IE43538B1

IE43538B1 - 3-heterocyclicthio-cephalosporins

Info

Publication number: IE43538B1
Application number: IE191275A
Authority: IE
Original assignee: Squibb & Sons Inc
Priority date: 1974-09-20
Filing date: 1975-09-01
Publication date: 1981-03-25
Also published as: CA1074298A; FR2285135A1; FR2285135B1; AU8451975A; GB1522164A; HU171053B; IE43538L; NL7511147A; DE2540804A1; JPS5156494A

Abstract

Compounds of the formula wherein R1 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl substituted phenyl and phenyl-lower alkyl and certain heterocyclic groups; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, phenyllower alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)stannyl, tri(lower alkyl)silyl, a salt forming ion, or the group wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl and phenyllower alky; and R4 represents certain heterocyclic groups are disclosed. These compounds are useful as antibacterial agents.

Description

This invention relates to cephalosporins.

Cephalosporins having in the 7-position certain α-ureido and alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl and heterocyclic groups are disclosed in U.S. Patent Specifications Nos. 3,673,183 and 3,833,568. Cephalosporins substituted in the 3-position with -CH»-S-heterocyclic groups and in the 7-position with 0 z 0 NH-C-CH-phenyl groups and NH- NH2 nh2 as possessing antibacterial activity in U.S. Patent Specifications Nos. 3,641,021; 3,759,904; 3,813,388; 3,821,207; and 3,796,801 (method of treating Enterobacter infections). Also disclosed as useful intermediates in U.S. Patent Specification No. 3,819,621 are cephalosporins substituted in the 3-position with -CH--S-heterocyclic groups 2 and in the 7-position with a -C-(CH2)-j-CH-COOH group.

NH I c=o nh2 This invention provides cephalosporins of the formula 0 R-L is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cyclo- alkadienyl, phenyl, phenyl-lower alkyl, substituted phenyl or phenyl-lower alkyl or certain heterocyclic groups; R2 represents hydrogen or lower alkyl; R3 represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, substituted phenyllower alkyl, tri(lower alkyl)stannyl, tri(lower alkyl)silyl, a 0 salt forming ion, or the group -CH2-O-C-R wherein R is lower 43B36 alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl or phenyl-lower alkyl; and R^ represents certain heterocyclic groups. The various groups represented by the symbols have the meaning defined below and these definitions are retained throughout this specification.

The lower alkyl groups referred to throughout this specification are straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms, preferably 1 to 4 carbons. Examples of the type of groups contemplated are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. The lower alkoxy groups include such lower alkyl groups attached to an oxygen, e.g., methoxy, ethoxy and propoxy. The phenyl-lower alkyl and diphenyl-lower alkyl groups are such lower alkyl groups attached to phenyl, e.g., benzyl, phenethyl and diphenyImethy1.

Cycloalkyl refers to groups having 3 to 7 carbons in the ring, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The terms cycloalkenyl and cycloalkadienyl also represent rings having 3 (4 in the case of cycloalkadienyl) to 7 carbons with one or two double bonds, i.e. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl and cyclohexadienyl. The double bond or bonds may be located at various positions, e.g., 1,4-cyclo-hexadienyl.

The substituted phenyl and substituted phenyl-lower alkyl groups (Rj,R3, or R) are defined as those having one or more (preferably only one) simple substituents selected from halogen (preferably chlorine or bromine), lower alkyl and lower alkoxy, e.g., 2-,3- or 4-chlorophenyl, 2-,3- or 4-bromophenyl, 3,4-dichlorophenyl, 2-methylphenyl, 4-ethoxyphenyl, 2-,3-, or 4-chlorobenzyl and 2-,3- or 4-ethylphenethyl. Also, in the case of R^, the phenyl substituent can be a hydroxyl group.

The salt forming ions represented by Rg may be metal ions, ., aluminium, alkali metal ions such as sodium or potassium, aline earth metal ions such as calcium or magnesium, or an ae salt ion, of which a number are known for this purpose, example, phenyl-lower alkylamines such as dibenzylamine, -dibenzylethylenediamine, lower alkylamines such as methylae, triethylamine, and N-lower alkylpiperidines such as Nflpiperidine.

The heterocyclics represented by R^ are thienyl, furyl, olyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, idiazolyl, and tetrazolyl. They are attached at any available .tion as for example 2- or 3-thienyl, 2- or 3-furyl, 2- or .3olyl,2-, 3- or 4-pyridyl, 2- or 5-thiazolyl, 3- or 5-isothiarl, 2- or 5-oxazolyl, 3- or 5-isoxazolyl,-and 3- or 5-(1,2,4-thia:olyl). Also included within the meaning of R^ are such sroeyclics having a halogen (preferably Cl or Br) or a lower Ί (preferably methyl or ethyl) substituent, l-methyl-5azolyl, 5-chloro‘-2-thienyl and 4-chloro-2-pyrroyl.

The heterocyclic groups represented by R^ are ’in R5 is hydrogen or alkyl of 1 to 4 carbons. 0 Preferred embodiments of this invention are as follows: Rj_ is phenyl, benzyl, phenethyl, substituted phenyl, benzyl phenethyl, cycloaikyl, cycloalkenyl or cycloalkadienyl of 7 carbons, thienyl, furyl,pyrrolyl or pyridyl. - 4 43838 R2 is hydrogen or alkyl of 1 to 4 carbons.

R3 is hydrogen, alkyl of 1 to 4 carbons, benzyl, phenethyl, diphenylmethyl, trimethylsilyl, trimethylstannyl, p aluminium,alkaline earth metal, alkali metal, or -CHZ-O-C-R. 5 R is.= alkyl of 1 to 4 carbons, phenyl, benzyl, or phenethyl.

The most preferred embodiments are: Rj_ is phenyl,1,4-cyclohexadien-l-yl, thienyl or pyridyl, especially phenyl, 2-thienyl, 3-thienyl or 3-pyridyl.

R2 is hydrogen or methyl, especially hydrogen.

R3 is hydrogen, diphenyl-methyl or potassium, especially hydrogen. ΑΧ,ΑΤ,. A? CH, especially 5-methyl-1,3,4-thiadiazol-2-yl and 1-methyl-1Htetrazol-5-yl.

Compounds of formula I are obtained by reacting an α-ureido compound of the formula (XI) R. -CH-COOH 1 I NH-C-N-R, ° h or an acylating derivative thereof with a 3-heterocyclic.thio-7-amino substituted cephalosporin of the formula (III) H2nCOOR, wherein R3 is preferably diphenyl-methyl or t-butyl or other ester protecting groups when the free..acid-product is desired.5 4S5J3O This reaction may be carried out by converting the a-ureido lound of formula II to a mixed carbonic or other anhydride :reating a solution of the α-ureido compound in an organic ent containing a tri(lower alkyl)amine with an anhydride ling agent, i.e. a lower alkyl ehloroformate, an aryl ohlorolate, or an acyl halide, at reduced temperatures of from to -20°C.

Alternatively, the α-ureido compound of formula II can be erted to an activated ester by reacting with a carboxyl group vating agent such as dicyclohexylcarbodiimide or N,N-carbonyl dazole.in some oases the carboxyl group may be activated by ersion to an aoid halide, e.g., the chloride, or to an azide.

The methods of preparing the α-ureido compounds of formula II known to those skilled in the art and a number of such methods iiscussed in U.S. patent Specification No.3,833,568 referred to above. The compounds of formula I cah also be prepared by ating the compound of .formula III with an acid chloride iormula _ (IV) Q II nh2-hci n a-(substituted) amino acid of the formula (V) R,-CH-COOH •ι γ NH-Y ein Y is a . leaving group such as <0 o or (ch3)3c-o4!- to yield the rmediate of formula Rq-CH-C-NH 1 I nh2 COOR. '3 43338 Various intermediates of formula VI where is phenyl are disclosed in U..S. Patent Specifications Nos. 3,821,207;__________ __3,813,388; 3,641,021; 3,759,904; and 3,796,801.

The intermediates of formula VI are converted to the final products of formula I by treatment with an isocyanate of the formula (VII) r2-n«c«o or when R2 is hydrogen or ah alkali or alkaline earth metal cyanate such as potassium cyanate in solution at a pH of from 7 to 8.

The final products of formula I can also be prepared by reacting the compound of formula II with 7-ACA preferably in the presence of dicyclohexylcarbodiimide to yield the compound of formula VIII (as disclosed in U.S. Patent Specification No. 3,673,183). n H followed by treatment with the compound of the formula (IX) R4-S-H in solution at a pH of from 7.8 to 8.0.

Similarly, the final products of formula I can be prepared by reacting the compounds of formula IV or V with an ester of 7-ACA preferably in the presence of dicyclohexylcarbodiimide followed by treatment with an acid (HX), preferably 'trifluoroacetic acid in the presence of anisole, to yield the salt of formula - 7 (X) The salt of formula X is treated with the .isocyanate of formula VII (or the alkali or alkaline earth metal cyanate where R2 is hydrogen) followed by treatment with the compound of formula IX to yield the final product of formula I.

The compounds of formula I wherein is lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, diphenyllower alkyl, Or the acyloxymethyl group -CH2-O-C-R may be obtained by reacting the 3-heterocyclicthio-7-amino substituted cephalosporin of formula III in which R3 is fl or the 7-ACA either before or after the acylation of the 7-amino substituent with one or two moles of a compound of the formula (XI) halo-R3 or (XII) R3+=N~ wherein halo is preferably chlorine or bromine in an inert solvent such as dimethylformamide, acetone, dioxane or benzene, at ambient temperature or below.

Similarly, the compounds of formula I wherein R3 is tri(lower alkyl)stannyl or tri(lower alkyl)silyl are obtained by introducing such groups onto the 3-heterocyclicthio cephalosporanic acid moiety either before or after the acylation reaction.

The carboxylate salts of the compound of formula I are formed by reacting the carboxyl group of the cephalosporanic acid moiety,· i.e. R3 is hydrogen, with any of the salt forming ions described above.

It will be appreciated that the compounds of formula I are optically active due to the presence of an asymmetric -843538 carbon atom in the 7-position side chain. By selection of the appropriate starting material it is possible to obtain the compounds of formula I as a mixture of optically active isomers or isolated as a single isomer. The various isomers as well as their mixtures are within the scope of this invention.

Where possible, it is generally preferred to obtain the D-isomer since that is the one which exhibits greater biological activity.

Illustrative process details are provided in the examples for the various reactions.

The compounds of formula I have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella Bchottmualleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or as surface disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a compound of formula I may be used in various animal species in an amount of 1 to lOO mg./kg. daily, orally or parenteraily, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.

Up to about 600 mg. of a compound Of formula I may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

Thus the invention provides a oharmaceutical composition comprising a compound of formula I and a pharmaceutical carrier. -943838 They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy equipment, at a concentration of 0.2 to 1Ϊ by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying.

They are also useful as nutritional supplements in animal feeds.

The following examples are illustrative of the invention. All temperatures are on the centigrade scale. -1043838 Example 1 78-[[[0-(Aminocarbonyl)amino3(phenyl)acetyl]amino]-3-[[time thyl-l&-tetrazol-5-yl) thiol methyl] -8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) Ethyl acetate adduct of 7-amino-3-[[(1-methyl-lS-tetrazol5-yl)thio]methyl]-8-oxo-5-thla-l-azabicyc]o(4.2.0)oct-2ene-2-carboxylic acid, 4-methylbenzenesulfonic acid salt 32.8 g. of 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabioyclo[4.2.0]oct-2-ene-2-carboxylic acid (produced from 7-aminocephalosporanic acid by treatment with l-methyl-tetrazole-5-thiol at G0°C at a pH of 7.5-8.0 in water/acetone) are finely pulverized and suspended in a mixture of 700 ml. of anhydrous dioxane and 575 ml. of anhydrous methanol. 20.6 g. of 4-methylbenzenesulfonic acid monohydrate are added to the suspension with vigorous stirring. After 30 minutes a clear solution results, which is then concentrated on a rotary evaporator. In order to completely remove water from the residue, 200 ml. of anhydrous dioxane are added and the solution again concentrated. This procedure is repeated twice more. The oily residue crystallizes upon trituration with ethyl acetate.

SI.2 g. of the ethyl acetate adduct of 7-amino-3-[[(1-methyllH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 4-methylbenzenesulfonic acid salt are obtained. b) 7-Amino-3-([(1-methyl-lH-tetrazol-5-yl)thio]methyll-8-oxo-5thia-l-azabicyclo[4.2.'0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester The product from part (a) is suspended in a mixture of 700 ml. dioxane and 300 ml. of ethyl acetate. To this mixture is added dropwise at 10-15° with vigorous stirring a solution -11of diphenyldiazomethane [produced from 40 g. of benzophenone hydrazone and 43.7 g. of mercuric oxide by stirring vigorously for 6 hours with 220 ml. of petroleum ether (b.p. 40 to 60), filtering and concentrating] in 200 ml. of anhydrous dioxane.

After stirring for 3 hours at room temperature a clear, wine red solution results, which is treated with 75 ml. of methanol to remove excess diphenyldiazomethane. After the wine red color disappears, the yellow brown solution is concentrated, the residue is dissolved in 800 ml. of methylene chloride and the solution is washed with a solution of 40 g. of dibasic potassium phosphate in 800 ml. of water and then with400 ml. of water, dried with magnesium sulfate and concentrated. The viscous residue is triturated with petroleum ether. 47.7 g. of 7-amino-3-[[time thyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained. The crude product is purified by stirring for 1 hour with 50 ml. of ice cold ethyl acetate and filtered under suction, to yield 28.5 g. of purified product, m.p. 153-156° (dec.).

The product is recrystallized from methylene chloride/petroleum ether, m.p. 166-168° (dec.). c) D-α-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino]-2-phenylacetic acid D-(2-phenyl)glycine and magnesium oxide are suspended in water. To this suspension is added a solution of (p-methoxyphenyUmethoxycarbonylazide in dioxane. The mixtuSF iFstirred at room temperature, filtered, and the filtrate is’extracted with diethyl ether. The aqueous phase is layered over with ethyl acetate, washed with water, dried, and concentrated to obtain D-α- [ [[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-phenylacetic acid. -1243838 d) 73-( [ [ [ [D-('4-Methoxjphenyl)methoxyJcarbowyljaminoj (phenyl)acetyl)amino]-3-(((l-methyl-lH-tetrazol-5-yl)thio(methyl]8“oxo“5-thia-l-azabicyclo[4,2.0}oct-2-ene-2-carboxylic acid, diphenylmethyl ester 4.95 g. (0.01 mol.) of 7-amino-3-[[(1-methyl-1Htetrazol-5-yl)thio lmethyl]-8-oxo-5-thia-l-azabicyclo[4.2.03 — oct-2-ene-2-carboxylic acid, diphenylmethyl ester from part (b) and 3.78 g. (0.012 mol.) of D-a-[[((4-methoxyphenyl)methoxy]carbonyl]amino]-2-phenylacetic acid from part (c) are suspended in a mixture of 100 ml. of tetrahydrofuran and 50 ml. of methylene chloride. To this suspension are added dropwise at 0-5eC over a period of 1 hour 2.27 g. (0.011 mol.) of dicyclohexylcarbodiimide dissolved in 40 ml. of absolute tetrahydrofuran This mixture is stirred for 90 minutes at 0-5°C (the solution becomes almost clear after about 30 minutes, then it again becomes turbid as the dicyclohexylurea precipitates) and 90 minutes at room temperature. The dicyclohexylurea is filtered off and the filtrate is concentrated. The residue is dissolved in 800 ml. of ethyl acetate and the solution is shaken twice with IN sodium bicarbonate solution and twice with water. The solution is then treated with activated carbon, dried with magnesium sulfate, filtered and concentrated to a volume of approximately 100 ml. 5.5 g. of 73-[[[[[D-(4-methoxyphenyl)methoxy]carbonyl]amino)(phenyl) acetylJamincO-3-EII(1-methyl25 lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester crystallize, which begins to decomuose at 143°C. -13e) 76-- CCD-(Amino)phenylacetyl]amino]-3-CC(1-methyl-l·Htetrazol-5-yl·)thio]Inethyl]-8-oxo-5-thia-l-azabicycloC4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 3.8 g. of 76-CCCCCD-(4-methoxyphenyl)methoxy]carbonyl]amlno](phenyl)acetyl]amlno]-3-EC(l-methyl-lH-tetrazol-5-yl)thioJmethyl]-8-oxo-5-thia-l-azabicycloC4.2.0]oct-2-ene-2carboxylic acid, diphenylmethyl ester from part (d) are added at 0-5°C to a mixture of 76 ml. of trifluoroacetic acid and 22.8 ml. of anisole. After 10 minutes, the solvent is evaporated under vacuum. The residue, upon trituration with diethyl ether, solidifies to yield 2.85 g. of 76-CCD-(a-amino)phenylacetyl]amino]-3-CC(1-methy1-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloC4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt, which decomposes above 126°C. f) 76-CCCP-(Aminocarbonyl)amino](phenyl)acetyl]amino -3-CC(1methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloC4.2.0]oct-2-ene-2-carboxylic acid 0.25 g. (0.003 mol.) of potassium cyanate are dissolved in 6 ml. of water and to the solution are added 0.86 g. (0.0015 mol.) of 7B-CED-u-amino-D-phenylacetyl]amino]-3-CE(1-methyl-lHtetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicycloC4.2.0]oct2-ene-2-carboxylic acid, trifluoroacetic acid salt from part (e). This mixture is stirred at room temperature and after about 15 minutes, the solution becomes practically clear. The solution is stirred at room temperature for a total of about three hours, filtered, and the filtrate is acidified to pH 1.5 with 2N hydrochloric acid. The resulting precipitate is filtered under suction and washed with water, to yield 0.6 g. of 76-CCCD-(aminocarbonyl) amino](phenyl)acetyl]amino -3-CC(1-methyl-lH-tetrazol5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyoloC4.2,0]oct-2-ene-2-1443838 carboxylic aoid, m.p. 163-165eC (dec.).

Example 2 78-[[[ff-(Aminocarbonyl)amino](phenyl)acetyl]amino]-3- [ [(1-methyllK-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4,2,0]5 oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from example 1 and potassium bicarbonate is freeze-dried to yield as a powder 7S-[[[D-(aminocarbonyl)amino](,phenyl)acetyl]amino]-3-[[(l-methyl-lK-tetrazol-5-yl)thio]methyl]-8-oxo-52.0 thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt.

• Example 3 78- [ [[g-(Aminocarbpnyl)amino](1,4-cyclohexadien-l-yl)acetyl]amino]-3-[[(l-methyl-ltj-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia15 l-azabicyclq[4.2.0]oct~2-ene-2-carboxylic acid Following the procedure of example 1 but substituting D-2-(1,4-cyclohexadien-l-yl)glycine for the D-(2-phenyl)glycine in part (c) one obtains the title product.

Examples 4-27 Similarly, following the procedure of example 1 but substituting for the D-(2-phenyl)glycine in part (c) the compound in Col. A one obtains the product in Col. B. -15Col. A R.-CH-COOK 1 I NHCol. B EX.

A CH, . -C2H5 t-C4Hgn-C5Hll /\2 H,C-CH H H,C-C — 2I I H2C— CH2H2 H,C-C< I >; H2C—cz H -1643538 -17Ex. 3 S 3 8 ^2O/-W3Br HO ' Ό -1843538 Ex.

Cl \ Cl H3co40rcv H5C2 •(ch2)2-19- Example 30 76-(1ίΡ-(Aminocarbonyl)amino](phenyl)acetyl]amino]-3-(((5methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) 7-Amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8oxo-5-thia-l-azabicyclo[4.2.0]oci»-2-ene-2-carboxylic acid, diphenylmethyl ester g. of 7-amino-3-[ [ (S-methyl-1,3,4-.thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabioyclo[4.2.0]oet-2-ene-2carboxylic acid are suspended in 350 ml. of tetrahydrofuran. 4.1 ml. of 705 'perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise.with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran. After 3 hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired productt is dried over Kieselgel in a desiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate. The aqueous solution obtained is extracted with chloroform. The chloro-2043338 form phase is treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3~ [ [ (5-methyl-l,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thial-azabicyclo[4.2,0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157-159°. The product is recrystallized from tetrahydrofuran/petroleum ether, b) 78-((ΓΡ-Aminocarbonyl)amino] (phenyl)acetyl]amino]-3-(((5.methyl-1,3,4-thiadiazol-2-yl)thiojmethyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Following the procedure of example 1, part (d), (e), and (f) but employing the 7-amino-3-[[(5-methyl-l,3,4-thiadiazol-2-yl)thiojmethyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester from part (a) in example 1(d) one obtains the title product.

Examples 31-55 Following the procedure of example 1 or 2 (changing the salt appropriately) but employing the 7-aminocephalosporanic acid derivatives shown in Col. A the products shown in Col. B are obtained Col. A Col. B h2n— EX.

H 4/ I Ex. Η C3H7 C2H5 Ν-Ν 43838 43 s TJ ‘C3H7 ΓΓ“3 .43538 Ex.

Ca/2 N-.N Λ J \NX<^h3 Mg/2 Na Na Al/3 N-N [ch3nh3] Nx Ah, [(c6h5ch2)2nh2] I© N-N ll II By also substituting the D-2-(1,4-cyclohexadien-l-yl)glycine from example 3 or the compounds of Col. A from examples 4 to 29, for the D-2-(phenyl)glycine in example 1 other compounds within the scope of this invention are obtained. - 24 X 43638 Examples 56 - 63 Following the procedure of example 1 but substituting for the potassium cyanate in part (f) one of the following: methylisooyanate 5 ethylisocyanate propylisocyanate i-propyllsocyanate butylisocyanate i-butylisocyanate t-butylisocyanate pentylisocyanate one obtains: 78-EEC(D-methylaminocarbonyl)amino] (phenyl)acetyl]amino]3—EC (l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l15 azabicycloC4.2.0]oct-2-ene-2-carboxylic acid; 78-CCCD- (ethylaminocarbonyl)amino](phenyl)acetyl]amino]3—EC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloC4.2.0]oct-2-ene-2-carboxylic acid; 78-CCCd-(propylaminocarbonyl)amino] (phenyl)acetyl]amino]20 3—E C(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo]4.2.0]oct-2-ene-2-carboxylic acid; 7b-I’LLD- (i-propylaminocarbonyl)amino](phenyl)acety1]amino]-3-L’E(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloC4.2.0]oct-2-ene-2-carboxylic acid; 78-CCCd-(butylaminocarbonyl)amino](phenyl)acety1]aminoj-3-Γ] (l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloL4.2.0]oct-2-ene-2-carboxylic acid; β—Ε E Ed— (i-butylaminocarbonyl)amino](phenyl)acetyl]amino]-3-EC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-530 thia-l-azabicyclo]4.2.0]oct-2-ene-2-carboxylic acid; •SS23S 76— t [ (D- (t-butylaminocarbonyl) amino] (phenyl) acetylamino] -3-[[(l-methyl-lH-tetrazol-5-yl)thioJmethyl]-8-oxo-5thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; and 7β-[[[D-(pentylaminocarbonyl)amino](phenyl)acetyl]amino]-3-[[(1-methyl-18-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicyclo(4.2.0]oct-2-ene-2-carboxylic acid respectively.

Similarly, these alkylisocyanates can be employed in the procedures of examples 3 to 55 to obtain other compounds within the scope of this invention.

Example 64 7B-[I[DL-(Aminocarbonvl)amino](2-thienyl)acetyl]amino]-3-[[[1methyl-lH-tetra2ol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) DL-a-ureido-2-thiopheneacetic acid .8 g (0.1 mol) of DL-2-thienylglycine are heated together with 8.2 g (0.1 mol) of potassium cyanate in 100 ml of water.

After 30 minutes, the mixture is cooled and acidified with dilute hydrochloric acid. The precipitated product, DL-a-ureido-2-thiopheneacetic acid, is filtered, washed with ice water and a small amount of ethanol. Recrystallization from methanol yields 17 g of white crystals, of DL-e-ureido-2-thiopheneacetic acid;m.p. 183-185°. b) 3-((Acetyloxy)methyl]-7 β-[[[DL-(aminocarbonyl)amino](2-thienyl). acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2carboxylic acid 9.2 g (50 mmol) of DL-a-ureido-2-thiopheneacetic acid from part (a) are dissolved in 40 ml of absolute dimethylformamide. .3 g (50 mmol) of dicyclohexylcarbodiimide dissolved in 10 ml of methylene chloride are added dropwise at 0°. After stirring for 1/2 hour, a solution of 13.5 g (50 mmol) of 7-aminocephalosporanic acid and 10 g (100 mmol) of triethylamine is added. This mixture -264 is stirred for 24 hours at 5°. After filtering, the filtrate is concentrated under vacuum, the oily residue is taken up in water, filtered and after treating with activated carbon at 5’ it is layered over with ethyl acetate and acidified with 2N hydrochloric acid. The ethyl acetate solution is washed with water, dried and concentrated. S.l g of a viscid residue are obtained. The product, 3-[(acetyloxy)methyl]-76-[[[(aminocarbonyl)-amino](DL-2thienyl)acetyl]amino]-8-oxo-5-thia-l-azabioyclo[4.2.0]oct-2-ene-2carboxylic acid, is recrystallized twice from isopropanol; yield 2.1 g. The intermediate of part (b) can also be obtained by the following synthesis: c) ΡΙ,-α-Ρ Γ (l,l-difnethylethoxycarbonylamino)-2-thiophene acetic a cid 3.8 g (25 mmol) of DL-2-thienylglycine and 2 g (50 mmol) of magnesium oxide in 50 ml of water/dioxane (1:1) are stirred for is one hour at room temperature. 4.25 g (28 mmol) of t-butyloxycarbonylazide dissolved in 15 ml of dioxane are added dropwise and the reaotion mixture is stirred for 24 hours at 50°. After filtering, the filtrate is concentrated under vacuum, the oily residue is treated with ethyl acetate and then taken up with water.

This is then acidified with citric acid while cooling with ice and the aqueous acid solution is extracted with ethyl acetate. The solvent is drawn off from the ethyl acetate solution to obtain 4 g of white product, DL-«-(1,1-dimethylethoxycarbonylamino)-2-thiophene acetic acid; m.p. 70-72°. '3 d) 3- [ (Acetyloxy)methyl] -76-((( ΓPT— (1 , l-dirngthylethoxv) carbonyl~lamlno] (DL-2-thienyl) acetyl^aminoll-B-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyllc acid, diphenylmethyl ester .4 g (20 mmol) of DL-α-(1,1-dimethylethoxy)carbonylamino)-2thiophene acetic acid from part (c) are dissolved in 50 ml of tetrahydrofuran and 4.05 g (20 mmol) of dicyclohexylcarbodiimide -2733SS8 = added at 0°. After stirring for 30 minutes, 8.8 g (20 mmol) 7-aminocephalosporanic acid, diphenylmethyl ester are added spwise. After 24 hours, the precipitated dicyclohexylurea is Ltered off. After drawing off the solvent and reorystallizing ϊ beige residue from methylene chloride/petroleum ether 10.5 g the product, 3-[(acetyloxy)-methyl-78-[[[[DL-(1,1-dime.thvle thoxy )rbonyl]amino] ¢1 -thienyl)acetyl]amino]-8-oxo-5-thia-l-azabi:lo[4.2»0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, are sained as a light beige powder; m.p. 78° (dec.). 3-[(Acetyloxy)methyl]-78-[[[DL- (aminocarbonyl)aminoj(2Lenyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene;arboxylic acid g of 3-[(acetyloxy)methyl]-70-[[[CDL-(aminocarbonyl)afnino]-2rbonyl] amino] (χ-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabi:lo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester im part (d) are stirred for 15 minutes in a mixture of 20 ml trifluoroacetic acid and 3 ml of anisole at 5.°. After evaporating ϊ trifluoroacetic aoid under vacuum and washing the residue withdiethyl ier, 2.3 g of 3-[(acetyloxy)-methyl]-70-[[dl- (a-amino-2-thienyl)ityl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-car— ylic acid, trifluoroacetic acid salt are obtained. This proit is dissolved in water and the solution is adjusted to pH 8 :h sodium hydroxide. It is then quickly heated to 80° and g of potassium cyanate dissolved in 2 ml of water are added. .er stirring for 1 minute, the reaction mixture is quickly led, layered over with ethyl acetate and acidified to pH 3.5 h 2N hydrochloric acid. This is extracted with 5 X 100 ml of yl acetate. The combined ethyl acetate extracts are dried, centrated to about 1/3 the volume, treated with activated carbon the product, 3-[ (acetyloxy)methyl] -70-[[[ DL- (aminocarbonyl) -28*3&38 amino1 (2-thienyl) acetyl]aminoj-8-oxo-5-thia-l-asabicyclo[4.2.0]oct-2-ene-2~carboxylic acid, is precipitated with petroleum ether. The product is crystallized from isopropanol as light beige crystals; m.p. 145° (dec.). b f) 7S-[XCDL-{Arainocarbonyl)amino] (-2-thienyl) acetyl]amino] -3[[(1-methyl-lH-tetrazol-5-yl)thiojmethyl]-8-oxo-5-thia-lazabicyclo[4.2.0)oct-2-ene-2-carboxylic acid 2.27 g. of the 3-[(acetyloxy)methyl)-7β-[[[PL-(aminocarbonyl) amino] ( 2-thienyl)acetyl]amino]-8-oxo-5-thia-l10 azabicyclo[4,2.0]oet-2-ene-2-carboxylic acid from part (b) or (e) are dissolved in a mixture of acetone/water (1:1) with the aid of 5N sodium hydroxide. The pH is adjusted to 7.6-8.0 and 5 mmol, of l-methyl-lH-tetrazole-5-thiol is added. The pH is maintained at 7.8 by the addition of 5N sodium hydroxide.

The reaction mixture is heated for 3 hours at 50-60°. After cooling and distilling off the acetone, the mixture is acidified to pH 2.5 with 2N hydrochloric acid while cooling with ice and the precipitate is extracted with ethyl acetate to yield the title product.

Example 65 78-[[[PL-(Aminocarbonyl)amino](-2—thienyl)acetyl]amino]-3[[(1-methyl-ia-tetrazol-5-yl)thiolmethyl]-8-oxo-5-thia-lazabicyclo[4.2,0]oct-2-ene-2-carboxylic acid a) DL-a-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino]72-thio2ΰ pbeneacetic acid 1.9 g. (12.5 mmol.) of DL-2-thienylglycine and 1 g. of magnesium oxide are suspended in SO mmol, of water. After stirring for 1/2 hour, 3 g. (15 mmol.) of (p-methoxybenzyloxycarbonyl)azide in 25 ml. of dioxane are added. After stirring for 48 hours at room temperature, the mixture is filtered. -29r Ths filtrate is extracted with 200 ml. of diethyl ether.The aqueous phase is layered over with an equal volume of ethyl acetate and vigorously stirred with 20 g. of ion exchange resin (Dowex 50, acid form) for 2 hours. The ethyl acetate is separated, washed with 100 ml. of water, dried and concentrated. A light oil remains as residue which crystallizes on trituration with petroleum ether. The DL-a-[([(4-methoxyphenyl) methoxy] carbonyl]amino]-2-thiopheneacetic aoid obtained melts at 153-156°. b) DL-ct-[([(4-Methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid, 2,5-dioxo-l-pyrrolidinyl ester 6.7 g. (20 mmol.) of the DL-a-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid from part (a) are dissolved in 150 ml. of tetrahydrofuran. 2.3 g. of N hydroxysuccinnamide and 4.1 g. (20 mmol.) of dicyclohexylcarbodiimide in tetrahydrofuran are added dropwise at 0°. After stirring for 24 hours, the mixture is filtered and the filtrate is concentrated. The oily residue crystallizes on rubbing.

Upon recrystallization from benzene/cyclohexane, 7.5 g. of light beige crystalline DL-ct-[[((4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid, 2,5-dioxo-l-pyrrolidinyl ester; m.p. 140-142°, are obtained. 13538 c) 7 ii—[_ [, ELEOL-(4-Methoxyphenyl)methoxy] carbonyl jaminoj (pL-2-thienyl)-acetyl lamlno]“3-[E (l-methyl-lH-tatrazol5-yl)thlolmethylj-8-oxo-5-thia-l-azablcycloE42.O]oct-2-ene2-carboxyllc acid, and its diphenylmethyl ester 3.2 g. (10 mmol.) of 7-amino-3-E(1-methyl-lH-tetrazol5-yl)thio]-8-oxo-5-thia-l-azabicycloE4.2.0]oct-2-ene-2carboxylic acid are dissolved in 20 ml. of dimethylformamide by the addition of 2.02 g. (20 mmol.) of triethylamine. 4.18 g. (10 mmol.) of DL-α-ΕΕΕ (4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid, 2,5-dioxo-lpyrrolidinyl ester from part (b) are added dropwise at room temperature. After three hours, the solvent is distilled off under oil vacuum. There remains a brown viscid residue which is completely soluble in water with the aid of a little sodium carbonate. The aqueous solution is shaken with ethyl acetate, the aqueous phase is treated with activated carbon, layered over with ethyl acetate and acidified with 2N hydrochloric acid. The solvent is drawn off from the ethyl acetate extract and the residue is recrystallized from methylene chloride/petroleum ether to obtain 2.5 g. of 7B-LEECLDL- (4-methoxyphenyl)-methoxy]carbonyl]amino] (2-thienyl)acetyl]amino]-3“EE(l-methyl-lH-tetrazol-5-yl)thio] methylJ-8-oxo-5-thia-l-azabicycloC4.2.0]-oct-2-ene-2carboxylic acid; m.p, 63° (dec.).

Similarly, by employing an equivalent amount of the diphenylmethyl ester of 7-amino-3-[ (l-methyl-lH-tetrazol-5-yl)thio.]-8-oxo-5-thia-l-azabicycloE4.2.0]oct-2-ene-2-carboxylic acid, m.p. 168-169° (dec.)., in the above procedure one obtains as a beige powder 76-EEEEEDL-(4-methoxyphenyl)methoxy] carbonylJamino](2-thienyl)acetyl]amino]-3-CE(1-methyl-lHtetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicycloE4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 98-100° (dec,). 4388© <3) 7 β— [ f [DL-Aminocarbonyl) amino] (2-thienyl) acetyl3aminol· 3[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1.2 g. (2.5 mmol.) of the 7β~CCLCEdL·- (4-methoxyphenyl)methoxy]carbonyl]amino] ’ (-.2-thienyl)acetyl] amino]-3-[[(1-methyllH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from part (c) or an equivalent amount of the diphenylmethyl ester are treated at 5° with a mixture of trifluoroacetic acid and 1.5 ml. of anisole. · The solvent is drawn off and the solid residue is washed with diethyl ether to obtain 0.7 g. of 7β-[(DL-^-amino-2-thienyl)acetylamino] -3-[[(1-methyl-IH- tetrazol-5-yl)thio]methyl]-8-OXO-5thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylie acid trifluoroacetic acid salt. This crude salt is converted with potassium cyanate .to the ureido compound by the procedure of example 1(e) The ureido compound is crystallized from isopropanol and recrystallized once from tetrahydrofuran/petroleum ether.

The product, 70-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is obtained as a beige powder; m.p. 165-167° (dec.).

Example 66?. 76— [ [ Γ PL-(Aminocarbonyl)amino](2-thienyl)acetyl]aminoZI-3[[(l-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo[4.20]oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from either example' 64'or 65 and potassium bicarbonate is freezedried to yield as a light powder 70-( [ [ pp- (aminocarbonyl) amino]' (2-thienyl)acetyl]amino]-3-(((1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabieyclo[4.2.0]oot-2-ene-2carboxylic acid, potassium salt; m.p. 183-186°, -32Examgle_67 4 3838 -ΕΓΪΡΙι- (Aminocarbonyl·)amino](2-thienyl)acetyl]amina]-3CEI?( 5-methyl-l,3,4-thiadiazol-2-yl)thlo]methyl]-8-oxo-5-thial-azabicycloC4.2.0]oct-2-ene-2-carboxyllc acid a) ' 7S—[[[(^DL-(4-H6thoxyphenyl)methoxy]carbonyl]amino](-2thienyl)acetyl]amino]-3-(((5-methyl-l,3,4-thiadiazol-2-yl)thiojmethyl]-8-oxo-5-thia-l-azabicyclo(4,2.0]oct-2-ene-2° carboxylic acid, diphenylmethyl ester 8.8 g. of the diphenylmethyl ester from Example 30 part (a), .77 g. of DL-a-(t[(4-methoxyphenyl)methoxy]carbonyl]amino]-2thiopheneacetic acid from example65 (a) and 3.55 g. of dicyclohexylcarbodiimide in 80 ml. of tetrahydrefuran are stirred for 24 hours at 0°, The tetrahydrefuran is drawn off under vacuum and the product is obtained from the filtrate by recrystallization from tetrahydrofuran/petroleum ether. Beige crystals of 78-(((((DL-(4-methoxyphenyl)methoxy]carbonyl]amino](2-thienyl)acetylJamino]-3-(((5-methyl-l,3,4-thiadiazol-2-yl)thiojmethyl]8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 104-106°, are obtained. b) 78- [ [ [DL- (Anilnocarbonyl)ainino](2“thieriyJ)acetyl]amino]-3“ [((5-methyl-l,3,4-thiadiazol-2-yl)thiojmethyl]-8-oxo-5-thialvazabicyelo(4.2.0]oct-2-ene-2-carboxylic acid The product from part (b) is treated with trifluoroacetic acid and anisole at 0°C followed by treatment at 80° with potassium cyanate at pH 7.8 according to tne procedure of example 64 -(e). The 76-((( DL- taminocarbonyl) amino] (2-thienyl)acetyl]amino]-3-(((5-methyl-l,3,4-thiadiazol-2-yl)thio]methyl]8-oxo-5-thia~l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid obtained is recrystallized from tetrahydrofuran/petroleum ether as a beige powder, m.p. 155-157° (dec.). 43S3S Example 68 7,g-CC[ DL- (Aminocarbonyl)amino] (2-thienyl) acetyl] amino] -3[[(5-methyl-1,3,4-thiadiazol-2-yl)thiojmethyl]-8-oxo-5-thial-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from example 67 and potassium bicarbonate is freeze-dried to yield as a beige powder 7β-[[[DL-(aminocarbonyl)amino](2-thienyl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt; m.p. 194-196° (dec.).

Example 69 7B-[.[ [DL- (Aminocarbonyl)amino] (,3-thienyl) acetyl] amino] -3[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazahicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) DL-tt-Bromo-3-thiopheheacetic acid 2-thienylbromide is treated with butyl lithium and chloral to obtain 2-[(l-hydroxy-2-trichloro)ethyl]thiaphene which is then treated with sodium methoxide to obtain amethoxy-3-thiopheneacetic acid [Gronowitz et al., Ark. Chemi., 17, 561 (1961)] . 150 ml. of 30% hydrogen bromide in acetic acid is added to a solution of 16 g. (100 mmol.) of a-methoxy-3tttiopheneacetic acid in 50 ml. of glacial acetic acid. The mixture is left to stand at room temperature for 24 hours and then poured into ice water. The solution is extracted three times with 60 ml. of diethyl ather. The ether phase is washed with water, dried over magnesium sulfate and evaporated.

The residue, 18 g. of crude DL-a-bromo-3-thiopheneacetic aoid are recrystallized from cyclohexane; yield 14 g.; m.p. 80-82°. 43838 b) DL-g-Azido-3-thiopheneacetic acid g. (62 mmol.) of sodium azide and 3.5 g. (33 mmol.) of sodium carbonate are added to a solution of 12 g. (54 mmol.) of DL-a-bromo-3-thiopheneacetic acid in 75 ml. of acetone (96%).

The mixture is stirred at room temperature for 12 hours in darkness and after this time the solvent is evaporated and the residue is dissolved in 75 ml. of water. 50 ml. of diethyl ether is added, the water phase is acidified with 2N sulfuric acid and extracted quickly twice more with 50 ml.of diethyl ether. After washing with water and drying over sodium sulfate, the combined ether phases are evaporated. Crystallization of the residue from cyclohexane yields 7.4 g. of white crystalline. DL-g-azido-3-thiopheneacetic acid; m.p. 58-59°. c) DL-a-Amino-3-thiopheneacetic acid 0.3 g. of palladium/barium sulfate catalyst are added to a solution of 6 g. of DL-a-azido-3-thiopheneacetic acid in 40 ml. of ethanol and 40 ml. of 0.5N hydrochloric acid. Hydrogenation takes place at about 60 psig. after 2 hours.

After filtration, the volume is concentrated to about 30 ml.

When the pH is brought to 6.5 with ammonia, the amino acid separates as a white powder. After washing with ethanol/ water and drying, 3.5 g. of the product, DL-a-amino-3thiopheneacetic acid, are obtained; m.p. 283-285°. d) DL-g-[[[(4-Methoxyphenyl)methoxy]carbonyl)amino]-3-thiopheneacetic acid 1.9 g. (12.5 mmol,') of DL-a-amino-3-thiopheoeacetic acid and 1 g. of magnesium oxide are stirred in 25 ml. of water, and 25 ml. of dioxane. After stirring for 1 hour, 3.0 g. (15 mmol) of ((p-methoxybenzyl)oxy]carbonylazide are added.

Stirring is continued for 24 hours. The mixture is filtered and -35:tracte<3 with 20 ml of diethyl ether. 50 ml of ethyl acetate and 20 g Dowex 50 (H+ form) are added to the filtrate and the mixture stirred well for two hours. The ethyl acetate phase is parated, washed with 50 ml of water, dried over sodium sulfate d evaporated. The oily residue crystallizes after the addition pentane to yield 3.4 g of white crystalline DL-a-[[[(4-raethoxyenyl)methoxy| carbonyl] amino]-3-thiopheneacetie acid; m.p; 118° (dec). 3-[ (Acetyloxy) methyl 3-76-( [ [ ( DL- (4-methoxyphenyl)methoxy]rbonyl]amino] (3-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabiclo[4.2.0]oct-2-ene-2-carboxylic acid g of the product from part (d), 1.5 g of triethylamine and J g of chloroformic acid ethyl ester in 50 ml of tetrahydrofuran 2 converted to the mixed anhydride. The mixed anhydride is icted with a solution of 4 g of 7-aminocephalosporanic acid and > g of triethylamine in methylene chloride for 12 hours. The .vent is then removed from the solution and the partially solid iidue is dissolved with water and a small amount of sodium carlate and extracted with 50 ml of ethyl acetate. The aqueous .se is cooled, acidified to pH 2.5 with 2N hydrochloric acid and iracted with ethyl acetate. The organic phase is treated with .ivated carbon and concentrated to obtain 3.7 g of light beige duot, 3-[(acetyloxy)methyl]-78-[[[[[DL-(4-methoxyphenyl)methoxyjbonyl]amino] (3-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabilo[4.2.0]oct-2-ene-2-carboxylie acid; m.p. 113? (dec.), which is rystallized from methylene chloride/petroleum ether. 3-((Acetyloxy)methyl]-7B-[[[dl- (amlnocarbonvl)aminol (3-thienvl)tyl]amino]-8-oxo-5-thia-l-azabicyclo[4.20]oct-2-ene-2-carylic acid The product from part (e) is stirred with 15 ml of :luoroacetic acid and worked up as in Example 64, and after -36reaction with potassium cyanate as in Example '64, the title compound is obtained. g) 7 β~ E[tPL-^minocarbonyl)amino](3-thienyl)acetyl]amlno]-3[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabi5 cyclo[4.2.0]oct-2-ene-2-carboxyllc acid The 3-[(acetyloxy)methyl]-76[[[DL- (.aminocarbonyl)amino] (3thienyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene2-carboxylic acid from part (f) is treated with 1-methyl-lH-tetrazole-5-thiol according to the procedure of Example 64 (f) to.yield the title compound.

Tha 76“[[[DL-(aminocarbonyl)amino](3-thienyl)acetyl]amino]-3[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-oarboxylic acid can also be obtained by following the procedure of Example 65 but substituting DL-3-thienyl15 glycine for the DL-2-thienylglycine in part (a) of Example 65.

Example 70.

I 76-[ [ [ D-fominocarbonyl)amino](2-thlenyl)'acetyl]amino]-3-CC(1~ methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 20 a) D-ft-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino-2-thiopheneacetic acid .7 g of D-(2-thienyl)glycine (m.p.) 218-219°,produced from the racemate with D-eamphor-10-sulfonic acid) and 8 g of magnesium oxide are suspended in 200 ml of water. To this suspension is added a solution of 22.8 g of (p-methoxyphenyl)methoxycarbonylazide in 200 ml of dioxane and this mixture is stirred for 3 days at room temperature. The mixture is filtered, the filtrate is extracted once with diethyl ether-, the agueous phase is layered over with ethyl acetate, cooled to about 10’ and acidified to pH 2 . with dilute hydrochloric acid. The agueous phase is once more - 37 18 ss© tracted vzith ethyl acetate, the combined extracts are washed ce with water, dried with magnesium sulfate and concentrated, e residue crystallizes upon trituration with petroleum ether, a crude product, D-a-CCC(4-methoxyphenyl)methoxy]carbony1]ino]-2-thiopheneacetic acid, is recrystallized from ethyl atate/petroleum ether, yield 25.2 g, m.p. 65-67°. b) 3-[(Acetyloxylmethyl]—7 B— [[[[D— (4-methoxyphenyl)methoxy]carbonyl]amino] ( 2-thienyl)acetyl]amino]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carb'oxylic acid 3.2 g. (0.01 mol.) of the product from part (a) is brought into solution in 40 ml. of methylene chloride with 1.1 ml. of N-methylmorpholine. The solution is cooled to -15°, 1.39 ml. of isobutylchloroformate are added, and the mixture is stirred for 10 minutes. To this is added a solution of 3.26 g. (0.1012 mol.) of 7-aminocephalosporanic acid and 3.1 ml. of triethylamine in 40 ml. of methylene chloride. The mixture is stirred for 1 hour at -5° and 1 hour at 5°. This mixture is then evaporated to dryness in a rotary evaporator.

The solid residue is triturated with diethyl ether and filtered under suction. The substance is then dissolved in ice water, layered over with ethyl acetate and acidified to pH 2.5. The layers are separated, the aqueous layer is extracted once more with ethyl acetate, the combined ethyl acetate extracts are washed with water, dried with magnesium sulfate and-concentrated. The residue (4.9 g.) is dissolved in 200 ml. of ethyl acetate and the solution is treated with activated -3843838 carbon. After filtration 2 g. of 3-[(acetyloxy)methyl]7Β-ΓΓΓ.ΓCd- (4-methoxyphenyl)methoxy]carbonyl]amino] (2-thienyl) acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, crystallize; m.p. 142-143° (dec.). c) 3- [ (Acetyloxy)methyl] -78-ΓΓΡτ- (α-amino-a—2-thienyl) acetyl] amino] 8-oxo-5-thia-l-azabicyclo[4.2,0]oct-2-ene-2-carboxylic acid 2.0 g. of the product from part (b) are added at -5° to a mixture of 10 ml. of trifluoroacetic acid and 4 ml. of anisole. The mixture is stirred for 10 minutes and is then concentrated in a rotary evaporator. The residue is treated with diethylether and filtered under suction. The crude 3-[(acetyloxy)methyl] - 7 8-ECD- («-amino-«-.2-thienyl) acetyl] amino] -8-oxo-S-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt is dissolved in 50 ml. of water and 20 ml. of a solution of the acetate form of the ion exchange resin Amberlite.LA 1 in isobutylmethylketone are added. The mixture is stirred for 2 hours at room temperature. The layers are separated, the aqueous phase is washed several times with diethyl ether and freeze-dried to yield 1 g. of 3-[(acetyloxyJmethyl]76-[fn- (*-amino-«-2-thienyl)acetyl]amino]-8-oxo~5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. d) 3-[(Acetyloxy)methyl]-78-[[CD-(aminocarbonyl)amino](2-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid A mixture of 1 g. of the product from part (c) and 0.194 g. of potassium cyanate in 7.5 ml. of water are quickly heated in a preheated bath at 80°. The mixture is then immediately cooled to room temperature and permitted to stand overnight. The reaction mixture is concentrated to -3943838 about 4 ml. and the pH is adjusted to 1.5 with 2N hydrochloric acid. The precipitate is filtered under suction to obtain 0.5 g. of 3-((acetyloxy)methyl]-7β-[[CD (aminocarbonyl)amino(2-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic aoid; m.p. 155-160° (dec.), e) 70-[ [ [ D-(^jninocarbqnyl) aminoj (2-thienyl)acetyl] amino]-3[[(l-methyl-ia-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 0.01 mol. of the produot from part (d) and 0.011 mol. of l-methyl-lH-tetrazole-5-thiol are heated in an aqueous acetone solution at pH 7 according to the procedure of example64(f) to yield the 7β-[[[D- (aminocarbonyl)aminoj(2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic aoid.

' Example 71 7β-[[fp- (Methylaminocarbonyl)aminoj(2-thienyl)acetyl] amino)-3[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) 3- [ (Aeetyloxy)methyl]-7β-[CCp- (methylaminocarbonyl)aminoJ' (2 -thienyl)acetyl]amino]-S-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1.5 g. of 3-[(acetyloxy)me'thyl]-7B-[Co(a-amino- 2.49 g. of a 10% solution of methylisocyanate in methylene chloride, This mixture is stirred for 2 hours at 0-5° and then concentrated. The residue is taken up in a little water, shaken with diethyl ether,filtered and acidified with 2N hydrochloric acid. -4043838 0.8 g. of 3-[(acetyloxy)methyl]-78-([Cd-(methylaminocarbonyl)amino] (2-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carhoxylic acid are obtained; m.p. 178-180° (dec.), b) 78-[[[D-(MethvlaminocarbonyUamino](2-thienyl)acetyl]amino]5 3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 0.1 mol. of the product from part (a) and 0.011 mol. of l-methyl-lH-tetrazole-5-thiol are reacted according to the procedure of example 64(f) to yield the 73—[[CD-(methylamino10 carbonyl)amino] (2-thienyl)acetyl]amino]-3-[[(1-methyl-lHtetrazol-5-yl)thiojmethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Example 72 78-[([OL-(Aminocarbonyl)amino](3-pyridyl)acetyl]amino]-315 f[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-lazabicyclo[4,2,0]oct-2-ene-2-carboxylic acid a) DL-ct-[ [ ((4-Methoxyphenyl)methoxy]carbonyl]amino]-3-pyridineacetic acid DL-2-(3-Pyridyl)glycine (prepared from pyridine-320 aldehyde by the Strecker synthesis) is reacted with (pmethoxybenzyloxycarbonyl)azide according to the procedure set forth in Example 65 (a) to yield DL-a-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-3-pyridineacetio aoid; m.p. 155-156° (dec.) b) 3-[ (Acetyloxy)methyl]—73— [[[[[PL- (4-methgxyphenyl)methoxy]25 carbonyl]amino] (3-pyridyl)acetyl]amino]-8-oxo-5~thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid The product from part (a) is reacted with isobutylchloroformate in the presence of N-methylmorpholine followed by reaction with 7-aminocephalosporanic acid according to the procedure of example95(b) to yield the 3-[(acetyloxy)methyl]-4143S3S 76- [ [ [ [ [DL- (4-methoxyphenyDmethoxylcarbcnyl lamino1 (3-’.yridyl' acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid. c) 3-[ (Acetyloxy)methyl]-78-[ [DL-(a-amino-ct-3-pyridyl)acetylZlamino]-8-oxo-5-thla-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt g. of the product from part (b) are added at -5° to a mixture of 50 ml. of trifluoroacetic acid and 20 ml. of anisole. After 10 minutes, the trifluoroacetic acid is evaporated under vacuum. The residue is treated with ether and filtered to yield the 3-[ (acetyloxy)methyl] -78-CCdl- (e-amino-a-3-pyridyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2catboxylio acid, trifluoroacetic acid salt; m.p. 138-140’ (dec.). d) 3-t(Acetyloxy)methyl]-76- [ [ΓΡΙ·~ (aminocarbonyl)amino](3pyridyl)acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4,2.0]oct2-ene-2-carboxylic acid 3.5 g. of the product from part (c) and 1.09 g, of potassium isocyanate are stirred overnight in 50 ml. of water at room temperature. The reaction mixture is filtered and the filtrate is freeze-dried to yield the 3-[(acetyloxy)methyl]7β-[ t [ DL-(aminocarbonyl)amino](3-pyridyl)acetyl]amino]-8-ΟΧΟ-5thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylio acid. e) 76-[[[DL- (Aminocarbonyl)amino](3-pyridyl)acetyl]amino]-3[ [ (l-methyl-lE(-tetrazol-5-yl)thio]tnethyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid The product from part (d) and 1-methyl-lH-tetrazole-5thiol are reacted according to the procedure of example 64 (f) to yield the 76-[[[DL-(aminoearbt>nyl)amino I (3-pyridyl)acetyl]amino]3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazahicyclo[4.2.0]oct-2-ene-2-carboxylic acid. -424 3538 Examples 73-92 Following the procedures of example 72 but substituting for the DL-3-pyridylglycine one of the following: DL-2-furylglycine DL-3-furylglycine DL-2-pyrrolylglycine DL-2-pyridylglycine DL-4-pyridylglycine DL-2-thia2olylglycine DL-5-thiazolylglyeine DL-3-isothiazolylglycine DL-5-isothiazolylglycine DL-2-oxazolylglyoine DL-5-oxazolylglycine DL-3-isoxa zolylglyoine DL-5-isoxazolylglycine DL-3-(1,2,4-thiadiazolyl) glycine DL-5-(1,2,4-thiadiazolyl)glycine DL-(l-methyl-5-tetrazolyl)glycine DL-.(5-chloro-2-thienyl) glycine DL-(4-methyl-3-thienyl)glycine DL-(4-chloro-2-pyrrolyl)glycine one obtains 76-[t[DL-(aminocarbonyl)amino](2-.furyl)acetyD amino]-3[[(l-methyi-lH-tetrazol-5-yl)thiojmethyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 78-[[[dl-(aminocarbonyl)amino](3-furyl)acetyl]amino]-3[[(l-methyl-lH-tetrazol-5-yl)thiojmethyl]-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; -4343S3S 7B-EEEdL-(aminocarbonyl)amino](2-pyrrolyl)acetyl]amino]3- EC (l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 76-EEEDL- (aminocarbonyl)amino ] (3-pyrrolyl)acetyllamino-3EE (l-methyl-lHytetrazol-S-yl)thiojmethylJ-8-oxo-5-t hia-lazabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 7B-EEEDL-(aminocarbonyl)amino](2-pyridyl)acetyl]amino-3EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloE4.2.0]oct-2-ene-2-carboxylic acid·; 78-EEEdl-(aminocarbonyl)amino](4-pyridyl)acetyl]amino]-3EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 7g-EEEDL- (aminocarbonyl)amino](2-thiazolyl)acetyl]amino-3EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloC4.2„0]oct-2-ene-2-carboxylie acid; 73-EEEdl- (aminocarbonylJamino](5-thiazolyl)acetyl]amino]-3 EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicyclo 4.2.0 oct-2-ene-2-carboxylic acid; 70-CCEDL- (aminocarbonyl)amino](3-isothiazolyl)acetyl]~ amino]-3-EE (l-msthyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 7B-EEEDL- (aminocarbonyl)amino](5-isothiazolyl)acetyl]amino]-3-EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloE4.2,0]oct-2-ene-2-carboxylic acid; 70-EEEDL-(aminocarbonyl)amino](2-oxazolyl)acetyl]amino]-3EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloE4.2,0]oct-2-ene-2-carboxylic acid; 70-EEEdl-(aminocarbonyl)amino](5-oxazolyl)acetyl]amino]-3EE(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-lazabicycloE4.2,0]oct-2-ene-2-carboxylic acid; -44135 38 76-llCdL- (aminocarbonyl)amino](3~isoxazolyl) acetyl]amino]-3-CC(l-methyl-lH-tetrazol~5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloC4.2,0]oct-2-ene-2-carboxylic acid; 75- CXCDL-(aminocarbonyl)ainino](5-isoxazolyl)acetyl]amino]-3-CC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-l-azabicycloL4.2.0]oct-2-ene-2-carboxylic acid; 76- ^^011- (aminocarbonyl)amino] £3- (1,2,4-thiadiazolyl)]acetyl]amino]-3-CC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8oxo-5-thia-l-azabicycloC4.2.O]oct~2-ene~2-carboxylic acid; 76-CCCDL- (aminocarbonyl)amino] 5- (1,2,4-thiadiazolyl)]acetyl]amino]-3-CC(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8oxo-5-thia-l-azabicycloC4.2.0]oct-2-ene-2-carboxylic acid; 75- CCCDIi- (aminocarbonyl)amino] (l-methyl-5-tetrazoIyl)]acetyl]amino]-3-EC (l-methyl-lH-tetrazol-5-yl)thio]methyl]-8oxo-5-thia-l-azabieycloC4.2.0]oct-2-ene-2-carboxylic acid; s-CCCot-(aminocarbonyl) amino]L(5-chloro-2-thienyl)]acetyl]amino]-3-[X (1-methyl-lH-tetrazol-5-yl)thio]methyl]-8oxo-5-thia-l-azabicycloC4.2.0]oct-2-ene-2-carboxylic acid; 76- ECCdl- (aminocarbonyl)amino]E3- (4-methy1-3-thienyl)]acetyl]amino]-3-CL(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8oxo-5-thia-l-azabicycloC4.2.o]oct-2-ene-2-carboxylic acid; and 76-CCCDL-(aminocarbonyl)amino]E(4-chloro-2-pyrrolyl)]acetyl]amino]-3-EC(1-methy1-lH-tetrazol-5-yl)thio]methyl]-8oxo-5-thia-l-azabicycloC4.2.0]oct-2-ene-2-carboxylic acid; respectively. -45Examples 93-99 Following the procedure of example 71 but substituting for the methylisocyanate one of the following: ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate i-butylisocyanate t-butylisocyanate and pentylisocyanate LO one obtains: 7$-CCCd-(ethylaminocarbonyl) amino](2-thienyl) acetyl] amino]- 3-EC(l-methyl-lH-tetrazol-5-yl) thio]methyl]-8-oXo-5thia-l-azabioycloE4.2.0]oct-2-ene-2-carboxylic acid; 78-CCCd-(propylaminocarbonyl)amino](2-thienyl)acetyl] .5 amino]-3-EC(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia 1-azabicyclo C4.2.0]oct-2-ene-2-carboxylic acid; 78-EECd-(i-propylaminocarbonyl)amino](2-thienyl)acetyl]amino]-3-CC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia l-azabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 7 β-EECD-(butylaminocarbonyl)amino](2-thienyl)acetyl]amino]-3“EE(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia l-azabieycloC4.2.0]oct-2-ene-2-oarboxylic acid; 78-ECEd-(i-butylaminocarbonyl)amino](2-thienyl)acetyl]amino]-3-CC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia l-azabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 70-CCCD-(t-butylaminocarbonyl)amino](2-thienyl )acetyl]amino]-3-EC(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia l-azabicycloE4.2.0]oct-2-ene-2-carboxylic acid; 13S38 and 7S-[[ID-(pentylaminocarbonyl)aminoj(2-thienyl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl)-S-oxo-S-thial-azabicyclo [4.2.0]oct-2-ene-2-carboxylio aoid respectively.

Similarly by employing the methylisocyanate from example 71 or the alkylisocyanates of examples ,93-99 in place of the potassium cyanate in examples 64,. 67 and 72 to 92 other compounds within the scope of this invention are obtained.

Examples 100-125 Following the procedures of examples 65,67,68,69 or 72 but em· ploying the substituted 7-aminocephalosporanic acid derivatives shown in Col. A the products shown in Col. B are obtained.

Col. A Col. B h2nΓ γ cn COOR, 2-S-ft4 Ex.

I H 101 a 102 -4743838 Be. 103 104 105 106 Η 107 Η 108 109 ο AJ-C2H5 Ν-Ν 110 JT7 13538 Ex.

Ill 112 113 114 115 H C ,n XT 116 XT 117 13538 Ex.

Ca/2 119 Mg/2 120 Na N-N -tsjL-CH3 121 Na 122 Al/3 123 [CH3NH3]® CH 124 [(c6h5ch2)2nh2] N—N AJ’CH3 These same compounds can also be prepared according to the procedures of examples 64. and 69_.to.72 by substituting for the l-methyl-lH-tetrazole-5-thiol .the compound R^-S-H wherein is as set-‘forth above in Col. B.

Claims

CLAIMS :

1. A compound of the formula 0 II NH 0 Z H C0OK 3 wherein R 1 is hydrogen, lower alkyl, eycloalkyl of 3 to 7 carbons, cycloalkenyl of 3 to 7 carbons, cycloalkadienyl of h to 7 carbons, phenyl, phenyl-lower alkyl, thienyl, furyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, tetrazolyl in whioh any of said heterocyclics may have a halogen or lower alkyl substituent, or substituted phenyl or phenyl-lower alkyl wherein said phenyl substituent is selected from halogen, hydroxy, lower alkyl and lower alkoxy; R^ is hydrogen or lower alkyl; R^ is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion, substituted phenyl-lower alkyl wherein said substituent is halogen, lower alkyl or lower alkoxy, or the group II CH^—0—C— R wherein R is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl or phenyl-lower alkyl wherein said phenyl substituent is halogen, lower alkyl or lower alkoxy; and R^ is wherein R^ is hydrogen or alkyl of 1 to 4 carbon atoms.

2. , A compound of the formula 0 II Ei—CH —C—NHNH I C-0 N-Rx H S' coor 3 therein R 1 is thienyl, furyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl or tetrazolyl Ln which any of said heterocyclics may have a halogen or lower ilkyl substituents; and Rg, R^ and R^ are as defined in Claim 1. ). A compound according to claim 2 wherein R^ is thienyl, furyl, lyrrolyl or pyridyl; Rg is hydrogen or alkyl of 1 to 4 carbons; is hydrogen, alkyl of 1 to 4 carbons, benzyl, phenethyl, iphenyImethyl, trimethylsilyl, trimethylstannyl, aluminium, an lkaline earth metal, an alkali metal, or the group II — CH A —O-C-R -5213538 wherein R is alkyl of 1 to h carbons, phenyl, benzyl or phenethyl

3. 4. A compound according to claim 3 wherein R 1 is thienyl or pyridyl; R,, is hydrogen or methyl; R^ is hydrogen, diphenylmethyl or potassium; and R^ is ch 3

4. 5. A compound according to claim 4 wherein R 1 is 2-thienyl, 3-thienyl, or 3-pyridyl; and is

5. 6. A compound according to claim 5 wherein R^ is 2-thienyl, lo R 2 is hydrogen, R^ is hydrogen, and is jl si

6. 7. 7jB-[[[d-( aminocarbonyl)aminoj (2 - thienyl) ace tyl] CH, -5343538 aminoj- 3 - [fi 1 - methyl - IH - tetrazol

7. 8 - oxo - 5 - thia - 1 - azabicyclo -[4.2.0J carboxylic acid. 5 - yl)thiojmethylj oct - 2 - ene - 2 8. A compound according to claim 5 wherein is hydrogen, R^ is potassium, and R^ is R^ is 2-thienyl, R, CH S N II N

8. 9· A compound according to claim 5 wherein is hydrogen, is hydrogen, and is is 2-thienyl, Rg

9. 10. A compound according to claim 5 wherein R 2 is hydrogen, R^ is potassium, and R^ is N-M CH,

10. 11. A compound according to claim 5 wherein R 1 is 2-thienyl, R 1 is 2-thienyl, -5443533 Rg as methyl, R^ is hydrogen, and R^ is

11. 12. A compound according to claim 5 wherein R^ is 3-thienyl, Rg is hydrogen, R^ is hydrogen, and R^ is

12. 13. A compound according to claim 5 wherein R 1 is 3-pyridyl, Rg is hydrogen, R^ is hydrogen, and R^ is

13. 14. A compound of the formula N-R x I, H wherein R^ is hydrogen lower alkyl, eycloalkyl of 3 to 7 carbons, •5513538 cycloalkenyl of 3 to 7 carbons, cycloalkadienyl of k to 7 carbons, phenyl, phenyl-lower alkyl, or substituted phenyl or phenyl-lower alkyl wherein said phenyl substituent is halogen, hydroxy, lower alkyl or lower alkoxy; and R 2 , Rg and R^ are as defined in claim 1.

14. 15· A compound according to claim 14 wherein R 1 is cycloaikyl of 5 to 7 carbons, cycloalkenyl of 5 to 7 carbons, cycloalkadienyl of 5 to 7 carbons, phenyl, benzyl, phenethyl, or substituted phenyl, benzyl or phenethyl wherein said substituent is Cl, Br, alkyl of 1 to 4 carbons, hydroxy, or alkoxy of 1 to 4 carbons; R g is hydrogen or alkyl of 1 to 4 carbons; Rg is hydrogen, alkyl of 1 to 4 carbons, benzyl, phenethyl, diphenyImethyl, trimethylsilyl, trimethylstannyl, aluminium, an alkaline earth metal, an alkali metal, or the group II — CH—0—C —R wherein R is alkyl of 1 to 4 carbons, phenyl, benzyl or phenethyl. l6. A compound according to claim 15 wherein R^ is phenyl or 1,4cyclohexadien-l-yl; R g is hydrogen or methyl; Rg is hydrogen, diphenyImethyl, or potassium; and R^ is W-Μ M-M AAAA CHq

15. 17· A compound according to claim 16 wherein Rj is phenyl; Il 2 and Rg are both hydrogen; and R^ is -5643838

16. 18. Ί β~ [[[» - ( aminocarbonyl)amino](phenyl)acetyljamino] - 3 [[(1 - methyl - ΙΗ - tetrazol - 5 -yl)thiojmethyl] - 8 - oxo - 5 thia - 1 - azabicyclo-pt.2.o]oct - 2 - ene - 2 - carboxylic acid, 70 -[[[n - (aminocarbonyl)amino](pbenyl)acetyl] amino] - 3 [[(5 - methyl - 1,3,4 - tbiadiazol - 2 - yl)thio]me thyl] - 8 oxo - 5 - thia - 1 - azabicyclo - [4.2.0] oct - 2 - ene - 2 carboxylic acid.

17. 20, A process for preparing a compound according to claim 1 which 10 comprises reacting an alpha-ureido compound of the formula K, -CH-COOH NH— C— N-R, II | λ 0 H or an acylating derivative thereof with a 3-heterocvclic - 7 - amino substituted cephalosporin of the formula CH^-S-R^ -57in which Rp Rg, and R^ are as defined in claim 1, R^ being optionally protected with an ester group when the free acid product is desired.

18. 21. A compound according to claim 1 when prepared by a process according to claim 20.

19. 22. A compound according to claim 2 as named or shown in any of Examples 64 to 124.