CS236000B2 - Method of pyridiniumthiomethylcefalosporines new derivatives preparation - Google Patents

Description

(54) Process for the preparation of new pyridinium thiomethylcephalosporins i

The invention relates to a process for the preparation of novel pyridinium thiomethylcephalosporins.

These derivatives are novel chemical compounds and have useful, particularly pharmaceutically useful properties.

If the compounds are specified in more detail, the invention relates to the preparation of novel cephalosporins substituted in the 3-position with pyridiniumthiomethyl.

Belgian patent 866 038 discloses a series of cephalosporin sulfoxides and sulfones of the following general formula I:

’X

C-CO-NH-Γ Ί '

I-N O I (I).

or ₂ coor ₃ wherein X is SO or SO4.

Particular values of the general substituent A in the Belgian patent mentioned are, in particular, CH 2 SR 4 groups in which it represents an optionally substituted pyridyl group.

The cephalosporins of formula (1) reportedly exhibit very potent antibacterial activity against gram-positive and gram-negative bacteria and are very effective against penicillinase-producing staphylococci.

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

(II) wherein Y may in particular be a group of:

I ch ₃

Said cephalosporins are presented herein as antibiotics with a broad spectrum of activity.

In contrast to the above compounds, the present invention relates to novel cephalosporins whose antibacterial activity is substantially different from the antibacterial activity of the compounds disclosed in Belgian patent 866 038 and in German patent application publication 2 921 332. These compounds prepared by the process of the invention have remarkable enterobecterial activity , including those enterobacteria that produce beta-lactamases, good activity against Pseudomonas and poor activity against staphylococci.

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

O

(III) wherein

R 1 is hydrogen or methyl,

R ₂ represents a methyl group or else

R 1 and R ₂ together represent a 1,3-propylene group,

R ^ represents 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 still a group

GHgCOO Alk, wherein Alk represents a lower alkyl group having 1 to 4 carbon atoms,

R1 represents a hydrogen atom or a hydroxyl group occupying the free position of the pyridine ring, wherein the sulfur atom of the thiomethyl group is 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

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

It is also possible, under certain conditions, to convert the quaternary ammonium salt into the salt by the carboxylic 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:

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

g denotes an aliphatic hydrocarbon radical containing a double bond and 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;

cation refers to an alkali metal or alkaline earth metal ion, preferably a sodium ion or calcium ion, or also an ammonium derivative resulting from the protonation of an organic pharmaceutically acceptable amine, such as ethylenediamine, ethanolamine, trometamine, to form an addition salt; and the term ester or semi-acetal readily hydrolyzable or metabolically labile and pharmaceutically acceptable refers to radicals such as phthalidyl radical, pivaloyloxymethyl radical, acetoxymethyl radical, ethoxycarbonyloxymethyl radical,

1- (ethoxycarbonyloxy) ethyl radical, acetonyl radical, alpha-methoxy-alpha-carbomethoxymethyl radical, carbomethoxymethyl radical, carbethoxymethyl radical.

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

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

H, N 'o ♦

² \ s

Ϊ4 \

CO -NH

J — nO-chjs —θ

CH,

O

-C-COOH

AND

CH,

T

COOH < ₁ H ₂

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

- inner quaternary salt of the isomer syn of the above acid, the inner salt having the following formula:

I ch ₃ β products obtained by conversion to a salt or by esterification or semiacetalization of the acid function of said inner quaternary salt and optionally converting to an amine salt of said inner quaternary salt.

More particularly, the present invention relates to trifluoroacetate of the isomer of syn 1- S -oxide of 7- (2-emino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimino) acetamido] -3- (N-allyl-2-pyridinothiomethyl) -3-Cephem-4-carboxylic acid or bromide hydrochloride of said acid or hydrochloride of said acid.

The present invention provides a process for the preparation of novel pyridinium thiomethylcephalosporin derivatives of formula III

-NH <j

COOA ch ₂ p

(III)

O — C-COOH

I in which ^ 2

R 1 represents a hydrogen atom or a methyl group,

R 8 is methyl or

R 1 and R ₂ together represent a 1,3-propylene group,

R ^ represents a C až-C alky alkyl group, a C až-C alk alkenyl group or a C až-C CH alkynyl group or a CH ,COOAlk group wherein:

Alk represents an alkyl group having 1 to 4 carbon atoms,

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 attached 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, pivaloyloxymethyl, acetoxymethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, acetonyl, alpha-methoxyethoxy -alpha-carbomethoxymethyl, carbomethoxyethyl and carbetoxymethyl,

X 'means an anion derived from a pharmaceutically acceptable organic or mineral acid such as chloride anion, bromide anion, acetate βηΐοη, trifluoroacetate anion and formate anion, said products being in the form of a syn or anti or a mixture of these isomers, by reacting pyridintione with an alkali salt of 7-formylaminocephalosporinic acid in an aqueous solution, in the presence of sodium iodide and at a temperature of 40 to 80 ° C, then releasing the acidic carboxylic function of the product obtained, the acid obtained is reacted with hydrogen peroxide or a peracid to form a sulfoxide group with a sulfur atom

- the sulfoxide thus obtained is esterified to form an ester group which can later be easily eliminated to recover the acid, the product obtained is deformylated by treatment with thionyl chloride in solution and the product thus obtained is acylated on the liberated nitrogen by treatment with an acid chloride of the formula

TrNH

C-COOH

NOC-COOC-CH, II n, ch ₃ wherein said acylation reaction is carried out in a solvent such as methylene chloride in the presence of dimethylaniline and the deprotected cephalosporin obtained is then optionally reacted with a mineral or organic base or with an alcohol.

In the process of the invention, compounds of formula III are prepared from 7-formylaminocephalosporonic acid according to the following reaction scheme:

OHC-N (villa)

CH ₂ O CO CH ₃

H

OHC-N

COOH

T

COOH

CHjS

N ^+> Z (IX) (X) o TN z COOH 1 * 3 (XI) o

OHC — N — 1J-N

CH ₂ S

COOY

HCl (XII) • ν-τ — ΤΊ _X

-ΝχγΛ-ΟΗ ^ -

COOY ' ^of (XIII)

H ^T '-V

N

C-CO — NH II

N-COOC-CH,

I ^{1 3} «2 CH ^ jX ^ -K ^ XCH

CH3 COOY | in which

Tr represents a trityl group and

Z is a mineral anion.

III (XI)

The first step consists in reacting the pyridintione VII with a 7-formylaminocephalosporanic acid IX or preferably an alkali salt thereof. The reaction is carried out in an aqueous solution in the presence of sodium iodide at a temperature of 40 to 80 ° C. The product of formula (X) is thus isolated in the form of pyridinium iodide and optionally in the form of an alkali salt.

In the next step, the acidic carboxylic function is liberated by treatment with an acid such as hydrochloric acid, whereupon, for stability reasons, pyridinium iodide is preferably converted to chloride by passing an ion exchange column in the chloride cycle.

The product of formula X is then converted to the corresponding sulfoxide of formula XI by treatment with hydrogen peroxide or a peracid such as metachloroperbenzoic acid. The sulfoxide of formula (XI) is converted to an ester of formula (XII) wherein Y is a group which can be easily separated later; this group is, for example, diphenylmethyl, tert-butyl or trimethylsilyl.

The compound of formula XII is deformylated on an amine nitrogen, for example by treatment with thionyl chloride in methanol, and the 7-amine compound is isolated as the chlorohydrate of formula XIII. This compound is then acylated on nitrogen using an acid chloride of the following formula:

in which

Tr represents a trityl group.

The acylation reaction is carried out in a solvent such as methylene chloride in the presence of dimethylaniline. In this way, a protected group cephalosporin of formula XIV is obtained which, after treatment in a strongly acidic medium, provides the compounds of formula III according to the invention. In particular, a mixture of hydrochloric acid and formic acid or also trifluoroacetic acid can be used to eliminate the protecting group.

The compounds of the formula III according to the invention in which the substituent A has a meaning other than a hydrogen atom are obtained from a compound of the formula III in which the substituent A represents a hydrogen atom by known reactions.

Likewise, the mineral salts are obtained from the compounds of formula III in which A is hydrogen by treatment with a mineral base such as sodium carbonate, potassium carbonate or sodium bicarbonate in an equinolar amount. The reaction is carried out in a solvent such as water or ethanol and the salt obtained is isolated by evaporation of the solution.

Salts derived from organic bases are obtained by treating an equimolar amount of an organic base with a solution of a compound of formula III wherein A is hydrogen in a suitable solvent or mixture of suitable solvents. The salt is then isolated by precipitation with ether.

Esters are obtained by known esterification procedures; preferably, for example, the effect of a halogenated derivative on a salt such as an acid sodium salt is used. This reaction is preferably carried out in a solvent capable of dissolving a starting acid derivative such as dimethylformamide.

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

In order that the invention may be more fully understood, a number of specific embodiments are set forth in the following which are not intended to be limiting and are illustrative only.

As is customary with this type of compound, the compounds produced by the process of the present invention do not have a definite melting point, but only a decomposition temperature which, however, cannot specifically characterize them.

Thus, these compounds will be characterized by their nuclear-magnetic resonance spectra, obtained at 60 MHz, using hexamethyldisiloxane as an internal standard. The following abbreviations are used:

S = singlet

D = doublet

T = triplet

Q = quadruplet

D-D = doubled doublet

S.e. = extended singlet

M = multiplet

AB = AB system

J = coupling constant.

In addition, elemental analysis was carried out in each case, and in all cases the elemental analysis was consistent with the formula.

For example,

7- [2- (2-Amino-4-thiazolyl) -2- (2-carboxy-2-propyloxyimino) acetamido] -3- (N-allyl-2-pyridinothiomethyl) -3- (N-allyl-2-pyridinothiomethyl) trifluoroacetate-3- cephem-4-carboxylic acid in the form of the syn isomer; Product 40874

Step a)

Potassium 3- (N-allyl-2-pyridinothiomethyl) -7-formylamino-3-cephem-4-carboxylate iodide

To a solution of 5.1 g of sodium iodide in 25 ml of water is added 17 g of potassium salt of 7-formylaminocephalosporanic acid and 12.7 g of N-allylpyridin-2-thione.

The mixture thus obtained was stirred for 4 hours at 60 ° C. After cooling, the solution obtained is poured into 1.7 l of acetone and the precipitate formed is centrifuged and rinsed with acetone and then with ether. It is then dried under vacuum.

Step b)

The 3- (N-allyl-2-pyridinothiomethyl) -7-formylamino-3-cephem-4-carboxylic acid chloride is dissolved in 100 ml of water and acidified with 2N hydrochloric acid to pH 1, 5. The aqueous phase is separated from the light precipitate and loaded onto an Amberlite IRA 68 ion exchange resin column in a chloride cycle. '

Elution is carried out with water. The water from the eluate was then evaporated to dryness under reduced pressure and the residue was taken up in absolute ethanol. The solution was re-evaporated to dryness and the residue was taken up in ether. The solid is then centrifuged and dried under vacuum.

NMR Spectrum:

2 H - 9.10 ppm (Hg pyridine, ICl CO, M); 1 H - 8.45 ppm (H 'pyridine, TD); 2 H - 8.10 ppm (H-CO-N, H-pyridine, M); 1 H - 7.95 ppm (Hg pyridine, TD); 1 H - 6.00 ppm (CH = M); 1 H - 5.70 ppm (Γγ, M); 5 H between 4. , 95 and 5.40 ppm (Hg , CH ₂ N ⁺ a = ( 2 H - 4.45 ppm (CHg in position 3. AB, J _ab · 2 H - 3.60 ppm (CHgS cycle, AB, J _{and ab} = 17

Step c)

3- (N-allyl-2-pyridinothiomethyl) -7-formylamino-3-cephem-4-carboxylic acid chloride as the 1-S-oxide g of the product obtained in step b) above was dissolved in 30 ml of formic acid. To the solution thus obtained was added 30 ml of methanol and the solution was cooled to 5 ° C. 2.7 g of metachloroperbenzoic acid are then added to the cooled solution over 5 minutes. The temperature was allowed to rise to 20 ° C and the mixture was stirred at this temperature for 30 minutes.

The solid is filtered off and the solution thus obtained is poured into 600 ml of ether. The solid is centrifuged, rinsed with ether and dried under vacuum.

NMR Spectrum:

H - 8.96 H - 8.30 H - 8.10 ppm (Hg ppm (H ppm ppm (H ppm ppm) (H ₅ pyridine, pyridine, pyridine, pyridine,

H = 7.80 H = 6.0 ppm (CH =, M);

D, J = 6Hz)

NH (CO, M); H-CO-N- (M); TD, J = 6Hz);

H = 5.90 ppm (γγ, M);

H between 5.0 and 5.50 µm (CH ₈ N *, CH ₂ =, H 8, M); H = 4.45 ppm (CH ₂ S, AB, J _AB = 13 Hz);

H = 3.95 ppm (CH ₂ S → O, AB, J _AB = 17 Hz).

Step d)

Diphenylmethyl 3- (N-allylpyridinio-2-thiomethyl) -7-formylamino-3-cephem-4-carboxylate 1-S-oxide

4.5 g of the product obtained in step c) above are dissolved in 45 ml of water and 130 ml of a solution of diphenyldiazomethane in methylene chloride are added to the solution thus obtained.

The mixture is then stirred vigorously, then added to 90 ml of absolute ethanol and the pH is maintained at 2 by the addition of concentrated hydrochloric acid.

After 45 minutes, the solution was discolored. The organic layer was decanted and the aqueous phase was re-extracted with methylene chloride. The organic extracts are combined and concentrated to dryness. The residue is taken up in absolute ethanol and the solution is evaporated to dryness. The residue is taken up in ether and the solid is centrifuged and dried under vacuum.

NMR Spectrum:

Η - 9.10 ppm (Hg pyridine, D, J = 5 Hz);

1H-8.45 ppm (CO KM, -D, J = 9 Hz);

H = 8.20 ppm (H 2 -pyridine, T, J = 7 Hz);

H = 8.10 ppm (H CO-, S);

H = 8.0 ppm (H 1 pyridine, D, J = 7 Hz);

H = 7.85 ppm (H 1 pyridine, T deformed); 10 H - 7.30 ppm (aromatic H, K);

H = 6.85 ppm (COO CH3, S);

H = 6.0 ppm (H 2 + CH =, M);

H between 5.5 and 5 ppm (Hg, CH ₂ K ⁺ , = CH ₂ , M);

H = 4.45 ppm (CH 3, AB, J _AB = 13 Hz);

H = 4.0 ppm (CH ₂ S → O, AB, J _AB = 7 Hz).

Step e)

1- (S-Allylpyridinio-2-thiomethyl) -7-amino-3-cephemarboxylate chloride hydrochloride g of the product obtained above was dissolved in 10 ml of methanol under an inert atmosphere. The solution thus obtained is cooled to 10 ° C and then 0.8 ml of thionyl chloride is added over 5 minutes, maintaining the temperature below 20 ° C.

The mixture was stirred for 30 minutes at 20 ° C and then poured into 300 ml of ether. The solid was centrifuged and washed with ether. Then, the washed product is dried over phosphorus pentoxide.

Step f)

7- [2- (2-Tritylamino-4-thiazolyl) -2- (2-tert-butoxycarbonyl-2-propyloxiimino) acetamido] -3- (N-allyl-2-pyridinothiomethyl) -3-S-oxide chloride diphenylmethyl-cephem-4-carboxylate in the form of the syn isomer

2- (2-Tritylamino-4-thiazolyl) -2- (2-tert-butoxycarbonyl-2-propyloxiimino) acetic acid chloride isomer syn

Under a nitrogen atmosphere, 3.4 g of 2- (2-tritylsmino-4-thiazolyl) -2-tert-butoxycarbonyl-2-propyloximino) acetic acid as the isomer syn 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 solution was then poured into 200 mL hexane. The solid is centrifuged and dried in a 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. The suspension was cooled to 5 ° C, then 1.7 ml of dimethyleniline was added and the temperature was allowed to rise to 20 ° C. After stirring for one hour, the solution is washed with 30 ml of a 0.5 N hydrochloric acid solution. The organic solution is then dried and concentrated to a volume of 10-15 ml. This solution is not poured into 150 ml of isopropyl ether. The solid was centrifuged, washed with isopropyl ether and dried in vacuo.

The crude product thus obtained was chromatographed on a silica gel column (120 g). A mixture of methylene chloride and methanol (85: 5 by volume) was used as eluent to give the desired product.

BKR spectrum:

H-9) 10 ppm (Hg pyridine, D, J = 6 Hz);

H = 8.85 ppm (NH trit, S.e,);

H = 3.25 ppm (H 2 -pyridine, NH CO, M);

H = 3.0 ppm (H ₃ pyridine, D, J = 7Hz);

H = 7.80 ppm (H 2, pyridine, TD);

H - 7.27 ppm (aromatic H, M);

H = 6.85 ppm (H thiazole, S);

H = 6.75 ppm (COOCH3, S);

H = 5.95 ppm (γγ + CH =, M);

H between 5.0 and 5.5 ppm (CH ₂ N ⁺ CH ₂ = Hg, m); 2 Η τ 4.45 ppm (CHgS, AB, J _AB = 12 Hz);

H = 4.0 ppm (CH _{2 -} t O, AB, J _AB = 17 Hz);

H-1.40 ppm (CH 3) ₂ -C-, S);

ch ₃

H-1.30 ppm (-C-CH ₃ , S).

^ CHj

Step g)

Product CM 40 874 g of the protected product obtained in step f) above are 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. The retention temperature of the mixture is then allowed to rise to 20 ° C and the mixture is left at this temperature for 2 hours.

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

NMR

H

H

H

H

H

H

H

H

H 1 H

H spectrum:

9.05 ppm (Hg pyridine, D, J = 5 Hz);

- 8.50 ppm (NHCO, D, J = 9Hz);

- 8.35 ppm (H 2 -pyridine, M):

8.20 ppm (H ₃ pyridine, D, J = 7 Hz);

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

6.82 ppm (H thiazole, S);

-6-, 0 ppm (γγ and CH =, M);

between 5.0 and 5.6 ppm (OH ₂ N ⁺ , CH ₂ = o Hg, K);

- 4.5 ppm (CH 2 S, A from AB, J and _B = 13 Hz);

- 4.32 ppm (CK _2, B of AB, J _AB = '3 Hz);

1

Η - 4.0 ppm (CH ₂ S -> 0, A from AB, J _ab = 17 Hz);

H = 3.3 ppm (CH ₂ S → O, B from AB, J _AB = 17 Hz);

CH,

H - 1.45 ppm (-C

ch ₃ , S)

CH.

'3

Using the method of the invention it was possible to prepare:

product CM 40874, wherein r ₃ = ch ₂ -ch = ch ₂

R. = H 4

A = 1!

X = cf ₃ coo, as well as the products listed in Table 1;

product 40914, wherein R 1 + R ₂ = (CH ₂ ) ₃ ^R 3 ^{= CH} 2 ' ^{CH = CH} 2

R. = H

A = H

X = cf ₃ coo 'as well as the products listed in Table II; and the CM 40800 product in which

R1 = H

A = Η x = cf ₃ coo.

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

The in vitro bokteriostatic effect was determined by n8 solid substrate dilution method. The results obtained are expressed as minimum inhibitory concentrations (ClI in µg / ml) and relate to different strains of Enterobacteria and Pseudomonas.

236000 12

For comparison, results with two products of close composition already described are also included, namely:

7- {2- (2-8mino-4-thiazolyl-2-carboxymethoxyiminoacetamido) -3- (2-pyridylthiomethyl) -3-cephem-4-carboxylic acid 1-S-oxide as isomer syn (compound A) of formula:

C — CO -NH

II \ ⁰ and ₂ cooh

COOH (Belgian Patent No. 886,038) 7- [2- (2-aminothiazolyl) -2- (2-carboxy-2-propyloxiimino) acetamido] -3- (N-methyl-2-pyridinothiomethyl) -3- (N-methyl-2-pyridinothiomethyl) trifluoroacetate cefem-4-carboxylic acid in the form of the syn (compound B) isomer of formula:

(NSE Patent Application Publication No. 2,921,332)

The results are summarized in Table 3.

These results show a particularly pronounced efficacy of the products according to the invention against strains which are generally of low sensitivity to the antiobiotics of the cephalosporin family, namely the Enterobacteries and Pseudomonas strains.

Compared to reference product A, the products of formula III exhibit surprising efficacy against the following strains: Citrobacter, Enterobacter, Serratie and Pseudomonas, while retaining efficacy against Klebsiella e Proteus strains which are comparable to that of reference compound A against these strains.

Compared to reference product B, the products of formula (III) show an efficacy which is higher with respect to Citrobacter, Proteus and Enterobacter, while maintaining the same efficacy against other strains and, in some cases, more efficacy.

In addition, animal tests have shown that the compounds of formula III according to the invention are not toxic. Their toxicity is comparable to that of compounds of the cephalosporin family.

Thus, the compounds of the invention may be used as entibiotics in human and veterinary medicine. They can be used to suppress all bacterial infections to which they are effective.

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

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

The dose of the active ingredient may vary within wide limits, particularly depending on the type and severity of the infection and the route of administration. Most often, this dose is 0.250 to 4 g per day for an adult and by injection.

An example of a pharmaceutical composition comprising a product of formula (III) of the invention is an injectable ampoule containing:

product CM 40 874 b 1 g water after injection 5 ml sodium carbonate in the amount necessary to reach pI = 6.3.

Table 1

C-CO-NH II

N ⁰ ) ^H3 O-C-COOH

AND

CH-j ^{L 'x} r 2 ^{_CH s_} 2L + N j i____

COOH cf ₃ coo number ΙΪ-, product ^J

R. Substituted ⁴ position pyridine

KNR spectrum

40763 CH 2 H 2 1 H - 9.00 ppm 4 H mesi 7.60 and H ₅ pyridine, M); WITH); 1 H-5.97 (Hg, D, J = 4 Hz) Se); 3 H - 4, 2 H - 3,80 ppm 6 Η - 1, 46 ppm (Hg pyridine, D, J = 6Hz); 8.60 ppm (NHCO, H 3, H ₄ , 1 H - 6.83 ppm (H thiazole, ppm (γ, 1 '); 1 H - 5.0Q ppm; 2 H - 4.40 ppm (CH ₂ , 20 ppm (CH ₃ -N ⁺ , S) 1 (Cl ₂ S 5); (-C < , S). CH-j 40876 CH ₃ H 4 2H - 8.64 ppm (h ₂ pyridine, D, J = 7 Hz);

H = 8.40 ppm (NHCO, D, J = 9Hz); 2H -7.95 ppm (1H, pyridine, D, J = 7 Hz);

H = 7.50 ppm (NH 4, 2 COOH, S.e.);

H = 6.80 ppm (H-tizole, S); 1 H - 5.95 ppm (γγ, D of D, J = 9 Hz, J ₂ = 4 Hz); 1H - 5.05 ppm (H, D, J = 4 Hz); 1H - 4.40 ppm (Hg, D, J = 4 Hz); 1H - 4.40 ppm); (CHgS,

A from AB, J _AB = 13 Hz); 1 H - 4.35 ppm _(CH2 S, B of AB, J _ab = '3 Hz);

Continuation of Table 1 Product Number

R. Substituted ⁴ position pyridine

NMR spectrum .delta

40912 gh ₂ g = ch

40972

CH,

3-OH

H = 4.16 ppm (CH 3 ⁺ N, S); 1H - 3.89 ppm (GHgS -> 0, A from - AE, J _ab = 17Hz); 1 H - 3.76 ppm (CH 2 S · - * · ·, B from AB, I _AB = 17 Hz); ΔT = 1.43 ppm

(-C, 2D).

^ CH3

H between 7.5 and 9.1 ppm (H 4, H 4, H 4 and H 8 pyridine and NHCO, M); 1H - 6.85 ppm (H thiazol. S); 1H - 6.0 ppm (γγ, M);

H = 5.65 ppm (CH ₂ N ⁺ , M); 3 H - 5.0 ppm (H ₆ and CH 8 S, M); 2-H-3.95 ppm (GHgS <-O, Se); 6 H -1.43 ppm

^ SCH. masked with dimethylsulfoxide

H between 6.5 and 10 ppm (HgN, 2 COOH, OH, M); 1H-8.60 ppm (Hg-pyridine, M);

H = 8.45 ppm (NHCO, D, J = 9Hz);

H = 7.9 ppm (H 4 and H 4 pyridine, M);

H = 6.80 ppm (H-thiazole, S); 1H - 6.0 ppm (γγ, t); 1H - 4.96 ppm

H ₆ , D, J = 5Hz); Δ H - 4.30 ppm (CH, N ⁺ and GHr 3 S, M); 2 H - 3.85 ppm (CH 2 S - = = O);

H-1.47 ppm

087

CH «C00C _about 2 JH-H

2 5

II - 9.2 ppm (NHCO, D, J = 9Hz); 4 H between

7.5 and 8.8 ppm (Hp 1, and Hz pyridine,

'); 1H - 6.90 ppm (H thiazole, S);

i JI - 6.0 ppm (γ, M); 2 H - 5.67 ppm (CH 2 N ⁺ , Se); 1H - 5.0 ppm (Hg, D,

J = 5Hz); 2H - 4.30 ppm (COOCJL · -, Q,

J = 7Hz); 2H-3.90 ppm (CH2-O, Se); 6H - 1.45 ppm ~~ ¹ 5

P.curling table 1

R number, product ^J

R. Substitution position of pyridine

NMR spectrum

H = 1.20 ppm (COOCH 3 CH 3, T, J = 7 Hz).

41607 -CH ₂ -CH = CH ₂ H 4 2 H - 8.70 ppm (H alpha pyridine, D,

J = 6 Hz); 1H - 8.45 ppm (NH-CO, D,

J = 9 Hz); 2 H - 8.0 ppm (H beta pyridine, D, J = 6 Hz); 1H - 6.80 ppm

41607 -CH ₂ -CH = CH ₂ H 4 (H thiazole, S); 2 H - 6.0 ppm (? + 011 =,

M); 2H-5.40 ppm (-CH3, K); 3 H - 5.05 ppm (H ₆ + CH ₂ N ⁺ , * ¥); 2Π- 4.45 ppm (CH 3 S, M); 2 H - 3.80 ppm (CH 3 S-O 2,

AB / J _ab = 1 Hz); 6 H-1.45 ppm (C- (CH ₃ ) ₂ , 2 S). '

Table 2

number product ^R 3 • r ₄ - The substitution position of pyridine NMR spectrum 40882 - CH ₃ H 2 9 H between 7.5 and 9.5 ppm (NH ₂ , 2 COOH, NHCO, H ₃ , H 2, H 2 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 (CH3 S-, M); 3 H - 4.25 ppm (0Η ^ Ν ⁺ S); 2 H - 3.93 ppm (CH ₂ S - ΛΟ, M); OH between 1.5 and 2.7 ppm (, «), 40954 CH ₃ H 4 7 H between 8.3 and 9.0 ppm (NHCO, NH ₂ , 2 COOH, H ₂ and Hg pyridine, M); 2 H -

7.90 ppm (H ₃ and pyridine, D, J = 6 Hz);

Ή - 6.82 ppm (B thiazole, S); 1 H 6.00 ppm (γ, D of D, Jj = 9 Hz, Jj = 5 Hz); 1H-5.0 ppm (Hg, D, J = 5Hz); 2H-4.40 ppm (CH3 S, S.e.); 3H-4.20 ppm

Continuation of Table 2 No. _R ⁿ product 3

The substitution position of pyridine

NMR spectrum

41647 -CH ₂ -CH = CH ₂ H (CH ₂ -, Ν, S); 2 H - 3.80 ppm (CH 3 S - * O, Se); 6 H between 1.5 ® 3 ppm) · »> ·

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

H - 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); 2 H - 6.00 ppm (γγ + ΟΗ =, K '); 2 H - 5.40 ppm (CH ₂ =, M); 3 H - 5.05 ppm (H _{2 N} + CH M ⁺ H MTJ 2 - 4.45 ppm (CHGS, m);

H = 3.80 ppm (CH 2 S → O, AB, J _AB = 16 Hz); 4 H - 2.45 ppm \ ^ xCOOH (_CH ₂ -, F);

ch ₂

H = 1.90 ppm

CH (CH

).

Table 3

Strain Product 4080C 40874 40914 40763 40876 Citrobactar 4 4 2 1 2 Proteus 1510 0,031 <0.125 <0.125 <0.125 0.25 Serratia KE 72 0.5 0.25 0.25 0.25 2 Klebsiella HO 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 Pseudomons A 22 IP 8 8 4 2 16 Pseudomonas RL 112 8 8 4 4 8

TAbulka 3 (continuation) Strain Product .40882 40954 41087 AND (B) Gitrobacter 49 4 2 0.5 16 8 Proteus 1510 <0.125 C0.125 0.25 0.25 4 < Serratie RL 72 0.5 0.25 2 32 2 - Klebsiella RO 30 CO, 125 CO, 125. 0.5 0.5 0.25 - Enterobacter RO 46 0.25 CO, 125 1 8 64 4 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 Ř E D M S T OF THE INVENTION

Claims (1)

A process for the preparation of novel pyridinium thiomethylcephalosporins derivatives of the general formula III in which: H ₂ N Á7 -C-CO-NH II NR, U and I ¹ O — C — COOH I r ₂ Ύ COOA CH ₂ (II) R 1 represents a hydrogen atom or a methyl group, R ₂ represents a methyl radical or R _(and R ₂ together are 1,3-propylene, R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl or GH 8 COOAlk where Alk is C 1 -C 4 alkyl radical, R1 represents a hydrogen atom or a hydroxyl group occupying the free position of the pyridine ring, the sulfur atom of the thiomethyl group being attached at the ortho or para position relative to the nitrogen atom of the pyridine ring, A is hydrogen, a cation or ester or a semi-acetal readily hydrolyzable or metabolically stable and pharmaceutically acceptable, selected from the group consisting of phthalidyl, pivaloyloxymethyl, acetoxymethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, acetonyl, alpha-methoxy- alpha-carbomethoxymethyl, carbomethoxyethyl and carbetoxymethyl, X 'means an anion derived from a mineral or organic pharmaceutically acceptable acid such as chloride, bromide, acetate, trifluoroacetate and formate, said products being in the form of syn or anti or in the form of a mixture of these isomers, the reaction of pyridintion and the alkali salt of 7-formylaminocephalosporanic acid, said reaction being carried out in aqueous solution in the presence of sodium iodide at a temperature of 40 to 80 ° C, for example the carboxylic acid function of the product obtained is deprotected and treated with hydrogen peroxide or peracid to form a sulfoxide group with a sulfur atom, the sulfoxide ester thus obtained is then esterified to form an ester group which is later readily cleavable to recover the acid, the product obtained is deformylated with thionyl chloride in solution and the product thus obtained is acylated to t. to the liberated nitrogen by treatment with an acid chloride of the formula TrNH 2 -S 2 C-COOH N - O - C - COOC - CH 2 I R, CH-, wherein said acylation reaction is carried out in a solvent such as methylene chloride in the presence of dimethylaniline and the cephalosporin thus obtained is deprotected and optionally reacted with a mineral or organic base or an alcohol to form the above salts and esters.