Classifications

• • 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
• • 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 penicillins, processes for their preparation and their use as medicaments, in particular as antibacterial agents and as agents for promoting the growth and improving the feed conversion in animals.
• the penicillins according to the invention have a broad, antibacterial activity. They are effective against gram-negative and gram-positive germs. Furthermore, the compounds according to the invention show great stability against ⁇ -lactamase or high activity against those bacteria which form ⁇ -lactamase. The penicillins according to the invention furthermore have the property of also protecting other penicillins from being destroyed by ⁇ -lactamase.
• Pharmaceutically usable salts of the compounds of formula (I) are salts of these compounds with inorganic and organic bases on the acidic carboxyl group or the acidic carboxyl and sulfonic acid groups. All bases normally used in pharmaceutical chemistry, in particular 1ft in the chemistry of antibiotics, can be used as bases for this purpose.
• inorganic bases are: alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates and alkali metal hydrogen carbonates, such as sodium and potassium hydroxide, calcium and magnesium hydroxide, sodium and potassium carbonate, calcium carbonate, sodium and potassium hydrogen carbonate; Aluminum hydroxide and ammonium hydroxide.
• Primary, secondary and tertiary aliphatic amines and heterocyclic amines can be used as organic amines.
• organic amines examples include: di- and tri-lower alkylamines, for example diethylamine, triethylamine, tri- ⁇ -hydroxyethylamine, procain, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl-ß-phenylethylamine, N-methyl and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N, N'-bis-dehydroabietylethylenediamine, N-lower alkyl piperidine.
• So-called basic amino acids such as lysine or arginine can also advantageously be used as bases.
• Particularly preferred salts are the sodium salts.
• R 1 , R 2 , R 3 and R 4 Possible substituents for R 1 , R 2 , R 3 and R 4 as alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl and optionally heterocyclylalkyl radical are halogen, preferably fluorine, chlorine and bromine, preferably fluorine and Chlorine, lower alkoxy with preferably 1 or 2 carbon atoms, protected hydroxyl, amino, lower alkylamino groups with preferably 1 or 2 carbon atoms and carbonyl and sulfonic acid groups, di-lower alkylamino groups with preferably 2 to 4 carbon atoms, keto groups and ester groups with preferably 2 or 3 carbon atoms, Carbonyl and sulfamyl residues, heterocyclic residues such as furanyl, thienyl, pyrrolyl and pyridinyl.
• halogen preferably fluorine, chlorine and bromine, preferably fluorine
• R 1 , R 2 , R 3 and R 4 as heterocyclic radical or heterocyclylalkyl radical are alkyl having preferably 1 or 2 carbon atoms or methyl or ethyl groups substituted by a carboxyl or sulfonic acid group.
• compounds which transmit positive chlorine such as t-butyl hypochlorite or chloroacetamide, are preferably used as the N-halogenating agent.
• Suitable bases are complex, and simple, but preferably simple alkali and alkaline earth hydrides, organometallic compounds and Grignard compounds.
• Examples include: lithium hydride, sodium hydride, butyllithium, phenyl lithium, alkyl magnesium bromides, for example methyl magnesium bromide, or other known acid binders such as alkali and alkaline earth metal alcoholates or carbonates, alkali and alkaline earth metal bicarbonates or oxides such as sodium bicarbonate or others
• Acid binders such as borax or open-chain or cyclic organic bases such as trialkylamines or aralkylamines or cyclic amidines such as 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (DBN) or 2,3,4 , 6,7,8,9.10-Octahydro-pyrimido [1,2-a] azepim (DBU).
• Suitable solvents are open-chain or cyclic ethers, aliphatic and aromatic hydrocarbons or halogenated hydrocarbons or the alcohols R 1 OH. Tetrahydrofuran is particularly suitable.
• reaction temperatures should be kept below 0 ° C if possible, preferably between -100 ° C and -45 ° C.
• 1 mol equivalent of the compound of the general formula V is added to the mixture of preferably 3 to 8 mol equivalents of base, 2 to over (if it itself serves as a solvent) 100 mol equivalents of the alcohol R 1 OH and the solvent at the specified low temperatures and then immediately 1 to 5, preferably 1 to 2 mol equivalent halogenating agent (for example t-butyl hypochlorite) added.
• the reaction time is generally about 10 minutes to several hours at -70 ° C.
• the active compounds according to the invention have a strong antimicrobial activity. These properties enable their use as active substances in medicine and as substances for the preservation of inorganic and organic materials, in particular of all kinds of organic materials, e.g. Polymers, lubricants, paints, fibers, leather, paper and wood, food and water.
• organic materials e.g. Polymers, lubricants, paints, fibers, leather, paper and wood, food and water.
• the active compounds 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 cured.
• the active compounds according to the invention are particularly effective against bacteria and bacterial-like 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.
• local and / or systemic diseases that are caused by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:
• Micrococcaceae such as staphylococci, e.g. Staphylococcus aureus, Staph. epidermidis, Staph. aerogenes (Staph. Staphylococcus);
• Lactobacteriaceae such as streptococci, e.g. Streptococcus pyogenes, ⁇ - or ⁇ -hemolytic streptococci, non ( ⁇ -) - hemolytic streptococci, Str.viridans, Str. Faccalis (enterococci), Str.agalactiae, Str. Lactis, Str. Equi, Str. Anaerobis and Diplococcus pneumoniae (Pneumococcus) (Str. - Streptococcus);
• streptococci e.g. Streptococcus pyogenes, ⁇ - or ⁇ -hemolytic streptococci, non ( ⁇ -) - hemolytic streptococci, Str.viridans, Str. Faccalis (enterococci), Str.agalactiae, Str. Lactis, Str. Equi, Str. Anaerobis and Diplococcus pneumoniae (Pneumococcus)
• Neisseriaceae such as Neisseria, for example Neisseria gonorrhoeae (gonococci), N. meningitidis ( M eningococci), N.catarrhalis and N.flava (N. - Neisseris);
• Corynebacteriaceae such as Corynebacteria e.g. Corynebacterium diphtheriae, C.pyogenes, C.diphtheroides, C.acnes, C.parvum, C.bovis, C.renale, C.ovis,
• Salmonella bacteria e.g. B. salmonella paratyphi A and B, S. typhi, S.ente
• Bacillaceae such as aerobic spore formers e.g. Bacillus anthracis, B. subtilis, B. cereus (B. - Bacillus), anaerobic spore-forming clostridia, e.g. Clostridium perfrigens, Cl. tetani, cl. botulinum (Cl. Clostridium);
• the present invention includes pharmaceutical preparations which, in addition to inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and methods for producing these preparations.
• the present invention also includes pharmaceutical preparations in dosage units.
• the preparations in the form of individual parts e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are available, the active ingredient content 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 contains 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.
• composition auxiliaries 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, ointments, gels, creams, lotions, powders and sprays may be mentioned as 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. B.
• 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 customary 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 materials, for example Polymer substances and waxes can be used.
• the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
• suppositories can contain the usual 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.
• 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 excipients in addition to the active ingredient (s), e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
• Sprays can also use the usual propellants 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, xylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glyceryl formaldehyde, fatty acid fatty acid, fatty acid, fatty alcohol of sorbitan or mixtures of these substances.
• solvents e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, xylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn 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 hydroxide, 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 hydroxide, bentonite, agar and tragacanth or mixtures or substances.
• the formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptus oil and sweeteners e.g. Contain saccharin.
• the therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95 percent by weight of the total mixture.
• the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.
• the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances after the carrier substance or substances.
• the present invention also includes the use of the active compounds according to the invention and of pharmaceutical preparations which contain one or more active compounds according to the invention in human and veterinary medicine in preventing, ameliorating and / or curing the diseases mentioned above.
• the active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously and intramuscularly.
• the active ingredient (s) according to the invention in total amounts of about 6 to about 800, preferably 15 to 300 mg / kg body weight per 24 hours, optionally in the form of several For example, to administer 3 individual doses to achieve the desired results.
• a single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 2 to about 300, in particular 10 to 150 mg / kg of body weight.
• the new compounds 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 and promotes growth.
• the invention accordingly also relates to an animal feed that contains the new penicillins in the presence of carriers or additives that can be used for animal nutrition, and to a method for producing such an agent.
• the new penicillins are characterized by strong antibacterial effects, which have been tested in vivo and in vitro, and by oral resorbability.
• penicillins according to the invention can also be combined, for example, with aminoglycoside antibiotics such as gentamicin, sisomicin, kanamicin, amikacin or tobramicin for the purpose of broadening the activity spectrum or increasing the activity.
• aminoglycoside antibiotics such as gentamicin, sisomicin, kanamicin, amikacin or tobramicin for the purpose of broadening the activity spectrum or increasing the activity.
• Examples two, five and eight, which can be regarded as typical representatives of the compounds according to the invention, were diluted with Müller-Hinton nutrient broth to a content of 100 / ⁇ g / ml. There were 1 x 10 5 to 2 x 10 5 bacteria per milliliter in the nutrient solution. The tubes with this approach were each incubated for 24 hours and then the degree of turbidity was determined. Freedom from turbidity indicates effect. At the dosage of 100 ⁇ g / ml, the following bacterial cultures were free of turbidity (sp. Species):
• the ED 100 is the dose at which 100% of the infected animals survive after 24 hours.
• the thin layer chromatogram shows a practically clean connection. (The following was used as the solvent system:
• TLC still contains some starting material, otherwise clean compound (approx. 90%) with a significantly higher R f value than the starting compound.
• the alcoholate solution is expediently prepared beforehand separately from butyllithium and i-propanol and then added to the cooled THF solution.
• the alcoholate solution is prepared again beforehand (see Example 5)
• the sodium salt was precipitated by adding the concentrated ethyl acetate solution after the acidic extraction) to an ethereal / methanolic solution of sodium, 2-ethylhexanoate, which contained 2/3 of the theoretical amount of sodium 2-ethylhexanoate, with vigorous stirring.
• the NMR spectrum corresponds to that from Example 11, except for the modified aromatic proton signals.
• TLC contains approx. 90%, 2 small impurities, IR spectrum: 1760 cm -1

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1977
  • 1977-07-15 DE DE19772732104 patent/DE2732104A1/de active Pending
• 1978
  • 1978-06-29 US US05/920,505 patent/US4218451A/en not_active Expired - Lifetime
  • 1978-07-07 EP EP78100322A patent/EP0000380A1/fr not_active Withdrawn
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