WO1984001776A1 - COMPOSES DE beta-LACTAME, LEUR PREPARATION ET LEUR UTILISATION - Google Patents

COMPOSES DE beta-LACTAME, LEUR PREPARATION ET LEUR UTILISATION Download PDF

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Publication number
WO1984001776A1
WO1984001776A1 PCT/GB1983/000258 GB8300258W WO8401776A1 WO 1984001776 A1 WO1984001776 A1 WO 1984001776A1 GB 8300258 W GB8300258 W GB 8300258W WO 8401776 A1 WO8401776 A1 WO 8401776A1
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group
formula
compound
carbon atoms
phenyl
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PCT/GB1983/000258
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English (en)
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Pamela Ann Hunter
John Sidney Davies
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Beecham Group Plc
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Priority to JP83503398A priority Critical patent/JPS59502063A/ja
Publication of WO1984001776A1 publication Critical patent/WO1984001776A1/fr

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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

Definitions

  • Beta-Lactam compounds preparation and use.
  • This invention relates to novel ⁇ -lactam antibacterial agents, their preparation and their use, and in particular to penicillins which are active against ⁇ -lactamase-producing bacteria.
  • R a is phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or a 3-thienyl group
  • R b is a primary amino or a carboxy group
  • R c is a hydrogen atom, or a lower alkyl, aryl or aralkyl radical
  • R d is a radical of a ⁇ -lactamase inhibitor.
  • the present invention provides a compound of formula ( I) : or an acid addition salt thereof,
  • R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 5-8 cycloalkenyl or an aromatic group;
  • R 2 is primary amino, or a carboxy group or an ester thereof
  • R 3 is hydrogen or a hydrocarbon moeity; any of the above groups R 1 , R 2 and R 3 being optionally substituted; and
  • R 4 is a group of formula (II):
  • R is an inert organic group of up to 18 carbon atoms.
  • Suitable inert organic groups R for inclusion in the residues of the formula (II) include hydrocarbon groups and hydrocarbon groups inertly substituted by halo, an ether group, acyloxy, acyl, ester, carboxy or salted carboxy, hydroxy, nitro, cyano, amino and substituted amino and the like so that suitable groups R include hydrocarbon and hydrocarbon substituted by halogen and/or groups of the sub-formulae OR 5 , OH, OCOR 5 , CO.R 5 , CO 2 R 5 .
  • NR 6 .CO.R 5 NR 6 CO 2 R 5 , SOR 5 , SO 2 R 5 , NH2 , NR 5 R 6 , NO 2 , CN or CO.NR 5 R 6 wherein R 5 is a hydrocarbon group of up to 8 carbon atoms and R 6 is a hydrocarbon group of up to 4 carbon atoms.
  • the term 'inert organic group' means that the organic group is one which does not render the compound inherently unstable or unsuitable for use as a medicinal agent.
  • hydrocarbon' includes alkyl, alkenyl and alkynyl groups and such groups substituted by phenyl or hydrocarbon substituted phenyl groups and the like.
  • Suitable inert organic groups R for inclusion in the residues of the formula (II) include hydrocarbon groups and hydrocarbon groups inertly substituted by halo and/or groups of the sub-formulae OR 5 , O.COR 5 , CO.R 5 , CO 2 R 5 wherein R 5 is a hydrocarbon group of up to 8 carbon atoms.
  • R 5 is an alkyl group of 1 - 4 carbon atoms or a phenyl or benzyl group.
  • a preferred group R 5 is the methyl group.
  • a preferred group R 6 is the methyl group.
  • a further suitable sub-group of residues of the formula (II) are those wherein R is a group CR 8 R 9 R 10 wherein R 8 and R 9 are independently alkyl groups of up to 3 carbon atoms or a phenyl group optionally substituted by halo or a group of the formula R 11 or OR 11 where R 11 is an alkyl group of up to 3 carbon atoms; and R 10 is a hydrogen atom or an alkyl group of up to 3 carbon atoms or a phenyl group optionally substituted by halo or a group of the formula R 12 or OR 12 where R 12 is an alkyl group of up to 3 carbon atoms.
  • R is a group CH 2 R 13 wherein R 13 is a naphthyl, phenyl or phenyl group substituted by halo or a group R 14 or OR 14 where R 14 is an alkyl group of up to 3 carbon atoms.
  • R 15 -COOH is a hydrocarbon group of 1 - 8 carbon atoms optionally inertly substituted by halo and/or OR 16 , OCOR 16 , CO.R 16 or OH group where R 16 is an alkyl group of 1 - 4 carbon atoms.
  • R 15 is an alkylene group of 1 - 4 carbon atoms, a phenylene group or an alkylene group of 1 - 4 carbon atoms substituted by a phenyl or phenylene group.
  • R 15 is an alkylene group of 1 - 4 carbon atoms such as the -CH 2 - or -CH 2 .CH 2 - groups.
  • a particularly suitable group of residues of the formula (II) are those of the formula (III):
  • R 16 is an alkylene group of 1 - 4 carbon atoms and R 17 is a hydrogen atom or an alkyl group of 1 - 4 carbon atoms or an alkyl group of 1 - 4 carbon atoms substituted by a phenyl group.
  • R 16 is a -CH 2 - or -CH 2 .CH 2 - group.
  • a further particularly suitable group of residues is that of the formula (IV):
  • R 18 is a divalent hydrocarbon group of 2 - 8 carbon atoms;
  • R 19 is a hydrogen atom or an alkyl group of 1 - 4 carbon atoms and
  • R 20 is a hydrogen atom or a R 21 , CO.R 21 or CO 2 R 21 group where R 21 is an alkyl group of 1 - 4 carbon atoms optionally substituted by a phenyl group.
  • R 21 is an alkylene group of 2 - 4 carbon atoms, a phenylene group or an alkylene group of 2 - 4 carbon atoms substituted by a phenyl or phenylene group.
  • R 22 is hydrogen, an alkyl group of 1 - 4 carbon atoms or a phenyl group or one of the aforenamed groups substituted by a carboxylic acid group or a salt or C 1-4 alkyl ester or R 22 is a carboxylic acid group or a salt of C 1-4 alkyl ester thereof.
  • R 22 is hydrogen or unsubstituted alkyl, preferably hydrogen.
  • R 1 is suitably C 1-6 alkyl such as methyl or ethyl; C 3-8 cycloalkyl such as cyclohexyl; or C 5-8 cycloalkenyl, such as cyclohexenyl or cyclohexadienyl such as 1,4-cyclohexadienyl.
  • R 1 is an aromatic group such as optionally-substituted phenyl or naphthyl, or heteroaryl wherein the heteroaryl ring comprises 5 to 7 atoms, preferably 5 to 6, up to 4 of which may be heteroatoms selected from oxygen, sulphur and nitrogen.
  • R 1 is an aromatic group
  • R 1 is an optionally substituted 5-membered heterocyclic ring comprising one or two heteroatoms selected from oxygen, sulphur and nitrogen
  • heterocyclic rings include furyl, thienyl, such as thien-3-yl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl and imidazolyl, any of which ring systems may be optionally substituted for example by halo, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy.
  • R 1 is an aromatic group
  • R 1 is phenyl; mono-substituted phenyl wherein the substituent is halo, hydroxy, C 1-6 alkoxy, nitro, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkanoyloxy or C 1-6 alkylsulphonylamino; or di-substituted phenyl wherein the substituents are selected from hydroxy, halo, methoxy, acetoxy and amino.
  • R 1 when R 1 is an aromatic group, R 1 is phenyl; phenyl mono-substituted by fluoro, chloro, hydroxy, methoxy, nitro, amino, acetoxy or trifluoromethyl; or di-substituted by substituents selected from acetoxy, hydroxy and methoxy.
  • R 1 is 1,4-cyclohexadienyl, phenyl, p-hydroxyphenyl, p-aminophenyl, p-acetoxyphenyl, thien-2-yl, thien-3-yl or 2-aminothiazol-4-yl.
  • R 1 is phenyl, p-hydroxyphenyl, 1,4-cyclohexadienyl or 3-thienyl.
  • R 1 is phenyl or substituted phenyl such as p-hydroxyphenyl; and when R 2 is a carboxy group or an ester thereof such as the optionally substituted phenyl ester, or benzyl or indanyl ester, R 1 is phenyl or thienyl such as 3-thienyl.
  • R 2 When R 2 is amino, it may be in the form of an acid addition salt thereof, such as the hydrochloride salt.
  • R 3 is a hydrogen atom, or a C 1-6 alkyl, aryl or aryl C 1-6 alkyl group.
  • the C 1-6 alkyl moiety may be straight or branched chained; and the aryl moiety is a monocyclic or bicy ⁇ lic carbocyclic radical.
  • R 3 is hydrogen, methyl, ethyl, phenyl or benzyl.
  • R 3 is a hydrogen atom, or a methyl, phenyl or benzyl group.
  • Especially preferred compounds of formula ( I ) are those wherein:
  • R 1 is phenyl, p-hydroxy-phenyl, 1,4-cyclohexadienyl or 3-thienyl;
  • R 2 is amino, carboxy, phenoxycarbonyl or benzyloxycarbonyl;
  • R 3 is a hydrogen atom, or methyl, phenyl or benzyl
  • R 4 is a residue of a clavulanate of formula (II) as defined above wherein R is alkyl such as methyl.
  • a carboxy group is present as a substituent in any of the compounds of this invention, then it may be presented as the free acid or in salified or esterified or zwitterionic form.
  • salts would suitably be in pharmaceutically acceptable form and include metal salts, for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with C 1-6 alkylamines such as triethylamine, hydroxy-C 1-6 alkylamines such as 2-hydroxethylamine, bis(2-hydroxyethyl)amine or tri(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine.
  • metal salts for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with C 1-6 alkylamines such as triethylamine, hydroxy-C 1-6 alkylamines such as 2-hydroxethylamine, bis(2-hydroxyethyl)amine or
  • any carboxy present in the compounds of this invention may be esterified with a pharmaceutically acceptable esterifying radical such as an alkyl, aryl or aralkyl group.
  • a pharmaceutically acceptable esterifying radical such as an alkyl, aryl or aralkyl group.
  • Preferred esterifying radicals would include C 1-6 alkyl such as methyl and ethyl, phenyl, benzyl and substituted benzyl such as nitrobenzyl, bromobenzyl, C 1-6 alkoxycarbonylbenzyl, C 1-6 alkoxybenzyl and C 1-6 alkylbenzyl, and in vivo hydrolysable esters such as phthalidyl.
  • the compounds of this invention may be presented in the form of their acid addition salts if a basic group (e.g. -NH 2 ) is present as a substituent.
  • the acid used to form the salt will most suitably be pharmaceutically acceptable, but non-pharmaceutically acceptable acid addition salts are also envisaged, for example as intermediates in the preparation of the pharmaceutically acceptable salts by ion-exchange.
  • Suitable pharmaceutically acceptable acid addition salts include those of inorganic and organic acids such as hydrochloric, phosphoric, sulphuric, methanesulphonic, toluenesulphonic, citric, maleic, acetic, lactic, tartaric, propionic and succinic acid.
  • the present invention provides a pharmaceutical composition which comprises a compound of formula (I) together with a pharmaceutically acceptable carrier therefor.
  • compositions of this invention may be prepared by conventional methods for preparing antibiotic compositions and in conventional manner may be adapted for oral, topical or parenteral administration.
  • Unit dose forms according to this invention normally contain from 50 to 1000 mg of a compound of this invention, for example about 62.5, 100, 150, 200, 250, 500 or 750 mg. Such compositions may be administered from 1 to 6 times a day or more conveniently 2, 3 or 4 times a day so that the total daily dose for a 70 kg adult is about 200 to 2000 mg, for example about 400, 600, 750, 1000 or 1500 mg.
  • Suitable pharmaceutically acceptable carriers used in the compositions of this invention include diluents, binders, disintegrants, lubricants, colours, flavouring agents or preservatives in conventional manner.
  • suitable agents include lactose, starch, sucrose, calcium phosphate, sorbitol, polyvinylpyrrolidone, acacia, gelatin, tragacanth, potato starch or polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • compositions of this invention are most suitably in the form of unit-dose units such as tablets or capsules.
  • Certain of the compounds of this invention tend to be sparingly soluble, so if it is preferred that their solubility be increased for use in pharmaceutical compositions, in one embodiment, if appropriate and an amino or carboxylic acid group is present, it is preferred to use an acid addition salt or carboxylic acid salt.
  • One feature of the compounds of the present invention is that they are believed to break down in-vivo to liberate the moieties of the antibacterial penicillin and the ⁇ -lactamase inhibitor. This is believed to occur more readily via the oral route.
  • the compounds of the formula (I) may be regarded as pro-drugs of the penicillin and as pro-drugs of the ⁇ -lactamase inhibitor.
  • the present invention further provides a synergistic pharmaceutical composition which comprises a pharmaceutical composition as hereinbefore described together with a penicillin or cephalosporin.
  • Suitable penicillins for inclusion in the synergistic compositions of this invention include benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxycillin, ticarcillin, suncillin, sulbenicillin, azlocillin or mezlocillin; in particular, amoxycillin as its sodium salt or trihydrate is preferred.
  • Suitable cephalosporins for inclusion in the synergistic compositions of this invention include cephaloridine, cefazolin and cephradine.
  • the penicillin or cephalosporin is generally included in its conventionallly-administered amount.
  • the weight ratio between the compound of this invention and penicillin or cephalosporin is generally in the range of from 20:1 to 1:5, more usually 10:1 to 1:2 and normally 5:1 to 1:1.
  • the compounds and compositions of this invention are suitable for use as agents to treat a bacterial infection in animals such as mammals including humans, for example infections of the repiratory tract, urinary tract or soft tissues, or mastitis in cattle.
  • the present invention provides a method of treatment of bacterial infections (such as those described above) to an animal in need thereof, which method comprises the administration to said animal of a non-toxic, effective antibacterial amount of a compound of formula (I) or a pharmaceutical formulation thereof.
  • the present invention provides a process for the preparation of a compound of the formula (I), which process comprises reacting together a source of the side-chain R 1 -CHR 2 -CO-, a source of the 6-amino penicillanic acid moiety and a source of the esterifying group -CHR 3 -O-CO-R 4 , wherein R 0 , R 3 and R 4 are as hereinbefore defined.
  • a process for the preparation of a compound of formula (I) which process comprises the reaction of a compound of formula (VI):
  • R 1 , R 2 and R 3 are as hereinbefore defined; and Y is a leaving group;
  • R 4 is as hereinbefore defined
  • Y is a good leaving group such as a halo atom for example chloro, bromo or iodo.
  • the reaction is suitably performed in a substantially inert organic solvent known to be convenient for esterification reactions, such as dimethylformamide, acetone, ethyl acetate or a halogenated hydrocarbon.
  • a reaction is performed at a depressed, ambient or elevated temperature such as between 0°C and 50°C, preferably at ambient temperature.
  • the compound of formula (VII) is reacted in the form of its salt, which need not be pharmaceutically acceptable.
  • Suitable salts include inorganic salts for example metal salts, alkali metal salts such as lithium, potassium or sodium salts; or tertiary amine salts.
  • the compounds of formula (VI) may be prepared by the reaction of a penicillin or salt or other reactive derivative thereof, with a compound of formula (VIII):
  • the compounds of formula (VII) may be prepared by a method described in, for example, British patent specification No. 1,565,209.
  • a process for the preparation of a compound of formula (I) which process comprises the reaction of a compound of formula (IX) or a derivative thereof which permits N-acylation to occur: wherein R 3 and R 4 are as hereinbefore defined, with an N-acylating derivative of a carboxylic acid of the formula (X):
  • R 1 and R 2 are as hereinbefore defined, and any reactive group is optionally protected; and thereafter if necessary:
  • Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (IX) include N-silyl, N-stannyl and N-phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula -P.R a R b wherein R a is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkloxy or dialkylamino group, R b is the same as R a or is halogen or R a and R b together form a ring; suitable such phosphorus groups being -P(OC 2 H 5 ) 2 , -P(C 2 H 5 ) 2 ,
  • N-acylating derivatives include an acid halide, preferably the acid chloride or bromide.
  • Acylation with an acid halide may be effected in the presence of an acid binding agent for example tertiary amine (such as triethylamine or dimethylaniline), an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction.
  • the oxirane is preferably a (C 1-6 )-1,2- alkylene oxide - such as ethylene oxide or propylene oxide.
  • the acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°C, in aqueous or non-aqueous media such as aqueous acetone, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
  • aqueous or non-aqueous media such as aqueous acetone, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
  • reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.
  • an aliphatic ester or ketone such as methyl isobutyl ketone or butyl acetate.
  • the acid halide may be prepared by reacting the acid (X) or a salt thereof with a halogenating (eg chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride.
  • a halogenating agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride.
  • the N-acylating derivative of the acid (X) may be a symmetrical or mixed anhydride.
  • Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example carbonic acid mono-esters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorus acids (such as phosphoric or phosphorous acids, sulphuric acid or aliphatic or aromatic sulphonic acids such as p-toluenesulphonic acid).
  • the mixed or symmetrical anhydrides may be generated using N-ethoxycarbonyl-2-ethoxyl-2-ethoxy-1,2-dihydroquinoline. When a symmetrical anhydride is employed, the reaction may be carried out in the presence of 2,4-lutidine as catalyst.
  • Alternative N-acylating derivatives of acid (X) are the acid azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thioalcohols such as thiophenol, methanethiol, ethanethiol and propanethiol, halo-phenols, including pentachlorophenol, monomethoxyphenol or 8-hydroxyquinoline, N-hydroxysuccinimide or 1-hydroxybenztriazole; or amides such as N-acylsaccharins or N-acylphthalimides; or an alkylidine iminoester prepared by reaction of the acid with an oxime.
  • esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thioalcohols such as thiophenol, methanethiol, ethanethiol and propanethiol, halo-
  • reactive N-acylating derivatives of acid (X) include the reactive intermediate formed by reaction in situ with a condensing agent such as a carbodiimide, for example N,N-diethyl-, dipropyl- or diisopropylcarbodiimide, N,N'-di-cyclohexylcarbodiimide, or N-ethyl-N'- -dimethylaminopropylcarbodiimide; a suitable carbonyl compound, for example N,N'-carbonyldiimidazole or N,N'-carbonylditriazole; an isoxazolinium salt, for example N-ethyl-5-phenylisoaxazolinium-3-sulphonate or N-t-butyl-5-methylisoxazolinium perchlorate; or an N-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, such as N-ethoxycarbonyl2-ethoxy-1
  • condensing agents include Lewis acids (for example BBr 3 - C 6 H 6 ); or a phosporic acid condensing agent such as diethylphosphorylcyanide.
  • the condensation reaction is preferably carried out in an organic reaction medium, for example methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
  • an organic reaction medium for example methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
  • R 3 and R 4 are as hereinbefore defined, and R 23 is an acyl group with an agent forming an imino halide
  • a suitable agent for preparing an imino halide is an acid halide in the presence of an acid binding agent such as a tertiary amine, e.g. pyridine, triethylamine, or N,N-dimethylaniline.
  • an acid binding agent such as a tertiary amine, e.g. pyridine, triethylamine, or N,N-dimethylaniline.
  • suitable acid halides are phosphorus pentachloride, phosgene, phosphorous pentabromide, phosphorus oxychloride, oxalyl chloride and p-toluene sulphonic acid chloride. Phosphorus pentachloride and phosphorus oxychloride are preferred.
  • the reaction may be conducted under cooling, preferably at temperatures from 0°C to -30°C when phosphorus pentachloride is employed.
  • the amount of the tertiary amine is preferably 3 - 5 mols per mol of phosphorus pentachloride. It is also preferable to use the phosphorus halide in an amount slightly in excess of that of the starting material.
  • the resulting imino compounds are then treated to introduce a -QR f group onto the imino carbon atom.
  • This is preferably effected by reacting the imino halide with a corresponding alchohol.
  • suitable alcohols for reaction with the imino halide are aliphatic alcohols containing from 1 to 12 carbon atoms, preferably 1 to 5 carbon atoms, such as methanol, ethanol, propanol, isopropyl alcohol, amyl alcohol and butyl alcohol, and aralkyl alcohols such as benzyl alcohol and 2-phenylethanol.
  • the reaction of the alcohol with the imino halide is preferably effected in the presence of an acid binding agent, such as a tertiary amine, preferably pyridine, and the reaction is usually carried out without isolating the imino halide from the reaction mixture.
  • an acid binding agent such as a tertiary amine, preferably pyridine
  • N-acylating derivative of an acid of formula (X) is caused to react with an N-acylating derivative of an acid of formula (X).
  • N-acylating derivatives and the conditions for carrying out acylations also apply in this case.
  • the presence of a tertiary amine such as pyridine of N,N-dimethylaniline in the reaction system is preferred.
  • the product is treated with water.
  • the water treatment may be conducted together with the isolation of the desired material. That is the reaction mixture may be added to water or a saturated aqueous solution of sodium chloride and then the aqueous layer formed is separated from the organic solvent layer.
  • protecting groups include benzyl or substituted benzyl esters for carboxylic groups, and N-benzyloxycarbonyl or substituted benzyloxycarbonyl groups for amino groups. Deprotection may take place by a standard method such as catalytic hydrogenolysis.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) où R1 représente un alcoyle C1-6, un cyclo alcoyle C3-6, un cyclo alcényl C5-8 ou un groupe aromatique, où R2 représente un amino primaire ou son sel d'addition acide, ou un groupe carboxy ou son ester, où R3 représente un hydrogène ou une partie hydrocarbure, chacun des groupes susmentionnés R1, R2 et R3 étant facultativement substitués, et où R4 est un groupe de formule (II) où R est un groupe organique inerte pouvant contenir jusqu'à 18 atomes de carbone. Sont également décrits et revendiqués des procédés de préparation de ces composés et des compositions pharmaceutiques les contenant.
PCT/GB1983/000258 1982-10-26 1983-10-13 COMPOSES DE beta-LACTAME, LEUR PREPARATION ET LEUR UTILISATION WO1984001776A1 (fr)

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JP83503398A JPS59502063A (ja) 1982-10-26 1983-10-13 化学化合物

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038521A1 (fr) * 1998-02-02 1999-08-05 Boehringer Ingelheim Vetmedica Gmbh Utilisation en medecine veterinaire, de combinaisons de principes actifs a base de substances a action antimicrobienne et d'extraits de plantes contenant du terpene

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2044255A (en) * 1979-02-13 1980-10-15 Leo Pharm Prod Ltd Penicillin derivatives
EP0074777A1 (fr) * 1981-09-09 1983-03-23 Pfizer Inc. Esters de 6-(2-amino-2-(4-acyloxy-phényl)acétamido) pénicillanoyloxyméthyle, antibactériens

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2044255A (en) * 1979-02-13 1980-10-15 Leo Pharm Prod Ltd Penicillin derivatives
EP0074777A1 (fr) * 1981-09-09 1983-03-23 Pfizer Inc. Esters de 6-(2-amino-2-(4-acyloxy-phényl)acétamido) pénicillanoyloxyméthyle, antibactériens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038521A1 (fr) * 1998-02-02 1999-08-05 Boehringer Ingelheim Vetmedica Gmbh Utilisation en medecine veterinaire, de combinaisons de principes actifs a base de substances a action antimicrobienne et d'extraits de plantes contenant du terpene

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JPS59502063A (ja) 1984-12-13

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