Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • 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
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • 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

• the present invention relates to new ⁇ -lactam compounds, processes for their preparation and their use as medicaments, in particular as antimicrobial agents and as agents for promoting the growth and improving the use of feed in animals.
• novel ⁇ -lactam antibiotics according to the invention differ chemically from the known compounds of the prior art, above all by the a-position heterocyclic ring in the acyl side chain, which surprisingly shows an improved activity.
• the compounds according to the invention have a broad antibacterial action, i.e. Effect against several bacterial families in the gram-negative area and against ⁇ -lactamase formers. Because of their strong antibacterial properties and because of their. Ability to improve the growth and feed conversion in animals, the compounds of the invention thus represent an enrichment of the technology.
• lower alkyl means everywhere, also in connection with 1 other atoms or groups (for example lower alkoxy, HCON- (lower alkyl), etc.) straight-chain or branched alkyl with preferably 1 to 6, in particular 1 to 4 Carbon atoms. Examples of optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl may be mentioned.
• “Lower alkyl” can be substituted by 1 to 5, in particular 1 to 3, identical or different halogen atoms, the halogen atoms preferably being fluorine, chlorine and bromine, in particular fluorine and chlorine. Examples include trifluoromethyl, chlorodifluoromethyl, bromomethyl, 2,2,2-trifluoroethyl and pentafluoroethyl.
• alkyl in alkyl-CO-O- preferably denotes alkyl having 1 to 4, in particular 1 or 2, carbon atoms. Examples include methyl and ethyl, with methyl being particularly preferred.
• the heterocyclic ring Het in ⁇ S ⁇ Het (definition of T) consists of 5 or 6 ring members and contains 1 to 4, preferably 1 to 3 identical or different heteroatoms, oxygen, sulfur and nitrogen being heteroatoms.
• the heterocyclic ring is preferably unsaturated and particularly preferably contains 2 double bonds.
• the heterocyclic ring can contain one or more, preferably 1 or 2, in particular one, substituent.
• substituents are: halogen, such as fluorine, chlorine and bromine, preferably chlorine and bromine, amino, Niederalkylamino, Diniederalkylamino, Niederalkyl, Cycloalkyl (with 3 to 7, preferably 5 or 6 carbon atoms in the cycloalkyl part), Niederalkyloxy (meaning of "Niederalkyl” see above), Trifluormethyl, Phenyl, Benzyl and Acylaminomit preferably 2 to 5, in particular 2 or 3 carbon atoms .
• the -S-phenyl radical in the definition of T can carry one or more, preferably 1 to 3, in particular 1 or 2 identical or different substituents, preference being given to those which are listed above as possible substituents for the -S-Het radical .
• R in the meaning of lower alkoxy preferably denotes an alkoxy group having 1 to 6, in particular 1 to 4, carbon atoms, but in particular methoxy or ethoxy.
• Halogen W represents fluorine, chlorine and bromine, preferably bromine or chlorine, in particular chlorine.
• Nucleofugic leaving groups in the definition of W are to be understood as meaning all nucleofugic groups usually used in organic chemistry, and above all those which are described in Angewandte Chemie, 81 (1969), page 543.
• the compounds of the formula (I) are often obtained in the form of salts during manufacture or can be easily converted into them.
• the pharmaceutically usable salts of the compounds of the formula (I) are particularly important for use as medicaments.
• 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 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, e.g. Diethylamine, triethylamine, tri-J3-hydroxyethylamine, procain, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl-ß-phenyl-ethylamine, N-methyl- and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N, N ' -Bis-dehydroabietylethylenediamine, N-lower alkylpiperidine.
• So-called basic amino acids such as lysine or arginine can also advantageously be used as bases.
• Particularly preferred salts are the sodium salts.
• Salts of the compounds of the formula II which can be used are preferably salts with bases which are listed as being suitable for salt formation with compounds of the formula.
• the sodium salts are particularly preferred.
• the compounds of general formula III used as starting materials can be obtained by known methods. They can be obtained, for example, in the following way (see also JACS 78 (1956) 5349):
• Phosgenation is also possible without prior silylation directly in an inert organic solvent in the presence of a base.
• the compounds of formula 11 used as starting materials are known or can be prepared by methods known per se (cf. DOS 2 555 159).
• Suitable diluents in the process according to the invention are water and all inert organic solvents, preferably those which are miscible with water. These primarily include lower dialkyl ketones, e.g. Acetone, methyl ethyl ketone, cyclic ether, e.g. Tetrahydrofuran and dioxane; Nitriles, e.g. Acetonitrile; lower dialkylformamides, e.g. Dimethylformamide; lower alkyl alcohols, e.g. Ethanol and isopropanol as well as dimethyl sulfoxide. These solvents can also be used in mixtures with one another and in any mixtures of one or more of these solvents with water.
• solvents can also be used in mixtures with one another and in any mixtures of one or more of these solvents with water.
• the process according to the invention can therefore be carried out in the presence of: (a) exclusively water, (b) exclusively one or more organic solvents or (c) water and one or more organic solvents. If a pH measurement is possible during the reaction according to the invention due to the presence of water, the pH of the reaction mixture is preferably kept between 6.5 to 7.5 by adding bases or by using buffer mixtures. However, the process according to the invention can also be carried out very well in another pH range, for example between 4.5 and 9.0 or at pH 2.0 to 4.5. It is also possible to carry out the reaction in water-immiscible solvents, e.g.
• halogenated hydrocarbons such as chloroform or methylene chloride
• organic bases preferably lower alkylamines, e.g. Triethylamine, diethylamine or cyclic bases, e.g. Perform N-ethyl piperidine.
• the reaction can be carried out in a mixture of water and a water-immiscible solvent, e.g.
• Lower alkyl ethers such as diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride; Carbon disulfide; Isobutyl methyl ketone; Esters such as ethyl acetate; aromatic hydrocarbons such as benzene, whereby it is advisable to stir vigorously and to adjust the pH by adding a base or using conventional buffer solutions, e.g. Phosphate, acetate or citrate buffers, between 4.5 and 9.0 or e.g. Keep 2.0 and 4.5.
• the reaction can also be carried out in water alone in the absence of organic solvents in the presence of an organic or inorganic base or with the addition of customary buffer substances.
• Acid binders customarily used in the chemistry of antibiotics can be used as acid binders. These include inorganic bases and organic bases, which, for. B. are difficult to acylate due to steric hindrance. Sodium and potassium hydroxide may be mentioned as examples of inorganic bases. Practically all open-chain or cyclic amines which are difficult or difficult to acylate and also heteroaromatic bases are suitable as organic bases. Examples of bases which may be mentioned are tertiary amines, preferably lower alkylamines, for example triethylamine and / or cyclic bases, for example pyridine, and dicyclohexylamine as secondary amine which is difficult to acylate.
• the addition of a base is only necessary if acidic compounds are formed during the reaction, e.g. in the case where W is halogen or azide.
• reaction temperatures can be varied within a wide range. Generally one works between about -20 ° C and about + 50 ° C, preferably between 0 and + 20 ° C. As with most chemical reactions, higher or lower temperatures can in principle be used.
• the reaction can be carried out under normal pressure, but also under reduced or elevated pressure. Generally one works at normal pressure.
• the proportions of the reactants of the formulas (11) and (111) can be varied within wide limits without the result being adversely affected.
• the starting materials can e.g. are reacted with one another in equimolecular amounts.
• the reactants of the general formula 11 can be used in an excess of 0.1 to 0.3 mol equivalents, and thereby a lower decomposition of the reactants of the general formula III in a water-containing solvent mixture can be achieved.
• the excess of the reactants of the general formula 11 can be easily removed because of the good solubility in aqueous mineral acids when working up the reaction mixture.
• the reactants of the general formula III with an excess of, for example, 0.1 to 1.0 molar equivalents. This will make the Reaction partners of the general formula II are better utilized and the decomposition of the reactants of the general formula III taking place as a side reaction in water-containing solvents is compensated. Since the compounds of the general formula III added in excess quickly convert into neutral nitrogen-containing heterocycles in water which can be easily removed, the purity of the antibiotics is hardly impaired thereby.
• the amount of the bases used is e.g. determined by the desired compliance with a certain pH value. Where there is no pH measurement and adjustment, or because of the lack of sufficient amounts of water in the diluent it is not possible or is not sensible, 2 molar equivalents of base are preferably added.
• reaction batches for the preparation of the compounds according to the invention and their salts are worked up in the manner generally known for these bodies.
• the isolation and purification of the compounds according to the invention and the liberation of the free acids from salts or the conversion of the free acids into salts are also carried out by generally known methods of organic chemistry, which are familiar to any person skilled in the art.
• a ⁇ -lactam compound of the formula (I) in which R is hydrogen is put in with 2-10 equivalents per equivalent of a ⁇ -lactam compound of a base in the presence of an excess of an alcohol of the formula R'OH the R 'denotes lower alkyl in an inert organic solvent, adds between about 1 to about 8 equivalents of an N-halogenating agent and isolates the compound of the formula.
• R denotes lower alkoxy, optionally after prior removal of the acid protecting group, conversion into isolated a salt or a pharmaceutically acceptable ester.
• 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, butyl lithium, phenyl lithium, alkyl magnesium bromide, for example methyl magnesium bromide, or other known acid binders such as alkali and alkaline earth metal alcoholates or carbonates, alkali metal and alkaline earth metal bicarbonates or oxides such as sodium carbonate or other acid binders such as borax or open-chain or cyclic organic bases such as trialkyl 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] azepine (DBU).
• DBN 2,3,4,6,7,8,9,10-octahydro-
• Suitable solvents are, for example, open-chain or cyclic ethers, aliphatic and aromatic hydrocarbons or halogenated hydrocarbons or the alcohols R'OH. Tetrahydrofuran is particularly suitable.
• reaction temperatures should be kept below 0 ° C, preferably between -70 ° C and -45 ° C.
• the compounds of the general formula I are both crystalline and amorphous in the form of the free acid and are both antibacterially active in the same way both anhydrous and in various forms of hydrate.
• the compounds of general formula I are also in the form of their salts, e.g. Sodium salts, both crystalline and amorphous and both water-free and water-containing, for example as a hydrate, antibacterial in the same way.
• the active compounds according to the invention have a strong and broad antimicrobial activity. These properties enable their use as chemotherapeutic agents 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, gram-negative and gram-positive bacteria and bacterial micro-organisms can be fought, and the diseases caused by these pathogens can be prevented, improved and / or cured.
• the active compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.
• the present invention includes pharmaceutical preparations which, in addition to non-toxic, 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 processes for the preparation of 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 present, 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.
• 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, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
• Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, for example starches, milk sugar, cane sugar, Glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) dissolving agents, e.g. paraffin and (f) absorption accelerators, e.g.
• fillers and extenders for example starches, milk sugar, cane sugar, Glucose, mannitol and silica
• binders e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone
• quaternary ammonium compounds (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the (a ) to (i) listed substances.
• wetting agents e.g. cetyl alcohol, glycerol monostearate
• adsorbents e.g. kaolin and bentonite
• lubricants e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the (a ) to (i) listed substances.
• 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 in such a way that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, if necessary with a delay, using as a preventative e.g. 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 4 alcohol with C 6 fatty acid) or 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 4 alcohol with C 6 fatty acid) or mixtures of these substances.
• ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
• carriers e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, 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 blowing agents e.g. Contain chlorofluorocarbons.
• active ingredient 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, especially cottonseedol, peanut oil, maize germol, olive oil, castor oil and sesamol, glycerol, glycerol formaldehyde, fatty alcohol sorbate, tetrahydrofuran glycolate, 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
• 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 athoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.
• liquid diluents e.g. Water, ethyl alcohol, propylene glycol
• suspending agents e.g. Contain athoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these 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. Saccharin.
• the therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of approximately 0.1 to 99.5, preferably approximately 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 with 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 for 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 orally or parenterally, such as intravenously or intramuscularly.
• the active compound (s) according to the invention in total amounts of about 5 to about 1000, preferably 20 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to deliver the results you want.
• a single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 1 to about 250, in particular 10 to 100 mg / kg of body weight.
• the new compounds When used as a feed additive, the new compounds can be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. This can prevent, ameliorate and / or cure an infection by gram-negative or gram-positive bacteria and also promote growth and improve the utilization of the feed.
• the new penicillins and cephalosporins are characterized by strong antibacterial effects that have been tested in vivo and in vitro.
• penicillins and cephalosporins according to the invention can be used with other antimicrobial active ingredients, e.g. can be combined with penicillins that are particularly resistant to penicillinase. Such a combination would be e.g. those with oxacillin or dicycloxacillin.
• penicillins and cephalosporins according to the invention can also be used with aminoglycoside antibiotics, for example for the purpose of widening the activity spectrum and to achieve an increase in activity.
• Gentamicin, Kanamicin, Sisomicin, Amikacin or Tobramicin can be combined.
• THF prepared from 5.0 parts by weight of 7-ACS and 5.6 parts by weight of bistrimethylsilylacetamide
• the mixture was stirred at ⁇ 20 ° for 10 minutes and allowed to come to RT.
• Ice water added, adjusted to pH 7.3 and the THF removed.
• the aqueous phase is extracted with ethyl acetate, acidified at 0-5 ° and extracted again with ethyl acetate.
• the latter extracts of ethyl acetate are dried over magnesium sulfate and concentrated.
• the product (7.5 parts by weight) is obtained as a yellow foam which is processed directly.
• the aqueous solution is extracted with ethyl acetate, cooled to 5 °, with 150 parts by volume. Layered ethyl acetate and acidified with 1 N hydrochloric acid, the product acid precipitating (3.5 parts by weight). It will be in 35 VoLTln. Suspended water, dissolved with 0.5 N sodium hydroxide solution and lyophilized this solution. 3.0 parts by weight are obtained. Sodium salt from decomposition. p. 170-180 °.
• ⁇ -lactam content 85% (substance contains approx. 6% ⁇ -lactam open product)
• the substance contains about 0.08 molar equivalents of sodium 2-ethylhexanoate and about 3.2 molar equivalents of water.
• reaction solution is poured into 80 parts by volume. ice-cold concentrated hydrochloric acid, rinsed with water and passes 50-60 g of HCl gas at 0-5 ° C into the solution, which is then left overnight (deduction). After dilution with 100 parts by volume. Water, 2.5 hours of refluxing and concentration, the residue is smoked twice with water in a porcelain bowl (to remove HCl).
• the loaded ion exchanger is suctioned off, washed well with water and finally eluted with ammonium carbonate solution. This solution is evaporated to dryness. The residue is washed with ethanol and 7.4 parts by weight from the mother liquors. (40%) of the desired amino acid.
• 7-Aminocephalosporanic acid 5.44 parts by weight 7-Aminocephalosporanic acid are in 100 vol. 80% aqueous tetrahydrofuran and 2% by weight tin. Triethylamine dissolved and cooled to -10 ° C. To do this, drop A at -10 ° C. The mixture is stirred for a further 1.5 hours at -10 ° C. and for a further 2 hours, allowing to come to room temperature.
• reaction solution is in 100 parts by volume. Given water, washed with ethyl acetate, acidified (pH 1.8), extracted with ethyl acetate and this ethyl acetate solution washed with saturated NaCl solution. After drying over MgS0 4 , the mixture is concentrated and the residue is dried under high vacuum.
• the trifluoroacetic acid is then largely distilled off (initial charge cooled to -70 ° C., high vacuum) and the residue in 10 parts by volume. Dissolved methylene chloride and stirred for 20 min. Then 100 vol. Parts of ether / ligroin are added 1: 1 and the mixture is stirred for a further 30 minutes.
• the pH is adjusted to 7 with amberlite (liquid ion exchanger, chloride as counterion), the phases are separated and the aqueous phase is washed very thoroughly with ether. The aqueous phase is freeze-dried.
• Thin layer chromatogram (eluent see example 5.1) a substance stain at the starting point.
• reaction solution is then placed in a 10% ammonium chloride solution and maintains the pH at 7 with further addition of dilute hydrochloric acid.
• the tetrahydrofuran is distilled off in vacuo and the aqueous phase is washed with ethyl acetate. Then you give 10 Vol.Tle. Acetone and, while stirring, slowly adjust the pH to 4 with dilute hydrochloric acid.
• the penicillanic acid slowly crystallizes out.
• the precipitate is filtered off and dissolved in water with the addition of 1 N sodium hydroxide solution at pH 7.
• the solution is finally lyophilized.
• Example 7.3 5.0 g of a substance prepared according to Example 7.3 (contains 2.0 g of NaCl) are suspended or dissolved in 70 ml of 60% aqueous tetrahydrofuran and the mixture is brought to pH 7.5 using 2N sodium hydroxide solution. Then 2.72 g of 1-chlorocarbonyl-2-oxo-3-furylideneaminoimidazolidine are introduced and the pH is kept at 7.5 using sodium hydroxide solution. When the pH no longer changes, the tetrahydrofuran is removed in vacuo, acidified to pH 2.3 with 2N hydrochloric acid, the precipitated low whipped and washed with water. The precipitate is suspended in hot aqueous ethanol, cooled and suction filtered.
• Example 9.5 0.7 g of the substance shown in Example 9.5 are suspended in 2.8 ml of anisole, cooled in ice / water, mixed with 14 ml of trifluoroacetic acid and the mixture is left to stand at 4 ° C. overnight. The solution is then evaporated in vacuo at -25 ° C., the residue is triturated with ether, suction filtered and dried in a desiccator over P 4 O 10 .

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Family Cites Families (8)

• 1977
  • 1977-07-16 DE DE19772732283 patent/DE2732283A1/de not_active Withdrawn
• 1978
  • 1978-07-10 US US05/923,518 patent/US4215118A/en not_active Expired - Lifetime
  • 1978-07-11 DE DE7878100352T patent/DE2861766D1/de not_active Expired
  • 1978-07-11 EP EP78100352A patent/EP0000392B1/de not_active Expired
  • 1978-07-13 IL IL55130A patent/IL55130A/xx unknown
  • 1978-07-13 AU AU38018/78A patent/AU525027B2/en not_active Expired
  • 1978-07-14 AT AT0510878A patent/AT365193B/de not_active IP Right Cessation
  • 1978-07-14 JP JP8525378A patent/JPS5439091A/ja active Pending
  • 1978-07-14 DK DK783182A patent/DK318278A/da not_active Application Discontinuation
  • 1978-07-14 CA CA307,367A patent/CA1122593A/en not_active Expired
  • 1978-07-14 IT IT25714/78A patent/IT1097816B/it active
  • 1978-07-14 ES ES471770A patent/ES471770A1/es not_active Expired
• 1979
  • 1979-06-04 US US06/045,474 patent/US4338434A/en not_active Expired - Lifetime

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