FI65780C - FRAMEWORK FOR THERAPEUTIC TREATMENT OF THERAPEUTIC EQUIPMENT - Google Patents

Description

65780

A process for the preparation of new therapeutically useful cephalosporins

This invention relates to a process for the preparation of novel cephalosporins of the formula

O O

M

AN / NC-NH-CH-CONH-X 1 '2 R 3 X-CH 2 r 4 (I> R oi COOR 1 1 2 15 wherein R is a hydrogen atom or a salt-forming cation, R is a 3 hydrogen atom or a methyl group, R is a phenyl- or a hydroxyphenyl group, A is a C 1-6 alkyl or phenyl group and R 1 is an acetoxy, methoxy, pyridinium or pyridine-1-oxid-2-ylthio group or a thiazolylthio group optionally substituted by a C 1-6 alkyl group. , a thiadiazolylthio, triazolylthio, oxadiazolylthio or tetrazolylthio group.

The compounds of the formula have a broad spectrum of anti-gram-positive and gram-negative bacteria, and their potent antibacterial activity is particularly directed against Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species.

In addition, the new compounds are very resistant to the action of bacterial β-lactamase and also have an effective antibacterial effect against clinical bacteria that are currently relevant in hospital settings.

Therefore, these new compounds are effective in the treatment of infectious diseases caused by the above-mentioned microorganisms in humans and animals.

It is known that 6-acylaminopenisil-35-sanoic acids and 7-acylaminocephalosporanic acids having an amino group at the © (position of the acyl group) have a potent 65780 2 antibacterial effect on both gram-positive and gram-negative bacteria. disadvantage that they do not have an effective antibacterial effect against the bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus, which cause serious infectious diseases, as well as many bacteria that are currently isolated from hospitals. 10 tolerant bacteria produce.

It has now been found that the compounds of the formula I having a group attached to the amino group in the acyl group of the cephalosporin of the formula 15 0 0 y ~ {A-N li-C-20 do not have the above-mentioned disadvantages while being excellent in therapeutic properties.

In formula (I), the salt-forming cations R1 are those which have hitherto been used in connection with the penicillin and cephalosporin compounds, however, cations which form non-toxic salts are preferred. Suitable salts include e.g. alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., ammonium salt, and salts with nitrogenous organic bases such as procaine, dibenzylamine, N-benzyl- / S-phenethylamine, 1-efen-amine, 1-efen With Ν-dibenzylethylenediamine, etc.

In addition to the above-mentioned cations, cations capable of forming a salt with other nitrogenous organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexyl can be used. In addition, suitable 3,65780 cations include pyridinium ammonium groups formed at the 3-position of the cephem ring. In this case, a betaine structure is formed in the molecule.

The above-mentioned novel compounds of formula (I) exist as optical isomers, and thus all their D-isomers and racemic mixtures are within the scope of the process according to the invention.

Preferred compounds of formula (I) are those wherein R is a hydrogen atom, R is a tetrazolylthio group which may be substituted by C 1-4 alkyl, and R "*" is a hydrogen atom or a cation which may form a non-toxic salt.

Compounds of formula (I) may be prepared by a) obtaining a compound of formula r5-nh-ch-conh-S ^ I JLcH R4 (II)

E3 y-n ^ -CH2R

COORla 20 5 wherein R is a hydrogen atom or a silicon or phosphorus-containing group, 1 cl R is a hydrogen atom, a salt-forming cation or a protecting group, 3 4 known in the context of cephalosporins, and R and R have the same meaning as above, to react with the formula AN with a reactive carboxyl derivative 2 of a compound of the formula NC-OH (III) N- (° R 30), in which formula A and R have the same meaning as above, or b) a compound of formula 4 65780 R 5 -NH-r- j- Ns ^ * CH2R (IV) COOR1a wherein R1a, R4 and R5 are as defined above, to react the formula

O. O

X

A-N Ti-C-NH-CH-C-OH (V) M n '3 "

O R3 O

With a compound of formula R2 or a reactive carboxyl derivative thereof in which A, R and R have the same meaning as above, or c) a compound of formula u is selected from NC-NH-CH-CONH-I 1 ° P J - (VI)

2 ° R2 0 T

COORla la 2 3 wherein B is an acetoxy group and A, R, R and R are as defined above, to react with a compound of formula r6M (VII) wherein M is a hydrogen atom, an alkali metal or an alkaline earth metal and R is methoxy or pyridine a 1-oxide-2-ylthio group or a thiazolylthio, thiadiazolylthio, triazolylthio or oxadiazolylthio or tetrazolylthio group optionally substituted by C 1-4 alkyl; or pyridine, and if necessary the protecting group R 1 is removed.

la

The protecting group R may be any of those hitherto used in connection with cephalosporin-type compounds. More specifically, suitable protecting groups include e.g.

5 65780 1) ester groups which can be removed by catalytic reduction, chemical reduction or hydrolysis under mild conditions, e.g. arylsulfonylalkyl groups such as toluenesulfonylethyl, etc.

Substituted or unsubstituted aralkyl groups such as benzyl, 4-nitrobenzyl, diphenylmethyl, trityl, 3,5-di (tert-butyl) -4-hydroxybenzyl, etc. substituted or unsubstituted alkyl groups such as tert-butyl, trichloroethyl, etc. phenacyl group, alkoxyalkyl groups such as methoxymethyl, etc. and unsubstituted or alkyl-substituted cyclic aminoalkyl groups such as piperidinoethyl, 4-methylpiperidinoethyl, morpholinoethyl, pyrrolidinoethyl, etc., such as ester groups which can be removed by enzymatically, etc. phthalide group and indanyl group, 3) silicon, phosphorus or tin-containing groups which can be easily removed by water treatment or alcohol treatment, such as (CH 2 Cl 2, C 10 H 50 P-, (C 4 H 9) 3 Sn) and the like .

C2H5 ° 25

The protecting groups mentioned in (1), (2) and (3) are only exemplary examples, and further exemplary groups that can be used in this invention can be found in U.S. Patent Nos. 3,499,909, 3,573,296 and 3,641,018 and DE-A-2. 301,014, 2,253,287 and 2,337,105. The salt-forming cations R "* - 3 are those mentioned above for R 1. The silicon or phosphorus-containing groups R 1 are the same as those described above for R 1. .

The compound of formula II may exist as the D-isomer, the L-isomer or a racemic mixture. As the reactive carboxyl derivative of the compound of the formula (III), a reactive carboxylic acid derivative commonly used in the synthesis of 65780 acid amides can be used. Reactive derivatives are, for example, acid halides, acid azides, acid cyanides / mixed acid anhydrides, active esters, active amides, etc. Very suitable are, for example, acid halides such as acid chlorides, acid bromides, etc. and active esters such as cyanomethyl ester, trichloromethyl ester, etc.

The reactive carboxyl derivative of the compound of formula (III) can be easily prepared, for example, by reacting 2,3-dioxopiperazine of the formula 0 0 y ~ (A-N NH (VIII) 15 N_ /) synthesized by the method mentioned in the literature references below.

V

2 wherein A and R are as defined above, to react with phosgene, chloroformic acid trichloromethyl ester or the like.

20 Literature references: J.L. Riebsomer, J. Org. Chem., 15, 68-73 (1950)

Edward F. Cluff, et al., U.S.P. 3,149,154 (1964) 7 65780 o o o o o o in m o r »m

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The compound of general formula (V) can be easily prepared, for example, by reacting the compound of formula H-N-CH-COOH (IX)

^ I

An alkali metal, alkaline earth metal or nitrogen-containing base salt of an amino acid (D-isomer, L-isomer or racemic mixture) of R3, wherein R: 11a has the meaning given above, to react with a compound of general formula (III) ) with a reactive carboxyl derivative in a reaction-inert solvent in the presence of an acid-binding reagent.

As the reactive derivative of the carboxyl group of the compound of the formula (V), a reactive carboxylic acid derivative commonly used in acid amide synthesis is used. These reactive derivatives include acid halides, acid anhydrides, mixed anhydrides of organic or inorganic acids, active acid amides, acid cyanides, active esters, etc. Acid chlorides, mixed acid anhydrides and active acid amides are very suitable. For example, mixed anhydrides of acids include mixed anhydrides of substituted acetic acids, alkylcarboxylic acids, arylcarboxylic acids, and aralkylcarboxylic acids, active esters include cyanomethyl esters of imidyl amides and substituted acyl esters, substituted phenyl esters, substituted benzyl esters, substituted benzyl esters, substituted benzyl esters, substituted , N-acylbenzoyl-30 amides, N, N-dicyclohexyl-N-acyl ureas, N-acyl sulfonamides, etc.

Compounds of formula (VI) may be prepared, for example, by method (ä) or (b). The D- or L-forms or racemic mixtures of the compounds of formula (VI) may be used.

65780 10

Methods (a) and (b) may be performed under substantially the same conditions. The compound of formula (II) or (IV) is dissolved or suspended in at least one inert solvent such as water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene, toluene, methylene chloride, chloroform, ethyl acetate, methyl isobutyl ketone and the like.

The solution or suspension thus obtained is reacted with a reactive derivative of a compound of formula (III) or a compound of formula (V) or a reactive derivative of the carboxyl group of a compound of formula (V), optionally in the presence of a base at -60 to + 80 ° C, preferably -40 to +3 at 0 ° C. The reaction time is usually 5 minutes to 15 hours. Suitable bases include e.g. alkali hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, etc. tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, lydidine, trimethylpyridine, etc. and 20 secondary amines, the compound of formula (V) is used in process (b) in the form of a free acid or salt, the reaction of process (b) may be enhanced by the addition of a water-binding condensing reagent such as N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N, N'-diethylcarbodiimide, N, N'-carbonyldi (2-methylimidazole), phosphoric acid trialkyl ester, phosphoric acid ethyl ester, phosphorus oxychloride, phosphorus trichloride, 2-chloro-1,3,2-dioxaphosphololide or oxazole.

Salts of the compound of formula (V) may be, for example, alkali metal salts, alkaline earth metal salts, ammonium salts and salts formed with organic bases such as trimethylamine, dicyclohexylamine and the like.

Process (c) is carried out as follows: A compound of formula (VI) is reacted with a compound of formula (VII) or pyridine in at least one solvent such as water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 11,65780 dioxane, acetonitrile, ethyl acetate, methoxyethanol, dimethoxyethane, dimethylformaride, dimethylsulfoxide, dichloromethane, chloroform, pH, the reaction is preferably in a highly polar solvent, the reaction is most suitable in a highly polar solvent. at 2-10, preferably at 4-8. The pH can be adjusted with a buffer solution such as sodium phosphate solution. The reaction does not require well-defined conditions, but a temperature of 0 to 100 ° C and a reaction time ranging from a few hours to ten hours are usually used.

Non-toxic salts of formula (I) wherein R 1 is a salt-forming cation can be readily prepared by conventional methods from compounds of general formula (I) wherein R 1 is a hydrogen atom or a protecting group.

15 The removal of the protecting group R is carried out in a manner known per se.

The sensitivity of some of the compounds of formula I was determined by the following experiments.

1) The minimum inhibitory concentration (MIC) of some standard strains of compounds is shown in Table 2.

The minimum inhibitory concentration (MIC) was determined by the plate method described in "Chemotherapy" (Japan), Vol. 16, (1968), ss. 98-99. Cardiac infusion agar (pH 7.4) was used as medium. Each plate was seeded with 10 cells (10 cells / ml).

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The MIC was determined as in the previous section (1).

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l · S 'H nm S to «J poooo I sä ä§g si sssss« -H to to to tn wsg I gg I a 1 a 1 s 2 «65780 3) Tolerance Proteus vulgaris GN 76 strain and Escherichia freundii For β-lactamase produced by strain GN 346:

The β-lactamase-tolerance-5 ability of each cephalosporin compound was determined as follows.

Δ & lactamase was prepared from strains of Proteus vulgaris GN 76 and Escherichia freundii GN 346. 10 ml of an overnight culture in cardiac infusion medium was diluted with 100 ml of medium containing 2 g of yeast extract, 10 g of polypeptone, 2 g of glucose, 7 g of disodium hydrogen phosphate, 2 g of potassium dihydrogen phosphate, 1.2 g of ammonium sulfate and 0.4 g of magnesium sulphate per liter and incubated at 37 ° C with shaking. After 2 hours of incubation, penicillin G (50 μg / ml) was added as an inducer and incubated for another 2 hours. The cells were centrifuged (5000 rpm, 10 min) and washed twice with 0.1 M phosphate buffer (pH 7.0). The cells were then sonicated (20 kHz, 50 min) and centrifuged for 60 minutes at 15,000 rpm. The foolactamase tolerance of the compounds was determined using a separated enzyme-20-containing liquid using an iodometric measurement method. The results obtained are shown in Table 4. The figures in Table 4 are relative tolerance values calculated by assigning a value of 100 to the cephaloricin used as a control.

25

Table 4 Comparison of β-lactamase tolerance

Compound Relative tolerance value (%) _

Check Proteus vulgaris Escherichia on GN 76 freundii _____GN 346_

Cephaloricin 100 100

Cefalexin sodium 150 29

Sodium cephaloglycine 1300 0.3

Cephalothin sodium 105 17

Cefazoline sodium 440 150

Compound No. 6 10 0.7

Compound No. 17 7 0.2

Compound No. 27 11 1 27 65780

Tables 2 and 3 show that the compounds of this invention have a broader antibacterial spectrum and much better antibacterial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus species and several drug tolerant bacteria than cephaloglycine as controls. a compound having an amino group at the o (position) of the acyl group. Table 4 also shows that the new compounds tolerate β-lactamase much better than the drugs used as controls. 10 These cephalosporins are generally only slightly toxic.

The novel compounds of formula (I) may be administered as free acids or as non-toxic salts.

The compounds of this invention can be administered to humans and animals as long as they are first formulated into physiological forms such as tablets, capsules, syrups and the like, which are commonly used in connection with penicillin and cephalosporin-type drugs.

Methods for preparing the novel compounds are described below by way of examples.

Example 1

To a suspension of 0.20 g of 7- [D (-) - N - (- aminophenylacetamido) -3-acetoxymethyl-N-cephem-4-carboxylic acid in 15 ml of anhydrous chloroform was stirred 0.17 ml of triethylamine. to give a solution, which was then cooled to 0. To this solution, 0.11 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was added, and the mixture was allowed to react at room temperature for 2 hours. After completion, the reaction liquid was evaporated under reduced pressure, and the residue was dissolved in 15 ml of water, the resulting solution was washed with 10 ml of ethyl acetate, an additional 20 ml of ethyl acetate was added to the aqueous layer, and the pH was adjusted to 1.5 with 2N hydrochloric acid under ice-cooling.

28 6 5780

The ethyl acetate layer was then separated, washed first with water and then with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. When the solvent was then distilled off under reduced pressure, 0.22 g of 5- [D (-) - Q - (- (4-methyl-2,3-dioxo-1-piperazinocarbonyl-λ amino) phenylacetamido] -3-acetoxymethyl-A was obtained. -cephem-4-carboxylic acid as white crystals, mp 175 ° C (decomposes), yield 76%.

IR (KBr) cm -1: δ Q-Q 1770 (lactam), 1720-1650 δ (-CON 2, -COOH) NMR (d 6 -DMSO) δ values: 0.23 (1H, d), 0.63 ( 1H, d), 2.66 (5H, s), 4.32 (1H, g), 4.43 (1H, d), 5.05 (1H, d), 5.21 (2H, q), δ , Δ (2H, bs), 640 (2H, bs), δ 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s).

When the above procedure was repeated substituting the reactive derivatives of the compounds of formula (III) listed in Table 5 for 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the corresponding final products shown in Table 5 were obtained. The structure of the final products was confirmed by IR and NMR.

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30 65780

The above procedure was repeated, but in addition to triethylamine, the following compounds were used to give 7- [D (-) - - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-acetoxy-5-methyl- N-cephem-4-carboxylic acid.

Compound Yield of final product (CH3) 3SiCl 83% Οχ 10 PCI 75%

_O

CH3

When the above-mentioned β- [(-) -? - (4-methyl-2,3-dioxo-15-piperazinocarbonylamino) phenylacetamide] -3-acetoxymethyl-N-cephem-4-carboxylic acid, m.p. 17 5 ° C (decomposes), recrystallized from aqueous acetone to give white crystals with a melting point of 198-200 ° C (decomposes).

Example 2 1) To a solution of 28.2 g of the sodium salt of D (-) - phenylglycine in 150 ml of water were added 200 ml of ethyl acetate and 18.2 g of triethylamine, and this mixture was cooled to 0 ° C. To this mixture was added 34.5 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride over 15 minutes, and the mixture was allowed to react for 15 minutes at 5-10 ° C. When the aqueous layer was separated and adjusted to pH 0.5 with 2N hydrochloric acid while cooling with ice, crystals separated. The crystals were collected by filtration and dried to give 42 g of D (-) - Okr (4-methyl-2,3-dioxo-1-piperazino-30-carbonylamino) phenylacetic acid as white crystals, m.p.

140-142 ° C (decomposes).

IR (KBr) cm -1 · 1: Yq_0 17 00.1660 NMR (d 6 -DMSO) δ values: 0.1 (1H, d), 2.65 (5H, s), 4.60 (1H, d) , 35 6.10 (2H, bs), 650 (2H, bs), 7.0 (3H, s).

2) To a suspension of 0.31 g of D (-) - Οζ- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid prepared in the above (1) in 15 ml of anhydrous methylene chloride was stirred 0 , 11 g of N-methylmorpholine 31,65780 to give a solution which was cooled to -20 ° C. When a solution of 0.13 g of ethyl chlorocarbonate in 3 ml of anhydrous methylene chloride was added to this solution, and the mixture was allowed to react at -10 to 20 ° C for 60 minutes, mixed acid anhydride was formed. To this acid anhydride was added dropwise a solution prepared by adding 0.50 ml of triethylamine to a suspension of 0.41 g of 7-amino-3- [2- (5-methyl-λ li-1,3,4-thiadiazolyl) - thiomethyl7-, A ”cephem-4-carboxylic acid in 5 ml of methanol. After dropwise addition, the mixture was allowed to react for 30 minutes at -50 to -30 ° C, 30 minutes at -30 to 20 ° C, 60 minutes at -20 to 0 ° C, and finally 30 minutes at room temperature. The reaction solution was then concentrated under reduced pressure, and the concentrate was dissolved in 10 ml of water, washed with 5 ml of ethyl acetate, 15 ml of ethyl acetate was added, and the pH was adjusted to 1.5 with 2N hydrochloric acid while cooling with ice. After the insoluble matter was filtered off, and the ethyl acetate layer was separated and washed first with water and then with saturated sodium chloride solution, dried over a magnesium sulfate-20 account, and the solvent was removed under reduced pressure to give 0.58 g of 7- / 5 (-) -O (- (4- Methyl 2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-3- [2- (5-methyl-1,3,4-thiadiazolyl) thio-methyl] -A3-cephem-4-carboxylic acid, mp 160 ° C (decomposes), yield 91%.

IR (KBr) cm-1: Vc = 0 1780 (lactam), 1650-1720 (-CON 2, -COOH) NMR (d 6 -DMSO) values: 0.2 (1H, d), 0.6 ( 1H, d), 2.60 (5H, s), 4.35 (1H, g), 4.40 (1H, d), 5.0 (1H, d), 5.70 (2H, g) , 6.10 (2H, bs), 6.25-6.55 (2H, 2H, bs), 7.0 (3H, s), 7.30 (3H, s).

When the above procedure was repeated, substituting the compounds of formula (V) shown in Table 6 for D (-) -? - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid was obtained. the corresponding end products mentioned. The structure of the final products was confirmed by IR and NMR.

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Example 3

Using 0.3 g of D (-) - δ (- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.33 g of 7-amino-3- [5- (1-methyl-1 , 2,3,4-tetrazolyl) thiomethyl-β-Δ 4 -cephem-4-carboxylic acid, and proceeding in the same manner as in Example 2, 0.5 g of 7 - [(D) - - (4-methyl-2 (3-dioxo-1-piperazinocarbonylamino) phenylacetamide (-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid, mp 161- 163 ° C (decomposes), yield 76%.

IR (nujol) cm-1: Vc = 0 1775 (lactam), 1720-1660 (-CONd, -COOK) NMR (d 6 -DMSO) C values: 0.02 (1H, d), 0.34 ( 1H, d), 2.48 (5H, s), 4.17 (1H, q), 4.26 (1H, d), 4.92 (1H, d), 5.66 (2H, s) , 6.01 (5H, s), 6.35 (4H, s), 7.0 (3H, s).

When the above procedure was repeated to replace D (-) - N - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid with the compounds of formula (V) promoted in Table 7, the corresponding the final products listed in Table 7. The structure of the final products was confirmed by IR and NMR.

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Example 4

Using 0.30 g of D (-) - O (- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.34 g of 7-amino-3- [5- (1,3,4 -thiadiazolyl) -thiomethyl) -N3-cephem-5 4-carboxylic acid, and proceeding in the same manner as in Example 2, 0.47 g of 7- (D) - (c) -L- (4-methyl-2,3-dioxo-1 -piperazinocarbonylamino) phenylacetamido [-3- [5- (1,3,4-thiadiazolyl) thiomethyl] -A3-cephem-4-carboxylic acid, mp 158-159 ° C (decomposes), yield 71.5% .

10 IR (nujol) cm -1 q = q 1775 (lactam), 1720-1660 (-CON 2, -COOH)

When the above procedure was repeated, D (-) - <X- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid was replaced by D (-) - ° (- (4-ethyl-2.3 -dioxo-15 1-piperazinocarbonylamino) phenylacetic acid, gave 7- [D (-) - θ (- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [5- (1,3, 4-Thiadiazolyl) -thio-methyl-Δ 3 -cephem-4-carboxylic acid, mp 123 ° C (decomposes), yield 64.5%.

The pH of the product thus obtained was adjusted to 7.0 by neutralization with aqueous sodium hydrogencarbonate solution, filtered and lyophilized to give the sodium salt of the product.

Example 5 Using 0.31 g of D (-) - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid and 0.39 g of 7-amino-3- [2- (1-methyl-1 (3,4-triazolyl) -thiomethyl-β-cephem-4-carboxylic acid, and proceeded in the same manner as in Example 2 except that methanol was replaced with anhydrous methylene chloride to give 0.43 g of 7- (D) - N- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [2- (1-methyl-1,3,4-triazolyl) thiomethyl] -N-cephem-4 carboxylic acid, yield 70%.

IR (nujol) cm-1 1780 (lactam), 1720-1650 35 (-CONC1, -COOH).

37 6 5 7 8 0

When the above procedure was repeated so that D (-) - <3 {- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid was replaced by the compounds of formula (V) listed in Table 8, the corresponding 5 vat, the final products shown in Table 8. The structure of the final products was confirmed by IR and NMR.

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Example 6

Following the same procedure as in Example 2, 7- [D (-) - o - (- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl- (.Alpha.-1,2,3,4-tetrazolyl) -thiomethyl] -Δ-cephem-4-carboxylic acid 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) ) -thiomethyl-N-cephem-4-carboxylic acid and D (-) - N- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino-p-hydroxy-phenylacetic acid.

Melting point (decomposes) 147-149 ° C, yield 62.0%.

10 IR (KBr) cm-1 1765 (lactam), 1720-1660 (-CON2, -C00H).

The pH of the product thus obtained was adjusted to 7.0 by neutralization with aqueous sodium hydrogencarbonate solution, filtered and lyophilized to give the sodium salt of the product.

Example 7 0.57 g of 7- / D (-) - ° (- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido) -3 was suspended in 10 ml of phosphoric acid buffer pH 6.3. acetoxy

O

20 methyl Δ-cephem-4-carboxylic acid, and 0.07 g of sodium hydrogencarbonate was dissolved in this suspension. To the solution thus obtained was dissolved 0.12 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, and the reaction was allowed to proceed in solution for 24 hours, and throughout the reaction, the pH was maintained with dilute hydrochloric acid and sodium hydrogencarbonate. at 6.5-6.7. After completion of the reaction, the reaction solution was cooled and its pH was adjusted to 5.0 with dilute hydrochloric acid. The reaction solution was washed sufficiently with ethyl acetate, after which the aqueous layer was separated, and its pH was adjusted to 1.5 with dilute hydrochloric acid. After the separated crystals were collected by filtration, dried and washed with ethyl acetate, 0.40 g of 7- [D (-) (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [5- (1 -methyl-1,2,3,4-tetrazolyl) thiomethyl-Δ 4 -cefe-35 ml-4-carboxylic acid, m.p. 163-165 ° C (decomposes), yield 74.5%.

40 65780 IR (KBr) cm -1: ν max C 1775 (lactam), 1720-1660 (-CON 2, -COOH) NMR (d 6 -DMSO) values: 0.18 (1H, d), δ , 55 (1H, d), 2.64 (5H, s), δ 4.3 (1H, q), 4.4 (1H, d), 5.0 (1H, d), 5.75 (2H , s), 6.05 (5H, s), 6.3-6.8 (6H), 8.92 (3H, t).

The pH of the product thus obtained was adjusted to 7.0 by neutralization with aqueous sodium hydrogencarbonate solution, filtered and lyophilized to give the sodium salt of the product.

Following the same procedure as above, the final products shown in Table 9 were prepared from 7- (D (-) - oC- (4-methyl-2,3-dioxo-1-piperazinocarbonyl) phenylacetamido] -3- (4-acetoxymethyl) -4-cephem-4-carboxylic acid. or 7- [D (-) - o (- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenyl]

O

acetamido / -3-acetoxymethyl-Δ-cephem-4-carboxylic acid-Posta and the compounds of formula (VII) shown in Table 9. All final products were D (-) isomers, and their structure was confirmed by IR and NMR.

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Example 8 1.15 g of 7- [D (-) - O- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenyl-λ-acetamido] -3-acetoxymethyl-Δ-cephem were suspended in 10 ml of water. -4-carboxylic acid, and 0.17 g of sodium hydrogencarbonate was dissolved in this suspension, followed by the addition of 0.48 g of pyridine and 4.1 g of potassium thiocyanate. The reaction was allowed to proceed in this mixture for 5 hours at 60 ° C, and the pH was maintained at 6.0-6.5 with dilute hydrochloric acid and sodium bicarbonate. After completion of the reaction, the reaction mixture was diluted with 20 ml of water and then washed sufficiently with chloroform. The aqueous layer was separated and adjusted to pH 1.5 with dilute hydrochloric acid. After the separated crystals were collected by filtration, dried and washed with acetone, 1.04 g (yield 79.6%) of 7- [D '(-) - of- (4-ethyl-2,3-dioxo-1-piperazine) were obtained. 3 thiocarbonylamino) phenylacetamido / -3-pyridinomethyl-Δ-cephem-4-carboxylic acid betaine thiocyanic acid salt, m.p. was 155-160 ° C and the chemical formula 20 _ Λ 0 .0 v> 4 »CH- * CH? -N N-CO-NHCHCO0HH - | —r" | KDr) cm: \ / Ct; 0 1780 (l narrowly) 1720 -

1660 (-COMO

^ SCN 2040 30 45 65780

By proceeding in the same manner as above, the thiocyanic acid salt of 7- [D (-) - o (- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-pyridinomethyl-A-cephem-4-carboxylic acid betaine 5 was prepared. 7- [D (-) - o (- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-em-4-carboxylic acid and pyridine, and the chemical formula of the product is 10 0 0 CH3-N N-CONHCHCONH —i — r '^ w (p); 07ν «* 2-ν

υ COOH SCWU

15

Melting point 180-185 ° C (decomposes), yield 82.0%.

Treatment of the two products with an ion exchange resin in the usual manner gave the desired 7- [D (-) - Q4 -20 (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-pyridinomethyl-A-cephem. -4-Carboxylic acid betaine and 7- [D (-) - O- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3-pyridinomethyl-N-cephem-4-carboxylic acid betaine .

Example 9 In 85 ml of anhydrous methanol was dissolved 1.5 g of 7- [D (-) - o (- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [2- (pyridyl-1-oxide) -thiomethyl-N, N-cephem-4-carboxylic acid To the solution thus obtained was added 0.65 g of anhydrous copper (2) chloride, and this mixture was stirred for 15 minutes at room temperature, and then the reaction was allowed to proceed for 14 hours at 50. At the end of the reaction, hydrogen sulfide gas was bubbled through the reaction solution for 20 minutes, and at the same time cooled with ice, the resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of 5% aqueous sodium hydrogencarbonate solution, the insoluble matter was filtered off, and the pH of the filtrate was adjusted to 6.5 with dilute hydrochloric acid, then the filtrate was washed with ethyl acetate (3 x 10 ml), the aqueous layer was separated and adjusted to pH with dilute hydrochloric acid. 1.8 When the separated crystals were collected by filtration, dry was washed under reduced pressure and washed with ethyl acetate-chloroform (1: 1 by volume) to give 0.40 g of 7- [D (-) - oC- (4-10 ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido Β-methoxymethyl-β-cephem-4-carboxylic acid, m.p. 162-166 ° C (decomposes), yield 30.5%.

IR (KBr) cm-1: [.alpha.] D @ 2070 (lactam), 1700 (-COOH), 1666 (-CON

15 (pO

NMR (d 6 -DMSO) C values: 0.13 (1H, d), 0.53 (1H, d), 2.61 (5H, s), 4.31 (1H, q), 4.41 ( 1H, d), 4.96 (1H, d), 582 (2H, s), 6.10 (2H, bs), 6.33 (2H, 2H, 2H, bs), 6.79 (3H, s); ), 8.89 (3 H, t).

Claims (3)

A process for the preparation of novel therapeutically useful cephalosporins of the formula O, O) - (S A-N N-C-NH-CH-CONH-j-S> io * 3 O 3 VC, 1,2R4 (I> COOR1 Wherein R is a hydrogen atom or a salt-forming cation, R 3 is a hydrogen atom or a methyl group, R is a phenyl or a hydroxyphenyl group, A is a C 1-6 alkyl group or a phenyl group and R * is an acetoxy, methoxy -, pyridinium or pyridine-1-oxide-2-ylthio group or an optionally substituted with C1-4 alkyl thiazolylthio, thiadiazolylthio, triazolylthio, oxadiazolylthio or tetrazolylthio group, characterized in that a) formula R 5 is -NH-CH-CONH-1- R3O 4 -mVn ^ Lch2r4 (II) COOR1a wherein R 2 is a hydrogen atom or a group containing silicon or phosphorus, R 2a is a hydrogen atom, a salt-forming cation or a protecting group known in the context of cephalosporins, and R and R are the same as above, reacting with a reactive carboxyl derivative of a compound of formula 65780 w / AN NC-OH (III) R 2 is A and R is the same as above, or b) produces a compound of formula R5-NH-j-j ^ Svi (IV) 0 <J- New ^ CH 2 R 4 COORla 20. Wherein R, R, and R are the same as above, reacting with a compound of formula 0 0 25 AN NC-NH-CH-C-OH (V) Wherein V, R and R are the same as above, or with a reactive carboxyl derivative thereof, or c) a compound of the formula