GB1598517A - 7-beta-(2-amino-1,2-dioxoethyl-amino)acyl cephalosporin derivatives - Google Patents

Description

(54) 7- C2-AMTNO-1 ,ZDIOXOETHYLAMINOT ACYL CEPHALOSPORIN DERIVATIVES (71) We, E. R. SQUIBB & SONS INC., a corporation organised and existing under the laws of the State of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey 08540 United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statememt: This invention provides new 7ss - [(2 - amino - 1,2 - dioxoethyl)amino]acyl cephalosporin derivatives which have the formula

R represents hydrogen, lovrer alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)-stannyl (except when R8 is H), trihaloethyl or a salt forming ion.

R, represents hydrogen, lower alkyl, saturated or unsaturated cycloalkyl (as defined below), phenyl, phenyl-lower alkyl, substituted phenyl (as defined below) or certain heterocyclic groups.

R2 represents hydrogen or methoxy. The R2 substituent is in the α-configuration as indicated by the broken lines.

Rs represents hydrogen, lower alkyl, phenyl-lower alkyl (except when Ra is H) or cyclcaikyl.

R8 represents hydrogen or -CR4R5-CN.

R4 and R5 each represent hydrogen or lower alkyl.

X represents hydrogen, lower alkanoyloxy, carbamoyloxy, lower alkoxy, lower alkylthio, certain heterothio groups,

When X is pyridinium or carbamoyl substituted pyridinium, the compounds can be structurally represented as having the formula

wherein Z is hydrogen or carbamoyl.

The asterisks indicate asymmetric carbon atoms.

The various groups represented by the symbols have the meanings 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 7 carbon atoms, preferably 1 to 4 carbons, and especially 1 or 2 carbons. Examples of the type of groups contemplated are methyl, ethyl, propyl, isopropyl, butyl and t-óutyl. The lower alkoxy and lower alkylthio groups are such lower alkyl groups attached to an oxygen or sulfur, respectively, e.g., methoxy, ethoxy, propoxy, methylthio, ethylthio and propylthio. The phenyllower alkyl and diphenyl-lower alkyl groups are such lower alkyl groups attached to one or two phenyl rings, preferably benzyl, phenethyl and diphenylmethyl.

The saturated and unsaturated cycloalkyl groups are the alicyclic groups having up to 7 carbons and up to 2 double bonds in the ring, i.e., the cycloalkyl groups cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, the cycloalkenyl groups having up to 7 carbons with one double bond, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl and the cycloalkadienyl groups having up to 7 carbons with two double bonds located at various positions such as 1,4-cyclehexadienyl which is especially preferred.

The substituted phenyl groups have one or two substituents selected from halogen (preferably chlorine or bromine), lower alkyl (preferably having 1 to 4 carbons, especially methyl or ethyl), lower alkoxy (preferably having 1 to 4 carbons especially methoxy or ethoxy), and hydroxy, e.g., 2-, 3-, or 4-chiorophenyl, 2-, 3-, or 4-bromophenyl, 2-, 3-, or 4-hydroxyphenyl, 3,5-dichlorophenyl, 2-, 3-, or 4-methylphenyl and 2-, 3- or 4-ethoxyphenyl.

The salt forming ions represented by R are metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, phenyl-lower alkylamines such as dibenzylamine, N,-dibenzylethylenediamine, lower alkylamines such as methylamine, triethylamine, and N-lower alkylpiperidines such as N-ethylpiperidine. Sodium and potassium are the preferred salt forming ions.

The halogens are the four common halogens, of which chlorine and bromine are preferred. In the case of the trihaloethyl group represented by R ,2,2,2-trichloroethyl is preferred.

Trimethylsilyl is the preferred tri(lower alkyl)silyl group.

The heterocyclic groups represented by R1 are thienyl, furyl or pyridyl, i.e., 2thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrodyl, 3-pyridyl or 4-pyridyl.

Lower alkanoyloxy refers to a group of the formula

lower alkyl preferably wherein the lower alkyl group is methyl. The lower alkanoyloxy groups normally have up to seven carbons of which those having up to 4 carbons are preferred and acetyloxy is especially preferred.

The heterothio groups represented by X are

(except when Rs is H)

(except when Rs is H)

wherein R6 is hydrogen or lower alkyl (preferably having 1 to 4 carbons, especially methyl or ethyl) and R7 is carboxy (COOH) or the ion-COO - ion+, -COO-lower alkyl, - SO3H, -SO2-lower alkyl or cyano. R6 is preferably hydrogen.

The products of this invention are produced by acylating a cephem compound having the formula (II)

with an acid having the formula

or an activated derivative such as the acid halide, activated ester such as the nitrophenyl ester or dinitrophenyl ester, or mixed anhydride, and/or in the presence of a coupling agent like dicyclohexylcarbodiimide.

The compound of formula II is preferably in the form of an ester, i.e., R is an easily removable group such as diphenylmethyl, which is preferred, t-butyl or trimethylsilyl.

One preferred synthesis comprises reacting the acid of formula III first with chloroformic acid alkyl ester in the presence of a base such as triethylamine and then with the diphenylmethyl ester of the compound of formula II. The resulting ester is then hydrolyzed with trifluoroacetic acid and anisole to obtain the free carboxyl group in the 4-position. A salt can be obtained from the acid by reaction with the base having the desired cation.

This reaction can be carried out, for example, by dissolving or suspending the acid in an inert organic solvent such as chloroform, tetrahydrofuran, methylene chloride, dioxane or benzene, and adding, at a reduced temperature of about 0--5" C., using about an equimolar amount of the compound of formula II. The product of the reaction is then isolated by conventional procedures, e.g., by concentration or evaporation of the solvent.

According to an alternative method a compound having the formula

preferably in the form of a salt such as the trifluoroacetic acid salt, is dissolved or suspended in an organic solvent such as acetonitrile, methylene chloride, chloroform, di methylformamide, tetrahydrofuran, dioxane or benzene, and converted to an ester, for example forming the trimethylsilyl ester by reaction with bis-(trimethylsilyl) acetamide. The product is then made to react with a compound having the formula

wherein hal represents a halogen, preferably chlorine, in an organic solvent such as those mentioned above at a reduced temperature, e.g., about 0" C. and in the presence of a neutral acid scavenger such as propylene oxide or butylene oxide.

The compounds of formula I wherein X is pyridinium or carbamoyl substituted pyridinium can be prepared by reacting a compound of formula I wherein X is acetoxy with pyridine or carbamoyl substituted pyridine in a polar solvent such as water and in the presence of a catalyst such as an alkali metal thiocyanate by the method described in U.S. Patent Specification No. 3,792,047 and German Offenlegungsschrift 2,234,280.

Compounds of formula I wherein X is a heterothio group can also be produced by first producing a compound of formula I wherein X is acetoxy and then reacting this product with a mercaptan of the formula hetero-SH (VI) or an alkali metal (preferably sodium) salt of the formula hetero;S-alkali metal (VII) by the methods described in U.S. patent Specifications 3,855,213; 3,890,309; and 3,892,737.

The starting material of formula III where Ra is hydrogen is produced from an a-amino acid ester having the formula

wherein R1 has the same meaning as defined above and Y is a readily removable group, e.g., diphenylmethyl, nitrophenyl, dinitrophenyl, t-butyl or trimethylsilyl, which is reacted with an oxalic acid derivative having the formula

wherein hal represents halogen, preferably chlorine, and Z is lower alkyl, in the presence of a base such as triethylamine. This reaction yields an intermediate having the formula

Treatment of this intermediate with an acid, e.g., trifluoroacetic acid and anisole, yields the free acid having the formula

Treatment of the product of formula IX with ammonia or an amine NHR3 and then acidifying yields the acylating agent III. Activated derivatives thereof are produced by reaction with thionyl chloride, an esterifying agent, or an anhydride, by conventional procedures.

Alternatively, an amino acid ester of formula VI, preferably the diphenylmethyl ester, nitrophenyl ester or dinitrophenyl ester, is reacted with an oxalyl halide such as oxalyl chloride to obtain a compound of the formula

wherein hal represents halogen, preferably chlorine, and Y is one of the foregoing ester groups such as diphenyl methyl, p-nitrophenyl or 2,4-dinitrophenyl. Reaction of this derivative with ammonia or an amine HN-R, yields a product of the formula

When Y is nitrophenyl or dinitrophenyl, the intermediate of formula XI can be reacted with the compound of formula II.

When Y is diphenylmethyl in formula XI it is preferable to react this intermediate with an acid, e.g., hydrochloric acid in glacial acetic acid, to form a compound of the formula

which is then reacted with the compound of formula II, preferably in the form of its diphenylmethyl ester, the ester group then being removed as described.

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

The starting material of formula III where Ra is other than hydrogen is produced from an a-amino acid ester having the formula

wherein R1 has the same meaning as defined above and Y is a readily removable group, e.g., diphenylmethyl, nitrophenyl, dinitrophenyl, t-butyl or trimethylsilyl, which is reacted with an oxalyl halide such as oxalyl chloride to form an intermediate having the formula

wherein hal represents halogen, preferably chlorine, in a solvent such as dioxane. This intermediate is then reacted with a compound having the formula

e.g., in an organic solvent such as those mentioned above in the presence of an organic base such as dimethylaniline at a reduced temperature, e.g., about 200 C, and treatment of this intermediate with an acid, e.g., trifluoroacetic acid and anisole, yields the free acid of formula III.

Alrernatively, the starting material of formula III can be produced from the starting material of formula VI by reacting the latter with a compound having the formula

The carboxylate salts of the compound of formula I are formed by reacting the carboxyl group of the cephalosporanic acid moiety, i.e., R 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 asymmetric carbon atoms indicated by the asterisks. 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.

Preferred compounds of this invention are the acids and alkali metal salts of formula I (i.e. R is hydrogen, sodium or potassium) wherein X is acetoxy or heterothio especially l-methyl-1H-tetrazol-5-ylthio; R1 is cyclohexadienyl, phenyl or heterocyclic selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl and 4-pyridyl; R2 is hydrogen or methoxy especially hydrogen; and R@, R@ and R@ each is hydrogen or lower alkyl, especially hydrogen, and especially the D-isomers thereof.

The most preferred final compounds are the acids and alkali metal salts of formula I wherein R1 is 2-thienyl, or phenyl most especially 2-thienyl; R2, R,, R4 and R5 each is hydrogen; and X is heterothio particularly wherein X is

The acid compounds of formula I have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as StaphyZolcoccms aureus, Salmonella schottmurllen, Pseudomonas aeruginosa, Protsus rettgeri, Eschertchia cofi, Enterobacter hafniae, Enterohacter cloacar, Klebsiella pneumoniae, and Serratia marcescens. They may be used as antibacterial agents to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephradine and other cephalosporins. For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of 1 to 100 mg/kg. e.g. 5.0 mg/Kg in mice, daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin.

Up to about 600 mg. of an acid compound of formula or & a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablet, capsule or elixir or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

Thus, the invention extends to pharmaceutical compositions comprising a compound of formula I and a pharmaceutical carrier.

Illustrative process details are provided in the examples. All temperatures are in degrees celsius.

Example 1.

[D - a - [(2 - Ethoxy - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid, diphenyl methyl ester.

3.2 g. (20 mM) of 2 - D - thienylglycine diphenylmethyl ester are dissolved in 50 ml. of methylene chloride. 1 g. of triethylamine is added and 1.3 g. (20 mM) of oxalic acid chloride ethylester in 20 ml. of methylene chloride are added dropwise at --20". After 2 hours, the reaction solution is shaken with water, dried over sodium sulfate and the solvent is distilled off in vacuum. The residual syrup is the pure product, [D - a - [(2 - ethoxy - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid, diphenylmethyl ester.

Example 2.

D - a - [(2 - Ethoxy - 1,2 - dioxoethyl)amino] - 2 - thiophene acetic acid.

To 9.5 g. of D - a - [(2 - ethoxy - 1,2 - dioxoethyl)amino] - 2 - thiophene acetic acid, diphenylmethyl ester are added 50 ml. of a mixture of trifluoroacetic acid and anisole (4:1) at --100. The trifluoroacetic acid and anisole are distilled off to yield an oily residue which is taken up in 100 ml. of saturated sodium bicarbonate solution. This is extracted twice with 20 ml. of ether and the aqueous phase is acidified with hydrochloric acid. Repeated extraction with ethyl acetate and evaporation of the ethyl acetate solution yields D - a[(2 - ethoxy - 1,2 - dioxoethyl)aminoj - 2 - thiophene acetic acid as a brownish syrup which does not crystallize, yield 6.5 g.

Example 3.

D - a - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid.

6.5 g. of D - a - [(2 - ethoxy - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid are dissolved in 100 ml. of 5N alcoholic ammonia solution and kept in a glass autoclave at 4050 for 10 hours. The reaction mixture is evaporated, the residue is dissolved in water and acidified to yield D - a - [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thiophenacetic acid in the form of white crystals which are recrystallized from water, yield 4.8 g.; m.p. 173-175 .

Example 4.

7 - - [[D - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thienylacetyl] - amino] 3 - [[(1 - methyl - lH - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 azabicyclo[4.2.0] oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester.

1.2 g. (5mM) of D - a - [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid are dissolved in 50 ml. of absolute tetrahydrofuran and 0.5 ml. of triethylamine is added. 0.55 g. (6 mM) of chloroformic acid ethyl ester in 10 ml. of tetrahydrofuran is added dropwise at - 100. After 30 minutes, this reaction solution is added dropwise to a solution of 2.5 g. (5 mM) of 7 - amino - 3 - [[(1 - methyl1H - tetrazol - 5 - yl)thio]methyl]cephalosporanic acid diphenylmethyl ester, in 30 ml. of tetrahydrofuran. The mixture is stirred for 3 hours at 5 . The reaction solution is filtered and the filtrate is evaporated to obtain a brown, solid foam which is dis solved in 25 ml. of methylene chloride and treated with charcoal. 200 ml. of ether are poured in whereupon 7 - p - [[D - [(2 - amino - 1,2 - dioxoethyl)amino] - 2thienylacetyl]amino] - 3 - [[(1 - methyl - !H - tetrazol - 5 - yl)thio] - methyl] 8 - oxo - 5 thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester precipitates as a beige powder, yield 3.2 g., m.p. 106 (dec.).

Example 5.

7 - [[D - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thienylacetyl] - amino] 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 thia - 1 azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.

2.3 g. of the product of Example 4 are stirred for 10 minutes at 0 in a mixture of trifluoroacetic acid and anisole (4:1). After evaporating the trifluoroacetic acid and anisole in vacuum, ether is added to the residual oil which then solidifies. The solid is dissolved in 3N sodium bicarbonate solution, filtered and acidified with 2N hydrochloric acid to pH 3. The product, 7 - [[D - [(2 - amino - 1,2 - dioxo ethyl)aminoj - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl) thio]methylj - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, precipitates as a brown powder which is dried, dissolved in tetrahydrofuran, treated with charcoal and the acid precipitated with ether as a light beige powder, yield 0.78 g., m.p. 158-161 .

Example 6.

D - α - [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetyl chloride.

2.3 g. of D - α - [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid are suspended in 80 ml. of acetonitrile and 1.2 g. of thionyl chloride are added all at once at 20o. The temperature is allowed to rise to room temperature and the solvent is distilled off in vacuum. The sticky, brownish residue is treated with ether to obtain a light beige, solid powder. The infrared spectrum shows the desired acid chloride which is used immediately since decomposition occurs on storage.

Example 7.

7 - [[D - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thienylacetyl]amino] - 3 [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - aza bicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.

2.2 g. (7.5 mM) of D - a - [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thio- pheneacetyl chloride are added at - 100 to a solution of 2.5 g. (7.5 mM) of 7 - amino3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)tbio]methylj - 8 - oxo - 5 - thia - 1 - aza bicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid and 3.7 g. of bistrimethylsilyl acetamide in 100 ml. of acetonitrile. The mixture is stirred for one hour and the solvent is then distilled off. The residue is taken up in 50 ml. of methanol and 1 ml. of 2N hydrochloric acid, treated with charcoal. The crude product, 7p - [[D - [(2 - amino 1,2 - dioxoethyl)amino] - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl -1H - tetrazol 5 - yl)thio]methylj - 8 - oxo - thia - 1 - azabicyclo[4.2.0] - oct - 2 - ene - 2 - carb- oxylic acid is obtained as a beige powder which is reprecipitated from tetrahydrofuran/ ether, m.p. 156-158 and is identical with the product of Example 5.

Example 8.

7P - [[D - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thienylacetyliamino] - 3 [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - aza bicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, potassium salt.

The product of Example 5 is reacted with an equimolar aqueous solution of potassium bicarbonate to obtain 7p - [[D - [(2 - amino - 1,2 - dioxoethyl)amino] - 2thienylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt as a brownish powder, m.p. 174--175".

Example 9.

7 - amino - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid.

To a stirred suspension of 27.2 g. 7 - aminocephalosporanic acid (0.1 mole) in 150 ml. of acetone and 100 ml. of H,O at O5 is added 50 ml. of 2N NaOH, with care being taken to keep the pH below 8.5. A solution of 12.7 g. (0.11 mole) of 1methyl - 5 - mercapto - 1H - tetrazole in 50 ml. of 2N NaOH is added, and the mixture is allowed to warm to room temperature. The stirred mixture is then maintained at 60 (internal temperature) under nitrogen for 3 hours at pH 7-7.5 by the periodic addition of dilute aqueous NaOH. The mixture is cooled in an ice-water bath, and while stirring, 3N HCl is added to adjust the pH to 3.9. Stirring is continued for 15 minutes, and the precipitate is collected by filtration, washed with water, and then acetone, and finally dried to give the desired product as a powder (18.4 g.).

Example 10.

7 - Amino - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester.

A mixture of 16.4 g. (0.05 mole) of the acid product from Example 9, 10.3 g.

(0.054 mole) p-toluenesulfonic acid monohydrate, 350 ml. of dioxane (dried by passage through basic alumina), and dry GHSOH is stirred at room temperature under nitrogen for 30 minutes. The clear solution is evaporated to a residue, and water and CH,OH are removed by four evaporations of 100 ml. quantities of dioxane. Fresh dioxane (300 ml.) is then added to the residue followed by a solution of crystalline diphenyldiazomethane (19.4 g., 0.10 mole) in 150 ml. of dry dimethoxyethane. The mixture is initially shaken vigorously for 1(W15 minutes and then stirred at room temperature for 3 hours. Methanol (25 ml.) is added, and the red solution is stirred until it has turned yellow-orange. The solvents are removed in vacua, and -the residue is treated with 400 ml. of CH2C12 and a solution cf 20 g. of K2HPO4 in 250 ml. of water. The CH2Cl2 layer is washed with water and saturated NaC1, and finally dried (MgSO4) to give a residue after removal of the solvent in vacua Treatment of the residue with Et2O gives a solid (27 g.). Column chromatography of this solid on silica gel by elution with CHCl3 and then EtOAc-CHCl8 (4:1) provides the desired product as a residue (12.9 g.). Treatment with EtOAc then provides 8.0 g. of the desired product as a pale yellow powder.

Example 11.

DL - a - [(2 - Ethoxy - 1,2 - dioxoethyl)amino]phenylacetic acid, diphenylmethyl ester.

By substituting DL - a - aminobenzeneacetic acid, diphenylmethyl ester, for the 2 - D - thienylglycine, diphenylmethyl ester in the procedure of Example 1, DLa - [(ethoxy - 1,2 - dioxoethyl)amino] phenylacetic acid, diphenylmethyl ester is obtained as a thick colorless oil.

Example 12.

DL - a - [(2 - Amino - 1,2 - dioxoethyl)amino]phenylacetic acid, diphenylmethyl ester.

A mixture of 10mM of DL - a - [(2 - ethoxy - 1,2 - dioxoethyl) - amino] phenylacetic acid, diphenylmethyl ester in 50 ml.-of ethanol containing 13mM of ammonia is stirred for 15 minutes. After a short time, 2 thick slurry forms. The product, DL - a [(2 - amino - 1,2 - dioxoethyl)aniino]phenylacetic acid, diphenylmethyl ester, is filtered off and recrystallized from toluene in the form of white filaments, m.p.

1680.

Example 13.

DL - a - [(2 - Amino - 1,2 - dioxoethyl)amino]phenylacetic acid.

13 g. of the product of Example 12 are added to 250 ml. of a 6N solution of hydrochloric acid in glacial acetic acid. After stirring for 15 minutes everything dissolves. The reaction solution is evaporated at room temperature and the white crystalline residue is triturated with ether, filtered under suction and recrystallized from water to obtain DL - a - [(2 - amino - 1,2 - dioxoethyl)amino]phenylacetic acid as white crystals, m.p. 1930.

Example 14.

7 - [[DL - [(2 - amino - 1,2 - dioxoethyl)amino]phenylacetyl)amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid, diphenyl methyl ester.

1.85 g. (7.5 mM) of DL - a - [(2 - amino - 1,2 - dioxoethyl)amino] - phenylacetic acid is made to react with chloroformic acid ethyl ester and 7 - amino - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio] - methyl] cephalosporanic acid, diphenylmethyl ester according to the procedure of Example 4 to obtain the product, 7, - [[DL - [(2amino - 1,2 - dioxoethyl)amino]phenylacetyl]amino] - 3 - [[(1 - methyl - 1Htetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene2 - carboxylic acid, diphenylmethyl ester as a beige powder, m.p. 146o.

Example 15.

7p - [[DL - [(2 - amino - 1,2 - dioxoethyl)amino]phenylacetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0]oct - 2 - ene - 2 - carboxylic acid.

By treating the product of Example 14 with trifluoroacetic acid and anisole according to the procedure of Example 5, 7p - [[DL - 1(2 - amino - 1,2 - dioxoethyl(amino]phenylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid is obtained as a beige powder, m.p. 1530 (dec.).

The sodium salt is obtained as a light beige powder by freeze drying an equimolar aqueous solution of the above acid and sodium bicarbonate, m.p. 1750 (dec.).

Example 16.

DL - a - [(Ethoxy - 1,2 - dioxoethyl)amino] - 2 - furanacetic acid, diphenylmethyl ester.

By substituting 2 - DL - furylglycine, diphenylmethyl ester for the 2 thienylglycine, diphenyl methyl ester in the procedure of Example 1, DL - a - ID=10. thiol - methyl - g - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester is obtained as a beige powder, m.p. 810 (dec.).

Example 20.

(6R - trans) - 7 - [[DL - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - furanylacetyl] aminoj - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - exo - 5 - thia- 1 - azabicyclo[4.2.0] oct - 2 - ene - 2 - carboxylic acid.

By substituting the diphenylmethyl ester obtained in Example 19 in the proX cedure of Example 5, (óR-trans) - 7 - [[DL - [(2 - amino - 1,2 - dioxoethyl)amino]- 2 - furanylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl]- 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid is obtained as a beige powder, m.p. 154 (dec.).

The sodium salt is obtained as a light powder by the procedure of Example 15, m.p. 171 (dec.).

Example 21.

L - a - [(2 - Amino - 1,2 - dioxoethyl)amino]thiopheneacetic acid, diphenylmethyl ester. a) 3.5 g. (lOmM) of a - thienylglycine, diphenylmethyl ester, hydrochloride, are suspended in 50 ml. of a mixture of carbon tetrachloride and methylene chloride (2:1).

1.2 g. (10 mM) of oxalyl chloride are added. The mixture is stirred and a stream of nitrogen is passed through at 350 until a clear solution results. The greenish reaction solution containing L - a - [(2 - chloro - 1,2 - dioxoethyl)aAnino] - thio- pheneacetic acid, diphenylmethyl ester is decolorized with activated charcoal and used directly in the next step. b) The reaction solution from part a is added dropwise to a cooled solution (-20 ) of 10mM of ammonia and 10 mM of dimethylaniline in 500 ml. of methylene chloride. After the addition, the reaction mixture is stirred for 15 more minutes, washed with 100 ml. of water, 100 ml. of 2N hydrochloric acid and again with 100 ml. of water, dried and evaporated. The residue is recrystallized from ethanol and then from toluene to obtain the product, L - a - [(2 - amino - 1,2 -dioxoethyl)amino]thiophene- acetic acid, diphenylmethyl ester as white crystals, m.p. 1571600; [α]D20=+50.0 (1% in methylene chloride).

Example 22.

N - α - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid.

L - α - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid acid is obtained as white crystals by treating the diphenylmethyl ester obtained in Example 21 with ammonia according to the procedure of Example 12, m.p. 140-141 ; [α]D20=+152 (1% in THF).

Example 23.

7 - ss - [[L - [(2 - Amino - 1,2 - dioxoethyl)amino] - 2 - thienylacetyl]amino]3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.

By substituting L - a - [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thiopheneacetic acid in the procedure of Example 4 and recrystallizing from isopropanol, 7p - [[L- [(2 - amino - 1,2 - dioxoethyl)amino] - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2- carboxylic acid, diphenylmethyl ester is obtained as a beige powder, m.p. 94 (dec).

By treating this product as in the procedure of Example 5, 7 - p - [[L - [(2 - amino1,2 - dioxoethyl)amino] - 2 - thienylacetyl]amino] - 3 - r[(1 - methyl- 1Htetrazol - 5 - yl)thio]methyl] - 8 - oxo - 1 - azabicyclo[4.2.0] - oct - 2 - ene - 2- carboxylic acid is obtained, m.p. 1500 (dec.). The sodium salt is obtained by the procedure of Example 15, m.p. 167-170 (dec.).

Example 24-75.

Following the procedure of Example 7 but employing the acylating agent A below having the substituents in the following table (which is prepared as described in Examples 1 to 3 and 6) and the 7p - aminocephalosporin Compound B below, one obtains the product C having the same substituents shown in the table. Where appropriate, the protecting group and ester group are removed as in Example 5. The salts are produced as in Example 8.

n rn I 3: u cD z Z 1. z z I= > R1 R2 R R3 x f z=f i tn H t-C4H9 H N en t { 25 H H H N -N -s D$ S 26 -OCH3 -CH2 H N-N S-s' m N CH3 27 it 3t C I E U N CH3 t I Qss | g v W b U N N N q X

Z=Z Z=Z zz en zo z-O l \z-uN Azgo Example zC zJ z~ I 1 vi N ,, X #I H H N-N CH3 30 H -CH2CCl3 C2H5 u ES C2H5 31 (Ti,'- H CH3 H u 1 Y o t t O H

zz zz U z z Example R1 R2 I R R x X 32 H Na H 50N 0 m"5 > m N U CH3 34 H H H N-N Ii I' 51 N CH3 m fI 35 H H H -O-C-CH A I ZZ U ON 36 -OCH3 -C2H5 -CH3 N- N Ii 0 -S N CH3 l Z Ct 20 0 S n

efzt Z G o u n x c) x I m R2 z R R3 x n l 37 (Thol H H H -O-C-CH3 tn m1 c4 39 -OCH3 H H -OCONH2 fo n 41 -OCH3 H H NONH2 H K H N-N 42 1 5: < N I o o 0 a, o < fN S > v v v x X st X

Exarnple R1 R2 R R3 x in x o ' ow 43 l z-O H X -OCH X 1 Z---i Z 49 Z~~~í 3 3 UÀ N N CH3 45 H K H N--N )-CH3 46 H H - (cH2) U H N-N 2 U9 m 0 6 V CI u 47 -C2H5 -00H3 V X H9 Y Z C NI O j u) i I Z aZ Cz S = uN D, m -r In v co 0 g tr tr sr sr wr -r vr X

x z f V R2 R R3 x vl v) 4' N H 51 -oCH3 H H -OCH3 52 H -CH%Q5\/)2 H N- N N C2H5 53 -OCH3 H H N----- N o A' p | Ú U CH3 0 m n 2 sn ', 3 55 -OCH H 3: H r ~lb b d t O 1 N mr n Z u n In ul l n x 4

Exa:nple R1 R2 R R3 x 56 Zi o I tn m H H H 58 H t-C4H9 H N-N I N CH3 59 (CH2)2 H H H N-N 3: JUCH3 S 60 H H CH3 N-N II 0 61 -OCH3 H H N- N m jiH3 S b b b X w l"] n W w

u Z = Zx SZZx zz ZV -U &verbar; z~u &verbar; O &verbar; tq X W Z / y Zz/ v, u, 3 62 H CH) 2 H N - N I CH3 .* ru N CH3 m 3: H U U A I Cl 65 H C:%\ H N rul &verbar; m m m m 0 N n w n X

m n U eSj Example R1 R2 R R3 x u) 66 vi M e m 67 3: H CH)2 H u u S cm 101 m m N 3: m 69 H H C:3 5mCH3 m I m m o S W X w

un Example R1 R2 R R3 x x ≈ {C Q m u) z =s u u) H H H S t x I I I | m m ^ m 72 H Na H -s m u a Z m m z m n C13: F Z m 75 OCH3 Si(CH3) 3 H N-N -s-k" A' N CH3 The acylating agents A may be in either the D- or L- form or may be a mixture of D- and L-isomers.

Example 76.

[(Cyanomethyl)amino]oxoacetyl chloride.

20 mM of cyanomethylamine hydrochloride and 25 mM of oxalyl chloride in 100 mM of absolute dioxane are heated at 60-70 while passing through a stream of nitrogen. After one hour a clear solution results and there is no evidence of hydrogen chloride in the nitrogen stream. The solvent is evaporated under vacuum and the residual, light brown oil is taken up in methylene chloride, filtered over charcoal and stored at - 30 until it is to be used.

Example 77.

D - a - [[[(Cyanomethyl)amino]oxoacetyllamino] - 2 - thiopheneacetic acid, di phenylmethyl ester.

10 mM of 2 - D - thienylglycine, diphenylmethyl ester are dissolved in 20 ml. of methylene chloride, 10mM of dimethylaniline are added and half the product of Example 76 is added dropwise with stirring at 200. After thirty minutes, the reaction solution is washed first with 50 ml. of 1 N hydrochloric acid and then with 50 ml. of water. After drying over sodium sulfate, it is concentrated by evaporation. A viscous yellow mass is obtained which solidifies upon treatment with ether. This is crystallized from a little ethanol to obtain D - a - [[[(cyanomethyl)amino] - oxoacetyl]- amino] - 2 - thiopheneacetic acid, diphenylmethyl ester in the form of white crystals, yield 63%, m.p. 160-1610.

Example 78.

D - a - l[[(Cyanomethyl)amino]oxoacetyl]amino] - 2 - thiopheneacetic acid.

By treating the diphenylmethyl ester obtained in Example 77 with trifluoroacetic acid and anisole (4:1) D - a - [[[(cyanomethyl)amino]oxoacetyllamino] - 2 - thiopheneacetic acid is obtained in 74% yield. The product is recrystallized from absolute ethanol to obtain white crystals, m.p. 199-200 .

Example 79.

7 - - [[D - [[2 - [(Cyanomethyl)amino] - 1,2 - dioxoethyl]amino] - 2 - thienyl acetyl]amino] - - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio] - methyl] - 8 - oxo- 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid.

10 mM of D - a - [ [ [ (cyanomethyl) amino oxoacetyl] amino] - 2 - thiopheneacetic acid and 10 mM of triethylamine are dissolved in 100 ml. of tetrahydrofuran, cooled to 50 and a solution of 11 mM of chloroformic acid ethyl ester is slowly added dropwise. This is permitted to react for 20 minutes and then a solution of 10 mM of 7 - amino - 2 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thiol]methyl] - 8 - oxo5 - thia - 1 -azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester in tetrahydrofuran is added. After stirring for eight hours at - 5 and one hour at room temperature, the solution is concentrated under vacuum and then taken up with methylene chloride and water. The organic phase is washed with 2N phosphoric acid solution and water, dried, treated with charcoal and concentrated. The product, 7 [[D - [[2 - [(cyanomethyl) - amino] - 1,2 - dioxoethyl]amino] - 2 - thienylacetyl] amino] - 3 - [[(1 - methyl- lH - tetrazol - 5 - yl)tllio]methyl] - 8 - oxo - 5 -thia1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester, is obtained as a solid brownish foam. By treating this with trifluoroacetic acid and anisole (4:1), 7 - ss - [[D - [[2 - [(cyanomethyl)amino] - 1,2 - dioxoethyl]amino] - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 yl)thiol] - methyl] - 8oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid is obtained in the form of a beige powder which is recrystallized from isopropanol/ethyl acetate, m.p. 1540.

Example 80.

Alternative synthesis of 7 - ss - [[D - [[2 - [(Cyanomethyl)amino] - 1,2 - dioxo ethyl] amino] - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)- thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] - oct - 2 - ene - 2 - carboxylic acid.

10 mM of 7ss - amino - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thiol - methyl]- 8 - oxo - 5 - thia-1-azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid, trifluoto- acetic add salt are suspended in acetonitrile. After the addition of 3 ml. of bis(tri methylsilyl)acetamide and 15 mM of. propylene oxide, a clear solution results in several minutes. This is cooled to 0" and 12 mM of chloroxoacetic acid, cyanomethylamide dissolved in methylene chloride is added dropwise. This is stirred for one hour and then the solvent is removed in vacuo. The residue is stirred for one hour in 300 ml. of ethyl acetate and 50 ml. of water. The organic phase is then dried, treated with charcoal and concentrated to 30 ml., whereupon the product -7 - ss - [[D - [[2 - [(cyano methyl)amino] - 1,2 - dioxoethyl] - amino] - 2 - thienylacetyl]amino] - 3 - [[(1 methyl - 1H - tetrazol - 5 - yl) - thio]methyl - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0]oct - 2 - ene - 2 - carboxylic acid crystallizes. By pouring the mother liquor into ether an additional quantity of product is obtained, m.p. 153-155 .

Example 81.

7ss - [[D - [[2 - [(Cynomethyl)amino] - 1,2 - dioxoethyl]amino] - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio] - methyl] - 8 - oxo 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, sodium salt.

By freeze drying an equimolar aqueous solution of the acid of Example 79 or Example 80 and sodium bicarbonate, 7ss - [[D - [[2 - [(cyanomethyl)amino] - 1,2dioxoethyl]amino] - 2 - thienylacetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5yl)thio] - methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2carboxylic acid, sodium salt is obtained as a light yellow powder, m.p. 1780 (dec.).

Examples 82-145.

Following the procedure of Example 79 but employing the acylating agent A below having the substituents in the following table (which is prepared as described in Examples 76 to 78) and the 7ss - aminocephalosporanic acid Compound B below, one obtains the product C having the same substituents shown in the table. Where appropriate, the protecting group and ester group are removed as in Example 79. The salts are produced as in Example 81.

rl X U c) zA z l z=z z- z v, 4 5 xl k'5 H f Z- ( Zi -S 83 H H H CH3 H N -N kn 3: 3: e 84 Th -OCH3 -CH2- H H H N-N -S--s N CH3 85 i5)I -OCH3 H H H H N CH3 5 = x o eJt 1

Example R1 R2 R R3 R4 R5 x rn 86 H H ,-, =z | =Z\ H H I z- u z-u Z --U 0 z z 2z C1 Z"/ XI I m I fq I I uz 11 N CH3 88 H CH)2 CH3 CH3 H N-N fi Srl n N CH3 XI N N N U 1 V U O N N 90 H -CH2CCl3 C 2H5 H H N-N S . Ii V N I x = U V C2H5 N &verbar; x , O e W F o O 4

ZZx R1 R2 R R3 O=U (Oz)o z~rZ I Ozy x I v X X N 3: U s: U sr; I 1 U x U 93 -OCH3 -CH %3o) 2 3E m I' un jC U m H SC ON X = CW N CH3 95 j7; H H H H H 0 Z I m s: N u x 7 x z t & 0 fi H o x

== Sz N z n mn - R2 R O 0 p 0 -s CH3 97 H H -CH2 H H -o -0C-CH3 0 &num;i m m 3: e x m e 99 n m * m c p | H H H m N 101 H - H H H Un n m m z m ≈ g I o m n x m o b I-,o 4 0 E to rv o ~ eq 4 o o o O o x F H H w

u z=\ z= z > o n x H K H H H N-N 104 H Sn(CH3)3 -CH3 H H 5N51---N N vrl srl P; H t-C4H9 -CH3 m c -OCH3 106 H CH) 2 H H H sffi) N N CH3 107 N H K H H H N-N N 0 N- N 108 m H -(CH2)2-G or chl n W &verbar; U ~ XNg = m n o to S aXz (t) 3; H X s g o o o o o o x H

Example R1 R2 R R3 R4 R5 x m z -OCH3 t z H7 H H -O-C-CH3 110 H -N(C2H5)3 H -C3H7 H 111 H H H H H rz 112 n 3: m s: m I m m m H 113 -OCH3 H H CH3 H -OCH3 rs "IU" s E 3: m m I CH 25 115 Q)/. OCH3 H H t ~~~~ 1 N CH3 KN I o c K c o b b e ~I as o ~4 N t 1 ffi O H H H H H H w

m m R1 R2 R R3 R4 R5 x 0 ou Z-í Z-í'8 | X( 1 3: U) X | c m n > m r m 119 H H m H H H c I m m m m c m H N- N 17 m CH3 nor fizz CH3 tC r N- N I, m xN l x go m m m m m IN Qs SD 1 > CO a I N E H H H H N N N X H H H H H H H W

Example R1 R2 R R3 R4 R5 zR N X -OCH3 H H H H z/ 1 S s l us N CH3 125 HO H -CH2 H H -C4H9 -S l m m > m m CH3 X Ú N 127 H CH&num;\ H H H N- N Cl N X m Q Q Q Q ú c m s < l b b =^ U U 0 H n v W F n H H H H H x

e) y =Z\ ZX l=Zs N tx z --/ L-=/ m H H H H H N-N 128 H3CO- I N CH3 129 H | m X n m -OCH3 -CH2 CH3 H H N ru U U ol m o m 0 Q oo a o H E N N tfl < ,

Example R1 R2 R R3 R4 R5 x uo m z z 132 HOffO H H z-S U t Un vi m I 133 H H H H H same N l 1TI 135 H H H H H n1 N K I AS c > m 3 x m N -N u K I 5 n Z m c CH3 KNt m m v*v m 3 uO N v tf X H H H H H- H

Example R1 R2 R R3 R4 R5 x 138 - OCH3 H H H H -OCONH2 S N N 8 U t t ZZ U Z O O I \ xN ss \ X I I I Zr Z=( U)l ss m m m x m H H H m 140 H H H H H I NN CH2COOH :141 9 H - CH3 H H N-N -s t cHSo3H K I m P M rn Nl C) K I O n a K I M o t co a o g

o cn cq z z z z= z z-u I z U I z cJ XI Z z Z -u m I I v, I cH2So2C3 a I m m crl vrl K I x C X 1 K I X c m -5- 3E N CH3 I x u Nl I m sc m o 0 x > w The acylating agents A may be in either the D- or L- form or may be a mixture of D- and L-isomers.

Because of Section 9 of the Patents Act 1949, attention is drawn to our copending patent application No. 80.24301 (Specification No. 1,598,518).

Claims (31)

WHAT WE CLAIM PS:-

1. A compound of the formula

wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri (lower alkyl)silyl, trihaloethyl or a salt forming ion; R1 is hydrogen, lower alkyl, saturated or unsaturated cycloalkyl (as hereinbefore defined), phenyl, phenyl-lower alkyl, substituted phenyl wherein said phenyl substituent is one or two radicals selected from halogen, lower alkyl, lower alkoxy, and hydroxy, or a heterocyclic selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; R2 is hydrogen or methoxy; R3 is hydrogen, lower alkyl or cycloalkyl; and X is hydrogen, lower alkanoyloxy,

(when X is pyridinium or carbamoylpyridinium, COOR is a carboxyl anion), carbamoyloxy, lower alkoxy, lower alkylthio, or a heterothio group selected from

and R4 is hydrogen or lower alkyl.

2. A compound as in Claim 1 wherein R1 is thienyl.

3. A compound as in Claim 1 wherein R1 is phenyl.

4. A compound as in Claim 1 wherein X is methyltetrazolyl.

5. A compound as in Claim 1 wherein R1, R2 and R, each is hydrogen.

6. A compound as in Claim 1 wherein R is hydrogen or alkali metal; R1 is cyclohexadienyl, phenyl, thienyl, furyl or pyridyl; R2 is hydrogen or methoxy; R3 is hydrogen or lower alkyl; and X is as defined in Claim 1.

7. A compound as in Claim 1 wherein R is hydrogen, sodium or potassium; R1 is phenyl or thienyl; R2 is hydrogen; R, is hydrogen or methyl; and X is acetoxy or (1-methyl-i H-tetrazol-5 -yl ) thio.

8. A compound as in Claim 1 wherein R, R2 and R, each is hydrogen; R1 is 2-thienyl; and X is (1-methyl-i H-tetrazol-5-yl) thio.

9. A compound as in Claim 1 wherein R is potassium; R2 and Rs each is hydrogen; R1 is 2-thienyl; and X is (1-methyl-tH-tetrazol-5-yl)thio.

10, A compound as in Claim 1 wherein R1 is furyl.

11. A compound as in Claim 1 wherein R, R1 and R, each is hydrogen; R1 is 2-furyl; and X is (1-methyl-lH-tetrazol-5-yl)thio.

12. A compound of the formula

wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, trihaloethyl or a salt forming ion; Rl is hydrogen, lower alkyl, saturated or unsaturated cycloalkyl (as hereinbefore defined), phenyl, phenyl-lower alkyl substituted phenyl wherein said phenyl substituent is one or two radicals selected from halogen, lower alkyl, lower alkoxy, and hydroxy, or a heterocyclic selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, and 4pyridyl; R2 is hydrogen or methoxy; R, is hydrogen, lower alkyl, phenyl-lower alkyl or cycloalkyl; R4 and R5 each is hydrogen or lower alkyl; and X is hydrogen, lower alkanoyloxy,

(when X is pyridinium or carbamoylpyridinium, X is a carboxyl anion), carbamoyloxy, lower alkoxy, lower alkylthio, or a heterothio group selected from

R6 is hydrogen or lower alkyl; and R7 is carboxy, COO e ion +, COO-lower alkyl, SO,H, VO2-lower alkyl or cyano.

13. A compound as in Claim 12 wherein R1 is thienyl.

14. A compound as in Claim 12 wherein R1 is phenyl.

15. A compound as in Claim 12 wherein R1 is furyl.

16. A compound as in Claim 12 wherein X is methyltetrazolyl.

17. A compound as in Claim 12 wherein R1, R2, R3, R4 and R5 each is hydrogen.

18. A compound as in Claim 12 wherein R is hydrogen or alkali metal; R1 is cyclohexadienyl, phenyl, thienyl, furyl or pyridyl; R2 is hydrogen or methoxy; R3, R4 and R5 each is hydrogen or lower alkyl; and X is as defined in Claim 12.

19. A compound as in Claim 12 wherein R is hydrogen, sodium or potasium; R1 is phenyl or thienyl; R2 is hydrogen; R3 is hydrogen or methyl; R4 and R5 each is hydrogen and X is acetoxy or (1-methyl-1H-tetrazol-5-yl)thio.

20-A compound as in Claim 12 wherein R, R2, R3, R4 and R5 each is hydrogen; R1 is 2-thienyl; and X is (1-methyl-1H-tetrazol-5-yl)thio.

21. A compound as in Claim 12 wherein R is sodium, R2, R3, R4 and R5 each is hydrogen; R1 is 2-thienyl; and X is (1-methyl-1H-tetrazol-5-yl)thio.

22. A compound as in Claim 12 wherein X is a heterothio group selected from

wherein R6 is hydrogen or C1-C4 alkyl.

23. The D-isomer of a compound as in Claim 12.

24. The D-isomer of a compound as in Claim 20.

25. The D-isomer of a compound as in Claim 21.

26. A compound as in claim 1, as named or shown in any of Examples 1-75.

27. A compound as in claim 12, as named or shown in any of Examples 76-144.

28. A pharmaceutical composition comprising a compound as in any one of claims 1-11 and 26 and a pharmaceutical carrier.

29. A pharmaceutical composition comprising a compound as in any one of claims 12-25 and 27 and a pharmaceutical carrier.

30. A composition as in claim 28, in the form of a tablet, capsule, elixir or sterile injectable preparation.

31. A composition as in claim 29 in the form of a tablet, capsule, elixir or sterile injectable preparation.