7-D-(.alpha.-Acylamino-arylacetamido)-cephalosporanic acid derivatives

#The invention relates to antibacterial agents and is particularly concerned with a class of novel cephalosporin derivatives with broad spectrum antibacterial activity, more especially against gram-negative organisms. In particular, the compounds of the invention constitute a series of 7-(.alpha.-amino-arylacetamido)-.DELTA..sup.3 -cephem derivatives having a novel type of acyl group attached to the .alpha.-amino group.

#British Pat. No. 1,328,340, published Aug. 30, 1973, describes cephalosporins having the above formula wherein X is a direct carbon-carbon link or a methylene group. However, such compounds as are claimed in the present invention are not structurally obvious over these prior art compounds. Additionally, they exhibit superior antibacterial activity relative to the prior art compounds.

#According to the invention, there are provided compounds having the general formula: ##STR2## wherein R.sup.1 represents a phenyl, 2- or 3-thienyl or 2-furyl group, the phenyl and thienyl groups optionally being substituted with one or more moieties chosen from halogen, hydroxyl, lower alkyl, lower alkoxy and trifluoromethyl; R represents a hydroxyl group, and R.sup.2 represents a hydrogen atom or a hydroxy, acetoxy, carbamoyloxy, N-pyridyl, substituted N-pyridyl, azido or heterocyclicthio group, for example, a 4,6-dimethyl pyrimidin-2-ylthio, 4,5-dimethylthiazol-2-ylthio, 1,3,5-triazin-2-ylthio, pyrimidin-2-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 1-substituted-1,2,3,4-tetrazol-5-ylthio group wherein the 1-substituent represents a lower alkyl, lower alkenyl, cycloalkyl, benzyl or phenyl group, the latter group optionally being substituted with one or more moieties chosen from halogen, lower alkyl and lower alkoxy; or R and R.sup.2 taken together represent an oxygen atom; R.sup.3 represents a sulpho group; or a group of the formula COOR.sup.4', wherein R.sup.4' represents hydrogen or R.sup.4 wherein R.sup.4 is lower alkyl, 5-indanyl, naphthyl or phenyl group, the phenyl group optionally being substituted with one or more moieties chosen from halogen, lower alkyl, lower alkoxy and trifluoromethyl; or a carbamoyl group of the formula CONR.sup.5 R.sup.6, wherein R.sup.5 and R.sup.6 each independently represent a hydrogen atom or a lower alkyl or a cycloalkyl group, or together with the nitrogen atom to which they are attached form a saturated heterocyclic group; X represents an oxygen or sulphur atom, a direct carbon-carbon link, or a carbonyl, methylene, hydroxymethylene, sulphinyl or sulphonyl group, or an imino group of the formula --NR.sup.7 --, wherein R.sup.7 represents a hydrogen atom or a lower alkyl, lower alkenyl, or a benzyl group; and alk.sup.1 and alk.sup.2 each independently represent a divalent saturated aliphatic hydrocarbon group containing from 1 to 3 carbon atoms; and the pharmaceutically acceptable salts thereof.

#The invention is illustrated by the following Examples.

#A mixture of 7-D-(.alpha.-aminophenylacetamido)cephalosporanic acid (cephaloglycin) (228 g., 0.562 mole) and diglycolic anhydride (62.2 g., 0.562 mole) in acetone (3.3 l.) was stirred at room temperature for 11/2 hours. After the removal by filtration of insoluble material, the filtrate was evaporated in vacuo at a temperature below 30.degree. C., and the resultong gummy residue was stirred in a mixture of ethyl acetate (4.4 l.) and water (3.2 l.). The aqueous phase was separated and extracted with ethyl acetate (b 2.2 l.), and the separated organic phase was combined with the initial ethyl acetate solution, the organic solution then being dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo, at a temperature below 30.degree. C., to dryness.

#Produced was a semi-solid foam (284.4 g.) which was shown from thin-layer-chromatographic and infra-red and nuclear magnetic resonance spectroscopic evidence to comprise substantially pure 7-D-(.alpha.-carboxymethoxyacetamido-phenylacetamido)cephalosporanic acid.