Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• Cephalosporins process for their preparation and pharmaceutical compositions containing them
• This invention relates to novel ⁇ -lactam containing compounds, in particular to a novel group of cephalosporin derivatives, their preparation and their use. These compounds have antibacterial properties and are therefore of use in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
• EP-A-153 709 discloses generically another class of such compounds wherein 'Het' is a bicyclic heterocyclic system comprising a pyridinium ring (bonded through carbon) which may be substituted on the pyridinium nitrogen by an amino group, optionally substituted by alkyl. No exemplification thereof is however provided.
• European Patent Application No. 90309493.6 (Beecham Group pic) discloses generically a class of cephalosporin derivatives having a 3-(optionally substituted N-amino pyridinium thiomethyl)substituent, in combination with a 7-[ (2-amino-4-thiazolyl)-2-(optionally substituted)- oxyimino)acetamido]substituent.
• the present invention provides a compound of formula (I) or a salt thereof:
• Y 1 is sulphur, -SO-, or -S0 2 -;
• R is hydrogen or an amino protecting group
• BX is hydrogen, optionally substituted ⁇ -i2 alkyl, or optionally substituted C ⁇ -- j cycloalkyl;
• CO2R is carboxy or a carboxylate anion, or the group R ⁇ is a readily removable carboxy protecting group
• Y ⁇ is a group of the formula:
• R 4 and R 5 which may be the same or different is each selected from hydrogen, optionally substituted C*-__g alkyl, optionally substituted C- j __g alkenyl, optionally substituted C 1 _g alkynyl, or R ⁇ and R ⁇ together form an optionally substituted ⁇ _ - alkylidene group;
• X is an inorganic or organic anion; and n is 0 or 1, with the proviso that when: (I) CO2R is carboxylate, n is 0, and
• CO2R ⁇ is carboxy or the group R ⁇ is a readily removable carboxy protecting group, then n is 1 and the anion X is present in the appropriate stoichiometric proportion to balance the positive charge on the pyridinium group.
• the compounds of formula (I) are quaternary salts and the positive charge on the pyridinium group must always be balanced by a counter anion.
• the counter anion may be present on a negatively charged group within the molecule, such as the carboxylate anion CO2R (when n is 0) , or the counter anion may be present as an external anion X (when n is 1) .
• one or more chiral centres may be present in the compound of formula (I) , for example in the oxime etherifying group.
• the invention includes within its scope the individual R and S forms at each chiral centre as well as mixtures thereof.
• Suitable C 1 _ 1 2 alkyl groups include straight and branched chain alkyl groups containing 1 to 12 carbon atoms. Preferred alkyl groups contain 1 to 6 carbon atoms, such as methyl or ethyl. Suitable C-_ ⁇ cycloalkyl groups include cyclopentyl. When used herein the term 'aryl' includes phenyl and naphthyl each optionally substituted with up to five, preferably up to three groups.
• heterocyclyl' and 'heterocyclic' suitably include unless otherwise defined aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups.
• Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
• a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
• substituents in groups for instance alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkylidene, aryl or heterocyclyl, mentioned hereinbefore as being optionally substituted include, unless otherwise defined, up to three groups (which may be the same or different) chosen from:
• 'halogen' refers to fluorine, chlorine, bromine and iodine.
• a substituent which may be present on those groups R ⁇ - defined hereinabove as being optionally substituted is selected from carboxyl, esterified carboxy, hydroxy, alkoxy, cyano, carbamoyl, N-substituted carbamoyl, aryloxy, aralkoxy, mercapto, alkylthio, arylthio, amino, substituted amino, halogen, nitro, azido, formyl, acyl, acyloxy, phthalimido, acylamino, alkoxycarbonylamino, aralkoxy-carbonylamino, aryl and heterocyclyl.
• a substituent for an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylidene, or alkynyl group is selected from halogen, cyano, azido, nitro, carboxy, (C- ⁇ .g)alkoxycarbonyl, carbamoyl, mono- or di-(C- ⁇ )alkylcarbamoyl, sulphono, sulphamoyl, mono- and di-(C- j __g)alkylsulphamoyl, amino, mono- and di-(C 1 _g)alkylamino, acylamino, (C 1 _ )alkoxycarbonyl amino, aryl, heterocyclyl, hydroxy, (C- ⁇ )alkoxy, acyloxy, oxo, arylcarbonyl, heterocyclylcarbonyl, ( ⁇ ⁇ - -)alkylthio, (C ⁇ .g
• a substituent for an aryl group is selected from halogen, (C- j ⁇ )alkyl, phenyl, (C- ⁇ )alkoxy, hydroxy(C- j ⁇ .g)alkyl, mercapto(C- j ⁇ g)alkyl, halo(C- ⁇ .g)alkyl, mercapto, hydroxy, amino, mono- or di-(C ⁇ g)alkylamino, nitro, carboxy, (C ⁇ g)alkoxycarbonyl,
• a substituent for a heterocyclyl group is selected from halogen, (C* ⁇ _g)alkyl, (C- j ⁇ g)alkoxy, halo(C- j __g)alkyl, hydroxy, amino, mono- and di- (C* ] __g)alkylamino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, (C- j __g)alkoxycarbonyl, aryloxycarbonyl, (C* ⁇ _g)alkoxycarbonyl(C* ] __g)alkyl, aryl, and oxo groups.
• Suitable amino protecting groups Rr are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule. A comprehensive discussion of the ways in which amino groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, 'Protective Groups in Organic Synthesis' by T. W. Greene •* - * (Wiley-Interscience, New York, 1981) . Particularly suitable protecting groups include, for example, amides and carbamates.
• amino protecting groups include (C 1 _g)alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (C1-4)alkyl, (C*- ⁇ )alkoxy, trifluoromethyl, halogen, or nitro; (C 1-4 )alkoxycarbonyl; benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl, trichloroethoxycarbonyl or chloroacetyl.
• the " C 1 _ 12 alkyl group for R 2 is methyl, substituted by aryl and optionally further substituted by carboxy.
• the aryl group is 3,4- dihydroxyphenyl.
• group R ⁇ examples include methyl, 1-carboxy-l-methylethyl, cyclopentyl, hydrogen, ethyl and carbox (3,4-dihydroxyphenyl)methyl.
• R ⁇ and R J include hydrogen, methyl, ethyl, 4-carboxybutan-l-yl, methoxycarbonylethyl, cyclopropylmethyl, isopropylidene, propyl, isopropyl, butyl, hexyl, cyclopentyl, prop-2-en-l-yl, and 2-hydroxyethyl.
• carboxy protecting groups for R J are, for example, ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups.
• Compounds of the present invention may exist as either syn or anti isomers, or may exist as mixtures of syn and anti isomers containing at least 75% of one such isomer, or preferably at least 90% of one such isomer.
• syn and anti refer to the terms
• Preferred compounds of the present invention are the syn-isomers of the formula (II) :
• R , R , R , X, Y , Y and n are as hereinbefore defined. It will be appreciated that also included within the scope of the invention are salts and carboxy-protected derivatives, including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substitutents in compounds of formula (I) . Also included within the scope of the invention are acid addition salts of any amino or substituted amino groups that may be present as optional substituents in compounds of formula (I) .
• the pyridinium ring may be bonded to sulphur by a carbon which is ⁇ -, ⁇ - or ⁇ -, preferably ⁇ - or ⁇ -, more preferably ⁇ -, to the pyridinium nitrogen.
• ⁇ -lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable, i.e. are compounds of formula (la) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof:
• R _?, Y1 , Y ⁇ and n are as hereinbefore defined, the group C0 2 R is carboxy or a carboxylate anion and Z is a pharmaceutically acceptable inorganic or organic anion present in the appropriate stoichiometric proportion to balance the positive charge on the pyridinium ring of the
• Suitable values of Z include chloride, bromide, iodide, phosphate (i.e. 1/3 P0 3 -) , and sulphate (i.e. ⁇ *. S0 4 2 -) , when the anion is an inorganic anion; and acetate, hydrogen maleate, methyl sulphonate,dihydrogen citrate, and hydrogen fu arate when the anion is an organic anion.
• Non-pharmaceutically acceptable salts of the compound of formula (I) wherein R ⁇ J is hydrogen are pri •marily of use as intermediates in the preparation of a compound of formula (I) wherein R J is hydrogen or a pharmaceutically acceptable salt thereof.
• Salts within compounds of formula (I) may be prepared by salt exchange in conventional manner.
• carboxy-protected derivatives of formula (I) i.e. those compounds of formula (I) wherein R J is a readily removable carboxy protecting group, may be used as intermediates in the preparation of a compound of the* formula (I) wherein R J is hydrogen, or a pharmaceutically acceptable salt thereof.
• readily removable carboxy protecting groups for R 3 are ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups.
• compounds of formula (lb) may also be described as betaines, a betaine being defined as an uncharged species having isolated non-adjacent cationic and anionic sites, and not possessing a hydrogen atom bonded to the cationic site.
• ⁇ -lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions, it will be further understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis) . Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will readily be understood that the substantially pure form is preferred as for the ⁇ -lactam antibiotic compounds. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
• solvent of crystallisation may be present in the crystalline product.
• This invention includes within its scope such solvates.
• some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
• This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
• the group -CO2R include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters.
• the derivative is preferably one which may readily be cleaved.
• Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions.
• a carboxyl group may be regenerated from any of the above . esters by usual methods appropriate to the particular R J group, for example, acid- and base- catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
• Suitable pharmaceutically acceptable in. vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
• Suitable ester groups of this type include those of part formula (i) , (ii) , (iii) and (iv) :
• R a is hydrogen, (C-_g alkyl), (C3_ 7 ) cycloalkyl, methyl, or phenyl;
• R b is (C ⁇ g) alkyl, (C 1 _g) alkoxy, phenyl, benzyl, (C3_ 7 ) cycloalkyl, (C ⁇ _g) alkyl (C3_ 7 ) cycloalkyl, 1-amino C ⁇ _ -) alkyl, or 1- (C 1 _g) alkylamino (C- ⁇ .
• R a and Rr together form a 1,2-phenylene group optionally substituted by one or two methoxy groups
• R c is (Ci _g) alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently are (C ⁇ _ -) alkyl
• R f represents (C* j __g)alkyl
• R ⁇ is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C- j __g) alkyl, or (C- ⁇ . ) alkoxy
• Y is oxygen or NH.
• Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl,
• (1-aminoethyl)-carbonyloxymethyl (1-aminoethyl)-carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second ⁇ -lactam antibiotic or to a ⁇ -lactamase inhibitor.
• alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl
• dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl,
• a further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that of the formula:
• R J is hydrogen, C ⁇ g alkyl or phenyl.
• Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts, for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium; and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)- amine, cycloalkylamines_such as dicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylene- diamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl- ⁇ - phenethylamine, dehydroabietylamine, N,N'-bisdehydro-abietylamine, ethylenediamine or
• N-methylglucosamine or basic amino acids such as lysine, arginine, or bases of the pyridine type such as pyridine, collidine or quinoline; or other amines which have been used to form salts with known penicillins and cephalosporins.
• Other useful salts include the lithium salt and silver salt.
• Suitable compounds of formula (I) include:
• the antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, according to techniques and procedures per se known in the art with reference to other antibiotics, and the invention therefore includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention such as, for example a pharmaceutically acceptable compound of formula (I) or a salt or in vivo hydrolysable ester thereof above together with a pharmaceutically acceptable carrier or excipient.
• the compositions may be formulated for administration by any suitable route, such as oral or parenteral, or by topical application. Normally administration will be via a parenteral route.
• compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone
• fillers for example lactose, sugar, maize-
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl- cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils) , for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p_-hydroxybenzoate or sorbic acid; and, if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl- cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monoole
• fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
• the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• the composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
• the dosage as employed for adult human treatment will preferably range from 100 mg to 12 g per day for an average adult patient (body weight 70 kg) , for instance 1500 mg per day, depending on the route and frequency of administration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.
• the daily dosage is suitably given by administering a compound of the invention several times in a 24-hour period. Typically, 250 mg is administered 4 times a day although, in practice, the dosage and frequency of administration which will be most suitable for an individual patient will vary with the age, weight and response of the patients, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of administration. Such dosage regimens are within the scope of this invention.
• the antibiotic compounds according to the present invention may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics and/or ⁇ -lactamase inhibitors may be employed.
• compositions also comprise a compound of formula (III) or a pharmaceutically acceptable salt or ester thereof:
• A is hydrox 1; substituted hydroxyl; thiol; a-group of formula S0 2 R 10 wherein R 10 is C--__g alkyl; substituted thiol; amino; mono- or di-(hydrocarbyl)substituted amino; mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP-A-0 053 893 (to Beecham Group pic) .
• a further advantageous composition comprises a pharmaceutically acceptable antibiotic compound of the formula (I) or a salt or an jLn vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier or excipient together with a ⁇ -lactamase inhibitor of formula (IV) or a pharmaceutically acceptable salt or jLn vivo hydrolysable ester thereof:
• B is hydrogen, halogen or a group of formula:
• R 1 ⁇ ⁇ 1 and R1 -9" are the same or different and each is hydrogen, C- ⁇ _g alkoxycarbonyl, or carboxy or a pharmaceutically acceptable salt thereof.
• ⁇ -lactamase inhibitors include 6-alkylidene penems as described in EP-A-0 041 768 and EP-A-0 154 132 (to Beecham Group pic) .
• ⁇ -lactamase inhibitors include
• compositions of this invention comprising a ⁇ -lactamase inhibitor are formulated in conventional manner.
• the present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of a pharmaceutically acceptable antibiotic compound of the present invention of the formula (I) or a salt or in vivo hydrolysable ester thereof.
• the present invention also provides for the use of a compound of the formula (I) for the manaufacture of a medicament.
• antibiotic compounds of the present invention of formula (I) or salts or in vivo hydrolysable esters thereof are active against a broad range of Gram-positive and Gram-negative bacteria, and may be used to treat a wide range of bacterial infections including those in immunocompromised patients.
• the pharmaceutically acceptable compounds of the invention of formula (la) or salts or in vivo hydrolysable esters thereof are of value in the treatment of respiratory tract and urinary tract infections in humans and may also be used to treat mastitis in cattle.
• a particular advantage of the antibacterially active compounds of this invention is their stability to ⁇ -lactamase enzymes and they are therefore effective against ⁇ -lactamase producing organisms.
• the present invention further provides a process for the preparation of a compound of formula (I) (as hereinbefore defined) which process comprises treating a compound of formula (V) :
• R , R , R , and Y are as hereinbefore defined, and RR ⁇ ⁇ ⁇ -- ii.ss aa lleeaavving group; and wherein any reactive groups may be protected;
• the ring Q is such that it is converted to the nucleus of the group Y ⁇ (as hereinbefore defined) in situ during the course of the reaction, and R - and R 5 are as hereinbefore defined;
• Suitable leavi .ng groups R ⁇ ⁇ ⁇ - ⁇ include halogen such as chlorine, bromine or iodine or an acyloxy group such as, for example, the acetoxy group.
• Preferred groups for R—' are chloro and iodo.
• This reaction is desirably conducted in a solvent.
• a solvent for example, use can be made of water, or of organic solvents inert to the starting compounds, such as dimethylformamide, dimethylacetamide, dioxane, acetone, dichloromethane, 1,2- dichloroethane, acetonitrile, dimethylsulfoxide or te ..ahydrofuran, or mixtures thereof.
• the reaction temperature and time depend, among other factors, upon the starting compounds and solvent to be employed but generally the reaction is carried out at a selected temperature within the range of 0 to 100°C for a selected time of a few minutes to several days.
• Preferred compounds of the formula (V) include salts and esters in which R 3 is as hereinbefore defined and in
• R J is diphenylmethyl, p-methoxybenzyl or trimethylsilyl.
• compounds of formula (VI) may be obtained from the corresponding pyridone by treatment with for instance Lawesson's reagent or phosphorus pentasulphide according to conventional procedures.
• Suitable pyridones may be prepared according to the methodology of Freeman et al. J. Amer. Chem. Soc, 1947, J59_, 858.
• the compounds of formula (I) may also suitably be prepared by reacting a compound of formula (VIII) or a salt thereof:
• R x is hydrogen or a readily removable carboxyl blocking group and the 7 ⁇ -amino group is optionally substituted with a group which permits acylation to take place; and any reactive groups may be protected;
• R 1 is as hereinbefore defined; and wherein any reactive groups may be protected; and thereafter, if necessary, carrying out one or more of the following steps:
• Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (VIII) include silyl, stannyl and phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, phosphorus groups of formula wherein R x - is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R ⁇ ⁇ is the same as R 1 ' or is halogen or R 16 and R 1 together form a ring; suitable such phosphorus groups being
• a group which may optionally be introduced in situ prior to acylation onto the amino group in the compound of formula (VIII) is trimethylsilyl.
• Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide.
• Acylation with an acid halide may be effected in the presence of an acid binding agent, for example a tertiary amine (such as pyridine or dimethylaniline) , molecular sieves, or an inorganic base (such as calcium carbonate or sodium bicarbonate) or a silylated derivate of acetamide [such as trimethylsilylacetamide or N,0-bis(trimethylsilylacetamide) ] or an oxirane, which binds hydrogen halide liberated in the acylation reaction.
• an acid binding agent for example a tertiary amine (such as pyridine or dimethylaniline) , molecular sieves, or an inorganic base (such as calcium carbonate or sodium bicarbonate) or a silylated derivate of acetamide [such as trimethylsilylacetamide or N,0-bis(
• the oxirane is preferably a (C ⁇ _g)- 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.
• the acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°c, in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
• reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.
• solvents include tetrahydrofuran, and anhydrous chlorinated hydrocarbons, especially dichloromethane.
• the acid halide may be prepared by reacting the acid (IX) or a salt or suitable derivative thereof with a halogenating * (eg chlorinating, or brominating) agent such as phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, or phosgene.
• a halogenating * eg chlorinating, or brominating
• phosphorus pentachloride phosphorus oxychloride
• thionyl chloride thionyl chloride
• oxalyl chloride oxalyl chloride
• phosgene phosgene
• Suitable derivatives of the acid (IX) which may be employed in the above process include labile esters such as silyl esters.
• Suitable silyl esters include, for example, tri (C 1 _g)alkyl silyl esters, especially the trimethylsilyl ester.
• the N-acylating derivative of the acid (IX) may be a symmetrical or mixed anhydride.
• Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example, carbonic acid monoesters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid,, benzoic acid, phosphorus acids (such as phosphoric, phosphorous, and phosphinic acids) or aromatic or aliphatic sulphonic acids (such as p_-toluenesulphonic acid or methanesulphonic acid) .
• phosphorus acids such as phosphoric, phosphorous, and phosphinic acids
• aromatic or aliphatic sulphonic acids such as p_-toluenesulphonic acid or methanesulphonic acid
• the N-acylating derivative is preferably prepared in the presence of an organic base such as triethylamine and/or N,N-diisopropylethylamine in a suitable solvent such as DMF or dichloromethane at between -50°C and room temperature.
• the N-acylating derivative may be prepared from an alkali metal salt of the acid of formula (IX) , such as the sodium salt, in a suitable solvent such as DMF at between -50°C and room temperature.
• the N-acylating derivative of the acid of formula (IX) so derived may then be reacted with a compound of formula (VIII) .
• the acylation reaction may conveniently be carried out at -50°C to +50°C in a suitable solvent such as water, acetonitrile, DMF or dichloromethane at a temperature of not more than 0°C.
• a suitable • base such as triethylamine or sodium hydrogen carbonate.
• N-acylating derivatives of acid (IX) are the acid azide, or activated esters such as esters with cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, N-hydroxybenzotriazole, or 8-hydroxyquinoline; or amides such as N-acylsaccharins, N-acylthiazolidin- 2- ;hione or N-acylphthalimides; or an alkylidene iminoester prepared by reaction of the acid (IX) with an oxime.
• esters such as esters with cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, N-hydroxybenzotriazole, or 8-hydroxyquinoline
• amides such as N-acyl
• N-acylating derivatives of the acid of formula (IX) are thioesters of formula (X)
• R 1 and R9 are as hereinbefore defined an represents a 5- or 6-membered heterocyclic ring, which may contain, in addition to the nitrogen atom, one or two further heteroatoms, selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted.
• Preferred acylating agents derived from the acid of formula (IX) are the thio-esters (Xa) or (Xb) :
• R 1 and R 9 are as hereinbefore defined.
• Compounds of the formula (Xa) and (Xb) may be prepared by treatment of the acid (IX) with 2,2'-dipyridyl-disulphide or 2,2'-dibenzothiazolyldisulphide respectively, in the presence of triphenylphosphine, analogously to the routes described in EP-A-0 037 380 (to Biochemie GmbH) .
• R 1 may be hydrogen.
• N-acylating derivatives of the acid (IX) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, N,N'-diethyl-, di-n-propyl- or diisopropylcarbodiimide, N,N'-di-cyclohexyl- carbodiimide, or N-ethyl-N'-[3-(dimethylamino)propyl]- carbodiimide; a suitable carbonyl compound, for example,
• N-alkoxycarbonyl 2-alkoxy-l,2-dihydroquinoline such as N-ethoxycarbonyl 2-ethoxy-l,2-dihydroquinoline.
• Other condensing agents include Lewis acids (for example BB ⁇ .CgHg); or a phosphoric acid condensing agent such as diethylphosphorylcyanide.
• the condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
• a further method of forming the N-acylating derivative of the acid (IX) is to treat the acid of formula (IX) with a solution or suspension preformed by addition of a carbonyl halide, preferably oxalyl chloride, or a phosphoryl halide such as phosphorus oxychloride, to a halogenated hydrocarbon solvent, preferably dichloromethane, containing a lower acyl tertiary amide, preferably N,N-dimethylformamide.
• the N-acylating derivative of the acid (IX) so derived may then be caused to react with a compound of formula (VIII) .
• the acylation reaction may conveniently be carrisd out at -40° to +30°C, if desired in the presence of an acid binding agent such as pyridine, trimethylsilylacetamide or N,( ⁇ -bis (trimethylsilyl acetamide) .
• an acid binding agent such as pyridine, trimethylsilylacetamide or N,( ⁇ -bis (trimethylsilyl acetamide) .
• a catalyst such as 4-dimethylaminopyridine may optionally also be added.
• a preferred solvent for the above acylation reaction is dichloromethane.
• a preferred am o protecting group R 1 m the intermediate of formula (IX) is trityl, which R group may be suitably removed from the product of formula (I) by treatment with formic acid or trlfluoracetic acid.
• Compounds of formula (IX) may be prepared by routes analogous to those disclosed in GB 2 025 398A and by Takasugi et al., J.Antibiotics [1983] 36., 846 et seq and modifications thereto described in EP-A-0 210 815 (Beecham Group pic) .
• R ⁇ , R1 ⁇ , and Y1 are as hereinbefore defined, and the 7 ⁇ -amino group is optionally protected with an amino protecting group; with a compound of the formula (VI) as hereinbefore defined;
• Compounds of formula (V) may be prepared by reacting a compound of formula (XI) as hereinbefore defined or a derivative thereof in which the 7 ⁇ -amino group is substituted with a group which permits acylation to take place; and any reactive groups may be protected; with an N-acylating derivative of an acid of formula (IX), as , hereinbefore defined and thereafter, if necessary,carrying out one or more of the following steps:
• the compounds of formulae (la) , (lb) , and (Ic) may be prepared by similar processes to those described hereinabove as suitable for the preparation of a compound of the formula (I) , except that each process for the preparation of the compound of formulae (la) , (lb) or (Ic) further comprises, if necessary, the step of converting the product into a pharmaceutically acceptable salt or pharmaceutically acceptable in. vivo hydrolysable ester. Conversion of betaines of formula (lb) into salts of formula (Ic) and vice versa may readily be carried out by conventional methods. For example salts of the formula (Ic) may be prepared from betaines of formula (lb) by treatment with a dilute mineral acid such as hydrochloric acid.
• Quaternary salts within formula (Ic) may also be prepared by salt exchange in a conventional manner, for example by means of an ion-exchange resin.
• the antibiotic compounds of the present invention are active against a wide range of Gram-negative and Gram-positive organisms including E.coli such as, for example ESS, JT4, JT425 and NCTC 10418; Pseudomonas Spp. such as Ps.aeruginosa for example 10662 and Dalgleish; Serratia marcescens US32; Klebsiella aerogenes A; Enterobacter cloacae Nl; P.mirabilis such as, for example C977 and 889; P.morganii; P.rettgeri; B.subtilis; Staph. aureus such as, for example Oxford and Russell; N.catarrhalis 1502.
• E.coli such as, for example ESS, JT4, JT425 and NCTC 10418
• Pseudomonas Spp. such as Ps.aeruginosa for example 10662 and Dalgleish
• Serratia marcescens US32 Klebsiella aerogenes
• [S]-2- (3,4-diacetoxyphenyl)-2-(phthalimidooxy)acetate (1.36g, 2.35mmol) was dissolved in dichloromethane (25ml) and cooled to -60°C. This solution was treated with methylhydrazine (0.125ml, 2.35mmol) and the temperature allowed to rise slowly to +5°C. The mixture was then stirred at ambient temperature for lh. The solid was removed by filtration and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in methanol (40ml) and treated with 2-(2-tritylamino-4- thiazolyDglyoxylic acid (0.95g, 2.3mmol) .
• N,N-dimethylformamide (5ml) under argon and the solution cooled to -40°C.
• N,N-Diiso ⁇ ropylethylamine (0.122g, 0.94mmol) then methanesulphonyl chloride (O.lO ⁇ g, 0.94mmol) were added and the mixture stirred at -20°C for 0.5h.
• the latter intermediate product (0.023g, 0.03mmol) was 25 dissolved in water (5ml) and methanol (5ml) and treated with dilute sodium hydroxide to pH 9.4. After 5 minutes the mixture was neutralised with 0.1M hydrochloric acid and the solvent removed under reduced pressure. The product was purified on Diaion HP20SS resin, eluting with mixtures of 30 water and tetrahydrofuran.
• the title compound is prepared as described in Example 15 except that l-amino-4-thiopyridone replaces 1 ethylamino)-4-thiopyridone.
• the title compound is prepared from 2-(Z)-[ (R)-(3,4- diacetoxyphenyl) (diphenylmethyl-oxycarbonyl)methyloxy imino]-2-(2-tritylamino-4-thiazolyl)acetic acid and l-amino-4-thiopyridone using the method described in Example 15.

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