Beecham Group Plc

Smithkline Beecham Corporation

Nigel J Broom

Frank Peter Harrington

Gerald Brooks

Brian P Clarke

Steven Coulton

Anthony C Marshall

Compounds of formula (I) in which: R.sup.1 is hydrogen or an organic substituent group; R.sup.2 is a fused bicyclic heterocyclic ring system of general formula (a) wherein R.sup.4 and R.sup.5 are independently hydrogen or one or more substituents replacing hydrogen atoms in the ring system shown; m is 2 or 3; p is 0, 1 or 2; and R.sup.3 is hydrogen, a salt-forming cation or an ester-forming group; and the symbol .dbd./.dbd. indicates that the double bond may be in either the E or Z configuration

6-(substituted methylene) penems and intermediates

6-(substituted methylene)penems and intermediates

Compounds of the general formula (II): ##STR1## in which N.sup.+ denotes an unsubstituted or substituted nitrogen-containing heterocyclyl ring bonded to the remainder of the molecule through a ring nitrogen atom and carrying a positive charge on said nitrogen atom;

Penem compounds

Compounds of the general formula (II): ##STR1## and pharmaceutically acceptable salts and in-vivo hydrolysable esters thereof, in which

During the preparation of 6-(substituted methylene)-2-penem compounds (which are known for their anti-bacterial and .beta.-lactamase inhibitory properties) mixtures of the E-isomer and the Z-isomer may be formed. The Z-isomer is, however generally preferred, and the present invention provides a process whereby the E-isomer may be converted into the Z-isomer by reaction with an aromatic heterocyclic thiol in the presence of a base.

Process for preparing penems

(5R) (Z)-6-(1-methyl,1,2,3-triazol-4-yl-methylene)-penem-3-carboxylic acid and its salts are provided in analytically pure crystalline form, and the salts in hydrated form, for example (5R) sodium (Z)-6-(1-methyl-1,2,3-triazol-4-yl-methylene)penem-3-carboxylate monohydrate.

Heterocyclic-methylene-penems

The present invention provides a process for the preparation of a compound of the formula (IV): ##STR1## or salt or ester thereof wherein R.sup.1 and R.sup.2 are independently hydrogen; an organic radical bonded via a carbon atom to the ring carbon atom; a free, etherified or esterified hydroxy or mercapto group; an amino or acylamino group; or together R.sup.1 and R.sup.2 represent a group .dbd.CR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are the same or different and each represent hydrogen or a hydrocarbon or heterocyclic group optionally substituted with a functional group; and R.sup.3 represents an organic radical; which process comprises reacting a compound of the formula (V): ##STR2## wherein R.sup.x is hydrogen or a blocking group and R.sup.4 is an organic radical; with a thiol or reactive derivative thereof. The compounds of the formula (IV) are useful as antibiotics and .beta.-lactamase inhibitors, as are the compounds of the formula (V). This invention also provides the novel compounds of the formula (V) and certain novel compounds within formula (IV). Their preparation and use are described.

Process for preparing penem derivatives

The compounds of the formula (II): ##STR1## and salts and cleavable esters thereof wherein R.sub.1 is a hydrogen atom or a lower alkyl group and R.sub.2 is a CN or CO.sub.2 R.sub.3 group where R.sub.3 is a hydrogen atom or a lower alkyl, aryl, or aralkyl group are antibacterially effective compounds. Their preparation and use is described.

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Betchworth, United Kingdom

Nigel J Broom