IL46955A - 7-(alpha-furoylureidoaryl)cephalosporing antibiotics) - Google Patents

Abstract

Novel substituted 7-(alpha-ureidoacetamido)cephalosporins of the following formula <IMAGE> wherein R' = H or denotes methyl and R+R1 have the meaning defined in Claim 1, are prepared by reacting a compound of the formula II <IMAGE> with furoyl isocyanate or N-(2-furoyl)-N-methylcarbamoyl chloride. The free acids of the formula I, thus obtained, are also converted to their indanyl esters, phthalidyl esters and alkanoyloxymethyl esters having 1-4 C atoms in the alkyl part and, if desired, to their pharmaceutically acceptable salts. The said cephalosporins exhibit a broad spectrum of antibiotic action against gram-positive and gram-negative microorganisms. [GB1502342A]

Description

46955/2 7- (ALPHA-FUROYLUREIDOARYL) CEPHALOSPORIN ANTIBIOTICS '-nSDI^NB-i (ι77ΤΝ1Τ,ΝΤ1Κ,7',ηΐ3-Κ3ι7Κ)-7 D"P1'2'P3K Ο'Ίί-ΙΠ The present invention relates to novel ureido substituted cephalosporin compounds which have a broad antibiotic spectrum against both the gram-positive and gram-negative microorganisms.

Several antibiotics of the cephalosporin class have achieved an important status in the treatment and control of infectious diseases of man. For example, the well known cephalosporin antibiotics, cephalothin, cephaloglycin , cephaloridine, and cephalexin have been widely used in the treatment of infections in man. Considerable effort continues to be extended in the development of new cephalosporin antibiotics with increased antibiotic activity and particularly with an expanded spectrum of activity against the gram-negative microorganisms.

Cephalosporin compounds having a substituted a-amino group in the 7-arylacetamido side chain have been previously described. For example, U.S. Patent No. 3,646,024 describes certain 7- [a- ( 3-imidoylureido) arylacetamido] -cephalosporanic acids. a-Ureido phenylacetamidocephalosporanic acids have been described in in U.S. Patent No. 3,673,183.

The compounds provided by the process of this invention differ structurally from the compounds of the prior art in that the cephalosporin dihydrothiazine ring is substituted in the 3-position with a heterocyclic-thiome hyl group. In addition, the cephalosporin antibiotics described herein can be characterized as expanded spectrum cephalosporin antibiotics in that they not only possess the usual high level of activity against gram-positive microorganisms but they also possess a high level of activity against a broad spectrum of gram-negative microorganisms which the prior art compounds did not possess .

This invention relates to new cephalosporin antibiotics represented by the following general formula wherein Z is O or S R ' is hydrogen or methyl; R is phenyl, mothylphonyl, hydroxyphenyl, halophenyl, hydroxy substituted halophenyl, thienyl, -furyl or 1,4' cyclohexadieny1 ; R, is I R or wherein R^ is C^-C^ lower alkyl; R2 is hydrogen, an indanyl group, a phthalidyl group, or an acyloxymethyl group of the formula 0 II -CH -0-C wherein Y is C^-C4 alkyl or phenyl; and when is hydrogen, the pharmaceutically acceptable salts thereof.

In the above formula I,—the term "mc hylphenyl" refers to the mono and dimothylp onyl groupc ouch ac—4-mothylphonyl-, 3 mcthylphenyl;—3 ; 4-dimothylphonyl ; or 3 , 5-dimcth lphonyli— "Hydroxyphenyl" refers to the 3- and 4-monohydroxyphenyl groups, and to the 3 , 4-dihydroxy^ and 2 , 4-dihydroxyphenyl groups.

"Halophenyl" refers to the fluoro, chloro, and bromophenyl groups such as 4-chlorophenyl , 3-chlorophenyl , 3 , 4-dichloro-phenyl, 4-bromophenyl , or 4-fluorophenyl . "Hydroxy substituted halophenyl" refers to 3-chloro-4-hydroxyphenyl , 3 , 5-dichloro-4- hydroxyphenyl, or 3 , 5-dibromo-4-hydroxyphenyl . "Thienyl" -and "fuiyl" refer to the roopootivo 2- and 3- isomers thereof.

As described above, the heterocyclic radical in the 3-position of the cephem ring is substituted with a C^-C^ lower alkyl group. Representative of these groups are the 1-methyl-lH-tetrazole-5-yl group, the l-ethyl-lH-tetrazole-5-yl group, the 5-methyl-l,3,4-thiadiazol-2-yl group, the 5-isopropyl-1, 3, 4-thiadiazol-5-yl group, and like lower alkyl substituted tetrazole and thiadiazole groups.

The compounds of formula I wherein R'—io hydrogon are prepared by reacting a 7-phenylglycylamido, a substituted phenylglycylamido or a 1, 4-cyclohexadienylglycylamido 3-tetrazolethiomethyl or thiadiazolethiomethyl substituted cephalosporin of the following formula II with furoyl or thenoyl isocyanate as illustrated by the following reaction scheme : 0 H Formula I (R'=R =H) wherein R, ^ and Z are as previously defined. q?ho oompoundo roprooontod whon R'—io methyl aro proparod by aoylating the compound of fcho formula II with N- (a-furoyl) -N-mothyloarbamoyl ohlorido or —(a theno l) - The acylation of the glycylamido cephalosporin of . formula II with the carbamoyl chloride is carried out in an inert solvent at a temperature between about -15 and 10°C. in the presence of a hydrogen halide acceptor.

Inert solvents such as acetonitrile and tetrahydro-furan can be used conveniently. Hydrogen halide acceptors such as the tertiary amines, triethylamine, and pyridine; and the alkylene oxides such as propylene oxide and butylene oxide can be used. Equimolar amounts of the starting material and the carbamoyl chloride are used. 46955/2 The 7-thienylglycylamido, 7-phenylglycylamido and 7-substituted phenylglycylamido- 3-heterocyclic thiomethyl cephalosporin starting materials of the formula II are prepared by acylating a 7-amino-3-heterocyclic-thiomethyl-substituted cephalosporin nucleus compound with an active derivative of phenylglycine or a substituted phenylglycine, for example, the acid chloride, in the presence of a hydrogen halid acceptor such as triethylamine or sodium carbonate, to provide the acylated phenylglycylamido cephalosporin starting material .

The reaction of the starting material of the formula II with furoyl isocyanate is carried out in the following manner. The starting material of the formula II is suspended in an inert solvent at about 20-25°C. and a silylat-ing agent such as bis-(trimethylsilyl)acetamide (BSA) or mono-silylacetamide (MSA) is added in excess to form a homogenous solution. Inert solvents such as tetrahydrofuran, dichloro-methane, chloroform, or dioxane can be used. After obtaining a solution of the silylated derivative of the starting material, the reaction mixture is cooled in a dry ice-acetone bath to a temperature of approximately -75 to -80 °C. To the cold solution is added, in excess, the isocyanate. The reaction mixture is then allowed to stir in the cold for about 3 hours and is thereafter allowed to warm to room temperature. Methanol is added to the reaction mixture to decompose excess silylating agent and the mixture is then evaporated under reduced pressure to remove the volatile solvents. The ureido reaction product is then extracted from the residue with ethyl acetate. The product is purified with an acid-base wash and can be further purified by recrystallization .

By way of illustration of the above preparation methods, 7-amino-3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid is acylated with phenylglycyl chloride hydrochloride in the presence of sodium carbonate to yield 7-phenylglycylamido-3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid. The above acylation product is then reacted with furoylisocyanate following the solubilization of the phenylglycylamido acylation product in tetrahydrof ran with MSA, to provide a compound of the invention wherein R is phenyl is the 1-methyl-lH-tetrazole substituent, R' is H and R is hydrogen .

The compounds represented by formula I wherein R2 is an acyloxymethyl group are prepared by reacting a salt, for example, an alkali metal salt of the free acid compound of formula I with a lower alkanoyloxymethyl halide or with a halomethyl benzoate. Lower alkanoyloxymethyl halides which can be employed are, for example, chloromethyl acetate, chloromethyl propionate, bromomethyl acetate, bromomethyl butyrate, chloromethyl pivaloate, and like halomethyl esters of the lower alkyl straight and branched chain C, -C . alkyl carboxylic acids.

When Υ is phenyl, bromo or chloromethylbenzoate can be used in like manner to prepare the benzoyloxymethyl ester. The reaction is carried out by reacting the salt of a cephalosporin acid of the formula I, for example, the sodium or potassium salt with the halomethyl ester in an inert solvent from about 20° to about 55 °C. Inert solvents which can be employed include, for example, dimethyIformamide (DMF) , dimethylacetamide (DMAC) , tetrahydrofuran, and dioxane. For example, sodium 7- [a- (3-furoyl-l-ureido) phenylacetamido] -3- ( 1-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylate is reacted in aqueous DMF with chloromethyl acetate to provide the acetoxymethyl ester of the cephalosporin acid.

The 5-indanyl esters of the formula I are prepared by esterifying the cephalosporin acid with the phenolic 5-indanol. The indanyl esters can be prepared by the conventional procedures used for preparing phenolic esters of carboxylic acids. For example, an active derivative of the cephalosporin acid such as is formed with ethylchloroformate is reacted with 5-indanol.

The phthalidyl esters of the formula I are prepared by reacting bromophthalide with a salt of the cephalosporin acid, for example, the sodium or potassium salt. Bromophthalide of the formula 0 is prepared in known manner by the reaction of phthalide with N-bromosuccinimide. τ The acyloxymethyl esters of the formula I are orally effective forms of the antibiotic acids.

Pharmaceutically acceptable salts of the compounds represented by formula I are prepared by methods commonly practiced in the cephalosporin art. Representative pharmaceutically acceptable salts include the alkali metal salts, for example, the sodium, potassium, and lithium salts, the calcium salt, the ammonium salt, the lower aliphatic ammonium salts, for example, those salts formed with methylamine, dimethylamine , diethylamine , or di-n-propylamine; and the hydroxyalkyl ammonium salts, for example, those formed with ethanolamine or diethanolamine . Preferred pharmaceutically acceptable salts include the alkali metal salts, for example, the sodium salt and the potassium salt. The pharmaceutically acceptable salts of the compounds of formula I are prepared by methods well known in the cephalosporin art. For example, the free acid form of the antibiotic is neutralized with an alkali metal hydroxide or carbonate or with ammonium hydroxide or with the desired alkylamine or ethanolamine to form the salt.

The compounds represented by formula I are illustrated by the following compounds. 7- [a- ( 3-a-furoyl-l-ureido) -a-phenylacetamido] -3- (1-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- [a- (3-a-furoyl-l-ureido) -a- (4-hydroxyphenyl) -acetamido] -3- ( 5-methyl-l, 3 , 4-thiadiazole-2-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- [a- ( 3-a-furoyl-l-ureido) -a- (a-thienyl) acetamido] -3-(l-ethyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- [α- ( 3-a-furoyl-l-ureido) -a- ( 3-chloro-4-hydroxy-phenyl) acetamidoj -3- ( l-methyl-lH-tetrazole-5-y1 thiomethyl) -3-cephem-4-carboxylic acid, 7- [a- (3-a-furoyl-l-ur'eido) -a- (3-hydroxyphenyl) -acetamido] -3- ( 5-me h 1-1 , 3 , 4-thiadiazole-2-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- [a- ( 3-a-furoyl-l-ureido) -a- ( -chlorophenyl) -acetamido] -3- (5-methy1-1,3, 4-thi'adiazole-2-ylthiomethyl) -3-cephem-4-carboxylie acid, 7- [a- (3-a-furoyl-l-ureido) -a- (3, 5-dichloro-4-hydroxyphenyl) acetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- [a- (3-a-furoyl-l-ureido) -a- ( 3-brpmophenyl) -acetamido] -3- ( l-methyl-lH-tetrazole-5-ylthiomethy1) -3- cephem-4-carboxylic acid, 7- [a- (3-a-thenoyl-l-ureido) -a- (4-hydroxyphenyl) -acetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4- carboxylic acid, 7- [a- (3-3-thenoyl-l-ureido)-a-phenylacetamido]-3- (5-methyl-l, 3 , -thiadiazole-2-ylthiomethyl) -3-cephem-4- carboxylic acid, The compounds represented by formula I and the pharmaceutically acceptable salts thereof inhibit the growth of microorganisms pathogenic to animals and man. In particula these compounds inhibit the growth of a broad spectrum of gram-negative and gram-positive microorganisms. They are further active in inhibiting the growth of penicillin resistant Staphylococcus organisms. Accordingly, the compounds of the invention are useful in combating infections in animals an man attributable to gram-positive and gram-negative micro- ureido organisms . The furoy^ and Lhenoylurcido-cephalosporins are effective against gram-negative microorganisms of the indole-positive and indole-negative Proteus sp. , the Aerobacter sp., the Pseudomonas , the Enterobacter sp. , the Serratia, e.g., S. marcescens , Escherichia coli , and Klebsiella. They are also highly effective against the Streptococcus D group of bacteria as well as Staphylococcus aureus and penicillin resistant strains of Staphylococcus .

The compounds of formula I can be administered by the parenteral route, for example, intramuscularly or intravenously. When administered in non-toxic doses ranging between about 25 and about 1,000 mg. per kg. of the patient's body weight, the compounds are effective in the treatment of infectious diseases attributable to both the gram-positive and gram-negative microorganisms. The compounds of this invention can be formulated for such administrative routes as aqueous suspensions or solutions suitable for injection.

For example, the compounds of the invention, as the alkali metal salts, can be employed in sterile aqueous solutions for injection or they can be prepared as sterile suspensions in an inert pharmaceutical carrier suitable for injection.

When administered intravenously, the salt form of the compound of the invention, for example, the sodium salt, can be dissolved in one of the standard clinical I.V. solutions, for example, I.V. dextrose, for administration via I.V. drip.

Pre rred compounds are thos© roprooontcd by formula ' I wherein P. is. phenyl,—hydroxypheny1 ,—halophonyl ,—hydroxy subsLibuted halophcnylj or thionyl.

A& eopceially preferred group of compounds are those represented when R is phenyl, hydroxyphenyl , or hydroxy substituted halophenyl especially hydroxy substituted chlorophenyl, and the pharmaceutically acceptable non-toxic salts thereof. The preferred compounds described above are illustrated by: 7- [a- (3-a-furoyl-l-ureido) -a-phenylacetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- [a- ( 3-a-furoyl-l-ureido) -a- ( 4-hydroxyphenyl) - acetamido] -3- (5-methyl-l, 3 , 4-thiadiazole-2-ylthiomethyl) -3- cephem-4-carboxylic acid, 7- [a- ( 3-a-furoyl-l-ureido) -a- ( 3-hydroxyphenyl) - acetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3- cephem-4-carboxylic acid, 7- [a- (3-a-furoyl-l-ureido) -a- (3-chloro-4-hydroxy- phenyl) acetamido] -3- ( 1-methyl-lH-tetrazole-5-ylthiomethyl) - 3-cephem-4-carboxylic acid, 7- [a- (3-a-furoyl-l-ureido) -a- ( 3 , 5-dichloro-4- hydroxyphenyl) acetamido] -3- (5-methyl-l , 3 , 4-thiadiazole-2- ylthiomethy1) - 3-cephem-4-carboxylie acid, ,£=> -?—£et—(3· a- furoyl- -mcthyl-l urcido)—a- (4 hydroxy- phenyl) acetamido]—3—(l-mcth l-lH-totragolG-5- lthiomethyl)— 3-oophom-4"oarboKylic acid,—and tho pharmaooutioally- trccepfeablc non-to.iio caltc thoroo£-> The antibiotic activity of the compounds of formula I is illustrated by the in vitro data presented in the following Tables I and II for two of the preferred compounds. In the tables, the minimum inhibitory concentrations (MIC) of the test compounds versus the indicated gram-positive and gram-negative microorganisms is presented. The MIC values were determined by 83A the gradient plate method which is essentially the method described by Bryson and Szybalski, Science , 116 , 45-46 (1952) Table I lists the in vitro antibiotic activity demonstrated by the test compounds against representative gram-negative microorganisms. Table II lists the inhibitory activity in terms of MIC values against clinical isolates of penicillin resistant Staphylococcus microorganisms both in the presence of and in the absence of serum.

TABLE I Antibiotic Activity of 7- [a- ( 3-Furoyl-l-ureido) phenyl- (hydroxyphenyl) acetamido] cephalosporins vs. Gram Microorganisms MIC (mcg/ml) Test Compound A1 B2 Shigella sp. 5.5 5.5 Escherichia coli 7.0 5.8 Klebsiella pneumoniae 5.0 6.3 Aerobacter aerogenes 7.5 6.5 Salmonella heidelberg 6.8 5.8 Pseudomonas aeruginosa 12.3 10.7 Serratia marcescens 19.5 14.5 ureido) -a-phenylacet- amido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem- 4-carboxylic acid.

Test Compound B=7- [a- (3-a-furoyl-l-ureido) -a- (4-hydroxy- phenyl) acetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) 3-cephem-4-carboxylic acid.

TABLE II Antibiotic Activity of 7- [a- ( 3-Furoyl-l-ureido) - (hydroxyphenyl) acetamidocephalosporins vs.

Resistant Staphylococcus Resistant MIC (mcg/ml) Staph . Test Compound B 2 NS S3 NS S V-41 3.0 8.0 5.0 >20 V-32 4.5 8.0 13.7 >20 X-400 >20 >20 >20 >20 V-84 0.4 1.0 1.0 1.0 XI.1 0.4 1.0 1.0 1.0 Test compounds A & B are respectively the test compounds of Table I. 2 Compound tested in the absence of serum. 3 Compound tested xn the presence of serum.

As indicated by the in vitro data presented above for two of the preferred compounds, the furoylureido cephalosporin compounds disclosed herein are resistant to the action of the enzymes, penicillinase and cephalosporinase , generated respectively by the penicillin-resistant Staphylococci and the gram-negative organisms .

The preparation of the compounds represented by formula I is further illustrated by the following examples.

Example 1 To a suspension of 0.6693 g. of 7-phenylglycyl-amido-3- ( l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid in 100 ml. of dry tetrahydrofuran was added an excess of monosilyl acetamide to form a solution. Linde 4A molecular sieve was added and the mixture was cooled in dry ice-acetone bath. An excess of furoyl isocyanate was added to the cold mixture with stirring. Stirring was continued in the cold for 2 hours and then the mixture was allowed to warm to room temperature. Fifty milliliters of methanol were added and the reaction mixture was filtered.

The filtrate was evaporated under reduced pressure to remove volatile solvents. The residue was dissolved in aqueous sodium bicarbonate and the solution was extracted with ethyl acetate. The aqueous phase was acidified to about pH 1.5-2.0 with dilute hydrochloric acid and was extracted with ethyl acetate. The extract was concentrated and was then diluted with about an equal volume of petroleum ether to precipitate the product, 7- [a- ( 3-a-furoyl-l-ureido) -a-phenyl- . acetamido] -3- ( l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

The nuclear magnetic resonance spectrum of the product run in deuterated dimethyl sulfoxide was in agreement showing peaks at 65.10 and 65.70 for the and 3- lactam protons; multiplets at 64.32 and 63.65 for the methylene protons and a singlet at 64.00 for the N-methyl protons of the tetrazole group.

Example 2 To a suspension of 0.955 g. of 7- (4-hydroxyphenyl-glycylamido) -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid in 100 ml. of tetrahydrofuran was added excess monosilylacetamide. To the resultant solution was added molecular sieve (Linde 4A molecular sieve) and the mixture cooled in a dry-ice acetone bath. A slight excess of furoyl isocyanate was then added with stirring.

The reaction mixture was stirred in the cold for 3 hours and was then allowed to warm to room temperature. Methanol, 100 ml., was added and the mixture was then evaporated under reduced pressure to remove volatile solvents. The residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was washed with ethyl acetate. The solution was then acidified with dilute hydrochloric acid to about pH 2 and extracted with ethyl acetate. The extract was concentrated and the concentrate diluted with petroleum ether to precipitate the reaction' product, 7- [a- ( 3-furoyl-l-ureido) -4-hydroxyphenylacetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid. The product was further purified by crystallization /from methanol-diethyl ether-pentane (Skelly-solve-B) .

(DKSO Hit 3. 2 (bSj 2 C2-E), 3. *. (s, 3, tf-CH.j, ^.32 (s 2, C -H), 5.0 (d, l, J = k.Q a=, C H), 3 ' 5.0 (ε, 2) an≤ 6.7-8.O (n, Ar-E) . 0 Example 3 Following the procedures of Example 1, furoyl isocyanate is reacted with 7-phenylglycylamido-3- (5-methyl-1, 3, -thiadiazole-2-ylthiomethyl) -3-cephem-4-carboxylic acid to obtain 7- [a- (3-a-furoyl- 1-ureido) -a-phenylacetamido] -3-(5-methyl-l, 3 , 4-thiadiazole-2-ylthiomethyl) -3-cephem-4-carboxylic acid.

Example 4 « 7- [a- (3-a-Furoyl-1-ureido) -a- (3-chloro-4-hydroxy-phenyl) acetamido] -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid is prepared by the reaction of furoyl isocyanate with 7- (3-chloro-4-hydroxyphenylglycyl-amido) -3- (l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

Example 5 7- [a- ( 3-a-furoyl-l-ureido) -a- (a-thienyl) acetamido] -3- ( l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

To a suspension of 467 mg of 7- la- (a-thienyl) -a-arnino-acetamido] -3- ( l-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid in 100 ml of dry THF were added 2 g of mono- (trimethylsilyl) aceta ide (MSA). When solution, had occurred a small amount of molecular sieve was added to maintain dryness and the solution was cooled to QIC. To the cold solution was added a solution of an excess of furoyl isocyanate in 2 ml of THF. The reaction mixture was stirred at 0°C. for 3 hours and was then allowed to warm to room temperature. The reaction mixture was filtered and 5 ml of methanol were added to the filtrate. The filtrate was evaporated and the residue was layered with ethyl acetate and water. The pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid and the organic layer was separated. The organic layer was treated with a dilute solution of sodium bicarbonate to pH 7.2. The aqueous layer 46955/2 was separated and acidified to pH 2 with dilute hydrochloric acid at ice bath temperature. The acidified solution was extracted with ethyl acetate. The extract was dried and evaporated and the residue recrystallized from a mixture of acetone-diethyl ether-petroleum ether to yield a first crop of product weighing 45 mg, a second crop weighing 83 mg and an additional 24 mg of product from the filtrate. n Vtf

Claims (7)

46955/2 WHAT IS CLAIMED IS:

1. Compounds of the formula I wherein Z is 0; R' is hydrogen^ R is phenyl, hydroxyphenyl, halophenyl, hydroxy substituted halophenyl or thienyl; R, is wherein is C^-C^ alkyl; R2 is hydrogen, indanyl, phthalidyl, or an acyloxymethyl group of the formula 0 t l -CH2-0-C-Y wherein Y is C^-C^ alkyl or phenyl; and when R2 is hydrogen, the phrmaceutically acceptable non-toxic salts thereof.

2. The compound of claim 1, wherein R is phenyl, hydroxyphenyl, or hydroxy substituted halophenyl, and R2 is hydrogen.

3. The compound of any of claims 1-2, wherein 1 is 46955/3

4. . The compound of any of claims 1-3, said compound being 7- [cyf-fS- ^-furo l-l-ureido) -^-phenylacetamido]-3- (l-methyl-lH-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

5. The compound of any of claims 1-3, said compound being 7-[e^-(3-V-furoyl-l-ureido)-c>^-(4-hydroxyphenyl) acetamido] -3- (1-methy1-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

6. The compound of claim 1 wherein R is thienyl.

7. The compound of claim 6, said compound being 7-[o^- , (3-oC-furoyl-l-ureido) -¾.-(«.<-thienyl) acetamido] -3- (1-methyl-lH-tetrazole-5-ylthiomethyl) -3-cephem-4-carbox lic acid. 46955/2 -r5.-.rl. A process for preparin^compounds of formula I wherein Z, R, R^, R' and R2 are as defined in claim 1, which comprises reacting a compound&f the formula II 0 H COOH with a compound of the formula III wherein A is -N=C=0 or -N-C-Cl ; and if desired converting the acid so obtained wherein R2 is hydrogen to the corresponding ester wherein R2 is other than hydrogen. A process for preparing compounds of the formula I wherein Z R, R', R^, and R2 are as defined in claim 1, substantially as hereinbefore described with particular reference to the examples. r?-. Compounds of the formula I wherein Z , R, R' , R^ and are as defined in claim 1, substantially as hereinbefore described with particular reference to the examples. AGENTS FOR APPLICANTS