Glaxo Group Limited

Glaxo Laboratories Limited

Barry E Ayres

Cynthia H O'Callaghan

David G Livermore

Christopher E Newall

Niall G Weir

Gordon H Phillipps

Michael W Foxton

Derek R Sutherland

Christopher Earle Newall

Peter C Cherry

Peter John May

Anthony W Cooper

There are described new compounds of formula (1) ##STR1## wherein R.sup.1 represents an acyl group;

Dipeptide compounds containing histidine or N-methyl histidine processes

Dipeptide compounds, processes for their preparation and compositions

Cephalosporin antibiotics of general formula: ##STR1## (wherein R.sup.a and R.sup.b, which may be the same or different, each represent a C.sub.1-4 alkyl group or R.sup.a and R.sup.b together with the carbon atom to which they are attached form a C.sub.3-7 cycloalkylidene group, and Y.sup..sym. represents a C-linked 5- or 6-membered heterocyclic ring containing at least one C.sub.1-4 alkyl-substituted quaternary nitrogen atom, which ring may also contain one or more sulphur atoms) exhibit broad spectrum antibiotic activity, the activity being unusually high against gram-negative organisms such as strains of Pseudomonas organisms. A particular antibiotic compound of formula (I) possessing excellent antibacterial activity against strains of Pseudomonas organisms, as well as other valuable therapeutic properties, is (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)ace tamido]-3-[(1-methylpyridinium-4-yl)-thiomethyl]ceph-3-em-4-carboxylate. The invention also includes the non-toxic salts and non-toxic metabolically labile esters of compounds of formula (I). Also described are compositions containing the antibiotics of the invention and processes for the preparation of the antibiotics.

Cephalosporin antibiotics

Cephalosporin antibiotics of general formula ##STR1## (wherein Y.sup..sym. represents a C-attached 1-C.sub.1-4 alkylpyridinium group) exhibit broad spectrum antibiotic activity with unusually high activity against strains of Pseudomonas organisms as well as high activity against various members of the Enterobacteriaceae. The invention also includes the non-toxic salts, non-toxic metabolically labile esters and 1-oxides of compounds of formula (I). Also described are compositions containing the antibiotics of the invention and processes for the preparation of the antibiotics.

Cephalosporin antibiotics of general formula ##STR1## (wherein R.sup.a and R.sup.b, which may be the same or different, each represent a C.sub.1-4 alkyl group, or together with the carbon atom to which they are attached form a C.sub.3-7 cycloalkylidene group and R.sup.1 represents a C.sub.1-4 alkyl group) exhibit broad spectrum antibiotic activity, the activity being unusually high against gram-negative organisms such as strains of Pseudomonas organisms. Particularly effective compounds of formula (I) are (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetami do]-3-(2-methylpyrazolium-1-ylmethyl)ceph-3-em-4-carboxylate and (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(1-carboxycyclobut-1-oxyimino)ac etamido]-3-(2-methylpyrazolium-1-ylmethyl)]ceph-3-em-4-carboxylate. The invention also includes the non-toxic salts and non-toxic metabolically labile esters of compounds of formula (I), compositions containing the antibiotic compounds of the invention, and methods for combatting bacterial infections utilizing the antibiotics.

Cephalosporin antibiotics of general formula ##STR1## (wherein R.sup.a and R.sup.b, which may be the same or different, each represent a C.sub.1-4 alkyl group, or together with the carbon atom to which they are attached form a C.sub.3-7 cycloalkylidene group). These compounds exhibit broad spectrum antibiotic activity, the activity being unusually high against gram-negative organisms such as strains of Pseudomonas organisms. Particularly effective compounds of formula (I) are (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetami o]-3-(pyridazinium-1-ylmethyl)ceph-3-em-4-carboxylate and (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(t-carboxycyclobut-1-oxyimino)ace tamido]-3-(pyridazinium-1-ylmethyl)ceph-3-em-4-carboxylate. The invention also includes the non-toxic salts and non-toxic metabolically labile esters of compounds of formula (I), compositions containing the antibiotic compounds of the invention and a method of combatting bacterial infection utilizing the antibiotics.

Cephalosporin antibiotics of general formula ##STR1## (wherein R.sup.1 and R.sup.b, which may be the same or different, each represent a C.sub.1-2 alkyl group, or together with the carbon atom to which they are attached form a C.sub.3-6 cycloalkylidene group and Y.sup..sym. represents a 1-carbamoylmethylpyridinium group) exhibit broad spectrum antibiotic activity, the activity being unusually high against gram-negative organisms such as strains of Pseudomonas organisms. Particularly effective compounds of formula (I) are (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetami do]-3-[(1-carbamoylmethylpyridinium-4-yl)thiomethyl]ceph-3-em-4-carboxylate and (6R,7R)-[(Z)-2-(2-aminothiazol-4-yl)-2-[(1-carboxycyclobut-1-oxyimino)acet amido]-3-[(1-carbamoylmethylpyridinium-4-yl)thiomethyl]-ceph-3-em-4-carboxy late. The invention also includes the non-toxic salts and non-toxic metabolically labile esters of compounds of formula (I), compositions containing the antibiotic compounds of the invention and processes for the preparation of the antibiotics.

Pregnanes and androstanes are described which essentially possess a 3.alpha.-hydroxy group, a 5.alpha.-hydrogen atom or a 4.5- or 5,6-double bond, a 17.alpha.-hydrogen atom and an 11.beta.-aminoester group. Other optional substituents or double bonds may be present. The compounds have anaesthetic activity.

Chemical compounds

Antibiotic compounds of the general formula ##STR1## [wherein R is a phenyl, thienyl or furyl group; R.sup.a and R.sup.b which may be the same or different, are each selected from hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, C.sub.2-5 alkoxycarbonyl and cyano, or R.sup.a and R.sup.b together with the carbon atom to which they are attached form a C.sub.3-7 cycloalkylidene or cycloalkenylidene group; m or n are each 0 or 1 such that the sum of m and n is 0 or 1; and R.sup.1 together with the nitrogen atom to which it is attached form a saturated or partially saturated 4-10 membered heterocyclic ring which may contain one or more further heteroatoms selected from 0,N and S and which may be substituted by a lower alkyl, lower alkoxy, lower acyloxy, lower alkoxycarbonyl, hydroxy, carboxy, amino, acylamino, substituted or unsubstituted carbamoyl or aryl group, or such a heterocyclic ring fused with a benzene ring] and non-toxic derivatives thereof, the compounds being syn isomers or existing as mixtures of syn and anti isomers.

Cephalosporins having a 7-(carboxy substituted .alpha.-etherified

A process for the preparation of a 3-hydroxymethyl cephalosporin compound which comprises selectively hydrolyzing a 3-formyloxymethyl cephalosporin compound under acidic conditions in the presence of a protic solvent whereby a 3-hydroxymethyl cephalosporin is produced.

Process for the preparation of 3-hydroxymethyl cephalosporins

This invention relates to steroids of the pregnane and 19-norpregnane series having anaesthetic properties and compositions containing them. More particularly the present invention relates to such steroids having a variety of substituents in the 2.beta.-position, a 3.alpha.-hydroxy group and a 5.alpha.-hydrogen atom and esters and 20-ketals thereof. At the 11-position of such steroids is preferably either two hydrogen atoms or an oxo group. The compounds according to the invention may conveniently be prepared by reaction of an appropriate 2.alpha.,3.alpha.-epoxy-pregnane or 19-norpregnane with a reagent which introduces the desired 2.beta.-substituent and various modifications of the compound produced are described to produce compounds within the scope of the invention. The present invention provides compositions containing certain steroids of the pregnane and 19-norpregnane series and such compositions generally may be administered intravenously to induce anaesthesia, the invention providing methods of inducing anaesthesia.

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Ickenham, United Kingdom

Barry E Ayres