AZA penem compounds

Abstract

Described is a novel process for the preparation of penems and carbapenems useful as antibacterial agents which comprises the reaction of an appropriate 4-substituted-azetidine-2-one with an acid halide in the presence of a tertiary amine and an alkaline earth metal carbonate, followed by reaction of the thereby formed 1-imido-4-substituted-azetidine-2-one with a trialkyl phosphite. Also described are novel penems useful as antibacterials which are prepared by the described process.

We claim: 
     
       1. A compound having the following structural formula: ##STR15## wherein R 1  is .[.hydrogen;.]. lower alkyl; .[.R 8  -C-amino.]. ##STR16## wherein R 8  is lower alkyl, lower alkyl substituted by one or more of one or two ring carbocyclic aromatic groups, lower alkoxy, phenyloxy, alkenyl of 2 to 6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 4-6 carbon atoms, unsubstituted or substituted heteroaryl .Iadd.selected from pyridyl, furanyl, thienyl, isoxazolyl, quinoxalinyl, isothiazolyl, imidazolyl, indolyl, triazolyl, thiadiazolyl and tetrazolyl .Iaddend.or heteroarylloweralkyl wherein the heteroaryl .[.contains one or two hetero atoms selected from oxygen, nitrogen or sulfur.]. .Iadd.group is as defined above .Iaddend.and wherein the substituents in the heteroaryl .Iadd.group .Iaddend.are from 1 to 3 lower alkyl groups, wherein said R 8  substituents are optionally substituted by hydroxy, thiol, loweralkylthio, lower alkyl, lower alkoxy, halogen, cyano, carboxy, nitro, amino, aminoloweralkyl or haloloweralkyl; or ##STR17## wherein R 4  is hydrogen, lower alkyl, phenyl substituted by lower alkyl, lower alkoxy or halogen, .[.heteroaryl wherein the heterocyclic ring is an aromatic heterocyclic containing a hetero atom selected from sulfur, oxygen or nitrogen,.]. .Iadd.pyridyl, furanyl or thienyl, .Iaddend.and R 5  is hydrogen or an O-protecting group; R 2  is lower alkyl, phenyl substituted by lower alkyl, lower alkoxy or halogen, alkylaryl, aminoloweralkyl, an N-protected amino-lower alkyl, hydroxy lower alkyl, an O-protected hydroxyloweralkyl, thio lower alkyl, an α-amino acid ester, an α-(N-protected) amino acid ester or a lower alkyl carboxylic acid ester;   R 3  is nitrile, tetrazole, or --COOR 6  wherein R 6  is lower alkyl, loweralkyltrihalogenomethyl, phenyl substituted by lower alkyl, lower alkoxy or halogen, allyl, a metabolisable ester, hydrogen, or an alkali metal cation;   Z is sulfur, oxygen.[.,--(CH 2 ) n  -- wherein n is 1 or 2,.]. or NR 7  wherein R 7  is hydrogen, lower alkyl, phenyl substituted by lower alkyl, lower alkoxy or halogen, ##STR18##  wherein .[.R8.]. .Iadd.R 8  .Iaddend.is as defined above, or an N-protecting group; and the pharmaceutically acceptable salts thereof.     
     
     
       2. A pharmaceutical composition comprising an antibacterially effective amount of a compound of claim 1 wherein R 7  is hydrogen, ##STR19## wherein R 8 is as defined above, lower alkyl, or phenyl substituted by lower alkyl, lower alkoxy or halogen, and all O- and, optionally, all N-protecting groups have been removed, together with a non-toxic pharmaceutically acceptable carrier. 
     
     
       3. A method of eliciting an antibacterial response in a warm-blooded animal having a susceptible bacterial infection which comprises administering to said animal a non-toxic antibacterially effective amount of a compound of claim 1 wherein R 7  is hydrogen, ##STR20## wherein R 8  is as defined in claim 1, lower alkyl, or phenyl substituted by lower alkyl, lower alkoxy or halogen, and all O- and, optionally, all N-protecting groups have been removed.