CS235998B2 - Method of pyridiniumthiomethylcephalosporines new derivatives production - Google Patents

Description

The invention relates to a process for the preparation of cephalosporin derivatives which are novel chemical compounds and which possess useful pharmacological properties.

In particular, the invention relates to a process for the preparation of novel cephalosporins substituted in the 3-position by a pyridinium thiomethyl group.

Belgian patent 866 038 discloses a series of cephalosporin sulfoxides which fall under the following general formula I

wherein X is SO or SOg.

Among the groups represented by the general substituent A, in the Belgian patent mentioned, there are mentioned in particular the groups GHgSH ', where it may be an optionally substituted pyridyl group.

Said cephalosporins of the general formula I generally have a strong antibacterial activity against gram-positive and gram-negative bacteria and are very effective against penicillinase-producing staphylococci.

In addition, German Patent Application No. 2,921,332 describes a group of cephalosporins of the following general formula 11:

H ₂ N

C-CO -NHNRa and C ^C-COOH

AND

Rb

COOH (II) wherein the general substituent Y may in particular represent a group

ch ₃

Said cephalosporins are described as having broad spectrum activity.

E

The present invention provides novel cephalosporins whose activity spectrum is different from the antibacterial activity spectrum of the compounds described in the two patents. The compounds of the invention have remarkable activity against enterobacteria, including those beta-lactamase producing enterobacteria, good activity against Pseudomonas species and poor activity against staphylococci.

The novel cephalosporins obtained by the process according to the invention correspond to the following general formula III

H ₂ N

O

II

C-C — NH

II

N _r 0

I 71

O -c — COOH

(III) wherein

Ιή means hydrogen or methyl,

R ₂ represents a methyl group or else

K and Rg together represent a 1,3-propylene group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms or a lower alkynyl group having 2 to 4 carbon atoms, or also a CHgCOOAlk group, where Alk represents a lower alkyl group,

R @ 1 represents a hydrogen atom or a hydroxyl group occupying one of the free positions of the pyridine ring, the sulfur atom of the thiomethyl group being bonded at the ortho- or para-position relative to the nitrogen atom of the pyridine ring,

A represents a hydrogen atom, a cation or ester or a semi-acetal readily hydrolyzable or metabolically labile and pharmaceutically acceptable; and

X 'is an anion derived from a mineral or organic pharmaceutically acceptable acid such as chloride, bromide, acetate, trifluoroacetate or formate.

Under certain conditions, it is also possible to convert the quaternary ammonium salt to a carboxyl function carried by the cephem core. In this case, X ”does not exist. These internal salts are also within the scope of the invention.

In the present application:

the term lower alkyl refers to a saturated aliphatic hydrocarbon radical containing up to 4 carbon atoms;

the term lower alkenyl refers to an aliphatic hydrocarbon radical containing a double bond of 8 at most 4 carbon atoms;

the term lower alkynyl refers to an aliphatic hydrocarbon radical containing a triple bond and no more than 4 carbon atoms;

the term cation refers to an alkali metal or alkaline earth metal ion, preferably sodium, potassium or calcium ions, or also an ammonium derivative resulting from the protonation of an organic pharmaceutically acceptable amine, such as ethylenediamine, ethanolamine, trometamine, to form editorial salts;

the term ester or semiacetal readily hydrolyzable or metabolically labile and pharmaceutically acceptable refers to groups such as phthalidyl, pivaloyloxymethyl, acetoxymethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, acetonyl, alphamethoxy, alpha-methoxy-alpha- a carbomethoxymethyl group, a carbomethoxymethyl group, a carbetoxymethyl group and the like.

The present invention provides a process for the preparation of the novel cephalosporins of formula III

About ^NH

N O | ? ’

O-C-COOH

n ^ch 3 ^s .

COOA I (III) r ₂ wherein

R 1 is hydrogen or methyl and is methyl or

R ₁ and R 8 together represent a 1,3-propylene group,

R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl or CH ₂ COOAlk, where Alk is C 1 -C 4 alkyl,

R ^ represents a hydrogen atom or a hydroxyl group occupying the free position of the pyridine ring, the sulfur atom of the thiomethyl group being bonded at the ortho- or para-position to the nitrogen atom of the pyridine ring, znamená represents a hydrogen atom, cation or ester or semiacetal readily hydrolyzable or non-metabolically labile and pharmaceutically acceptable, selected from the group consisting of phthalidyl, pivaloyloxymethyl, acetoxymethyl, ethoxycarbonyloxymethyl, - (ethoxycarbonyloxy) ethyl, acetonyl, alpha-methoxy-alpha-carbomethoxymethyl, carbomethoxyethyl and carbethoxymethyl, and

X 'means an anion derived from a mineral or organic pharmaceutically acceptable acid such as chloride, bromide, acetate, trifluoroacetate or formate, said products being in the form of syn or anti, or in the form of a mixture of these isomers, using cephalosporins C as the starting product, which blocks the primary amine function with a known protective group, and then transforms the obtained product into a quaternary ammonium product with the action of pyridintion, <4 being carried out in aqueous solution in the presence of sodium iodide and bicarbonate sodium chloride, followed by cleavage of the acyl chain of the compound obtained by treatment with phosphorus pentachloride in a solvent such as an alcohol, and the product is then treated with hydrogen peroxide or peracid to obtain the sulfoxide of formula

Wherein Z is a mineral anion, and the sulfoxide thus obtained is esterified with a labile group, and the ester thus obtained is acylated with an acid chloride of the formula

wherein Tr is an amino function protecting group, whereupon the amino and carboxylic acid protecting groups are eliminated by the action of a strong mineral or organic acid and the acid thus obtained is optionally reacted with a mineral or organic base and / or an alcohol.

In particular, the invention relates to compounds of formula III selected from the group consisting of:

- a pharmaceutically acceptable mineral or organic quaternary salt of the 7-? 2- (2-amino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimino) acetamido -3- (N-allyl) isomer of syn 1- S -oxide -2-pyridinothiomethyl) -3-cephem-4-carboxylic acid

ch ₃

and products obtained by converting to a salt or by esterifying or semiacetalizing at least one carboxyl function of said salt and optionally converting it to an amine function salt of said salt,

- and the inner quaternary salt of the syn isomer of the above acid, said product having the following formula: ‘

I> 235998 and products obtained by conversion to a salt or by esterification or semi-acetalization of the acid function of said inert salt, optionally by conversion to a salt of the amine function of said salt. '

More particularly, the invention relates to the trifluoroacetate isomer of syn 1- S -oxide of 7- [2- (2-amino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimino) acetemido] -3- (N-allyl-2-) pyridinothiomethyl) -3-cephem-4-carboxylic acid or chlorohydride bromide of said acid or chlorohydrate chloride of said acid.

Compounds of formula III are prepared from cephalosporin C according to the following reaction scheme:

H ₂ N-CH- (CH 3 I-CO-nh COOH or

N CH ₂ O-CO-CH ₃ COOH (XV) (H)

A - N - CH - (CH ₂ ) ₃ - CO - NH COOH, (XVI) (H)

AN-CH - (CH ₂ ) ₃ - CO-NH-iCOOH rf (' ^N fXVII)

N 1 x CH 2 O-CO-CH 3

COOH

COOH

CHjjS

VII

R ₄

V of ^R 3

HCl, NH ₂ - If

N, CH ₂ S COOH

(XVIII)

N Z

I ^R 3

N Z ‘

AND

R,

HCI / NHj-i-f '

2ν, Λ- ch ₂ with COOY

«! of (XIV) -> (III).

The first step of the reaction scheme consists in blocking the primary amine group of cephalosporin C with a protective group A in a manner known per se.

Examples of useful protecting groups include phthalidyl and ethoxycarbonyl. From a compound of formula XVI, a quaternary ammonium compound of formula XVII is obtained by treatment with a pyridintione of formula VII. The reaction is carried out in an aqueous solution in the presence of sodium iodide and sodium bicarbonate to be converted to the carboxylic acid salt of the starting product.

by photomecipitation of the acyl chain of a compound of formula XVII. After blocking the carboxyl groups of the compound of formula (XVII), for example by forming a trimethylsilyl ester, the acyl chain is cleaved by phosphorus trichloride in an alcohol such as methanol or a diol such as 2,3-butanediol. In this way, the compound of formula XVIII is isolated as the primary amine chlorohydrate and pyridinium chloride (X = Cl ').

The compound of formula XVIII is converted to the corresponding sulfoxide derivative of formula XIX by treatment with an organic peracid, such as metachloroperbenzoic acid, in an acidic medium.

The acid of formula (XIX) is esterified with a labile group, such as a diphenylmethyl group or a tert-butyl group, to obtain an ester of formula (XIII) or protected with a trimethylsilyl group.

From the compound of formula XIII, the compound of formula III is obtained in two steps:

- acylation at the nitrogen atom using the acid chloride of the following formula

Tr-NH

Yj)

NTr = trityl

C-COOH

II

N - O - n, ch

I ¹ I

C — COOC-CH,

L ^{1 R} 2 CH, wherein said acylation reaction is carried out in a solvent, chloride, in the presence of dimethylaniline, and - elimination of the protecting groups of the obtained product by treatment such as methylenesilic acid.

Compounds of formulas XII, XIII, XIX and XX are novel compounds and form key intermediates of the process of the invention. These compounds may be included under the following formula XXI,

I (XXI) in which

8 and 8 are as defined above.

U is hydrogen or a group readily cleavable by hydrolysis or hydrogenolysis; and

W is hydrogen or formyl.

The compounds of formula XXI as well as their acid addition salts are also within the scope of the invention.

Compounds of formula XXI in which:

U, R ^ and W are hydrogen,

R 6 represents an allyl group and

Z is chlorine and its chlorohydrate,

as well as a compound of formula XXI in which:

U is a hydrogen, _w is a formyl group, β is an allyl group and

Z is chlorine, they are preferred intermediates in the process of the invention.

Compounds of formula III in which A represents a substituent other than hydrogen are obtained from compounds of formula III in which A represents hydrogen by known reactions.

Likewise, the mineral salts are obtained by reacting compounds of formula III in which A is hydrogen with an mineral base such as sodium carbonate or potassium carbonate or sodium bicarbonate in equimolar amounts. This reaction is carried out in a solvent such as water or ethanol and the salt thus obtained is isolated by evaporation of the solution. Salts derived from organic bases are obtained by reacting a solution of an acid of formula III in which A is hydrogen in a solvent or a mixture of suitable solvents with an equimolar amount of an organic base. The salt obtained is isolated by precipitation with ether.

Esters are obtained by known esterification procedures; preferably, for example, the effect of a halogen derivative on a salt such as an acid sodium salt is used.

The reaction is preferably carried out in a solvent capable of dissolving the starting acid derivative, for example dimethylformemide.

The syn and anti isomers are obtained by appropriately selecting the reactants.

The following examples are provided to illustrate the invention and are not intended to limit the scope of the invention in any way.

As is customary with this type of compound, the compounds of formula (III) produced by the process of the present invention do not have a clear and sharp melting point, but only exhibit a decomposition temperature which does not allow a precise specification of these products.

Thus, the compounds of formula III will be characterized in their examples by their nuclear magnetic resonance spectra, recorded at 60 MHz and using an internal standard, which is hexamethyldisiloxane.

The following abbreviations are used:

S singlet

D doublet

T triplet

Q kverduplet

D-D doublet of doublets

With widespread singlet

M multiplet

AB. systém AB

J coupling constant

In addition, elemental microanalysis was performed in each case and the results of these microanalyses are in accordance with the respective formulas.

Example 1

1- [2- (2-Amino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimino) acetamido] -3- (N-allyl-2-pyridinothiomethyl) T3-cefem-4 trifluoroacetate 1-S-oxide -carboxylic acids in the form of the syn isomer (CM 40874)

Step a)

7- (5-phthalalamino-5-carboxyvaleramido) -3-cephem-4-carboxylic acid iodide

To a solution of 213 g of sodium iodide in 90 ml of water is added a mixture of 71 g of N-phthalylcephalosporin O and 23.3 g of sodium bicarbonate. The mixture was heated to 60 ° C and maintained at this temperature with stirring for one hour and 45 minutes.

After cooling to 10 ° C, the reaction mixture was poured into 5 liters of acetone with vigorous stirring. The solid was centrifuged and washed with acetone and then with ether.

The product obtained is dried and then dissolved in 500 ml of water. The solution was cooled to 5 ° C and acidified with stirring by adding 2 N hydrochloric acid to pH 2.5. The solid was centrifuged, washed with ice water and dried under vacuum in the presence of phosphorus pentoxide.

Step b)

Chloride, 7-amino-3- (N-allyl-2-pyridinothiomethyl) -3-cephem-4-carboxylic acid chlorohydrate

The product obtained in the previous step under a nitrogen atmosphere is suspended in an amount of 15 g in 150 ml of methylene chloride, then 13 ml of dimethylaniline and 12 ml of chlorotrimethylsilane are added. The temperature was raised to 32 ° C and the mixture was stirred at this temperature for 1 hour. The resulting solution was then cooled to -50 ° C and 10 mL of dimethylaniline was added followed by 16 g of phosphorus pentachloride. The mixture was stirred at -50 ° C for one hour and then at -30 ° C for two hours and 30 minutes.

The reaction mixture was poured into a solution of 30 mL of 2,3-butanediol in 200 mL of methylene chloride cooled to -20 ° C. The mixture is stirred until the temperature rises to about 20 ° C, after which the solid is centrifuged. The solid thus isolated was washed with methylene chloride, then with ether and dried under vacuum in the presence of phosphorus pentoxide.

NMR Spectrum: 3H-9.70 ppm (CH3 *, Se); 1H - 9.10 ppm (Hg pyridine, D, J = 5Hz); 1H - 8.50 ppm (H ₄ 'pyridine, D, J = 7 Hz); 1H - 8.10 ppm (1H, pyridine, D, J = 7 Hz);

1H - 7.35 ppm (H ₅ 'pyridine, T); 1H - 6.05 ppm (CH =, M); 6H between 5 and 5.5 ppm (Hg, _H? CH, N ⁺ = CH-, m); 2H - 4.50 ppm (CH 3 in position 3, AB, J 1 _B = 13 Hz);

3 H - 3.80 ppm (CH 2 S * cycle, S). ~

Step c)

Chloride, 7-amino-3- (N-allyl-2-pyridinothiomethyl) -3-cefeta-4-carboxylic acid 1-S-oxide, chlorohydrate The product obtained in the above manner is dissolved in 15 ml of formic acid and then added. 20 ml of methanol are added.

The solution was cooled to 0 ° C and 1.85 g of methachloroperbenzoic acid was added to the cooled solution over 10 minutes. The mixture was stirred at 10 ° C for 10 minutes, then the resulting solution was not poured into 800 mL of ether. The precipitate formed is centrifuged, washed with ether and then dried in vacuo over phosphorus pentoxide.

NMR Spectrum: 1H - 9.05 ppm (Hg 'pyridine, D, J = 6 Hz); 1H - 8.40 ppm (H 4 + pyrrine, V);

1H - 8.10 ppm (H 2 -pyridine, M); 1H-7.90 ppm (H 2 -pyridine, M); 1H - 6.00 ppm (= CH, M); 6H between 4.70 and 5.50 ppm (Hg, H ₂ , CH ₂ N ⁺ , = CH ₂ , M); 2H - 4.40 ppm _(CH2 S, AB, J _AB = 13 Hz); 2H - 3.90 ppm (CH 2 S 2 Z-Λ-Ο, AS, J _AB = 17 Hz).

Step d)

3- (N-allyl-2-pyridinothiomethyl) -7-araino-3-cephem-4-carboxylic acid diphenylmethyl-1-S-oxide chloride hydrate

To a solution of 3.5 g of the product obtained in step c above in 30 ml of methanol at 20 DEG C. is added 30 ml of a diphenyldiazomethane solution. The mixture is left at this temperature for 30 minutes, 40 ml of diphenyldiazomethane solution are again added and the mixture is again left at 20 ° C for one hour.

The reaction mixture was then evaporated to dryness and the residue was taken up with a small amount of methylene chloride and the solution was poured into ether. The solid was centrifuged, washed with ether and dried under vacuum.

Step e)

(4-Diphenylmethyl) -7- [2- (2-tritylamino-4-thiazolyl) -2- (2-tert-butoxycarbonyl-2-propyloxyimino) acetamido] -3- (N-allyl-2) -1-S-oxide chloride -pyridinothiomethyl) -3-cephemarboxylate as the isomer syn

2- (2-Tritylamino-4-thiazolyl) -2- (2-tert-butoxycarbonyl-2-propyloxyimino) acetic acid chloride

Under the nitrogen atmosphere, 3.4 g of 2- (2-tritylamino-4-thiazolyl) -2- (2-tert-butoxycarbonyl-2-propyloxyimino) acetic acid is suspended in 20 ml of methylene chloride.

1.4 g of phosphorus pentachloride are then added to the suspension and the mixture is stirred for 30 minutes while maintaining the temperature below 0 ° C. The resulting solution was poured into 200 mL hexane.

The solid is centrifuged and dried under vacuum over phosphorus pentoxide. The acid chloride is used as such.

3.3 g of the derivative obtained in (e) are suspended in 30 ml of methylene chloride under a nitrogen atmosphere. The suspension is cooled to 5 ° C and 1.7 ml of dimethylaniline and then the acid chloride obtained as described above are added thereto while allowing the temperature to rise to 20 ° C. After stirring for 1 hour, the solution was washed with 30 ml of 0.5 N hydrochloric acid. This organic solution is then concentrated under vacuum to a volume of 10-15 ml.

This solution is then poured into 50 ml of isopropyl ether. The solid is then centrifuged, rinsed with isopropyl ether and dried under vacuum.

The crude product thus obtained is chromatographed on silica gel (120 g). An eluent of methylene chloride-methanol (85:15 by volume) is used to elute the desired product.

NMR Spectrum: 1H - 9.05 ppm (Hg 'pyridine, D, J = 6 Hz); 1H - 8.85 ppm (NH trit, Se);

1 H-8.25 ppm (H 2 -pyridine, NH, CO, M); 1H - 8.0 ppm (H 2 -pyridine, D, J = 7 Hz);

H - 7.80 ppm (H 2 -pyridine, TD); 25H - 7.27 ppm (aromatic H, M); 1H - 6.85 ppm (H-thiazole, S); 1H - 6.75 ppm (COOCH <,S); 2H - 5.95 ppm (H 2 + CH =, M);

5H between 5.0 and 5.5 ppm (CIL, *, CHg =, Hg, M); 2H - 4.45 ppm (CH3 S, AB, J _AB = 13 Hz);

2H - 4.00 ppm (CH ₂ 9H - 1.30 ppm (

»0.0, AB, J _{and ab} = 17 Hz); 6H-1.40 ppm ((CH3) ₂ -C-, S);

CH,

-C

Step f)

CM 40 874 g, the product obtained in step 5, is dissolved in 2 ml of anisole and the solution thus obtained is cooled to 5 DEG C. and 10 ml of trifluoroacetic acid are added to the cooled solution. The temperature is allowed to rise to 20 DEG C. and the solution is left at that temperature for two hours.

The trifluoroacetic acid was evaporated in vacuo and the product was precipitated by addition of ether. The solid product is centrifuged, washed with ether and dried.

NMR spectrum: 1H - 9.05 ppm (Hg-pyridine, D, J = 5 Hz); 1H - 8.50 ppm (NHCO, D, J = 9Hz);

1H -8.35 ppm (δ 'pyridine, M) ^H-8.20 ppm (H ₃ ' pyridine, D, J = 7 Hz);

1H - 7.95 ppm (Hg 'pyridine, M); 4H between 7 and 10 ppm (2 COOH, NHg);

H - 6.82 ppm (H thiazole, S); 2H - 6.00 ppm (Oj and CH = M); 5H between 5.0 and

Using the procedure given in the above example, it is possible to prepare:

(a) product CM 40 874 a, analogous products listed in Table I;

(b) product CM 40 914, in which:

H, + K ₂ = (CH ₂ ) ₃ f H ₃ = CH ₂ -CH ₂ CH ₂ ;

K ₄ = H;

A - H a

X = CF-COO as well as the products listed in Table 2; and

(c) the product CM 40 800, in which:

Η, = H;

K ₂ = CH ₃ ;

R ₃ = CH _3;

4 4 = H;

A = H and

X = CF-COO.

The products according to the invention of the general formula (III) have been studied with an emphasis on their pharmacological properties, in particular their bacteriostatic effect.

Said bacteriostatic effect was determined in vitro on a solid medium by the dilution method. The results obtained are expressed as the minimum inhibitory concentration (CI) in [mu] g / ml, and these results relate to different strains of enterobacteria and the Pseudomonas strain.

For comparison, the results obtained with similar two prior art products are also given. The two products are:

7- / 2- (2-Amino-4-thiazolyl-2-carboxymethoxyiminoacetamido) -3- (2-pyridylthiomethyl) -3-cephem-4-carboxylic acid 1-S-oxide in the form of the syn (compound A) isomer of the formula

(Belgian Patent No. 886,038) and 7- [2- (2-emino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimino) acetamido] -3- (N-methyl-2-pyridinothiomethyl) trifluoroacetate -3-cephem-4-carboxylic acid isomer syn (compound B) of formula

(German Patent Application No. 2,921,332).

The results obtained are summarized in Table 3 below.

These results show an extremely pronounced efficacy of the products according to the invention against bacterial strains, which are generally of low sensitivity to antibiotics of the cephalosporin family, namely Enterobacteries and Pseudomonas.

Compared to reference product A, the compounds according to the invention of the formula III show surprising activity against the following strains: Citrobacter, Enterobacter, Serratie and Pseudomonas, which have at least the same activity as said reference product with respect to the Klebsiella and Proteus strains.

With respect to reference product B, the compounds according to the invention of the general formula (III) have a much higher activity against the strains of Citrobacter, Proteus and Enterobacter, which compounds have the same activity against the other strains as the reference product, and often do.

In addition, animal testing did not show any toxicity of the compounds of the formula III; therefore, these products have a toxicity comparable to that of the compounds of the many cephalosporins.

Accordingly, the products of formula (III) of the present invention may be used as antibiotics in human and veterinary medicine. They can be applied to all bacterial infections to which they are effective.

Applicable pharmaceutical preparations are prepared from the compounds of formula III in acid form or, if their solubility is insufficient, in salt form.

These pharmaceutical preparations may be solid or liquid and may take the form of, for example, tablets, gelatin capsules, granules, creams, ointments or injections.

The dosage of these compositions may vary within wide limits, particularly depending on the severity of the infection being treated and the mode of administration of the compositions. In an adult patient, most often the daily dose is 0.250 to 4 g using an injection. An example of a pharmaceutical composition containing the active ingredient of the invention is injection ampoules comprising:

Product C 40 40 874 1 g water for injections 5 ml and sodium carbonate in an amount necessary to reach pH = 6.3.

Table 1

4 / ^ 4

CF-COO 3 ³

Number R.

product code

R. Substituted ⁴ position pyridine

NMR spectrum

40 763 CH ₃ H

1H - 9.00 ppm (Hg pyridine, D,

J = 6Hz); 4H between 7.60 and 8.60 ppm (NHCO, H ₃ , H ₄ , H 3 pyridine, M);

1H-6.83 ppm (H thiazole, S);

1H - 5.97 ppm (H 2, M); 1H - 5.00 ppm (Hg, D, J = 4Hz); 2H - 4.40 ppm (CH3 S, Se); 3H-4.20 ppm (CH, -N ⁺ , S)

2H - 3.80 ppm (CH 2 S -> O, Se);

6H-1.46 ppm

40 876 CH ₃ H

2H - 8.64 ppm (Hg, Hg pyridine, D,

J = 7Hz); 1H - 8.40 ppm (1¾ CO, D,

J = 9 Hz); 2H - 7.95 ppm (HI, _H? Pyridine, D, J = 7 Hz); 4H-7.50 ppm (NH 4, 2 COOH, Se); 1H - 6.80 ppm thiazole, S); 1H - 5.95 ppm VLj,

D-D, J 1 = 9 Hz, J g = 4 Hz); 1H - 5.05 ppm

Product code number

R. Substitute 'position of pyridine

NMR spectral (Hg, D, J = 4Hz); 1H - 4.40 ppm _(CH2 S, A of AB, J _AB = 13 Hz);

1H-4.35 ppm (CH.s, B of AB, ^J AB = ^{13 Hz);} 3H-4.16 ppm (CH3 ⁺ , S); 1H - 3.89 ppm ^(CH 2 S - * 0, A from AB, ^J AB ^{= 7 Hz);}

B of AB, J _A b = 17 Hz); 6H-1.43 ppm

40912 ch ₂ c ~ ch H

40972

CH ₃ 3-0Η

5Η between 7.5 and 9.1 ppm (Hp H 2, and Hg pyridine and NHCO, M); 1H - 6.85 (thiazole, S); 1H - 6.0 ppm (γγ, M):

2H - 5.65 ppm (CH 3 N +, M); 3H-5.0 ppm (Hg and CH ₂ S, M); 5% - 3.95 ppm (CH 2 S 2 O 2, Se); 6H-1.43 ppm

£ 2CH masked with dimethylsulfoxide /

5H between 6.5 and 10 ppm (H _g N, 2 COOH,

OH, M); 1H - 8.60 ppm T9g pyridine,

Μ); 1H _r 8.45 ppm (NHCO, DJ = 9 Hz);

2H - 7.9 ppm (H 2 and H pyridine, M) with 1H - 6.80 ppm (H thiazole, S); 1H -6.0 ppm (γγ, M); 1H - 4.96 ppm Hg, D, J = 5 Hz); 5H-4.30 ppm (CH ² Cl ^{2 * 4,} CH 3 S, M); 2H - 3.85 ppm (CH _G - = 4o, Μ); 6H -1.47 ppm

41087

CH ₂ COOC ₂ H ₅ η

1H - 9.2 ppm (NHCO, D, J = 9Hz);

4H between 7.5 and 8.8 ppm (H 3, H 2, H g and H g pyridine, Μ); 1H - 6.90 ppm (H thiazole, S); 1H - 6.0 ppm (γγ, M);

2H - 5.67 ppm (CH 3 N ⁺ , Se); 1H - 5.0 ppm (Hg, D, J = 5 Hz); * 11 - 4.30 ppm (COOCIL-, Q, J = 7 Hz); 2H-3.90 ppm (CH 2 Si-4 O, Se); 6H-1.45 ppm

Number R.

product code

R. Substitution position of pyridine

NMR spectrum

41607 -CH ₂ -CH = CH ₂ H

2H - 8.70 ppm (H elpha pyridine, D,

J = 6 Hz)} 1H - 8.45 ppm (Iffi-CO, D,

J = 9 Hz); 2H - 8.0 ppm H beta pyridine, D, J = 6 Hz); Ή - 6.80 ppm (H thiazole, S); 2H-6.0-ppm (H 2 + CH =, M);

2H - 5.40 ppm (CH = _g, M); 3H-5.05 ppm (Hg + CH ₂ N ⁺ , M); 2H - 4.45 ppm (CH2 --S,

M); 2H - 3.80 ppm (CH ₂ S -> 0, AB,

J _AB = 16Hz); 6H - T7Í5 ppm (C _{(CH3) 2,} S 2). -Table 2

N CF.COO i 3

Number code product ^R 3 ^R 4 Substitution position pyridine NMR spectrum 40882 CHg H 2 9H between 7.5 and 9.5 ppm (NH 2 COOH, NHCO, H _3, H _4, Hg and Hg pyridine, m); 1H - 6.88 ppm (H-thiazole, S); 1H - 6.0 ppm (γγ, M); 1H - 5.07 ppm (Hg, D, J = 4Hz); 2H - 4.45 ppm (CH 2 S -, S); 2H - 3.93 ppm (CH3S-K &gt;M); 6H between 1.5 and 2.7 ppm ~ «>,’ 40954 CHg H 4 7H between 8.3 and 9.0 ppm (NHCO, NH 4,

COOH, H ₂ b Hg pyridine Μ); 2H -7.90 ppm (Hg and Hg pyridine, D,

J = 6Hz); 1H - 6.82 ppm (H thiazole, S); 1H - 6.00 ppm (H ?, DD, J? 9 Hz, product number R, R code ^J 4)

The substitution position of pyridine

NMR spectrum

41647 -CH ₂ -CH = CH ₂ H

J ₂ = 5Hz); 1H (J = 5 Hz); [0100] 2H

5.0 ppm (Hg, D,

4.40 ppm (CH 3 S, Se); 3H-4.20 ppm (CH2-N ⁺ , S); 2H - 3.80 ppm (CH 2 S - + O, Se); 6H between, 5 and 3 ppm / < Κ) ·

1H - 8.80 ppm (NH-CO, D, J = 9Hz);

2H - 8.70 ppm (H alpha pyridine, D,

J = 6Hz); 2H-8.0 ppm (H beta pyridine, D, J = 6 Hz); 1H - 6.80 ppm (H thiazole, S); 2H - 6.00 ppm (γγ + σ ^, M); 2H - 5, # 0 ppm (CH3),

M); 3H - 5.05 ppm (H + _g + CHgN -7 M);

2H - 4.45 ppm (CH3 S, .delta.); 2H - 3.80 ppm = 16Hz); 4H _(CH2 -eO, AB - "2745 ppm

, M);

2H - 1.90 ppm r - (ch ₂ )

Table 3 Strain Product 40874 40914 40763 40876 40800

Citrobacter 49 4 4 2 1 2! Proteus 1510 0,031 <0.125 <0.125 <0.125 0.25 Serratia RL 72 0.5 0.25 0.25 0.25 2 Klebsiella RO 30 0.25 <0.125 0.25 <0.125 0.25 Enterobacter RO 46 0.5 0.25 0.5 0.25 0.25 Enterobacter P 99 0.5 0.5 1 0.5 1 Pseudomonas SS IP 8 8 4 2 16 Pseudomonas RL 112 8 8 4 4 8

»

Table 3 (continued)

Strain 40882 Product AND (B) 40954 41087 Citrobacter 49 4 2 0.5 16 8 Proteus 1510 0.125 0.125 0.25 0.25 4 Serratia RL 72 0.25 0.25 2 32 2 Klebsiella E0 30 0.125 0.125 0.5 0.5 0.25 Enterobacter RO 46 0.25 0.125 1 8 64 Enterobacter P 99 0.5 0.5 2 16 256 Pseudomonas 22 IP 2 2 - 256 8 Pseudomonas RL 112 4 4 256 16

P 8 E I I OF THE INVENTION

Claims (1)

Process for the preparation of novel pyridinium thiomethylcephalosporins derivatives of the general formula III O I in which 2 f R ₁ is H or CH 2 E ₂ represents CH 2 or R ₁ and R ₂ together represent a 1,3-propylene group, R represents an alkyl group having 1-4 carbon atoms, alkenyl having 2 to 4 carbon atoms or an alkynyl group having 2 to 4 carbon atoms or CH ₂ COOAlk in which Alk is an alkyl having 1 to 4 carbon atoms, R1 represents H or a hydroxyl group occupying the free position of the pyridine ring, the sulfur atom of the thiomethyl group being bonded at the ortho- or para-position relative to the nitrogen atom of the pyridine ring, A is hydrogen, a cation or ester or a semiacetal readily hydrolyzable or metabolically labile and pharmaceutically acceptable, selected from the group consisting of phthalidyl. a group, pivaloyloxymethyl, acetoxymethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, acetonyl, alpha-methoxy-alpha-carbomethoxymethyl, carbomethoxyethyl and carbomethoxymethyl; and X is an anion derived from a pharmaceutically acceptable mineral or organic acid such as chloride, bromide, acetate, trifluoroacetate and formate, wherein said derivatives are in the form of syn or anti or mixtures of both isomers, characterized in that The product is cephalosporin C, which is blocked with a primary run group with a protecting group, and the product is converted by treatment with pyridintion to a quaternary ammonium product in aqueous solution in the presence of sodium iodide and sodium bicarbonate, followed by cleavage of the acyl chain. the compound obtained by treatment with phosphorus pentachloride in a solvent such as an alcohol, followed by treatment with hydrogen peroxide or peracid to form a sulfoxide of the formula wherein Z is an anion derived from a mineral acid, the sulfoxide thus obtained is esterified The ester obtained is acylated with chloride chloride C-COOH 1? H ₃ o — C — COO — c — CH · » II * r ₂ ck ₃ wherein Tr represents an amine protecting group, cleaving off the protective group borne amine functionality and the carboxylic acid groups by treatment with a strong mineral or organic acid, and the acid thus obtained shall optionally treated with an inorganic or organic base or with an alcohol to form a compound of formula III wherein A is other than hydrogen.