EP0000526B1 - Pharmazeutische Präparate die Penicilline oder Cephalosporine und Clavulansäure enthalten, Verfahren zu deren Herstellung - Google Patents

Pharmazeutische Präparate die Penicilline oder Cephalosporine und Clavulansäure enthalten, Verfahren zu deren Herstellung Download PDF

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Publication number
EP0000526B1
EP0000526B1 EP78100407A EP78100407A EP0000526B1 EP 0000526 B1 EP0000526 B1 EP 0000526B1 EP 78100407 A EP78100407 A EP 78100407A EP 78100407 A EP78100407 A EP 78100407A EP 0000526 B1 EP0000526 B1 EP 0000526B1
Authority
EP
European Patent Office
Prior art keywords
carbonylamino
oxo
imidazolidin
methoxy
acid
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.)
Expired
Application number
EP78100407A
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German (de)
English (en)
French (fr)
Other versions
EP0000526A1 (de
Inventor
Karl Georg Dr. Metzger
Hans-Bodo Dr. König
Wilfried Dr. Schröck
Michael Dr. Preiss
Peter Dr. Feyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Publication of EP0000526A1 publication Critical patent/EP0000526A1/de
Application granted granted Critical
Publication of EP0000526B1 publication Critical patent/EP0000526B1/de
Expired legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M2201/00—Inorganic compounds or elements as ingredients in lubricant compositions
    • C10M2201/02—Water
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M2209/00—Organic macromolecular compounds containing oxygen as ingredients in lubricant compositions
    • C10M2209/10—Macromolecular compoundss obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C10M2209/103—Polyethers, i.e. containing di- or higher polyoxyalkylene groups
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M2209/00—Organic macromolecular compounds containing oxygen as ingredients in lubricant compositions
    • C10M2209/10—Macromolecular compoundss obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C10M2209/103—Polyethers, i.e. containing di- or higher polyoxyalkylene groups
    • C10M2209/104—Polyethers, i.e. containing di- or higher polyoxyalkylene groups of alkylene oxides containing two carbon atoms only
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M2219/00—Organic non-macromolecular compounds containing sulfur, selenium or tellurium as ingredients in lubricant compositions
    • C10M2219/04—Organic non-macromolecular compounds containing sulfur, selenium or tellurium as ingredients in lubricant compositions containing sulfur-to-oxygen bonds, i.e. sulfones, sulfoxides
    • C10M2219/044—Sulfonic acids, Derivatives thereof, e.g. neutral salts
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
    • C10N2020/00—Specified physical or chemical properties or characteristics, i.e. function, of component of lubricating compositions
    • C10N2020/01—Physico-chemical properties
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
    • C10N2040/00—Specified use or application for which the lubricating composition is intended
    • C10N2040/20—Metal working

Definitions

  • the present invention relates to new antibiotic synergistic active substance combinations of ⁇ -lactam antibiotics on the one hand and the clavulanic acid acting as a synergist or its pharmaceutically usable salts or esters, in particular its sodium salt, on the other hand.
  • clavulanic acid can have an inhibitory effect on ⁇ -lactamases. It is also known and experimentally proven that the minimum inhibitory concentrations of ampicillin, amoxicillin, carbenicillin and benzylpenicillin are significantly reduced by clavulanic acid as a synergist (see DT-OS 2 517 316, examples 42 and 44).
  • Examples of ⁇ -lactam antibiotics of the formula I which are preferably used as component (1) are: D - ⁇ [(imidazolidin - 2 - oxo - 1 - yl) - carbonylamino] - benzyl - penicillin, D - ⁇ [(3 - methylsulfonyl - 2 - oxo - imidazolidin - 1 - yl) - carbonylamino] - benzylpenicillin, D - ⁇ [(4 - Methyl - 5 - oxo - 1,2 - diazole - 3 - in - 2 - yl) - carbonylamino] - benzylpenicillin, D - a [(3 - furfurylidenamino - 2 - oxo - imidazolidin - 1 - yl) - carbonylamino] - p-hydroxy
  • ⁇ -lactam antibiotics mentioned and their pharmaceutically usable salts are known [see. e.g. DT-OS 2 104 580, DT-OS 2 152 967, DT-OS 2 525 541, DT-OS 2 525 541.2 519 400, U.S. Patent 3,974,288].
  • Clavulanic acid as well as its pharmaceutically usable salts and in vivo cleavable esters are described in DT-OS 2 517 316.
  • the antibacterial activity of the active ingredient combination according to the invention is significantly higher than the sum of the effects of the individual active ingredients. So there is a real synergistic effect.
  • the active ingredient combinations thus represent a valuable addition to the pharmaceutical industry.
  • the weight ratios of the active ingredients (1) and (2) can vary within relatively large ranges, namely from the ratio (1) to (2) such as 1 to 10 to the ratio (1) to (2) such as 10 to 1.
  • the invention further relates to medicaments containing an active ingredient combination consisting of a penicillin or cephalosporin of the general formula I or a pharmaceutically acceptable salt thereof and clavulanic acid or its pharmaceutically acceptable salts or esters.
  • the sodium salts are preferred.
  • esters of clavulanic acid the methyl and ethyl esters are preferred.
  • the present invention includes those pharmaceutical formulations that can be used parenterally, locally or orally.
  • Parenteral and oral, very particularly parenteral, forms of use are preferred.
  • the use forms preferably comprise sterile formulations suitable for injection or infusion purposes.
  • clavulanic acid or its esters or salts e.g. their sodium salt
  • penicillins or cephalosporins e.g. D - a - [(3 - methylsulfonyl - 2 - oxo - imidazolidin - 1 - yl) - carbonylamino] - benzylpenicillin - sodium and D - ⁇ - [(imidazolidin - 2 - oxo - 1 - yl) - carbonylamino] - benzylpenicillin.
  • the pharmaceuticals according to the invention have a strong tolerance to a strong antimicrobial activity.
  • the pharmaceuticals according to the invention are active against a very broad spectrum of microorganisms. With their help e.g. Gram-negative and gram-positive bacteria and bacteria-like microorganisms are combated and the diseases caused by these pathogens are prevented, improved and / or treated.
  • the active substance mixtures according to the invention are particularly effective against bacteria and bacteria similar microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.
  • Bacteroidacea such as Bacteroides bacteria, e.g. Bacteroides fragilis.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, clavulanic acid and one or more penicillins or cephalosporins according to the invention, and processes for the preparation of these preparations.
  • the present invention also includes pharmaceutical preparations in dosage units.
  • the preparations are in the form of individual parts. e.g. Tablets, dragees, capsules, pills, suppositories and ampoules are available, the active ingredient mixture of which corresponds to a fraction or a multiple of a single dose.
  • the dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
  • a single dose preferably receives the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes are preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. Glycerin, (d) disintegrant, e.g. Agar-agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g.
  • fillers and extenders e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone
  • quaternary ammonium compounds (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite and (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • wetting agents e.g. Cetyl alcohol, glycerol monostearate
  • adsorbent e.g. Kaolin and bentonite
  • lubricants e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • the tablets, dragees, capsules, pills and granules can be provided with the usual coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as embedding compounds, for example Polymer substances and waxes can be used.
  • the active compound mixtures according to the invention can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
  • suppositories can contain the customary water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat, and higher esters (for example C 14 alcohol with C 16 fatty acid) and mixtures of these substances.
  • customary water-soluble or water-insoluble carriers for example polyethylene glycols, fats, for example cocoa fat, and higher esters (for example C 14 alcohol with C 16 fatty acid) and mixtures of these substances.
  • ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • carriers e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • powders and sprays can contain the usual carriers, e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays can also use the usual blowing agents e.g. Contain chlorofluorocarbons.
  • solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formate, fatty alcohol ester fatty acid, tetrahydrofuran desorbate or mixtures of these substances.
  • solvents e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil
  • solutions and emulsions can also be in sterile and blood isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures or substances.
  • liquid diluents e.g. Water, ethyl alcohol, propylene glycol
  • suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures or substances.
  • the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. Peppermint oil and eucalyptus oil, and sweeteners e.g. Contain saccharin.
  • colorants e.g. Peppermint oil and eucalyptus oil
  • sweeteners e.g. Contain saccharin.
  • the therapeutically active combinations of active ingredients should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95 percent by weight of the total mixture.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active ingredient mixture with pharmaceutically usable carriers and additives.
  • the active substance mixtures or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously and intramuscularly.
  • a single dose contains the active ingredient mixture (s) according to the invention preferably in amounts of about 0.1 to about 20 g, in particular 0.1 to 1.5 g / person.
  • the doses mentioned may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place.
  • the new active ingredient mixtures When used as a feed additive, the new active ingredient mixtures can be given in the usual way together with the feed or with feed preparations or with the drinking water. This prevents infection by gram-negative or gram-positive bacteria and also improves the utilization of the feed.
  • the new drug combinations are characterized by strong antibacterial effects, which have been tested in vivo and in vitro, and by oral resorbability.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP78100407A 1977-07-26 1978-07-17 Pharmazeutische Präparate die Penicilline oder Cephalosporine und Clavulansäure enthalten, Verfahren zu deren Herstellung Expired EP0000526B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2733642 1977-07-26
DE19772733642 DE2733642A1 (de) 1977-07-26 1977-07-26 Antibiotische mittel

Publications (2)

Publication Number Publication Date
EP0000526A1 EP0000526A1 (de) 1979-02-07
EP0000526B1 true EP0000526B1 (de) 1980-11-12

Family

ID=6014859

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100407A Expired EP0000526B1 (de) 1977-07-26 1978-07-17 Pharmazeutische Präparate die Penicilline oder Cephalosporine und Clavulansäure enthalten, Verfahren zu deren Herstellung

Country Status (8)

Country Link
EP (1) EP0000526B1 (da)
JP (1) JPS5435219A (da)
AT (1) AT361618B (da)
DE (2) DE2733642A1 (da)
DK (1) DK330478A (da)
ES (1) ES471984A1 (da)
IL (1) IL55206A (da)
IT (1) IT1097330B (da)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0008905B1 (en) * 1978-09-06 1983-02-16 Beecham Group Plc Pharmaceutical compositions containing two beta-lactam derivatives
EP0049968A1 (en) * 1980-10-15 1982-04-21 Beecham Group Plc Pharmaceutical compositions
DE3039243A1 (de) * 1980-10-17 1982-05-27 Dr. Karl Thomae Gmbh, 7950 Biberach Antibiotisch wirksame arzneimittelkombination
JPS59104319A (ja) * 1982-12-06 1984-06-16 Chugai Pharmaceut Co Ltd 抗菌剤およびそのキツト
JPS60146825A (ja) * 1984-01-10 1985-08-02 Asahi Chem Ind Co Ltd 経口医薬製剤
AT413015B (de) * 2001-04-12 2005-10-15 Sandoz Ag Tablette enthaltend das k-salz der 3-(2-hydroxyethyliden)-7-oxo-4-oxa-1- azabicyclo(3.2.0)heptan-2 carbonsäure in hydrophobisierter form

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2648770A1 (de) * 1975-10-31 1977-05-05 Beecham Group Ltd Penicillin-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel

Also Published As

Publication number Publication date
AT361618B (de) 1981-03-25
DE2860275D1 (en) 1981-02-05
ATA534478A (de) 1980-08-15
EP0000526A1 (de) 1979-02-07
DE2733642A1 (de) 1979-02-08
IT7826041A0 (it) 1978-07-24
IT1097330B (it) 1985-08-31
ES471984A1 (es) 1979-10-16
IL55206A (en) 1981-12-31
DK330478A (da) 1979-03-02
IL55206A0 (en) 1978-09-29
JPS5435219A (en) 1979-03-15

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