CS249132B2 - Method of new 7-(2-oximino-2-/2-aminothiazol-4yl/acetamido)cephaeme derivatives' production - Google Patents

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

The present invention relates to a process for the production of novel cephalospoirin derivatives, in particular to a process for the production of nium polar cefemderivatives which are substituted in the 3-position of the cerium ring by certain quinolinioactive and isoquinolioium methyl groups and which have very good antimicrobial activity against gramopositive and gram-negative bacteria. to treat microbial infections.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel 7- (2-oximino-2- (2-amino-thiazol-4-yl) acetamido] -cephem derivatives of general formula I

(I) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylalkyl and having 1 to 6 carbon atoms in the alkyl moiety;

R ¹ is a hydrogen atom or a halogen atom,

R ² is hydrogen or methoxy;

R ³ is optionally halogen, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy or substituted thiazolyl

R ⁴ I (CH 2) n (C) _m R 6

R ⁵ where man represents the number · 0 or 1,

R ⁴ and R ⁵ are the same or different from each other and represent a hydrogen atom, a (C 1 -C 4) alkyloxy group, since, together with the carbon atom to which they are attached, they form a methylene group or a C 3 -C 7 cycloalkylidene group,

R ⁶ represents a group -CO ² R ⁷ in which

R ⁷ is hydrogen, C 1 -C 4 alkyl or an alkali metal, alkaline earth metal or ammonium equivalent, nitrile or carbamoyl-CONH 2,

A represents chinoliniovlou group or isoquinolinium group which is optionally substituted by alkyl having 1 to 6 carbon atoms, alkolxyskuplnloiu having 1 to 6 carbon atoms, halogen or hydroxyskupinloíu wherein the group - OR ³ is in position son, and their physiologically acceptable acid addition salts with acids.

In particular, the present invention provides a process for the preparation of compounds of formula I wherein:

R ^1, R ² and A have the abovementioned meanings and shjora

R ³ is C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkylthio, C 1 -C 6 alkyloxy or thiazolyl, furthermore C 2 -C 6 alkenyl, alkynyl C 2 to C 3 cycloalkyl, C 3 to C 7 cycloalkyl, C 3 to C 7 cycloalkylalkyl in the cycloalkyl moiety of up to about 6 carbon atoms in the alkyl moiety, or a depicted group of formula

R ⁴

- (CH 2) n - (C) _m - R ⁶

An R5 group, an isopropyl group, a butyl group, an isobutyl group, a target, a butyl group, in particular a methyl group, an ethyl group;

halogen, for example chlorine, bromine, iodine or fluorine-substituted alkyl, in particular trifluoromethyl,

2,2,3,3-tetrafluoropropyl; (C 1 -C 6) alkylthio substituted alkyl, such as methylthio, ethylthio or propylthio substituted alkyl;

(C 1 -C 6) alkyloxy, for example, methylOX or ethyloxy substituted alkyl;

a thiazolyl group, for example a 1,3-thiazol-4-yl-substituted alkyl group, in particular a 1,3-thiazol-4-ylmethyl group;

a (C 2 -C 4) alkenyl group such as a vinyl group, an allyl group, an isopropenyl group, a methylallyl group, in particular an allyl group, a methyl allyl group; (C 2 -C 3) alkynyl, in particular propargyl; C 3 -C 7 cycloalkyl such as, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, especially cyclopenityl;

a (C 3 -C 7) cycloialkylmethyl group such as, in particular, a cyclopropylmethyl group; group formula

R ⁴ I

- (СНз) п- (C) _m —R ⁶

R ⁵ in which

R ⁴ and R ⁵ are the same or different and are hydrogen, C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyloxy, sec-butyl, preferably methyl, ethyl, especially methyl, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a methylene group or a C 3 -C 7 cycloalkylidein group such as cycloprolylidene, cyclobutylidein, cyclopentylidene, cyclohexylidene, cycloheptylldene, preferably cyclopropylidene, m is 0 or 1 and n is 0 or 1 as defined above, and also in these preferred compounds the -OR ³ group is in the syn position.

Particularly preferred substituents are, for example, the following substituents:

R ¹ represents hydrogen, fluorine, chlorine, bromine, in particular fluorine and chlorine;

R ² represents hydrogen, methoxy;

R ³ represents a C 1 -C 4 alkyl group, for example methyl, ethyl, propyl, the following groups may be mentioned:

In case of women = 0 and m = 1:

wherein the sum of m + n is 1 or 2.

As, preferred examples of a group of formula

R ⁴

AND

- (CH 2) n - (CJ _m -CH (CHJ -Č (си ₃ ) з)

In case m = 0 and n = 1:

—CH2—

In case n and m - 1: —CH2 —C—

II

CHz

R ⁶ is -CO ² R ⁷ in which R ⁷ is hydrogen, C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl a group, preferably a methyl group, an ethyl group, especially a methyl group, or an alkali metal equivalent, such as ₍ for example, sodium, potassium, lithium, preferably sodium and potassium, an equivalent of an alkaline earth metal, preferably calcium or magnesium, ammonium, further nitrile or carbamoyl group

A represents a quinolinium radical of the formula

which is optionally substituted in the same manner as above for the quinolinium residue.

Preferred examples for substituent A include:

quinolinium, 2-, 3-, 4-, 5-, 6-, 7-, or 8-methylquinolinium, 3-, 5-,

A 6-, 7- or 8-hydroxy-quinolinium group,

3-, 4-, 5-, 6-, 7- or 8-methoxyquinolinium, 3-bromo, 3-chloro, 5-chloro, isoquinolinium, 1-, 3-, 4-, 5 -, 6-, 7- or 8-methyl-isoquinolinyl, 4-chloro,

A 4-bromo-, 4-hydroxy- or 5-hydroxyisoquinolinium group.

According to the invention, the compounds of formula (I) and their physiologically tolerable acid addition salts are prepared by the formation of a compound of formula (IA)

which is optionally substituted by C 1 -C 4 alkyl, such as, in particular, methyl, ethyl, propyl, isopropyl, butyl, alkoxy of 1 to 6 carbon atoms, for example ethoxy or methoxy; halogen such as fluorine, chlorine, bromine or iodine; or hydroxy; or - represents an isoquinolinium radical of the formula

in which

R2 is as defined above and

R ⁹ is a quinine or isoquinoline-exchangeable group which corresponds to residues A in formula I, for example acetoxy or propionyl, in any order 2- (2-amino-thiazol-4-yl) -2-yn-0 ' XiminOcot | owu acid of formula IV

And in formula I, such an embodiment of the process of the invention can be described in more detail as follows:

Reaction of a compound of formula IA

R ²

A — r ^COOH (IV)

COOH (IA) in which

R ¹ and R ³ are as defined above, and

R ⁸ is an amino or protected amino group, for example an tert-butyl protected amino group, a benzyl group or a trityl group, or an activated derivative thereof and those quinoline or isoquinololine bases corresponding to residues A in formula I, whereupon any protecting group present is cleaved; the compound of formula I obtained is optionally converted into a physiologically acceptable salt.

If the compound of formula (IA) is first reacted with a compound of formula (IV) or an activated derivative thereof, and the resulting intermediate is reacted with a quinoline base or an isoquinoline base corresponding to a residue in which

R ² and R @ ⁹ have the abovementioned meanings, with 2- ^{[2-aminothiazol!} ol-4-yl) -4-amino-oxirinoacetic acid of formula IV

R »

C-C ^C ^OH II

Ov>

in which

R 1, R ^3, and · R ⁸ are as defined above, or with an activated derivative of this compound is obtained as an intermediate compound of formula II

in which

R1, ^{R2, R3,} R8 and R9 have the above meanings, and the thus obtained compound of formula II or · a salt thereof or its silyl derivatives is treated with quinolinic bases or isoquinolyl] IT) Иιnι (tvι (the bases that The corresponding protecting group is cleaved and the product obtained is optionally converted to an acid addition salt with a physiologically tolerable acid addition salt.

On the other hand, in the process according to the invention, the compound of formula IA is first reacted with a quinoline base or an isoquinol base which corresponds to the residue A in formula I and the resulting intermediate is then reacted with 2- (2-amino-thiazole). The compound of formula (IV) or an activated derivative of the compound may be described in more detail as follows:

Reaction of a compound of formula IA

in which

R ² and R ⁹ are as defined above, with a quinoline base or isoquinoline base corresponding to residue A in formula I is obtained as an intermediate 7-aminocephemerivative of formula III

in which

A and R 2 are as defined above, wherein the amino group may also be present in the form of a silyl derivative, and the compound or its acid addition salts is then treated with 2- (2-aminothiazol-4-yl) -2-syn-amino (acetic acid of general formula IV (IV) in which

R @ 1, R @ ³ and R @ ⁸ are as defined above, or an activated derivative of the compound, whereupon the optionally present protecting group is cleaved and the compound of formula I obtained is optionally converted into a physiologically usable acid addition salt.

If the compounds of the formula I are prepared by the inucleophilic exchange of the radical R9 in the compounds of the formula II or IA with quinoline, isoquinoline or one of its derivatives, the acetyloxy groups of the lower aliphatic carboxylic acids, in particular 1 to 4, are preferred. carbon atoms such as acetoxy or pnoipionyloxy, especially acetoxy, which may be optionally substituted, such as chloroacetoxy or acetylacetoxy. Further groups for the radical R9 are also possible, such as, for example, halogen, in particular chlorine, bromine or iodine, or a carbamoyloxy group.

According to the invention, the nucleophilic exchange reaction uses starting compounds of the formula II or IA in which R 9 is acetoxy or salts thereof, such as sodium salts or potassium salts. This reaction is carried out in a solvent, preferably water or a mixture of water and an organic solvent which is readily miscible with water, such as acetone, dioxane, acetinitrile, dimethylformamide, dimethylsulfoxide or ethanol. Reaction temperatures generally range from about 10 to about 100 ° C, preferably from 20 to 80 ° C. The basic component is added in an amount ranging between about equimolar and up to about 15 times the excess. The exchange of the residue R 9 is facilitated by the presence of neutral salt ions in the reaction medium, preferably iodide or thiocyanate ions. In particular, about 10 to about 80 equivalents of iodine are added ^; potassium, sodium iodide, potassium thiocyanate or sodium thiocyanate. The reaction is preferably carried out near a neutral point, preferably at a pH in the range of about 5 to about 8.

When R8 is present in the form of a protected amino function, for example, an optionally substituted alkyl group such as a tert-butyl tertiary group, a tert-amyl group, a benzyl group, a p-methoxybenzyl group, a trityl group are suitable as amino protecting groups. a benzhydryl group, preferably a trityl group; a trialkyisyl group such as a trimethylsilyl group; optionally substituted aliphatic acyl such as tormyl, chloroacetyl, bromoacetyl, triacetacetyl, and t-fluoroacetyl, preferably formyl; or an optionally substituted alkoxycarbonyl group such as a trichloroethoxycarbonyl group, a benzyloxycarbonyl group or a tert-butyloxycarbonyl group, preferably a tert-butyloxycarbonyl group and an benzylcarbonyl group; or a dimethylaminomethyl group.

The protecting group may be cleaved off in a manner known per se, for example a trityl group with a carboxylic acid such as acetic acid, trifluoroacetic acid, formic acid or a benzyl oxycarbonyl group hydrogenolytically.

The reaction products of the formula I can be isolated from the reaction mixture in a customary manner, for example by freeze drying the aqueous phase, or also by precipitation as a sparingly soluble salt, for example a hydroiodide salt or a hydrothiocyanate salt.

The nucleophilic exchange reaction in the compounds of formula (II) or (IA) may also be carried out by carrying out the reaction in the presence of a base corresponding to residues A, such as quinoline or isoquinoline, and trimethyl iodosilane. This variant of the exchange reaction is preferably carried out by adding trimethyl iodosilane to a mixture of a compound of formula II or IA and a base in a suitable solvent. Alternatively, the compound of formula (II) or (IA) may be reacted first with trimethyl iodosilane under the following reaction conditions, and then the base may be added.

Suitable solvents are chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, carbon tetrachloride or lower alkylnitriles such as acetoinitrile or propionitrile.

The base is added in at least a sto-bibometric amount up to a twentyfold excess. Preferably, a 5- to 15-fold excess is used.

Trimethyl i bidsilain is also added in at least a stoichiometric amount of up to 20 times the excess, preferably in a 5 to 15 times excess.

The reaction is carried out at temperatures between -5 ° C and +100 ^° C, preferably between 10 ° C and 80 ° C. The reaction products of formula (I) may be isolated from the aqueous phase in a conventional manner, for example by freeze drying, chromatography or the like, after the hydrolysis of the reaction mixture by adding water or free mineral acids such as dilute hydrochloric acid, hydrobromic acid, hydrobromic acid or hydrogen sulfide. Preferably, the polar reaction products precipitate out of the aqueous solution in the form of a sparingly soluble salt, for example after addition of KSCN or KJ in the form of the hydrothiocyanate salt or the hydride iodide salt.

In the case where the radical R ⁹ is carbamoyloxy, the exchange reaction is carried out in an analogous manner.

When R ^{9 is} halogen, especially bromine or iodine, the exchange reaction is carried out in a manner known from the literature.

When the compound of formula (II) is present in the form of reactive! the silyl derivatives which are formed in the reaction of the compounds of the formula II with a silyl derivative, such as trimethylchlorosilane, bis- (trimethylsilyl) acetamide or bis- (trimethylsilyl) trifluoroacetamide, are suitable. In this case, the reaction is expediently carried out in the presence of an inert solvent such as methylene chloride or acetonitrile.

The acylation of the compounds of formula III or their acid addition salts with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or an organic acid such as methanesulfonic acid, p-toluenesulfonic acid or maleic acid is carried out. with carboxylic acids of the formula IV or with a reactive derivative of such an acid. In many cases, it is preferred to protect the 2-amino group in the compounds of formula IV from the reaction. Suitable amino protecting groups are those described above for R ⁸ . After the acylation, the protecting group may be cleaved in a manner known per se, for example a trityl group by treatment with a carboxylic acid such as formic acid or trifluoroacetic acid or a chloiracetyloyl group by treatment with thiourea. When the carboxylic acids of the formula (IV) and the amino-protected derivatives themselves are used as acylating agents, they are expediently carried out in the presence of a condensing agent, for example a carbodiimode such as N, N'-dicyclohexylcarbodiimide.

The activation of the carboxylic acids of the formula IV can be carried out in a particularly favorable manner by the action of certain carboxylic acid amides and, for example, phosgene, phosphorus pentachloride, tosylchloride, thionylchloride or oxoixalyl chloride, as described in German Patent No. 2,804,040.

Also suitable as activated derivatives of the carboxylic acids of the formula IV are halides, preferably chlorides, which can be obtained in a manner known per se by treatment with halogenating agents such as phosphorus pentachloride, phosgene or thionylchloiride under gentle reaction conditions known from the literature for cephalosporin chemistry.

Also suitable as activated derivatives of the carboxylic acids of the formula IV are the ainhydrides and mixed anhydrides, azides, activated esters and thiloiesters, preferably with. , 6-chloro-1-hydroxybenzotriazole and 2-mercaptobenzthiazole. Particularly suitable mixed anhydrides are mixed aynhydrides with lower alkanoic acids, such as acetic acid, and particularly preferably substituted acetic acids, such as trichloroioic acid, pivalic acid or cyanoacetic acid. However, mixtures of anhydrides with carbonic acid pploesters, which are obtained, for example, by reacting carboxylic acids of the formula IV in which the amino group is protected with benzyl chloroformate, p-nitroibenzyl chloroformate, isobutyl chloroformate, ethyl chloroformate or ethyl formate, are also particularly suitable. acid. The activated derivatives may be reacted as isolated substances or else in situ.

In general, the reaction of cefemerivatives of formula III with a carboxylic acid of formula IV or an activated derivative thereof is carried out in the presence of an inert solvent. Particularly suitable are chlorinated hydrocarbons, such as preferably methylene chloride and chloroform; ethers, such as diethyl ether, preferably tetrahydroturan and dioxane; ketones such as preferably acetone and butanone; amides such as preferably dimethylformamide and dimethylacetamide were not pyridine. It may also be advantageous to use mixtures of the solvents mentioned. This is often the case when the cephemed derivative of formula III is reacted with an activated carboxylic acid derivative of formula IV which has been prepared in situ.

The reaction of formula III with cephem karboixylovými acid of formula IV or their activated derivatives can be carried out in a temperature range from about -80 to about + 80 ^Q C, preferably between -30 and +50 ° C, in particular between about -20 ° C and room temperature.

The reaction time depends on the reactants, the temperature and the solvent or solvent mixture, and is usually between about + and about 72 hours.

The reaction with acid halides may optionally be carried out in the presence of an acid binding agent to bind the hydrogen halide that is released. Tertiary amines such as triethylamine, dimethylaniline or pyridine are particularly suitable as such; inorganic bases such as potassium carbonate or sodium carbonate; alkylene oxides such as propylene oxide. Optionally, the presence of a catalyst such as dimethylaminopyrldine may also be advantageous.

When the amino group is present in the form of a silyl derivative in the compounds of the formula (III), the silyl derivatives which are formed in the reaction of the compounds of the formula (III) with the silyl derivative, such as trimethylchlorosilane or thylsilyl] lactamide, are suitable. When the reaction is carried out with an activated amino compound, it is expedient to carry out the reaction in an inert solvent such as methylene chloride, tetrahydrofuran ¹ or dimethylformamide.

Physiologically tolerable acid addition salts of the compounds of formula I include, for example, addition salts with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sinic acid or organic acids, such as methanesullifonic acid, p-toluenesulfonic acid or maleic acid.

The compounds of formula (III) can be obtained in a manner known per se, for example from 7-aminocephalpsporanic acid or amine-protected amino-aminocaphalpsporanic acid in a conventional manner as described above for the nucleophilic exchange of R ⁹ .

The compounds of formula (IV) as well as the quinoline and isoquinoline derivatives corresponding to residues A are known from the literature or can be prepared according to methods known from the literature.

· Compounds of the formula I and their physiologically tolerated addition salts with acids, which can be prepared according to · the invention, having a ^{d p from d} oruhodn ° sharpening ^of antibacterial activity against both Gram positive and versus Gram negative bacteria ·.

Unexpectedly, the compounds of formula I are also effective against ptnicillinase and cephalosporininase-forming bacteria. In addition, since they possess favorable toxicological and pharmacological properties, these compounds are valuable chemotherapeutic agents.

Accordingly, the present invention also relates to pharmaceutical compositions for the treatment of microbial infections which are caused by the contents of at least one compound of the invention.

The compounds produced by the process according to the invention can also be used in combination with other active substances, for example from the series of penicillins, callalospoein or nHU; aminoglycosides.

The compounds of formula I and their physiologically tolerable acid addition salts can be administered orally, intramuscularly or intravenously. Pharmaceutical preparations containing one or more compounds of the formula I as active ingredient can be prepared by mixing the compounds of the formula I with one or more pharmacologically usable carriers or diluents, such as fillers, emulsifiers, lubricants, flavoring agents, coloring agents or buffers and converted into a suitable galenic form such as tablets, dragees, capsules, or suspensions or solutions suitable for parenteral administration.

Carriers or diluents include, for example, tagaint, milk sugar, talc, agar-agar, polyglycols, ethanol, and water. As buffers, for example, organic compounds such as N, N‘-dibenzylethylenediamine, dethanolamine, ethylenediamine, N-methylglucamine, min, diethylamine, teis (hydroxymethylmethylamine) methane, or, inorganic compounds such as phosphate buffer, sodium bicarbonate, sodium carbonate. Suspensions or solutions in water, optionally with the addition of buffers, are suitable for pareinteral administration. It is also possible to administer the active ingredients as such without the carrier materials of the net diluents in a suitable form, for example in capsules.

Suitable doses of the compounds of formula I or their physiologically compatible acid addition salts are from about 0.4 to 20 g / day, preferably from about 0.5 to 4 g / day, for adults of about 60 kg body weight.

These doses may be administered as a single dose or generally in multiple doses, the single dose containing the active ingredient in an amount of from about 50 to 1000 µg, preferably from about 100 to 500 mg.

Cephem product containing at position 3 · cephem ring methyl group substituted by a nucleophilic radical, are already subject to protection in DE-OS 27 16 707. Ne249132 ^IS 1.8 bvlo however be expected that the compounds obtained according to the invention are compared to compounds known from DE- OS 27 16 707 'exhibit unexpectedly higher antibacterial effects.

The following examples illustrate the preparation of the syn-derivatives according to the invention, but do not limit the scope of the invention in any way.

Example 1

3 - [(2-isoquinolin-1-ylmethyl) methyl] -7- [2-synimethoxyimino-2H

- (- aminothlothiazol-1-yl) ace tamido] -? -? - carboxylate

a) A mixture of 4.55 g (0.01 mol) of 7- [2- (2-aminothiazol-4-yl) -2-syn-methylamino-acetamido] -cephalosporanic acid, 66.4 g (0.4 mol) of iodide 0.3 g Ascorbic acid, 12.9 g (0.1 mol) of isoquinoline, 75 ml of water and 25 ml of acetone are heated to 66-68 ^° C for 4 hours. After cooling, the reaction mixture is diluted with 600 ml of acetone and chromatographed over 400 ml. g of silica gel (Merck, 0.063-0.2 mm), eluting with 1 liter of a mixture of acetone and a paste (8: 1), 500 ml of a mixture of acetone and water (5: 1), followed by a mixture of acetone and water (2: The title compound was eluted with acetone / water (2: 1) to give the fractions containing the product by freeze drying to give 2.36 g (45%) of a colorless amorphous solid.

IR spectrum (KBr technique):

765 cm ^@ -1 (lactam-CO).

4 H-NMR spectrum (deuterated trifluoroacetic acid):

S = 3.45 and 3.93 (AB, J = 18 Hz, 2H, SCH2),

4.21 (s, 3H, OCH 3),

5.25-6.50 (m, 4H, 3-CH2 and 2 lactam-H)

7.41 (s, 1H, thiazole);

7.95-8.80 (m, 6H, isoquinoline-H),

9.79 ppm (broad s, 1H, isoquinoline-H).

/ 3) To a mixture of 4.55 g (0.01 moil of 7- [2- (2-α-2-methyl-2-amino-4-yl) -2-isynimeihoxyliminomethyl amido] cephalosploiranoic acid and 11 g (0.085 mol) of isoquinoline In 100 ml of methylene chloride, 14 g (0.07 mol) of trimethyl iodosilane are added at 5 DEG C. The mixture is heated under reflux for 2 hours and after cooling, 80 ml of 2N hydrochloric acid are added and the resulting gummy precipitate is separated by decantation. This precipitate was dissolved in aqueous sodium bicarbonate solution and chromatographed as described above, after freeze-drying the fractions containing the product to give 1.95 g (37%) of a colorless solid, which was identical in all properties to the substance described above.

Example 2

3 - [(1-quinolinium) methyl] -7- [2S-methino] xylinIn121

- (2-aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

a) a) In an analogous manner as described in Example 1, 4.55 g (0.01 mol) of 7- [2- (2-aminothiazol-4-yl) -2-8 (P-ethoxyiminoacetamido) cephaloisporainic acid is reacted with 12.9 g (0.1 mol) of quinoline. Chromatography gave 1.42 g (27% of theory) of a colorless solid.

IG spectrum (KBr technique):

765 cm @ -1 (lactam-CO) ^X H-NMR spectrum (deuterated trifluoroacetic acid):

δ == 3.40 and 3.80 (AB, J = 19 Hz, 2H, SCHz),

4.21 (s, 3H, OCH 3),

5.30-6.50 (m, 4H, 3-CH2 and 2-lactam-H each with 1 d at 5.41 and 6.10, J = 5 Hz, Ca and / or C7-H),

7.42 (s, 1H, thiazole);

7.95-8.65 (m, 5H, quinoline-H),

8.95- 9.40 ppm (m, 2H, quinoline-H).

(3) The reaction was carried out as in Example 1/3) using 11 g of quinolines.

Yield: 2.15 g (41% of theory) of a colorless solid. This compound is identical in all its properties to the substance described above.

(b) 0.4 g (2 mmol) of 2- (2-amino-1,3-thiazol-4-yl) -1,2-syn-methoxy-oxoacetic acid is dissolved in 6 ml of N, N,-dimethylformamide. After the addition of 0.28 g (2.1 mmol) of 1-hydrobenzotriazole hydrate and 0.41 g (2 mmol) of N, N'-dicyclohexylcarbodiimide, the reaction mixture was stirred at room temperature for 2 hours, the dicyclohexylurea was filtered off and a solution of 0 was added. 83 g (2 mmol) of 7-amino-3 - [(1-quinolinyl) methyl] cef-3-em-4-carboacyl-dihydrochloride in 8 ml of N, N'-dimethylformamide and 1 ml of water, reaction mixture The mixture is stirred at room temperature for 3 hours, concentrated in vacuo and the residue is dissolved in 10 ml of water. A small amount of insoluble matter was filtered off and the solution obtained was chromatographed on silica gel (Merek, "Lobar" column C, pressure about 10 bar) using a mixture of -acetone and water (2: 1) as eluent. The product-containing fractions were concentrated in vacuo and then freeze-dried.

0.74 g (70.8% of theory) of the title compound is obtained as a colorless solid. This compound is identical in all its properties to the compound described above.

The compounds described in Examples 3 to 37 were obtained using the appropriate starting materials in an analogous manner to those described in Examples 1 and 2 as amorphous solids.

Example 3

3 - [[2,4-dihydro-methyl] -7- [2-syn-methoxyimino-2-

- (2-5-am'no khlortlh.iazol-4-yl] acetamido] ^{ceph-3-em-4-ι} t ka'rbhιxylá

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.44 and 3.91 (AB, J = 18 Hz, 2H, SCH2),

4.21 (s, 3H, OCH 3),

5.20- 6.48 (m, 4H, 3-CH ₂ -A 2 lactam-H), 7.92 to 8.80 (m, 6H, isocУinю.l · In-H)

9.78 ppm (bt, 1H, isochl.).

Example 4

3 - [(1-quinolinium) methyl] -7-

- [2-syn-methoxyimino-2-

- (2-amiιno ^ -5-chllli: othУazol-4-yl] acetamide ^'!' DOijcef-3-em-4-carboxylate I-d-NMR spectrum (deuterated М1ио1ГО £ tetraacetic acid)

= 3.39 and 3.80 (AB, J = 19 Hz, SCH2, 2H),

4.21 (s, 3H, OCH 3),

5.25-6.55 (m, 4H, 3-CH2 and 2-lactam-H),

7.90 - 8.60 (m, 5H, hinoline-H),

9.00-9.45 ppm (m, 2H, quinorn-B).

Example 5

3 - ((2-2-chloroimino-methyl) -7- [2-syn-methoxyimino-2-

- (2-Amino-5-bromo-indolazol-4-yl) -acetamido] cis-α-carboxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.45 -a 3.90 (AB, J = 19 Hz, 2H, SCH2),

4.22 (s, 3H, OCH 3), δ = 5.22-6.50 (m, 4H, Z-N 2 and 2-lactam-H),

7.90-8.80 (m, 6H, isoocolin-H),

9.76 ppm (broad s, 1H, isoquinoline-H).

Example 6

3 - ((1-quinolinium) methyl] -7-

- [2-oylene-methoxylimino-2-

- (2-Amino-5-bromothiiazol-4-yl) acetamido] cef-3-em-4-carboxylate

H-I-NHR spectrum (deuterated trifluoroacetic acid):

δ = 3.40 and 3.82 (AB, J = 19 Hz, 2H ;, SCH2), 4.21 (s, 3H, OCH 3),

5.21-6.57 (m, 4H, 3-CH2 and 2-lactam-H), 7.85-8.65 (m, 5H, quinoline-H), 9.05-9.50 ppm (m, 2H, ChlorOH-K).

Example 7

3 - [(2-isoquinolinium) methyl] -718

- [β-syn-ethoxyiminio - ^ -

- (2-Amino-thiazol-4-yl) -acetam: do] cef-3-em-4-cartoixylate

@ 1 H-NMR Spectrum: (acid, deuterated) = 1.40 (t, J = 7 Hz, 3H, CH2CH3),

3.46 and 3.85 (AB, J = 18 Hz, 2H, SCH2),

4.50 (q, J = 7Hz 2H, CH2CH3),

5.20-6.45 (m, 4H, 3-CH2 and 2 lactam-H)

7.42 (s, 1H, thiazole-H);

8.0-8.75 (m, 6H, isoquinolin-H),

9.80 ppm) broad s, 1H, - ^I ^ iooch NO? Lin-H).

r

l 8

3 - [(1-quinolinyl) methyl] -7- [2-aminoethoxy-4- (2-amino-thiazol-4-yl) acetamido] cef-3-em-4-carboxylate),

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 142 (t, J = 7Hz, 3H, CH 2 CH 3),

3.43 and 3.72 (AB, J = 19 Hz, 2H, SCH2),

4.51 (q, J = 7Hz, 2H, CH 2 CH 5).

5.25-6.50 (m, 4H, 3-CH 2 and 2 lactam-H),

7.45 (s, 1H, thiazole-H),

8.00-8.70 (m, 5H, quinolin-M), 8.97-9.45 ppm (m, 2H, quinolin-H).

clay

3 - [(2-thiocolinolinyl) methyl] -7- [2- syn-propylpyrimidine-4- (2-amino-thiazol-4-yl) -acetamido] -cep-3-em-4-carboxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 1.05 (t, J = 6Hz, 3H, CH 3 (,

1.55-2.15 (m, 2H, CH2),

3.45-3.88 (AB, J = 18Hz, 2H, SCH2),

4.48 (t, J = 7Hz, NOCH 2),

5.28-6.30 (m, 4H, 3-CH 2 and 2 lactam-H),

7.42 (s, 1H, ^s thι .azιO (-)

7.90-8.80 (m, 6H, isoquinoline-H),

9.80 ppm (broad s, 1H, isohhinoline-H).

Example 10

3 - [(1-quinolinium) methyl] -7- [2-o-propylcyclohexyl] -2- (2-aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 1.02 (t, J = 6Hz, 3H, CH 3),

1.5-2.2 (m, 2H, CH2), [delta] = 3.40 and 3.70 (AB, J = 18 Hz, 2H, SCH2),

4.45 (t, J = 6 Hz, NO);

5.30-6.50 (m, 4H, 3CH2 and 2 lactam-H),

7.42 (s, 1H, thiazole);

7.95-8.70 (m, 5H, quinoline-H),

8.93-9.42 ppm (m, 2H, quinoline-H).

Example 15

3 - [(2-isoquinolininiummethyl) -7- [2-synmethylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

Example 11

3 - [(2-isioquinoline) methyl] -7- [2-syn-isopropyloxyimino-2- (2-31-4011113301-4-71) acetamido] cef-3-em-4-carboxylate

Ή-NMR spectrum (deuterated trifluoroacetic acid):

δ = 1.40 and 1.50 (d, J = 6Hz, 6H, 2СNз),

3.45 and 3.88 (AB, J = 18 Hz, 2H, SCH2),

4.75 (m, 1H, C H),

5.20-6.40 (m, 4H, 3-CH2 and 2-lactam-H),

7.41 (s, 1H, thiazole),

8.01-8.85 (m, 6H, isoquinoline-H),

9.80 ppm (broad s, 1H, isoquinoline-H).

Example 12

3 - [(i-quinolinium) methyl]] - 7-

- [2-syn-rsoñnopypyloxyimido]> 2-

- (2-amino _and othiazoi-4-yl) acetamido] ceph-3-em-4-carboxylate] H-NMR (deuterated trifluoroacetic acid):

δ = 1.45 and 1.55 (d, J = 6 Hz, 2CH3),

3.43 and 3.80 (AB, J = 19Hz, 2H, SCH2),

4.72 (m, 1H, (C H),

5.15-6.35 (m, 4H, 3-CH 2 and 2-lactam-H),

7.41 (s, 1H, thiazole),

7.95-8.62 (m, 5H, quinoline-H),

8.96-9.45 ppm (m, 2H, quinoline-H),

Example 13

3 - [(2-iso.colinolinium) methyl] -7- [2-syn-allyl-xxximino-2-

- (2-Amino-thiazol-4-yl) acetamido] cef-3-em-4-carboxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.47 and 3.86 (AB, J = 18 Hz, 2H, SCH2), 4.85-6.45 (m, 9H, 5 alpha-H, 3-CH2 and 2 lactam-H),

7.41 (s, 1H, thiazole),

8.00-8.85 (m, 6H, isoquinoline-H),

9.80 ppm (broad s, 1H, isoquinoline-H).

Example 14

3 - [(i-quinniinium) methyl] -7- [2-syn-allylioxyimino-2-

(2-aminothriazol-4-yl) acetamido) cef-3-em-4-carboxylate

Ή-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.40 and 3.78 (AB, J = 18 Hz, 2H, SCH2), 4.80-6.50 (m, 9H, 5 aryl-H, 3-CH2 and 2actam-H),

7.41 (s, 1H, thiazpia),

7.98-8.65 (m, 5H, quinoline-H],

9.00-9.45 ppm (m, 2H, quinoline-H).

Ή-NMR spectrum (deuterated trifluoroacetic acid):

δ = 2.28 (s, 3H, SCH 3),

3.47 and 3.88 (AB, J = 18 Hz 2H, SCH2),

5.15-6.30 (m, 6H, CH 2 S, 3-CH 2 and 2 lactam-H),

7.42 (s, 1H, thiazole),

7.90-8.82 (m, 6H, quinoline-H),

9.75 ppm (broad s, 1H, isocholinium-H).

Example 16

3 - [(i-quinolinium) methyl] -7- [2-quinomethylmethylaminomethoxyimino] -4- (4-carboxylic acid)

(2-Aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 2.25 (s, 3H, SCH 3),

3.45 and 3.85 (AB, J = 18Hz, 2H, SCH2),

5.10-6.35 (m, 6H, CH 2 S, 3-CH 2 and 2 lactam-H),

7.41 (s, 1H, thiazole),

7.95-8.66 (m, 5H, quinoline-H),

8.92-9.41 ppm (m, 2H, quinoline-H).

Example 17

3 - [(2-isoquinolininylmethyl) methyl] -7- [2-syn-ethyloxyethoxyimino-2-

- (2-Amino-thiazol-4-yl-Jacetamido) cef-3-em-4-carboxylate;

Ή-NMR spectrum (deuterated trifluoroacetic acid):

δ = 1.33 (t, J = 7Hz, 3H, CH 2 CH 3),

3.42 and 3.83 (AB, J = 18 Hz, 2H, SCH 2), 4.35-6.23 (m, 10H, OCH 2 CH 2 OCH 2, 3-CH 2 and 2 lactam-H),

7.41 (s, 1H, th ^: azoi),

7.90-8.85 (m, 6H, isoquinoline-H),

9.80 ppm (broad s, 1H, isoquinoline-H).

Example 18

3 - [(i-quinolinomethylmethyl) -7- [2-syn-ethyioxyimino-2-

- (2-aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

1 H-NMR spectrum (deuterated ИШШтттаеt ky ky::):

δ = 1.35 (t, J = 7Hz, 3H, CH 21 CH 3),

3.45 and 3.80 (AB, J = 18 Hz, 2H, SCHa),

4.30-6.35 (m, 10H, OCH 2 CH 2 OCH 2, 3-CH 2 and 2 lactam-H),

7.41 (s, 1H, thiazole),

7.95-8.65 (m, 5H, chiroOnn-H),

8.95-9.42 ppm (m, 2H, quinolin-H),

Example 19

3 - [(2-isoquinolinium) methyl] -7- [2-syn-cyclopropylmethylthioxy] ^-1- iodo-2-

- (2-Axniino thliiazol-4-yl) ace tamido] cef-3-em-4-carbioxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

<5 = 1.05-1.7 (m, 5H, cyclopropyl),

3.40 and 3.85 (AB, J = 18 Hz, 2H, SCH2),

4.25 (d, J = 7 Hz, 2H, NOCH 2),

5.25-6.35 (m, 4H, 3-CH2 and 2 lactam-H),

7.42 (s, 1H, thiazole).

7.90-8.80 (m, 6H, isoquinoline-H),

9.79 ppm (broad s, 1H, isoquinoline-H),

Example 20

3 - [(1-quinolium) methyl] -7- [2-quinocyclopropylmethoxyimino-2-

- (2-Amino-1H-azod-4-yl-Jacetamido) cef-3-em-4-carboxylate

4 H-NMR spectrum (deuterated trifluoroacetic acid):

= 1.1-1.7 (m, 5H, cyclopropyl)

3.42 and 3.78 (AB, J = 18Hz, 2H, SCH2),

4.26 (d, J = 7Hz, 2H, NOCH2),

5.23-6.32 (m, 4H, 3-CH 2 and 2 lactam-H),

7.41 (s, 1H, thiazole).

7.95-8.65 (m, 5H, quinoline-H),

8.95- 9.40 (m, 2H, quinoline-H),

Example 21

3 - [(2-isoquinolinolium) methyl] -7-

- [2-syn-cyclopentyloxyimino-2-

- () acetamido] - cef-3-em-4-carboylate ^X H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 1.4-2.2 (m, 8 cyclopentyl-H),

3.42 and 3.88 (AB, J = 18Hz, 2H, SCH2,

4.9-6.3 (m, 5H, cyclopentyl-H), 3-CH2 and lactam-H),

7.42 (s, 1H, thiazole).

7.95-8.80 (m, 6H, isoquinoline-H),

9.80 ppm (broad s, 1H, isoquinoline-H),

Example 22

3 - [(1-quinolinyl) methyl] -7- [2-syn-cyclopentyloxyimide ^; Jno-2-

- (2-Aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

4 H-NMR spectrum (deuterated trifluoroacetic acid:

? = 1.4-2.2 (m, 8 cycloipentyl-H),

3.40 and 3.75 (AB, J = 18Hz, 2H, SCH2),

5.1 (m, 1 cyclopentyl-H),

5.30-6.38 (m, 4H, 3-CH 2 and 2 lactam-H),

7.42 (s, 1H, thiazoil);

7.95-8.65 (m, 5H, quinoline-H),

8.95- 9.40 ppm (m, 2H, quinoline-H],

Example 23

3 - [(2-isocyclopropyl) methyl] -7- (2-syn- (1, 3, 3-thiazol-4-yl) methyloxyimino-2-

- (2-Amino-thiazol-4-yl-Jacetamido) cef-3-em-4-carboxylate

4 H-NMR spectrum (deuterated trifluoroacetic acid):

δ - = 3.45 and 3.88 (AB, J = 18 Hz, 2H, SCH2),

5.25-6.20 (m, 6H, NOCH2, 3-CH2 and 2 lactam-H),

7.35 (s, 1H, thiazole);

7.90-9.85 (m, 2H, 1 isoquinoline and 1 thiazole-H each),

Example 24

3 - [(2-isoquinolinyl) methyl] -7- [2-syn-oxo-oxylmethyloxyimino-2-

- (2-aminothiazol-4-yl) ace tamido] cef-3-em-4-carboixylate

Ή-ΝΜΗ spectrum (deuterated trifluoroacetic acid):

δ = 3.43 and 3.90 (AB, J = 19 Hz, 2H, SCH2),

5.10 (s, 2H, OCH 2),

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 (m, 1H, isoquinoline-H),

Example 25

3 - [(1-quinolinium) methyl] -7- [2-syn- (2-carbonyl-2-piperidin-1-yl-oxyimino) -2- (2-amino-thiazol-4-yl) -acetamido] - 3-em-4-carboxylate

NMR-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.42 and 3.88 (AB, J = 18 Hz, 2H, SCH >),

5.1-6.45 (m, 6H, NOCH 2, 3-CH 1 and 2 lactam-H),

6.55-6.92 (m, 2H, C 1 CH 2),

7.42 (s, 1H, thiazole).

7.93-8.64 (m, 5H, quinoline-H),

8.92-9.40 ppm (m, 2H, quinoline-H),

Example 26

3 - [(1 H -quinolin-4-yl) methyl] -7- [2-syn- (2-carboxy-2-propyloxy-1 H) -2- (2-amino-thiazol-4-yl) -acetamide cef-3-em-4-kairbo ^, xylate

4Η-ΝΜΒ spectrum (deuterated tritiuoroacetic acid):

δ = 1.80 (s, 6H, 2CH 3),

3.42 and 3.88 (AB, J = 18Hz, 2H, SCH2),

5.25-6.30 (m, 4H, 3-CH 2 and 2 lactam-H),

7.40 (s, 1H, thiazole);

7.95-8.60 (m, 5H, quinoline-H),

8.90-9.35 (m, 2H, quinolin-H),

Example 27

3- [[24sochiinoll.nium) methyl] -7- [2-yn with [l-carboxy ethylaxyimiinci) -2- (2-ia ^ ii'n othiazoi-4-yl) acetamide monitor For ^1] ceph-3- em-4-carboxylate

4 H-NMR spectrum (deuterated trifluoroacetic acid):

<5 - 1.71 (d, J = 7Hz, 3H, NN),

3.45 and 3.90 (AB, J 18 Hz, 2H, SCH2),

4.92-6.40 (m, 5H, CH-CH 3, 3-CH 2 and 2 lactam-H),

7.42 (s, 1H, thiazole).

7.96-8.80 (m, 6H, cis-2-yne);

9.80 ppm (broad s, 1H, isochtnoline-H),

Example 28

3- [(2-iso (±! Molirnum) methyl] -7- [2-s.yn- (1-karboxycyklopropyloxyimino) -2- (2-Amiina Шпаго! - ^) acetamide ¹ 'to] ceph-3 -em-4-carboxylate

4 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 1.52-1.95 (m, 4 cyclopropyl-H),

3.46 and 3.90 (AB, J = 18Hz, 2H, SCH2),

5.15-6.30 (m, 4H, 3-CH 2 and 2 lactam-H),

7.42 (s, 1H, thiazole);

7.95-8.80 (m, 6H, isoquinoline-H),

9.80 ppm (broad s, 1H, isochlorin-H),

Example 29

3 - [(1-quinolinium) methyl] -7- [2-syn- (1-carboxycyclobutyloxyminin) -2- (2-amianothiazol-4-yl Jacetamido) cef-3-em-4-carbolxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 2, 3 - 3, 2 (m, 6 cyclobutyl-H),

3.45 and 3.92 (AB, I-18 Hz, 2H, SCH 2),

5.25-6.38 (m, 4H, 3-CH 2 and 2 lactam-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

3 - [(1- quinolimum) methyl] -7- [2-syn- (1-carboxycyclic-4-pentyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

1 H-NMR spectrum (deuterated trichloroacetic acid):

δ = 1,4-2,4 (m, 8 cyclopentyl-H),

3.45 and 3.90 (AB, J = 18Hz, 2H, SCH2),

5.15-6.35 (m, 4H, 3-CH2 and 2 lactam-H),

7.42 (s, 1H, thiazole);

7.90-8.62 (m, 5H, quinoline-H],

8.93- 9.40 ppm (m, 2H, quinoline-H),

Example 31

3 - [(2- (4-quinolinyl) -1H-methyl) -7-

- [2-methoxy-syin ⁱ xykairbonylmethyloxyimino-2- (2-aminoChiazol-4-yl) acetamido] ceph-3-em-4-karbdxylát

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.43 and 3.90 (AB, J = 19 Hz, 2H, SCHa),

3.94 (s, 3H, CH 3),

5.03 (s, 2H, NOCH2),

5.20-6.45 (m, 4H, 3-CH 2 and 2 lactam-H),

7.42 (s, 1H, thiazole),

7.90-8.75 (m, 6H, isoquinoline-H),

9.80 ppm [br s, 1H, isoquinoline-H),

Example 32

3 - [(1-quinulinium methyl) -7- [2-syncyanomethyl] oxyimino-2-

- [2-aminothiazol-4-yl) acetamido] cef-3-em-4-carboxylate

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.42 and 3.78 (AB, J = 19 Hz, 2H, SCHz),

5.12 (s, 2H, NOCH 2),

5.25-6.38 (m, 4H, 3-CH 2 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),

Example 33

3 - [(2-Isopropylamino) methyl] -7- [2- (5-aminocarbamoyl) methylmethyloxyimino] -2-

- (2-Amino-thiazol-4-yl-Jacetamido)] cef-3-em-4-carboxylate

-H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.42 and 3.92 (AB, J = 19 Hz, 2H, SCH2),

4.95-6.35 (m, 6H, NOCH2, 3-CH2 and 2 lactam-H],

7.44 (s, 1H, thiazole);

7.90-8.75 (m, 6H, isoquinolin-H],

9.78 ppm (broad s, 1H, isoquinoline-H),

Example 34

3 - [(1-quinolinium) methyl] -7- [2-syn-carbamoylmethyloxyimine-2-

- (2-Aminothiazol-4-yl Jacetiamido) cef-3-em-4-carboxylate] - 1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.42 and 3.85 (AB, J = 19 Hz, 2H, SCHa),

4.92-6.40 (m, 6H, NOCH 2, 3-CH 3 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),

243132

Example 35

3- ['(6-Methyl-1-quinolinyl) methyl] -7- [2-syn-methoxyiminio-2-

- (2-Aminothiazol-4-yl Jacetamido) cef-3-em-4-carboxylate

3 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.15 (s, 3H, CH 3),

3.40 and 3.80 (AB, J = 18Hz, 2H, SCH2),

4.23 (s, 3H, OCH 3),

5.30-6.40 (m, 4H, 3-CH 2 and 2 lactam-H each with 1 d at 5.42 and 6.11, J = 5 Hz, C-6 or C-7-H, respectively),

7.42 (s, 1H, thiazole).

7.80-8.75 (m, 5H, quinoline-H),

9.06 ppm (d, J = 6Hz, 1 quinoline-H),

Example 36

3 - [(5-Hydroxy-isoolecyl) methyl] -7- [2-syn-methoxyimino-2-

- (2-Aminothiazol-4-yl Jacetamido) cef-3-em-4-carboxylate

3 H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 3.45 and 3.91 (AB, J = 18 Hz, 2H, SCH2),

4.21 (s, 3H, OCH 3),

5.25-6.35 (m, 4H, 3-CH 2 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

3 - [(1-quinolinium) methyl] -7-α-methoxy-7-

- [2-syn-methoxyimino-2-

- (2-aminothiazol-4-yl-acetamido) cef-3-em-4-carboxylate 1 H-NMR spectrum (deuterated trifluoroacetic acid):

<5 = 3.30-3.95 (m, 5H, OCH3 and SCH2),

4.23 (s, 3H, OCH 3),

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),

-2-syn-difluoro-methoxyiminoacetamido] -3-isoquinolinomethyl-cef-3-em-4-carboxylate

Procedure 2, Option (b):

Solution A:

0.53 g of 2- (2-aminothiazol; 14-yl) -2-syn-d ^; of fluoromethoxyimidoacetic acid, 9.30 g of 1-hydroxybenzothalaol hydrate and 0.41 g of dicyclohexylcarbodamide were suspended in 25 ml of N, N -dimethylformamide, stirred at room temperature for 2 hours and then filtered through dicyclohexane.

Solution B:

0.68 g of 7-amino-3-iodoethylcef-3-em-4-carboxylic acid is suspended in 40 ml of N, N-dimethylformamide and, after adding 0.05 g of isoquinoline, the reaction mixture is stirred at room temperature for 4 hours. Under ice-cooling, solution A is added dropwise to solution B and the mixture is stirred overnight at room temperature. The solution is concentrated in vacuo, then the residue is dissolved in a small amount of water with sodium bicarbonate until pH = 6 and the solution obtained is chromatographed on silica gel (column "bobar-B", Merck fum) using a 3: 3 mixture of acetone and water. The fractions containing the product were freeze-dried to give 0.09 g of a colorless amorphous solid.

1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ - = 3.40 and 3.90 (ABq, j = 18 Hz, 2H, SCH2),

5.30-6.42 (m, 4H, CH 2 N '1' 'and 2 lactam-H),

6.70 (t, I = 72Hz, 1H, CHF 2),

7.45 (s, 1 thiazole-H),

8.0-8.8 (m, 6 isoquinoline-H),

9.80 ppm (wide s, 1 isoquinoline-H),

In an analogous manner to that described in Examples 1, 2 and 38, the following compounds were obtained, which corresponded to the general formula I in which R? is hydrogen, and wherein R 1, R 3 and A are as defined in Table 1:

Example 38

7- [2- (2-Amino-thiazol-4-yl) -il

4 913 2 Example R ¹ R ³

AND

Table 1 ^J H-NMR in deuterated trifluoroacetic acid: A (ppm) =

H СНз

3.2-4.05 (AB, J = 18 Hz, 2H, SCH2),

4.25 (s, 3H, OD),

5.05-6.38 (m, 4H, CH 2 N ⁽⁺ > and 2 lactam-H),

7.40 (s, 1H, thiazole);

7.45-9.0 (m, 6 quinoline-H).

3.1-3.9 (AB, J = 19Hz, 2H,

H СНз

Cl СНз

SCH2), 3434, 11 (s, 3H, quinoline-СН), 4.23 (s, 3H, ССз), 5.26—6.43 (m, 4H, №г№ ⁺⁾ and 2 lactam-H )

7.39 (s, 1H, thiazole), 7.42-8.54 (m, 4 quinoline-H), 8.71-9.22 (m, 2 quinoline-H).

3.15 (s, 3H, lepidin-Sn), 3.16-4.0 (AB, J = 18 Hz, 2H,

SCH2),

4.19 (s, 3H, [delta]), 5.19-6.4 (m, 4H, CH2 N ⁽⁺⁾ and lactam H), 7.8-8.7 (m, 5 lepidin-H), 9.0 ( "D", J ₂₃ = 6 Hz, adhesin-2H).

Br СНз

3.13 (s, 3H, lepidine-Sn),

3.05-4.0 (AB, J = 18Hz, 2H, SCH2),

4.19 (s, 3H, OD),

5.13-6.36 (m, 4H, CH 2 N ^{1 +)} and 2 lactam-H),

7.75-8.74 (m, 5 lepidin-H),

9.04 ("d", J ₂₃ = 6 Hz, lepidine 2-H).

H СНз

H C2H5

Br

3.05-4.0 (AB, J = 18Hz, 2H,

SCH2),

4.2 (s, 3H, OD2), 5.05-6.65 (m, 4H, CH2 N ^{, +)} and lactam-H),

7.39 (s, 1H, thiazole), 7.45-7.98 (m, isoquinoline-H),

83 (mc, 1 isoquinoline-H).

1.42 (q, J = 7Hz, ZN, OC2H5),

3.15 (s, 3H, lepidin-Sn), 3.05-3.95 (AB, J = 18 Hz, 2H,

SCH2),

4.52 (q, J = 7Hz, 2H, O-C2 H5),

5.23-6.55 (m, 4H, CH 2 N ^{, +)} and lactam-H),

7.4 (s, 1H, thiazole).

75-8.75 (m, 5 lepidin-H),

9.05 ("d", J ₁₃ = 6 Hz, lepidine-2H).

Example ¹ R

R ⁵

A 1 H-NMR spectrum in deuterated trifluoroacetic acid: δ (ppm) =

H

C2H5

1.42 (q, J = 7Hz, ZN, OC2H5),

3.1-4.0 (AB, J = 18Hz, 2H)

SCH2),

4.1 (s, 3H, choline-ОСНз),

4.52 (q, J = 7 Hz, 2H, OC 2 H 5), 5.22-6.6 (m, 4H, CH 2 N ¹¹¹ and lactam-H),

7.39 (s, 1H, thiazole),

7.52-8.56 and 8.82-9.15 (m, quinoline-H).

OH

H

C2H5

1.4 (broad t, J = 7Hz, 3H,

OC2H5),

3.15-4.0 (AB, J = 18Hz, 2H)

SCH2),

4.51 (broad q, J = 7Hz, 2H,

OC2H5),

5.16- 6.52 (m, 4H, CH ₂ N ⁽⁺⁾ and lactam-H)

7.39 (s, 1-thiazole-H),

7.53-9.0 (m, 5 isochmolin-H),

9.66 (mc, 1'-isoquinoline-H).

H — СНзСН = СН2

H = CH 2 CH = CH 2

3.1-4.1 (AB, J = 19Hz, 2H,

SCH2),

4.9 (mc, 2H, CH2 allyl groups),

5.03-6.68 (m, 7H, CH 2 N ⁽⁺⁾ , lactam-H and 3 allyl-H),

7.4 (s, 1H, thiazole), 7.5-9.0 (m, 5 isoquinolin-H), 9.82 (mc, 1 isoquinolin-H).

3.15 (s, 3H, lepidin-IV). 3.05-3.95 (AB, J = 18Hz, 2H,

SCH2),

4.9 (mc, 2H, CH2 allyl groups),

5.05-6.63 (m, 7H, CH 2 N ^(; lactam-H and 3 allyl-H), 7.43 (s, 1H, thiazole), 7.76-8.75 (m, 5 lepidine -H), 9.05 ( "d", J _3.2 = 6 Hz, 2 H lepidine).

; ^Cl ^ l

0.23-0.9 (m, 4 cyclopropyl-H),

1.1-1.6 (m, 1 cyclopropyl-H),

3.15 (s, 3H, lepidin-Sn), 3.05-3.95 (AB, J = 19 Hz, 2H,

SCH2),

4.28 (d, J = 7.5Hz, 2H, CH2-cyclopropyl),

5.2-6.6 (m, 4H, CH 2 N ⁽⁺⁾ and lactam-H),

7.43 (s, 1H, thiazole),

7.79-8.74 (m, 5 lepidin-H),

9.04 ("d", J ₂₃ = 6 Hz, lepidine 2-H).

Example R 1 R ³

Ή-NMR spectrum in deuterated trifluoroacetic acid: δ (ppm) =

H CH2CF3

CH

3.13 (s, 3H, lepidine-CH 3),

3.15-3.86 (AB, J = 18Hz, 2H, SCH2),

4.69 (broad q, J = 8 Hz, 2H,

CH2-CF3),

5.26-6.68 (m, 4H, CH2 N <+> and lactam-H),

7.39 (s, 1H, thiazole);

7.76-8.79 (m, 5 lepidin-H), 9.04 ("d", J2.3 = 6 Hz, lepidiin-2H),

H

CH2CF3

H - CH 2 - C = CH

53 11 —CH2 — C = CH 54 H CH2CO2CH3

3.2-4.06 (AB, J = 19Hz, 2H, SCH2),

66 (broad q, J = 8 Hz, 2H, —CH2-CF3),

5.23-6.53 (m, 4H, CH2 N <+ ¹ and lactam-H),

7.36 (s, 1H, thiazole);

7.86-8.8 (m, 6 isoquinoline-H),

9.76 (mc, 1 isoquinolin-H).

2.58 (mc, 1H, propargyl-H),

3.15 (s, 3H, lepidine-CH 3),

3.05-4.0 (AB, J = 18Hz, 2H, SCH2),

4.96 (d, J 1.5 Hz, 2H, —CH2 — C = CH),

5.16-6.6 (m, 4Η, CH 2 N ⁽ + 'and lactam-H),

7.39 (s, 1H, thiazole);

7.75, 8.75 (m, 5 lepidin-H);

9.04 ("d", J = 6Hz, lepidine-2H).

2.56 (mc, 1H, piropargyl-H),

3.13-4.1 (AB, J = 19Hz, 2H, SCH2),

4.95 (d, J = 2Hz, 2H, —CH2 —CsCH),

5.15-6.55 (m, 4H, CH 2 N ⁽ + 'and lactam-H),

7.38 (s, 1H, thiazole),

7.86-8.8 (m, 6 isoquinoline-H),

9.75 (mc, 1 isoquinoline-H).

3.42 and 3.85 (AB, J = 18 Hz, 2H, SCH2),

3.95 (s, 3H, OCH 3),

5.02 (s, 2H, OCH 2),

5.15-6.35 (m, 4H, CH 2 N +> and lactam-H),

7.41 (s, 1H, thiazole), 7.95-8.65 (m, 5 quinoline-H), 9.00-9.45 (m, 2 quinoline-H),

А example R ¹ R ^{3 X} H-NMR spectrum in deuterated trifluoroacetic acid: ό (ppm) =

H

CH2CO2C2H5

H

CH2CO2H

H

С (СНз) 2СОгН

H

-СН (СНз) СО2

1.38 (t, J = 7Hz, 3H, OC 2 H 5),

3.51 and 3.83 (AB, J = 18 Hz, 2H,

S1CH2),

4.36 (q, J = 7Hz, 2H, OC 2 H 5),

4.85 - 5.15 (AD, 2H, OCH2),

5.23- 6.55 (m, 4H, CH ₂ N ^<+) and lactam-H)

7.39 (s, 1H, thiazole).

7.85 - 8.80 (m,

Isoquinolin-H),

9.78 (mc, 1 isoquinoline-H).

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, CH ₂ N ⁽⁺⁾ and lactam-H)

7.43 (s, 1H, thiazole);

7.85-8.65 (m, 5 quinolin-H), 8.95-9.43 (m, 2 quinoline-H).

1.77 (s, 6H, doubled),

3.50 and 3.87 (AB, J = 18 Hz,

2H, SCH2)

5.25-6.50 (m, 4H, CH 2 N ⁽⁺⁾ and lactam-H),

7.40 (s, 1 H, thiazole),

7.55-8.75 (m, isoquinoline-H),

9.75 (mc, 1 isoquinoline-H).

1.75 (broad d, J = 7 Hz, 3H, NH-CH),

3.1-3.95 (AB, J = 18Hz, 2H, SCH2),

4.9-6.55 (m, 5H, CH 2 N ⁽⁺⁾ , lactam-H and CH 2 S);

7.34 (s, 1H, thiazole), 7.79-8.68 (m, 5 quinoline-H), 8.91-9.3 (m, 2 quinoline-H).

H

1.95-3.0 (m, 6 cyclobutyl-H),

3.17-4.06 (AB, J = 18Hz, 2H, SCH2),

5.15 to 6.55 (m, 4H, CH ₂ ^{N +)} and a lactam-H)

7.38 (s, 1H, thiazole).

7.63-8.83 (m, isoquinoline-H),

9.77 (mc, 1 isoquinoline-H).

H

1.63-2.7 (m, 8 cyclopentyl-H), 3.2-4.13 (AB, J = 19 Hz, 2H,

SCH2),

5.26 to 6.56 (m, 4H, CH ₂ ^{N +)} and a lactam-H)

7.36 (s, 1H, thiazole),

7.7-8.83 (m, 6 isoquinolin-H),

9.76 (mc, 1 isoquinoline-H).

Claims (5)

A process for the preparation of novel 7- [2-oximino-2- [2-amino-1-thiazol-4-yl) acetamido] cephem derivatives of the general formula I R‘- in which R-1 represents a hydrogen atom or a halogen atom, R [is replaced by hydrogen or methoxy, R ³ onzmená ztom optionally halogen alkylthioskupinon 1 .zž breaks 6 carbon zlkyloxyykupmou 1 ZZ ztomy 6 atoms or a substituted zlkylovou thizoolytovou group having 1 ZZ ztomy 6 alkyl group having 2 zlkesnylioivoiu ZZ ztomy 6 atoms, alkinyl having 2 ZZ 6 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms in the cycloalkyl moiety of from 1 to 6 carbon atoms in the alkyl moiety; R ⁴ I (CH 2) o (iC) o R 'where m of n is pure at 0 or 1, R 4 of R ^{5 *} are the same or different from the hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or together with the carbon atom which they are attached to form a methylene group or a cycloalkylidene group having 3 to 7 carbon atoms, R 6 is -CO ² R ⁷ in which R ⁷ is hydrogen-substituted by alkyl. a 1 to 4 carbon group or an equivalent of an alkali metal, an alkaline earth metal, or a mercuric acid group, furthermore an aryl group or a carbonyl group - CONH2; And said choline or isoquinolino group, which are optionally substituted by an alkyl group having 1 to 6 carbon atoms, a alkoxy group having 1 to 6 carbon atoms, a halogen or a halogen atom. hydroxy group, in which the group —OR @ 3 is in the plateau, from their physiologically tolerable acid addition salts, by treating the compound of general formula IA r @ ² <1 COOH (IA) in which R2 has the aforementioned benefit, R ^{9, the} quinoline or isoquinoline-exchangeable group which corresponds to residues A in formula I, for example the acetloxy or propylpolythio-V 4 group, acts in any order 2- (2-zminloithizzol-4-yl) -2-syn-4-oximino acetic acid. voorce IV (IV) in which: R 1 of R 3 have the above mentioned a and R ⁸ is ammonio or mmiotected, for example tert-butylamino, benoyl or trityl, or an activated derivative thereof of such quinoline or isoquinoline bases corresponding to the A moieties in formula I, or the protecting group present is split off the compound of interest. Optionally, in Formula I, the physiologically usable acid salt is converted. 2. The method of claim 1, wherein the nucleophilic exchange of the substituent R &lt; 9 &gt; is carried out in the presence of neutral salt ions, in particular of iodide or thiocyanate ions. 3. The method of claim 1, wherein the nucleophilic exchange of the R &lt; 9 &gt; substituent is carried out in the presence of a moiety which resides at residue A and trimethyl iodosilane. 4. A method according to claim 1, characterized in that starting from the corresponding chiinolinjové isoichiinolinové or a base, compounds of formula IA а IV to give compounds of formula I wherein R ¹ is hydrogen or halogen, R ² R @ ³ is hydrogen, R @ ³ is C1 -C4 alkyl, and A is quinoline or isoquinoline. 5. A method according to claim 1, characterized in that starting from the appropriate isoquinoline chiniolinové or Ba, the compounds of formula IA а IV to give compounds of general formula I, ·, wherein R ¹ is Cl, R ³ a methyl or ethyl group; and A is as defined in point 4.