WO1984003092A1 - Derives de clavame - Google Patents

Derives de clavame Download PDF

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Publication number
WO1984003092A1
WO1984003092A1 PCT/GB1984/000024 GB8400024W WO8403092A1 WO 1984003092 A1 WO1984003092 A1 WO 1984003092A1 GB 8400024 W GB8400024 W GB 8400024W WO 8403092 A1 WO8403092 A1 WO 8403092A1
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WIPO (PCT)
Prior art keywords
formula
compound
group
salt
ester
Prior art date
Application number
PCT/GB1984/000024
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English (en)
Inventor
John Barry Harbridge
Gerald Brooks
Original Assignee
Beecham Group Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group Plc filed Critical Beecham Group Plc
Publication of WO1984003092A1 publication Critical patent/WO1984003092A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • This invention relates to novel ⁇ -lactam containing compounds, their preparation and their use, and in particular to a novel class of clavams. These compounds have antibacterial and ⁇ -lactamase inhibitory properties, and therefore are of use in the treatment of bacterial infections in humans and animals either alone or in a synergistic composition with other ⁇ -lactam antibacterial agents, such as penicillins and cephalosporins.
  • UK Patent Publication No. 2 006 769 A discloses a compound with antibiotic activity having the formula
  • R is a carboxyl or esterified carboxyl group and Rx and Ry are each independently hydrogen, substituted or unsubstituted alkyl, aralkyl, aryl, cyano, formyl, nitro, carboxyl, esterified carboxyl, etherified thiol or a sulphone derivative thereof, acyl, etherified hydroxyl, carbamoyl, substituted carbamoyl, sulphamoyl, substituted sulphamoyl, hydrazinocarbonyl or protected hydrazinocarbonyl group and carboxyl salts thereof.
  • Rx and Ry are each independently hydrogen, substituted or unsubstituted alkyl, aralkyl, aryl, cyano, formyl, nitro, carboxyl, esterified carboxyl, etherified thiol or a sulphone derivative thereof, acyl, etherified hydroxyl, carbamoyl, substituted carbamoyl
  • X is an optionally substituted 1,2,4 triazolyl group, attached via a nitrogen atom thereof.
  • the group X may be a group (A) or (B):
  • R 1 and R 2 are each independently hydrogen, an optionally substituted hydrocarbon group or a functional group.
  • hydrocarbon' includes groups having up to 18 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable hydrocarbon groups include C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C l-6 )-alkyl, aryl, and aryl(C 1-6 ) alkyl.
  • R 1 and R 2 is hydrocarbon
  • suitable optional substituents include C 1-6 alkyl, heterocyclic, amino, C 1-6 alkanoylamino, mono, di- and tri- (C 1-6 ) alkylamino, hydroxy, C 1-6 alkoxy, C 1-6 alkoxy carbonyl, mercapto, C 1-6 alkylthio, heterocyclyl-thio, arylthio, carbamoyl, amidino, quanidino, nitro, chloro, bromo, fluoro, halo-(C 1-6 )-alkyl, carboxy and salts and esters thereof, C 1-6 alkanoyloxy, aryl, aryl-carbonyl, heterocyclylcarbonyl, oxo, C 1-6 alkoxycarbonyl-(C 1-6 ) -alkyl, C 1-6 alkylcarbonyloxy, and C 1-6 alkylcarbonyl groups.
  • Suitable functional groups include halo, cyano, formyl, nitro, carboxyl, esterified carboxyl, etherified thiol or a sulphone derivative thereof, acyl, acylamino, etherified hydroxyl, carbamoyl or substituted carbamoyl.
  • R 1 and/or R 2 are esterified carboxyl, acyl, amide, etherified hydroxy, etherified thiol or a sulphone derivative thereof, they may be represented by the formulae -COOR 3 , -COR 3 , -NH COR 3 , -OR 3 , -SR 3 and SO 2 R 3 respectively where R 3 is a substituted or unsubstituted alkyl, aralkyl, aryl or heterocyclic group.
  • R 1 and R 2 are carbamoyl or substituted carbamoyl, they may be represented by the formulae -CONR 4 R 5 , where R 4 and R 5 are each independently hydrogen, a substituted or unsubstituted alkyl, aralkyl or aryl group or R 4 and R 5 in combination with the nitrogen atom to which they are attached form a 5 - 7 member heterocyclic ring which is optionally substituted.
  • Suitable optional substituents for the groups R 3 , R 4 and R 5 include those listed above for R 1 and R 2 when these are hydrocarbon.
  • R 1 and R 2 are both hydrogen.
  • alkyl' includes straight or branched chain alkyl groups containing, for example, up to 12 carbon atoms, suitably from 1 to 6 carbon atoms.
  • the group may be substituted methyl, ethyl, n-, or iso-propyl, or n-, sec-, iso- or tert-butyl.
  • heterocyclic' includes single or fused rings comprising up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur.
  • the 'aryl' includes phenyl and naphthyl.
  • 'aralkyl' includes groups having up to six carbon atoms in the alkyl portion and is desirably carbocyclic and more preferably monocyclic e.g. benzyl.
  • R 6 is hydrogen or an optionally substituted hydrocarbon group as hereinbefore defined in relation to R 1 and R 2 .
  • R 6 is an unsubstituted hydrocarbon group such as C 1-6 alkyl or aryl.
  • R 6 is methyl
  • Suitable pharmaceutically acceptable salts of the compounds of formulae I or II include metal salts, e.g. 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 tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline.
  • metal salts e.g. aluminium, alkali metal salts such as sodium or potassium
  • Suitable esters of the compounds of the formula (I) or (II) include those cleavable by biological methods such as enzymatic hydrolysis, in-vivo hydrolysis, and those cleavable by chemical methods such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
  • carboxylic acid is esterified by a group of the sub-formula (a), (b), (c), (d), (e) or (f):
  • a 1 is a hydrogen atom, C 1-6 alkanoyl or an C 1-5 alkyl group optionally substituted by C 1-7 alkoxy or C 1-7 carboxylic acyloxy, or an alkenyl or alkynyl group of up to 5 carbon atoms;
  • a 2 is a hydrogen atom or a methyl group;
  • a 3 is a phenyl group or a phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, C 1-8 alkyl or C 1-3 alkoxy group;
  • a 4 is a hydrogen atom or a phenyl group or phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, C 1-3 alkyl or C 1-3 alkoxy group;
  • a 5 is a hydrogen atom or a methyl group;
  • a 6 is a C 1-4 alkyl, phenyl or C 1-4 alkoxy group or A 5 is joined to A
  • Favourably A 1 is a hydrogen atom or a methyl, ethyl, or ethenyl group.
  • Favourably A 2 is a hydrogen atom.
  • Favourably A 3 is a phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl group.
  • Favourably A 4 is a hydrogen atom.
  • Favourably A 6 is a methyl, t-butyl or ethoxy group or is joined to A 5 .
  • Favourably A 7 is a methyl group.
  • Preferred groups of the sub-formula (a) include the methyl, ethyl and acetonyl groups.
  • Preferred groups of the sub-formula (b) include the benzyl and p-nitrobenzyl groups.
  • Preferred groups of the sub-formula (c) include the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxymethyl and phthalidyl groups.
  • a preferred group of the sub-formula (d) is the methoxymethyl group.
  • Preferred groups of the sub-formula (e) include the trimethylsilyl, tert-butyidimethylsilyl, tertbutyldiphenylsilyl groups and tri-isopropylsilyl.
  • a preferred group of the sub-formula (f) is p-methoxycarbonylbenzyl.
  • Particularly preferred esterifying groups are benzyl, p-nitrobenzyl and phthalidyl groups.
  • esters which hydrolyse in the human body to produce the parent acid or its salt.
  • esters may be identified by administration to a test animal such as a rat or mouse by intravenous administration and thereafter examining the test animal's body fluids for the presence of the compound of the formulae (I) or (II) or salt thereof;
  • Suitable esters of this type include those of sub-formula (c) as hereinbefore defined.
  • esters include di(C 1-6 ) alkylamino C 1-6 alkyl esters such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl and diethylaminoethyl.
  • the present invention also provides a process for producing a compound of formula I or a salt or ester thereof; which process comprises reacting a compound of formula III
  • R 8 is a carboxy protecting group
  • R a or R b represents a group R 1 the other represents a group R 2 , wherein R 1 and R 2 are as defined with respect to formula I;
  • R 9 and R 10 are each independently C 1-6 alkyl, aryl or aryl (C 1-6 ) alkyl;
  • l, m and n are each independently 0 or 1 and R 11 , R 12 and R 13 are each independently C 1-6 alkyl, aryl or aryl (C 1-6 ) alkyl;
  • isomers of formula I where X is of sub-formula (A) or (B) can be separated subsequently by conventional methods.
  • Suitable compounds of formula V include those wherein R 9 and R 10 are each independently methyl, ethyl, propyl, butyl, phenyl or benzyl. It is generally convenient that R 9 and R 10 represent the same moiety. Particularly suitable compounds of the formula V include those wherein R 9 and R 10 each represent ethyl, t-butyl or isopropyl.
  • Suitable compounds of formula VI include those where R 11 , R 12 and R 13 are each independently methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl or methoxyphenyl. It is generally convenient that R 11 , R 12 and R 13 each represent the same moiety.
  • Favoured compounds of formula VI include tri-arylphosphines and tri-alkylphosphites. Particularly suitable compounds of formula VI include triphenylphosphine and tri-pmethoxyphenylphosphine, but especially triphenyl-phosphine.
  • Suitable carboxy-protecting groups for the group -CO 2 R 8 in formula (III) include ester derivatives of the carboxylic acid.
  • the derivative is preferably one which may readily be cleaved at a later stage of the reaction.
  • Suitable ester-forming carboxy-protecting groups are those which may be removed under conventional conditions.
  • Such groups for R 8 include benzyl, p-methoxybenz ⁇ l, 2,4,6-trimethylbenzyl, 3,5-di-t-butylbenzyl, 4-pyridylmethyl, allyl, diphenylmethyl, triphenylmethyl, 2-benzyloxyphenyl, 4-methylthiophenyl, methoxymethyl, a silyl or a phosphorus-V-containing group, or methyl or ethyl, but especially benzyl.
  • the free carboxylic acid or a salt thereof may be regenerated from any of the above esters by usual methods appropriate to the particular R 8 group; for example, by base-catalysed hydrolysis, by enzymically-catalysed hydrolysis or by hydrogenation.
  • Acidic or significantly basic groups present in the compound of formula IV are preferably protected prior to the reaction.
  • Such groups include carboxyl when R 1 and/or R 2 and consequently R a and/or R b is carboxyl, and hydroxy, carboxyl and mercapto where R 1 and/or R 2 and consequently R a and/or R b includes one or more of these groups as a substituent.
  • Suitable carboxyl protecting groups are those described above for R 8 . These groups can be removed by similar methods to those described for R 8 .
  • Hydroxy or mercapto substituents are preferably protected by a group which can subsequently be easily removed by conventional methods in step (i).
  • groups include ester groups, preferably hydrogenolysable ester groups, in particular benzyloxycarbonyl or p-nitrobenzyloxycarbonyl groups.
  • the reaction between the compounds of formulae III - VI normally takes place in a solvent inert under the reaction conditions such as toluene, dichloromethane, tetrahydrofuran or dioxane.
  • the reaction is generally carried out at a depressed or non-elevated temperature, for example -80° to +30°C, and preferably at a depressed temperature, for example -40o to 0oC, and conveniently at about -10oC.
  • the compounds of formulae (V) and (VI) are not mixed together with the compound of formula (III) in the absence of nucleophile. More preferably, the compound of formula (V) is added rapidly to the reaction mixture as the last ingredient.
  • the reaction is suitably performed in an inert organic solvent such as dichloromethane, dichloroethane or chloroform.
  • the reaction may be carried out at a non-extreme temperature such as from -20°C to +40°C, preferably from -10°C to ambient temperature and most preferably at about 0oC.
  • Suitable non-nucleophilic strong bases for use in the reaction include tetramethylguanidine,
  • Y is a chlorine atom.
  • R 6 as defined in relation to formula II and R 8 is as defined in relation to formula III, with a chlorinating agent in the presence of a base.
  • Suitable chlorinating agents include phosphorus pentachloride, thionyl chloride, phosgene and phosphorus oxychloride.
  • Suitable bases include pyridine.
  • the reaction is suitably carried out in an inert chlorinated organic solvent such as dichloromethane, dichloroethane or chloroform.
  • the reaction may be carried out at a non-extreme temperature such as from -20°C to +40°C preferably from -10°C to ambient temperatures and most preferably at about 0°C.
  • R 6 is hydrocarbon substituted with a group which is unstable to chlorination, such as hydroxy, mercapto or amino, this group is preferably protected prior to the chlorination reaction.
  • the protecting groups can be removed subsequently.
  • Suitable protecting groups are conventional groups such as benzyloxycarbonyl.
  • the compound of formula VII is prepared and converted in situ to the compound of formula II.
  • the present invention provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof in combination with a pharmaceutically acceptable carrier.
  • the compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of the infection in mammals including humans.
  • Tablets and capsules for 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 cellulsoe, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoleate, 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 cellulsoe, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan mono
  • 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.
  • Parental 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.
  • the compound of formula I may be the sole therapeutic agent in the composition or it may be employed in a synergistic combination with a penicillin or cephalosporin.
  • Suitable penicillins for inclusion in the compoisitions of this invention incoude benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, azlocillin, mezlocillin, sulbenicillin, piperacillin, and other well known penicillins including pro-drugs thereof such as their in vivo hydrolysable esters thereof such as the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl or phthalidyl esters of ampicillin, benzylpenicillin or am ⁇ xycillin, and aldehyde or ketone adducts of penicillins containing a 6- ⁇ aminocetamide side chain (such as hetacillin, metampicillin and analogous derivatives of amoxycillin) or ⁇ -esters of carbenicillin or ticarc
  • Suitable cephalosporins for inclusion in the compositions of this invention include, for example, cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin, cefaparole, cephaloglycin, cefoperazone, and other well known cephalosporins or pro-drugs thereof.
  • the composition will be adapted for parenteral administration.
  • the ratio of a compound of the invention to the penicillin or cephalosporin agent may vary over a wide range of ratios, such as from 10:1 to 1:10, for example about 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6 (wt/wt, based on pure free antibiotic equivalent).
  • the total quantity of a compound of the invention in any unit dosage form will normally be between 25 and 1000 mg and will usually be between 50 and 500 mg, for example about 62.5, 100, 125, 150, 200 or 250 mg.
  • Normally for adult (70kg) human treatment between 50 and 3000 mg of the compounds of the invention will be administered each day of treatment. This corresponds to a dosage of 0.7 to 50 mg/kg per day. More usually between 100 and 1000 mg of the compounds of the invention will be administered per day, for example at 1-6 doses, more usually as 2, 3 or 4 doses.
  • higher doses may be used in accordance with clinical practice.
  • the penicillins or cephalosporin in the synergistic composition of this invention will normally be present at approximately the amount at which it is conventionally used which will usually be expected to be from about 62.5 to 3000 mg per dose, more usually about 125, 250, 500 or 1000 mg per dose.
  • composition of this invention will contain from 150 to 1000 mg of amoxycillin as the trihydrate or sodium salt and from 25 to 500 mg of a compound of this invention.
  • composition of this invention will contain from 150 to 1000 mg of ampicillin or a pro-drug thereof and from 25 to 500 mg of a compound of this invention.
  • the present invention also provides a method of treating bacterial infection in humans or animals which method comprises administration of a composition of the invention.
  • compositions of this invention may be used for the treatment of infections of inter alia, the respiratory tract, the urinary tract and soft tissues in humans.
  • the following Examples illustrate the preparation of compounds of this invention .
  • Mixture B was rechromatographed on silica, eluting with methyl acetate. Appropriate fractions were combined and evaporated under reduced pressure to provide benzyl 9-(1',2',4'-triazol-4'-yl)-9-deoxyclavulanate (125 mg) as a gum.
  • Benzyl-9-azido-9-deoxyclavulanate (2 g) was dissolved in tetrahydrofuran (40 ml) /water (20 ml) and the solution ice cooled and stirred vigorously. Zinc powder (5 g) was added in small quantities over 1% hours, while maintaining the pH of the solution between 3 and 4 by dropwise addition of 2N HCl. When benzyl 9-azido-9-deoxyclavulanate could no longer be detected in the solution (silica tic, eluent ethyl acetate/petroleum ether 1:2), the pH was adjusted to 6 with 1N aqueous sodium bicarbonate and the solution filtered.
  • the filtrate was saturated with NaCl and extracted with ethyl acetate (3 x 30 ml).
  • the combined ethyl acetate extract were dried over MgSO 4 and evaporated under reduced pressure to ca. 50 ml to provide a solution containing benzyl 9-amino- 9-deoxyclavulanate.
  • This solution was treated with acetic anhydride (1.0 ml) and pyridine (0.52 ml), stirred 1 hour at room temperature, washed with 0.1 N HCl (50 ml), 1N aqueous sodium bicarbonate solution (50 ml) and water (50 ml), dried over MgSO 4 and evaporated under reduced pressure.
  • Benzyl 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9-deoxyclavulanate (125 mg) was dissolved in distilled tetrahydrofuran (7 ml) and treated with 10% palladium on carbon (100 mg) .
  • the suspension was shaken under hydrogen at atmospheric pressure for 21 ⁇ 2 hours, treated with water (20 ml) and then dropwise with 0.5N sodium hydroxide solution until the pH reached 7.5.
  • the suspension was filtered and the filtrate evaporated under reduced pressure.
  • the residue was chromatographed on silica (2 cm. long column), eluting with n-butanol/ethanol/water 4:1:1. Appropriate fractions were combined and evaporated under reduced pressure.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I), son sel ou son ester où X est un groupe facultativement 1,2,4 triazolyl substitué fixé par l'un de ces atomes d'azote. Procédés de production de ces composés et compositions les contenant.
PCT/GB1984/000024 1983-02-10 1984-01-31 Derives de clavame WO1984003092A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB838303649A GB8303649D0 (en) 1983-02-10 1983-02-10 Beta-lactam compounds

Publications (1)

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WO1984003092A1 true WO1984003092A1 (fr) 1984-08-16

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PCT/GB1984/000024 WO1984003092A1 (fr) 1983-02-10 1984-01-31 Derives de clavame

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EP (1) EP0135521A1 (fr)
JP (1) JPS60500620A (fr)
BE (1) BE900322A (fr)
GB (1) GB8303649D0 (fr)
WO (1) WO1984003092A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001516A1 (fr) * 1977-10-10 1979-04-18 Glaxo Group Limited Composés beta-lactames, procédés pour leur préparation, compositions pharmaceutiques les contenant et intermédiaires utilisés pour leur préparation
EP0053893A1 (fr) * 1980-12-09 1982-06-16 Beecham Group Plc Dérivés de l'acide clavulanique, leur préparation et leur application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001516A1 (fr) * 1977-10-10 1979-04-18 Glaxo Group Limited Composés beta-lactames, procédés pour leur préparation, compositions pharmaceutiques les contenant et intermédiaires utilisés pour leur préparation
EP0053893A1 (fr) * 1980-12-09 1982-06-16 Beecham Group Plc Dérivés de l'acide clavulanique, leur préparation et leur application

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EP0135521A1 (fr) 1985-04-03
JPS60500620A (ja) 1985-05-02
BE900322A (fr) 1985-02-08
GB8303649D0 (en) 1983-03-16

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