WO1984002134A1 - COMPOSES CONTENANT DES beta-LACTAMES - Google Patents

COMPOSES CONTENANT DES beta-LACTAMES Download PDF

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Publication number
WO1984002134A1
WO1984002134A1 PCT/GB1983/000283 GB8300283W WO8402134A1 WO 1984002134 A1 WO1984002134 A1 WO 1984002134A1 GB 8300283 W GB8300283 W GB 8300283W WO 8402134 A1 WO8402134 A1 WO 8402134A1
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WO
WIPO (PCT)
Prior art keywords
compound
salt
formula
ester
pharmaceutically acceptable
Prior art date
Application number
PCT/GB1983/000283
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English (en)
Inventor
John Sydney Davies
Pamela Ann Hunter
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
Priority claimed from GB838310346A external-priority patent/GB8310346D0/en
Application filed by Beecham Group Plc filed Critical Beecham Group Plc
Publication of WO1984002134A1 publication Critical patent/WO1984002134A1/fr

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Classifications

    • 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 a class of novel ⁇ -lactam compounds, to the process for their preparation and to pharmaceutical compositions containing them.
  • Clavulanic acid has the formula (A):
  • the present invention provides a compound of formula (I) or a salt or ester thereof :
  • A represents -CH 2 - or -CH 2 -CH 2 -.
  • the major utility of the compound of formula (I) is as a pharmaceutical and, accordingly, the salts and esters of the compound of formula (I) are preferably pharmaceutically acceptable.
  • the compound of formula (I) may also be used as an anti-bacterial or ⁇ -lactamase inhibitor in non-pharmaceutical uses such as, for example, as a disinfectant or paint additive; those salts and esters which are not normally considered to be pharmaceutically acceptable are suitable for this application.
  • A represents -CH 2 -.
  • A represents -CH 2 -CH 2 -.
  • Suitable pharmaceutically acceptable esters of the compound of formula (I) include in vivo hydrolysable esters,
  • Suitable pharmaceutically acceptable salts of the compound of formula (I) include metal salts, eg 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, cycloalkylamines such as bicyclohexylamine, or with dibenzylamine, N,N-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, or N-benzyl- ⁇ -phenethy ⁇ - amine.
  • metal salts eg 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, cycloalkylamines such as bicyclohexylamine, or with dibenzylamine, N,N-
  • Particularly suitable pharmaceutically acceptable salts of the compound of formula (I) are the alkali metal salts such as lithium, sodium and potassium.
  • the preferred pharmaceutically acceptable salts are the sodium and potassium salts.
  • 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, for example acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl and ⁇ -pivaloyloxmethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl; dialkylamino alkyl groups such as dimethylaminoethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl and lactone groups such as phthalidyl or dimethoxyphthalidyl.
  • the present invention also provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier.
  • 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 animals including humans.
  • compositions of this invention include tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials such, as diluents, binders, colours, flavours, preservatives, disintegrant and the like in accordance with conventional pharmaceutical practice in the manner well understood by those skilled in the art of formulating anti-biotics.
  • compositions of a compound of the invention are particularly suitable as high blood levels of the compound can occur after administration by injection or infusion.
  • one preferred composition aspect of this invention comprises a compound of the invention in sterile form and most suitably in sterile crystalline form.
  • the injectable solution of the compound of this invention may be made up in a sterile pyrogen-free liquid such as water, aqueous ethanol or the like.
  • An alternative approach to administering the compounds of this invention is to utilise an injectable suspension.
  • Such suspensions may be made up in sterile water; sterile saline or the like, and may also contain suspending agents such as polyvinylpyrrolidone, lecithin or the like.
  • suspending agents such as polyvinylpyrrolidone, lecithin or the like.
  • Such compositions may be prepared in an acceptable oil suspending agent such as arachis oil or its equivalent.
  • the compounds of this invention should be in the form of fine particles.
  • Unit dose compositions comprising a compound of this invention adapted for oral administration form a further suitable composition aspect of this invention.
  • Unit dose compositions comprising a compound of this invent! on adapted for topical administration are also presented by this invention.
  • 'topical administration' also includes local administration to internal surfaces of mammary glands of cattle, for example during the treatment of mastitis by intra-mammary administration.
  • the compound of the formula may be present in the composition as sole therapeutic agent or it may be present together with other therapeutic agents such as a penicillin or cephalosporin.
  • a penicillin or cephalosporin which shows instability to ⁇ -lactamases since the resulting composition shows enhanced effectiveness (synergy).
  • Suitable penicillins, cephalosporins or other ⁇ -lactam anti-biotics for inclusion in such synergistic compositions include not only those known to be highly susceptible to ⁇ -lactamases but also those which have a degree of intrinsic resistance to ⁇ -lactamases.
  • Suitable penicillins for inclusion in the compositions of this invention include benzylpenicillin, phenoxymethyl-penicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azlocillin, mezlocillin, sulbenicillin, pipericillin, and other known penicillins including pro-drugs therefor such as their in vivo hydrolysable esters such as the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl or phthalidyl esters of ampicillin, benzylpenicillin or amoxycillin, and aldehyde or ketone adducts of penicillins containing a 6- ⁇ -aminoacetamide side chain (such as hetacillin, metampicillin and analogous derivatives of amoxycillin) or ⁇ -esters of carbenicillin or ticarcillin
  • Suitable cephalosporins for inclusion in the compositions of this invention include cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole nafate, cephapirin, cephradine, 4-hydroxycephalexin, cefaparole, cephaloglycin, cefoperazone and other known cephalosporins or pro-drugs thereof.
  • compositions are frequently used in the form of a salt or hydrate of the like.
  • penicillin or cephalosporin present in the composition is not suitable for oral administration then the composition will be adapted for parenteral administration.
  • Such penicillins may be used as a pharmaceutically acceptable salt such as the sodium salt.
  • the ampicillin or amoxycillin may be used in the form of find particles of the zwitterionic form (generally as ampicillin trihydrate or amoxycillin trihydrate) for use in an injectable suspension, for example in the manner hereinbefore described for a compound of this invention.
  • the preferred penicillin for use in the synergistic composition is amoxycillin, for example as its sodium salt or trihydrate.
  • 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 anti-biotic equivalent).
  • Orally administrable compositions containing a compound of the invention will normally contain relatively more synergist than corresponding injectable compositions.
  • 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.
  • 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 and mastitis in cattle.
  • the penicillin 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.
  • a further particularly favoured composition of this invention will contain from 150 to 1000 mg of ampicillin or a pro-drug therefor and from 25 to 500 mg of a compound of this invention.
  • this form of composition will contain ampicillin trihydrate, ampicillin anhydrate, sodium ampicillin, hetacillin, pivampicillinhydrochloride, bacampicillin hydrochloride, or talarapicillin hydrochloride. Most suitably this form of the composition will contain a compound of the formula (I) when in crystalline form.
  • the preceding composition will contain from 200 to 700 mg of the penicillin component. Most suitably the preceding composition will comprise from 50 to 250 mg of a compound of the formula (I) preferably in crystalline form.
  • compositions may be adapted for oral or parenteral use except when containing an in vivo hydrolysable ester of ampicillin or amoxycillin in which case the compositions will not be adapted for parenteral administration.
  • composition of this invention will contain from 200 to 2000 mg of carbenicillin, ticarcillin or a pro-drug therefor and from 50 to 500 mg of a compound of the invention.
  • this form of composition will contain di-sodium carbenicillin.
  • this form of the composition will contain di-sodium ticarcillin. More suitably this form of the composition will contain from 75 to 250 mg of a compound of the formula (I) preferably in crystalline form.
  • Such compositions containing di-salts of carbenicillin and ticarcillin will be adapted for parenteral administration.
  • the present invention also provides a method of treating bacterial infections in humans or animals including domestic mammals which comprises the administration of a composition of this invention.
  • the infection treated will be due to a strain of Staphylococcus aureus, Klebsiella aeroqenes, Escherichia coli, Proteus sp. , Bacteroides fraqilis or the like.
  • the organisms believed to be most readily treated by an anti-bacterially effective amount of a compound of this invention is Staphylococcus aureus.
  • the other organisms named are more readily treated by using a synergistically effective amount of the compound of the invention and a penicillin or cephalosporin.
  • the administration of the two components may take place separately but in general we prefer to use a composition containing both the synergist and the penicillin or cephalosporin.
  • the indications for treatment include respiratory tract and urinary tract infections in humans and mastitis in cattle.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a salt or ester thereof, which process comprises mildly oxidising a compound of formula (II):
  • R x is a carboxy protecting group and Z is S-A-CN or SO-A-CN wherein A is as hereinbefore defined
  • the oxidation may take place at an ambient or depressed temperature, for example at -20°C to +20°C, more suitably at -12°C to +5°C, for example at about 0°C.
  • the oxidation is best brought about using an organic per-acid as the oxidizing agent.
  • Suitable acids include m-chloroperbenzoic acid arid equivalent reagents.
  • the compounds of formula (II) wherein Z is S-A-CN may be prepared by reactirig a compound of formula (III) with a thiol of formula (IV) or a salt thereof in the presence of a Lewis acid catalyst.
  • R x is as defined for formula (II)
  • Suitable Lewis acid catalysts include boron trifluoride or its equivalent such as a boron trifluoride etherate, for example BF 3 .O(C 2 H 5 ) 2 .
  • the preceding reaction normally takes place in a solvent inert under the reaction conditions such as chloroform, dichloromethane, tetrahydrofuran or dioxane or may be carried out using the thiol reagent as solvent.
  • the reaction is generally carried out at a depressed or non-elevated temperature for example -80oC to +30oC, and preferably at a depressed temperature, for example -20oC to 0oC, and conveniently at about
  • the compounds of formula (II) wherein Z is S-A-CN may also be prepared by the reaction of a compound (V) with a thiolate of a thiol of formula (IV).
  • R x is as defined for formula (II) and Z 1 is a displaceable atom or group.
  • Suitable moieties Z 1 displaceable by the thiolate include conventional displaceable groups such as sulphonate or carboxylate esters such as OSO 2 R y , OCOR y or OCO 2 R y where R y is an inert organic group such as a lower alkyl group (such as a methyl, ethyl, propyl or butyl group) optionally substituted by one or more halogen atoms, a phenyl, benzyl, methoxyphenyl, methylphenyl, halophenyl, nitrophenyl or like group.
  • R y is an inert organic group such as a lower alkyl group (such as a methyl, ethyl, propyl or butyl group) optionally substituted by one or more halogen atoms, a phenyl, benzyl, methoxyphenyl, methylphenyl, halophenyl, nitrophenyl or like
  • Suitable moieties Z 1 displaceable by the thiolate are halogen atoms, for example a chlorine or bromine atom.
  • Z 1 are a chlorine or bromine atom, or a dichloroacetoxy, mesyloxy, tosyloxy or phenylsulphonyloxy group. Particularly preferred values of
  • Z 1 are chlorine and dichloroacetoxy.
  • the thioetherification reaction may be carried out at a non-extreme temperature such as -60oC to +60oC, preferably from -30°C.
  • the thioetherification reaction may be performed in an inert non-hydroxylic solvent such as dimethylformamide.
  • Suitable carboxy protecting groups for the group -CO 2 R x in formula (II) 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 carboxyl-blocking groups are those which may be removed under conventional conditions.
  • Such groups for R x include benzyl, p-methoxybenzyl,p-nitrobenzyl, 2,4,6-trimethylbenzyl, 3,5-di-t-butyl - benzyl, 4-pyridylmethyl, allyl, diphenylmethyl, triphenymethyl, 2-benzyloxphenyl, 4-methylthiophenyl, methoxymethyl, a silyl, or phosphorus-V-containing group, or methyl or ethyl.
  • the carboxylic group or a salt thereof may be regenerated from any of the above esters by usual methods appropriate to the particular R x group, for example, base-catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenation, or by dissolving metal reduction.
  • Acids within formula (I) may also be prepared by the careful acidification of a corresponding salt such as the sodium salt.
  • Salts within formula (I) may be prepared by treatment of an acid within formula (I) with, for example, sodium ethyl hexanoate or potassium ethyl hexanoate. Salts within formula (I) may also be prepared by salt exchange in conventional manner, for example a solution of the lithium salt in water may be passed through a bed of ion exchange resin in the sodium form (e.g. Amberlite 120; a sodium salt of a sulphonated polystyrene divinyl benzene co-polymer)
  • ion exchange resin in the sodium form e.g. Amberlite 120; a sodium salt of a sulphonated polystyrene divinyl benzene co-polymer
  • the resulting sodium salt may be obtained by freeze drying or by evaporaition to crystallisation.
  • a sodium salt may be converted to a lithium salt or to a potassium salt in similar manner.
  • p-Nitrobenzyl clavulanate (1g.) was dissolved in methylene dichloride (30ml) and 3-mercaptopropionitrile (0.26g) was added. The solution was cooled to -10°C and boron trifluoride (0.1ml) was added and the mixture was stirred under nitrogen at -10° for 0.5 hour. The mixture was washed with 3% sodium bicarbonate solution (2x50ml) and water (50ml).
  • p-Nitrobenzyl-9-carbamoylmethylthio-9-deoxyclavulanic acid (1.8g) was dissolved in dry redistilled tetrahydrofuran (40 ml.), the solution cooled in an ice-bath to 0o, and pyridine (0.73ml.) added. Trifluoroacetic anhydride (0.65 ml.) was added and the mixture stirred at 0o for 1 ⁇ 2 hour. The solution was allowed to warm up to room temperature and evaporated to a small volume. Ethyl acetate (100 ml.) was added and the organic solution washed with water (2 x 50 ml.) and dried over anhydrous magnesium sulphate.
  • p-Nitrobenzyl-9-cyanomethylsulphonyl-9-deoxyclavulanate (0.13g; 0.3mmol) in tetrahydrofuran (20ml) was added to a prehydrogenated suspension of 10%Pd/C(0.13g) in tetrahydrofuran (10ml). The mixture was shaken under 1 atmosphere of hydrogen at room temperature for 1 ⁇ 4 hour. After filtration through celite the solution was reduced to 10ml, diluted with water (10ml) and 0.2N lithium hydroxide solution added dropwise to bring the solution to pH 7.0.
  • the Inhibitors alone showed no antibacterial activity at concentrations of 1 ug/ml and 5 ⁇ g/ml.
  • Geometric mean MIC value ( ⁇ g/ml) for Amoxycillin alone and in the presence of Inhibitors against Amoxycillin resistant E.coli.
  • the Inhibitors alone showed no antibacterial activity at concentrations of 1 ⁇ g/ml and 5 ⁇ g/ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) ou son sel ou son ester dans laquelle A représente -CH2- ou -CH2-CH2-.
PCT/GB1983/000283 1982-11-25 1983-11-10 COMPOSES CONTENANT DES beta-LACTAMES WO1984002134A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8233626 1982-11-25
GB838310346A GB8310346D0 (en) 1983-04-16 1983-04-16 Compounds containing beta-lactams

Publications (1)

Publication Number Publication Date
WO1984002134A1 true WO1984002134A1 (fr) 1984-06-07

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PCT/GB1983/000283 WO1984002134A1 (fr) 1982-11-25 1983-11-10 COMPOSES CONTENANT DES beta-LACTAMES

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EP (1) EP0127636A1 (fr)
WO (1) WO1984002134A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1574906A (en) * 1976-01-31 1980-09-10 Beecham Group Ltd Therapeutic compounds containing - lactams
GB1579531A (en) * 1976-02-27 1980-11-19 Glaxo Lab Ltd Oxazolo-azetidinine antibiotic derivatives
EP0027324A1 (fr) * 1979-09-27 1981-04-22 Beecham Group Plc Dérivés de l'acide clavulanique, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0055062A1 (fr) * 1980-12-23 1982-06-30 Beecham Group Plc Composés contenant des bêta-lactames

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1574906A (en) * 1976-01-31 1980-09-10 Beecham Group Ltd Therapeutic compounds containing - lactams
GB1579531A (en) * 1976-02-27 1980-11-19 Glaxo Lab Ltd Oxazolo-azetidinine antibiotic derivatives
EP0027324A1 (fr) * 1979-09-27 1981-04-22 Beecham Group Plc Dérivés de l'acide clavulanique, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0055062A1 (fr) * 1980-12-23 1982-06-30 Beecham Group Plc Composés contenant des bêta-lactames

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EP0127636A1 (fr) 1984-12-12

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