DE2927462A1 - Antibacterial cephalosporin 1-oxide and 1,1-di:oxide derivs. - prepd. by oxidation of corresp. 1-unsubstd. cephalosporin cpds. - Google Patents

Abstract

Cephalosporin 1-oxide and 1,1-dioxide derivs are cpds of formula (I) and their salts are new. Where Z is SO or SO2; R1 is H, 1-(methoxycarbonyl)acetonyl; pivaloyloxymethyl, 1-((1-4C alkoxy)carbonyloxy)ethyl, phthalidyl or 1-((1-4C alkyl)carbamoylaoxy)-ethyl;R2 is H, 1-4C alkyl, halogen, OH, 1-4C alkoxy, -CH2OH, -CH2-O-CHO,(1-4C alkyl)carbonyloxymethyl, carbamoyloxymethyl, pyridinio-methyl, 4-carbamoyl-pyridiniomethyl or -CH2-S-Het in which Het is 1-(R14)-1H-tebrazol-5-yl,1H- 1,2,3-biiazol-5-yl, 2-(R15)-1,3,4-thiadiazol-5-yl, hydroxypyridazin-6-yl or 3-methyl-1,2,4-thiadiazol-5-yl; R14 is e.g. H,Me, -CH2-CH2-NMe2, R15 is H or Me; R3 is H or 1-4C alkoxy; R4 is H, 1-4C alkyl, -X-R8 or -X-CY-R8; R5 is H, -X-R8 or -X-CY-R8; or R4+R5 is;C(R6)(R7) or -X-A-X-; R6 and R7are opt substd alkyl or aryl;X is CO, SO2, Csor C:N(R16):R8 is e.g opt substd amino, alkyl, alkenyl, cycloalkyl etc or, when X is other than SO2, opt substd. alkoxy , alkenyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkadienyloxy, aryloxy, alkylthio, cycloalkylthio or arylthio; A is -CH2CH2-, -(CH2)3-, -CH:CH- or (R9) n-substd o-phenylene; R9 is 1-4C alkyl, 1-4C alkyl, 1-4C alkoxy, halogen, NO2 or CN; R16 is opt. substd alkyl or aryl; Y is O, S or N(R17):R17 is H, opt substd. alkyl, aryl, alkoxy, aryloxy or -N(R18)(R19); and R18 and R19 are opt substd alkyl or aryl. (I)are orally active antibacterial agents. They can also be used in combination with other antibacterial agents (e.g. beta-lactam antibiotics)to increase their activity or extend their antibacterial spectrum, esp against betal lactamase- forming bacteria. (I) may used as antibacterials in humans and veterinary medicine, and as preservatives for organic and inorganic materials.

Description

Cephalosporin-1,1-dioxides, their manufacture and their

Use The present invention relates to cephalosporin 1-oxides or -1,1-dioxide, process for their production and their use as pharmaceuticals in human and veterinary medicine, as feed additives and in particular theirs Use as antibacterial agents and as components of synergistic antibacterial agents Combinations.

The invention relates in particular to compounds of the general formula (I) and their pharmaceutically acceptable salts, in which Z is SO or SO2, R1 is hydrogen, CH2-OCO-C (CH3) 3, R2 is hydrogen, C1-C4-alkyl, halogen, in particular chlorine or bromine, hydroxy, C1-C4-alkoxy, hydroxymethyl, formyloxymethyl, C1-C4-alkylcarbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthiomethyl, where the heterocyclylthiomethyl is Formulas R14 is hydrogen, methyl, imethylaminoethyl, carboxymethyl, carboxymethyl or sulfomethyl, R15 is hydrogen or methyl, R3 is hydrogen or C1-C4-alkoxy, R4 is hydrogen, C1-C4-alkyl, R8-X or R5 is hydrogen, R4 and R5 together R6 and R7 optionally substituted alkyl or aryl, X CO, SOz, CS or R8 optionally substituted amino, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl or heterocyclyl from the group optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolrazolyl, thiazoliazolyl, oxdiazolyl, thiadiazolyl, oxdiazolyl, thiadiazolyl, oxdiazolyl, thiadiazolyl , Pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyronyl-2 and -4, 2-oxotetrahydrofuryl-5, 2-oxo-2,5-dihydrofuryl-5- and sydnonyl or, in the event that X is not SO2, also optionally substituted alkoxy, alkenyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkadienyloxy, aryloxy, alkylthio, cycloalkylthio or arylthio, A -CH2-CH2-, - {CH2) 3-, -CH = CH- or Rg C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro or cyano, n is a number 0 to 4, if R9 is halogen or a number 0 or 1 for the other meanings of R9 R16 optionally substituted alkyl or aryl, Y 0, S or NR17, R17 hydrogen, optionally substituted alkyl, aryl, alkoxy, aryloxy or R18 and R19 denote optionally substituted alkyl or aryl.

Optionally substituted alkyl R6, R7, R16, R17, R18 and R19 is in particular optionally substituted once by halogen, C1-C4-alkoxy or phenyl C 1 -C 4 alkyl.

Optionally substituted aryl is R6, R7, R16, R17, R18 and R19 in particular optionally once by halogen, C1-C4-alkoxy, C1-C4-alkyl, nitro or cyano substituted phenyl.

Alkoxy R17 and aryloxy R17 correspond to Ir and aryloxy above R17 given definitions for alkyl and aryl.

Optionally substituted alkyl R8 is in particular optional C1-C20-alkyl substituted one to three times by R10.

Optionally substituted alkenyl R8 is in particular optional C2-C20-alkyl substituted one to three times by R10.

Optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl R8 is in particular mono- or mono-, optionally substituted one to three times by R10 bi- and tricyclic cycloalkyl, cycloalkenyl and cycloalkadienyl with 3 to 10 Ring carbon atoms, preferably with 3, 5 or 6 ring carbon atoms, in particular monocyclic cycloalkyl.

Optionally substituted aryl R8 is, in particular, optional aryl with 6 to 10 carbon atoms substituted one or three times by R10, phenyl which is optionally substituted one to three times by R10.

Alkylthio, cycloalkylthio, arylthio, alkoxy, alkenyloxy, cycloalkoxy, Cycloalkenyloxy, cycloalkadienyloxy and aryloxy R8 correspond with regard to their definition the above-listed alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl and aryl groups.

The heterocyclyl radicals R3 are in particular optionally one to Substituted three times by R11 and can also be used with another of those mentioned Heterocycles or condensed with benzo.

In the following statements, the term "lower alkyl" means attack, also in connection with other atoms or groups (e.g. lower alkoxy, NCON (lower alkyl) etc.) straight-chain or branched alkyl with preferably 1 up to 10, in particular 1 to 6 carbon atoms. Examples may be substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl called. "Lower alkyl" can by 1 to 5, in particular 1 to 3 identical or different halogen atoms, where the halogen atoms are preferably fluorine, chlorine and bromine, in particular fluorine and Are chlorine, its substituted Examples are trifluoromethyl, chloro-di-fluoromethyl, Bromomethyl, 2,2,2-tri-fluoroethyl and pentafluoroethyl called.

R10 preferably denotes halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine; Amino; Mono-lower alkylamino, preferably methylamino, ethylamino, especially methylamino; Di-lower alkylamino, preferably dimethylamino, diethylamino, especially dimethylamino; Pyrrolidyl; Piperidyl; ECO-NH-; Lower alkyl-CO-NH-, preferably CH3-CO-NH-; H-CO-N (lower alkyl) -, preferably H-CO-N (CH3) -, H-CO-N (C2H5) -; di-lower alkylamino-lower alkyl; Lower alkyl-CO-N (lower alkyl) -, preferably CH3CO-N (CH3); (Niedera33wl) 2C = N-; lower alkyl-SO2-NH-, preferably CH3-SO2-NH-, C2H5-SO2-NH-, in particular CH3-SO2-NH-; Lower alkyl-SO2-N (lower alkyl) -, preferably CH3-SO2-N (cH3) -; HO-SO2-NH-; HO-SO2-N (lower alkyl) -, preferably HO-SO2-N-CCH3) - HO-SO2-N (C2H5) -; Amidino; (Lower alkyl) 2-N-CH = N-, especially (CH3) 2N-CE = N-; Guanido, nitro, azido, hydroxy, lower alkyloxy-, preferably CH3-O-, C2H5-0-, especially CH30-, H-CO-O-, lower alkyl-CO-O-, preferably CH3-CO-O, C2H5-CO -O-, (CH3) 3C-CO-O-; Lower alkyl-O-CO-O-, preferably CH3-O-CO-O-, C2H5-O-CO-O-, (CH3) 3C-O-CO-O-; H2N-CO-O-; Lower alkyl-NH-CO-O-, preferably CH3-NH-CO-O-, C2H5-NH-CO-O-, (lower alkyl) 2N-CO-O-, preferably (CH3) 2N-co-o-, ( C2H5) 2N-CO-O- H2N-SO2-O-; Lower alkyl-NH-SO2-O-, preferably CH3-NH-SO2-O-, C2H5-NH-SO2-0-; (Lower alkyl) 2N-SO2-O-, preferably (CH3) 2N-SO2-O- (C2H5) 2N-SO2-O-; HOOC-, H2N-CO-; (Lower alkyl) 2N-CO-, especially (CH3) 2N-CO- and (C2H5) 2N-CO-; OHC-, HO-SO2-O-, HS-; Lower alkyl-S-, preferably CH3-S-, CF3-S-, C2H5-S-, (CH3) 2CH-S-; low- preferably H03S-; Lower alkyl-SO2-, preferably CH3-SO2-, CF3 SO2-, C2H5-SO2-; the group H2N-SO2-; Lower alkyl-NH-SO2-, preferably CH3-NH-SO2-, C2H5-NH-SO2-; (Lower alkyl) 2N-SO2-, preferably (CH3) 2N-SO2-, (C2H5) 2N-SO2-; the group HO-SO2-S-; phenoxy optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, carboxy, C1-C4-alkoxycarbonyl or cyano; Heterocyclyl, where heterocyclyl corresponds to the meaning given for R8; and, in the event that R8 is not alkyl or alkenyl, C1-C6-alkyl.

In the event that R11 is on one or more carbon atoms in the heterocyclyl R11 is preferably lower alkyl, preferably methyl, ethyl, isopropyl, especially methyl; the group trifluoromethyl; Halogen, preferably fluorine, chlorine, Bromine; Amino; Lower alkylamino, preferably CH3-NH-, C2H5-NH-; Di-lower alkylamino, preferably (CH3) 2N-, (C2H5) 2N-; Formylamino; Acetylamino; CH3-0-CO-KH-, C2HsO-CO-NH-; CH3-SO2-NH-; Hydroxy; Methoxy, ethoxy; Methylthio, ethylthio; CH3-s02-; CH3-SO-; the groups HOOC-; H03S-; HCO-; Again alkyl-CO-, preferably CH3-CO-; Lower alkyl-O-CO-, preferably CH3-0-CO-, C2H50-CO-; and -CN.

In the event that R11 is in a nitrogen-containing heterocyclyl as a substituent is on one or more nitrogen atoms, R11 is preferably lower alkyl, preferably methyl, ethyl, propyl, isopropyl, especially methyl and methyl; the Group -C = N; -CHO; -COO-lower alkyl, preferably -COO-CH3, -COOC2H5-, -COOCH (CH3) 2, -COO-C (CH3) 3, -Co-Nil2; -CO-NH-lower alkyl, preferably -CO-NH-CH3, -CO-WH-C2H5, -CO-NH-CH (CH3) 2; and -CO-lower alkyl, preferably -CO-CH3, -CO-c2H5, -CO-CH (CH3) 2.

Optionally substituted amino R8 is NH2 and also mono- or disubstituted Amino, where optionally substituted alkyl, optionally substituted alkenyl, aryl, heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl and optionally cycloalkadienyl in Question come, the meaning of the amino substituents being the same as those mentioned above Definitions for the individual residues correspond.

Preferred compounds within the general formula () correspond to the general formula (11) in which Z has the meaning given above and R12 is optionally substituted by hydroxy, carboxy, amino, C1-C4-alkoxy, halogen, phenyl, furyl, thienyl.

Aminothiazolyl, aminopyridinyl or isoxazolyl-substituted C1-C20-alkylcarbonyl or -sulfonyl; C2-C20 alkenylcarbonyl; phenylcarbonyl or sulfonyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, cyano, amino, carboxy, C1-C4-alkoxy carbonyl or aminocarbonyl; C1-C4 alkoxycarbonyl; Benzyloxycarbonyl, phenoxycarbonyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, nitro, cyano, carboxy, C1-C4-alkoxycarbonyl or aminocarbonyl; mono- and di-C1-C4-alkylaminocarbonyl or -sulfonyl optionally substituted by phenyl; phenylaminocarbonyl or sulfonyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, cyano, carboxy, C1-C4-alkoxycarbonyl or aminocarbonyl; Cyclohexylcarbonyl; Cyclohexenylcarbonyl or cinnamyl or a radical of the formula where R20 is phenyl, furyl or aminopyridinyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, cyano, carboxy, amino, hydroxy or C1-C4-alkoxycarbonyl and R21 is C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, phenyl, phenoxy or phenylamino, where phenyl such as phenyl, R20 can be substituted and R13 is hydrogen, hydroxy, acetoxy, aminocarbonyloxy, mono- or di-C1-C4-alkylaminocarbonyloxy mean.

It has also been found that the new cephalosporin-1-oxides or -1,1-dioxides of the formula (I) are obtained when compounds of the general formula (III) wherein R1, R2, R3, R4 and R5 have the meaning given above, oxidized in a suitable solvent.

The cephalosporins of the formula (III) used as starting materials are either already known or by known methods, for example by acylating 7-aminocephalosporanic acid or its derivatives will.

In particular, polar solvents, for example water, acetic acid, formic acid, methanol, tetrahydrofuran and mixtures of these three in question. The reaction temperatures are generally between -20 and + 500C, preferably between 0 and 200C. The reaction is generally carried out at normal pressure carried out. The pH of the reaction solution can be between 2 and 8, preferably between 3.5 and 7.5.

When carrying out the reactions are in each case preferably stoichiometric Amounts of the reactants used. However, one of the reaction partners can certainly do so be added in an excess, preferably the oxidizing agent, in particular in the representation of the 1,1-dioxides. The reaction products are worked up according to the methods customary in preparative organic chemistry.

The oxidation is preferably carried out with the following oxidizing agents: Potassium permanganate, ozone, hydrogen peroxide, hydrogen peroxide in the presence of catalytic Amounts of ammonium molybdate, hydrogen peroxide in glacial acetic acid, organic peracids such as Peracetic acid or m-chloroperbenzoic acid, chromium trioxide, ruthenium tetroxide, nitric acid and N-chlorosuccinimide in methanol / water.

Are in the compounds of the formula used as starting material (III) free amino groups or hydroxyl groups are present, these are generally according to methods customary in peptide chemistry before the oxidation with protective groups such as tert. -Butyloxycarbonyl or B-dicarbonyl derivatives. provided that after oxidation be split off again in the usual way.

It has also been found that cephalosporin-1-oxides or l, 1-dioxides of the formula (I), in which R5 is not hydrogen, are obtained if 7-amino-cephalosporanic acid-1-oxide or -1,1-dioxide compounds of the formula (1V) wherein Z, R1, R2, R3 and R4 have the meaning given above and R1 can also mean residues of easily cleavable esters such as tert-butyl or 2,2,2-trichlorethylene esters, with a reactive derivative of a carboxylic acid or sulfonic acid of the formula (V) R5-OH (V) in which R5 has the abovementioned meaning with the exception of hydrogen, causes the reaction and, if appropriate, splits off the further radicals R1 in the customary manner.

With the appropriate reactive carboxylic acid or sulfonic acid derivative The compound (V) can be an acid analogue, an acid anhydride, an activated one Act amide, an activated ester and the like. For example, acid chloride, Acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid, e.g. dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid or halogenated phosphoric acid, diaDylphosphorous acid, sulphurous Acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, an aliphatic carboxylic acid, e.g. pivalic acid, pentacarboxylic acid, isceentanecarboxylic acid, 2-ethy1butyric acid or trichloroacetic acid or an aromatic carbic acid, for example benzoic acid, a symmetrical acid anhydride, an activated amide with imidazole, dimethylpyrazole, Triazole or tetrazole or an activated ester such as cyanomethyl, methoxymethyl, Dimethyliminomethyl vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, Pentachlorophenyl, mesylphenyl, phenylazophenyl, phenylthio, p-nitrophenylthio, p-cresylthio, carboxymethylthio, pyranyl, pyrridyl, piperidyl, 8-quinolyl thioesters or an ester with N, N-dimethylhydroxylamine, 1-hydroxy-2- (1 H) pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1X-benzotriazole called.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, Tetrahydrofuran, ethyl acetate, N, N-dimethylformaide, pyridine or any other organic solvent which does not adversely affect the reaction, in particular a polar solvent. Of these solvents, the hydrophilic solvents can be used in admixture with water.

When the compound (V) is in the form of a free acid or in the form of its Salt is used in the reaction, the reaction is preferably carried out in the presence a conventional condensing agent such as N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N ' -morpholinoethylcarbodiimide, N-cyclohexyl-N. ' - (4-diethylaminocyclohexyl) -carbodiimide, N, N-diethylcarbodiimide,, N-diisopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide, N, N-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, Diphenylketene-N-cyclohexylimine, ethoxyacetylene, ethyl polyphosphate, isopropyl polyphosphate, Diethylphosphorochloride. I phosphorus oxychloride, phosphorus trichloride, thionyl chloride, Oxalyl chloride, triphenylphosphine, N-ethyl-7-hydroxybenzisoxazolium fluoroborate, -N-ethyl-5-phenylisoxazolium-3'-sulfonate, 1- (p-Chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, a so-called Vilsmeier reagent such as (chloromethyl) dimethylammonium chloride (produced by reacting dimethylformamide with thionyl chloride or phosgene) or a compound produced by reaction carried out by dimethylformamide with phosphorus oxychloride.

The reaction can also be carried out in the presence of an inorganic or organic Base, e.g. an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate nats, an alkali metal acetate, a trialkylamine, pyridine, N-alkylmorpholine,, N-dialkylbenzylamine, N, N-dialkylaniline can be carried out. When the base or the condensing agent is liquid, it can also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature carried out.

Are in the compounds of the formula used as starting material (IV) free amino groups are present, these are generally initially after a customary in ãen Peptidcnenie method with protective groups, for example tert. -Butyloxycarbonyl provided. After the reaction has ended, these protective groups are in usually split off again.

The 7-aminocephalosporanic acid 1-oxide used as the starting material or -l, l-dioxide can be produced by adding 7-aminocephalosporanic acid first converted into 7-tert-butoxycarboflylaminocephalosporanic acid, then with 3-chloroperoxibenzoic acid oxidized and then the protective group with trifluoroacetic acid in the usual way splits off.

The compounds of the formula (1) according to the invention have low Toxicity antimicrobial activity on these properties allow their use -as chemotherapeutic agents in medicine as well as fabrics for the preservation of inorganic and organic materials, especially of organic materials of all kinds, e.g. polymers, lubricants, paints, fibers, Leather, paper and wood, food and water.

Microorganisms against which the active compounds according to the invention of the formula (I) are effective are, for example, Micrococcaceae such as Staphylococci, e.g. Styphylococcus aureus and Staphylococcus epidermidis; Lactobacteriacea such as streptococci, e.g. Streptococcus pyogenes and Diplococcus pneumoniae, Neissiriaceae such as Neisserien, e.g., Neisseria gonorrhoeae, Neisseria meningitids, and Neisseria catarrhalis; Bazillaceae such as aerobic spore formers, e.g. Bacillus anthracis and Bacillus subtilis.

The above list of pathogens is only exemplary and by no means to be understood as restrictive.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carrier substances or contain more than one active ingredient according to the invention or one or more There are active ingredients according to the invention, as well as processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, Dragees, capsules, pills, suppositories and ampoules present whose active ingredient content is a fraction or a multiple of a single dose correspond. The dosage units can be, for example, 1, 2, 3 or 4 single doses or Contain 1/2, 1/3 or 1/4 of a single dose A single dose preferably contains the amount of active ingredient that is administered in one application and which is usually a whole, half, or a third or a quarter of a daily dose is equivalent to.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions, Called pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can be the or contain the active ingredients in addition to the usual carriers, such as (a) fillers and extenders, z.

B. starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, e.g. glycerine, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retarders, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, Glycerine monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably delayed in a certain part of the intestinal tract using e.g. polymer substances and waxes as embedding compounds can be.

The active ingredient (s) can optionally be combined with one or more of the above-mentioned carriers are also in microencapsulated form.

In addition to the active ingredients, suppositories can contain the usual water-soluble or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures of these Fabrics.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g. animal and vegetable fats, waxes, Paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be the usual ones in addition to the active ingredient or ingredients Contain carrier substances, e.g. lactose, talc, silica, aluminum hydroxide, Calcium silicate and polyamide powder or mixtures of these substances.

Sprays can additionally contain the usual propellants e.g.

Chlorofluorocarbons contain.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary 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, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient or ingredients, suspensions can contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures contain these substances.

The formulation forms mentioned can also contain colorants and preservatives as well as additives that improve smell and taste, e.g. peppermint oil and eucalyptus oil and sweeteners such as saccharin.

The therapeutically active compounds are intended in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture be.

The pharmaceutical preparations listed above can except the active ingredients according to the invention also contain further pharmaceutical active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the Active ingredients with the carrier (s).

The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations that contain one or more of the invention Contains active ingredients in human and veterinary medicine for prevention and improvement and / or cure the diseases listed above.

The active ingredients or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or parenterally how to be administered intravenously or intramuscularly.

In general it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient (s) according to the invention in total amounts from about 5 to about 1000, preferably from 10 to 200 r.g / kg: body weight per 24 hours given = all in the form of several individual gifts to achieve the desired results to administer. A single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 1 to et. 250, in particular 10 to -100 mg / kg Body weight. However, it may be necessary to deviate from the stated dosages, depending on the type and weight of the person to be treated Object, the nature and severity of the disease, the type of preparation and the Application of the drug and the period or interval within which the administration takes place. So can.

In some cases it may be sufficient with less than the above-mentioned active ingredient get along, while in other cases the above-mentioned amount of active ingredient is exceeded must become. Determining the optimal dosage and type of application required in each case the active ingredients can easily be made by any person skilled in the art on the basis of his specialist knowledge.

The new cephalosporanic acid-l-oxide or -l, 1-dioxide derivatives draw are distinguished by their antibacterial effect and oral absorbability.

The cephalosporanic acid 1-oxide or -1,1-dioxide derivatives according to the invention can be used for the purpose of expanding the spectrum of activity and increasing its effectiveness spe- aimed at B-lactamase-producing bacteria with other antimicrobial agents, e.g. with B-lactam antibiotics such as penicillins, be combined.

The cephalosporanic acid-1-oxide or

-1,1 -dioxide derivatives can be used for the purpose of expanding the spectrum of activity and to achieve an increase in effectiveness also with aminoglycoside antibiotics such as Gentamicin, Kanamicin, Sisomicin, Amikacin or Tobramicin can be combined.

Example 1 0.01 mol of 7-pivaloylaminocephalosporanic acid are dissolved in 50 ml of water with 1N sodium hydroxide solution at pH 7.5 to 8. While cooling with ice, 0.021 mol of potassium permanganate in 100 ml of water are added dropwise over the course of 20 minutes in such a way that the temperature remains below 100.degree. The pH is kept at 6.5 by adding 0.1 molar phosphoric acid. The batch is stirred for a further 10 minutes and filtered through a filter aid (Celite), which is washed with water. The combined filtrates are covered with a layer of ethyl acetate at 0 ° C. and acidified to pH 2 with 2N hydrochloric acid. The phases are separated and the aqueous phase is extracted three more times with ethyl acetate. The organic solution is washed with water, dried over magnesium sulfate and evaporated in vacuo. The compound of the formula is obtained which is recrystallized from ethyl acetate.

M.p .: i730C (dec.).

Accordingly, the following compounds are obtained M.p. 1450C (dec.) 1 H-NMR (DMSO, 100 MHz): # = 8.80, 7.3, 6.8, 5.91, 5.30, 5.02, 4.60, 4.31, 4.01, 3.78, 1.99.

M.p. 1780C (dec.) 1H-NMr (DMSO, 100 MHz): O = 9.14, 7.4, 6.04, 5.4, 5.07, 4.70, 4.3, 3.98, 2.0 Example 45 In 6 g of the compound of formula the solution of 3.9 g of 3-chloroperoxybenzoic acid in 10 ml of tetrahydrofuran is added dropwise to 100 ml of methanol at 20 ° C. while stirring. After 24 hours, the mixture is poured into 1000 ml of diethyl ether, the precipitate is filtered off with suction, washed with diethyl ether and a little water and dried in vacuo. 4 g of the corresponding S-dioxide are obtained.

The following compounds are obtained accordingly: Example 49 4.4 g of 2-methoximino-2- (2-tritylaminopyridin-6-yl) acetic acid in 150 ml of methylene chloride are added dropwise at 50 ° C. with stirring to a solution of 12.3 g of dicyclohexylcarbodiimide (97%) in 100 ml Methylene chloride is stirred for a further 40 minutes and the temperature is allowed to rise to 200 ° C. in the course of 30 minutes. Precipitated dicyclohexylurea is filtered off with suction and a solution of 17.2 g of 7-aminocephalosporanic acid tert-butyl ester 1,1-dioxide in 150 ml of methylene chloride is added dropwise to the filtrate at -100 ° C. while stirring.

The mixture is stirred for 90 minutes at room temperature, concentrated, and the residue dissolved in 500 ml of ethyl acetate and added 8 ml of diethylamine.

After cooling with ice for one hour, the diethylamine salt is filtered off with suction. That After clarification, the filtrate will be with a little charcoal with 200 ml of 0.5N hydrochloric acid shaken, the organic phase separated, washed neutral with water, over Sodium sulfate dried and concentrated until a thick crystal slurry forms. This is stirred with ether, filtered off with suction, washed with ether and dried in vacuo.

The trityl and tert-butyl groups are raised with trifluoroacetic acid known way split off.

A compound identical to that obtained in Example 8 is obtained Product.

Example 50 1.98 g of the acid of the formula are dissolved in 30 ml of tetrahydrofuran and 1.9 g of m-chloroperbenzoic acid are added while cooling with ice. The precipitate which has separated out after a short time is brought into solution by adding formic acid. After 2 hours, a further 0.95 g of m-chloroperbenzoic acid is added and the mixture is stirred for 24 hours at room temperature.

For work-up, the batch becomes dry in vacuo at 20-300C evaporated, the residue slurried with 100 ml of diethyl ether, the precipitate suctioned off, the mother liquor evaporated to dryness in vacuo and the residue treated in the same way three more times. The fractions 3 and obtained in this way 4 consist of the corresponding 1,1-dioxide.

(TLC eluent: upper phase of 50 ml butyl acetate, 9 ml butanol, 25 ml of glacial acetic acid and 15 ml of phosphate buffer pH 7; TLC prefabricated plates, silica gel 60 F254, Layer thickness 0.25 mm, Merck).

The product is identical to the compound obtained according to Example 3.

Example 51 1 mmol of the compound of the formula are dissolved in 10 ml of tetrahydrofuran and, while stirring and cooling with ice, a solution of 1 mmol of 3-chloroperbenzoic acid in 10 ml of tetrahydrofuran is added dropwise. The sulfoxide still precipitates during the dropwise addition. The mixture is stirred for 2 hours, treated with about 100 ml of diethyl ether, stirred for 30 minutes, filtered off with suction and washed with diethyl ether.

The compound of the formula is obtained with the m.p .: 1900C (decomp.) Correspondingly the following are obtained: 52. (H3C) 3-CO-ACSO m.p .: 1870C (decomp.)

Claims (8)

Claims 1. Compounds of the general formula and their pharmaceutically acceptable salts, in which Z is SO or S02, R1 is hydrogen, CH2-OCO-C (CH3) 3, R2 is hydrogen, C1-C4-alkyl, halogen, hydroxy, C1-C4-alkoxy, hydroxymethyl, formyloxymethyl, C1-C4-alkylcarbonyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthiomethyl, where for the radicals of the formulas R14 is hydrogen, methyl, 2-dimethylaminoethyl, carboxyethyl, carboxymethyl or sulfomethyl, R15 is hydrogen or methyl, R3 is hydrogen or C1-C4-alkoxy, R4 is hydrogen, C1-C4-alkyl, R8-X or R5 hydrogen, R8-X above R4 and R5 together ode R6 and R7 optionally substituted alkyl or aryl, X Co, SO2, CS or R8 optionally substituted amino, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl or heterocyclyl from the group consisting of optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyricolrazolyl, oxdiazolyl, thiadrazoliazolyl, oxdiazolyl, thiadrazoliazolyl , Pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyronyl-2 and -4, 2-oxotetrahydrofuryl-5, 2-oxo-2,5-dihydrofuryl-5 and sydnonyl or, in the event that X is not SO2, also optionally substituted alkoxy, alkenyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkadienyloxy, aryloxy, alkylthio, cycloalkylthio or arylthio, A CH2 CH2 (CH2) 3, -CH = CH- or Rg C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro or cyano, n is a number 0 to 4, if Rg is halogen or a number 0 or 1 for the other meanings of Rg R16 optionally substituted alkyl or aryl, Y 0, S or NR17, R17 hydrogen, optionally substituted alkyl, aryl, alkoxy, aryloxy or R18 and R19 denote optionally substituted alkyl or aryl. 2. Compounds according to claim 1 of the general formula where Z is SO or SO2, R12 is optionally replaced by hydroxy, carboxy, amino, C1-C4-alkoxy, halogen, phenyl, furyl, thienyl. Aminothiazolyl, aminopyridinyl or isoxazolyl-substituted C1-C20-alkylcarbonyl or -sulfonyl; C2-C20 alkenylcarbonyl; phenylcarbonyl or sulfonyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, cyano, amino, carboxy, C1-C4-alkoxycarbonyl or aminocarbonyl; C1-C4 alkoxycarbonyl; Benzyloxycarbonyl, phenoxycarbonyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, nitro, cyano, carboxy, C1-C4-alkoxycarbonyl or aminocarbonyl; mono- and di-C1-C4-alkylaminocarbonyl or -sulfonyl optionally substituted by phenyl; phenylaminocarbonyl or sulfonyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, cyano, carboxy, C1-C4-alkoxycarbonyl or aminocarbonyl; Cyclohexylcarbonyl; Cyclohexenylcarbonyl or cinnamyl or a radical of the formula where R20 is phenyl, furyl or aminopyridinyl optionally substituted by C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, cyano, carboxy, amino, hydroxy or C1-C4-alkoxycarbonyl and R21 is C1-C6-alkyl, C1 -C6-alkoxy, C -C6-alkylamino, phenyl, phenoxy or phenylamino, where phenyl such as phenyl, R20 can be substituted, and R13 denotes hydrogen, hydroxy, acetoxy, aminocarbonyloxy, mono- or di-C1-C4-alkylaminocarbonyloxy. 3. Process for the preparation of compounds according to Claim 1, characterized in that compounds of the formula wherein R1, R2, R3, R4 and R5 have the meaning given in claim 1, oxidized in a suitable solvent. 4. Process for the preparation of compounds according to Claim 1, in which R5 is not hydrogen, characterized in that compounds of the formula wherein Z, R1, R2, R3 and R4 have the meaning given in claim 1 and R1 additionally denotes residues of easily cleavable esters, with a reactive acid derivative of the formula R5-OH wherein R5 has the meaning given in claim 1 with the exception of hydrogen, for Bringing implementation and, if appropriate, splitting off the other radicals R1 in the customary manner. 5. Medicines, characterized by the content of a compound according to claim 1. 6. Medicament according to claim 5, characterized by the additional Content of a B-lactam antibiotic. 7. Use of compounds according to Claim 1 in combating bacterial infections. 8. Use of compounds according to claim 1 for expanding the Spectrum of activity of B-lactam antibiotics.