EP0746558A1 - Derives phenylalcoylamino de carbapenemes condenses - Google Patents

Derives phenylalcoylamino de carbapenemes condenses

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Publication number
EP0746558A1
EP0746558A1 EP95911265A EP95911265A EP0746558A1 EP 0746558 A1 EP0746558 A1 EP 0746558A1 EP 95911265 A EP95911265 A EP 95911265A EP 95911265 A EP95911265 A EP 95911265A EP 0746558 A1 EP0746558 A1 EP 0746558A1
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European Patent Office
Prior art keywords
compound
ethyl acetate
group
solution
compounds
Prior art date
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EP95911265A
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German (de)
English (en)
Inventor
Alcide Perboni
Giampaola Sbampato
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GlaxoSmithKline SpA
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Glaxo Wellcome SpA
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Publication of EP0746558A1 publication Critical patent/EP0746558A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to phenylaikyiamino derivatives having antibacterial activity, to processes for their preparation, to compositions containing them and to their use in medicine.
  • European Patent Application publication No. 0 16953A2 describes 10-(1- hydroxyethyl)-11 -oxo-1 -azatricyclo[7.2.0.0 3 ' 8 ]undec-2-ene-2-carboxylic acid and certain 4 substituted derivatives thereof, including 4-amino, 4-alkylamino and 4- dialkylamino derivatives which have antibacterial activity.
  • R 1 is inter alia a 1-hydroxyethyl group
  • CO 2 R 2 is a carboxy group which may optionally be esterified
  • ring B is a cyclic group which may be optionally substituted.
  • Ring B may inter alia be a cyclohexane ring.
  • the compounds have antibacterial activity.
  • the specification specifically teaches compounds wherein B is an unsubsituted cyclohexane ring, but there is no teaching of specfic compounds wherein the cyclohexane ring is substituted.
  • R 1 is inter alia an optionally substituted lower alkyl group
  • C0 2 R 2 is a carboxy group which may be esterified
  • ring A is inter alia a cyclohexane ring
  • R a is the group W ⁇ U 3 [W 3 is a bond, sulphur (which may be in the form of mono- or dioxide), oxygen, NH (which may be substituted) or a straight-chain or branched lower alkylene or alkenylene group which may be interrupted by sulphur (which may be in the form of mono- or dioxide), oxygen or NH (which may be substituted);
  • U a is carbamoyl, acyl which may be substituted, alkylammonium which may be substituted or a group of the formula
  • R a is (CH 2 )m K a (CH 2 )nU a (wherein K a is CH 2 , 0, S or NH; m and n each is a whole number of 0 to 3; and U a is an N-linked quaternary ammonium group.
  • R. represents hydrogen or a hydroxyl protecting group
  • R 2 represents hydrogen or a carboxyl protecting group
  • R 3 represents hydrogen or a nitrogen protecting group
  • Z represents a methylene group optionally substituted by methyl
  • X represents a bond or a C- ⁇ alkylene chain or an ethenylene chain
  • A represents a C 2 ⁇ alkylene chain or A is a chain of 2 to 4 members one of which is an oxygen or sulphur atom or the group NH or a substituted derivative thereof and the other members are methylene groups
  • R 4 represents an optionally substituted phenyl group.
  • the molecule contains a further asymmetric carbon atom at the 8-position, and another at the 4-position. It will be appreciated that all stereoisomers including mixtures thereof arising from these additional asymmetric centres, are within the scope of the compounds of formula (I).
  • the compounds of formula (I) are antibacterial agents and/or of use as intermediates for the preparation of other active compounds within the general formula (I).
  • Compounds wherein R- represents a hydroxyl protecting group and/or wherein R 2 represents a carboxyl protecting group and/or wherein R 3 represents a nitrogen protecting group are in general intermediates for the preparation of other compounds of formula (I).
  • Salts of compounds of formula (I) include base addition salts, acid addition salts compounds and internal salts formed with the carboxylic acid grouping.
  • Base addition salts for use in medicine are formed with bases that have a physiologically acceptable cation. Suitable cations include those of alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium), amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, and N-methyl glucosamine). Acid addition salts may be formed with organic acids or inorganic acids. For use in medicine the salts will be those derived from physiologically acceptable acids e.g. acetic acid, succinic acid, hydrochloric acid, sulphuric acid and phosphoric acid.
  • physiologically acceptable acids e.g. acetic acid, succinic acid, hydrochloric acid, s
  • Salts derived from bases wherein the cation is not physiologically acceptable or acids which are not physiologically acceptable may be useful as intermediates for the preparation and/or isolation of other compounds of the invention, and these salts also form part of the invention.
  • the compounds of formula (I) may be produced in vivo by metabolism of a suitable metabolically labile ester.
  • suitable metabolically labile esters include acyloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g.
  • pivaloyloxymethyl 1-pivaloyloxyethyl, acetoxymethyl, 1- acetoxyethyl.l ⁇ l-methoxy-l-methy ethylcarbonyloxyethyl, 1- benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1 -isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl. 1-(4- tetrahydropyranyloxy)carbonyloxyethyl or 1-(4- tetrahydropyranyl)carbonyloxyethyl or 3-phthalidyl.
  • the compound of formula (I) salts thereof and metabolically labile esters thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
  • Particularly useful compounds of formula (I) for use in medicine as antibacterial agents are those in which the group R 1 , R 2 and R 3 represent a hydrogen atom and physiologically acceptable salts and metabolically labile esters thereof. These compounds exhibit antibacterial activity against a wide range of gram positive and gram negative, aerobic and anaerobic pathogenic microorganisms.
  • R- i is a hydroxy protecting group
  • the group OR ⁇ is conveniently an ether or an acyloxy group.
  • particularly suitable ethers include those in which R- j is a hydrocarbylsilyl group such as trialkylsilyl, e.g. tri(C ⁇ alkyl)silyl such as trimethylsilyl or more especially t-butyldimethylsilyl.
  • R-j represents an acyloxy group then examples of suitable groups R-j includes alkanoyl e.g. acetyl or pivaloyl; alkenoyl e.g. allylcarbonyl; aroyl e.g.
  • alkoxycarbonyl e.g. t-butoxycarbonyl
  • haloalkoxycarbonyl e.g. 2.2,2-trichloroethoxycarbonyl, or 1,1,1-trichloro-2-methyl-2- propoxycarbonyl
  • aralkyloxycarbonyl e.g. benzyloxycarbonyl or p- nitrobenzyloxycarbonyl
  • alkenyloxycarbonyl e.g. allyloxycarbonyl.
  • R 2 is a carboxyl protecting group
  • suitable groups R 2 include arylmethyl groups such as benzyl, p-nitrobenzyl, t-butylbenzyl or trityl, or alkenyl groups such as allyl or substituted allyl, t-butyl, haloalkyi e.g. trichloroethyl or tnalkylsilylalkyi e.g. trimethylsilylethyl.
  • Preferred protecting groups R 2 include allyl or arylmethyl e.g. benzyl or p-t-butylbenzyl.
  • R 3 is a nitrogen protecting group
  • suitable groups include optionally substituted allyloxycarbonyl, alkyloxycarbonyl or arylmethyloxycarbonyl.
  • R is a subsituted phenyl group this phenyl group substituted by one to 3 substituents which may be the same or different and selected from halogen or amino, alkylamino, dialkylamino, acylamino, alkoxy, alkylenedioxy, alkyl, alkylthio, alkylsulphinyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, CO 2 R 5 or SO 2 NR6R 7 ;
  • R 5 represents hydrogen, C ⁇ alkyl, C 2 ⁇ alkenyl or C3 ⁇ alkynyl
  • Re represents hydrogen, alkoxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl
  • R 7 represents hydrogen, C ⁇ alkyl, C- ⁇ alkenyl or pheny C- ⁇ alkyl.
  • alkyl as a group or part of a group refers to a straight or branched chain group e.g. methyl, ethyl, propyl or butyl.
  • acylamino refers to alkanoylamino, alkoxycarbonylamino, allyloxycarbonylamino or optionally substituted benzyloxycarbonylamino.
  • alkylenedioxy refers to C1.3 alkenedioxy e.g. methylenedioxy or ethylenedioxy.
  • A is a C 2 - 4 alkylene chain this may be an ethylene, propylene or butylene chain.
  • A is chain of 2 to 4 members and wherein one of the members is a group selected from oxygen sulphur or NH (or a substituent derivative thereof)
  • examples of such chains include:
  • -OCH 2 - -OCH 2 CH 2 -, -CH 2 -OCH 2 -, -CH 2 CH 2 0-, -SCH 2 CH 2 -, -CH 2 SCH 2 - - CH 2 CH 2 S-, or -CH 2 NH-CH 2 -.
  • substituents include C ⁇ alkyl e.g. methyl, benzyl, acetyl, C ⁇ alkoxycarbonyl, allyloxycarbonyl or an optionally substituent phenylmethyloxycarbonyl group.
  • halogen when used herein means fluorine, chlorine, bromine or iodine unless otherwise specified.
  • the general formula (I) as drawn includes at least 4 stereoisomers and mixtures thereof and these may be represented by the formulae (1a, 1b, 1c and 1d).
  • the solid wedge shaped bond indicates that the bond is above the plane of the paper.
  • the broken bond indicates that the bond is below the plane of the paper.
  • the 8-position corresponds to the S isomer and the ⁇ -configuration at the 4-position to the R isomer.
  • the ⁇ configuration at the 8-position corresponds to the R isomer and the ⁇ -configuration at the 4-position corresponds to the S isomer.
  • the group R-i is a hydrogen atom
  • the group R 2 is a hydrogen atom
  • the group R 3 is a hydrogen atom
  • a further preferred class of compounds are those wherein X is a bond.
  • A is a 2-4 alkylene chain or more particularly a propylene chain
  • A is a C 2 ⁇ alkylene chain
  • those in which the carbon atom at the 8- position is in the ⁇ configuration are preferred and within this class those compounds in which the carbon atom at the 4- position is in the ⁇ configuration are particularly preferred.
  • R 4 groups include phenyl or a phenyl substituted by one to 2 groups selected from halogen e.g. fluorine, chlorine, bromine, alkoxy e.g. methoxy, methylenedioxy, hydroxy, nitro, trifluromethyl, alkylthio, e.g. thiomethyl, alkylsulphinyl e.g. methylsulphinyl, acylamino e.g.
  • halogen e.g. fluorine, chlorine, bromine
  • alkoxy e.g. methoxy, methylenedioxy, hydroxy, nitro, trifluromethyl
  • alkylthio e.g. thiomethyl
  • alkylsulphinyl e.g. methylsulphinyl
  • acylamino e.g.
  • allyloxycarbonylamino amino, C0 2 R 5 (wherein R 5 is hydrogen or allyl) or SO 2 NR 6 R 7 (wherein R 7 is hydrogen, methyl, allyl or benzyl, and Re is hydrogen, allyloxycarbonyl or benzyloxycarbonyl).
  • a preferred class of compounds of formula (I) are those wherein R 4 is phenyl or phenyl substituted by one or 2 groups selected from halogen e.g. chlorine, fluorine or bromine, alkoxy e.g. methoxy, trifluoromethyl, carboxy, amino, nitro, allylaminosulphonyl, methylaminosulphonyl, benzylaminosulphonyl, methylenedioxy or alkylthio e.g. methylthio.
  • halogen e.g. chlorine, fluorine or bromine
  • alkoxy e.g. methoxy
  • trifluoromethyl carboxy
  • R4 represents phenyl or phenyl substituted by one or two groups selected from chlorine, fluorine, nitro, methylenedioxy or allylaminosulphonyl.
  • a preferred group of compounds of formula (I) are those wherein R-i, R 2 and R 3 represent hydrogen, X is a bond Z, is methylene, and A is a propylene group and physiologically acceptable salts or metabolically labile esters thereof.
  • R 4 is phenyl or phenyl substituted by one or two groups selected from halogen, alkoxy, trifluoromethyl, carboxy, amino, nitro, methylenedioxy, alkylthio or SO 2 NHR 7 wherein R 7 is methyl, allyl, or benzyl. More especially R-j represents phenyl, or phenyl substituted by one or 2 groups selected from chlorine, fluorine, nitro, methylenedioxy or allylaminosulphonyl.
  • Particularly preferred compounds of the invention include : (4S,8S,9R, 10S, 12R)-4-(4-nitrobenzylamino)-10-(1 -hydroxyethyl)-11 -oxo-1 -
  • Compounds according to the invention not only exhibit a broad spectrum of antibacterial activity against a wide range of pathogenic microorganisms but also have a very high resistance to all ⁇ -lactamases. Compounds of the invention are also relatively stable to renal dehydropeptidase.
  • the compounds of the invention may therefore be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals.
  • a compound of formula (I) or a physiologically acceptable salt thereof for use in the therapy or prophylaxis of systemic or topical bacterial infections in a human or animal subject.
  • a method of treatment of the human or non-human animal body to combat bacterial infections comprises administering to the body an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
  • a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • compositions comprising a compound of the invention adapted for use in human or veterinary medicine.
  • Such compositions may be presented for use in conventional manner with the aid of one or more suitable carriers or excipients.
  • suitable carriers or excipients include those in a form especially formulated for parenteral, oral, buccal, rectal, topical, implant, ophthalmic, nasal or genito-urinary use.
  • the compounds according to the invention may be formulated for use in human or veterinary medicine by injection (e.g. by intravenous bolus injection or infusion or via intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative.
  • the compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, solubilising and/or dispersing agents.
  • the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds of the invention may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, mouth washes or suspensions, or a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and colouring agents.
  • Solid compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powder, pastes, granules, bullets or premix preparations may also be used.
  • Solid and liquid compositions for oral use may be prepared according to methods well known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.
  • the compounds of the invention may also be administered orally in veterinary medicine in the form of a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.
  • a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may also, for example, be formulated as suppositories e.g. containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g. containing conventional pessary bases.
  • the compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, lotions, shampoos, powders, (including spray powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye ear or nose drops) or pour-ons.
  • Aerosol sprays are conveniently delivered from pressurised packs, with the use of a suitable propellant, eg dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebuliser.
  • compositions for topical administration may also contain other active ingredients such as corticosteroids or antifungals as appropriate.
  • compositions may contain from 0.01-99% of the active material.
  • the composition will generally contain from 0.01- 10%, more preferably 0.01-1% of the active material.
  • the daily dose as employed for adult human treatment will range from 5-100mg/kg body weight, preferably 10-60mg/kg body weight, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient.
  • each unit will preferably contain 200mg to 1g of active ingredient.
  • the duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
  • the compounds of formula (I) may be prepared by the cyclisation of a compound of formula (II)
  • R 1( R 2 , R 3 , X, Z, A and R 4 have the meanings defined in formula (I) or is a group convertible thereto, and Y is an oxygen atom or a phosphine group, and if required or desired subjecting the resulting compound prior to or subsequent to any separation into its stereochemical isomers, to one or more of the following operations
  • the cyclisation of a compound of formula (II) in which Y is oxygen is conveniently carried out by heating in the presence of an organic phosphite.
  • the reaction is preferably carried out in a solvent or mixture of solvents at a temperature within the range 60-200°.
  • Suitable solvents include hydrocarbons with an appropriate boiling point, for example aromatic hydrocarbons, such as toluene or xylene.
  • Suitable organic phosphites include acyclic and cyclic trialkylphosphites, triarylphosphites and mixed alkylarylphosphites. Particularly useful organic phosphites are the trialkylphosphites e.g. triethylphosphite or trimethylphosphite.
  • a compound of formula (II) in which Y is a phosphine grouping is preferably carried out in a solvent at a temperature between 40- 200°C.
  • suitable solvents include hydrocarbons such as aromatic hydrocarbons, for example xylene or toluene, aliphatic hydrocarbons and halogenated hydrocarbons such as dichioromethane, chloroform and trichloroethane.
  • suitable phosphine groups are triarylphosphines e.g. triphenyl phosphine or trialkylphospines e.g. th-t-butylphospine.
  • the hydroxyl, carboxyl and nitrogen protecting groups R 1f R 2 and R 3 may be removed by conventional procedures and in any order. More preferably however the hydroxyl protecting group R ⁇ is removed prior to the removal of the carboxyl and or nitrogen protecting group. Such removal of the protecting groups is a further feature of the invention.
  • the hydroxyl protecting groups may be removed by well known standard procedures such as those described in Protective Groups in Organic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973).
  • R 1 is a t-butyldimethylsilyl group
  • this may be removed by treatment with tetrabutylammonium fluoride and acetic acid or by reaction with fluoride ions and a suitable phase transfer catalyst such as tetrabutylammonium bromide in the presence of acetic acid.
  • a suitable solvence of fluoride ions included potassium fluoride or caesium fluoride. This process is conveniently carried out in a solvent such as tetrahydrofuran.
  • R 1 is a trichloroethoxycarbonyl group this may be removed by treatment with zinc and acetic acid.
  • the carboxyl protecting group R 2 may also be removed by standard processes such as those described in Protective Groups in Organic Chemistry, pages 192- 210, Edited by J F W McOmie (Plenum Press 1973).
  • R 2 represents an arylmethyl group this may be removed by conventional procedures using hydrogen and a metal catalyst e.g. palladium.
  • R 2 represents an allyl or substituted allyl group then this is preferably removed by treatment with an allyl acceptor in the presence of tetrakis(triphenylphosphine) palladium and optionally in the presence of triphenylphospine.
  • Suitable allyl acceptors include sterically hindered amines such as tertbuylamine, cycNc secondary amines such as morpholine or thiomorpholine, tertiary amines such as triethylamine, aliphatic or cycloapliphatic ⁇ -dicarbonyl compounds such as acetylacetone, ethyl acetoacetate or dimedone, an alkanoic acids or alkali metal salts thereof such as acetic acid, propionic acid or 2-ethyl hexanoic acid or the potassium or sodium salt thereof, or 5,5-dimethyl-1,3-cyclohexadiene.
  • sterically hindered amines such as tertbuylamine, cycNc secondary amines such as morpholine or thiomorpholine, tertiary amines such as triethylamine, aliphatic or cycloapliphatic ⁇ -
  • a particularly useful allyl acceptor is 5,5-dimethyl 1 ,3-cyclohexadiene.
  • the reaction is preferably carried out in an inert solvent such as an ether e.g. diethyl ether or tetrahydrofuran, an alkanol e.g. ethanol, an ester e.g. ethyl acetate or a halohydrocarbon e.g. methylene chloride, or mixtures thereof.
  • an inert solvent such as an ether e.g. diethyl ether or tetrahydrofuran, an alkanol e.g. ethanol, an ester e.g. ethyl acetate or a halohydrocarbon e.g. methylene chloride, or mixtures thereof.
  • the reaction is conveniently carried out in the temperature range 0°-40° more particularly at room temperature.
  • the nitrogen protecting group R 3 may be removed by conventional procedures. Thus for example if R 3 is an allyloxycarbonyl group this may be removed using the conditions described for removal of the carboxyl protecting group where R 2 is allyl.
  • compounds of formula (I) may be converted into other compounds of formula (I).
  • compounds of the invention in which the group R 2 is a physiologically acceptable cation may be prepared from compounds of the invention in which R 2 is hydrogen by treatment with a suitable base.
  • the salt is formed in solution and then if required precipitated by the addition of a non- solvent e.g. a non polar aprotic solvent.
  • the sodium or potassium salt may be prepared by treating a solution of a compound of formula (I) in which R 2 represents a hydrogen atom with a solution of sodium or potassium 2- ethylhexanoate in a non-polar solvent such as diethyl ether.
  • R 2 is a metabolically labile ester
  • R 2 is a hydrogen atom or a cation by use of conventional esterification procedures.
  • Compounds of formula (I) wherein the group R 2 is a carboxyl protecting group and R 4 represents a phenyl group substituted by alkylsulphinyl may be prepared by oxidation of the corresponding compounds of formula (I) wherein R 4 is a phenyl group substituted by alkylthio.
  • the oxidation is preferably carried out using a peracid e.g. peroxybenzoic acid such as m-chloroperoxybenzoic acid in an organic solvent such as a halogenated hydrocarbon e.g. methylene chloride.
  • the reaction is carried out at a low temperature e.g. -78°C to -20°C.
  • Acid addition salts of compounds of formula (I) may be prepared by reaction with the appropriate acid, conveniently under non aqueous/conditions.
  • Suitable activated derivatives of the acid (IV) includes the corresponding acid halides e.g. acid chloride.
  • the reaction is preferably carried out in the presence of an acid acceptor such as a tertiary organic base for example pyridine or a trialkylamine in an aprotic solvent such as dichloromethane.
  • an acid acceptor such as a tertiary organic base for example pyridine or a trialkylamine in an aprotic solvent such as dichloromethane.
  • the compound of formula (II) in which Y is a phosphine group may be prepared by treating the intermediate (V) in which L is a leaving group such as a halogen e.g. chlorine.
  • the reaction is conveniently carried out in a solvent such as dioxan in the presence of a tertiary organic base, e.g. 2,6 lutidine.
  • a tertiary organic base e.g. 2,6 lutidine.
  • the compounds of formula (V) may be prepared from the corresponding hydroxy derivative (VI) by conventional means for converting hydroxyl groups into leaving groups.
  • a compound of formula (V) in which L is a chlorine atom may be prepared by treating a compound of formula (VI) with thionyl chloride in an aprotic solvent such as dioxan or tetrahydrofuran and in the presence of a tertiary organic base e.g. 2,6-lutidine.
  • Compounds of formula (VI) may be prepared from the reaction of a compound of formula (III) with glyoxylic ester (VII; CHOCO 2 R 2a ) preferably in the form of its hydrate or hemiacetal. The reaction is preferably carried out in an aprotic solvent such as toluene and in the presence of an activated molecular sieve.
  • Compounds of formula (III) wherein R 3 is hydrogen may be prepared by reaction of the epoxide (VIII) wherein R 1 is a hydroxyl protecting group and R 8 is an alkyl group.
  • reaction is preferably carried out in a solvent such as tetrahydrofuran or ethyl acetate and in the presence of a base such as potassium carbonate or triethylamine.
  • a solvent such as tetrahydrofuran or ethyl acetate
  • a base such as potassium carbonate or triethylamine.
  • R 3 is a nitrogen protecting group e.g. an alkoxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl
  • R 3 is hydrogen
  • This reaction is preferably carried out in a solvent such as tetrahydrofuran or ethyl acetate and in the presence of a base such as a tertiary amine e.g. triethylamine pyrridine or 2,6-lutidine.
  • the epoxides (VIII) are either known compounds or may be prepared by methods described for preparing the known compounds such as those described in EPA No. 0502488, or EPA No. 0586017.
  • stereoisomers of the compounds of formula (I) as defined in formulae 1a, 1b, 1c and 1d, essentially free of the other stereoisomers may be prepared by using the general processes described above starting with the appropriate stereoisomer of formula (II), (III) or (VIII) .
  • the processes described above for preparing the compounds of formula (II) will in general give a mixture of stereoisomers.
  • the individual stereoisomers of the compounds of formula (II) may be prepared using the processes described above starting with the appropriate steroisomer of formula (lll) or (VIII).
  • reaction mixture was stirred for 1.30 hours at 0°, then washed with a saturated aqueous solution of ammonium chloride (100ml), slightly acidic water (100ml), brine (2x100ml) dried and evaporated in vacuo.
  • the titie compound was prepared as described for intermediate 2p from Intermediate 1 (2.388g), 4-chloro-2-nitro-benzylamine (1.86g), allyl chloroformate (1.59ml), and 2,6 lutidine (2.33ml) as a yellow foam (1.274g).
  • the titie compound was prepared as described in example 2a from example
  • the titie compound was prepared as described in example 2a from of example
  • the titie compound was prepared as described in example 2a from of example
  • the titie compound was prepared as described in example 2a from example (1t)
  • Example (1v) To a solution of Example (1v) (226.8mg) in dry tetrahydrofuran (3.5ml) at 20° under nitrogen, was added 5,5-dimethyl-1 ,3-cyclohexandiene (132mg). After 5 minutes a solution of of tetrakis(triphenylphosphine)palladium (28.4mg) in dry tetrahydrofuran (1ml) was added to the above solution. After 45 minutes, of ethyl acetate (30ml) was added and the product was extracted with water (30ml). The aqueous solution was washed with ethyl acetate (2x40ml) and diethyl ether (2x40ml).
  • the product may be constitute by dissolving in Water for Injection (10ml) or other suitable sterile vehicle for injection shortly before administration.
  • the antibacterial activity of the compounds of the invention may be readily determined using conventional test procedures.
  • the antibacterial activity of the compounds of the invention was determined using a standard mictoriter broth serial dilution test. In this test the broth was incubated with approximately 10 5 colony forming units of the test organism and incubated at 35° for 18 hours in the presence of test compound. Results obtained using the rest procedure are given in the table below and are expressed as minimum inhibitory concentrations (MIC) in micrograms/ml.
  • MIC minimum inhibitory concentrations
  • the compounds of the invention are essentially non toxic at therapeutically useful doses. For example no adverse effects were observed when compounds of the invention were administered to mice or rats at therapeutically useful dose levels.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Composés de la formule générale (I) ainsi que leurs sels et esters métaboliquement labiles, dans laquelle R1 représente hydrogène ou un groupe protecteur hydroxyle; R2 représente hydrogène ou un groupe protecteur carboxyle; R3 représente hydrogène ou un groupe protecteur azote; Z représente un groupe méthylène facultativement substitué par méthyle; X représente une liaison ou une chaîne alcoylène C1-2 ou une chaîne éthylène; A représente une chaîne alcoylène C2-4 ou A représente une chaîne possédant 2 à 4 chaînons, l'un de ceux-ci représentant un atome d'oxygène ou de soufre ou le groupe NH ou un dérivé substitué de celui-ci, les autres chaînons représentant des groupes méthylène; et R4 représente un groupe phényle facultativement substitué. L'invention se rapporte également à un procédé de préparation de ces composés ainsi qu'à l'utilisation de ceux-ci en tant qu'agents antibactériens.
EP95911265A 1994-02-26 1995-02-24 Derives phenylalcoylamino de carbapenemes condenses Withdrawn EP0746558A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9403729 1994-02-26
GB9403729A GB9403729D0 (en) 1994-02-26 1994-02-26 Amine derivatives
PCT/EP1995/000676 WO1995023149A1 (fr) 1994-02-26 1995-02-24 Derives phenylalcoylamino de carbapenemes condenses

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EP0746558A1 true EP0746558A1 (fr) 1996-12-11

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EP95911265A Withdrawn EP0746558A1 (fr) 1994-02-26 1995-02-24 Derives phenylalcoylamino de carbapenemes condenses

Country Status (5)

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EP (1) EP0746558A1 (fr)
JP (1) JPH09510193A (fr)
AU (1) AU1891795A (fr)
GB (1) GB9403729D0 (fr)
WO (1) WO1995023149A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI9600371B (sl) 1996-12-18 2005-04-30 LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. Etilidenski derivati tricikličnih karbapenemov
US6271222B1 (en) 1998-05-28 2001-08-07 Merck & Co., Inc. Penem antibacterial compounds, compositions and methods of treatment

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ435990A3 (cs) * 1989-09-08 1999-11-17 Glaxo S.P.A. Kyselina 10-(1-hydroxyethyl)-11-oxo-1-azatricyklo/7,2,0,03,8/-undec-2en-2-karboxylová a její deriváty, způsob jejich výroby, použití pro výrobu farmaceutických prostředků a farmaceutické prostředky s jejich obsahem
GB9104838D0 (en) * 1991-03-07 1991-04-17 Glaxo Spa Heterocyclic compounds
EP0507313A1 (fr) * 1991-04-05 1992-10-07 Takeda Chemical Industries, Ltd. Composés polycycliques de carbapénèmes, leur préparation et leur utilisation

Non-Patent Citations (1)

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Title
See references of WO9523149A1 *

Also Published As

Publication number Publication date
WO1995023149A1 (fr) 1995-08-31
JPH09510193A (ja) 1997-10-14
GB9403729D0 (en) 1994-04-13
AU1891795A (en) 1995-09-11

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