NZ206659A

NZ206659A - Cephalosporin derivatives and pharmaceutical compositions

Info

Publication number: NZ206659A
Application number: NZ206659A
Authority: NZ
Inventors: R Lattrell; W Durckheimer; R Kirrstetter; W Schwab; N Klesel
Original assignee: Hoechst Ag
Priority date: 1982-12-23
Filing date: 1983-12-21
Publication date: 1986-11-12
Also published as: EP0111935A2; PT77877B; ES8406494A1; PT77877A; EP0111935A3; PH20088A; DD216026A5; HUT34036A; ZA839526B; GR81360B; AU2280983A; FI834710A; CS249132B2; HU189792B; DK594383D0; DE3247614A1; DK594383A; EP0111935B1; ES528247A0; NO834775L

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. Cephem derivatives of the general formula see diagramm : EP0111935,P10,F1 and physiologically acceptable acid addition salts thereof in which R**1 denotes hydrogen, R**2 denotes hydrogen, R**3 denotes C1 -C4 -alkyl optionally substituted by fluorine, A denotes a quinolinium or an isoquinolinium radical, each of which can also be substituted once or twice by C1 -C4 -alkyl and in which the R**3O group is in the syn position. For the Contracting State : AT A process for the preparation of cephem derivatives of the general formula I see diagramm : EP0111935,P11,F1 and physiologically acceptable acid addition salts thereof in which R**1 denotes hydrogen, R**2 denotes hydrogen, R**3 denotes C1 -C4 -alkyl optionally substituted by fluorine, A denotes a quinolinium or an isoquinolinium radical, each of which can also be substituted once or twice by C1 -C4 -alkyl and in which the R**3O group is in the syn position, which comprises a) reacting a compound of the general formula II see diagramm : EP0111935,P11,F2 or salts thereof or a reactive derivative of the compound II in which R**1, R**2 and R**3 have the abovementioned meaning and R**8 denotes an amino group or a protected amino group and R**9 denotes a group which can be replaced by quinoline, isoquinoline or substituted quinolines or isoquinolines corresponding to the radicals A of the formula I, with quinoline, isoquinoline or one of their derivatives, and alpha) splitting off a protective group which is present where appropriate and beta) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or b) reacting a 7-aminocephen compound of the general formula III see diagramm : EP0111935,P12,F3 or acid addition salts thereof in which R**2 and A have the abovementioned meaning, it also being possible for the amino group to be present in the form of a reactive derivative, with a 2-(2-aminothiazol-4-yl)-2-syn-oximinoacetic acid of the general formula IV see diagramm : EP0111935,P12,F4 in which R**1, R**3 and R**8 have the above meaning, or with an activated derivative of this compound, and alpha) splitting off a protective group which is present where appropriate and beta) if necessary, converting the resulting product into a physiologically acceptable acid addition salt

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £06659 206659 Complete Spocification Filed: ?V? Class: f*!/&<.*7, .. &JJK.V.IS&f. 'tfZ'Ndv Publication Date: ......V. 7, .'!Y,¥. J???. ^ 0. Journal, No: N. Z.No. HO IIAWIMS NEW ZEALAND atents Act, 1953 COMPLETE SPECIFICATION "CEPHALOSPORIN DERIVATIVES AND A PROCESS FOR THEIR PREPARATION." We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt/ Main 80. Federal Republic of Germany, do heareby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - -1- - 2 - 206659 The invention relates to new cephalosporin derivatives and a process for their preparation, in particular to polar cephem derivatives which are substituted in the 3-position of the cephem ring by specific qui no I iniummethy I and isoquinoIiniummethyl radicals and which have a very good antimicrobial action against Gram-positive and Gram-negative bacteria and are therefore suitable for use as medicaments for treating microbial infections. The invention therefore relates to cephem derivatives of the general formula I k2 N C _ CONrl Jl I II2U II N iR3 (I) and physiologically acceptable acid addition salts* thereof in which denotes hydrogen or halogen, R denotes hydrogen or methoxy, R^ denotes hydrogen, optionally substituted -C^-a Ikyl, optionally substituted C^-C^-aIkenyI, C2-C$-alkinyI, Cj-Cy-cyc loa Iky I, Cj-Cy-cyc loa Iky l-C-j-C^-a Ikyl or ' / ■ . « C^-C^-cycloa IkenyI, the group R / k c in which m. or n can each be 0 or 1, RH and R can be identical or different and denote hydrogen, aryl, or 4 5 a C^-C^-alkyl group or, R and R taken together form a methy- ,'V -r-\\ i'z "Vv "■ 5F£B I986 206659 - 3 - lene or taken together with the carbon atcms to which they are attached form a C^-C^-cycloalkylidene group, it being possible for alkyl and cycloalkyl to be further monosubstituted or 6 7 7 polysubstituted, and R denotes a group -CO^R in which R denotes hydrogen, C.j-C^-alkyl, -C^OC^-C^-alky I , -CH^OOC-C^-C^-alkyl or one equivalent of an. alkali metal, alkaline earth metal, ammonium or an organic amine base; a nitrite group or a carbamoyl group -CONH^ which can be monosubstituted or disubstituted on the nitrogen, and A denotes a quinolinium or an isoquinolinium radical, each of which can also be monosubstituted or polysubstituted, with identical or different substituents, by C-C,-alkyl which can also be substituted, C^-C^-alkoxy, halogen, tri-fluoromethyl or hydroxyl, '' and in which the R^O group is in the syn-position. The present invention relates particularly to c o m -1 2 pounds in which R , R and A have the above meanings and R^denotes hydrogen, C^-C^-aLkyl which can be monosubstituted or poIysubstituted by halogen, C^-C^-a Iky11hio, C^-C^-alkyloxy, aryl or hetero-aryl, C^-C^-alkenyl which can be monosubstituted or polysubstituted by halogen, C^-C^-alk-inyl, Cj-C-^-cyc loalkyl, C^-C^-cycIoa I kyI-C^-C^-aIkyI or -C^-c y c loa I k eny I , and in which the group R1^ (CH0) JC) R6 2 n j jti •5' R has the above meaning, the R^O group also being in the isyn-position in these preferred compounds. The following are examples of substituents which -J are particularly preferred: R : hydrogen, fluorine, - 4 - 206659 chlorine or bromine, especially fluorine and chlorine. 2 3 R : hydrogen or methoxy. R : hydrogen, C^-C^-alkyl, such as, for example, metfiyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl, especially methyl or ethyl, alkyl which is substituted by halogen, for example chlorine, brumihe, iodine or fluorine, especially trifluoroethyI or 2,2,3,3-tetrafluoropropyl; alkyl which is substituted by C,j-C^-a I k y 11 h i o, for example methylthio, ethylthio or pro-pylthio; alkyl which is substituted by -C^-aIkoxy, for example methyloxy or ethyloxy; alkyl which is substituted by aryl, for example phenyl, tolyl or chloroph«nyI, especially benzyl; alkyt which is substituted by hetero-aryl, for example, 1,3-thi azol-A-y1, especially 1,3-thiazol-4-yl-methyl; C2-C^-alkenyl, such as, for example, vinyl, allyl, isopropenyl or methylallyl, especially allyl or methylallyl C^-C^-alkenyl which is substituted by halogen, such as, for example, chlorine or bromine, especially 3-chloropropen-2-yl, 2-bromopropen-2-yl or 2-chloropropen-2-yl; Cg-C^-alk-inyl, such as, in particular, propargyl; C^-Cy-cyc loa I ky I, such as, in particular, cyclopropyl, cyclobutyl, cyclopen-tyl or cyclohexyl, especially cyclopentyl; C^-C^-cycloalk-ylmethyl, such as, in particular, cyclopropyl methyl; C^-C^-cycIoaIkenyt, such as, in particular, eye IopentenyI R4 ' - 1 6 4 or cyclohexenyl, or the group (CH_) -(C) R in which R 2 n | m R5 and Rcan be identical or different and can denote hydrogen , aryl, preferably phenyl, C^-C^-alkyl, such A-' O f*1 ^ f9 V I. -5F£BI98#I '•,v-v"*■*«:♦ -. 206659 10 - 5 - example, methyl, ethyl, propyl, isopropyl, butyl or sec.- butyl, preferably methyl or ethyl and especially methyl, A 5 or in which R and R , taken together form a methylene group or a C-j-C^-cycloalkylidene group, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and in which the cycloalkylidene group can be substituted, for example by C^-C^-alkyl, preferably methyl, or by halogen, preferably fluorine or chlorine, or can also be substituted by alkylene having 3-6 carbon atoms; 15 20 m = 0 or 1, and n = 0 or 1, the sum of m and n being 1 op 2. The following are preferred examples of the group R< -(CH2'ir'9k- : R5 in the event that n is 0 and m is 1: I I I -CH(CH3), -C(CH3)2, -CH(C6H5), A CII CH. 3 , F F in the event that m is 0 and n is 1: -CH2-, and, if n and m are 1: -CH--C- , ' fl CH, R^ denotes the group -CO^R^ '' ;v . Is: in which . \\ FEB 1986 - 6 - denotes hydrogen, C^-C^-alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl or tert.~butyl, preferably methyl or ethyl and particularly methyl, or one equivalent of an alkali metal, such as, for 5 example, sodium, potassium or lithium, preferably sodium or potassium, one equivalent of an alkaline earth metal, ^ preferably calcium or magnesium, ammonfum and one equiva lent of an organic amine base, such as, for example, tri-methylamine, diethylamine, triethylamine, methylamine, pro-10 pylamine, N,N-dimethylethanolamine, t r i s - (hydroxymethyl)-^ ' am i nome t h a ne, arginine or lysine; a nitrile group or a : carbamoyl group which can be monosubstituted on the nitrogen by C^-C^-alkyl, hydroxy-C^-C^-al k'y I, C'^-C^-alkoxycar-bonyl, C.j-C^-alkylcarbonyl, carboxymethyl, C^-C^-alkyloxy-15 carbonylmethyl, aminocarbonylmethyl, C^-C^-alkylaminocar-bonyl, carbamoyl, hydroxyl or -C^-aIkyIoxy, or which can be disubstituted on the nitrogen by C^-C^-alkyl, A denotes a'quinolinium radical // \ which can be mono- substituted or polysubstituted, preferably monosubstituted 20 to trisubstituted and especially monosubstituted or disubsti tuted, by identical or different substituents, for example by C^-C^ralkyl, such as, in particular, methyl, ethyl, propyl, isopropyl or butyl, by hydroxy-C^-C^-alkyl, - especially hydroxymethyI, by C^-C^-a I kyIoxy-C^-C^-aIkyI, 25 especially methoxymethyI; by C^-C^-a Ikoxy, for example ethoxy or met h oxy; by halogen, sucfi as, for example, 206659 - 7 - fluorine, chlorine, bromine or iodine; or by trifluoro-methyl or hydroxyl; or A denotes an isoquino I inium radi- quinolinium radical above. The following., for example, are preferred examples of A: quinolinium^ 2-, 3-, 4-, 5-, 6-, 7- or 8-methylquinolinium, 3-, 5-, 6-, 7- or 8-hydroxy-quinolinium, 3-, 4-, 5-, 6-, 7- or 8-methoxyquino I inium, 3-bromoquinolinium, 3-chloroquinolinium, 5-chloroquinolin-ium, 5,7-dichloroquinolinium, 7-trifluoromethylquinolin-ium, 5-ch loro-8-hydroxyquino Iinium or 5-cbloro-7-iodo-8-hydroxyquinolinium; isoquino Iinrum, 1-, 3-, 4-, 5-, 6-, 7- or 8-methylisoquinolinium, 4-chloroisoquinolinium, 4- • « » bromoisoquino I inium, 4-hydroxyisoquino I inium or 5-hydroxy-isoquinolinium. preparation of compounds of the formula I and their physiologically acceptable acid addition salts, which comprises a) reacting a compound of the general formula II c a I which can be substituted like the The invention also relates to a process for the R "ONH 2 "ONH ' NvNx^CH2R 9 II or salts thereof or a reactive derivative of the compound II in which R^, R^ and have the abovementioned meaning g and R denotes an amino group or a protected amino group - 8 - and r9 denotes a group which can be replaced by quino-line, isoquinoline or substituted quinolines or is uino-lines corresponding to the radicals A of the formula with quinoline, isoquinoline or one of their derivatives 5 and O splitting off a protective group which may be present ^ and jS) if necessary, converting the resulting product Into a physiologically acceptable acid addition salt, or 10 b) reacting a 7-aminocephem compound of the general foi— mu I a 111 k2 (III) COO or acid addition salts thereof in which R and A have the abovementioned meaning, it being also possible for the 15 amino group to be present in the form of a reactive derivative, with a 2-(2-aminothiaj:ol-4-yl)-2-syn-oximinoacetic acid of the general formula IV, N- ..A. C — COOH II Nx 3 R8 S R1 IV 20 7 O in which R, R° and r have the above meaning, or with an activated derivative of this compound, and 206659 - 9 - <v> splitting off a protective group which may be present and ft) if necessary, converting the resulting product into a physiologically acceptable acid addition salt. If the preparation of the compounds of the general formula I is to be effected by ntc I eophi I ic replacement of in the compounds of the general formula II by quinoline, isoquinoline or one of their derivatives mentioned, suitable radicals R^ are, in particular, acyloxy radicals of lower aliphatic carboxylic acids, preferably having 1 to 4 carbon atoms, such as, for example, acetoxy or propionyl-oxy, especially acetoxy, which can optionally be substituted, such as, for example, chloroa'Cetoxy or acety lacetoxy. o Other groups are also suitable for R , such as, for example, halogen, especially chlorine, bromine or iodine, or carbamoyloxy. In accordance with the invention, starting com- Q pounds of the general formula II in which R represents acetoxy, or salts thereof, such as, for example, a sodium or potassium salt, are employed in the nucleophilic replacement reaction. The reaction is carried out in a solvent, preferably in water or in a mixture of water and an organic solvent which is readily miscib I e. with water, such as, for example, acetone, dioxane, ac€tonitri Ie, dimethyIforma-mide, dimethyl sulfoxide or ethancl. In general, the reaction temperature is within the range from about 10 to about 100°C, preferably between 20 and 80°C. The base component is added in quantities between approximately 2 066 5 9 - 10 - equimolar quantities and an excess of up to about 15-fold. The replacement of the radical is facilitated by the presence in the reaction medium of neutral salt ions, preferably iodide or thiocyanate ions. In particular, about 10 to about 80 equivalents of potassium iodide, sodium iodide, potassium thiocyanate or sodium thiocyanate are added. The reaction is advantageously carried out near to the neutral point, preferably at a pH value within the range from about 5 to about 8. Q If the group R is in the form of a protected amino function, examples of suitable amino protective groups are optionally substituted alkyl, such as, for example, tert.-butyl, tert.-amyl, benzyl, p-me t ho x'ybe nzy I, trityl or benz-hydryl, preferably trityl; tria I ky Isi lyI, such as, for example, trimethyIsilyI; optionally substituted aliphatic acyl, such as, for example, formyl, ch loroacetyI, bromo-acetyl, trichloroocetyl and trifLuoroacetyl, preferably formyl; or optionally substituted aIkoxycarbony I , such as, for example, trich loroethoxyearbony I , benzyloxycarbonyI or tert.-butoxycarbonyI, preferably tert.-butoxycarbonyI and benzylox^carbonyl; or dimethylaminomethylene. The protective group can be split off in a manner known per se after the replacement reaction, for example the trityl group can be split off by means of a carboxylic acid, such as, for example, acetic acid, trif luoroacetic acid or formic acid, or the benzyIoxycarbonyI group can be s.plit off by hydrogeno lys i s. The reaction products of the formuLa I can be 2066 5% - 11 - isolated from the reaction mixture in a customary manner, for example by freeze-drying the aqueous phase, chromatography or by precipitation in the form of a sparingly soluble salt, for example the hydriodide or hydrothiocyanate salts. 5 The nucleophilic replacement reaction on compounds of the general formula II can also be effected by carrying out the reaction in the presence of the base corresponding to the radicals A, such as, for example, quinoline or isoquinoline, and of trimethyIiodosiIane . This variant 10 of the replacement reaction is advantageously carried out by adding trimethyIiodosi I ane to a mixture of the compound II and the base in a suitable solvent. A procedure which can also be followed is first to r'6act the compound II with trimethyliodosilane in accordance with the reaction 15 conditions mentioned below and then to add the base. Suitable solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, trichloroethane or carbon tetrachloride, or lower alkyl-nitriles, such as acetonitrile or propionitrile. 20 The base is added in at least a stoichiometric quantity, up to a twenty-fold excess; the reaction is preferably carried out using a five-fold to fifteen-fold excess. Trimethyliodosilane is also added in at least a stoichiometric, quantity, up to a twenty-fold excess, pre-25 ferably a five-fold to fifteen-fold excess. The reaction is carried out at temperatures between ^ -5° and +100°, preferably between 10° and 80°C. After the reaction mixture has been hycfrolyzed by adding water or <2 066 59 - 12 - aqueous mineral acids, for example diluted HC1, HBr, HJ or diluted ^2^4' reacti°n products of the formula I can be isolated frem the aqueous phase in a customary manner, for example by freeze-drying the aqueous phase, chromatography and similar 5 methods. It is preferable to precipitate the polar reaction products from the aqueous solution in the form of a sparingly soluble salt, for example in the form of the hydrothiocyanate or hydriodide salts, after adding KSCN or KI, respect ively. Q 10 In the event that R represents a carbamoyloxy group, the replacement reaction is carried out analogously, o If R represents halogen, in particular bromine or iodine, the replacement is carr'ied out in a manner known from the literature. 15 If the compound II is present here in the form of a reactive derivative, examples of suitable derivatives are silyl derivatives which are formed when compounds of the general formula II are reacted with a silyl compound, such as, for example, trimethylchlorosilane, bis-Ctrime-20 thy Isi ly I)-acetamide or bis-<trimethy Isi ly I)-trifluoroacet-amide. In this case the reaction is advantageously carried out in the presence of an inert solvent, such as methylene chloride or acetonitrile. , . The .a c-ylat i on of the compounds of the general foi— 25 mula III or of acid addition salts thereof, for example salts with hydrochloric acid, hydrobromic acid, nitric ^ acid, sulfuric acid, phosphoric acid or an organic acid, such as, for example^ methanesuIfonic acid, p-toluene- 206659 - 13 - sulfonic acid or maleic acid, is carried out by means of carboxylic acids of the general formula IV or by means of a reactive derivative of such an acid. In this acylation it 1s advantageous in some cases to protcct the 2-amino group, in the compounds of the general formula IV, from the reaction. Suitable amino protective groups are the O protective groups described above for R . After the acyla tion, the protective group can be split off in a manner known per se, for example the trityl group by means of a carboxylic acid, such as, for example, formic acid or tri-fluoroacetic acid, or the chloroacetyl group by means of thiourea. If the carboxylic acids of the general formula IV and their derivatives which are*"protected at the amino group are themselves employed as the acylating agent, it is advantageous to carry out the reaction in the presence of a condensation agent, for example a carbodiimide, such as, for exampLe, N,N'-dicyclohexylcarbodiimide. The activation of the carboxylic acids of the general formula IV can be effected in a particularly advantageous manner by treatment with specific carboxamides and for example, phosgene, phosphorus pcntachloride, tocyl chloride, thionyl chloride or oxalyl chloride, as described in New Zealand Patent Specification No. 191034. Halidejs, preferably chlorides, are also particularly suitable as activated derivatives of the carboxylic acids of the generat formula IV; these halides are obtained in a manner'known per se by treatment with halo-genating agents, such as, for example, phosphorus : \ - 14 - pentach loride,phosgene or thionyl chloride, under mild reaction conditions which are known for cephalosporin chemistry from the literature. Further suitable activated derivatives of the cai— boxylic acids of the general formula IV are the anhydrides and mixed anhydrides, azides, activated esters and thioesters, preferably those formed with p-nitrophenol, 2,4-dinitrophenol, methylene cyanohydrin, N-hydroxysuccinimid« and N-hydroxy-phtha Iimidc, particularly those formed with 1-hydroxybenzo-triazole and S-chloro-1-hydroxybenzotriazole and 2-rnercaptobenzotriazole Mixed anhydrides which are particularly suitable are those formed with lower alkanoic acids, such as, for example, acetic acid, and particularly preferentially those formed with substituted acetic acids, such as, for example, trichloroacetic acid, pivalic acid or cyanoacetic acid. Derivatives which are particularly suitable are, however, also the mixed anhydrides formed with carboxylic acid half-esters, which are obtained, for example, by reacting the carboxylic acids of the formula IV, in which the amino group is protected, with benzyl, p-nitrobenzyI, isobutyl, ethyl or allyl chloroformate. The activated derivatives can be reacted in the form of isolated substances, but can also be reacted in situ. In general, the reaction of the cephem derivatives of the general formula III with a carboxylic acid of the general formula IV or with an activated derivative thereof is effected in the presence of an inert solvent. Solvents which are particularly suitable are chlorinated - 15 - hydrocarbons, such as, preferably, methylene chloride and chloroform; ethers, such as, for example, diethyl ether, preferably tetrahydrofuron and dioxane; ketones, such as, preferably, acetone and butanone; amides, such as, preferably, dimethylformamide and dimethylacetamide, or pyridine. It can also be advantageous to use mixtures of the said solvents. This is often the case if the cephem compound of the general formula III is reacted with an activated derivative, produced in situ, of a carboxylic acid of the formula IV. The reaction of cephem compounds of the formula III with carboxylic acids of the formula IV or with activated derivatives thereof can be effected within a temperature range from about -80 to about +80°C, preferably between -30 and +50°C, but particularly between about -20°C and room temperature. The duration of the reaction depends on the reac-tants, the temperature and the solvent or mixture of solvents, and is normally between about 1/4 and about 72 hours. The reaction with acid halides can, if appropriate, be carried out in the presence of an acid-binding agent for binding the hydrogen halide liberated. Suitable acid-binding agents are, in particular, tertiary amines, such as, for example, triethvlamine, dimethylaniline or pyridine; inorganic bases, such as, for example, potassium carbonate or sodium carbonate; or alkylene oxides, such as, for example, propylene oxide. The presence of a catalyst, * 2 066 5 9 - 16 - such as, for example, dimethylaminopyridine, can also be advantageous in certain cases. If the amino group in the compounds of the general formula III is present in the form of a reactive deriva-5 t i v e , this can be a derivative such as is known from the literature for amidations. Thus, examples of suitable derivatives are silyl derivatives which are formed when compounds of the general formula III are reacted with a silyl compound, such as, for example, trimethy I ch lorosi l-10 ane or bis-(trimethyIsi ly I)-acetamide . If the reaction is carried out with such a compound, which is activated on the amino group, it is advantageous to carry out the reaction in an inert solvent, such as,"for Example, methylene chloride, tetrahydrofuran or dimethylformamide. 15 Examples of physiologically acceptable acid addi tion salts of the compounds of the general formula I which may be mentioned are those with hydrochloric acid, hydro-bromic acid, nitric acid, phosphoric acid, sulfuric acid or organic acids, such as, for example, methanesulfonic 20 acid, p-toluenesulfonic acid or maleic acid. The compounds of the general formula III can be obtained in a manner known per se, for example from 7-am-inocephalosporanic acid or 7-aminocephalosporanic acid which is prote.cted at the amino group, in the same manner 25 as has been described above for the nucelophilic replacement of R^. V The compounds of the general formula IV and the quinoline and isoquinoline derivatives corresponding to 206659 - 17 - the radicals A are known from the literature or can be prepared by processes known from the literature. The compounds of the general formula I which are obtained in accordance with the invention and their physiologically acceptable acid addition salts exhibit a remarkably good antibacterial activity against both Gram-positive and Gram-negative bacterial organisms. The compounds of the formula I also have an unexpectedly good activity against penici 11inase-forming and cephalosporinase-forming bacteria. Since they possess in addition, advantageous toxicologicaI and pharmacological properties, they constitute valuable chemotherapeutic agents. " • The invention also relates, therefore, to medicinal formulations^for the treatment of microbial infections, which contain one or more of the compounds according to * theinvention. The products according to the invention can also be used in combination with other active compounds, for example those belonging to the series comprising the penicillins, cephalosporins or aminoglycosides. The compounds of the general formula I and their physiologically acceptable acid additipn salts can be, administered p.rally,- i nt ramu s cu la r Ly or intravenousl Medicinal formulations containing one or more compounds of the general formula I as the active compound can be prepared by mixing the compounds of the formula I with one or more pharmacologically acceptable excipients or diluents, - 18 - such as, for example, fillers, emulsifiers, lubricants, taste correctives, colorants or buffer substances, and bringing the mixture into a suitable pharmaceutical form, such as, for example, tablets, dragees, capsules or a sus-5 pension or solution suitable for parenteral administration. Examples of excipients or diluents which may be mentioned are tragacanth, lactose, talc, agai—agar, poly-glycols, ethanol and water. Examples of buffer substances are organic compounds such as, for example, N,N'-dibenzyl-10 ethylenediamine, diethanolamine, ethylenediamine, N-methyl-glucamine, N-benzyIphenethyI amine, diethy lamine or tris-(hydroxymethyI)-aminomethane, or inorganic compounds such as, for example, phosphate buffers',' sodium bicarbonate or sodium carbonate. Suspensions or solutions in water with 15 or without buffer substances are preferentially suitable for parenteral administration. It is also possible to administer the active compounds as such without excipients or diluents, in a suitable form, for example in capsules. Suitable doses of the compounds of the general for-2C mula I or of their physiologically acceptable acid addition salts are about 0.4 to 20 g/day, preferably 0.5 to 4 g/day, for an adult of about 60 kg body weight. It is possible to administer individual doses .or, in general, mu.ltiple doses, and the individual dose can 25 contain the active compound in an amount of about 50 to 1,000 mg, preferably about 100 to 500 mg. Cephem compounds carrying a methyl group substituted by a nucelophilic radical in the 3-position of the N. •/ / ... ^ f 1 "r-V1"' " "'.-•A'" - ,•» • _.... 206659* - 19 - cephem ring are already claimed in New Zealand Specification No. 186842. However, it could not have been expected that the compounds obtained in accordance tilth the invention would be distinguished, compared with the com-5 pounds obtained in Nsw Zealand Patent No. 186842 by an unexpected superiority of their antibacterial prope rt i es. The following illustrative embodiments of syn-compounds which can be prepared in accordance with the 10 invention serve to illustrate the invention further, but do not limit it thereto. t Examp le 1: 3-C(2-Isoquinolinium)methylI]-7-lI2--syn-metho>:y1mino-2-(2-aminothiazol-4-yt)-acetamidoI3-ceph-3-em-4-carboxylate 15 > A mixture of 4.55 g (0.01 mole) of 7-C2-(2-am- inothiazol-4-yl)-2-syn-methoxyimino-acetamidoD—cephalospo-ranic acid, 66.4 g (0.4 mole) of potassium iodide, 0.3 g of ascorbic acid, 12.9 g (0.1 mole) of isoquinoline, 75 ml of water and 25 ml of acetone is heated at 66-68°C for 4 20 hours, while stirring. After cooling, the mixture is diluted with 600 ml of acetone and is chromatographed over 400 g of silica gel (Merck 0.063-0.2 mm). Elution is carried out with 1 liter of 8:1 acetoneiwater, 500 ml of 5:1 acetone:water and then with 2:1 acetone:water. The title 25 substance is eluted with 2:1 acetone:water. Freeze-drying the product fractions gives 2.36 g (45% of theory) of a colorless, amorphous solid, IR (KBr): 1765 citT^ co). ,.?v . • - h % c . »/ C. JS-S"' 2 06 6 5 9' - 20 - 1H-NMRCCF3C02D): 5 = 3.45 and 3.93 (AB, J = 18Hz, 2H, SCH2); 4.21 (s, 3H, OCHj); 5.25-6.50 (m, 4 H, 3 - C H 2 and 2 lactam-H); 7.41 (s, 1 H, thiazole); 7.95-8.80 (m, 6H, 5 isoquinoline-H); 9.79 ppm (broads, 1H, isoquinoline-H) ft) 14 g (0.07 mole) of trimethyliodosilane are added at 5$otf to a mixture of 4.55 g (0.01 mole) of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamidoJ-cephalo-10 sporariic acid and 11 g (0.085 mole) of isoquinoline in 100 ' ml of methylene chloride, and the mixture is heated under reflux for 2 hours. After cooling, 80 ml of 2N HCl are added. The liquid is decanted off t'he resinous precipitate which is deposited. The precipitate is dissolved in aque-15 ous sodium bicarbonate solution and the solution is chrom-atographed as above. Freeze-drying the product fractions gives 1.95 g (37% of theory) of a colorless solid which is identical in all its properties with the solid described above. 20 Example 2: 3-f(1-Quinolinium)n)ethyO-7-f2-syn-methoxyimino-2-(2-am-inothiazol-4-yl)acetaniido3-ceph-3-em-4-carboxylate ^ a) . . ) Analogously to Example 1) 4.55 g (0.01 mole) of 25 7-[2-(2-aminothiazol-4-yl)-2-syH-methoxyimino-acetamidoJ-cephalosporanic acid are reacted with 12.9 g (0.1 mole) of quinoline. Chromatography gives 1.42 g (27% of theory) of a coLorless solid. 2066 59 IB(KBr): 1765 cm ^ (lactam-CO) 1H-NMRCCF3C02D): & = 3.AO and 3.80 CAB, J = 19Hz, 2H, SCH^; 4.21 (s, 3H, OCHj); 5.30-6.50 (m, 4H, 3-CH2 and 2 lactam-H each 5 having 1 d at 5.41 and 6.10, J = 5Hz, C ^ and C ^ - H ) ; 7.42 (s, 1H, thiazole); 7.95-8.65 (m, 5H, quino I ine-H); 8.95-9.40 ppm (m, 2H,quinoline-H) /^) The reaction is carried out as described in 10 Example 1 (^) , using 11 g of quinoline- Yield: 2.15 g CA1 % of theory) of a colorless solid. The compound is identical in all its properties with the compound described above. •• » b) 15 0.4 g (2 mmoles) of 2-(2-amino-1,3-thiazol-4-yl)- 2-syn-methoxyiminoacetic acid is dissolved in 6 ml of N , N ' - dimethylformamide. After adding 0.28 g (2.1 mmoles) of 1-hydroxybenztriazole hydrate and 0.41 g (2 mmoles) of N,N 1-dicycIohexyIcarbodiimide, the mixture is stirred at 20 room temperature for 2 hours, the dicycI ohexyIurea is filtered off and a solution of 0.83 g (2 mmoles) of 7-amino-30 ["(1 -qu i no I i n i um)-me t hy ij - c ep h-3-em-4-c a rbo xy I a t e dihy-dro'chloride in 8 ml of N,N '-di met hy I f ormami de and 1 ml of water is added to the filtrate. The mixture is stirred 25 at room temperature for 3 hours and concentrated in vacuo, and the residue is dissolved in 10 ml of water. A little undissolved material is filtered off and the solution is chromatographed over silica gel (Merck,. "Lobar" column C, 206659 - 22 - pressure approx. 1 bar) using 2:1 acetone:water. The product fractions are concentrated in vacuo and are freeze-dri ed. 0.74 g C70.8%) of the title compound are obtained 5 in the form of a colorless solid. The compound is identical in all its properties with that described above. The compounds described in Examples 3-3 7 are obtained, as amorphous solids, using the appropriate starting materials in a manner analogous to that described in 10 Examples 1 find 2. ■ Example 3: 3-f(2-Isoquinolim'um)methyl3-7-Q2-syn-n)ethoxyirnino-2-C2-amino-5-chlorothiazol-4-yL)acetamido3-ceph-3-em-4-carboxy-, I at e 15 1H-NMR(CF3C02D): ^ = 3.44 and 3.91 (AB, J = 18Hz, 2H, SCH2); 4.21 (s, 3H, OCH3); 5.20-6.48 (m, 4H, 3-CH2 and 2 lactam-H); 7.92-8,80 (m, 6H, isoquinoline-H); 9.78 ppm (broad s, 1H, isoquinoline-H) 20 Example 4: 3-C.(1-QuinoliniunOmethyLl-7-C2-syn-niethoxyimino-?-(2-amino- 5-chloro-thiazol-4-yl)acetamido3-ceph-3-em-4-carboxylate 1,-NMR (C F,C0,D) : &= 3.39 and 3.80 (AB, J = 19Hz., SCH , rl 3d 2 H) ; 4.21 (s, 3 H, 0CH3); 5.25-6.55 25 (m, 4H, 3-CH2 and 2 lactam-H); 7.90- 8.60 (m, 5H, qu i no I'i ns-H) ; 9.00-9.45 ppm (m, 2H, quinoline-H) 206659 - 23 - Example 5; 3-("(2-Isoquinolinium)methyQ - 7- C2-syn-methoxyimino-2-(2- amino-5-bromothiazol-4-yl)acetamido3-ceph-3-em-4-car- boxylate 5 1H-NMR (CFjCO^t)) : <£ = 3.45 and 3.90 CAB, J = 19Hz, 2H, S C H g); 4.22 (s, 3H, OCHj); 5.22-6.50 (m, 4H, S-CH^ and 2 lactam-H); 7.90-8.80 (m, 6H, isoquinoline-H); 9.76 ppm (broad s, 1H, isoquinoline-H) 1 0 Example 6: 3-C.(1-Quinolinium)methylJ-7-C2-syn-methoxyimino-2-(2-amino-5-bromothiazol-4-yl)acetamidoJ-ceph-3-em-4-carboxylate 1H-NMR (CF3C02D): 3.40 and 3.82-(AB, 'J = 19Hz, 2H, S C H £ ) ," 4.21 (s, 3H , OCHj); 5.21-6.57 15 (m, 4H, 3-CH2 and 2 lactam-H); 7.85- 8.65 (m, 5 H , quinoline-H); 9.05-9.50 ppm (m, 2H, quinoline-H) Example 7: 3-C(2-Isoquinolinium)methyi)-7-C2-syn-ethoxyimino-2-(2-20 aminothiazol-4-yl)aceta(nidoJ-ceph-3-em-4-carboxylate . 1H-NMR (CF3C02D): & = 1.^0 (t, J = 7 Hz, 3H, CH2CH^); 3.46 and 3.85 (AB, J = 18Hz, 2H, SCH2); 4.50 Cq, J = 7Hz, 2H, CH2CH3); 5.20-6.45 Cm, 4H, 3-CH2 and 2 lactam-H); 25 7.42 (s, 1H, thiazole-H); 8.0-8.75 Cm, 6H, isoquinoline-H); 9.80 ppm (broad s, 1H, isoquinoline-H) 206659 - 24 - Example 8: 3 - C(1-Quinol iniunOmethyl )me t h y Q -7-£2-syn-ethoxyimino-2-C2-aminothiazol-4-yl)acetamidoJ-ceph-3-em-4-carboxylate 1 H-NMR (CF3C02D): $= 1.42 Ct, J = 7Hz, 3H, CI^CH^); 3.43 5 and 3.72 CAB, J = 19Hz, 2H, SCH2); 4.51 Cq, J = 7Hz, 2H, CH^Hj); 5.25-6.50 Cm, 4H, 3-CH2 and 2 Lactam-H); 7.45 Cs, 1H, thiazole-H); 8.00-8.70 Cm, 5H, qui no Iine-H ) ; 8.97-9.45 ppm 10 Cm, 2H, quinoline-H) • Example 9: 3-C(2-Isoquinolinium)methyl]-7-[/?-syn-propoxyim i no-2-C2-aminothiazol-4-yl)acctamidol-ceph-3-em-4-,carboxylate 1H-NMR CCF3C02D): £= 1.05 Ct, J = 6Hz, 3H, CHj); 1.55-2.15 15 Cm, 2H, C H ^); 3.45-3.88 CAB, J = 18Hz 2H, SCH2); 4.48 Ct, J = 7Uz, NOCHg); 5.28-6.30 (m., 4H, 3-CH2 and 2 lactam-H); 7.42 Cs, 1H, thiazole); 7.90-8.80 Cm, 6H, isoquinoline-H); 9.80 20 ppm Cbroad s, 1H, isoquinoline-H) Examp1e 10: 3-CC1-Quinolinium)methyO-7-j"2-syn-proppxyimino-2-(2-amino thiazol-4-yl)acetamido*)-ceph-3-eni-4-carboxylate 1 H-NMR CCF3C02D): =.1.02 Ct, J = 6Hz, 3H*, CH3); 1.5-2.2 25 Cm, 2H, CHg); 3.40 and 3.70 CAB, J = 1 8H z , 2 H , SC H 2); 4.45 Ct, J = 6Hz, NOCH2); 5 .30-6.50 Cm, 4H, 3CH2 and 2 lactam-H); 7.42 Cs, 1H, thiazole); 206659 - 25 - 7.95-8.70 (m, 5H, quinoline-H); 8.93-9. A 2 ppm ( m , 2 H , quinoline-H) ExampL c 11: 3- C.C 2 - 1 soquinolini um)methyQ - 7- (~2-syn- isopr.opoxyimino-2-5 (2-ami'nothiazol-A-yl)acet3mido3-ceph-3-etn-A-carboxylate ^ H-NMR (CF3C020):S= 1.A0 and 1.50 (d, J = 6Hz, 6H, 2CH3); 3. A 5 and 3.88 (AB, J = 18Hz, 2H, SCH2); A.75 Cm, 1H, CH); 5.20-6.AO Cm, 4H, 3-CH2 and 2 lactam-H); 7.A1 C s , 1 H , 10 thiazole); 8.01-8.85 Cm, 6H, isoquino line-H); 9.80 ppm (broad s, 1H, iso-quinoline-H) Example 12: •< > 3-r(1-Quinolinium)methyl3-7-r2-syn-isopropoxyimino-^-C-2-1 5 aminothi azol-A-yl)acetamido3-ceph-3-em-A — carboxylate 1H-NMR (CF3C02D): £ = 1.A5 and 1.55 (d, J = 6Hz, 6H, 2CH3); 3.A3 and 3.80 (AB, J = 19Hz, 2H, SCH2); A.72 Cm, 1H, CH); 5.15-6.35 (m, AH, 3-CH2 and 2 lactam-H); 7.A1 (s, 1H, 20 thiazole); 7.95-8.62 (m, 5H, quinoline- H); 8.96-9.A5 ppm (my 2H, quinoline-H) Example 13: 3-CC2-Isoquinolinium)methylJ-7-Q2-syn-allyloxyimino-2-(2-aminoth-iazol-A-yl)acetamido3-ceph-3-em-A-carboxylate 25 1H-NMR (CF3C02D): <J = 3.A7 and 3.86 (AB, J = 18Hz, 2H, SCH2) A.85-6.A5 (m, 9H, 5 allyl-H, 3-CH2 and 2 lactam-H); 7.A1 (s, 1H, thiazole); 8.00-8.85 (m, 6H, isoquinoline-H); 9.80 ppm (broad s, 1H, isoquinoline-H) 206659 - 26 - Example 1 A : 3-Cci-Quinolinium)methyl3-7-f2-syn-allyloxyamino-2-C2-aminothiazol-4-yl)acetamido3-ceph-3-em-4-carboxylate 1H-NMR CCF3C02D>: J = 3.AO and 3.78 CAB, J = 18Hz, 2H, 5 SCH2); A.80-6.50 Cm, 9H, 5 allyl-H, 3-CH2 and 2 lactam-H); 7.41 Cs, 1H, thiazole); 7.98-8.65 Cm, 5H, quinoline-H); 9.00-9.45 ppm Cm, 2H, quinoline-H) 10 Example 15: ■ 3-CC2-Isoquinolir>ium)methylvJ-7-^2-syn-methylthiomethoxyim-ino-2-C2-aminothiazol-4-yl)acetamido3~ceph-3-em-4-car-boxylate 1 K H-NMR CCFjC02D): o = 2.28 Cs, 3H, SCHj); 3.47 and 3.88 15 CAB, J = 18Hz, 2H, SCH2); 5.15-6.30 Cm, 6H, CH2S, 3-CH2 and 2 lactam-H); 7.42 Cs, 1H, thiazole); 7.90-8.82 (m, 6H, isoquinoline-H); 9.75 ppm (broad s, 1H, isoquinoline-H) 20 Example 16: 3-tC1-Quinolinium)methyO-7-C2"Syn-methylthiomethoxyin)ino- 2-(2-aminothiazol-4-yl)acetamido7"ceph-3-em-A-carhoxylate ^ H-NMR (CF3C02D): £ = 2.25 (s, 3H, SCHj); 3.A5 and 3.85 (AB, J = 18 Hz, 2H,"SCH,); 5.10-6.35 • ' ^ *■ 25 (m, 6H, CHgS, 3--CH2 and 2 lactam-H); 7.A1 (s, 1 H ,. thiazole); 7.95-8.66 (m, 5H, quinoline-H); 8.92-9.41 ppm (m, 2H, quinoline-H) 206659 - 27 - Example 17: 3-C(2-Isoquinolinium)rnethyC3-7-C2-syn-ethyloxyethoxyimino- 2-(2-aminothiazol-4-yl)acetamidoj-ceph-3-em-4-carboxylate ^ H-NMR (CF3C020): 3 = 1.33 (t, J = 7Hz, 3H, CH^Hj); 3.42 and 3.83 (AB, J = 18Hz, 2H, SCH2); 4.35-6.32 (m, 10H, OCH2CH2OCH2, 3-CH2 and 2 lactam-H); 7.41 (s, 1H, thiazole); 7.90-8.85 (m, 6H, isoquinoline-H); 9.80 ppm (broad s, 1H, i soqu i no Ii ne-H) Example 18: 3-C(1~Quinolinium)methyQ~7-f2-syn-ethyloxyethoxyimino-2- (2-aminothiazol-4-yl)acetamidoj-ceph';-3-em-4-carboxyl. ate ^ H-NMR (CF3C02D): § = 1.35 (t, J = 7Hz, 3H, CH2CH3); 3.45 and 3.80 (AB, J = 18Hz, 2H, SCH2); 4.30-6.35 (m, 10H, OCH2CH2OCH2, 3-CH2 and 2 lactam-H); 7.41 (s, 1H, thiazole); 7.95-8.65 (m, 5H, quinoline-H); 8.95-9.42 ppm (m, 2H, quinoline-H) Example 19: 3-C^2-Isoquinolinium)methy0-7-^2-syn-cyclopropylmethoxy- imino-2-(2-aminothiazol-4-yl)acetamido~|-ceph-3-em-4- carboxylate ^H-NMR (CF3C02D): £ = 1.05-1.7 (m, 5H, cyclopropyl); 3.40 and 3.85 (AB, J = 18Hz, 2H, SCH2); 4.25 (d, J = 7Hz, 2 H, N0CH2); 5.25-^ 6.35 (m, 4H, 3-CH2 and 2 lactam-H); 10 - 28 - 7.42 ( s , 1 H , thiazole); 7.90-8.80 ( m , 6 H , isoquinoline-H); 9.79 ppm (broad s , 1 H , isoquinoline-H) Example 20: 3 -Ql-Quinoliniuni)methy 0-7-^2-syn-cyclopropylmethoxyim i no-'2-(2-aminothiazol-4-yl)acetamido3-ceph-3-em-4-carboxylate ^ H-NMR (CF3C02D): i = 1.1-1.7 (m, 5H, cyclopropyl); 3.42 and 3.78 <AB, J = 16Hz, 2H, SCHg); 4.26 (d, J = 7Hz, 2H, N0CH2); 5.23-6.32 (m, 4H, 3-CH2 and 2 lactam-H); 7.41 (s, 1H, thiazole); 7.95-8.65 ( m , 5 H , quinoline-H); 8.95-9.40 ppm Cm, 2H, quinoline-H) Example 21: 15 3-C(2-Isoquinolinium)methylJ-7-£2-syn-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido3 - ceph-3-em-4-carboxylate 1H-NMR (CF3C02D): & = 1.4-2.2 (m, 8 eyelopentyl-H); 3.42 and 3.88 (AB, J = 18Hz, 2H, SCH2); 4.9-6.3 (m, 5H, cyc I openty I-H, 20 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.95-8.80 (m, 6H, iso-quinolin-H); 9.80 ppm (broad s, 1H, isoquinolire-H) Example 22: 25 3-C(1-Quinolinium)methyO-7-C2-syn-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamidoj-ceph-3-em-4-carboxylate ^H-NMR (CF^CO^D): 5 = 1.4-2.2 (m, 8 cyclopentyl-H); 3.4 0 and 3.75 (AB, J = 18Hz, 2H, SCH2); 2 066 5 9 - 29 - 5.1 (m, 1 eye IopentyL-H); 5.3Q-6.38 (m, 4H, 3-CH2 and 2 lactam-H); 7.42 (s, 1 H , thiazole); 7.95-8.65 ( m , 5 H , quinoline-H); 8.95-9.40 ppm (m, 2H, 5 quinoline-H) Example 23: 3-C(2-Isoquinolinium)methyl3~7-C2-syn-(1^3-thia2ol-4-yl) methyloxyimi n o - 2 -(2- a mi nothi azol-4-yI)acetamido'] -ceph-3-em- 4-carboxylate 10 1H-NMR (CF3C02D): £ = 3.45 and 3.88 (AB, J = 18Hz, 2H, SCH2); 5. 25-6.20 Cm, 6H, N 0 C H 2 , 3-CH2 and 2 lactam-H); 7.35 (s, 1H, thiazole); 7.9-0-8.80 (m, 7H, 6 i soqu inoline-H,and 1 thiazole-H); 9.70-15 9.85 (m, 2H, each having 1 isoquino line and 1 thiazole-H) Example 24: 3-CC2-Isoquinolinium)methyl3-7-Q2-syn-carboxymethyloxyim-ino-2-(2-atm'nothiazol-4-yl)acetamido~)-ceph-3-em-4-carboxylate 1H-NMR (CF3C02D): 3.43 and 3.90 (AB, J = 19Hz, 2H, SCH2); 5.10 (s/ 2H, 0CH2); 5.15-6.30 (m, 4H, 3-CH2 and 2 lactam-H); 7.42 . ( s , 1 H , thiazole),; 7.95-8.80 (m, 6 H , isoquinoline-H); 9.80 ppm (m, 1H, i soqu inoline-H) 20 25 j 2 06659 10 15 20 25 - 30 - Example 25: 3- Cc 1 -Q u i n o I i n i um ) m e t h y 1*3 - 7 - C2 - s y n - C 2 - c a r bo x y- 2 - p r ope n -1 -yl-oxyimino)-2-C2-aminothiazol-4-yl)acetamido3-ceph-3-em- 4-ca rboxy late 1H-NMR (CF3C02D) 3.A 2 and 3.88 CAB, J = 18Hz, 2H, SCH2); 5.1-6.45 Cm, &H, N0CH2, 3-CH2 and 2 lactam-H); 6.55-6.92 Cm, 2H, C=CH2); 7.42 Cs,1H, thiazole); 7.93-8.64 Cm, 5H, quinoline-H); 8.92-9.40 ppm Cm, 2H, quinoline-H) Example 26: 3-CC1-Quinolinium)methyQ-7-C2-syn-C2-carboxy-2-propyloxy-imino)-2-C2-aminothiazol-4-yl)acetam*ido"l-'c<:ph-3-em-4- carboxylate 1H-NMR CCFjCOgO) $ = 1.80 Cs, 6H, 2 x C H ^); 3.42 and 3.88 CAB, J = 18Hz, 2H, SCH2); 5.25-6.30 Cm, 4H, 3-CH2 and 2 lactam-H); 7.40 Cs, 1H, thiazole); 7.95-8.60 Cm, 5H, quinoline-H); 8.90-9.35 ppm Cm, 2H, quinoline-H) Example 27: 3-rC2-Isoquinolinium)methyl^)-7-C2-syn-C1-carboxyethyloxy-imino)-2-C2-aminothiazol-4-yl)acetamido3-ceph-3-em-4-carboxylate - ^ ^H-NMR CCF3C02D): 5 = 1.71 Cd, J = 7Hz, 3H, CH3); 3.45 and 3.90 CAB, J = 1 8 H z , 2tf, SCH2); 4.92-6.40 (m, 5H, ClH-CH3, 3-CH2 and 2 lactam-H); 7.42 Cs, 1H, thiazole); 2 06 6 59 10 - 31 - 7.96-8.80 (m, 6H, isoquinoline-H); 9.80 ppm (broad s, 1H, isoquinoline-H) Example 28: 5 3-(7(2-Isoquinolinium)methyl']-7-C2-syn-(1-carboxycyclopro-pyloxyimino)-2-(2-aminothiazol-4-yl)acetamido*|-ceph-3-em-A-carboxylatc 1H-NMR CCF3C02D): £ = 1.52-1.95 (m, 4 cycIopropyl-H>; 3.46 and 3.90 (AB, J = 18Hz, 2H, SCHg); 5.15-6.30 (m, 4H, 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.95-8.80 (m, 6H, isoquinoline-H); 9.80 ppm (broad s, 1 H , •isoquinoline-H) Example 29: 15 3-C(1-Quinolinium)methyl3-7-C2-syn-(1-carboxycyclobutyloxy-imino)-2-(2-aminothiazol-4-yl)acetamido*}-ceph-3-em-4-carboxylate ^ H - N M R (CF3C02D): ^ = 2.0-3.2 ( m , 6 cyclobutyl-H); 3.45 and 3.92 (AB, J = 18Hz, 2H, SCH2); 20 5.25-6.38 (m, 4H, 3-CH2 and 2 lac- tam-H); .7.42 (s, 1H, thiazole); 7.95-8.60 (m, 5H, quinoline-H); 8.93-9.42 ppm (m, 2H, quinoline-H) Example 30: __ ^ 2 5 3~C(1-Quinolin iun))methyl3-7-C2-syn-(1-carboxycyclopentyl-oxyimino-2-(2-aminothiazol-4-yl)acetamido3-ceph-3-em-4-carboxylate ^ H-NMR (CF3C02D): £ = 1.4-2.4 (in, 8 c y c I open t y I-H ); 3.45 ...w-.'fs-'*..v.r'v«T-£ W? 10 15 20 - 32 - and 3.90 (AB, J = 18Hz, 2H, SCH2>; 5.15-6.35 Cm, AH, 3-CH2 and 2 lactam-H); 7.A2 (s, 1H, thiazole); 7.90-8.62 (m, 5H, quinoline-H; 8.93-9.40 ppm (m, 2H, quinoline-H) Example 31 : 3-£*2-IsoquinoLinium)methyl3-7-C2-syn-methoxycarbonylmethyl-oxyifnino-2-(2-aminothiazol-4-yl)acetamido]-ceph-3-em-4- carboxylate 1H-NMR (CF3C02D) & = 3.A3 and 3.90 (AB, J = 19Hz, 2H, SCH2>; 3.9A (s, 3H, CH3); 5.03 (s, 2H, M 0 C H 2); 5.20-6.A5 (m, AH, 3-CH2 and Z lactam-H); 7.42 (s , 1H, thiazole); 7.90-8.75 (m, 6H, isoquinoline-H); 9.80 ppm (broad s, 1H, i soqu i no I i ne-H) Example 32: 3-r(1-Quinolinium)tnethyl3-7-{l2-syn-cyanomethoxyimino-2-(2-aminothiazol-A-yl)acetamido*]-ceph-3-em-A-carboxylate H-NMR (CF3C02D) 25 & = 3.42 and 3.78 (AB, J = 19Hz, 2H, SCH2); 5.12 (s, 2H, N0CH2); 5.25-6.38 (m, AH, 3-CH2 and 2 lactam-H); 7.43 <s, 1H, thiazole); 7.95-8.65-(m, 5H, quinoline-H); 8.93-9.38 ppm (m, 2H, quinoline-H) ZV66 59 - 33 - Example 33: 3-CC2-IsoquinoLim'um)methylJ-7-C?~syn-carbamoylmethoxy- imir>o-2-(2-aminothiazol-4-yl)acetarcido}-ceph-3-em-4- carboxyLate 5 ^ H-NMR <CF3C02D): 6 = 3.42 and 3.92 CAB, J = 19Hz, 2H, SCH2); 4.95-6.35 Cm, 6H, NOCH2, 3-CH2 and 2 lactam-H); 7.44 Cs, 1H, thiazole), 7.9C-8.75 Cm, 6H, isoquinoline-H); 9.78 ppm (broad s, 1 H, 10 isoquino Iine-4) . E xamp I e 34: 3-C.Cl-Quinolinium)methyO-7-{72-syn-carbamoyin)ethoxyimino- 2-C2-aminothiazol-4-yl)acetamido']-cep'h-3-e'm-4-carboxylate ^ H-NMR CCF3C02D): & = 3.42 and 3.85 (KB, J = 19Hz, 2H, 15 SCH2) ; 4.92-6.40 (m, 6H, N0CH2, 3-CH2 and 2 lactam-H); 7.44 (s, 1H, thiazole); 7.95-8.65 (m, 5H, quinoline-H); 8.95-9.40 ppm (m, 2H, quinoline-H) 20 E xamp I e 35 : 3-CC4-Methyl-1-quinolinium)methyl*)-7-[2-syn-methoxyimino-•2-(2-aminothiazol-4-yl)acetamidoJ-ceph-3-em-4-carboxylate 1H-NMR CCF3C02D): 3.15 Cs, 3H, CH3); 3-40 and 3.80 CAB, J = 18Hz, 2 H, SCH2); 4.23 (s, 25 3H, OCHj); 5.30-6.40 (m, 4H, 3-CH2 and 2 lactam-H each having 1 d at 5.42 and 6.11; J = 5Hz, C-6 and C-7-H); 7.42 (s, 1H, thiazole); 7.80-8.75 (m, 206659 - 34 - 5H, quinoline-H); 9.OS ppm (d, J = 6Hz, 1 quinoline-H) Example 36: 3- C(S-Hydroxy-2-i soquinolinium)methyQ-7-C2-syn-methoxy- imino-2-(2-aminothiazol-4-yl)acetamido*]-ceph-3-em-4- carboxylate ^ H-NMR <CF3C02D): & = 3.45 and 3.91 (AB, J = 18Hz, 2H, SCH2); 4.21 (s, 3H, 0CH3); 5.25-6.35 . (m, 4H, 3-CH2 and 2 lactam-H); 7.41 (s, 1H, thiazole); 7.95-8.80 (m, 5H, isoquinoline-H); 9.78 ppm (broad s, 1H, isoquinoline-H) Example 37: '* 1 3-£(1-Quinolinium)methyl3 -7-c<'-me t hoxy-7 - Q? ~ syn-methoxy-imino-2-(2-aminothia7.ol-4-yl)acetamido3-ceph-3-em-4-car-boxyI at e ^ H-NMR (CF3C02D): & = 3.30-3.95 (m, 5H, 0CH3 and SCH2); 4.23 (s, 3H, 0CH3); 5.25-6.45 (m, 4H, 3-CH2 and 2 lactam-H); 7.43 (s, 1H, thiazole); 7.90-8.63 (m, 5H, quinoline-H); 8.90-9.35 ppm (m, 2H, quinoline-H) - 35 - 205659 Example 38: 7-/2-(2-Aminothlazol-4-yl) -2-syn-difluoromethoxyimino-acetamidQ/-3-isoquinolinium-methyl-ceph-3-em-4-carboxylate Process 2, Variant b Solution A: 0.53 g of 2-(2-aminothiazol-4-yl)-2-syn-difluoro-methoxyiminoacetic acid, 0.30 g of 1-hydroxybenztriazole hydrate and 0.41 g of dicyclohexylcarbodiimide are suspended in 25 ml of N/N-dimethylformamide (DMF), the suspension is stirred at room temperature for 2 hours and the dicyclo-hexylurea is filtered off. • Solution B: 0.68 g of 7-amino-3-iodornethyi-ceph-3-em-4-carboxylic acid are suspended in 40 ml of DMF. After adding 0.65 g of isoquinoline the suspension is stirred at' room temperature for 4 hours. While cooling with ice, solution A is dropped into solution B and the resulting solution is stirred at room temperature overnight. Then the solution is concentrated in vacuo, dissolved in a small quantity of water, while adding sodium bicarbonate until a pH of 6 is reached and chromatographed over silica gel (Merck, "Lobar" column B) using 3:1 acetone:water. The product fractions are freeze-dried to give 0.09g of a colorless, amorphous solid. 1 H-NMR (CF3C02D) : (T = 3.40 and 3.90 (ABg, J = 18 Hz, 2H, SCII2) , 5.30.- 6.42 (m, 4H, CH2fP and 2 lactam-H), 6.70 (t, J= 72 Hz, 1H, CHF~), 7.45 (s, 1 thiazole-H), 8.0 - 8.8 (m, 6 isoquinoline-H), 9.80 ppm (broad s, 1 isoquinoline-H). 2 The compounds listed in Table 1 below, which correspond to the general formula I, wherein R is hydrogen, and which carry, as the radicals , R3 and A, the substituents indicated in Table 1, are obtained analogously to the Examples 1, 2 and 38. Table 1 Example R1 R3 A 1H-NMR in CF3C02D: <f (ppm) = 39 h ch3 Br 3.2-4.05 (AB, J ^18 Hz, 2H, SCH2) , 4.25 (s, 3H, OMe) , 5.05-6.38 (m, 4H, CH2^ and w I 2 lactam-H), 7.40 (s, 1H, thiazole), 7.45- © 9.0 (m, 6 quinoline-H). 40 H CH3 N. /^s/OCH3 3.1-3.9 (AB, J= 19 Hz, 2H, SCH2), 4.11 (s, 3H, quinoline-OMe), 4.23 (s, 3H, OMe), 5.26-6.43 (m, 4H, CH2N® and 2 lactam-H), 7.39 (s, 1H, thiazole), 7.42-8.54 (m, 4 0 quinoJLine-H) , 8.71-9.22 (m, 2 quinoline-H) 41 Cl % ch3 jH3 \\ 1 0 3.15 (s, 3H, lepidine-CH3), 3.16-4.0 (AB, 18 Hz, 2H, SCH9), 4.19 (s, 3H, OMe), 5.19-6.4 (m, 4H, CH2N® and 2 lactam-H), 7.8-8.7 (m, 5 lepidine-H), 9.0 ("d", J2 3= 6 Hz, lepidine-2-H). © Table 1 Example (Cont.) R1 R3 A 1H-NMR in CF3C02D:cT(ppm) = 42 Br ch3 CH3 3.13 (s, 3H, lepidine-CHj), 3.05-4.0 (AB, • Cjt © 1 J= 18 Hz, 2H, SCH2), 4.19 (s, 3H, OMe), 5.13-6.36 (m, 4H, CH2N® and 2 lactam-H), 7.75-8.74 (m, 5 lepidine-H), 9.04 ("d", J2 3= 6 Hz, lepidine-2-H). . 43 H- ch3 Br 3.05-4.0 (AB, J = 18 Hz, 2H, SCH2), 4.2 (s, 3H, OMe), 5.05-6.65 (m, 4H, CH2N® and 1 © a— 2 lactam-H), 7.39 (s, 1H, thiazole); 7.45- 7.98 (m, 5 isoquinoline-H), 9.83 (mc, 1 isoquinoline-H). 44 H C2H5 i?3 a 1 © ' 1.42 (q, J= 7 Hz, 3H, OEt), 3.15 (s, 3H, lepidine-CH3), 3.05-3.95 (AB, J= 18 Hz, 2H "SCH2), 4.52 (q, J= 7 Hz, 2H, OEt), 5.23-6.55 (m, 4H, CH2ll^ and 2 lactam-H), 7.4 (s 1H, thiazole), 7.75-8.75 (m, 5 lepidine-H) 9.05 ("d", J2 3 = 6 Hz, lepidine-2-H). ( ) Table 1 (Cont.) 1 H-NMR in CF3C02D: cP (ppm) = Example R1 R3 A 45 H C2H5 Oc och3 1.42 (q, J= 7 Hz, 3H, OEt), 3.1-4.0 (AB, J= 18 Hz, 2H, SCH2), 4.1 (s, 3H, quinoline-OMe), 4.52 (q, J= 7Hz, 2H, OEt), 5.22-6.6 (m, 4H, CH2I^ and 2 lactam-H), 7.39 i © (s, 1H, thiazole), 7.52-8.56 and 8.82- 9.15 (m, 6 quinoline-H). i 5 > 46 h C2H5 0 OH V| 1.4 (broad t, J= 7 Hz, 3H, OEt), 3.15- £ 4.0 (AB, J= 18 Hz, 2H, SCH2), 4.51 (broad ' q, J= 7 Hz, 2H, OEt), 5.16-6.52 (m, 4H, CH2N® and 2 lactam-H), 7.39 (s, 1 thiazole-H) ,. 7.53-9.0 (m, 5 isoquinoline-H), 9.66 (mc, 1 isoquinoline-H). . 47 ' i H -CH2CH^ =ch2 gr ' 3.1-4.1 (AB, J= 19 Hz, 2H, SCH-), 4.9 (mc, 2 Q 2H, CH2 of allyl), 5.03-6.68 (m, 7H, CH2N , 2 lactam-H and 3 allyl-H), 7.4 (s, 1H, j thiazole), 7.5-9.0 (m, 5-isoquinolone-H), 9.82 (mc, 1 isoquinoline-H). Dr Q\ Of s0 (J Table 1 (Cont.) Example R1 R' 1H-NMR in CF3C02D: cf (ppm) = 48 H -CH2CH=CH2 CH 3.15 (s, 3H, lepidine-CH3), 3.05-3.95 b (AB, J= 18 Hz, 2H, SCH~) , 4.9 (mc, 2H, Q CH2 of allyl), 5.05-6.63 (m, 7H, CH2N , • 2 lactam-H and 3 allyl-H), 7.43 (s, 1H, » • & 1 thiazole), 7.76-8.75 (m, 5 lepidine-H), 9.05 ("d", J2 3= 6 Hz,lepidine-2-H). 49 H -CH, 0.23-0.9 (m, 4 cyclopropyl-H), 1.1-1.6 (m, 1 cyclopropyl-H), 3.15 (s, 3H, lepidine-CH3), 3.05-3.95 (AB, J= 19 Hz, 2H( SCH2), 4.28 (d, J= 7.5 Hz, 2H, cyclopropyl), 5.2-6.6 (m, 4H, CH2tP and 2 lactam-H), 7.43 (s, 1H, thiazole), 7.79-8.74 (m, 5-lepidine-H), 9.04 ("d", J2 3= 6 Hz, lepidine-2-H). U) VO 50 H CH2CF3 3.13 (s, 3H, lepidine-CH^), 3.15-3.86 (AB, J= 18 Hz, 2H, SCH2), 4.69 (broad q, J= 8 Hz, 2H, CH.2-CF3) , 5.26-6.68 (m, 4H, N) O CH2N® and 2 lactam-H), 7.39 (s, 1H, thiazole) 7.76-8.79 (m, 5 lepidine-H), 9.04 ("d" ^ J2 3= 6 Hz, lepidine-2-H). Ul KO I Table 1 (Cont.) Example R 1 R~ 1H-NMR in cf3c02d: ^(ppm) = 51 h ch2cf3 3.2-4.06 (AB, J= 19 Hz, 2H, SCH2), 4.66 (broad q, J= 8 Hz, 2K , -CH2"CF3), 5.23-6.53 (m, 4H, CH2N® and 2 lactam-H), 7.36 (s, 1H, thiazole), 7.86-8.8 (m, 6 isoquinoline-H), 9.76 (mc, 1 isoquinoline-H). 52 h -ch2c=ch 2.58 (mc, 1H, propargyl-H), 3.15 (s, 3H, lepidine-CH^), 3.05-4.0 (AB, J= 18 Hz, 2H, , SCH-) , 4.96 (d, J ^1.5 Hz, 2H, -CH0-C=CH),^ © 1 ° 5.16-6.6 (m, 4H, CH2N and 2 lactam-H), 7.39 (s, 1H, thiazole), 7.75, 8.75 (m, 5 lepidine-H), 9.04 ("d", J= 6 Hz, lepidine-2-H.) . 0 1 53 h -ch2-c=ch 2.56 (mc, 1H, propargyl-H), 3.13-4.1 (ab, J= 19 Hz, 2H, SCH2), 4.95 (d, J2 Hz, 2H, -CH2-C=CH), 5.15-6.55 (m, 4H, CHjN® and 2 lactam-H), 7.38 (s, 1H, thiazole), 7.86-8.8 (m, 6 isoquinoline-H), 9.75 (mc, 1 isoquinoline-H) . O"* Table 1 (ContJ Example R 1 1h-nmr in CF^CO^D: J* (ppm) = 54 H CH2CO2CH3 I 1 3.42 and 3.85 (AB, J= 18 Hz, 2H, SCH2), 3.95 (s, 3H, OCH3) , 5.,02 (s, 2H, OCH2) , 5.15-6,35 (m, 4H/ CH2N® and 2 lactam-H), 7.41 (s, 1H, thiazole), 7.95-8.65 (m, 5 0 1 quinoline-H), 9.00-9.45 (m, 2 quinoline- H) . . 55 H- CH2C02C2H5 1.38 (t, J= 7 Hz, 3H, OEt), 3.51 and 3.83 (AB, J= 18 Hz, 2H, SCH2), 4.36 (q, J= i 7 Hz, 2H, OEt), 4.85-5.15 (AB, 2H, OCH2), ^ 5.23-6.55 (m, 4H, CH-N® and 2 lactam-H), i - z 7.39 (s, 1H, thiazole), 7.85-8.80 (m, 6 isoquinoline-H), 9.78 (mc, 1 isoquinoline-: H) . 56 h ch2co2h 3.48 and 3.92 (AB, J= 18 Hz, 2H, SCH2), 4.9-5.2 (broad s, 2H, OCH2), 5.23-6.45 (m, 4H, CH21^ and 2 lactam-H), 7.43 (s, 1H, thiazole), 7.85-8.65 (m, 5 quinoline-H), 8.95-9.43 (m, 2 quinoline-H). K) O o e Table 1 (Cont.) Example .1 R" 1 H-NMR in CF CO.D: cf (ppm) = 57 h c(ch3)2co2h 1.77 (s, 6H, CH^ twice), 3.50 and 3.87 (AB, J= 18 Hz, 2H, SCH2), 5.25-6.50 (m, 4H, CH2n® and 2 lactam-H), 7.40 (s, 1H, thiazole), 7.55-8.75 (m, 6 isoquinoline-H), 9.75 (mc, 1 isoquinoline-H). 58 h -ch(ch3)c02h 1.75 (broad d, J= 7Hz, 3H, CH.3-CH) , 3.1-3.95 (AB, J= 18 Hz, 2H, SCH_), 4.9-6.55 0 (m, 5H, CH2N , 2 lactam-H and CH-CH3), 7.34 (s, 1H, thiazole), 7.79-8.68 (m, 5 quinoline-H), 8.91 - 9.3 (m, 2-quinoline-H) . •fit to 59 h co2h 1.95-3.0 (m, 6 cyclobutyl-H), 3.17-4.06 (AB, J= 18 Hz, 2H, SCH0), 5.15-6.55 (m, 4H, s Z CH2N and 2 lactam-H), 7.38 (s, 1H, thiazole), 7.63-8.83 (m, 6 isoquinoline-H), 9.77 (mc, 1 isoquinoline-H). Ch ui </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Table 1 (Cont.) 1 Example R ) 1 1H-NMR in CF3C02D: <f (ppm) = 1.63-2.7 (m, 8 cyclopentyl-H), 3.
2-4.13 (ABr J= 19 Hz, 2H, SCH2), 5.26-6.56 (m, 4H, CH2N® and 2 lactam-H), 7.36 (s, 1H, thiazole), 7.7-8.83 (m, 6 isoquinoline -H), 9.76 (mc, 1 isoquinoline-H) i ui l K) O O o Ui o 206659 - Uk - WHAT"T/WE CLAIM !S: (I) and physiologically acceptable acid addition salts thereof in which 1 R denotes hydrogen or halogen, 2 R denotes hydrogen or methoxy, 3 R denotes hydrogen / optionally substituted C^-C^-a Iky I, optionally substituted C_-C,-alkenyl, C,-C,-alkinyl, C,-C.,- co ' c o 5 ( cycloalkyl, Cj-C^-cycloalkyl-C^-C^-alkyl, C^-C^-cyclo- R4 or/ K alkenylX the group (CH.J (C) R6 ✓ in ' z n , m R which m or n can each be 0 or 1 , R ^ and R ^ can be identical or different and 4 denote hydrogen, aryl, or a C^-C^-alkyl group, or R 5 and R taken together, form a methylene group or taken together with the carbon atom to which they are attached form a C^-Cj- cycloalkylidene group, it being possible for alkyl and cycloalky] to be further monosubstituted or polysubstituted, and R^ denotes 7 7 a group -CC^R in which R denotes hydrogen, C^-C^-alkyl, -CH^OC^-C^-alkyl, CH2OQO-C1-C4-alkyl or one equivalent of an alkali metal, alkaline earth metal, ammonium or an organic amine base; a nitrile group or a carbamoyl group - C 0 N H _ which can be monosubstituted or disubstituted on the nitrogen, and A denotes a quinolinium or an isoquino Iinium radical each - k5 - 206659 of which can also be monosubstituted or polysubstituted by identical or different substituents, by C^-C^-alkyl which can also be substituted, -C^-a tkoxy, halogen, trifluoro-methyl or hydroxyl, and in which the R^O group is in the syn-position. 2- A process for the preparation of a compound of the acoortjina to claim 1 formula IAand its physiologically acceptable acid addition salts, which comprises a) reacting a compound of the general formula II N or salts thereof or a reactive derivative of the compound II in which R^, and have the abovementioned meaning g and R denotes an amino group or a protected amino group 9 and R denotes a group which can be replaced by quinoline, isoquinoline or substituted quinolines or isoquinolines corresponding to the radicals A of the formula I, with quinoline, isoquinoline or one of their derivatives, and ©{■) splitting off a protective group which may be present and p) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or b) reacting a 7-aminocephem compound of the general formula I I I 206659 kS - R 2 (III) or acid addition salts thereof in which R^ and A have the abovementioned meaning, it also being possible for the amino group to be present in the form of a reactive derivative, with a 2-(2-aminothiazol-4-yI)-2-syn-oximinoacetic acid of the general formula IV with an activated derivative of this compound, and cy) splitting off a protective group which may be present and ^3 > if necessary, converting the resulting product into a physiologically acceptable acid addition salt.
3. The process as claimed in claim 2, wherein the rucleophilic replacement of the substituent R^ is effected in the presence of neutral salt ions. A.
The process according to claim 3 wherein the neutral salt ions are iodide or thiocyanate ions. IV 13 8 in which R , R and R have the above meaning, or i ■ 206659 - 47 -
5. The process as claimed in claim 2,'wherein the nucleophilic replacement of the substituent R9 is effected in the presence of the base from which the radical A is derived, and of trimethyliodosilane.
6. A pharmaceuticaI formulation which is effective against bacterial infections and contains cephem derivatives of the formula I according to claim 1.
7. A process for the preparation of a pharmaceutical formulation which is effective against bacterial infections, which comprises bringing a cephem derivative of the according r-lairr| 1 formula I\into a pharmaceutically suitable administration form and it appropriate together with pharmaceutically customary excipients, diluents or buffer substances. according to claim 1
8. The use of cephem derivatives of the .formula I^tor ~~ combating bacterial infections with the proviso that the use does not represent a method of treatment of the human body.
9. a cephem derivative as claimed in claim 1, wherein, affording to xlainLJ. .. . 2 in the general formula lJ(^R represents Hydrogen and halogen, R represents hydrogen, R^ represents C-j-C^-atkyl and A represents quinoline or isoquinoline.
10. A cephem derivative as claimed in claim.9, wherein halogen represents chlorine and the C-J-C^-a I ky I- group represents methyl or ethyl.
11. A cephem derivative according to claim 1 substantially as herein described or exemplified.
12. A process, according to claim 2 substantially as herein described or exemplified. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED By: </div>