EP0000615A1 - Composés béta-lactame, préparation et utilisation dans compositions pharmaceutiques et comme produits chimiques intermédiaires - Google Patents

Composés béta-lactame, préparation et utilisation dans compositions pharmaceutiques et comme produits chimiques intermédiaires Download PDF

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Publication number
EP0000615A1
EP0000615A1 EP78300054A EP78300054A EP0000615A1 EP 0000615 A1 EP0000615 A1 EP 0000615A1 EP 78300054 A EP78300054 A EP 78300054A EP 78300054 A EP78300054 A EP 78300054A EP 0000615 A1 EP0000615 A1 EP 0000615A1
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EP
European Patent Office
Prior art keywords
compound
formula
preparation
isomer
compounds
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP78300054A
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German (de)
English (en)
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EP0000615B1 (fr
Inventor
Eric Hunt
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Beecham Group PLC
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Beecham Group PLC
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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
    • 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

Definitions

  • the present invention relates to S-lactam containing compounds to the process for their preparation, to pharmaceutical compositions containing them and to their use as intermediates and synergists.
  • Belgian Patent No: 840, 252 disclosed the compounds of the formula (II): and their salts. Such compounds were shown to possess ⁇ -lactamase inhibitory activity which enables them to enhance the effectiveness of penicillins and cephalosporins against ⁇ -lactamase producing bacteria.
  • Belgian Patent No: 847,044 disclosed inter alia that esters of esters of the compound of the formula (III): may be used to prepare compounds such as esters of 9-dibenzylaminodeaxyclavulanic acid.
  • Belgian Patent No: 849,308 disclosed that the esters of the compound of the formula (III) also possessed ⁇ -lactamase inhibitory activity.
  • the present invention provides the compounds of the formula (I): wherein X represents a moiety of the sub-formula (a) or (b):
  • the monoenes within formula (I), that is the compounds of the formula (IV): are envisaged as ⁇ -lactamase inhibitors which may be used to enhance the effectivenessof penicillins or cephalosporins.
  • the E-isomer of the compound may be used or the Z-isomer of the compound may be used or mixtures of the E- and 2-isomers may be used.
  • the diene within formula (I), that is the compound of the formula (V): is also envisaged as a -lactamase inhibitor which may be used to enhance the effectiveness of penicillins or cephalosporins but its chemical reactivity also makes it a useful intermediate, for example it is able to take place in 1,4-addition reactions as will become apparent hereinafter.
  • the compounds of the formulae (I), (IV) or (V) are at least 50% w/w pure so that unwanted effects due to possible by-products of their formation are reduced. (The % purity is calculated on a solvent free basis since it is conventional to prepare and isolate the compound of the formula (V) in an organic solvent.)
  • the present invention also provides a process for the preparation of the compounds of the formula (IV) which process comprises the hydrogenation of the compound of the formula (V) in the presence of a palladium or platinum catalyst.
  • reaction will be carried out in an inert organic solvent, for example in tetrahydrofuran or other similar solvent.
  • the hydrogenation reaction normally produces a mixture of E- and Z-isomers of the compound of the formula (IV). These isomers may be separated chromatographically if desired, for example by preparative high pressure liquid chromatography or column chromatography.
  • the hydrogenation of the compound of the formula (V) exemplifies the 1,4-addition reactions (in this case the 1,4-addition of a molecule of hydrogen) to which the compound of the formula (V) is susceptible.
  • This invention also provides a process for the preparation of the compound of the formula (V) which process comprises the reaction of clavulanic acid with either
  • R' examples include alkyl of 1-6 carbon atoms such as the groups of the formula -CH 2 ) q CH 3 wherein q is 1, 2, 3, 4 or 5. Most suitably q is 1 or
  • Suitable compounds of the formula (VII) include those wherein R 2 and R 3 are independently selected from benzyl, phenyl or alkyl groups of up to 6 carbon atoms. Particularly suitable R 2 and R represent the same moiety, for example both represent methyl, ethyl, propyl or butyl groups. Particularly suitable compounds of the formula (VII) include those therein R 2 and R 3 each represent an ethyl or t-butyl group.
  • Suitable compounds of the formula (VIII) include those therein R 4 , R 5 and R 6 are selected from methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl and methoxyphenyl groups. It is generally convenient that R 4 , R 5 and R 6 each represent the same moiety. Particularly suitable compounds of the formula (VIII) include triphenylphosphine, trimethylphosphite and triethylphosphite. A preferred compound of the formula (VIII) is triphenylphosphine.
  • the compound of the formula (V) tends to polymerise when free of solvent at room temperature so that it must either be stored in solution (optionally with hydroquinone) or at a low temperature. Preferably the compound of the formula (V) is used shortly after its preparation.
  • the reaction of clavulanic acid with the compound of the formula (VI) takes place in an inert organic solvent such as tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, tetrahydrofuran/toluene, tetra- hydrofuran/benzene or solvents of similar properties.
  • an inert organic solvent such as tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, tetrahydrofuran/toluene, tetra- hydrofuran/benzene or solvents of similar properties.
  • the reaction will generally take place at a non-extreme temperature such as -30°C to 40°C, for example 0°C to 25°C. It is generally most convenient to carry out the reaction at ambient temperature.
  • reaction of clavulanic acid with the compounds of the formula (VII) and (VIII) will take place in an inert organic solvent such.as tetrahydrofuran, 1,2-dimethoxyethane or solvent of similar properties.
  • the reaction will generally take place at 10°C to 40°C.
  • reaction medium is maintained free of hydroxylic materials other than clavulanic acid.
  • the present invention also provides a process for the preparation of a compound of the formula (V) which comprises maintaining a salt of an 0-acyl derivative of clavulanic acid at a non-extreme temperature in solution in an aqueous ether.
  • Suitable derivatives of clavulanic acid for use in this process include the acetyl derivative, for example as its potassium salt.
  • Acylated derivatives of clavulanic acid are described in Belgian Patent N0. 834,645.
  • the decomposition process tends to be slow and low yielding so it is desirable to warm the reaction to above ambient temperature, for example to 30-45°C, to encourage reaction.
  • Suitable solvents include aqueous tetrahydrofuran and aqueous 1,2-dimethoxyethane.
  • the present invention also provides pharmaceutical compositions which comprise a compound of the formula (I) and a pharmaceutically acceptable carrier.
  • composition will comprise a compound of the formula (IV) which may be in the form of the Z-isomer, the E-isomer or, less favourably as a mixture thereof.
  • compositions of the invention include those in a form adapted for oral or parenteral use and may be used for the treatment of the infection in mammals including humans.
  • the infections to be treated include those due to gram-positive bacteria and gram-negative bacteria and less commonly fungal infections.
  • compositions of this invention include tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, colours, flavours, preservatives and the like in accordance with conventionl pharmaceutical practice in the manner well understood by those skilled in the art of formulating liquid or oily pharmaceuticals.
  • Injectable or infusable compositions of a compound of the formula (I) are suitable.
  • a sterile compound of the formula (I) may be sealed in a glass vial, bottle or the like and made up into an injectable solution by the addition of aqueous ethanol or the like.
  • Unit dose compositions comprising a compound of the formula (I) adapted for oral administration form a further preferred compositions aspect of this invention.
  • Particularly favoured forms include soft gelatin capsules (with polyethyleneglycol) or other solid forms in which the compound of the formula (I) is absorbed on an inert carrier such as lactose, starch or the like.
  • the compound of the formula (I) may be present in the composition as sole therapeutic agent or it may be present together with other therapeutic agents such as a a-lactam antibiotic.
  • Suitable 8-lactam antibiotics for inclusion in the compositions of this invention include benzylpenicillin, phenoxymethyl- penicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cycla- cillin, cefatriazine, pirbenicillin, d-sulphonyloxy- benzylpenicillin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, nafate, cephapirin, cephradine, 4-hydroxy-cephalexin, cefaparole, cephalo- glycine and other well known penicillins and cephalosporins or pro-drugs therefore.
  • the composition will be adapted for parenteral administration.
  • the ratio of a compound of the formula (I) present to the other antibacterial agent may vary over a wide range of ratios, for example 3:1 to 1:10 and advantageously may be from 1:1 to 1:8, for example, 1:2, 1:3, 1:4, 1:5 or 1:6.
  • the total quantity of compound of the formula (II) in any unit dosage form will normally be between 25 and 1000 mg and will usually be between 50 and 500 mg, for example 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 and mastitis in cattle.
  • Normally between 50 and 1000 mg of the compounds of this invention will be administered each day of treatment but more usually between 100 and 750 mg of the compounds of the invention will be administered per day, for example as 1-6 doses, more usually 2-4 doses.
  • the concentrated solution was made up to 70 ml using dry toluene. From an aliquot (8 ml) of this solution the solvent was removed under reduced pressure to yield a yellow oil (55 mg) which was immediately redissolved in CDCl3 (1 ml). An nmr spectrum of this solution showed absorptions for only the title compound, dimethylformamide, and toluene. On the basis of this the estimated yield of title compound was 2.9 mmole (83%).
  • Benzyl 9-O-acetylclavulanate (90 mg., 0.27 mmole) was dissolved in tetrahydrofuran (10 ml) and the solution was shaken with 10% palladium-on-charcoal (30 mg) under one atmosphere of hydrogen at room temperature for 20 minutes. The catalyst was removed by filtration and was washed with tetrahydrofuran. The filtrate was concentrated to 5 ml by evaporation of solvent under reduced pressure to yield a solution of 9-O-acetyl- clavulanic acid in tetrahydrofuran.
  • Example 4 The product of Example 4(60 mg) was subjected to high pressure liquid chromatography under the following conditions:
  • the Z-isomer under these conditions had a retention time of 10 minutes which allowed easy separation from the E-isomer which had a 12 minute retention time.
  • the isomers were obtained by evaporation of the solvent: Z-isomer (33 mg), E-isomer (8 mg).
  • Example 1 The compound from Example 1 was a potent inhibitor of ⁇ -lactamase enzymes as illustrated in the following Table. I 50 values were determined using the process described in Belgium Patent No. 827,926..
  • the Z-isomer also synergised the antibacterial activity of caphaloridine.
  • the M.I.C. of cephaloridine against E. coli JT410 was lowered from 125 ⁇ g/ml to 8 ⁇ g/ml.
  • the E-izomer is able to synergise the antibacterial activity of ampicillin.
  • the M.I.C. of ampicillin against Staph. aureus Russell was lowered from 500 ⁇ g/ml to 3.1 ⁇ g/ml.
  • the Z-isomer is able to inhibit the growth of Candida albicans.
  • a loading of 250 ug of the Z-isomer on a paper tape which was contacted with a blood agar base plate seeded with Candida albicans BRL 1003 and incubated at 28°C for 24 hours produced a zone of inhibition with diameter 22.1 mm.
  • Example 4 The compound from Example 4 (containing 26% E-isomer and 62% Z-isomer) was tested for acute toxicity in mice as described below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (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 And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP78300054A 1977-07-23 1978-06-20 Composés béta-lactame, préparation et utilisation dans compositions pharmaceutiques et comme produits chimiques intermédiaires Expired EP0000615B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB3101577 1977-07-23
GB3101577 1977-07-23

Publications (2)

Publication Number Publication Date
EP0000615A1 true EP0000615A1 (fr) 1979-02-07
EP0000615B1 EP0000615B1 (fr) 1981-04-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300054A Expired EP0000615B1 (fr) 1977-07-23 1978-06-20 Composés béta-lactame, préparation et utilisation dans compositions pharmaceutiques et comme produits chimiques intermédiaires

Country Status (5)

Country Link
US (1) US4145430A (fr)
EP (1) EP0000615B1 (fr)
JP (1) JPS5424890A (fr)
DE (1) DE2860640D1 (fr)
IT (1) IT1105922B (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE850593A (fr) * 1976-01-27 1977-07-20 Beecham Group Ltd Antibiotiques a cycle beta-lactame
BE850942A (fr) * 1976-02-04 1977-08-01 Beecham Group Ltd Composes contenant un cycle beta-lactame
BE855467A (fr) * 1976-06-08 1977-12-07 Glaxo Lab Ltd Clavames substitues et leur preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE850593A (fr) * 1976-01-27 1977-07-20 Beecham Group Ltd Antibiotiques a cycle beta-lactame
BE850942A (fr) * 1976-02-04 1977-08-01 Beecham Group Ltd Composes contenant un cycle beta-lactame
BE855467A (fr) * 1976-06-08 1977-12-07 Glaxo Lab Ltd Clavames substitues et leur preparation

Also Published As

Publication number Publication date
DE2860640D1 (en) 1981-08-06
EP0000615B1 (fr) 1981-04-29
JPS5424890A (en) 1979-02-24
US4145430A (en) 1979-03-20
IT7850416A0 (it) 1978-07-21
IT1105922B (it) 1985-11-11

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