WO1993003042A1 - Derives de 6-ethylidene penem - Google Patents

Derives de 6-ethylidene penem Download PDF

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Publication number
WO1993003042A1
WO1993003042A1 PCT/GB1992/001306 GB9201306W WO9303042A1 WO 1993003042 A1 WO1993003042 A1 WO 1993003042A1 GB 9201306 W GB9201306 W GB 9201306W WO 9303042 A1 WO9303042 A1 WO 9303042A1
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formula
compound
penem
group
ethylidene
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PCT/GB1992/001306
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English (en)
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Andrew Valentine Stachulski
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Smithkline Beecham Plc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2

Definitions

  • This invention relates to novel chemical compounds being penems, to methods for their preparation, to intermediate compounds in their preparation, to pharmaceutical formulations incorporating them, and to uses thereof.
  • Penems are a known class of compounds having antibiotic properties and in some cases also having ⁇ -lactamase inhibitory properties. Chem.
  • X is -CH 2 S-Het, where Het is a heteroaromatic ring system, thiazol-4-yl, 2-methylthiadiazol-4-yl, 1-hydroxyethyltetrazol-4-yl and 1-acetamidotetrazol-4-yl being exemplified, R being hydrogen, a cation or an ester forming group.
  • Chem. Pharm. Bull. 33(10) 4382-4394 discloses compounds of formula (A) wherein X is -CH 2 OCOCH 3 .
  • 6-ethylidene penems are disclosed in EP 0041768A and EP 0232966A.
  • R 1 is (C 1-6 ) alkyl or substituted (C 1-6 ) alkyl
  • R 2 is -CH 2 X or -COY where;
  • X is halogen, COR, OCOR, NR 2 , NR(COR), N(COR) 2 ,
  • CONR 2 CONR(COR), CON(COR) 2 , OCONR 2 , OCONR(COR),
  • Y is R, NR 2 , NRCCOR), N(COR) 2 , or OR 6 ;
  • each R being independently hydrogen, (C 1-6 ) alkyl, substituted (C 1-6 ) alkyl, (C 1-12 ) heterocyclyl or (C 1-12 ) aryl;
  • R 3 is (CH 2 ) n R or (CH 2 ) n OR where n is 0 to 3 and R is hydrogen, (C 6- 6 ) alkyl, substituted (C 1-6 ) alkyl, (C 1-12 ) heterocyclyl or (C 1-12 ) aryl;R 4 - is hydrogen, a salt-forming cation or an ester-forming group;
  • R 5 being R or a hydroxy-protecting group
  • R 6 being R or a carboxy-protecting group
  • alkyl as used herein includes straight chain, branched chain and cycloalkyl groups.
  • 'heterocyclyl' as used herein includes aromatic and
  • 'aryl' as used herein includes phenyl and naphthyl, which may be unsubstituted or substituted by up to five, preferably up to three, groups selected from halogen, substituted or unsubstituted, (C 1-6 ) alkyl, phenyl, (C 1-6 ) alkoxy, halo(C 1-6 ) alkyl, hydroxy, amino, nitro, carboxy, (C 1- 6)alkoxycarbonyl, (C 1-6 ) alkoxycarbonyl (C 1-6 ) alkyl, (C 1- 6 ) alkylcarbonyloxy, (C 1-6 ) alkylcarbonyl (C 1-6 ) alkylthio, arylthio, and mercapto groups.
  • hydrocarbon substitutents include (C 1-6 ) alkanoyl, (C 1-6 ) alkanoyloxy, heterocyclyl, amino, sulphonylamino, (C 1-6 ) alkanoylamino, (mono or di)-(C 1-6 ) alkylamino, hydroxy, (C 1-6 ) alkylsulphinyl, (C 1- 6 )alkylsulphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters,arylcarbonyl and heterocyclylcarbonyl and carbonyloxy groups.
  • heterocyclyl or aryl group includes a carboxy salt or carboxy ester substituent, that substituent is suitably a pharmaceutically
  • R 1 is methyl
  • R 2 is -CH 2 X
  • X is suitably halogen, typically fluorine, or OR, typically with R being hydrogen, or OCOR, typically with R being (C 1-6 ) alkyl such as methyl.
  • R 5 is a hydroxy-protecting group it may be a conventional
  • protecting group such as an alkanoic ester group such as a (C 1-4 ) alkoxy carbonyl group such as tert-butyloxycarbonyl. a (C 1-4 )
  • halogenoalkoxycarbonyl group such as 2-iodoethyloxycarbonyl or 2,2,2- trichloro- ethyloxycarbonyl, an aralkyloxycarbonyl group such as
  • benzyloxycarbonyl a tri (C 1-4 ) alkylsilyl group such as tert- butyldimethylsilyl or trimethylsilyi, a (C 4-10 ) tert-alkyl group such as tert-butyl and a substituted or unsubstituted mono-, di or triphenylmethyl group such as benzyl, p -methoxybenzyl, diphenylmethyl, di(p-anisyl)methyl or tritzyl.
  • Hydroxy-protecting groups BP may be removed by conventional methods which are appropriate to the R 5 groups concerned.
  • R 3 is -(CH 2 ) n -R
  • n is O and R is hydrogen (so that the 2- position is unsubstituted), or n is O and R is heterocyclyl.
  • Typical heterocyclyl groups R when R 3 is -(CH 2 ) n -R are optionally substituted 5 or 6 membered heterocyclyl groups, for example containing one oxygen atom as the sole hetero atom, such as 2-tetrahydro furanyl.
  • R 3 is (CH 2 ) n OR
  • n is O and R is (C 1-6 ) alkyl, for example methyl.
  • R 4 is a salt-forming cation, preferably it is a pharmaceutically acceptable salt forming cation.
  • Suitable pharmaceutically acceptable salts of the 3-carboxylic acid group of the compound of formula I or of other carboxylic acid groups which maybe present as optional substituents include those in which R 4 is a metal ion e.g. aliiminium salts, alkali metal salts (e.g. sodium, lithium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts, and substituted ammorium salts, for example those with lower alkylamines (e.g.triethylamine), hydroxy-lower
  • alkylamines e.g. 2-hydroxyethylamine, di(2-hydroxyethyl)amine tri(2-hydrGxyethyl)amine), bis-(2-hydroxyethyl)amine, tris-(2- hydroxyethyl)amine, lower-alkylamines (e.g. dicyclohexyl- amine), or with procaine, dibenzylamine, N,N-dibenzyl- ethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylanrine, ethylenediamine,
  • procaine dibenzylamine, N,N-dibenzyl- ethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylanrine, ethylenediamine,
  • N,N'-bishydroabietylethylenediamine, bases of the pyridine type e.g.
  • pyridine collidine and quinoline
  • other amines which have been or can be used to form quaternary ammonium salts with penicillins.
  • the compound of formula I may be a pharmaceutically acceptable in vivo hydrolysable ester, being an ester which hydrolyses in the human body to produce the parent acid or its salt.
  • esters may be identified by the test process of oral or intravenous administration to a test animal, and subsequent examination of the test animal's body fluids for the presence of the compoun d of the formula I or a salt thereof.
  • the in vivo hydrolysable ester moiety may constitute a link between two different active ingredient moieties, one of which is a compound according to the invention and the other of which may be another therapeutically active compound, such that on in vivo hydrolysis of the ester moiety, the ester link breaks to give the two separate active compounds.
  • the linked entity may be referred to as a 'mutual pro-drug'.
  • 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 in which R 4 has the formula (i), (ii), (iii) or (iv):
  • R a is hydrogen, (C 1-6 ) alkyl, (C 3-7 ) cycloalkyl, methyl, or phenyl
  • R b is (C 1-6 ) alkyl, (C 1-6 ) alkoxy, phenyl, benzyl, (C 3-7 ) cycloalkyl, (C 1-6 ) alkyl (C 3-7 ) cycloalkyl, 1- amino (C 1-6 ) alkyl, or 1- (C 1-6 ) alkyl) amino (C 1-6 ) alkyl; or R a and R b together form a 1,2-phenylene group optionally substituted by one or two methoxy phenyl, benzyl, (C 3-7 ) cycloalkyl, (C 1-6 ) alkyl (C 3-7 ) cycloalkyl, 1-amino (C 1-6 ) alkyl, or 1-(C 1-6 alky)amino (C 1-6 ) alkyl; or
  • suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, (1-acetoxy)ethyl, (1-pivaloyloxy)ethyl, 1-(cyclohexylcarbonyloxy)prop-1- yl, and (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
  • a further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that in which R 4 has the formula:
  • R h is hydrogen, (C 1-6 ) alkyl or phenyl.
  • R 4 may also be a readily removable carboxy protecting ester group, other than a pharmaceutically acceptable in vivo hydrolysable ester group, or a non-pharmaceutically acceptable salt-forming cation.
  • Such compounds of formula I are primarily useful as intermediates in the preparation of compounds of formula I and pharmaceutically acceptable salts and esters thereof.
  • Suitable ester-forming carboxy-protecting groups from which R 4 and R 6 may be selected include those which may be removed under conventional conditions.
  • Such groups include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl,
  • a CO 2 R 4 group in which R 4 is hydrogen may be regenerated from any of the above-mentioned esters by usual methods appropriate to the particular R 4 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.
  • Certain compounds of formula I may include an amino group which may be protected. Suitable amino protecting groups are those well known in the art which may be removed under conventional conditions if required without disruption of the remainder of the molecule.
  • amino protecting groups include (C 1-6 ) alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (C 1-4 ) alkyl, (C 1-4 ) alkoxy, trifluoromethyl, halogen, or nitro; (C 1-4 ) alkoxycarbonyl; benzyl oxyearbonyl or trityl substituted as for benzyl above; allyloxycarbonyl,trichloroethoxycarbonyl or chloroacetyl.
  • Amino or substituted amino group(s) that may be present as optional substituents on the compound of formula I, or of any heterocyclic group ring nitrogen atoms may also be present as acid addition salts, which may be pharmaceutically acceptable.
  • Suitable salts include for example hydrochlorides, sulphates, acetates, phosphates etc. and other
  • Preferred addition salts are the hydrochlorides.
  • the compound of formula (I), its salts and esters, may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric forms are encompassed within the scope of the present invention.
  • a preferred isomeric form is the (5R) form.
  • the orientation of the 6-position ethylenic side chain may be E or Z and the present invention includes both such forms or mixtures of these isomers in a 1:1 ratio or in which one such isomer predominates, although an isomerically pure compound is preferred.
  • the Z-isomer is preferred.
  • R 1A is -CH 2 -R wherein R is hydroxyl, (C 1-6 ) acyloxy, or halogen particularly fluorine
  • R 3A is hydrogen, -R where R is 5 or 6 membered heterocyclyl which has oxygen as its sole heteroatom or -CH 2 O-R where R is (C 1-6 ) alkyl
  • R 4A is hydrogen or a pharmaceutically acceptable saltforming cation or pharmaceutically accsptable ester-forming group.
  • Some compounds of formula I and IA may be crystallised or recrystallised from solvents such as organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of solvents such as water that may be produced by processes such as lyophilisation.
  • the compounds of formula (I) and (IA) are antibiotics and are intended for use in pharmaceutical compositions it will readily be understood that they are preferably each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85% pure, especially at least 95% pure particularly at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or (IA) or ester or salt thereof.
  • specific compounds of formula (I) include the following acids, and pharmaceutically acceptable salts (especially the sodium salt) and in vivo hydrolysable esters thereof:
  • the present invention further provides a first process for the preparation of a compound of formula I as defined above, where R 2 is a group - CH 2 OR 5 where R 5 is a hydroxy-protecting group or R 2 is a group -COOR 6 where R 6 is a carboxy-protecting group; wherein R 4 is a carboxyprotecting ester-forming group; which process comprises the step of removing at least one of protecting groups R 4 , R 5 or R 6 and replacing them with at least one other group R 4 , R 5 or R 6 , so as to produce a compound of formula (I) in unprotected form.
  • the invention provides a further process for the preparation of compounds of formula (I), in which a compound of formula (II)
  • R 1 , R 2 , R 3 and R 4 are as defined in formula (I)); W and Z are substituents which may be eliminated together, is subjected to an elimination process to form a compound of formula (I); and thereafter if necessary or desired carrying out one or more of the following steps;
  • one of W and Z may be hydrogen
  • n denotes 0 or 1
  • R 7 denotes (C 1-6 ) alkyl or substituted alkyl, aryl or aryl (C 1-6 ) alkyl
  • R 8 denotes (C 1-6 ) alkyl or substituted alkyl or aryl.
  • the elimination may be carried out by subjecting the compound of formula (II) to to dehydration elimination process as described in EP 041768A P7 line 24 - P9 line 8 or EP 0150781A P11 line 14 - P17 line 28, the contents of which are included by reference.
  • the elimination may be carried out by subjecting the compound of formula (II) to an elimination process as described in EP 041768A P9 line 10 - P11 line 6 or EP 0150781 A P17 line 30 - p 18 line 36, the contents of which are included by reference.
  • Suitable leaving groups include sulphoxide, selenoxide and xanthate groups, which can be eliminated by known methods, see for example W.
  • Z is a halogen, particularly bromine, and W is a leaving group which is
  • a halogen atom preferably a halogen atom, a hydroxy group, a substituted hydroxy group, an -S(O) n R 9 or an -Se(O) m R 9 group; in which n is 0, 1 or 2, m is 0 or 1, and R 9 is hydrogen, a hydrocarbon group or a heterocyclyl group and the elimination reaction is a reductive elimination reaction.
  • Preferred substituted hydroxy groups are the leaving groups of formula (i), (ii) and (iii) referred to above.
  • a particular preferred substituted hydroxy group is one of formula (ii) above having n as zero and R 7 as alkyl ie an acyloxy group, preferably an acetoxy group.
  • the reductive elimination step may be carried out in a manner which is generally known per se for such elimination reactions.
  • the reductive elimination may be carried out by reaction of the compound of formula (II) with a metal, such as zinc, magnesium, aluminium or iron, in the presence of an acid, such as acetic acid or a mineral acid, or by reaction with a triorganophosphous compound such as
  • triphenylphosphine suitably at a temperature between -20°C and +40°C, preferably from 0° to 20°C.
  • the reaction may be carried out in the presence of a solvent, which may be polar or non-polar, protic or aprotic, for example an organic solvent such as dioxane, dimethoxyethane or tetrahydrofuran, or alternatively the neat acid and metal may be used.
  • a solvent which may be polar or non-polar, protic or aprotic, for example an organic solvent such as dioxane, dimethoxyethane or tetrahydrofuran, or alternatively the neat acid and metal may be used.
  • R 1 and R 4 are as defined in formula (I).
  • the anion of formula (IIIA) may be prepared from the compound of formula (III) by reaction of the compound of formula (III) with an organometallic compound of the formula M-R 10 where M is an alkali metal, especially lithium, and R 10 is the residue of an organic base such as diphenylamine.
  • M-R 10 may for example be prepared by reaction of a metal alkyl such as n-butyllithium with the corresponding base such as diphenylamine in a suitable organic solvent such as tetrahydrofuran at a temperature of for example -20°C to +20°C under an inert atmosphere.
  • Ketone compounds of formula (IV) are generally known or may be prepared from standard literature routes.
  • the reaction beween the anion of formula (IIIA), and ketone (IV) may be carried out using the anion in situ as prepared above, for example by mixing the anion (IIIA) and ketone (IV) in a suitable solvent such as tetrahydrofuran at a temperature from - 100°C to +20oC under an inert atmosphere.
  • the product of the reaction between the anion of formula (IIIA) and the compound of formula (IV) is a compound of formula (II) having W as hydroxy, and this hydroxy group W may be converted into a leaving group such as (i), (ii) or (iii) above by reaction with a suitable acid or acid derivative such as an acid halide or anhydride.
  • a suitable acid or acid derivative such as an acid halide or anhydride.
  • the hydroxy compound product may be reacted with an acid anhydride such as acetic anhydride, which may conveniently be done with the hydroxy compound of formula (II) in situ prepared as described above.
  • R 3 and R 4 are as defined in formula (I)
  • R 11 denotes oxygen, sulphur or a phosphorylidene group
  • the cyclisation may be carried out in a generally known manner. General methods of carrying out this cyclisation are for example described in EP 0232966, with reference to routes A to F on P 13-25 thereof.
  • a compound of formula (V) may conveniently cyclise spontaneously or by heating in an inert solvent such as toluene either under reflux or at a sub-reflux temperature preferably in an inert atmosphere optionally in the presence of a trivalent phosphorus compound.
  • a tri-organo phosphorus compound such as PR 13 where PR 13 is as defined above
  • R 4 and PR 12 are as defined in formula (V)
  • M is a metal, especially silver, and a is the ionic charge of the cation of metal M, by reaction with an acyl halide of formula R 3 COX where X is a halogen especially chlorine.
  • a group R 4 such as p- methoxybenzyl
  • a silver salt for example of an inorganic or (C 1-10 ) alkanoic acid, such as silver acetate, typically in the presence of ⁇ -picoline and a base, suitably 1, 8-diazabicyclo [5,4,0]undec-7- ene.
  • this reaction is carried out in an organic solvent, for example acetonitrile, at a low temperature, suitably 3°C to -15°C, preferably in the dark.
  • an organic solvent for example acetonitrile
  • the silver salt and the picoline are first reacted together in a solvent, then the base is added.
  • the compound of formula (VII) is then added.
  • Protecting groups may be removed from protected positions such as R 4 and -OR 5 (when R 5 is a hydroxy-protecting group) by methods which are conventional in the art.
  • R 4 is the carboxy-protecting group paramethoxybenzyl it may for example be removed by reaction with aluminium chloride or a mono- or di-alkylalumimum chloride and anisole in a suitable solvent such as dichloromethane, followed by addition of a suitable buffer such as sodium citrate or sodium phosphate.
  • R 5 is the hydroxy-protecting group trialkylsilyl, e.g. trimethylsilyl, this may be removed by reaction with tetra-n-butylammonium fluoride under acid conditions, e.g.
  • R 5 is the hydroxy-protecting group acyl, e.g. acetyl, this may be removed by reaction with diisobutyl aluminium hydride, e.g. at -70°C.
  • R 2 contains a functional group
  • X is halogen
  • R is hydrogen
  • these functional groups such as halo, hydroxy, carboxylate or amino
  • R 2 may be acylated using acids or conventional acylating derivatives thereof
  • carboxylate functional group R 2 may acylate hydroxyl or amino groups either directly or via conventional acylating derivatives thereof
  • halogen atoms may be replaced by amino or substituted amino groups.
  • the present invention also provides a pharmaceutical composition which comprises a compound of formula (I), particularly (IA) or a
  • compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
  • the antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • compositions may be formulated for administration by any route, such as oral, topical or parenteral.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • 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.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • 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 for example letithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • 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.
  • Suppositories will contain conventional suppository bases, e.g.
  • cocoa-butter or other glyceride cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing 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 a 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 lyophilized 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 sterilization 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.
  • compositions may contain from 0.1% by weight, preferably from
  • 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 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.
  • the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or with a ⁇ -lactamase inhibitor may be employed.
  • compositions also comprise a compound of formula (VIII) or a pharmaceutically acceptable salt or ester thereof:
  • R i is hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, mono- or di-hydrocarbyl-substituted amino, or mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP O 053 893.
  • a further advantageous composition comprises an antibiotic compound of formula (I) or (IA) according to the invention and a pharmaceutically acceptable carrier or excipieat together with a ⁇ -lactamase inhibitor of formula (IX) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof:
  • R j is hydrogen, halogen (especially chlorine) or a group of formula:
  • R k and R l are the same or different and each is hydrogen, (C 1-6 ) alkoxycarbonyl, or carboxy or a pharmaceutically acceptable salt thereof.
  • suitable ⁇ -lactamase inhibitors include 6-alkylidene penems of formula (X) below:
  • R m and R n are the same or different and each represents hydrogen, or a C 1-10 hydrocarbon or heterocyclic group optionally substituted with a functional group; and R 16 represents hydrogen or a group of formula R or -SR where R is an optionally substituted (C 1-10 ) hydrocarbon or heterocyclic group, as described in EP 041 768A.
  • ⁇ -lactamase inhibitors include 6 ⁇ -bromopenicillanic acid and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof and 6 ⁇ -iodopenicillanic acid and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof described in, for example, EP-A-0 410 768 and EP-A-0 154 132 (both Beecham Group).
  • Such compositions of this invention which include a ⁇ -lactamase inhibitory amount of a ⁇ -lactamase inhibitor are formulated in a conventional manner using techniques and procedures per se known in the art.
  • the present invention provides a compound of formula (I) or a
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in the treatment of bacterial infections.
  • 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 an antibiotic compound of this invention of the formula (I) or a pharmaceutically acceptable in vivo hydrolysable ester thereof.
  • the present invention includes the use of a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, in the manufacture of a medicament for the treatment of bacterial infections.
  • the antibiotic compounds of the present invention are active against a wide range of organisms including both Gram-negative organisms and Gram-positive organisms.
  • Freshly-ground aluminium trichloride (0.078g, 0.58m mol) was dissolved in anhydrous dichloromethane (DCM, 1ml) and anisole (3ml) and stirred under argon at -40°C.
  • DCM dichloromethane
  • 0.5M trisodium citrate 7.5ml
  • the mixture was stirred vigorously and allowed to regain ambient temperature. The organic phase was removed, then the aqueous was washed again with DCM and evaporated to dryness. Purification was effected by
  • Example 1(a) then reacted with fluoroacetone (0.074g, 0.97mmol) followed by subsequent reaction and workup as in Example 5(f). Following chromatography as described therein, the first-eluted product was the E- ester (0.020g, 5%) [assigned by analogy with Example 6(a), but not characterised in view of the small amount of material]; further elution afforded the Z-ester (0.095g, 25%) (Found: M, 393.1031.

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Abstract

Composé de la formule (I), où R?1, R2 et R3¿ peuvent représenter différents substituants, et R4 peut représenter hydrogène ou un groupe formant un sel ou un ester, et =≃= indique que la chaîne latérale =CR1R2 peut être présente soit sous forme d'isomères (a) or (b), soit en tant qu'un mélange des deux isomères. Les composés présentent une activité antibactérienne.
PCT/GB1992/001306 1991-07-27 1992-07-16 Derives de 6-ethylidene penem WO1993003042A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9116236.2 1991-07-27
GB919116236A GB9116236D0 (en) 1991-07-27 1991-07-27 Novel compounds

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WO1993003042A1 true WO1993003042A1 (fr) 1993-02-18

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PCT/GB1992/001306 WO1993003042A1 (fr) 1991-07-27 1992-07-16 Derives de 6-ethylidene penem

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GB (1) GB9116236D0 (fr)
WO (1) WO1993003042A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7018997B2 (en) 2002-05-01 2006-03-28 Wyeth Tricyclic 6-alkylidene-penems as β-lactamase inhibitors
US7112582B2 (en) 2002-05-01 2006-09-26 Wyeth Bicyclic 6-alkylidene-penems as β-lactamase inhibitors
US7459551B2 (en) 2002-03-26 2008-12-02 Asubio Pharma Co., Ltd. Method for preparing cyclic compounds

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002210A1 (fr) * 1977-11-17 1979-06-13 Merck & Co. Inc. Acides pen-2-em-3-carboxyliques substitués en position 6- et 2- ou en position 6,6- et 2-; leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0041768A2 (fr) * 1980-04-24 1981-12-16 Beecham Group Plc Composés de bêta-lactame, leur préparation et application
GB2144126A (en) * 1983-07-27 1985-02-27 Shionogi & Co Penem carboxylix acids and the preparation thereof
EP0232966A1 (fr) * 1986-01-17 1987-08-19 Beecham Group Plc Procédé de préparation de dérivés de pénème et intermédiaires pour cette préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002210A1 (fr) * 1977-11-17 1979-06-13 Merck & Co. Inc. Acides pen-2-em-3-carboxyliques substitués en position 6- et 2- ou en position 6,6- et 2-; leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0041768A2 (fr) * 1980-04-24 1981-12-16 Beecham Group Plc Composés de bêta-lactame, leur préparation et application
GB2144126A (en) * 1983-07-27 1985-02-27 Shionogi & Co Penem carboxylix acids and the preparation thereof
EP0232966A1 (fr) * 1986-01-17 1987-08-19 Beecham Group Plc Procédé de préparation de dérivés de pénème et intermédiaires pour cette préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL & PHARMACEUTICAL BULLETIN vol. 33, no. 10, 1985, pages 4371 - 4381 MITSURU IMUTA cited in the application *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459551B2 (en) 2002-03-26 2008-12-02 Asubio Pharma Co., Ltd. Method for preparing cyclic compounds
US7018997B2 (en) 2002-05-01 2006-03-28 Wyeth Tricyclic 6-alkylidene-penems as β-lactamase inhibitors
US7112582B2 (en) 2002-05-01 2006-09-26 Wyeth Bicyclic 6-alkylidene-penems as β-lactamase inhibitors
EP1988093A1 (fr) 2002-05-01 2008-11-05 Wyeth a Corporation of the State of Delaware 6-alkylidene-penems bicycles en tant qu'inhibiteurs beta-lactamases
US7691842B2 (en) 2002-05-01 2010-04-06 Wyeth Llc Tricyclic 6-alkylidene-penems as β-lactamase inhibitors
US7812014B2 (en) 2002-05-01 2010-10-12 Wyeth Llc Bicyclic 6-alkylidene-penems as β-lactamase inhibitors

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AU2329092A (en) 1993-03-02

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