CS245754B2 - Production method of 7beta-acylamido-3-cefem-4-carboxyl acids - Google Patents

Abstract

1399086 Cephalosporin compounds GLAXO LABORATORIES Ltd 12 May 1972 [14 May 1971 1 Oct 1971] 15082/71 and 45884/71 Heading C2C Novel 7 - acylamidoceph - 3 - em carboxylic acids and their salts, esters and 1-sulphoxides, wherein the acylamido group has the structure in which R is hydrogen or an organic group and R<SP>a</SP> is an etherifying monovalent organic group linked to the oxygen atom through a carbon atom, the said compounds having the syn isomeric form as regards the configuration of the group OR<SP>a</SP> with respect to the carboxamido group, or being a mixture of the syn and anti isomers containing at least 75% of the syn isomer, are prepared by acylating a 7-amino or 7-isocyanato-cephem carboxylic acid or its salt, ester or 1-oxide, with an acylating agent corresponding to the acid of formula and then recovering the desired acylamidocephem compound, if necessary after separation of the syn and anti isomers.

Description

The invention relates to a process for the production of a novel antibiotic of the cephalosporin series.

The nomenclature of cephalosporin compounds and the like. as used in the description is in agreement with (J. Amer. Chem. Soc. · 1962, 84).

400). This, .cefem ^'£ · therefore relates to' basic cefamové structure with one double bond.

It is known that cephalosporin antibiotics are, for example, 7 / 3acylamidoceph-3-em-4-carboxylic acids and various non-toxic derivatives thereof, for example salts, esters, lactones, if desired, amides, hydrates and the corresponding sulfoxides. These antibiotics can carry various substituents, especially at the 3-position, including substituted or unsubstituted methyl groups, which can further carry various substituents, as described in the literature.

The novel compounds of the present invention have the property that the acylamide group of the cephalosporin antibiotic is a (α-etherified oximinojacylamide group), wherein the compounds may be syn-isomers or occur in mixtures in which the syn-isomer form predominates.

According to one embodiment of the process of the invention, a compound from the group of N-acylamidoceph-3'em-4-carboxylic acids in which the acylamido group has the structure

R — C — CONH—

II N \ OR ^and where

R is hydrogen or an organic radical and

Ra is an etherified monovalent organic group that is bonded to an oxygen atom by a carbon atom, the entire compound may be in the form of the syn-isomer or in a mixture containing at least 75% of the syn-isomer. It is preferred that the mixture of isomers comprises at least 90% of the syn-isomer and at most 10% of the anti-isomer #

The compounds of the invention have the syn- (cis) isomeric form with respect to the configuration of the OR group ^and relative to the carboxamide group. The configuration is considered to be a syn-isomer

R — C — CO — NH—

II

The N \ OR a ^and anti-isomer configuration is considered

R — C — CO — NH—

II

N /

R ^and O

These configurations are named after Ahmad and Spencer (Can. J. Chem., 1961, 39, 1340).

The compounds of the invention can be represented by the general formula I

COOH (I) wherein

^And R and R are as defined above,

B represents a sulfur atom or S-O and

Z represents a group in which 2 carbon atoms are bonded to the sulfur atom contained in the nucleus and a carbon atom which carries a carboxyl group while being Δ3 unsaturated.

Accordingly, the present invention provides a process for the preparation of 7 ₍ 3-acylamido-3-cephem-4-carboxylic acids of formula I).

(i) where

R is hydrogen or a group R ⁱⁿ which

Ru represents a (C 6 -C 12) carbon ring aryl group, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic aryl group containing at least one hetentate selected from the group consisting of sulfur, nitrogen and oxygen, or such a benzene ring fused hetocyclic group such as 2-thienyl, 3-thienyl, furyl, pyridyl, pyrrolyl, N, N-ethylpyridyl, N-benzyloxymethylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or

4-isoxazylol, 3-phenyl- or 3-halo-phenyl-5-methyl-4-isoxazolyl, benzothienyl, benzofuryl, indolyl or sydnon, cycloalkyl of 3 to 7 carbon atoms, e.g. or any cyclohexyl group, any of the above being optionally substituted by halogen, hydroxy, C 1-6 alkyl, nitro, amino, C 1-6 alkylamino, C 1-6 dialkylamino in each alkyl moiety, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoylamido, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio or cyclohexadienyl, or R is represented by the formula

R ^u (CH2) mQr (CH2) p, wherein

R ^u is as defined above, m is 0 or an integer of 1-4, n is 0 or 1, p is an integer from 1 to 4 and

Q represents a sulfur atom, an oxygen atom or a group = NR 2 where

R2 represents a hydrogen atom or R represents a group of the formula

Wherein n · is an integer from 1 to 7, wherein the groups have a straight or branched chain and are optionally interrupted by an oxygen atom or a sulfur atom. or with the group = NR2, where ......

R2 is as defined above, or is optionally substituted by cyano, carboxy, or alkoxycarbonyl having 2. up to 7 carbon atoms, a hydroxy group or a carboxycarbonyl group of the formula

HOOO-CO or halogen or R represents a group of the formula

Wherein n is an integer from 2 to 7, wherein the group is straight or branched, optionally interrupted by an oxygen or sulfur atom or a group = NR ² , wherein:

R2 is as defined above, or R is a group of formula

Where n is an integer of 2 to 7, or R is cyano, amido or alkoxycarbonyl of 2 to 7 carbon atoms in the alkoxy moiety,

R ^a represents a C 1 -C 16 alkyl group, for example a methyl, ethyl, propyl, butyl, octyl or ¹ dodecyl group, a C 2 -C 16 alkenyl group, for example a vinyl, allyl, isopropenyl or dimethylallyl group, a 2-alkynyl group up to 16 carbon atoms, for example propargyl, 3 to 7 carbon cycloalkyl, for example cyclopropyl, cyclopeontyl or cyclohexyl, 4 to 7 carbon cycloalkenyl, for example cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl, aryl with a C 6 -C 12 carbon ring, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen or sulfur, optionally fused with a benzene ring or other a heterocyclic group such as a pyridyl, pyrimidyl, furyl, thienyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl or purinyl or C 1 -C 4 alkyl or carbon-substituted group; A heterocyclic ring as defined above, for example, benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, thienylmethyl, furylmethyl, pyridylmethyl or pyrrolylmethyl, each of which is optionally substituted with a halogen atom such as chlorine or bromine, a hydroxy group having 1 to 6 alkoxy carbon atoms, for example methoxy, ethoxy or propoxy, aryloxy of 6 to 12 carbon atoms, for example phenoxy, phenylalkoxy of 1 to 4 carbon atoms in the alkyl portion, for example benzyloxy, mercapto thio, C 1 -C 6 alkylthio, for example methylthio or ethylthio, C 6 -C 12 arylthio, C 1 -C 4 phenylalkylthio, amino, C 1 -C 6 alkylamino, for example methylamino or ethylamino, (C 1 -C 6) dialkylamino in each alkyl moiety, e.g., dimethylamino, nitro, azidoscopic, carboxy, (C 2 -C 7) alkoxycarbonyl, e.g., methoxycarbonyl or ethoxycarbonyl, benzyloxycarbonyl, acyl to 1, acyloxy, propionyl or benzoyl, acyloxy of 1 to 10 carbon atoms, for example acetoxy, propionyloxy or pivaloyloxy, cyano, phthalimido, acylamido of 1 to 10 carbon atoms, for example aceta mido or benzamido, alkoxycarbonylamino having 2 to 7 carbon atoms in the alkoxy moiety, for example methoxycarbonylamino, or. phenylalkoxycarbonylamino having 2 to 5 carbon atoms in the alkoxy moiety, for example benzyloxycarbonylamino,

Y represents a pyridine base residue, N-pyrimidine, N-purine, N-pyridazine, N-pyrazine, N-pyrazole, N-imidazole, N-triazole or N-thiazole cation optionally substituted by an alkyl group having 1 to 6 C 6 -C 12 aryl, C 1 -C 4 phenylalkyl, C 2 -C 7 alkoxymethyl, formyl, C 1 -C 8 acyloxy, C 2 -C 8 acyloxymethyl 9 carbon atoms in the acyl moiety, C 2 -C 7 alkoxycarbonyl, benzyloxycarbonyl, C 1 -C 6 alkoxy, C 6 -C 12 aryloxy, C 1 -C 4 phenylalkoxy, alkylthio C 1 -C 6 aryl, C 6 -C 12 arylthio, C 1 -C 4 phenylalkylthio, cyano, hydroxy u, carbamoyl, N-monoalkylcarbamoyl of 1 to 6 carbon atoms in the alkyl moiety, N, N-dialkylcarbamoyl of 1 to 6 carbon atoms in each alkyl moiety, N-hydroxyalkylcarbamoyl of 1 to 6 carbon atoms in the alkyl moiety or a carbamoylalkyl group having 1 to 6 carbon atoms in the alkyl moiety, an azido group, an amino group or an acylamido group having 1 to 8 carbon atoms, a group derived from a derivative obtained by reacting a compound wherein Y is an azidocup group with dipolarophilic acetylene or ethylene or cyano group;

24S754

R ³ —C — CO — R 5 where

R ³ and R ⁴ which are the same or different denote hydrogen, cyano, C 1 -C 6 alkyl, phenyl, halophenyl, C 1 -C 6 alkylphenyl, alkoxyphenyl C 1 -C 6 alkoxy, nitrophenyl, aminophenyl, C 1 -C 6 alkylaminophenyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 5 mono or diphenylalkoxycarbonyl a C 1 -C 7 alkylcarbonyl group, a C 1 -C 4 phenylalkyl group or a C 5 or C 6 cycloalkyl group; and

R 5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a halophenyl group, an alkylphenyl group having 1 to 6 carbon atoms in the alkyl moiety, an alkoxyphenyl group having 1 to 6 carbon atoms in the alkoxy moiety, nitrophenyl group, aminophenyl, (C 1 -C 6) alkylaminophenyl, (C 1 -C 4) phenylalkyl or C 5 or C 6 cycloalkyl;

-S (O) _n R ®, where

R 6 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having a "carbon ring having 6 to 12 carbon atoms" or a phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety, or a heterocyclic group as defined above, for example, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimldazxHyl, benzoxazolyl, benzothiazolyl, triazolopyridinyl, purinyl, pyridyl or pyrimyl substituted with up to 6 carbon atoms, or any one of these or nitro, n is 0, 1 or. 2, preferably 0, further Y represents a group of the formula —OR ‘, where

R‘ represents a hydrogen atom, an acetoxy group, a group of the formula —O — COR9, wherein

R ⁹ represents an organic group having an atomic mass of at least 16, which is selected from the group consisting of the formula

CnH2n + b wherein n is an integer from 1 to 7 and the group has a straight or branched chain optionally interrupted by an oxygen or sulfur atom or an imino group or substituted by cyano, carboxy, alkoxycarbonyl of 2 to 7 carbon atoms in the alkoxy moiety, hydroxy, a carboxycarbonyl, halogen or amino group of the formula

Wherein n is an integer from 2 to 7 and the group has a straight or branched chain optionally interrupted by an oxygen atom, a sulfur atom or an imino group, a group of the formula

R ^at , where

R ^v is a C 6 -C 12 aryl ring, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic aryl group containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, or such a benzene ring fused heterocyclic group such as 2-thien,

3-thien, furyl, pyridyl, pyrrole-various diseases which are caused by methyl methylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or

4-isoxazolyl, 3-phenyl- or 3-haliogenphenyl-5-methyl-4-isoxazolyl, benzothienyl, benzofuryl, indolyl or sydnon, cycloalkyl of 3 to 7 carbon atoms, for example cyclopentyl or cyclohexyl, any of the above groups being optionally substituted with halogen, hydroxy, C 1 -C 6 alkyl, nitro, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkanoyl C 1 -C 6 alkanoylamido, C 1 -C 6 alkoxy or C 1 -C 6 alkylthio or cyclohexadienyl, or formula

R ^V - (CH 2 U where

R ^v is as defined above and m is an integer from 1 to 4, a group of the formula -O-CO-AR ^9a , wherein

A is O, S or NH

R ^9a represents a hydrogen atom, the methyl group R ⁹ as defined above, a group of the formula -O-CO-NH (CH 2) ₁ D 1, wherein

D represents a halogen atom, for example a chlorine, bromine, iodine or fluorine atom, and m is an integer from 1 to 4, for example 2-chloroethylaminocarbonyloxy or a chlorine, bromine or iodine atom, as well as their nontoxic farinocubly acceptable salts and sulfoxides.

The term non-toxic means derivatives of the compounds of the invention which are physiologically acceptable at the dosages at which they are administered.

Salts which can be formed from the compounds of the invention are, for example,

(a) salts with an inorganic base such as an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium and an organic base such as procaine, phenylethylbenzylamine and dibenzylethylenediamine;

b) acid addition salts such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, para-toluenesulfonic and methanesulfonic acids.

The salts may also be in the form of resins formed, for example, with a polystyrene resin that contains amino groups, a quaternary ammonium group or a sulfonic acid residue, or with a resin that contains carboxyl groups, for example a polyacrylate. It is also possible to use a resin which contains cross bridges, for example a copolymer of styrene and divinylbenzene, which contains one of the abovementioned groups. In addition, the compounds of the invention may be chelated with a heavy metal such as iron or copper.

The compounds of the present invention and their non-toxic derivatives have high antibacterial activity against a wide variety of gram-positive and gram-negative microorganisms and at the same time very high stability to β-lactamase enzymes which are produced by various gram-negative microorganisms.

Stability to β-lactamases is determined, for example, by comparison with cephaloridine, whose rate of decomposition is determined as being one with respect to the microorganism used.

The properties of the compounds of the invention allow the use of these compounds for the treatment of various diseases caused by pathogenic bacteria in humans and animals.

Preferred cephalosporin compounds of the invention can be represented by the general formula ΙΓ

where

R, R ^and а В mean the same as above and

P is an organic residue or is a non-toxic derivative of these compounds. In the formula Ι.Γ, V is preferably a divalent sulfur atom.

The invention also includes cephalosporin compounds which do not specifically fall within the general formula ΙΓ, for example 2-methylcephalosporin and 2-ethylencephalosporin.

The group R &lt; a ^&gt; ^and in the above formula can be any group which contains a carbon atom with one free valence, so that the group can form the desired ether group with the carbon atom. The group R ^a contains no more than 16 carbon atoms.

R ^a can be, for example, alkyl of 1 to 16 carbon atoms, in particular lower alkyl of up to 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, octyl or dodecyl, alkenyl of 2 to 16 carbon atoms, preferably 2 to 8 carbon atoms, such as vinyl, allyl, isopropenyl, or dimethylalkyl, alkynyl of 2 to 16 carbon atoms, preferably up to 8 carbon atoms, for example propynyl or propargyl, cycloalkyl; 3-7 carbon atoms, such as cyclopropyl, cyclopentyl or cyclohexyl, cycloalkenyl of 4 to 7 carbon atoms, such as cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl, aryl containing a carboxyl group such as phenyl or naphthyl, a heterooyl group, especially with 5 or 6- a black ring containing at least one heteroatom, namely oxygen, nitrogen, or sulfur such as pyridyl, pyrimidyl, furyl, thienyl, thiazolyl, thiadiazolyl,

24S754 diazOlyl, triazolyl, terazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidaziolyl, benzoxyzolyl or purinyl, or lower alkyl, further substituted with aryl containing a carboxyl group or a heterocyclic radical, the alkyl portion of which contains 1 to 4 carbon atoms, for example benzyl, phenylethyl diphenylmethyl, triphenylmethyl, thienylmethyl such as thien-2-ylmethyl, furylmethyl such as furfuryl, pyridylmethyl or pyrrolylmethyl.

The group R ^a may be unsubstituted or carry 1 or more substituents, for example hydroxyl, alkoxy, such as methoxy, ethoxy, n-propoxyl or isopropioxyl, methoxymethyl or 1-ethoxyethyl, further aryloxy, for example phenoxyl, arylalkoxy, for example benzyloxy, mercapto, alkylthio, such as methylthio or ethylthio or ethylthio, arylthio, arylalkylthio, amino, such as 2-aminoethyl, substituted amino, such as methylamino or ethylamino or dimethylamino, halo such as chloro or bromo, such as chloro or bromo, an azide group, a carboxyl group, an esterified carboxyl group, for example a lower alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl _; benzyloxycarbonyl, formyl, acyl such as acetyl, propionyl or benzoyl, acyloxy such as acetoxy ·, piropionyloxyskupinu or pivaloyloxy, cyano, phthalimido group, acylamido group, e.g., acetamido or benzamido, alkoxycarbonylamino, e.g. · methoxykarbonylaminoskupinu or ethoxycarbonylamino or arylalkoxykarbonylaminoskupinu, for example, benzyloxycarbonylamino.

The group R in the above formula may have the following meaning. This meaning is not entirely limiting:

i) hydrogen, ii) a group R ^u where R ^u is aryl and carbocyclic or heterocyclic, cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl or non-aromatic group or a group containing an amphoteric ion. Examples of such groups may be, phenyl, naphthyl such as naphth-1-yl, phenyl or naphthyl further substituted by a halogen atom such as chlorine or bromine to form, for example, o-chlorophenyl, hydroxy, lower alkyl such as methyl, nitro, amino, lower alkylamino, for example methylamino, dl (lower) alkylamino such as dimethylamino, lower-alkanoyl, for example acetyl, lower alkanoylamido, lower alkoxy, such as methoxy or ethoxy, lower alkylthio, such as methylthio. R ^u can also represent a 5-membered or 6-membered heterocyclic ring containing at least one heteroatom and a sulfur, nitrogen no bo oxygen, for example thien-2-yl, thien-3-yl, furyl, such as fur-2-yl, pyridyl such as pyrid-3-yl, pymolyl, N-substituted pyrrolyl such as N-methylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or 4-isoxazolyl, substituted 3- or 4-isoxazolyl such as 3-aryl-5-methylisoxazole- 4-yl, wherein aryl is phenyl or halophenyl, fused heterocyclic groups containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, such as benzothienyl, for example benzothien-3-yl, benzofuryl, indolyl, cyclohexyl, cyclopentyl, sydnon and cyclohexadienyl.

iii) R ^u (CH 2) _m Q _n (CH 2) _p , wherein R ^u is as defined above, m is 0 or an integer from 1 to 4, n is 0 or 1, p is an integer from 1 to 4 and Q is an atom a sulfur atom, an oxygen atom or an NR group wherein R represents a hydrogen atom or an organic group, for example an alkyl such as methyl or an aryl such as phenyl. Examples of such groups are methyl, ethyl, butyl or, substituted with groups R ^u as listed in Section II) napříkílad benzyl, and appropriately substituted benzyl.

iv) CnHin + ь where n is an integer from 1 to 7. These groups may be straight or branched and optionally interrupted by an oxygen or sulfur atom or by an NR group where R is a hydrogen atom or an organic group such as an alkyl such as methyl or aryl such as phenyl, or it may be substituted by cyano, carboxyl, alkoxycarbonyl, hydroxycarbonyl or carboxycarbonyl or halogen. Examples of such groups are hexyl, heptyl, butylthiomethyl, cyanomethyl or trihalomethyl.

v) СпНгп-ь where n is an integer from 2 to 7. This group may be straight or branched methyl and ethyl, from unsaturated organic or sulfur, or NR where it is hydrogen or an organic group, for example alkyl such as methyl or aryl such as phenyl . Examples of such groups are vinyl or propenyl.

vi) C _n H ₂ n-3, wherein n is an integer from 2 to 7. An example of such groups is ethynyl.

vii) Various organic groups bonded to a carbon atom, for example cyano, amido or lower alkoxycarbonyl.

The substituent at the 3-position of the aforementioned compounds of formula (ΙΓ) may be any organic group since the essential group for the properties of the compounds of the invention is the group at position, thus being an organic group saturated or unsaturated, substituted or unsubstituted of 1 to 20 carbon atoms. Of the saturated organic groups, vinyl and substituted vinyl groups of the general formula are optionally interrupted by an oxygen atom

R3 / —СН- = С \ R4 where

R ³ and R ⁴ , which may be the same or different, represent a hydrogen atom or a substituted or unsubstituted alkyl group, preferably an alkyl of 1 to 8 carbon atoms such as methyl, ethyl, isopropyl, n-propyl, etc. C 5 -C 7 cycloaliphatic, such as cyclopentyl or cyclohexyl, C 7 -C 10 arylaliphatic, for example benzyl or phenylethyl, C 6 -C 12 aromatic (for example phenyl or nitrophenyl) nitrile or lower alkoxycarbonyl.

If the Π substituent at the 3-position is substituted with methyl, this group can be represented by the formula —C 11 ZY where

Y represents an atom or a group, for example a nucleophile residue or a substituted nucleophile residue.

Thus, Y may be derived from a wide variety of nucleophilic substances which are characterized in that they contain a nucleophilic nitrogen, carbon, sulfur or oxygen atom. These compounds have previously been extensively described in the patent literature and in the literature on cephalosporin chemistry. Examples of nucleophilic groups include:

Nucleophiles containing nitrogen

Examples of such compounds are tertiary aliphatic, aromatic, arylaliphatic and cyclic amines such as trialkylamines, for example triethylamine, pyridine bases such as pyridine and alkylpyridines, heterocyclic amines of more than one heteroatom, at least one of which is a nitrogen atom such as pyrimidines, purines, pyridazines, pyrazines, pyrazoles, imidazoles, triazoles and thiazoles.

A preferred group of nitrogen-containing nucleophiles are compounds of the formula

0.- ⁽ R ') wherein n represents 0 or · an integer from 1 to 5 a

R ^d , which when n is 2 to 5 may be the same or different, represents an aliphatic group, for example a lower alkyl such as methyl, ethyl, n-propyl, isopropyl, etc., aryl such as phenyl, arylaliphatic

243754 a group such as phenyl substituted by lower alkyl ie benzyl, phenylethyl, etc., alkoxymethyl such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl and so on, acyloxymethyl such as alkanoyloxymethyl such as acetoxymethyl, formyl, carbamoyl, acyloxy such as alkanoyloxy such as acetoxyl , esterified carboxyl, alkoxy such as methoxy. ethoxy, n-propoxy, isopropoxy, and the like, aryloxy such as phenoxy, arylalkoxy such as benzyloxy, alkylthio such as methylthio and ethylthio, arylthio, arylalkylthio, cyanocoyl, methyl, N-mono (lower alkyl) N-mono (lower alkyl) N-mono (lower alkyl) N, N-di (lower alkyl) carbamoyl, such as N, N-dimethylcarbamoyl, Ν, Ν-diethylcarbamoyl and the like, N-hydroxy (lower alkyl) carbamoyl, such as N (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl etc., carbamoyl (lower alkyl) such as carbamoylmethyl, carbamoylethyl and the like.

Another suitable group of these are azides, for example with alkali metals such as sodium azide.

When Y is a derivative or residue of a nucleophile, it may be an amino group or an acylamido group. Compounds? in which Y is an amino group may be derived by reduction of the corresponding azide, for example by catalytic hydrogenation of the azide, using a precious metal such as palladium or platinum as the catalyst.

The amino group can be subjected to acylation to form a compound containing an acylaminomethyl group at the 3-position. These compounds can be formed by any method suitable for acylating an aminocephalorin, for example by reacting an S-aminomethyl compound with an acid chloride, acid anhydride, mixed anhydride or acid. of which acyl is a desirable group. The aminomethyl compounds can also be reacted with a substituted isocyanate or isothiocyanate to form urea derivatives or thioureas. Other compounds in which Y is a derivative or residue of a nucleophile can be obtained by reacting a 3-azidomethyl compound with a dipolarophile group. A preferred class of dipolarophilic substances are acetylene, ethylene and cyano-containing compounds.

The dipolar film of the acetylene-type group can be represented by the general formula

R ^{1 -} C = C - R 2 wherein

R 1 and R 2, which may be the same or different, represent atoms or groups.

It is preferred that R1 and preferably R2 are of an electro-negative nature. Examples of such groups are cyano, CO ² R ³ , COR ³ (where R 3 is, for example, 2,475,784 lower alkyl, aryl or lower arylalkyl), and trihalomethyl such as trifluoromethyl.

And preferably R 1 and R ² but can also be electropositive nature, can mean for example alkoxy or alkylaminoskuplnu.

R1 and R2 may form a ring together to form, for example, arine.

In case that R1 and R2 are separated by atoms or groups ¹ are however the same form in the reaction with azidocefalosporinem compound which is a single type. When these symbols have different meanings, a mixture of positional isomers is usually obtained.

Dipolarophilic groups of the ethylene type can be represented by the general formula

1S

Carbon nucleophiles

Organic cyanides, pyrroles and substituted pyrroles, for example indoles and compounds which can be a source of stable anions based on a carbon atom, for example acetylenes and compounds containing (i-diketone groups such as acetic acid esters and malonic, cyclohexane-1,3-diones, enamines, inamines or enols.

These groups can give rise to cephalosporin compounds having a substituent at the 3-position in which the carbonyl group is attached to the cephalosporin nucleus by two carbon atoms. These compounds therefore have a group of the general formula at the 3-position

R2

I — CHa — C — CO — R ⁴

where

R ⁵ , R ®, R ⁷ and R ⁸ may be the same or different and are atoms or groups.

Although R 5, R 7, R 7 and R ⁸ may all be hydrogen, ethylene alone, as well as acetylene, reacts slowly with azide groups. R 5 and R 7 together may form a ring, for example a carbon, in which two double bonds may be adjacent to each other. Examples of groups containing chained double bonds are norbornenes, trans-cycloalkenes and acenaphthalene.

Other dipolarophile compound of ethylenic type, which may be used include the compounds themselves "type R5R®-C = CR ⁷ R ^8, wherein at least one of R5, ^R6, R7 and R8 is an electronegative group. R 5 and R 7 can be the same electronegative groups and R ® and R 8 can be other negative groups as desired. R ⁶ and R 8 may form a ring together. Examples of such groups are benzoquinone and nucleosubstituted benzoquinone, as well as maleic imide. All R 5, R 7, R 7 and R ⁸ groups may be the same electronegative groups. Groups which may be used include those already mentioned in the calculation of acetylene type dipolarophilic substances. Examples thereof are dicyanoethylene and lower mono- and dialkoxycarbonylethylenes.

One or more of R5, R®, R7 and R® may be electropositive.

The cyano compounds, especially those which are activated by tltrontgative groups, can act as dipolarophilic substances containing cyano groups. Examples of such groups are cyanogen and lower alkoxycarbonyl cyanides.

where

R 2 and R ³ , which may be the same or different, are hydrogen, cyano, lower alkyl such as methyl or ethyl, phenyl substituted with halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino, lower alkoxycarbonyl, mono- or diaryl (lower alkoxycarbonyl, (lower alkylcarbonyl, aryl (lower alkyl)) or cycloalkyl of 5 to 6 carbon atoms and

R ⁴ is hydrogen, lower alkyl such as methyl or ethyl, phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino, aryl (lower alkyl) or cycloalkyl of 5 to 6 carbon atoms.

Sulfur-containing nucleophiles

Examples of sulfur-containing nucleophilic groups are thiourea and thioureas, substituted with aliphatic, aromatic, arylaliphatic, allicyclic and heterocyclic diihiocarbamates, aromatic aliphatic and cyclic thioamides, e.g. dithiocyanine.

Preferred are those which can be represented by the formula

R 1 -S (O) n H where

R 1 represents an aliphatic group, for example lower alkyl such as methyl, ethyl, n-propyl etc., an alicyclic group such as cyclohexyl, cyclopentyl and the like, an aromatic group such as phenyl, naphthyl and the like, an aryl aliphatic group such as benzyl or heterocyclic, n represents an integer of 0, 1 or 2.

A particularly preferred class of these compounds are those which can be represented by the general formula

R ⁶ SH where

R ⁶ represents an aliphatic group, for example methyl, ethyl, n-propyl and the like, an arylaliphatic group such as phenyl substituted by lower alkyl, i.e. benzyl, phenylethyl and the like, or substituted phenyl further substituted by lower alkyl, alicyclic groups such as cyclopentyl or cyclohexyl aromatic groups such as phenyl or substituted phenyl or a 5- to 6-membered heterocyclic ring containing at least 1 oxygen, nitrogen and sulfur atom, for example triadiazolytic groups, in particular 5-methyl-1,3,4-thiadiazol-2-yl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatrlazole, oxazolyl, oxadiazolyl, pyridyl and pyrimidyl, or a substituted heterocyclic group, including groups that are substituted with divalent groups, to form a fused nucleus such as benzimidazolyl, benzoxazolyl, triazolopyridyl and purrinyl.

Oxygen-containing nucleophiles

Examples of such compounds are water, alcohols, for example akanols such as methanol, ethanol, propanol and butanol, and acids derived from lower alkanes and alkenes.

The term "oxygen-containing nucleophiles" includes compounds of the general formula

ROH where

R1 represents lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl etc., lower alkenyl such as allyl, lower alkynyl, such as propynyl etc., lower cycloalkyl, such as cyclopropyl, cyclopentyl , cyclohexyl, etc., lower cycloalkyl (lower alkyl), for example cyclopropylmethyl, cyclopentylmethyl, cyclohexylethyl and the like, aryl such as phenyl or naphthyl, aryl (lower alkyl) such as behzyl, heterocyclic group, lower alkyl substituted heterocyclic group such as furfuryl or any of these groups further substituted, for example, with one or more lower alkoxy groups such as methoxy, ethoxy and the like, lower alkylthio such as methylthio or ethylthio, and the like with a halogen atom such as chlorine, bromine, iodine or fluorine; alkyl such as methyl, ethyl and the like, nitro, hydroxyl, acyloxy, carboxyl, carboloxyl, lower alkylcarbonyl, lower alkyl alkylsulfonyl, lower · ..... alkoxysulfonyl, amino, lower alkyl amino or acylamino.

When the nucleophilic group containing oxygen is water, 3-hydroxymethylcephalosporin is obtained, which can be represented by the general formula A

R and Ra mean the same as above.

Compounds of formula (A). their non-toxic derivatives have an antibacterial effect and can in principle be metabolites of compounds of formula (II) in which B represents a sulfur atom and P represents acetoxymethyl. The compounds of formula (A) may be acylated to derivatives containing groups

3-CH 2 -O-CO-R ⁹ or

3-CH 2 —O — CO — AR10 wherein

A is oxygen, sulfur or NH,

R ⁹ represents a methyl or organic group having an atomic mass of at least 16 and

R10 is hydrogen or R9.

The group R ⁹ CO- or R ^W ACO- may be any of a wide group of residues that have been described in the literature and contain up to 20 carbon atoms. Thus, R 9 may be a hydrocarbon radical which may be optionally substituted by one or more atoms or one or more groups. The groups R9 can be selected, for example, from the following groups:

(i) C 11 H 2 n + 1, where n is an integer from 1 to 7, for example from 2 to 4. The group may have a straight or branched chain and, if desired. it may be interrupted by an oxygen or sulfur atom or an imino group, or it may be substituted by a cyano, carboxyl, alkoxycarbonyl, hydroxyl, carboxycarbonyl, halogen atom such as chlorine, bromine or iodine, or an amino group. Examples of these groups are ethyl, propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and 2-chloroethyl.

(ii) C 11 H 1 -, wherein n is all purely 2 to 7. The group may have a straight or branched chain and, if desired, may be. interrupted by an oxygen or sulfur atom or an imino group. Examples of such groups are vinyl or propenyl.

(iii) Rv, wherein Rv is ethyl, with a carbon ring or ¹ heterocyclic, cycloalkyl, substituted aryl or substituted cycloalkyl such as phenyl, substituted phenyl such as hydroxyphenyl, chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl or methylthiophenyl, and also trien-2-yl and trien-3-yl, pyridyl, cyclohexyl, cyclopentyl, cyclopropyl, sydnon, naphthyl, substituted naphthyl such as 2-ethoxynaphthyl.

(iv) R ^v (CH _{2 m} , where R ^v is as hereinbefore defined and _m is an integer from 1 to 4. Examples of these groups are methyl, ethyl or butyl substituted by the various R ^v groups as indicated in (iii). for example benzyl and appropriately substituted benzyl groups.

An important group of cephalosporin compounds are those containing the 3-CH 2 Hal group, where Hal is a chlorine, bromine or iodine atom. These compounds are also very valuable intermediates in the production of active cephalosporin compounds.

An important group of antibiotics which can be produced by the method of the invention and which have a broad spectrum of antibiotic activity, including activity against different strains of Haemphilus influenzae together with stability to β-lactamase, which is produced by different gram-negative organisms, can be represented by formula B

COOH (в) or are nontoxic derivatives of these compounds. In formula B, R 1 is phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl or. pyridyl. or any of these groups further substituted by a halogen atom such as chlorine, bromine, iodine or fluorine, hydroxy, lower alkyl, nitro, amino, lower alkylamino, di (lower alkyl amino, lower alkanoyl, lower alkanoylamido), lower alkoxy, lower alkylthio or carbamoyl, Rb is lower alkyl, cycloalkyl of 3 to 7 carbon atoms or aryl with a carbon or heterocyclic ring, lower alkyl or any of these groups further substituted by hydroxyl, carboxyl, esterified carboxyl, amido, cyano, Alkanoyl, amino, substituted amino, halogen or lower alkoxy The groups Y are selected from the group consisting of (a) acetoxy, (b) a nucleophile radical containing nitrogen

where

R d and n are as defined above, in which case the 4-position of the compound of formula B is -CC 2 -, (c'SW, wherein W is thiadiazolyl, preferably 5-methyl-1,3,4-thiadiazol-2) -yl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridine, purinyl, pyridyl or pyrinidyl, (dj lower alkylthio) of 1 to 4 carbon atoms, (e) -O-CO —R9 where R9 · represents alkyl of 2 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms, (f) —O — CO — NH— (CH2) mD where m represents an integer of 1 to 4 · And · D · represents a chlorine, bromine, iodine or fluorine atom and (g) an azido group.

Particularly. An important group of compounds of formula B in width. of antibiotic spectrum including activity against various strains of Pseudomionas pyocyanea are compounds of general formula C

R-C-CO-NH II

N n ^X Off

COOH (c)

where

R ^x is phenyl, naphthyl, _1? Thienyl, furyl, benzothienyl or benzopuryl; and

R ^c represents alkyl of 2 to 4 carbon atoms, benzyl, phenylethyl, thienylmethyl or furylmethyl, as well as non-toxic derivatives thereof. Important compounds within the scope of the compounds of formula (C) are the following compounds in their syn-isomeric form:

3-acetoxymethyl-75-

- {2-ethoxyimino-2-phenylacetamido} -3-em-4-carboxylic acid, 3-acetoxymethyl-7 / 3-

- [2-t-butoxyimino-2- (2-thienyl) acetamido] cef-3-em-4-carboxylic acid, 3-acetoxymethyl-73-

- [2- (2-Thienyl) methoxyimino-2-

- (2-thienyl) acetamido ·] ceph-3-em-4-carboxylic acid, 3-acetoxymethyl - 7 _l 3-

- [2-t-butoxyimino-2- (2-furyl) acetamido] cef-3-em-4-carboxylic acid, 3-acetoxymethyl-78-

- [2-benzyloxyimino-2- (2-thienyl) acetamido] cef-3-em-4-carboxylic acid, 3-acetoxymethyl 1-7 / 3-

- [2-t-butoxyimino-2- (1-naphthyl) acetamido] cef-3-em-4-carboxylic acid, and β-β-β-α-β-β-β-

- [2-n-butoxyimino-2- (2-thienyl) acetamido] cef-3-em-4-carboxylic acid, especially in the form of its sodium or potassium salts. An important group of compounds falling under formula B due to their broad antibiotic spectrum together with high activity against various strains of Maernophilus influenzae are compounds of formula D

X

R-O-O0-NH II

CH ^ T

CO OH (o)

0R ^b where

R ^x and R ^b have the above meanings of a

T represents an acetoxy group, an azide group, a nitrogen-containing nucleophile residue of the formula wherein

Rd and n are as hereinbefore defined, or a group -O-CO-R9, where ^R9 is alkyl of 2-4 carbon atoms, alkenyl of 2-4 carbon atoms or phenyl · as well as non-toxic derivatives of these compounds.

Another important group of compounds of formula B with a large absorption coefficient for oral administration in animal experiments and with a broad spectrum of activity are compounds of formula E wherein:

R x and R ^b are as hereinbefore defined ·,

V is lower alkylthio of 1 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms or alkenoyl of 2 to 4 carbon atoms, as well as non-toxic derivatives of these compounds.

Another important class of compounds of formula B with a high degree of activity against various gram-positive and gram-negative microorganisms, as well as high stability due to the effect of the β-lactamases produced by the various microorganisms,

CHhOCOOH ₃ (F) wherein

Rx is the same as above in formula C as well as the non-toxic derivatives of these compounds.

A particularly preferred compound of formula (F) is 3-acetoxymethyl 1-7 / 3- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of its syn-isomer, particularly as a setter or potassium salt .

The compounds of formula (I) and their non-toxic pharmaceutically acceptable salts and sulfoxides are prepared according to the invention by reacting a compound of formula (II) in the reaction.

/ kde

R and R ^{and <} are as defined above, V is> S or>S-> O, R ¹⁰ is a hydrogen atom or a carboxy protecting group,

Y * represents a chlorine, bromine or iodine atom, a hydroxy or acetoxy group, with a nucleophilic compound introducing a group Y into the compound of formula II,

Y is as defined above, with a reactive derivative of the compound, such as a salt or acylating agent such as an acid chloride or anhydride, whereupon the R ¹⁰ carboxy protecting group is removed and, when V is> S- »0, optionally reduced to the corresponding sulfide and the desired compound of formula I is isolated in the form of an isomeric mixture containing at least 75%, preferably at least 90% of the synisomer or preferably in the form of a syn-isomer free of the corresponding anti-isomer, optionally of formula I to its non-toxic pharmaceutically acceptable salt or sulfoxide, for example by reaction with a base such as sodium or potassium 2-ethylhexanoate.

It is usually preferred to condense the acylating agent corresponding to the acid of formula VII

R — C — COOH

II

N \

OR ^and (VII), where

R and R ^a are as defined above, with an amino compound of formula III

(Ifl) where

В represents a divalent sulfur atom or a group \

/ S- * O,

Z represents a group in which 2 carbon atoms are bonded both to the sulfur atom in the nucleus and to the atom which carries the carboxyl group, the group being A ^3- unsaturated

R ¹⁰ is a hydrogen atom or a carboxyl-blocking group, for example, an ester-forming alcohol residue, aliphatic or arylaliphatic, phenol, silanol, stannanol or acid, wherein condensation may be carried out in the presence of a condensing agent and followed by removal of R if necessary ¹⁰ .

In the case of producing preferred cephalosporin compounds of formula II, the amino compound of formula III may have the formula VIII

R 10, V and Y are as defined above.

Derivatives of these amino compounds, for example their salts as tosylate, may also be used.

Thus, the compounds of formula (I) may be prepared by using an acid halide, especially chloride or bromide, as the acylating agent. The acylation is carried out at temperatures of -50 to +50 ° C, preferably -2 to +30 ^° C. The acylating agent can be prepared by reacting an acid of formula VII or a salt thereof with a halogenating agent, for example phosphorus pentachloride, thionyl chloride. or oxalyl chloride. The use of oxalyl chloride together with the sodium or potassium salt of the acid of formula (VII) is advantageous since isomerisation is minimal under these conditions. The acylation may be carried out in both aqueous and non-aqueous media such as a mixture of water and ketone, for example a mixture of water and acetone, esters such as ethyl acetate, amides such as dimethylacetamide, or nitriles such as acetonitrile or a mixture of these solvents.

The acylation with the acid halide is preferably carried out in the presence of an acid binding agent, for example a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bicarbonate or oxirane, thereby binding the hydrogen carbonate released in the acylation reaction. . The oxirane is preferably a lower 1,2-alkylene oxide, for example ethylene oxide or propylene oxide.

When the acids of the formula VII are used in free form, suitable condensing agents for the preparation of the compounds of the invention are carbodiimides such as N, N'-diethyl-, dipropyl- or diisopropalkarbodiimide, N, N'-dicyclohexylcarbodimide, or N-methyl-N'-γ-Dimethylammopiylcarbodiimide. A suitable carbonyl compound is, for example, carbonymidimidazole or an isoxazolinium salt thereof, for example N-ethyl-5-phenylisoxazolinium-SCsulfanate and N-tert-butyl-5-nitro The condensation reaction is preferably carried out in an anhydrous reaction medium such as methylene chloride, dimethylformamide or acetonitrile because in this case, reaction conditions such as temperature can be much better controlled.

The acylation may also be carried out using other acid derivatives capable of forming amides, such as symmetrical anhydride or mixed anhydride with, for example, pivalic acid or a haloformate, for example a lower alkyl haloformate. The mixed or symmetric anhydride may be formed in situ. For example, a mixed anhydride may be formed using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed using phosphoric acids such as phosphoric acid or phosphorous acid, sulfuric acid, or aliphatic and aromatic sulfonic acids such as para-toluenesulfonic acid. Another preferred acylating agent is an activated ester, for example a compound of formula IX

R-C-CO-L 'II

N (IX) where

L is, for example, azide, oxysuccinimide, oxybenztriazole, pentachlorophenoxy or p-nitrophenoxy.

Compounds of formula I may also be prepared from compounds of formula V

(IN)

R10 has the above meaning that R10 cannot be an atom anywhere

B, Z and up. by reacting the compound with an acid of formula (VII) or a precursor thereof, and then removing the R 10 group, as already described, for example, in Belgian Patent No. 76 ° 494.

The reaction of the compound of formula (III) or (V) can be carried out in one step, so that further reactions to be carried out are purely deprotection and purification.

If desired, a compound of formula (X) may be prepared first

COOR (fX) where

R, R 1 °, B and Z is the same as above, whereafter · to · reacting a compound of formula X. · With R ^and O-NHZ, wherein R ^a is as defined above and additionally if necessary, removing R1 °. The reaction product can be isolated by obtaining the desired syn-isomer before or after removal of the R 10 group.

A suitable precursor of the desired group

R — C — CO—

II

N

OR ^a is the corresponding 2-hydroxyiminoacyl group of the formula

R-C-COII

OH because these groups can be easily converted to the desired group by etherification. Thus, compounds of formula (I) may be prepared by reacting a compound of formula (XI)

R, R ^10, B and Z are as hereinbefore defined, with etherifying reagent serving to introduce the group _ _ R ^and, then, if necessary, carry out any of the reactions D (ii) to (viii) have been previously described and the compound of formula I is separated by separation into isomers, if necessary.

The etherifying agent may be, for example, an organic hatogenide or a sulfate or sulfonate, such as a tosylate. Other etherifying agents may be diazoalkanes such as diazomethane or diazoethane, alkyl fluorosulfonates such as methyl fluorosulfonate and alkyloxonium tetrafluoroborates such as triethyloxonium tetrafluoroborate and diphenyloxonium bromide. Etherification using diazo compounds, fluorosulfonates or tetrafluorobritanes may still require adjuvant ¹ , for example a Lewis acid, for example BF3.

Compounds of formula I in which R is an activating group such as cyano or 2- or 4-pyridyl can be prepared by nitrosation and etherification of the resulting oxox. A compound which contains an acylamide group can be nitrosated

R = CH2CONH- or

R — CH — CO — NH—

AND

COOH using, for example, nitrous acid, which can be prepared directly in the reaction mixture by reacting an alkali metal nitrite with a weak acid, such as acetic acid, or a nitrosyl chloride or organic nitrosating agent, such as an alkyldusite, cyloalkyldusite or arylalkyldusite. In the case of nitrosation of a compound containing a group

R — CH — CO — NH—

AND

COOH decarboxylation occurs. After nitrosation - or etherification, the product can be separated into the syn-isomer and the - anti-isomer, if necessary.

If desired, the CH 2 Y group may be replaced with another more preferred group after acylation of the 7-α-amino compound or the 7-isocyanate compound. In particular, the group Y can be introduced as described in the literature. Compounds in which Y represents a halogen atom, an ether group or a thioether group can be prepared by the method described in Belgian Patent Nos. 719 711, 719 710, 734 532 and 734 533. Compounds in which Y represents a nucleophile residue can also be produced by reacting 3-acetoxymethylcephatosporic acid with a nucleophile, for example pyridine or another tertiary amine, as previously described, further with sulfur and a nitrogen-containing inorganic nucleophile as described in British Patent Nos. 1,059,562, 1,101423 and 1, respectively. 206,305 as well as British Patent No. 1,012,943 or a nitrogen-containing nucleophile as described in British Patent Nos. 1,030,630, 1,082,943 and 1,082,962.

Compounds in which Y - is a derivative of a nucleophile residue, such as an amino group or an acylamide group, derived from an azide group - can be produced by the method described in British Patent Nos. 1,057,883 and 1211,694. Y represents an azido group with a dipolarophilic compound. Compounds of the invention wherein Y is a nucleophile residue can also be prepared by reacting 3 of the aforementioned nucleophiles, e.g. In the case where Y is a hydroxyl group, the compounds can be prepared by the method of British Patent No. 1,121,308.

Compounds containing a 3-vinyl or substituted vinyl group at the 3-position can be prepared by the method of Belgian Patent No. 761,897.

When Y is a halogen atom, for example chlorine, bromine or iodine, the starting cef-3-em compounds can be prepared by halogenating the 70-acylamido-3-methylceph-3-em-4-carboxylic acid 1 H -oxide ester. subsequent reduction of the 1 / S-oxide group as described in Belgian Patent No. 755,256.

The corresponding cef-2-em-compounds can be produced by the method of published Dutch patent application No. 6-902 013 by reacting a cef-2-em-3-methylated compound with N-bromosuccinimide to give cef-2-em-3-bromomethylated compound.

When Y is hydrogen, these compounds can be prepared according to British Patent No. 957,569 or from penicillin as described in U.S. Patent Nos. 3,275,626 and Belgian Patent Nos. 747,119 and 747,120.

Cephalosporin compounds containing an acyloixylmethyl group at the 3-position can be produced by any suitable method, for example, from a cephalosporin having a 3-CH 3 Y group in the 3-position wherein Y = OH or the acid residue HY o · pKa not higher than 4.0 and preferably lower than 3.5 in water at 25 ° C.

The group Y may be a chlorine, bronze or iodine atom, formyloxyl or acetoxyl containing at least one substituent which binds an electron on a &quot; carbon atom &quot; or on a benzyloxy group substituted on a nucleus, the substituent on the nucleus being a substituent that binds at least one electron; as described in British Patent No. 1,241,657, and the reaction that removes the nucleophilic group to introduce the desired substituent can be carried out by the method of the aforementioned British Patent No. 1,241,657.

In the case where Y is hydroxy, the desired 3-acyloxymethyicephalosporin can be prepared by acylation according to British Patent No. 1,141,293, the same specification also describes a process for preparing A3-cephalosporin which also contains acyloxymethyl at the 3-position of the 3-hydroxymethyl analogue by attaching an arylalkyl group to the carboxy group at the 4-position, then acylating the 3-hydroxymethyl group of the compound so protected and finally removing the arylalkyl protecting group.

The acylation is carried out by any suitable method, for example an acid chloride, acid anhydride or mixed acid anhydride or mixed anhydride as acylating agent, preferably in the presence of an acid binding agent, for example an organic base such as pyridine or lower alkylene oxide such as ethylene oxide; Propylene oxide, wherein the reaction is preferably carried out in an inert anhydrous solvent, for example methylene chloride. The acylation can also be carried out in a mixture of water, acetone and aqueous sodium bicarbonate solution. The preferred acylating agent is acid chloride.

The acylation reaction should be carried out as quickly as possible, otherwise the formation of the A2 derivative may occur under conditions suitable for acylation, especially when the aryloxy is introduced into the methylene group at the 3-position, which is not bound directly to the nucleus atom.

The compounds of formula (III) may be used in the form of an ester; A free amino acid or a free amino acid addition salt or ester thereof can also be used. Salts which may be used include hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, p-toluenesulfonic and methanesulfonic acid addition salts.

Esters can be formed with an alcohol, phenol, silanol or stannanol of up to 20 carbon atoms, as these groups can be easily separated again at a later stage of the reaction.

The esterifying group to substitute the 4-carboxyl group in the compounds of formula III, V and X is preferably an alcohol, an aliphatic or arylaliphatic phenol, silanol, stannanol or acid, as these groups can be readily separated in a later reaction step.

Thus, suitable esters are compounds which contain as the ester group a group selected from the following list of compounds, but other ester groups may also be used.

(i) -COOCR ¹ R ^g R ^h , wherein at least one of F ^f , R g and R ^h is an electron donor, for example p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxyl or fur- 2-yl. The remaining R ^f , R g and R ^h may be hydrogen or an organic group. Suitable ester groups of this type are p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.

(ii) The group - COOR ^f RRR ^h , wherein at least one of R ^f , R g and Rh is an electron recipient, for example benzoyl, p-nitrophenyl,

4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitrophenyl or cyano. The remaining Rf, R® and Rh may be hydrogen or an organic group. Suitable esters of this type are benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4- (4-pyridylmethoxycarbonyl), 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromethoxycarbonyl.

(iii) —COOCRf R ^g R ^h , wherein at least two of Rf, R R and R ^h are a hydrocarbon radical, for example methyl, ethyl, or aryl such as phenyl, and the remaining R f, R R and R ^h may also be a hydrocarbon residue or a hydrogen atom. Suitable esters of this type are t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl.

(iv) -COOR 1 wherein R is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl or tetrahydropyran-2-yl.

(v) Silyloxycarbonyl groups obtained by reacting a carboxyl group with a silanol derivative. The silanol derivative is preferably a halosilane or a silazane of the formula

R3 SiD ^11;

R + SiD 2;

R 3 ^1x Si -NR ¹¹ ;

¹¹ R 3 Si-NH-SIR5 ^11;

R 3 ^for Si-NH-COR ¹¹ ;

R 5 = Si-NH-CO-NH-S ¹ R ^{3 11} ; R ⁿ NH-CO-NR ¹¹ R ¹¹ or SiR 3 ¹¹ C (OSiR3 ¹¹⁾ SiR 3 ^11, where

D represents a halogen atom, and a group

R ¹¹ , which may be the same or different, represents a hydrogen atom or an alkyl group, for example methyl, ethyl, n-propyl isopropyl, aryl such as phenyl, arylalkyl or benzyl.

Preferred silanol derivatives are silyl chlorides, for example dimethylchlorosilane and trimethylchlorosilane.

The carboxyl groups can be regenerated from the ester by any conventional means, for example by hydrolysis, catalyzed using an acid or base, or enzymatic hydrolysis. However, it may happen that aqueous solutions are poor solvents for these compounds and that isomerization, rearrangements in the molecule, side reactions and decomposition occur for this reason, so special methods have to be used.

A suitable method of de-esterification of the above compounds is

1) Reaction with Lewis acids

Suitable acids of this type are trifluoroacetic acid, formic acid, hydrochloric acid and acetic acid, zinc bromide in benzene and aqueous solutions, or suspensions of copper (III) compounds. The reaction with acids can be facilitated by the addition of a nucleophile, for example anisole.

2) Reduction

Suitable reduction systems are mixtures of zinc and acetic acid, zinc and formic acid, zinc and the lower alcohol, zinc and pyridine, palladium-hydrogen-activated charcoal, and a mixture of sodium and liquid ammonia.

3) Effect of nucleophiles

Suitable nucleophiles are those containing a nucleophilic oxygen or sulfur atom, for example alcohols, mercaptans and water.

4) Oxidation methods, for example those involving the use of hydrogen peroxide and acetic acid

Where the reaction product is a compound in which V is S-O and it is necessary to obtain a compound in which V is \

S, it is possible to convert for example /

reduction of the corresponding acyloxysulfonium or alkyloxysulfonium salt, which is prepared directly in the reaction mixture by treatment with, for example, acetyl chloride when the acetoxysulfonium salt is to be prepared, for example, with sodium dithionite or an iodine ion, for example with potassium iodide in a solvent miscible with water. e.g. acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature of -20 to Ц-50 ° С.

The reduction of the 1-sulfinyl group can also be carried out with phosphorus trichloride or bromide in a solvent such as methylene chloride, dimethylformamide or tetrahydrofuran, preferably at a temperature of -20 to -50 ° C.

In case the resulting compound is

4-estercef-2-em, the desired cef-3-em compound can be obtained by treatment with a base.

The acid of formula IV, which is an acylating agent, can be produced by reacting a glyoxylic acid of formula

R - CO - COOH where

R is as defined above, or an ester thereof with a compound of the type R ^and O-NH 2, wherein R ^a is as defined above.

The resulting acid or ester is then optionally resolved into individual isomers by crystallization, chromatography, or distillation followed by ester hydrolysis, if necessary.

Especially in the case of 2-alkoxyiminoarylacetic acid esters, i. the esters of formula IV wherein R is an aryl group with a carbon or heterocyclic ring and R ^a is alkyl, can be accomplished separation of the two isomers by selective hydrolysis of the ester, as the anti isomer can be rapidly saponified and thus better to remove the free acid form, so that in the mixture left the purified synester. The separated syn-isomer in ester form can then be converted at any time to the corresponding acylating agent.

The acid of formula IV may also be prepared by O-alkylation or O-arylation, the reaction being of the type where the compound of formula

R = C-COOH

N

Oh

5) Irradiation of, for example, a 2-hydroxyimino acid, more preferably using an ester of the acid. The reaction may be carried out by treatment with an organic halide, sulfate or sulfonate, for example a compound of formula R ^and J, wherein R ^a is as defined above and J represents a halogen atom, a sulfate or sulfonate group such as a tosylate. The 2-hydroxyimino acid or ester thereof may also be reacted with a diazoalkane, for example, diazomethane, an alkylfluorosulfonate, for example methylfluorosulfonate, an alkyloxonium tetrafluoroborate, for example a trialkyloxoniumtetrafluoroborate such as .

These reactions with diazo compounds, fluorosulfonate or tetrafluoroborate may require an adjuvant such as Lewis acid BF3.

When converting an acid of formula IV to an acylating agent, it should be noted that any amino group present in the R or R substituent ^and should be protected to avoid unwanted side reactions, similar protection of the amino groups is desirable also when the acylating agent is mentioned in reaction with compounds of formula III or V.

The syn-isomer and the anti-isomer may be distinguished from each other in a suitable manner, for example by ultraviolet absorption spectrum, thin layer or paper chromatography, or nuclear magnetic resonance. For example, the compound of formula I in dimethylsulfoxide-d6 solution has a doublet for the lower amide NH amide in the case of the syn-isomer or the anti-isomer. These factors can also be used for monitoring reactions.

The antibacterial compounds of the invention may be incorporated into the compositions for administration by any suitable route analogous to the routes of administration of other antibiotics, and the invention also encompasses pharmaceutical compositions having as active ingredient compounds of formula I or non-toxic derivatives thereof, e.g. These preparations are suitable for use in human and veterinary medicine. The active substances are usually employed in these preparations together with a pharmaceutical carrier.

The compounds of the invention may be incorporated into injectables, ampoules or larger containers with the addition of a preservative. These preparations may take the form of a suspension, solution, emulsion in an oily or aqueous type liquid and may contain excipients, for example suspending aids, stabilizing agents and / or dispersing agents. The active ingredient may also be in the form of a powder and mixed just before preparation with a suitable liquid carrier, for example sterile pyrogen-free water.

The compositions may also be in a form suitable for absorption by the gastrointestinal tract. Tablets and capsules for oral administration may be presented in unit dosage form and may contain other excipients such as binding agents such as syrups, acacia, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone, and may contain fillers such as lactose, sugars, corn starch, calcium phosphate , sorbitol or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica or potato starch, as well as acceptable wetting agents such as sodium laurine sulfate. The tablets may be coated in a known manner. Liquid preparations for oral administration may take the form of a suspension in water or in an oil, solution, emulsion, syrup, elixirs or the like, or may be administered as a powder for reconstitution in water or other liquid carrier just prior to use. These preparations may conveniently contain adjuvants such as suspending aids, for example sorbitol syrup, methylcellulose, syrup consisting of a mixture of glucose and cane sugar, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents such as lecithin, monooleate , sorbitan or acacia rubber. Non-aqueous liquids, for example, edible oils such as almond oil, coconut oil, oil esters, propylene glycol or ethyl alcohol, preservatives such as methyl or prupyl p-hydroxybenzoates or sorbic acid may also be used in the compositions. Suppositories consist of a conventional base such as cocoa butter or other triglycerides.

Formulations suitable for absorption through the mucous membranes of the nose, nasopharynx, or bronchial mucosa may also be prepared, which are in the form of a powder or aerosol and are used as inhalants, sprays. longets and the like. Where the preparation is to be used for the treatment of eye or ear diseases, the preparation may be in the form of capsules in liquid or semi-solid form or in the form of drops. For application to the skin, the preparation may take the form of an ointment, cream, powder, paste in a hydrophobic or hydrophilic base.

For use in veterinary medicine, preparations such as intramammary preparations can be made, either with rapid or slow release of the active ingredient.

The compositions contain at least 0.1%, preferably 10 to 60%, of active compound, depending on the route of administration. In the case of a unit dose preparation, each dose preferably contains 50 to 500 milligrams of active ingredient. The dosage for adults ranges from 100 to 3,000 milligrams, for example 1,500 mg per day, depending on the route of administration and the frequency of administration.

The compounds can also be administered together with other therapeutic agents, e.g., antibiotics such as other cephalosporins, ^Pen: GLM or tetracyclines.

The following examples illustrate the invention.

Example 1

7β- (2-Methoxy-amino-2-phenylacetamido) -3-pyridmiummethylcef-3-em-4-carboxylate in the form of the syn-isomer g of 3-acetoxymethyl-7- (2-methoxyimino-2-phenylacetamido) cef-3- ε-4-carboxylic acid in the form of the syn-isomer in solution in a mixture of 30 ml of water, 30 ml of acetone and

2.8 ml of pyridine was heated at 50 ^° C for 4 hours. Another 2.8 ml of pyridine was then passed through and the solution was heated at 50 ° C for 16 hours at pH 5. The dark brown solution was decanted from the gummy residue, evaporated to remove acetone and washed with methylene chloride. Excess solvent was removed by evaporation and the solution was passed through an ion exchange resin column (Dowex-1 in an acetate cycle), eluting with water. The eluate was lyophilized and the resulting solid was triturated with acetone to give 0.84 g of the title product as a beige solid, [α] _D ²³ - 6.4 ° (c = 0.94 in water) Amax (pH 6, 0 phosphate buffer) 257 nm (ε 19 900),

.Lambda.max (nujol <ol) 1770 (.beta.-lactam), 1660, 1540 (CONH) and 1604 cm ^-1 (CO), τ (DZO) values including 1.03, 1.90 and 1.40 ( α, β and у-protons in the pyridinium ring),

2.2-2.6 (multiplet, Ph)

5.99 (singlet, ОСНз), (DMSO-de) values show 0.27 (doublet,

J 8 Hz, NH)

6.10 (singlet, OMN).

Example 2

7H-2-Methoxy-2-phenylacetamido) -3- (4-carbamoylpyridiniummethyl) cef-3-em-4-carboxylate in the form of the syn-isomer g of 3-acetoxymethyl-7R- (2-methoxyimino- 2-phenylacetamido ^|) ceph-3-em-4-karhoxylové syn isomer and 4.2 g of isonicotinamide was introduced into a mixture of 150 ml water and 30 ml of acetone and the suspension was heated at 50 ° C for 20 hours. The mixture was cooled, filtered, evaporated to remove acetone, and the aqueous solution was passed through an ion exchange column (Doiwex-1 3 x 16 cm in an acetate cycle). The column was washed with water and the eluate was lyophilized and the resulting solid is mixed with 250 ml acetone for 30 min, the suspension is filtered, yielding 1.4 g [a] _D ^{23-50 C} C (c - = 1.06 in DMSO)

Amax (pH 6 buffer) 260 nm (ε 20 900), Amax (nujol) 1,770 (β-lactam), 1,675 and 1560 (CONH) and 1,605 cm ^-1 (CO 2), τ (DMSO-d6) ) values show 0.33, 1.49 (.alpha. -protons in the pyridinium ring),

1.19 and 1.74 (- CONHz),

2.4 to 2.6 (multiplet, Ph)

0.26 (j, 8 Hz, NH),

6.10 (singlet, OMN).

Example 3

3-hydroxymethyl-7 -

Sodium (2-methoxyimino-2-phenylacetamido cef-3-em-4-carboxylate) as a synisomer

Dissolve 2.0 g of 3-acetoxymethyl-N- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of a syn-isomer and dilute the solution with 160 g of saturated sodium bicarbonate. ml of water and heated to 37 degrees Celsius. 15 grams of defatted wheat bran are added and the mixture is stirred for 3.5 hours at pH 7.4. The mixture was poured into 200 mL of acetone and filtered through diatomaceous earth. The acetone is evaporated under reduced pressure at 30 ° C and the aqueous solution is covered with a layer of ethyl acetate, brought to pH 2.7 by addition of concentrated hydrochloric acid, the layers are separated and the aqueous layer is extracted again with ethyl acetate. The ethyl acetate extracts were combined, washed with water, then more water was added to the extract and the pH was adjusted to 7 by carefully adding 2 N sodium hydroxide solution. The organic layer was then further extracted with water and the combined aqueous solutions were washed with ethyl acetate and ether, degassed and lyophilized to yield 1.52 g of the resulting methoxime as a brown solid at [ _.alpha. ] _D + 104 DEG (82% yield) ( c = 1.1, DMSO)

Amax (pH 6, phosphate buffer) 258,5 nm (ε 14 100)

Amax (nujol) 1730 (0-lactam), 1570 ^l (COO), 1640 and 1520 спг ¹ (CONH), τ (D2O, m 100 MHz)

2.2 to 2.6 (multiplet, aromatic protons),

4.16 (doublet, 14 Hz, C-7H),

4.79 (doublet, J 4 Hz, C-6H),

5.72 (singlet, C-2 CH2),

5.97 (singlet, NOCH 3),

6.32 and 6.59 [2 doublets (quartet parts)]

J 18 Hz, C-3 C, 2].

Example 4

3-Hydroxymethyl-7 -

- (2-benzyloxyiminothien-2'-ylacetamido) -ep-3-em-4-carboxylic acid in the form of the syn-isomer

To a suspension of 1.0 g of 3-acetoxyme

243734 thyl-7 / h (2-benzyloxyiminothin-2'-ylacctamido) cef-3-em-4-carboxylic acid in 50 ml of water add sufficient saturated sodium bicarbonate solution to dissolve the solid and to pH 7.0. 8.0 g of defatted wheat germ are added and the mixture is stirred for 21 hours at pH 6.8 to 7.0. The pH is maintained by the addition of acetic acid. After 5 hours, the pH no longer changed and thin-layer chromatography (CHCl 3: CH 3: acetic acid = 18: 2: 1) showed that the reaction was nearly complete.

The mixture was filtered and the pH of the filtrate adjusted to 4.5. Filtration with diatomaceous earth gave a yellow solution, which was adjusted to pH 2.5 under a layer of ethyl acetate. The aqueous mixture was extracted with ethyl acetate, and the combined extracts were washed with water and saturated sodium chloride solution, freed from water and evaporated to dryness to a brown solid. Trituration with methylene chloride afforded 480 mg of a colorless solid, the nuclear magnetic resonance spectrum of which corresponds to the hydroxymethyl derivative.

Dissolve 366 mg of this solid in 10 mL of 50% aqueous ethanol and carefully neutralize the mixture with 0.1 N sodium hydroxide (approximately 3.02 mL). The ethanol was evaporated and the aqueous mixture was extracted three times with ether. Evaporation of the aqueous solution yielded 132 mg of 3-hydroxymethyl-7 sodium salt _; S (2-benzyloxyxothiothien-2'-ylacetamido) cef-3-ene-4-carboxylate as dihydrate, [α] D + 88 ° (c = 0.89,

DMSO,)

Amax (pH 6, phosphate buffer) 262 nm (ε 16 100)

Amax (nujol) 1,744 (3-akkam),

650 and 1,522 (CONH),

580 (CO2-) cmΛ τ (DMSO-d6) values show 0.13 (doublet,

NH),

2.54 (Ph),

4.76 (CHaPh),

4.26 (quartet, 7-proton).

Example 5

Acid

3- (2-chloroethylcarbamoyloxymethyl) -7 / 3- (2-methoxyiminophenylacetamido) cef-3-cn-4-carboxylic acid in the form of the syn-isomer

A solution of 0.35 g of 3-Hydroxymethyl-7β- (2-methoxyiminolenylacetamido) cef-3-ene-4-carboxylic acid in the form of the syn-isomer, 0.097 g of 2-chloroethyl isocyanate and 1.79 g of triethylamine in 10 ml of dimethylformamide was added. Stir at room temperature for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and the aqueous phase was washed with ethyl acetate, acidified and extracted with ethyl acetate. The extracts are decanted, dehydrated and concentrated to a volume of approximately 5 ml, then added dropwise to 250 ml of petroleum ether with stirring. The resulting solid was filtered and dried to give 1.157 g (35%) of the title acid,

Amax (pH 6 buffer) 258 nm (ε 16,800),

.Lambda.max (nujol) 3250 (NH), 2600 and 1715 (CO2H), 1700 and 1530 (NHCO2R), 1660 and 1540 ^cm-1 (CONH), τ (DMS0-d6) values show 0.22 (doublet

J 9 Hz, 7 (S-NH),

2.3 to 2.6 (multiplet, aromatic protons), 6.05 (singlet, OCH3),

6.40 (muttiptet, (- 2 CH · and —CH 2 Cl)),

6.65 (multlpeet, —NHCH2).

Example 6

Tert-Butyl 3-crotonyloxymethyl-73- [2- (fur-2-yl) -2-methoxyiminoacetamido] cef-3-ene-4-carboxylate (syn-isomer)

A solution of 1.39 g of tert-butyl 7 -3- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylcee-3-em-4-carboxylate (syn-isorner) in 15 ml of anhydrous Tetrahydrofuran is mixed with 1.4 ml, i.e. approximately 5 equivalents of crotonyl chloride at 20 ° C. 1.18 ml, i.e. approximately 5 equivalents of pyridine, are added with stirring, and the mixture is stirred for 45 minutes. The resulting suspension was poured into water (30 ml) and extracted with ethyl acetate. The organic phase was separated and washed with aqueous sodium bicarbonate solution, 2N hydrochloric acid and saturated aqueous sodium chloride solution, dried and evaporated. The resulting oily liquid was extracted with ether and the insoluble material (lactone) was collected by filtration. The ether was removed in vacuo to give 1.32 g of crude crotonate as a foamy product. This material was purified by chromatography on silica gel (Merck Kieselgel 60) in an amount of 40 g, eluting sequentially with toluene / ethyl acetate (20: 1, 10: 1 and finally 5: 1). 0.6 (using system 3) were combined and evaporated in vacuo. The solution of the foam residue in ethyl acetate was then extracted with ethyl acetate and the precipitated material was collected by filtration. 450 mg of amorphous product are obtained, m.p. 68 DEG-88 DEG C. with decomposition. [.alpha.] D @ -4-43 DEG (c = 1.8, CHCl3), .lambda.max (C2 H5 OH) 275.5 nm (ε 16 844).

Example 7

3-Kronoyloxymethyl-7S- [2- (furyl)] -

- 2-N-methoxy mino [etamido] cef-3-em-4 carboxylic acid (syn-isomer)

A solution of 1.06 g of tert-butyl 3-crotonoyloxymethyl-3- [2- (fur-2-yl) -2-methoxyiminoacetamido] cef-3-em-4-carboxylate (syn-isomer) was mixed with 1 ml of anisole and 4 ml of trifluoroacetic acid at 20 ° C and stirred for 5 minutes. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase still contains a small amount of the starting ester. For this reason, the oily residue is re-mixed with trifluoroacetic acid and anisole as described above after evaporation of the solvent. The phases in the bicarbonate solution are combined and the pH is adjusted to 2 and then, after adjusting the pH with concentrated hydrochloric acid, this phase is overlaid with 400 ml of ethyl acetate. The ethyl acetate layer was separated and washed with 20 ml of water and 20 ml of brine, dried and evaporated in vacuo. 795 mg of a bovine residue in 10 ml of ethyl acetate are treated with 400 ml of petroleum ether to give 660 mg of the title product as an amorphous solid, mp 75-100 ^° C with decomposition.

Α d ²² 4-47.5 ° (c -1.3, dioxane), _λmax 273 nm (ε 17,970).

Example 8

7β- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-methylsulfonylmethylcef-3-em-4-carboxylic acid (syn-isomer)

A solution of 1.00 g (2.36 nuncio) of 3-acetoxymethyl-7β- [2- (fur-2-yl) -2-methoxyiminoacetamido] cef-3-em-4-carboxylic acid (syn-isomer) and 0.866 g (4.73 mmol) of methylsilphonylmagnesium bromide in 25 ml of 0.2 M phosphate buffer at pH 6.4 was stirred at 60 ° C for 5 hours under a nitrogen atmosphere. The solution, which has a pH of 5.0, is clarified after this time, washed five times with 50 ml of ethyl acetate and then acidified to pH 1.7 with hydrochloric acid, then extracted three times with 75 ml of ethyl acetate. The extracts are combined, washed twice with 100 ml of water and 25 ml of saturated aqueous sodium chloride solution, dried and the solvent is evaporated off under vacuum. The residue was triturated with ether to give the title carboxylic acid (0.563 g) as a pale yellow solid.

[α] _D + 41 °, R _pac 0.84 (ethanol: n-butanol: water = 1: 4: 5),

Amax (pH 6.0 buffer) 279 nm (ε 16 850).

Example 9

Diphenylmethyl-7 - [- 2-phenoxyimino-2-

- (fur-2-yl) acetamido] -3-

- (2-thiazolin-2-ylthiomethyl) cef-

З-ет-4-carboxylate (syn-isomer)

A solution of 1.721 g of diphenylphenyl-7 / 3- [2-phenoxyimino-2- (fur-2-yl) acetamido] -3-bromomethylceph-3-em-4-carboxylate-1/3-oxide (synisomer) and 298 mg of 2-mercaptothiazole in 15 ml of anhydrous dimethylformamide was stirred at 0 ° C and a solution of 0.346 ml of triethylamine in 5 ml of dimethylformamide was added dropwise over 5 minutes. The resulting solution was stirred for 30 minutes while heating to 23 ° C if thin layer chromatography showed only partial reaction: 200 ml of 2-mercaptothiazoline was added and the mixture was stirred for 3 hours. 1.66 g of potassium iodide are added, the suspension is cooled to -15 ° C and 0.355 ml of acetyl chloride is slowly added, followed by stirring at 23 ° C for one hour. 150 ml of aqueous sodium metabisulphite solution are added and the suspension is stirred for 10 minutes and then extracted twice with 50 ml of ethyl acetate. The extract was washed with 2 N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine (50 ml each), dried and evaporated to give 2.0 g of a foamy product. This product was purified by chromatography on 70 g of silica gel (using benzene and ethyl acetate = 10: 1).

Example 10

7β- [2-Phenoxyimino-2- [fur-2-yl] acetamido-3- (2-thiazolin-2-ylthiomethyl) cef-3-em-4-carboxylic acid (syn-isomer)

500 mg of diphenylmethyl 1-7 / 3- [2-phenoxyimino-2- (fur-2-yl) acetamido] -3- (2-thiazolin-2-ylthiomethyl) cef-3-em-4-carboxylate (synisomer) is dissolved in 0.5 ml of anisole, 2 ml of trifluoroacetic acid are added, the solution is kept at 20 DEG C. for 5 minutes and then the solvent is evaporated at 40 DEG C. at a pressure of 266 Pa. The residue is suspended in 40 ml of ether, and the suspension is extracted with 60 ml of 1: 1 sodium bicarbonate and water, 1: 5 mixture of sodium bicarbonate and water, each using twice 50 ml of each solution.

The aqueous extracts were combined, washed with ether (40 ml) and filtered. The solution was overlaid with 100 ml of ethyl acetate and acidified to pH 2 by addition of 2N hydrochloric acid solution. The extract was washed with water and brine (50 ml each), dried and evaporated to give 290 mg of a foamy product. This material was dissolved in ethyl acetate and precipitated with petroleum ether to give the title product (192 mg) as an off-white amorphous solid, mp 120-130 ° C (dec.).

Example 11

Tert -Butyl-3-benzoyloxymethyl-7/3245754

- [2-methoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylate (syn-isomer)

A solution of 1.393 g of tert-butyl 7 / 3- [2-methoxyimino-2- (fur-2-yl) acetamido] -3-hydroxymethylcef-3-em-4-carboxylate (syn-isomer) in 15 ml of anhydrous tetrahydrofuran The mixture was stirred at 23 ° C and added

1.69 ml of benzoyl chloride. Then, 1.18 ml of pyridine was added and after a few minutes a slurry was observed. After 1 hour the starting ester is consumed. The solid was collected by filtration and the filtrate was evaporated to an oil. This liquid was dissolved in 40 mL of ethyl acetate and poured into 40 mL of 1: 1 water and saturated sodium bicarbonate with stirring. The yellow solution turns red. The organic phase is separated and the aqueous phase is extracted with 40 ml of ethyl acetate. The organic phases are combined, washed with 40 ml of a 1: 1 mixture of water and saturated sodium bicarbonate in each case, with 2 N hydrochloric acid solution, water and brine, and the solution is dried and evaporated to 3 g of an oily liquid.

This liquid in toluene was purified by silica gel chromatography (Kieselgel 60 Merck on a 3 X 14 cm column containing 50 g of this material), eluting with a toluene / ethyl acetate (20: 1) mixture and the same. The Rf 0.7 fractions obtained by eluting the column with toluene / ethyl acetate (2: 1) were combined, dried and evaporated to give the title compound as a white solid.

1.79 g of a foamy product.

Amax (C2H5OH) 227 ¹³⁶¹ E1.

Example 12

3-Benzoyloxymethyl-7 / 3- (2-methoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylic acid (syn-isomer)

1.63 g of tert-butyl 3-benzoyloxymethyl-7β- [2-methoxyimino-2- (flur-2-yl Jacetamido) cef-3-em-4-carboxylate (syn-isomer) was dissolved in mixture 1 7 ml of anisole and 6.8 ml of anisole and 6.8 ml of trifluoroacetic acid at 20 DEG C. A purple solution was formed, after 1 hour the solvent was evaporated at 40 DEG C. under a pressure of 10 mm Hg. and the solvent is removed at 40 DEG C. and a pressure of 10 mbar. The resulting gum is dissolved in 20 ml of ethyl acetate and treated with 150 ml of a 1: 1 mixture of water and saturated sodium bicarbonate. The organic phase is separated and the aq. phase is washed with 20 ml of ethyl acetate, the aqueous phase is overlaid with 750 ml of ethyl acetate and acidified to pH 2 with concentrated hydrochloric acid, the organic phase is separated off and the aqueous phase is extracted with 50 ml of ethyl acetate. NaOH, dried and evaporated to a residue A solution of this product in 10 ml of ethyl acetate was added dropwise to 250 ml of petroleum ether. The resulting precipitate was filtered off and dried in vacuo to give 963 mg of the title compound, m.p. 85-105 ° C with decomposition.

Preparation

Diphenylmethyl-3-bromomethyl-N- [2-phenoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylate-1'-oxide (syn-isomer)

A suspension of 11.126 g of diphenylmethyl-7H-amino-3-bromomethylceph-3-em-4-carboxylate β-oxide as the hydrobromide (syn-isomer) in 1 liter of methylene chloride is stirred for 30 minutes at 20 ° C with a mixture of sodium bicarbonate and 1: 1 water at 1 liter. 500 ml of methylene dichloride are added and the suspension is stirred for a further 15 minutes. The organic phase is separated and the aqueous phase is extracted four times with 500 ml of methylene dichloride. The organic phases are combined, washed with 600 ml of sodium chloride solution, dried and evaporated to 18.8 g of solid.

This solid was suspended in 550 ml of anhydrous methylene dichloride, 4.583 g of dicyclohexylcarbodiimide was added, and the suspension was further stirred at 20 ° C. A solution of 5.136 g of 2-phenoxyimino-2- (fur-2-yl) acetic acid as a syn-isomer in 300 ml of anhydrous methylene dichloride was added dropwise over 30 minutes, and the resulting solution was stirred at 20 ° C for 16 hours. TLC (2: 1 benzene / ethyl acetate) indicated complete reaction The solid was collected by filtration and the filtrate was washed with 150 mL of a 1: 1 saturated aqueous solution of sodium bicarbonate and water, 150 ml of water, 150 ml of brine, dried and evaporated to a solid which was suspended in 200 ml of ethyl acetate and collected by filtration, and the filtrate was evaporated to give 15.67 g of a solid. substances.

This solid was dissolved in 30 mL of methylene chloride and purified by chromatography on 400 g of Kieselgel 60 in a 5 X 38 cm * column using 1.2 liters of methylene dichloride / acetone (200: 1), followed by methylene dichloride / acetone 100: 1 ratio and 50: 1 methylene dichloride / acetone mixture. Fractions o-Rf 0.4 (phenol: ethyl acetate 5: 1) were combined, dried and evaporated to give 12 g of a foam. This product was dissolved in 130 methylene dichloride and added dropwise to 600 ml of diethyl ether with stirring. The resulting precipitate was filtered off and dried in vacuo to give 5.32 g of the title product.

The filtrate is evaporated to a solid (3.0 g) which is suspended in 10 ml of acetone and 100 ml of diethyl ether are added dropwise with vigorous stirring. The suspension is filtered, the solid is washed with 20 ml of diethyl ether and dried under vacuum to 2.19 g of product.

The filtrate was evaporated to 700 mg of the foamed product, m.p. 125-145 ° C with decomposition.

Example 13

Diphenylmethyl-3- (3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl) -7β- [2-phenoxyimino-2- (fur-2-yl) acetamido] cef-3 -em-4-carboxy (syn-isomer)

A solution of 1.97 g of diphenylmethyl-3-bromomethyl-7,3- [2-phenoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylate-1,3-oxide (syn- isomer) and 444 mg of 1,2-dimethyltriazoline-5-thione in 7 ml of anhydrous dimethylformamide were stirred at 20 ° C for 20 hours, at which time thin layer chromatography using a 2: 1 mixture of methylene dichloride and acetone showed that the reaction was complete. It will be added

1.9 g of potassium iodide and the solution was cooled to 10 ° C. 0.41 ml of acetyl chloride is added dropwise over 2 minutes and the solution is allowed to warm to 20 ° C by standing for 60 minutes. The solution was then added dropwise to a solution of 3 g of sodium metabisulphite in 150 ml of water over 5 minutes at 0 ° C. The resulting suspension was extracted with ethyl acetate (3.times.50 ml), the extracts were combined, washed with 2N hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, water and brine (75 ml each), dried and evaporated to give 2.22 g of a foam. The foam obtained is dissolved in 15 ml of benzene and purified by chromatography on 70 g of silica gel (Kieselgel 60, 3 X 17 cm column), eluting with 5: 1, 2: 1, 1: 1 benzene: ethyl acetate. and finally pure ethyl acetate. TLC Rf 0.24 (CH 2 Cl 2: (CH 2 Cl 2 = 2: 1) to give the title compound was combined, dried and evaporated to give 1.549 g of a foam. the solution was added dropwise with stirring to 100 ml of petroleum ether over 5 minutes to give a precipitate which was collected by filtration and dried in vacuo to give the title compound (1.267 g), m.p. 115-135 ° C (dec.).

Example 14

3- (3,4-Dimethyl-2,4-thiriazol-5-yl-thiomethyl) -7 / 3-

- [2-phenoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylic acid (syn-isomer)

1.128 g diphenylmethyl-3- (3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl) -7,3- [2-phenoxyimino-2- (fur-2-yl) acetamido] cef-3 The ε-4-carboxylate (syn-isomer) was dissolved in a mixture of 1.13 ml of anisole and 4.52 ml of trifluoroacetic acid. After 5 minutes, the solvent was evaporated at 40 ° C and 1 mm Hg. 100 ml of diethyl ether and 190 ml of a 3: 1 mixture of water and saturated sodium bicarbonate were added and the solution was stirred for a further 40 minutes. The aqueous phase is separated and the organic phase is extracted with 50 ml of a 9: 1 mixture of water and saturated sodium bicarbonate. The aqueous phases are combined, layered with 150 ml of ethyl acetate and acidified to pH 2 with 2 N hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with 2 X 100 mL of ethyl acetate.

The organic phases are combined, washed with 100 ml of water and twice with 50 ml of brine and then evaporated to 1.07 g of an oily liquid.

This material was triturated with 20 mL of ethyl acetate, the solid collected by filtration and dried in vacuo to give 600 mg of product.

The filtrate was evaporated to 278 mg of an oily liquid which was dissolved in methylene dichloride and added dropwise to 100 ml of petroleum ether with stirring. A precipitate formed, which was collected by filtration and dried in vacuo to give 128 mg of the title compound, m.p. 110-140 ° C (dec.).

Example 15

Diphenylmethyl-7 / 3- [2- (fur-2-yl) -2-phenoxyiminoacetamido] -3-

- (5-methyl-1,2,4-oxadiazol-2-ylthiomethyl) cef-3-em-4-carboxylate (syn-isomer)

A solution of 2.123 g of diphenylmethyl-7β- [2- (fur-2-yl) -2-phenoxyiminoacetamido] -3-bromomethylceph-3-em-4-carbloxylate-1,3-oxide (syn-isomer) and 359 mg of 2-methyl-1,3,4-oxadiazoline-5-thton in 8 ml of anhydrous dimethylformamide is stirred at 20 DEG C. for 40 hours, at which time the reaction is complete. 2.047 g of potassium iodide are added, the solution is cooled to -10 DEG C. and 0.44 ml, i.e. 2 equivalents of acetyl chloride, is added dropwise over 2 minutes.

The mixture was stirred at 23 ° C for 60 minutes and then added dropwise with stirring to a solution of 3 g of sodium metabisulphite in 150 ml of water at 0 ° C. The resulting suspension was extracted three times with 50 ml of ethyl acetate. The extracts were combined, washed with 2N hydrochloric acid solution, saturated sodium bicarbonate solution, water and brine (75 ml each), dried and evaporated to give 2.318 g of a foamy product. This product was dissolved in 7 ml of benzene and purified by column chromatography (3 x 22 cm) containing 75 g of silica gel (Kieselgel 60) using 10: 1 benzene / ethyl acetate as eluent. The fractions of Rf 0.52 are combined, dried and evaporated to give 1.22 g of a foamy product. This material was dissolved in 8 mL of ethyl acetate and added dropwise with stirring to 100 mL of petroleum ether over 5 minutes. The resulting precipitate was collected by filtration and dried in vacuo to give 943 mg of the title compound, m.p. 90-130 ° C (dec.).

Example 16

7 / 3- [2-Phenoxyimino-2- (fur-2-yl) acetamido] -3- (5-methyl-1,3,4-oxadiazol-2-ylthiomethyl) cef-3-em-4- carboxyl (syn-isomer)

806 mg diphenylmethyl-7- [2- (fur-2-yl) -2-phenoxyiminoacetamido] -3- (5-methyl-1,3,4-oxadiazol-2-ylthiomethyl) cef-3-em-4 The carboxylate (syn-isomer) is dissolved in a mixture of 0.81 ml of anisole and 3.3 ml of trifluoroacetic acid. After 5 minutes, the solvent was evaporated at 40 ° C and 1 mm Hg. 100 ml of ether and 150 ml of a 3: 1 mixture of water and saturated sodium bicarbonate were added and the mixture was stirred for 10 minutes. The aqueous phase is separated and the organic phase is extracted with 50 ml of a 3: 1 mixture of water and saturated sodium bicarbonate. The aqueous phases are combined and overlaid with 150 ml of ethyl acetate, then acidified to pH 2 by addition of 2 N hydrochloric acid. The organic phase was separated, washed with water and brine (60 ml each), dried and evaporated to give 647 mg of a foamy product. This product was dissolved in acetone (60 ml), charcoal and anhydrous magnesium sulfate were added with stirring. The suspension was filtered through a pad of diatomaceous earth and the resulting solution was evaporated to a foamy product which was dissolved in 6 ml of ethyl acetate and added dropwise to 200 ml of petroleum ether over 5 minutes with stirring. The resulting precipitate was collected by filtration and dried in vacuo to give 390 mg of product, m.p. 120-135 ° C.

Example 17

2- [4 ^{<-difenylmethoxykarbonyl-7} /? '-

- [2- (fur-2-yl) -1- (methoxyimino) acetamido] - [(3'-em-4'-ylmethylthio) -1-methylpyridinium bromide and -trifluoroacetate (syn-isomer)

1.25 g of diphenylmethyl-3-bromomethyl-7β- [2- [fur-2-yl] -2-methoxyiminoacetamido] c-5-η 5 -carboxylate-1-oxide (syn-isomer) in 2 ml Dimethylformamide was treated with 375 mg of 1-methylpyridyl-2-thioin, stirred for 2 hours and then added dropwise to ethyl acetate with stirring, and the resulting precipitate was washed with ethyl acetate and dried to give the title bromide (1.48 g). _max in nujol 3,400, 3,250, 1,785, 1,715, 1,705, 1,670, 1,615, 1,570, 1,535 cm ¹ .

1.33 g of this material in 5 ml of dimethylformamide were mixed at -10 ° C

1.33 g of potassium iodide and then with 0.28 ml of acetyl chloride. The resulting suspension was stirred at -10 to 0 ° C for 55 minutes and then added dropwise to 50 ml of water containing 1 g of sodium metabisulphite. After stirring for 10 minutes, the resulting salt was collected by filtration, washed with plenty of water and dried over phosphorus pentoxide. The resulting material was dissolved in 20 ml of dichloromethane and the solution was applied to the top of a column containing the resin [Deacidite FF (CF 3 CHCl 3) in dichloromethane]. The eluate fractions containing the ultraviolet absorbing material were combined and evaporated, and the residue was triturated with ether to give 1.17 g of the resulting trifluoroacetate.

in _niax in nujol 3 300, 1 775, 1 715, 1 680. 1 620, 1 570, 1 560, 1 505 cm " ¹ .

Example 18

2- [4‘-carboxy-7 / 3‘- / 2- (fur-2-yl) -

-2- (methoxyimino ·] acetamido / ^{ceph-3-em-t-3'ylmethylthi'O} '] -1-methylpyridiniumtrifluoracetát (syn-isomer)

1.07 g of 2- [4'-diphenylmethoxycarbonyl-1- [4- (2- (fur-2-yl) -2- (methoxyimino) acetamido) - ^[ eta] &lt; 3 & gt ^; -em-3'-ylmethylthio] -1- of methylpyridinium trifluoroacetate (syn-isbmer) and 1 ml of anisole are shaken with 4 ml of trifluoroacetic acid for 5 minutes. The solution is evaporated in vacuo, the residue is shaken with ethyl acetate and the evaporation is repeated. The residue is triturated with ether and the solid is filtered off and dried. The crude salt was extracted four times with water, the extracts were washed with ethyl acetate and ether, then evaporated on a rotary evaporator for a short time and lyophilized. The resulting material was triturated with ether to give 615 mg of the title compound.

in Nujol 3250, 1775 1700, 1680, 1625, 1570, 1505 ^cm-first

Claims (10)

Process for the preparation of 7-3-acylamido-3-cephem-4-carboxylic acids of the general formula I fr-C-CO-H-η <S А _о л-у- ^с / W со он (i) where R is hydrogen or a group R ⁱⁿ which R ^u represents an aryl group having carbon ring having 6 to 12 carbon atoms such as phenyl or naphthyl, five or six membered heterocyclic aryl containing at least one heteroatom loose from the group consisting of sulfur, nitrogen and oxygen, or a heterocyclic group fused with a benzene ring, for example, 2-thienyl, 3-thienyl, furyl, pyridyl, pyrrblyl, N-methylpyrrolyl, N-benzyloxymethylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3 or 4-isoxazolyl, 3-phenyl- or 3-halophenyl-5-methyl-4-i-5-methyl-4- , benzothienyl, benzofuryl, indolyl or sydnon, cycloalkyl of 3 to 7 carbon atoms, for example cyclopentyl or cyclohexyl, any of the above being optionally substituted by halogen, hydroxy, alkyl of 1 to 6 carbon atoms, nitro , amino, alkylamino (C 1 -C 6), (C 1 -C 6) dialkylamino, (C 1 -C 6) alkanoyl, (C 1 -C 6) alkanoylamido, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio carbon atoms in the alkyl moiety or cyclohexadienyl or R is a formula of the formula R ^u _[CH2) m Q _n (CH2) _p, wherein R ^u is as defined above, m is 0 or an integer of 1-4, n is 0 or 1, p is an integer from 1 to 4 and Q represents a sulfur atom, an oxygen atom or a group -NR ² where R ² represents a hydrogen atom or R represents a group of the formula _{CnH2n +} I where n is an integer '1 to 7, wherein said groups are straight or branched chain and are optionally interrupted by an oxygen or sulfur atom or -NR ^2, wherein R ² has the abovementioned meaning, or the group is optionally substituted by cyano, carboxy, alkoxycarbonyl with 2-7 carbon atoms, hydroxy, or carbonyl group of formula HOOC-CO- or a halogen atom, or • R represents a group of formula Where n is an integer from 2 to 7, wherein the group is straight or branched, optionally interrupted by an oxygen or sulfur atom or a group - NR ² , where R ² is as defined above, or R represents a group of formula C _n H ₂ n- ₃ , wherein n is an integer of 2 to 7, or a cyano, amido or alkoxycarbonyl group having 2 to 7 carbon atoms in the alkoxy moiety, R ^a represents a C 1 -C 16 alkyl group, for example methyl, ethyl, propyl, butyl, octyl or dodecyl, a C 2 -C 16 alkenyl group, for example a vinyl, allyl, isopropenyl or dimethylallyl group, a C 2 -C 2 alkynyl group C prop-C,,, e.g., propargyl, C až-C cyk cyk cycloalkyl. for example cyclopropyl, cyclopentyl or cyclohexyl, cycloalkenyl of 4 to 7 carbon atoms, for example cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl, aryl of 6 to 12 carbon ring carbon, for example phenyl or naphthyl, heterooyl or five-membered a six membered ring containing at least one heteroatom selected from oxygen, nitrogen or sulfur, optionally fused to a benzene ring or another such heterocyclic group, for example, pyridyl, pyrimidyl, furyl, thienyl, thiazolyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl , a thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl or purinyl or C 1 -C 4 alkyl group which is substituted with an aryl with a carbon or heterocyclic ring as defined above, for example, benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, thienylmethyl, furylmethyl, pyridylmethyl or pyrrolylmethyl, each of which is optionally substituted with a halogen atom such as chlorine or bromine, hydroxy, alkoxy of 1 to 6 carbon atoms, e.g. , ethoxy or propoxy, aryloxy of 6 to 12 carbon atoms, for example phenoxy, phenylalkoxy of 1 to 4 carbon atoms in the alkyl portion, for example benzyloxy, inercapto, alkylthio of 1 to 6 carbon atoms, for example methylthio or ethylthio; carbon atoms, C 1 -C 4 phenylalkylthio, amino, C 1 -C 6 alkylamino, for example methylamino or ethylamino, C 1 -C 6 dialkylamino in each alkyl moieties such as dimethylamino, nitro, azido, carboxy, alkoxycarbonyl of 2 to 7 carbon atoms in the alkoxy moiety, for example methoxycarbonyl or ethoxycarbonyl, benzyloxycarbonyl, formyl, acyl of 1 to 10 carbon atoms, for example acetyl, acyloxy having 1 to 10 carbon atoms, for example acetoxy, propionyloxy or pivaloyloxy, cyano, phthalimido, acylamino having 1 to 10 carbon atoms, for example acetamido or benzamido, alkoxycarbonylamino with 2. up to 7 carbon atoms in the alkyl moiety, for example methoxycarbonylamino, or phenylalkoxycarbonylamino of 2 to 5 carbon atoms in the alkoxy moiety, for example benzyloxycarbonylamino, Y represents a pyridine base residue, N-pyrimidine, N-purine, N-pyridazine, N-pyrazine, N-pyrazole, N-imidazole, N-triazole or N-thiazole cation, optionally substituted by an alkyl group having 1 to 2 C 6 -C 6 aryl, C 1 -C 12 aryl, C 1 -C 4 phenylalkyl in the alkyl moiety (C 1 -C 4 alkoxymethyl) C 2 -C 7, formyl, C 1 -C 8 acyloxy, C 2 -C 9 acyloxymethyl, C 2 -C 7 alkoxycarbonyl, benzyloxycarbonyl, C 1 -C 6 alkoxy C 1 -C 4 aryloxy, C 1 -C 4 phenylalkoxy, C 6 -C 12 alkylthio, C 1 -C 4 phenylalkylthio, cyano, hydroxy, carbamoyl, N-monoalkylcarbam C1-C6-alkyl, N, N'-alkylcarbamoyl. (C 1 -C 6) alkyl, N-hydroxy (C 1 -C 6) alkyl; or (C 1 -C 6) carbamyl-alkyl, azido, amino or C 1 -C 8 acylamido; , a derivative derived from the reaction of a compound wherein Y is an azido group with a dipolanophilic acetylene or ethylene group or a cyano group, R3 I — C — CO — R ⁵ ! R4 where R ³ and R ^4. which are the same or different, are hydrogen, cyano, (C1-C6) -alkyl, phenyl, halogen-phenyl, (C1-C6) -alkyl, (C1-C6) -alkoxyphenyl , nitrophenyl, aminophenyl, C 1 -C 6 alkylaminophenyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 5 mono- or diphenylalkoxycarbonyl, C 2 -C 7 alkylcarbonyl C 1 -C 4 -phenylalkyl or C 5 -C 6 -cycloalkyl; R 5 is hydrogen, C 1 -C 6 alkyl, phenyl, haloufenyl, C 1 -C 6 alkylphenyl, C 1 -C 6 alkoxyphenyl, nitrophenyl an aminophenyl group, an alkylaminophenyl group having 1 to 6 carbon atoms in the alkyl moiety, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety, or a cycloalkyl group having 5 or 6 carbon atoms, and Y is a group of the formula —S (O) nR6 where R 6 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having a carbon ring of 6 to 12 carbon atoms, or a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety, or a heterocyclic group; as defined above, for example, thiadiazolyl, diazolyl, tri-left azoles. tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolopyridinyl, purinyl, pyridyl or pyrimidyl groups, or any of these groups substituted with a 1 to 1 alkyl group N is 0, 1 or 2, preferably 0, furthermore Y is a group of the formula —OR ‘, wherein: R1 represents a hydrogen atom, an acetoxy group, a group of the formula -O-COR9, wherein R 9 represents an organic group having an atomic mass of at least 16, which is selected from the group consisting of the formula Cn ^ n + 1, where n is an integer · 1 to 7 and the group has a straight or branched chain optionally interrupted by an oxygen or sulfur atom or an imino group or substituted by a cyano, carboxy, alkoxycarbonyl group of 2 to 7 7 carbon atoms in the alkoxy moiety, a hydroxy group, a carboxycarbonyl group, a halogen atom or an amino group, a group of the formula CnHnn-b where n is an integer from 2 to 7 and the group has a straight or branched chain optionally interrupted by an oxygen atom, a sulfur atom or an imino group, a group of the formula R ^at , where R ^v represents an aryl group having a carbon of 6 to 12 carbon atoms, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic aryl group containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, or such a benzene-fused heterocyclic group a ring such as 2-thien, 3-thien, furyl, pyridyl, pyrrolyl, N-methylpyrrolyl, N-benzyloxymethylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or 4-isoxazolyl, 3-phenyl- or 3-halophenyl-5-methyl-4-isoxazolyl, benzothienyl, benzofuryl, indolyl or sydnon, cycloalkyl of 3 to 7 carbon atoms, for example cyclopentyl or cyclohexyl, with any optionally substituted with halogen, hydroxy, C 1 -C 6 alkyl, nitro, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkanoyl C 6 -C 6 alkanoylamido, C 1 -C 6 alkoxy or C 1 -C 6 alkylthio or a cyclohexadienyl group or formula R ^V - (CsmeU where R ^v is as defined above and m is an integer from 1 to 4, a group of the formula -O-CO-AR ^9a , wherein A represents an oxygen atom, a sulfur atom or a group -NH and ^And R9 is hydrogen, methyl or · R 9 having the meaning given above, --O - CO-NH (CHžj D _m wherein D is a halogen atom, for example, chlorine, bromine, iodine or fluorine; and m is an integer of 1 to 4, for example 2-chloroththylaminocarbonyloxy or a chlorine, bromine or iodine atom, as well as their non-toxic pharmaceutically acceptable salts and sulfoxides. that it is mentioned in the carboxy-protecting reaction, rc-co-nh II N \ ^'Ah 0R "Λ Ύ cr <- ^H 10 T = ¹ COOR where ^And R and R are as defined above, \ \ B is S or S-O, / / R10 represents a hydrogen atom or a carboxy protecting group, Y ‘represents a chlorine, bromine or iodine atom, a hydroxy group or an oethoxy group with a nucleophilic compound introducing a group Y into the compound of formula II, wherein Y is as hereinbefore defined, or with a reactive derivative thereof, such as a salt or acylating agent, for example an acid chloride or anhydride, whereupon the carboxy protecting group R ^w is removed and, when B is S-> 0, the product thus obtained is if desired, it is reduced to the corresponding sulfide and the desired compound of formula I is isolated in the form of an isomeric mixture containing at least 75%, preferably at least 90% of the syn-isomer or preferably in the form of a syn-isomer free of the corresponding anti-isomer or after converting the initially obtained compound of formula (I) to its non-toxic pharmaceutically acceptable salt or sulfoxide, for example by reaction with a base such as sodium 2-ethylhexanetate or potassium. 2. A process according to claim 1, for the preparation of compounds of the formula: pargyl, C3 -C6 cycloalkyl, phenyl, C1 -C4 phenylalkyl, triphenylmethylQU, thienylmethyl, furylmethyl or phenylalkyl. pyridylmethyl, which groups JSO _.mu.l optionally substituted with at least one substituent selected · from the group consisting Уydroxyskupinu, methoxy, etУoxyskupinu, bromine, nitro, amino, carboxyl or benzoyl group, and · Y 'represents a pyridinium radical, a carbamoylpyridinium radical or a heterocyclic amine radical containing more than one luternatom, wherein at least one heteroatom is a nitrogen atom, an azido group, a group of the formula - S (O) n R ⁶ ', R6 'represents an alkyl group having 1 to 4 carbon atoms or a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and n is 0, 1 or 2, hydroxy, a group of the formula --O - CO - R9 'where R ⁹ 'represents an alkyl group having 1 to 4 carbon atoms, a vinyl, propenyl, phenyl or cycloalkyl group having 3 to 6 carbon atoms, a group of the formula -O-CO-NH (CH 2) _m D', wherein D 'represents a hydrogen, fluorine, chlorine, bromine or iodine atom; and m represents an integer from 1 to 4 or a carbamoyloxy or pyridylcarbamoyloxy group, as well as non-toxic pharmaceutically acceptable salts and sulfoxides thereof, characterized in that the compound is reacted of the general formula R-C-COWH CO OR where R ‘represents an aryl 5- or 6-membered Aetheroyl group containing at least one of sulfur, nitrogen or oxygen, R ^a 'represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a propynyl group, R and R ^{and <} are as defined above, \ \ B is S or S-> O; R10 represents a hydrogen atom or a carboxy-protecting group, Y * represents a chlorine, bromine or iodine atom, a hydroxy or acetoxy group, with a nucleophilic compound introducing the group Y 'into the parent compound, or with a reactive derivative thereof, and then, if necessary, removing the R ¹⁰ carboxy protecting group; if V is S-> 0, the product thus obtained is optionally reduced to the corresponding sulfide and the desired compound of formula I is isolated in the form of an isomeric mixture containing at least 75% syn-isomer or free of the corresponding anti-isomer as syn-isomer or optionally converting the initially obtained compound of formula I to its non-toxic pharmaceutically acceptable salt or sulfoxide. 3. A process according to claim 1, wherein the compound of formula (II) is used R represents a hydrogen atom or a group selected from the group consisting of R ^11a , wherein R ^11a represents a phenyl, hydroxyphenyl, chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl, methylthiophenyl, naphthyl or 2-ethoxynaphthyl group, a five or six membered heterocyclic group containing at least one heteroatom selected from oxygen, 2-nitrogen and sulfur thienyl, 3-thienyl, furyl, pyridyl, 4-isoxazolyl, 3-phenyl- or 3-halophenyl-5-methyl-4-isoxazolyl, or a sydnon group, or a cyclopentyl or cyclohexyl group of the formula R ^ua (CH2) MQN (CH2) _p, wherein R ^11a is as defined above, m is 0 or an integer from 1 to 4, n is 0 or 1, p is an integer from 1 to 4, and Q represents a sulfur atom, an oxygen atom or a group = NH, or represents a group of the formula Where n is an integer from 1 to 7, wherein the groups are straight or branched and optionally interrupted by an oxygen or sulfur atom, or optionally substituted by a cyano, carboxy, hydroxy- or carboxycarbonyl or halogen atom, or represents a group Where n is an integer from 2 to 7, wherein the group is straight or branched, optionally interrupted by an oxygen atom or a sulfur atom, or represents a group of the formula С _п Н _2п. - _З , where n is an integer from 2 to 7 and cyano or -amido, R ^a is R ^aa , a C 1 -C 8 alkyl group, for example methyl, ethyl, propyl or butyl, optionally substituted with hydroxy, carboxy, amido, cyano, acetyl, or amino, or benzyl, phenethyl, phenyl, or - a naphthyl group, and and the remaining substituents are as defined in point 1, and a nucleophilic compound introducing a Y group or a reactive derivative thereof into the parent compound, Y is a group selected from pyridine base, N-pyrimidine, N-purine, N-pyridazine, N-pyrazine, N-pyrazole, N-imidazole, N-triazole or N-thiazole cation, these residues being optionally substituted (C 1 -C 6) alkyl, (C 6 -C 12) aryl, (C 1 -C 4) phenylalkyl, (C 2 -C 7) alkoxymethyl, formyl, (C 1 -C 8) acyloxy group C 2 -C 9 acyloxymethyl, C 2 -C 7 alkoxycarbonyl, benzyloxycarbonyl, C 1 -C 6 alkoxy, C 1 -C 12 aryloxy, C 1 -C 12 phenylalkoxy 4 carbon atoms in the alkoxy moiety, C 1 -C 6 alkylthio, C 6 -C 12 arylthio, C 1 -C 4 phenylalkylthio carbon atoms in the alkyl moiety, cyano, hydroxy, carbamoyl, N-monoalkylcarbamoyl of 1 to 6 carbon atoms in the alkyl moiety, N, N-dialkylcarbamoyl of 1 to 6 carbon atoms in each alkyl moiety, N-hydroxyalkylcarbamoyl of 1 up to 6 carbon atoms in the alkyl moiety or a carbamoylalkyl group having 1 to 6 carbon atoms in the alkyl moiety, an azido group derived from a derivative obtained by the reaction of a compound in which Y 'represents an azido group with a dipolarophilic acetylene or ethylene group or a cyano group formulas R ³ —С — CO — R ⁵ AND R ⁴ where R ³ and R ^4, which are identical or different, are hydrogen, cyano, alkyl having 1 to 6 carbon atoms, phenyl, halophenyl, alkylphenyl-U group having 1 to 6 carbon atoms in the alkyl moiety, alkoxyphenyl having 1 to C 6 alkoxy, nitrophenyl, aminophenyl or C 1 -C 6 alkylaminophenyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 5 mono- or diphenylalkoxycarbonyl, (C 2 -C 7) alkylcarbonyl, (C 1 -C 4) phenylalkyl or C 5 or C 6 cycloalkyl; and R ⁵ is hydrogen, C 1 -C 6 alkyl, phenyl, halogenphenyl, C 1 -C 6 alkylphenyl, C 1 -C 6 alkoxyphenyl, nitrophenyl, aminophenyl, alkylaminophenyl; C 1 -C 6 alkyl, phenylalkyl C 1 -C 4 alkyl or C 5 -C 6 cycloalkyl. 4. A process according to claim 1, wherein the compound of formula (II) is used R and R ^and are as defined in point 3, Y ‘represents a hydroxy group and and the remaining substituents are as defined in 1, and nucleophilic compounds introducing a Y group or a reactive derivative thereof into the parent compound, wherein: Y represents a group of the formula - S (O) _n R ⁶ where R ⁶ is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 12 aryl ring, C 1 -C 4 phenylalkyl, 5-membered or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, optionally substituted with 1 to 6 carbon atoms, phenyl or nitro and / or fused to a benzene ring or another heterocyclic group as defined above, for example thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, pyridyl or pyrimidyl or one of these groups substituted by C 1 -C 6 alkyl, phenyl or nitro and n is 0, 1 or 2, preferably 0. 5. The process of claim 1, wherein the compound of formula (II) is used R is R ^1b selected from the group consisting of phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, pyridyl or any of these groups substituted with a halogen atom such as chlorine, bromine, iodine or fluorine, hydroxy, alkyl of 1 to 6 carbon atoms, nitro. amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoylamino, C 1 -C 6 alkoxy, alkylthio having 1 to 6 carbon atoms or carbamoyl, R ^a represents an R ^b group selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkyl substituted with C 6 -C 12 aryl, or 5- or 6-membered a heterocyclic aryl group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, or any of them substituted by hydroxy, carboxy, alkoxycarbonyl of 2 to 7 carbon atoms, benzyloxycarbonyl, amino, cyano, alkanoylamino of 1 to 6 carbon atoms , (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino in each alkyl moiety, halogen or C 1 -C 6 alkoxy, Y ‘represents a chlorine, bromine or iodine atom or an acetoxy group, and the remaining groups are as defined in point 1, and nucleophilic compounds, where Y is selected from the group consisting of pyridinium, optionally substituted alkyl ^gr: Nou having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, phenylalkyl-U group with 1 to 4 carbon atoms in the alkyl moiety, an alkoxymethyl group having 2 to 7 carbon atoms, a formyl group, an acyloxy group having 1 to 8 carbon atoms, an acyloxymethyl group having 2 to 9 carbon atoms in the acyl moiety, an alkoxycarbonyl group having 2 to 7 carbon atoms, a benzyloxycarbonyl group, an alkoxy group having 1 to 6 carbon atoms, (C až-C 12) phenylalkoxy, (C až-C alkyl) alkylthio, (C až-C aryl) arylthio, (Canan,, hydroxy, carbamoyl, N-monoalkylcarbamoyl) 1-6 carbon atoms in the alkyl moiety, N, N-dialkylcarbamoyl having 1-6 carbon atoms in each alkyl moiety i, an N-hydroxyalkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety or a carbamoylalkyl group having 1 to 6 carbon atoms in the alkyl moiety, an azido group, a-SW group, wherein W represents a thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolopyridyl, purinyl, pyridyl or pyrimidyl group or one of these groups substituted with methyl, ethyl, or nitro methyl-l, 3,4-thiadiazol-2-yl group, alkylthio of 1-4 carbon atoms, -O-CO-R ⁹ where R 9 represents an alkyl or alkenyl group having 2 to 4 carbon atoms or a phenyl group, and a group of the formula -O-CO-NH- (CH 2) m -D wherein m is an integer of 1 to 4 and D represents a chlorine, bromine or iodine atom. 6. A process according to claim 5, wherein the starting compound of formula (II) is used R ^u b is R ^x selected from the group consisting of phenyl, naphthyl, thienyl, furyl, benzothienyl and benzofuryl, and the remaining substituents are as defined in point 1 and the nucleophilic compound introducing into · the starting compound Y group, or a reactive derivative thereof · the compound where Y represents a group selected from pyridinium optionally substituted with C1-6 alkyl, C6-12 aryl, C1-4 phenylalkyl, C2-7 alkoxymethyl carbon, formyl, C 1 -C 8 acyloxy, C 2 -C 9 acyloxymethyl, C 2 -C 7 alkoxycarbonyl, benzyloxycarbonyl, C 1 -C 6 alkoxy, aryloxy (C až-C uhlíku) phenylalkoxy, (C až-C alkyl) alkylthio, (C až-C aryl) arylthio, (C až-C aryl aryl) arylthio, (C až-Ceny) phenylalkylthio (C 4-C 4) alkyl moieties, cyano, hydroxy, carbamoyl, N-monoalkylcarbamoyl of 1 to 6 and t carbon atoms in the alkyl moiety, N, N-dialkylcarbamoyl of 1 to 6 carbon atoms in each alkyl moiety, N-hydroxyalkylcarbamoyl of 1 to 6 carbon atoms in the alkyl moiety or carbamoylalkyl of 1 to 6 carbon atoms in the alkyl moiety , azido, and a group of the formula —O — CO — R9 wherein R 9 represents an alkyl or alkenyl group having 2 to 4 carbon atoms or a phenyl group. 7. A method according to claim 5, characterized in that a compound of formula II wherein R ¹ 'is R ^x selected from the group consisting of phenyl, naphthyl, thienyl, furyl, benzothienyl and benzofuryl, and the remaining substituents are as defined in point 1, and nucleophilic compounds introducing into the parent compound a group Y or a reactive derivative thereof, wherein: Y represents a group selected from C1-C4alkylthio, C2-C4alkanoyloxy and C2-C4alkenyl. 8. A method according to claim 1, wherein R @ 1 is a Rub group selected from or substituted by a phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl or pyridyl group, or one of these groups. halogen, such as chlorine, bromine, iodine or fluorine, hydroxy, alkyl of 1 to 6 carbon atoms, nitro, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl moiety, alkanoyl (C 1 -C 6) alkyl, (C 1 -C 6) alkanoylamino, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio or carbamoyl group, R ^a represents a group R ^b selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkyl substituted by C 6 -C 12 aryl or 5- or 6-membered aryl a heterocyclic aryl group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, or any of them substituted by hydroxy, carboxy, C 2 -C 7 alkoxycarbonyl, benzyloxycarbonyl, amino, cyano, C 1 -C 7 alkanoyl 6 carbon atoms, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, halogen or C 1 -C 6 alkoxy, Y ‘is hydroxy and the remaining substituents are as defined in point 1, and the nucleophilic compound or reactive derivative thereof is an acylating agent corresponding to the acid of formula HY, where Y is -O-CO-R ⁹ wherein R ⁹ represents a C 2 -C 4 alkyl or alkenyl group or a phenyl group. 9. A process according to claim 8, wherein the compound of formula (II) is used R ^11b represents a group R ^x selected from the group consisting of phenyl, naphthyl, thienyl, furyl, benzothienyl and benzofuryl and the remaining substituents are as defined in point 1. 10. The process of claim 1, wherein the compound of formula (II) is used R is a group R ^x selected from phenyl, naphthyl, thienyl, furyl, benzothienyl and benzofuryl, R ^a is R ^b , selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 alkyl C 1 to C 4 substituted by C 6 -C 12 aryl or a 5- or 6-membered heterocyclic aryl group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, or any of them substituted by hydroxy, carboxy, C 2 -C 2 alkoxycarbonyl C 7, benzyloxycarbonyl, amino, cyano, C 1 -C 6 alkanoylamino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, halogen or C 1 -C 6 alkoxy carbon, Y ‘is hydroxy and the remaining substituents are as defined in point 1, and the nucleophilic compound or reactive derivative thereof is an acylating agent corresponding to the acid of formula HY, where Y represents a group of formula ^V wherein V ^a represents an alkanoyloxy group having 2 to 4 carbon atoms or an alkenoyloxy group having 2 to 4 carbon atoms; 2 to 4 carbon atoms.