyl, Λ ι 15

7. A compound as claimed in any one of claims 1 to 4 or 6, wherein COB is benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-methylbenzyloxycarbonyl,.p-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxyearbonyl or 2,2,2-trichloroethoxyoarbonyl. 1 2

8. A compound, as claimed in any one of claims 1 to 4, wherein COB , COB 3 20 and COB , if present, are each independently any protected carboxy group referred to hereinbefore. 65 4 4794

9. 7g-(op-acetoxyphenyl-a -carboxyacetamido)-3-(1-methyltetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

10. $ -(a-p-carbamoyloxyphenyl-a-carboxyacetamido)-3-(2-methyl-l,3,4thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-Cahboxylic acid. 5

11. Tg-(crP-carbamoyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

12. 7p-(crp-N-methylcarbamoyloxyphenyl-a-carboxyacetamido)-7a-methoxy3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid

13. 7&-(a-p-ureidocarbonyloxyphenyl-crtarboxyacetamido)-7a-methoxy10 3-(l-methyltetrazol-5-yl)-thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

14. 7g-[«-phenyl-a-(5-indanyloxy)carbonylacetainido]-3-(l-methyl tetrazol5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

15. 7g-^t -phenyl-a-(5-indanyloxy)carbonylacetamidq}-7a-methoxy-315 (l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

16. 76-js-(3-thienyl)-a-(5-indanyloxy)carbonylacetamido|-7tt-tnethoxy3-(l-methyltetraze>l-5-yl)thiomethyl-l-oxadethia-3-cephem-4-car'boxylic acid. - 67 ,4l 94

17. 78-Ja-(3_thienyl)-a-phenoxycarbonylacetamidq[-7ffi-methoxy-3-(l- . methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

18.. 7(3-ja-(3-thienyl)-a-(3,4-dimethylphenoxy)carbonylacetamidoj7ct-methoxy-3-(l'-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem5 Φ-carboxylic’acid.

19. 7 (5- fct -p-hydroxyphenyl-α -(5-indanyloxy )carbonylacetamido )-72 -methoxy 3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid. • 1-

20. A compound as claimed in claim 1 substantially as hereinbefore 10 . described in·any one of the Examples.

21. A salt of a compound as claimed in any one of claims 1 to 20.

22. A salt as claimed in claim 21 which is a ph^armaGeutically acceptable salt.

23. A compound of the formula: wherein Ar is phenyl, p-hydroxyphenyl, 2-thienyl, or 3-thienyl; Het is l-methyltetrazol-5-yl, l-carboxymethyltetrazol-5-yl, or 2-methy1-1,3,4-thiadiazol-5-yl, and derivatives thereof at the carboxy. 68 447a J

24. A compound as claimed in claim 23, wherein derivatives thereof at the carboxy are alkali metal salts.

25. A compound as claimed in claim 23, wherein derivatives thereof at the carboxy are diphenylmethyl, p-nitrobenzyl, indanyl, alkanoyloxy5 methyl,or benzyl esters.

26. 7g-fct -(2-thienyl )-a-carboxyacetamidqj -3-(l-xnethyltetrazol-5-yl )thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

27. 7g-ja -(2-thienyl)-a-oarboxyacetamido] -3-(l-carboxymethyltetrazol5-yl) thiomethyl-l-oxadethia-3-cephein-4~carboxylic acid. 10

28. 7(3—|ce -(2-thienyl)-a-carboxyacetamidoj -3-(2-methyl-l,3,4-thiadiazol 5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

29. 7β- Ja-t3-thienyl)-tj-carboxyacetamidoJ-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid. - 69

30. 7P-5d‘-(3-thienyl)-a-carboxyacetamidoJ-3-(l-carboxymethyltetrazol5-yl)thiofnethyl-l-oxadethia-3-cephem-4-car'boxylic acid.

31. 73-[a-(3-thienyl)-o(-carboxyacetamidoj-3-(2-iiiethyl-l,3,4-thiadiazol5-yl)thiomethyl-l-oxadsthia-3-cephem-4-carboxylic acid. 5

32. 70--(a-phenyl-a-carboxyaceta/nido)-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylie acid. s

33. 7 0-(a-phenyl-a-carboxyacetamido)-3-(l“Carboxymethyltetrazol-5-yl) thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

34. 70-( α-phenyl-a-carboxyacstamido)-3-(2-methy 1-1,3,4-thiadiazol10 5-yl)thiomethyl~l-oxadethia-3-cephem-4-carboxylic acid.

35. 73-(a-p-hydroxyphenyl-a-carboxyacetamido)-3-(Hnethyltetrazol-5-yl )thiomethyl-l-bxadethia-3-cephem-4-carboxylic acid.

36. 70-(a-p-hydroxyphenyl-a-carboxyacetajnido)-3-(l-carboxymethyltetrazol 5-yl)thiomethyl-l-oxadethia-3-csphem-4-carboxylic acid. 15 37. 70-(a-p-hydroxypJienyl-a-carboxyacetamido)-3-(2-fnetbyl-l,3,4thiadiazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid. - 70 38. A compound as claimed in claim 23 substantially as hereinbefore described in any one of the Examples. (XIII) wherein Ar is phenyl, p-hydroxyphenyl, p-acyloxyphenyl, 2-thienyl, or 3-thienyl, and derivatives thereof at the carboxy.

37. 40. A compound as claimed in claim 39, wherein the derivatives at the carboxy are alkali metal salts.

38. 41. A compound as claimed in claim 39, wherein the derivatives at 10 the carboxy are diphenylmethyl, p-methoxy-benzyl, p-nitrobenzyl, indanyl, alkanoyloxymethyl, t-butyl, or benzyl ester.

39. 42. 70-(a-p‘hydroxypheny) -a carboxyacetanrido/’-7a-methoxy-3 -(1 -methyl tetrazol-5-j/l )thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

40. 43. 73-[cc-(3-thienyl)-«-carboxyacetamid0}-'P -methoxy-3-( 1-methy 115 tetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid. - 71

41. 44. 7g (a-phenyl-a-carboxyacetamido)-7x-methoxy-3-(l-methyltetrazol-5yl)thiomethyl-i-oxadethia-3-cephem-4-carboxylic acid.

42. 45. . 7g-( ce-p-hydroxyphenyl-a-cart)oxyacetamido)-7H-methoxy-3-( 1-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid. 5

43. 46. ' 7g-( crp-acetoxyphenyl-Cc-carboxyacetamido)-7K-methoxy-3-(I-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylic acid.

44. 47. A compound as claimed in claim 39 substantially as, hereinbefore described in any one of the Examples.

45. 48. process A process for preparing a compound as claimed comprises reacting an amine of the formula: in claim 1, which wherein malonic acid of the formula: (II) with an arylLb 1 ArCHCOOH ,1 (III) wherein Ar and COB 1 are each as defined in Claim lor reactive derivatives 15 ..-thereof. - 72

46. 49. A process m claimed in claim 48 wherein the amino group at position 7 of the anrin.’ (IT) is protected or activated.

47. 50. A process as claimed in claim 48 or claim 49, wherein the arylmalonio acid (III) is used in the form of the free acid. 5

48. 51. A process as claimed in claim 50 wherein the reaction is effected in a solvent and in the presence of a condensing reagent.

49. 52. A process as claimed in claim 51 wherein the condensing reagent 1 is a N,N -dialkylcarbodimide, a carbonyl compound, or aoylamine or an isoxazolinium salt. 10 53. A process as claimed in any one of claims 50 to 52, wherein the reaction is effected at a temperature of from - 10°C to 70°C. . 54. A process as claimed in claim 48 or claim 49, wherein the arylmalonio aoid (III) is used in the form of an anhydride, a reactive ester, a diaoylamino ester, a reactive amide or a formimino derivative. 15 55. A process as claimed in any one of claims 48 to 54, wherein the reaction is effected in the presence of an aoid receptor or a molecular sieve. - 73 44 7 9 456. A process for-preparing a compound as claimed in claim 1, which process comprises heating in an- inert solvent an azetidinone of the formula: ArCHCONHx i 1 COB OCH 2 &H 2 SHet (IV) C=PR_ COB 1 2 5 wherein Ar, COB , COB , Het and Y are each as defined m claim 1 and each of the three groups R is the same or different and is optionally substituted alkyl or aryl.

50. 57. A process for preparing a compound as claimed in claim 1 wherein 12 3 --: COB , COB , and/or COB is carboxy, which process comprises deprotecting 12 3 a compound, as claimed in claim 1 wherein COB , COB , ahd/or COB is 10 ‘ protected carboxy.

51. 58. A process as claimed in claim 57 wherein the deprotection is effected by a method substantially as hereinbefore described.

52. 59. A process for preparing a compound as claimed in claim 1, wherein 1 2 3 COB , COB , and/or COB is a carboxylic acid salt group, which process 12 15 comprises treating a Compound as claimed in claim 1 wherein COB , GOB , and/or COB is carboxy with a base. .- 74 -:

53. 60. A process for preparing a compound as claimed in claim 1 and having the formula: which process comprises removing the protectimg group(s) in the moiety 5 Ar' of a compound of the formula: 1 2 whereinAr' is p-protected hydroxyphenyl, and COB , COB Het and Y are each as defined in claim 1 but are not necessarily the same in the product as in the starting material. 10

54. 61. A process as claimed in claim 60, wherein removal of the protecting group(s) is achieved, in the case of cleavage of acylates or ethers, by treatment with an acid or a base in the presence of a cation scavenger, or, in the case of removal of p-nitrobenzyloxycarbonyl or benzyloxycarbonyl groups, by hydrogenation in the presence of platinum or palladium. 15

55. 62. A process for preparing a compound as claimed in claim 1 and having the formula: 75 which process comprises acylating a compound of the formula: with an acylating reagent for introducing a group Acyl.

56. 63. A process for preparing a compound as claimed in claim 1 g substantially as hereinbefore described in any one of the Examples.

57. 64. A process as claimed in any one of claims 57 to 62 wherein the starting compound as claimed in claim 1 has been prepared by a process as claimed in any one of claims 48 to 56.

58. 65. A process as claimed in any one of claim 57 to 62 wherein the 10 ·' starting compound as claimed in claim 1 has been prepared by a process as claimed in any one of claims 57 to 62.

59. 66. A compound as claimed in claim 1 which has been prepared by a process as claimed in any one of claims 48 to 65.

60. 67. - A salt of a compound as claimed in claim 66. 15

61. 68. A salt as claimedin.claim 67 which is a pharmaceutically acceptable salt. - 76 44794

62. 69. A process for preparing a compound as claimed in claim 23, which process comprises reacting an amine of the formula: wherein Het is as defined in claim 23, or a derivative thereof at the 5 carboxy with a malonic aoid derivative of the formula: ArCHGOOH wherein Ar -is ad defined in claim 23, or with a reactive derivative thereof in which one of the carboxy groups may be protected.

63. 70. A process as claimed in claim 69, wherein the reaction is effected 10 under conditions as specified in any one of claims 51 to 53 and 55.

64. 71. A process as claimed in claim 69 or claim 70, wherein the malonic aoid derivative (XI) is used in the form of an anhydride, a reactive ester, a diacylimino ester, a reactive amide or a formimino derivative.

65. 72. A process for preparing a compound as claimed in claim 23, which process comprises heating in an inert solvent an azetidinone of the formula: Η H 0 ; : '1 ArCHOONH^. . 'y' OCH CCH 2 SHet COOH C=PR„ COOH (XII) - 77 ή &7 94 wherein Ar and Het are each as defined in claim 23, and each of the three groups R is the same or different and is optionally substituted alkyl or aryl, or a derivative thereof at the carboxy. .

66. 73. A process for preparing a compound as claimed in claim 23 5 which contains one or more free acid groups, which process comprises deprotecting a compound as claimed in claim 23, wherein one or more of the carboxy groups is protected.

67. 74. A process as claimed in claim 73, wherein the deprotection is , I effected by a method substantially as hereinbefore described. 10

68. 75. , A process for preparing a compound as claimed in claim 23 iri which one or more of the carboxy groups is a carboxylic acid salt group, which process comprises treating a compound as claimed in claim 23 which contains one or more free acid groups with a base.

69. 76. A process for preparing a compound as claimed in claim 23 substan15 tially as hereinbefore described in any one of the Examples.

70. 77. A compound as claimed in claim 23 which has been prepared by a process as claimed in any one of claims 69 to 76.

71. 78. A orocess for preparing a compound as claimed in claim 39, which process comprises reacting an amine of the formula: (XIV) or a derivative thereof at the carboxy with a malonic acid derivative of the formula: ArCHCOQH (Loh (V) wherein Ar is as defined in claim 39, or with a reactive derivative thereof in which one of the carboxy groups may be protected.

72. 79. A process as claimed in claim 78, wherein the reaction is effected under conditions as specified in any one of claims 51 to 53 and 55.

73. 80. A process as claimed in claim 78 or claim 79, wherein the malonic acid derivative (XV) is used in the form of an anhydride, a reactive ester, a diacylimino, a reactive amide or a formimino derivative.

74. 81. A process for preparing a compound as claimed in claim 39, which process comprises heating in an inert solvent as azetidinone of the Ν N formula: CH 0 3. ArCHCONhK COOH γί (XVI) 0' A, CH„ C=PFL COOH - 79 wherein Ar is as defined in claim 39, and each of the three groups R is the same or different and is optionally substituted alkyl or aryl, or a derivative thereof at the carboxy.

75. 82. A process for preparing a compound as claimed in claim 39 which contains one or more free acid groups, which process comprises deprotecting a compound as claimed in claim 39 wherein one or more of the carboxy groups is protected.

76. 83. A process as claimed in claim 82, wherein the deprotection is effected by a method substantially as hereinbefore described.

77. 84. A process for preparing a compound as claimed in claim 39 in which one or more of the carboxy groups is a carboxylic acid salt group, which process comprises treating a compound as claimed in claim 39 which contains one or more free acid groups with a base.

78. 85. A. process for preparing a compound as claimed in claim 39 substantially as hereinbefore described in any one of the Examples.

79. 86. A compound as claimed in claim 39 which has been prepared by a process as claimed in claims 78 to 85. - 80 ·$'

80. 87. A pharmaceutical or veterinary formulation which comprises a compound as claimed in any one of claims 1 to 20 and 66 or a salt as claimed in any one of claims 21, 22, 67 and 68.

81. 88. A pharmaceutical or veterinary composition which comprises a 5 compound as claimed in any one of claims 1 to 20 and 66 or a salt as claimed in any one of claims 21, 22, 67 and 68 together with a pharmaceutical acceptable or veterinarily acceptable respectively, diluent, carrier or excipient.

82. 89. A pharmaceutical or veterinary formulation which comprises a 10 compound as claimed in any one of claims 23 to 38 and 77.

83. 90. A pharmaceutical or veterinary composition which comprises a compound as claimed in any one of claims 23 to 38 and 77 together with a pharmaceutically acceptable or veterinarily acceptable, respectively diluent, carrier or excipient. 15

84. 91. A pharmaceutical or veterinary formulation which comprises a compound as claimed in any one of olaims 39 to 47 and 86.

85. 92. A pharmaceutical or veterinary composition which comprises a compound as claimed in any one of claims 39 to 47 and 86 together with a pharmaceutically acceptable - 81 ; · Ϊ' '1, or veterinarily acceptable, respectively, diluent, carrier or excipient.

86. 93. A pharmaceutical or veterinary composition as claimed in any one of claims 88, 90 and 92 in the form of an injectable composition or a vial.

87. 94. A pharmaceutical or veterinary composition as claimed in any one of claims 88, 90 and 92 in the form of sterilized micrQcrystals or lyophilizate.

88. 95. A formulation as claimed in any one of claims 87, 89 and 91 or a composition as claimed in any one of claims 88, 90 and 92 to 94 in unit dosage form.

89. 96. A method for inhibiting the growth of bacteria in an environment which method comprises administering to the environment an effective amount of a compound as claimed in any one of claims 1 to 20, 23 to 47, 66, 77 and 86 or a salt as claimed in any one of claims 21, 22, 67 and 68, or of a formulation as claimed in any one of claims 87, 89, 91 and 95, or of a composition as claimed in any one of claims 88, 90 and 92 to 94.

90. 97. A method as claimed in claim 96 when used in the prevention or cure of disease in a hon-humah animal.

91. 98. A method as claimed in claim 96 when used in the prevention of decay in a perishable substance or material. - 82 4 »1 f i>4

92. 99. A method as claimed in claim 96 when used in disinfecting a substance, material article or building structure.

93. 100. A method as claimed in claim 97 when effected by the use of intravenous injection or a drip.

94. 101. A method as claimed in claim 97 or claim 100 wherein from 0.05 to 50 mg of compound (I) or salt thereof, whether in a formulation or composition or in the free form, is administered per kilogram body weight per day.