Glaxo Laboratories Limited

Glaxo Operations UK Limited

Other

Gordon Ian Gregory

Martin Christopher Cook

Janice Bradshaw

Michael Gregson

Michael W Foxton

David M Rogers

Peter C Cherry

William Kingston Warburton

Godfrey Basil Webb

Peter Ward

Christopher Earle Newall

Nigel S Watson

Victor Malcolm Clark

Peter William Seale

John Anthony Claisse

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 from a C.sub.3-7 cycloalkylidene or cycloalkenylidene group; R.sup.c is hydrogen or lower alkyl; R.sup.d is hydroxy, lower alkoxy, aralkoxy or aryloxy; m and n are each 0 or 1 such that the sum of m and n is 0 or 1; and P is selected from a hydrogen atom, a halogen atom and various organic groups] and non-toxic derivatives thereof.

Cephalosporins having a carbamoylalkoxyiminoarylacetamido group at

2-Vinylclavem compounds are disclosed which have been found of value in the synthesis of thio-derivatives of clavulanic acid which possess antibiotic and .beta.-lactamase inhibitory activity. Methods for preparing the vinylclavem compounds are disclosed and processes for preparing the thio-derivatives are given.

Esters of 2-vinylclav-2-em-3-carboxylic acid and process for preparing

Novel halogen derivatives of clavulanic acid are described which are of value in the preparation of a range of clavulins which either inhibit .beta.-lactamases or show activity against strains of both gram-positive and gram-negative bacteria. Processes for preparing the halogen derivatives are described and methods for converting them into the active clavulins are given.

Halogen derivatives of clavulaic acid

The invention provides novel antibiotic compounds which are 7.beta.-acylamidoceph-3-em-4-carboxylic acids, and non-toxic derivatives thereof, and 6.beta.-acylamidopenam-3-carboxylic acids, and non-toxic derivatives thereof, characterized in that the acylamido group has the structure ##STR1## where R is a hydrogen atom or an organic group and R.sup.a is a hydrogen atom or an acyl group. The compounds are syn isomers or exist as mixtures containing at least 75% of the syn isomer. These antibiotic compounds possess high antibacterial activity against a range of gram positive and gram negative organisms coupled with particularly high stability to .beta.-lactamases produced by various gram negative organisms. The invention is also concerned with the administration of the compounds.

Syn isomers of cephalosporins having .alpha.-hydroximino- or

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 wth the carbon atom to which they are attached form a C.sub.3-7 cycloalkylidene or cycloalkenylidene group; R.sup.c and R.sup.d, which may be the same or different, each represents a hydrogen atom or a substituting group e.g. an alkyl group or substituted alkyl group; or R.sup.c and R.sup.d together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which contains 5-7 ring members and which may contain additional hetero atoms, and may be substituted by lower alkyl; R.sup.e represents hydrogen or C.sub.1-4 alkyl; m and n are each 0 or 1 such that the sum of m and n is 0 or 1 and Y is selected from various oxygen and sulphur nucleophiles] and non-toxic derivatives thereof.

Caphalosporin compounds having at position-7 an .alpha.-etherified

Cephalosporin antibiotics in which the 7.beta.-acylamido group has the formula ##STR1## (where R.sup.1 is furyl or thienyl and R.sup.2 is C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, furylmethyl or thienylmethyl) and in which the 3-position substituent is a pyridiniummethyl group wherein the pyridine ring is optionally substituted by carbamoyl, carboxy, carboxymethyl, sulpho or methyl exhibit high antibacterial activity against a broad range of gram-positive and gram-negative organisms, coupled with particularly high stability to .beta.-lactamases produced by various gram-negative organisms and good stability in vivo, particularly to esterases.

Cephalosporins

Cephalosporin antibiotics having the formula: ##STR1## (where R is thienyl, furyl or phenyl; R.sup.a is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl or phenyl, and R.sup.b is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl, phenyl, carboxy or C.sub.2-5 alkoxycarbonyl, 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: and Y is the residue of a nitrogen nucleophile and their physiologically acceptable derivatives exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce .beta.-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly high in vitro activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms; and unusually high activity against Pseudomonas organisms.

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

3-Carbamoyloxymethyl and 3-N-methylcarbamoyloxymethyl cephalosporin antibiotics in which the 7.beta.-acylamido group has the structure ##STR1## where R is thienyl, furyl or phenyl; R.sup.a is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl or phenyl, and R.sup.b is hydrogen, carboxy, C.sub.2 -C.sub.5 carbalkoxy or any of the groups designated for R.sup.a, 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; exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce .beta.-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly high in vitro activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms; and also shown unusually high activity against Pseudomonas organisms.

3-Carbamoyloxymethyl-7-substituted oximino acetamido cephalosporanic

3-Acetoxymethyl cephalosporin antibiotics in which the 7.beta.-acylamido group has the structure ##STR1## where R is thienyl, furyl or phenyl; R.sup.a is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl or phenyl, and R.sup.b is hydrogen, carboxy, C.sub.2 -C.sub.5 carbalkoxy or any of the groups designated for R.sup.a, 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; exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce .beta.-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly high in vitro activity against strains of Escherichia coli. Haemophilus influenzae and Proteus organisms; and also shown unusually high activity against Pseudomonas organisms.

3-Acetoxymethyl cephalosporins having at position-7 a carboxy

Cephalosporin antibiotics having the formula: ##STR1## (where R is thienyl, furyl or phenyl; R.sup.a is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl or phenyl, and R.sup.b is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl, phenyl, carboxy or C.sub.2-5 alkoxycarbonyl, 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; R.sup.13 is C.sub.1 -C.sub.6 alkyl, C.sub.3-7 cycloalkyl, phenylalkyl, phenyl or naphthyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolopyridyl or purinyl, and n is 0, 1 or 2 and their physiologically acceptable derivatives exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce .beta.-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly high in vitro activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms; and unusually high activity against Pseudomonas organisms.

Cephalosporins having at position-7 a carboxy substituted

Cephalosporin antibiotics in which the 7.beta.-acylamido group has the structure ##STR1## where R.sup.1 is a furyl, thienyl or phenyl group and R.sup.2 is a C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl or phenyl group and in which the 3-position substituent is a carbamoyloxymethyl group possess a particularly valuable combination of properties, exhibiting high antibacterial activity against a broad range of gram positive and gram negative organisms, paticularly high stablity to .beta.-lactamases produced by various organisms, and stability in vivo. The compounds are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer. Particularly important compounds of this type are (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph- 3-em-4-carboxylic acid (syn isomer) and its non-toxic derivatives, e.g. the sodium salt.

(6R,7R)-7-[2-aryl-2-(etherified

Cephalosporin antibiotics in which the 7.beta.-acylamido group has the structure ##STR1## (where R is thienyl or furyl; R.sup.a and R.sup.b 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; and m and n are each 0 or 1 such that the sum of m and n is 0 or 1) exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce .beta.-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly high in vitro activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms; compounds wherein at least one of R.sup.a and R.sup.b is other than hydrogen have also shown unusually high activity against Pseudomonas organisms. Important compounds of the above type include those in which the 7.beta.-acylamido group is a syn-2-carboxymethoxy-2-(fur-2-yl)acetamido, syn-2-(2-carboxyprop-2-yloxyimino)-2-(fur-2-yl)acetamido or syn-2-(1-carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetamido group.

7-(Carboxy substituted .alpha.-etherified oximino arylacetamido)

3-Carbamoyloxymethyl or

The invention provides novel antibiotic compounds which are 7.beta.-acylamidoceph-3-em-4-carboxylic acids, and non-toxic derivatives thereof characterized in that the acylamido group has the structure ##STR1## where R is a hydrogen atom or an organic group and R.sup.a is an etherifying monovalent organic group linked to the oxygen atom through a carbon atom. The compounds are syn isomers or exist as mixtures containing at least 75% of the syn isomer. These antibiotic compounds possess high antibacterial activity against a range of gram positive and gram negative organisms coupled with particularly high stability to .beta.-lactamases produced by various gram negative organisms. The invention is also concerned with the administration of the compounds.

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Chalfont St. Peter, United Kingdom

Gordon Ian Gregory