CS248714B2 - Production method of new 7-(2 syn-oxomino-(5 amino-1,2,4-thiadiazol-3-y)cefeme derivatives - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LU, LI, NL, SE) A cephem derivative of the formula I see diagramm : EP0111934,P10,F3 and physiologically acceptable acid addition salts thereof in which R**1 denotes C1 -C2 -alkyl, R**2 denotes a pyridinium radical see diagramm : EP0111934,P10,F4 which is substituted by 2 alkyl groups in the ortho-position which are linked to form a trimethylene to pentamethylene ring in which one carbon atom can be replaced by an oxygen atom, or denotes a 1-quinolinium radical or a 2-isoquinolinium radical and in which the R**1 O group is in the syn-position. 1. Claims (for the Contracting State AT) A process for the preparation of a cephem derivative of the formula I see diagramm : EP0111934,P11,F4 and physiologically acceptable acid addition salts thereof in which R**1 denotes C1 -C2 -alkyl, R**2 denotes a pyridinium radical see diagramm : EP0111934,P12,F1 which is substituted by 2 alkyl groups in the ortho-position which are linked to form a trimethylene to pentamethylene ring in which one carbon atom can be replaced by an oxygen atom, or denotes a 1-quinolinium radical or a 2-isoquinolinium radical in which the R**1 O group is in the syn-position which comprises a) reacting a compound of the general formula II see diagramm : EP0111934,P12,F2 or salts thereof or a reactive derivative of the compound II in which R**1 has the meaning mentioned above and R**7 denotes an amino group or a protected amino group and R**8 denotes a group which can be replaced by the pyridine, quinoline or isoquinoline derivatives corresponding to the radicals R**2 of the formula I, with these pyridine, quinoline or isoquinoline derivatives, and alpha) splitting off a protective group which may be present and beta) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or b) reacting a 7-aminocephem compound of the general formula III see diagramm : EP0111934,P12,F3 or acid addition salts thereof in which R**2 has the abovementioned meaning and in which the amino group can also be present in the form of a reactive derivative, with a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-synoximinoacetic acid of the general formula IV see diagramm : EP0111934,P12,F4 in which R**1 and R**7 have the meaning mentioned above, or with an activated derivative of this compound, and alpha) splitting off a protective group which may be present, 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 cephalosporin derivatives, in particular polar cefemderivatives which are substituted at the 3 'position of the cephalosphere by certain pyridine, quinolinium and isoquinolinium residues and which have a very good antimicrobial action against Gram positive and Gram negative bacteria. microbial infections.

Accordingly, it is an object of the present invention to provide novel 7- [2-syn-oximino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -cephem derivatives of formula (I)

(C 1 -C 6) alkyl moieties, (C 2 -C 6) alkenyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7) cycloalkyl and (C 1 -C 6) alkyl group, group formula

where man is 0 or · 1,

R ³ and R ⁴ are the same or different and are hydrogen, C 1 -C 4 alkyl, or together with the carbon atom to which they are attached form a methylene group or a C 3 -C 7 cycloalkylidene group,

R ⁵ is -CO ² R ⁶ wherein R ⁶ is hydrogen, C 1 -C 4 alkyl, or an alkali metal, alkaline earth metal or ammonium equivalent; further represents a carbamoyl group —CONH2,

R ² represents a pyridinium group of the formula ω

in which

R ¹ represents an alkyl group having 1 to 6 carbon atoms, an alkylthioalkyl group

-O which is substituted by 2 ortho-alkyl groups which are closed to form an optionally hydroxy-substituted di- to decamethylene ring in which the ring carbon atom is optionally replaced by an oxygen or sulfur atom; or • two double bonds, or a 1-quinolinium group or a 2-isoquinolinium group, which are also optionally substituted by a C1-C6 alkyl group in which the —OR1 group is in the syn position, and their physiologically tolerable addition groups salts with acids.

In particular, the compounds of the formula I according to the invention are produced in which:

R1 is C1 -C6 alkyl, C1 -C6 alkylthioalkyl in both alkyl portions, C2 -C6 alkenyl, C3 -C7 cycloalkyl, C3 -C7 cycloalkyl. carbon in the cycloalkyl moiety having 1 to 6 carbon atoms in the alkyl moiety, and a group of formula

R 3 - (CH ₂ ) _n - (C jm-R ^s

R4 is as defined above,

R2 represents a pyridinium group of the formula

which is substituted with 2 ortho-alkyl groups which are closed into an optionally hydroxy-substituted di- to decamethylene ring in which the ring carbon atom is optionally replaced by oxygen or sulfur, and further may also contain one or two double bonds.

The ring not fused to the pyridinium group may be a 2- to 10-membered ring (di-deca-methylene), but preferably a ring of 3-5 members in the ring, e.g., a cyclopentene, cyclohexene or cycloheptene ring. If such a non-fused ring contains a double bond, a decahydrocyclopentadiene ring may be exemplified by a dehydrocyclohexadiene ring or a dehydrocycloheptadiene ring. Fused rings containing an oxygen atom and containing two or one double bond include, for example: a furo, pyrano-dihydrofuro- and dihydropyrano group. Examples of non-fused single sulfur rings containing one or two double bonds include thieno, thiopyrano, di-thieno and dihydrothiopyrano. Of the non-fused rings containing the heteroatom, especially those mentioned above, especially those containing only one double bond, are suitable for substitution.

R @ 2 may furthermore be in particular a 1-quinolinium group or a 2-isoquinolinium group, which are optionally substituted by a C1 -C6 alkyl group, and also in the preferred compounds the --OR @ 1 group is in the syn position.

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

R 1: (C 1 -C 4) -alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, especially methyl or ethyl;

(C 1 -C 6) alkylthio substituted by (C 1 -C 4) alkyl, for example, methylthio or (C 1 -C 4) ethylthio substituted alkyl;

(C 2 -C 4) alkenyl such as vinyl, allyl, isopropenyl, methylallyl, especially allyl or methylHyl;

C 3 -C 7 cycloalkyl such as, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, especially cyclopentyl;

cycloalkylmethyl of 3 to 7 carbon atoms in the cycloalkyl moiety, such as, in particular, cyclopropylmethyl;

group of formulas

R3

- (CH 2) _n - (C) _m - R 5

R4 taking

R ³ and R 4 are the same or different and are hydrogen, C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, preferably methyl, ethyl, in particular methyl or R3 and R4

Together with the carbon atom to which they are attached represent a methylene group or a C3-7 cycloalkylidene group such as cyclopropylidene, cyclobutylidene group, cyclopentylidene group, cyclohexylidene group, cycloheptylideide group, preferably cyclopropylidene group, m is 0 or 1, n is a number of · 0 or · 1, where the sum of m + n is 1 or 2, for example a cyclopentylidene group, a cyclopentylidene group or a cyclohexylidene group.

Preferred examples for a group of formula

R3

I - (CH ₂ ) n - (C) _m R 4 are as follows:

In case n = 0 and m = 1:

in case m = 0 and n = 1:

—CH2— in case n and m = 1:

—CH2 — ΟΙ!

CH2

R ⁵ is -CO ² R ⁶ wherein R ⁶ is hydrogen, C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl preferably a methyl group, an ethyl group, especially a methyl group, or an alkali metal equivalent such as sodium, potassium, lithium, preferably sodium and potassium, an equivalent of an alkaline earth metal, preferably calcium or magnesium, ammonium, furthermore a kaoibamoyl group,

R2 represents a pyridinium group which is substituted by two alkyl groups closed to form a di- to decamethylene ¹ ring and this is again one or more times, preferably once substituted by hydroxy and optionally contains one or two double bonds, preferably by the following non-fused ring systems:

cyclopenteno, hydroxycyclopenteno, cyclohexeno, hydroxycyclohexeno, cyclohepteno, hydroxycyclohepteno, dehydrocyclopenteno, dehydrocyclohexeno and dehydrocyclohepteno.

In the above non-fused ring systems, if one carbon atom is replaced by oxygen or sulfur, the following ring systems are particularly suitable:

2,3- and 3,4-furo, 2,3- and 3,4-pyrano,

2,3- and 3,4-dihydrofuro, 2,3- and 3,4-dihydropyrano and hydroxydihydropynano;

R 2 represents a quinolinium group or an isoquinolinium group, which are optionally also mono- or poly-substituted, equally or differently, with a C 1-6 alkyl group such as methyl, ethyl, propyl, preferably methyl.

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

COOH (LA) in which

R8 represents a group exchangeable with such pyridine, quinoline or isoquinoline bases, which correspond to the R2 radicals in formula I, such as, for example, acetoxy or propionyloxy, acting in any order 2- (5-amino-1, 2) -

2,4-thiadiazol-3-yl-n-amino-oxoacetic acid of formula IV

(IV) in which:

R ¹ has the abovementioned meaning and

R ⁷ is amino or protected amino, for example tert-butyl, benzyl, trityl or trimethylsilyl, or an activated derivative thereof and those pyridine, quinoline or isoquinoline bases corresponding to the radicals R ² in formula I, whereupon the optionally present protecting group cleaves and the compound of formula I obtained is optionally converted into a physiologically usable acid addition salt.

If allowed to the process of this invention by reacting a compound of formula IA initially with a compound of formula IV or with an acylated derivative thereof and then with pyridine, quinoline or isoquinoline bases corresponding to residues R ² in Formula I, then this process may be described further as follows:

Reaction of a compound of formula IA

COOH in which

R ⁸ is as defined above, with 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-syn-oximinoacetic acid of formula IV

N — n— с-соон ^R (I v) in which

R ¹ and R ⁷ are as defined above, or with an activated derivative of this acid, a compound of formula (II) in which:

R ^1, R ⁷ and R ⁸ are as defined above, then this compound of formula II or its salt or its silyl derivatives treated with such the pyridine, quinoline or isoquinoline bases corresponding to residues R ² in Formula I, eventually present protecting the group is cleaved and the compound of formula I obtained is optionally converted into a physiologically acceptable acid addition salt.

In the process of the invention, if a compound of formula IA is first reacted with pyridine, quinoline or isoquinoline bases corresponding to the R ² residues of formula I, and then the reaction product or its acid addition salt is reacted with 2- (2). -amino-1,2,4-thiadiazol-3-yl) -2-syn-oximinoacetic acid of formula (IV) or with an activated derivative of this acid can be described in more detail as follows:

Reaction of a compound of formula IA

COOH (IA) in which

R < ⁸ & gt ^; is as defined above, with the pyridine, quinoline or isoquinoline bases corresponding to the radicals R < ^{2 >} in formula I, the 7-aminocephemerivative of formula III is obtained

(lil) in which

R ² is as defined above, wherein the amino optionally is present in the form of silyl derivative, and the compound thus obtained or its acid addition salt is reacted with 2- (2-amino-l, 2,4-thiadiazol-3-yl) -2-syn-oximinoacetic acid of formula IV

in which

R ¹ and R ⁷ are as defined above, or with an activated derivative thereof, whereupon the optionally present protecting group is cleaved and the compound of formula (I) is optionally converted into a physiologically usable acid addition salt.

When preparing the compounds of formula I by nucleophilic residue R ⁸ in the compounds of formula II mentioned pyridine derivatives, quinoline or isoquinoline, possible radicals R ⁸ particular account acyloxy lower aliphatic carboxylic acids, preferably having from 1 to 4 carbon atoms, is, for example, acetoxy or propionyloxy, in particular acetoxy, which may be optionally substituted, such as chloroacetoxy or acetylacetoxy. Other groups are also suitable for the radical R @ ⁸ , such as, for example, halogen, in particular chlorine, bromine or iodine, or carbamoyloxy.

According to the invention in a nucleophilic displacement reaction using starting compounds of formula II wherein R ⁸ is an acetoxy group, or their salts, 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 that is readily miscible with water, such as acetone, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide or ethanol. Reaction temperatures are generally in the range from about 10 ^C to about 100 C, preferably CD 20-80 ° C. The base component is added in an amount ranging between about equimolar and up to about 15 fold excess. The exchange of R ⁸ residues 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 potassium iodide, sodium iodide, potassium thiocyanate or sodium thiocyanate are added. The reaction is preferably carried out near a neutral point, preferably at a pH in the range of about 5 to about 8.

When R ⁷ is present in the form of a protected amino function, for example, an optionally substituted alkyl group such as a tert-butyl group, a tert-amyl group, a benzyl group, a p-methoxybenzyl group, a trityl group, a benzhydryl group are suitable as amino protecting groups. a group, preferably a trityl group; a trialkylsilyl group such as a trimethylsilyl group; optionally substituted aliphatic acyl such as formyl, chloroacetyl, bromoacetyl, trichloroacetyl and trifluoroacetyl, 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 a benzyloxycarbonyl group; or a dimethylaminomethylene group.

The protecting group may be cleaved off in a manner known per se, for example a trityl group by a carboxylic acid such as acetic acid, trifluoroacetic acid, formic acid or a benzyloxycarbonyl 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 in the form of a sparingly soluble salt, for example a hydroiodide salt or a hydrothiocyanate salt.

The nucleophilic displacement reaction of the compounds of formula II can also be conducted such that the reaction is carried out in the presence of a base which corresponds to residues R ² and trimethyliodosilane. This variant of the exchange reaction is preferably carried out by adding trimethyl iodosilane to a mixture of the compound of formula II and a base in a suitable solvent. Alternatively, the compound of formula II can be reacted first with trimethyl iodosilane under the reaction conditions below, and then the base is added.

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

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

Trimethyl iodosilane is also added in at least a stoichiometric amount up to a twentyfold excess, preferably in a five to fifteenfold excess.

The reaction is carried out at temperatures between -5 ° C and 4-100 ° C, preferably between 10 ° C and 80 ° C.

After hydrolysis of the reaction mixture by addition of water or aqueous mineral acids, for example dilute hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid, the reaction products of the formula I can be isolated from the aqueous phase in a conventional manner, for example freeze drying of the aqueous phase. 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 a hydrothiocyanate salt or a hydroiodide salt.

In the case where R ⁸ is carbamoyloxy, the exchange reaction is carried out in an analogous manner.

When R ^{8 is} halogen, especially bromine or iodine, the exchange reaction is carried out in a manner known from the literature.

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

The acylation of compounds of formula III or their acid addition salts with, for example, 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. by treatment 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 5-amino group in the compounds of formula IV from the reaction. Suitable amino protecting groups are those described above for the radical R ⁷ . 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 chloroacetyl group by treatment with thiourea.

When the carboxylic acids of the formula IV are used as well as the amino-protected derivatives themselves as acylating agents, the reaction is expediently carried out in the presence of a condensing agent, for example a carbodiimide 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, tosyl chloride, thionyl chloride or oxalyl chloride, as described in German Patent No. 2,804,040.

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

Suitable activated carboxylic acid derivatives of the general formula IV are furthermore suitable anhydrides and mixed anhydrides, azides, activated esters and thioesters, preferably with p-nitrophenol, 2,4-dinitrophenol, methylenecyanhydrin, N-hydroxysuccinimide and N-hydroxyphthalimide, in particular 1-hydroxybenzotriazole , 6-chloro-1-hydroxybenzo triazole and 2-mercaptobenzthiazole. Particularly suitable mixed anhydrides are mixed anhydrides with lower alkanoic acids, such as acetic acid, and particularly preferably substituted acetic acids, such as trichloroacetic acid, pivalic acid or cyanoacetic acid. However, mixed anhydrides with carbonic acid semi-esters, which are obtained, for example, by reacting carboxylic acids of the formula IV in which the amino group is protected with benzyl chloroformate, p-nitrobenzyl chloroformate, isobutyl chloroformate, ethyl chloroformate or allyl chloroformate . 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 tetrahydrofuran and dioxane; Ketones, such as preferably acetone and butanone; amides such as preferably dimethylformamide and dimethylacetamide or pyridine. It may also be advantageous to use mixtures of the solvents mentioned. This is often the case when the cefemerivative of formula (III) is reacted with an activated carboxylic acid derivative of formula (IV) prepared in situ.

The reaction of the cefemerivatives of formula III with the carboxylic acids of formula IV or their activated derivatives can be carried out in a temperature range of about -80 to about +80 ° C, preferably between -30 and +50 ° C, in particular between about -20 ^{° C.} C and room temperature.

The reaction time depends on the reactants, the temperature and the solvent or solvent mixture, and is usually between about 1/4 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 dimethylaminopyridine may also be advantageous.

When the amino group is present in the form of a reactive derivative in the compounds of formula III, it may be as known from the literature for amidation reactions. Thus, for example, silyl derivatives which are formed in the reaction of the compound of formula III with a silyl derivative, such as trimethylchlorosilane or bis- [trimethylsilyl) acetamide, are suitable. If the reaction is carried out with an amino-activated compound, it is expedient to carry out the reaction in an inert solvent such as methylene chloride, tetrahydrofuran or dimethylformamide.

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

Compounds of formula III may be obtained in known manner, for example the 7-position; aminocephalosporanic acid or 7-aminocefalGsporanGvé of protected amino acids in a conventional manner as described above for nucleophilic replacement R ^eighth

Compounds of formula IV as well as the derivatives of pyridine, quinoline and isoquinoline corresponding '· R ² radicals are known from the literature or can be prepared by processes known from the literature.

The compounds of formula I and their physiologically tolerable acid addition salts produced by the process of the invention have remarkably good antibacterial activity against both Gram-positive and Gram-negative bacteria.

Unexpectedly, the compounds of formula I are also effective against penicillinase and cephalosporinase-forming bacteria. Moreover, since they have 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 characterized by containing 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, cephalosporins or 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 substance can be prepared by mixing the compounds of the formula I with one or more pharmacologically usable excipients 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, which are suitable for parenteral administration.

Carriers or diluents include, for example, tragacanth, milk sugar, talc, agar-agar, polyglycols, ethanol, and water. As buffers, for example, organic compounds such as N, N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, tris [hydroxymethyl] aminomethane, 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 parenteral administration. It is also possible to administer the active substances as such without carriers or diluents in a suitable form, for example in capsules.

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

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

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

Example 1

3 - [(2,3-cycloocteneno-11-pyridinium) methyl] -7- [2-syn-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cef-3-em -4-carboxylate

and)

a) A mixture of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-syn-methoxy-amino-acetamido] -cep alosporanic acid trilluoroacetate (0.57 g, 1 mmol), 30 mg ascorbic acid, 6.65 g (40 mm-ol) of potassium iodide, 1.8 ml (15 mmol) of 2,3-cyclopentennopyridine, 7 ml of water and 3 ml of acetone are heated at 65 DEG-67 DEG C. for 4 hours with stirring. C.

After cooling, the dark colored solution is chromatographed on silica gel ("Lobar-C" column, manufactured by Merek) using acetone: water (2: 1) as eluent.

The fractions containing the product are concentrated and freeze-dried. 0.14 g (27% of theory) of a colorless amorphous solid is obtained. IR [KBr) 1770 cm ^-1 (lactam-CO) H-NMR spectrum (deuterated trifluoroacetic acid):

δ = 2.20 - 2.80 (m, 2Η, cyclopentene-H),

3.10-4.05 (m, 6H, 4-cyclopentene-H) and SCHa),

4.30 (s, ЗН, ОСНз),

5.20 - 6.25 (m, 4 N, C-N and 2-1-oct-H),

7.66 - 8.70 ppm (m, 2H, RT).

β) To a mixture of 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-syn-methoxyiminoacetamido] cephalosporanic acid trifluoroacetate (0.57 g, 1 mmol) and 1.07 g ( 9 mmol) of 2,3-cyclopentenopyridine in 10 ml of methylene chloride was added at 5 ° C 1.4 g (7 mmol) of trimethyl iodosilane and then the reaction mixture was heated under reflux for 2 hours. After cooling, 7 ml of 2N hydrochloric acid solution are added, the mixture is stirred for 10 minutes at a temperature of about 15 ° C, and the pH is adjusted to 6.5 by addition of solid potassium bicarbonate. The aqueous phase was separated and chromatographed over a "Lobar-C" column eluting with acetone: water (2: 1). After freeze-drying the product-containing fractions, 0.29 g (56% of theory) of a colorless solid is obtained, which in all its properties is identical to that described above.

(b)

404 mg (2 mmol) of 2- (5-amino-1,2,4-thiazol-3-yl) -2-synmethoxyiminoacetic acid was dissolved in 6 ml of N, N-dimethylformamide. After addition of 280 mg (2.1 mmol)

Of 1-hydroxybenzotriazole hydrate and 410 mg (2 mmol) of N, N‘-dicyclohexylcarbodiimide was stirred at room temperature for 2 hours. The precipitated dicyclohexylurea is filtered and a solution of 808 mg (2 mmol) of 7-amino-3 - [(2,3-cyclopenteno-1-pyridinium) methyl] cef-3-em-4-carboxylate dlhydrochloride in 10 ml of N is added to the filtrate. , N-dimethylTormamide and 1 ml of water. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and the residue was dissolved in 10 mL of water. A small amount of insoluble material was filtered off and the filtrate was chromatographed over a "Lobar-C" column using acetone / water 2: 1 as eluent.

Product containing fractions were freeze-dried to give 580 mg (56% of theory) of the title compound as an amorphous solid.

This compound is identical in all its properties to the compound described above.

In an analogous manner to that described in Example 1, the following compounds are obtained as amorphous solids which correspond to the general formula I in which R ¹ represents a methyl group and R ² represents a residue which is shown in the second column of Table 1 below:

TABLE 1 example

R ^{2 J} H-NMR in deuterated trifluoroacetic acid: δ (ppm)

OH

2.15-4.0 (m, 6H, 4 cyclopentene-H, SCH2)

4.30 (s, ЗН, ОСНз),

5.15-8.35 (m, 5H, Z-SN, cyclopentene-H, 2 lactam-H),

7.7 - 8.8 ppm (m, 3H, Py)

2.2-3.9 (m, 8H, 6 cyclopentene-H, SCH2),

4.27 (s, ЗН, ОСНз),

5.10-6.30 (m, 4H, Z-N2 and 2 lactam-H),

7.7 - 8.8 ppm (m, 3H, Py) .delta

1.7-2.4 (m, 4 cyclohexene-H),

2.8-4.0 (m, 6H, 4 cyclohexene-H and SCH2),

4.30 (s, ЗН, ОСНз),

5.15-6.20 (m, 4H, Z-N2 and 2 lactam-H),

7.55 - 8.68 ppm (m, 3H, Py)

1.8-2.35 (m, 4 cyclohexene-H),

2.7-3.9 (m, 6H, 4 cyclohexene H and SCH2),

4.28 (s, ЗН, ОСНз),

5.10-6.25 (m, 4H, Z-N2 and 2 lactam-H),

7.6-8.7 (m, 3H, Py) 1 H-NMR spectrum in deuterated trifluoroacetic acid: S (ppm) Example

⁷ .......)

1.8-2.4 (m, 4 cyclohexene-H),

2.58 (s, 3H, 2H),

2.8-3.9 (m, 6H, 4 cyclohexene-H and SCH2),

4.28 (s, 3H, OD),

5.15-6.30 (m, 4H, Z-N2 and 2 lactam-H),

8.15 and 8.42 ppm (1 wide s, 2 Py-H each)

1.6-2.4 (m, 6 cyclohepten-H),

3.0-4.0 (m, 6H, 4 cyclohepten-H and SCH2),

4.30 (s, 3H, OD),

5.20-6.35 (m, 4H, Z-N2 and 2-lactam-H),

7.6 - 8.7 ppm (m, 3H, Py)

8 From i) 4 К 4 3.43 and 3.90 (AB, J = 19 Hz, 2H, SCH2), 4.30 (s, 3H, OD), 1 and 5.25-6.40 (m, 4H, Z-N2 and 2 lactam-H), 7.90 - 8.60 (m, 5H, quinoline-H), 8.90 - 9.40 ppm (m, 2H, quinoline-H)

fž 'Z

© 1 '

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

4.28 (s, 3H, OD),

5.26-6.30 (m, 4H, Z-N2 and 2 lactam-H each with 1 d at 5.42 and 6.11, J = 5H, C-6 and C-7-H respectively),

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

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

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

4.30 (s, 3H, OD),

5.25-6.40 (m, 4H, Z-N2 and 2 lactam-H),

7.8-8.8 (m, 5H, quinoline-H),

9.1 pp, (d, J = 6Hz, 1-quinoline-H),

3.17 ppm (s, 3H, 2H)

In an analogous manner to that described in Example 1, the following compounds are obtained as amorphous substances which correspond to the general formula Г (R ² - 2,3-cyclopenteno

-1-pyridinium), and that a radical R ¹ include the same substituent as in the second column of the following Table 2.

243714

TABLE 2

C-CONH !! N

example

Π

R ¹

C2H5

CH2CH2CH3

СН (СНз) 2

СНгСН = СН1

CH2SCH3

—CH2CO2CH3 ^X H-NMR spectrum in deuterated trifluoroacetic acid: S (ppm)

1.42 (t, J = 7 Hz, 3H, CH 2 CH 3),

2.15-2.80 (m, 2H, cyclopentene-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

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

5.15-6.35 (m, 4H, Z-N 2 and 2 lactam-H),

7.65 - 8.70 ppm (m, 3H, Py)

1.10 (t, J = 6Hz, 3H, 2H),

1.5-2.1 (m, 2H, CH 2),

2.15-2.8 (m, 2H, cyclopentene-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

4.45 (t, J = 6 Hz, NOCH 2),

5.15-6.30 (m, 4H, Z-N2 and 2 lactam-H),

7.6 - 8.7 ppm (m, 3H, Py)

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

2.2-2.8 (m, 2 cyclopentene-H),

3.10-4.00 (m, 6H, 4 cyclopentene-H and SCH2),

4.73 (m, 1H, C H),

5.20-6.30 (m, 4H, Z-N2 and 2 lactam-H),

7.65 - 8.72 ppm (m, 3H, Py)

2.2-2.8 (m, 2H, cyclopentene-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

4.80-6.42 (m, 9H, 5 allyl-H, Z-N2 and 2 lactam-H),

7.65 - 8.70 ppm (m, 3H, Py)

2.2-2.8 (m, 5H, 2 cyclopentene-H and SCH3),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2), 5.15-6.30 (m, 6H, CH2S, Z-N2 and 2 lactam-H),

7.67 - 8.72 ppm (m, 3H, Py)

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

2.2-2.8 (m, 2H, cyclopentene-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

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

5.20-6.30 (m, 4H, Z-N2 and 2 lactam-H),

7.66 - 8.70 ppm (m, 3H, Py)

1.3-2.8 (m, 10H, 2 cyclopentene-H,

8-cyclopentyl-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

5.15-6.25 (m, 4H, Z-N2 and 2 lactam-H),

7.6 - 8.7 ppm (m, 3H, Py)

2.2-2.8 (m, 2H, cyclopentene-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

3.95 (s, 3H, 2H),

5.05 (s, 2H, NOCH 2),

5.2-6.4 (m, 4H, Z-N2 and 2 lactam-H),

7.65 - 8.7 ppm (m, 3H, Py)

243 714 ^X H-NMR spectrum in deuterated trifluoroacetic acid: δ (ppm) Example

R 1 = CH 2 CONH 2

2.2-2.8 (m, 2H, cyclopentene-H),

3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH2),

4.90-6.35 (m, 6H, NOCH 2, 3-CH 2 and 2 lactam-H),

7.65-8.70- ppm (m, 3H, Py) - CH 2 COOH

2.15-2.8 (m, 2H, cyclopentene-H),

3.1-3.9 (m, 6H, 4 cyclopentene-H and SCH2),

5.08 (s, 2H, OCH 2),

5.15-6.25 (m, 4H, Z-N2 and 2 lactam-H),

7.65-8.70 ppm (m, 3H, Py) - (CH 2 CH 2) 2 COOH

1.8 (s, 6H, 2 * CH3),

2.10-2.8 (m, 2H, cyclopentene-H),

3.1-3.9 (m, 6H, SCH 2, 4 cyclopentene-H),

5.20-6.30 (m, 4H, 3-CH2 and 2 lactam-H),

7.68 - 8.72 ppm (m, 3H, Py) - CH 2 CCOOH 1 CH 2

2.1-2.8 (m, 2H, cyclopentene-H),

3.1-3.9 (m, 6H, 4 cyclopentene-H and SCH2),

5.1-6.40 (m, 6H, NOCH 2, 3-CH 2 and 2 lactam-H),

6.50-6.88 (m, 2H, C.dbd.CH2),

7.66 - 8.70 ppm (m, 3H, Py)

..... L ~

ΖΔ

j.-t

1.5-2.3 (m, 6H, 2 cyclopentene-H, cyclopropyl-H),

3.1-3.9 (m, 6H, 4 cyclopentene-H and SCHa),

5.15-6.30 (1 ^, 4H, Z-N2 and 2 (c ^ O ^ tam-HI),

7.66 - 2.77 cpm (m, 2H, 6p)

2.0-4.0 (m, 14H, 6 cyclobutyl-H, cyclopentene-H and SCH2),

5.15-6.0 (m, 4H, C-CH2 and 2 tactam-1H),

7.60 - 8.70 ppm (m, 3H, Py) as described

Analogously to Example 1 yields the title compound as amorphous solids which correspond to the formula I in which ^R1 represents a methyl group and R2 represents a substituent which is listed in the second column of the following Table 3:

example

R2 ';

TABLE 3

4 H-NMR spectrum in deuterated trifluoroacetic acid: δ (ppm)

1.9 - 2.45 (m, 2H, [beta] -z-η).

2.65-3.25 (m, 2H, pyran-H),

3.42 and 2.75 2 AB,> 19Hz, 2H, 20½))

4.26 (s, 3H, OCH 3),

4.4-4.8 (m, 2H, pyran-H),

4.85 - 6.20 2 (4, 4H, 2-OH and 2 (2-α),

7.25 (d, J = 7 Hz, Py-H),

8.2 - 2.6 2 m, 2H, PP)

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

4.22 (s, 3H, OCH 3),

5.2 - 6.45 (m, 4H, CHaPy and 2 lactam-H),

7.3 (m. 1H);

8.0-8.3 (m, 2H);

8.88 (d, (j = 7Hz, 2Η, a)

9.43 (s, 1H) furopyridine-H Example

R ²

i ^X H-NMR spectrum in deuterated trifluoroacetic acid: δ (ppm)

3.47 and 3.85 (AB, J = 19Hz, 2H, SCH2),

4.22 (s, 3H, OCH 3),

5.25 - 6.5 (m, 4H, CH2 -Py and 2 lactam-H).

7.90 and 8.18 (one d each, J = 5Hz, thiophene-H),

8.35 - 8.8 (m, 2H, Py),

9.50 (s, 1 H, Py)

3.50 and 3.86 (AB, J = 19Hz, 2H, SCH2),

4.21 (s, 3H, OCH 3),

5.3 - 6.5 (m, 4H, CHaPy and 2 lactam-H),

7.85 (d, J = 5 Hz, 1 thiophene-H),

8.2 - 8.8 (m, 3H);

9.63 (s, 1 H, Py)

3.26 (s, 3H, CH 3);

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

4.23 (s, 3H, OCH 3),

5.25-6.45 (m, 4H, CH 2 Pγ and 2 lactam-H),

7.75 (d,) = 5Hz, thiophene-H), 8.0-8.7 (m, 3H, thienopyridine)

3.46 and 3.75 (AB, J = 19Hz, 2H, SCH2),

4.21 (s, 3H, OCH 3),

5.2 - 6.5 (m, 4H, CH2Py and 2 lactam-H),

7.6-8.2 (m, 3H);

8.5-9.3 (m, 2H), thienopyridine

Claims (3)

OF THE INVENTION 1, A process for the preparation of the novel 7- [2-syn-oximino-2- (5-amino-1,2,4-thia'diazol-3-yl) acetamide amide derivatives of the formula I II N ⁴ OR ¹ bU - ^ - C - CONH - T -------- I ¹ A co; (') 1 to 6 wherein R @ ¹ represents an alkyl group having carbon atoms, an alkylthioalkyl group having 1 to 6 carbon atoms in both alkyl moieties, an alkenyl group having 2 to 6 carbon atoms. (C 6-Clo) cycloalkyl, (C až-C 7) cycloalkyl, (C až-C 7) cycloalkyl- (C až-C cyk) alkyl group, of formula R ³ AND - (ch 2 -r 2 -rs AND R4 in which m or n are 0 or · 1, R 3 and R 4 are the same or different from hydrogen, a C 1 -C 4 alkyl group or, together with the carbon atom to which they are attached, form a methylene group or a C 3 -C 7 cycloalkylidene group, R ⁵ is -CO ² R ⁶ in which R 6 is hydrogen, C 1 -C 4 alkyl, or an alkali metal, alkaline earth metal or ammonium equivalent; further denotes a carbamoyl group —CONHz, R ² represents a pyridinium group of the formula the residues R 2 in formula I, such as acetoxy or propionyloxy, is active in any order 2- (5-amino-l, 2,4-thiadiazol-3lyl) -2-syn-oximinoacetic acid of the formula IV which is substituted by 2 ortho-alkyl groups which are closed to form an optionally hydroxy-substituted di- to decamethylene ring in which the ring carbon atom is optionally replaced by an oxygen or sulfur atom, and may also contain one or more other two double bonds, or a 1-quinolinium group or a 2-isoquinolinium group, which are also optionally substituted by an alkyl group having 1 to 6 carbon atoms and in which the -OR 1 group is in the syn position, and their physiologically tolerable acid addition salts characterized in that the compound of formula (IA) is formed ...... 7 Ί Jy --------. * _: Χί'ίχ _r 'Д cH] COOH (ia) in which R ⁸ represents a group exchangeable with pyridine, quinoline or isoquinoline bases corresponding to 0 V) in which R1 is as defined above and R ⁷ represents an amino or protected amina2kupinu-Kupino example aminaskupinu protected TE ^ι rc.butзlavou group benzзlovau group, rub-yl group or trimethзlsilзlovou group or an activated derivative of this acid, and such the pyridine, quinoline or isoquinoline bases that correspond to residues in R2 wherein the optionally present protecting group is cleaved off and the compound of formula I obtained is optionally converted into a physiologically acceptable acid addition salt. Method according to claim 1, characterized in that the nucleophilic exchange of the substituent R 8 is carried out in the presence of neutral salt ions, in particular iodide or thiocyanate ions. 3. The method of claim 1, wherein the nucleophilic replacement of the substituent R 8 in the presence of a base which _ corresponds to radical R ^2, and trimethyljodsilasu.