DE3339667A1 - CEPHALOSPORINE COMPOUNDS FOR ORAL ADMINISTRATION - Google Patents

Abstract

1 There are described cephem compounds of the general formula (I) where R [high] 1 denotes an amino-substituted-thiazolyl group, which optionally bears a halogen atom; R [high] 2 represents a lower alkyl group; R [high] 3 represents a lower alkyl group; and R [high] 4 represents an esterified carboxyl group. Pharmaceutically acceptable salts of the above compounds are also described. When administered orally, the compounds exhibit improved absorbability from the digestive tract.

Description

The invention relates to 7- [2- (2-substituted-amino-thiazol-4-yl-2-alkoxyiminoacetamido] -3-alkylthio-3-cephem-4-carboxylic acid ester derivatives and their pharmaceutically acceptable salts.

More specifically, the invention relates to cephem compounds according to the following general formula (I) (I) where R [high] 1 denotes an amino-substituted thiazolyl group, optionally with a halogen atom; R [high] 2 represents a lower alkyl group; R [high] 3 represents a lower alkyl group; and R [high] 4 represents an esterified carboxyl group; as well as pharmaceutically acceptable salts thereof.

A number of 3-subst .- (or unsubst.) -3-Cephem-4-carboxylic acids have already been prepared, which have a 2-amino-thiazol-4-yl-2-subst. (or unsubst.) - have alkylimino-2-acetamido group. However, these compounds have disadvantages. Although they are active against gram-negative bacteria and against resistant bacteria, their antibiotic effect on gram-positive bacteria is relatively small [see The Journal of Antibiotics, Volume 35, page 585 (1982)].

Like cephem compounds which have an unsubstituted hydrogen atom at the 3-position, these compounds are poorly absorbed from the digestive tract when administered orally. Thus, only injection preparations of these compounds are known. Efforts have therefore been made to improve the absorbability upon oral administration (JA-OS 57-139015).

With regard to the present invention, those processes are mentioned as prior art in which cephem compounds are prepared which have a methylthio group, an aromatic thio group or a heterocyclic thio group in the 3-position, as described, for example, in JA-OS 51-48690; Helvetica Chimica Acta, vol. 58, p. 2437 and p. 2450 (1975); the JA-OS 51-82292 and the JA-ASs 53-119888, 57-145883 and 53-103493 are described. These include compounds which, like the compounds according to the invention, have side chains in the 3- and 7-position of the cephalosporin. These are 4-carboxylic acid compounds with a combination of 2-amino-thiazol-4-yl-2-methoxyimino-2-acetamido groups in the 7-position and methylthio groups in the 3-position (JA-OS 53-119888).

Although the cited document describes the use of a lower alkylthio group as a substituent at the 3-position, neither experimental examples nor physical properties of compounds having C [deep] 2 or a larger number of carbon atoms are described. This is partly attributed to the fact that it is not until a process disclosed in our copending Japanese patent application 56-135759 is available a process for the preparation of a compound having an alkylthio group having 2 or more carbon atoms which is useful from the viewpoint of yield.

On the other hand, the methoxyimino group is primarily used as the alkyloxyimino group. Recently, there have also been proposed: the ethyloxyimino group (JA-OS 57-59894, where a methoxymethyl group is used in the 3-position); the carboxypropyloxyimino group (JA-OSen 53-119887 and 55-89289) and the carboxymethylimino group (ditto). Accordingly, cephem compounds which have any combination of alkylthio groups with 2 or more carbon atoms in the 3-position and alkyloxyimino groups on the side chain of the 7-position, with the exception of the case that both alkyl units each represent a methyl group represent new compounds. In addition, the esterified cephem compounds, which have improved absorbability when administered orally, are clearly new.

In order to overcome the drawbacks of the prior art, the inventors conducted extensive studies. A large number of compounds were prepared which have 2-amino-thiazol-4-yl-2-alkyloxyimino-2-acetamides on the side chain of the 7-position, with a change in the number of carbon atoms in the alkyl group of the alkyloxyimino group 3-cephem compounds as well as the type of substituent at the 3-position. Various 4-carboxylic acid ester derivatives were also prepared. The compounds obtained were evaluated in a microorganism test. As a result, it was found that compounds having a combination of an alkylthio group at the 3-position and an alkyl chain of the alkyloxyimino group at the side chain at the 7-position are excellent in activity.

The object of the present invention is thus to provide cephem compounds of the above-mentioned formula (I) and pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the present invention are given below.

1. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

2. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

3. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

4. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

5. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

6. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

7. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

8. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

9. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

10. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

11. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

12. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

13. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

14. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

15. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

16. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid phthalidyl ester

17. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid phthalidyl ester

18. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

19. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid pivaloyloxyethyl ester

20. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

21. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

22. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

23. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

24. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid phthalidyl ester

25. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

26. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

27. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

28. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid phthalidyl ester

29. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxoles -4-yl) methyl ester

30. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester

31. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester

32. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid phthalidyl ester

33. 1- (ethoxycarbonyloxy) ethyl 7- [2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid

34. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

35. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

36. 7- [2- (2-Amino-thiazol-4-yl) -2-propoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

37. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylic acid (2-oxo-1,3-dioxolen-4-yl ) methyl ester

38. 7- [2- (2-Amino-thiazol-4-yl) -2-ethoxyiminoacetamido] -3-propylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

The preparation of these compounds according to the invention is described below.

A first manufacturing process comprises the following process steps. A starting compound according to the following general formula (II), which was obtained by a method described by the inventors (JA-PA 56-135759) (II)

where A is an aryl group; R [high] 3 stands for a lower alkyl group and R [high] 4 'has the meaning given above for R [high] 4 or stands for a protected carboxyl group, was subjected to a deacylation reaction of the cephem nucleus at the 7-position, namely after a any known method, for example the iminohalide or iminoether method. In this way, a 7-amino-cephem compound of the following general formula (III) or a salt thereof is obtained: (III)

wherein R [high] 3 and R [high] 4 'are as defined above.

The compound obtained is then acylated in a conventional manner with a known compound of the following general formula (IV) or a derivative thereof which has a reactive substituent in the carboxyl group: (IV)

where B is a hydrogen atom or an amino protecting group, X is a halogen atom or a hydrogen atom and R [high] 2 is as defined above. An amido bond is formed in the process. In order to obtain a compound of the formula (I) of the present invention, the 7-position substituent or the protective group is optionally removed.

A second method is as follows: A compound represented by the following general formula (V) or a reactive derivative thereof (V) where R [high] 2, R [high] 3 and B are as defined above, with a compound of the general formula (VI), (VII) or (VIII) (VI)

wherein Ra represents a hydrogen atom or a lower alkyl group, Rb represents a lower alkyl group or a lower alkoxy group, and X represents a halogen atom; (VII)

wherein X represents a halogen atom and Rc represents a hydrogen atom, a lower alkyl group or an unsubstituted or substituted phenyl group; or (VIII)

wherein X represents a halogen atom and Rd represents a hydrogen atom or a lower alkyl group; implemented. A compound of the general formula (I) is obtained. The above reaction is known per se. One can use a procedure similar to that used for ordinary esterification reactions. Protecting groups can then be removed by any known method to obtain the desired compound.

The compound of the general formula (V) is obtained, for example, by preparing a compound which by

Reaction of compounds of general formulas (III) and (IV) and whose carboxyl group is protected at the 4-position of the cephem nucleus, is reacted in a known manner, that is, a reaction for removing a protective group of the carboxylic acid group of the small beta-lactam compound subject.

The substituents and protective groups for the compounds of the general formulas (I) to (VIII) are explained in more detail below. The term "lower alkoxy and lower alkyl groups" denotes, unless otherwise stated, alkoxy or alkyl groups having 1 to 4 carbon atoms, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and methyl, ethyl, propyl, isopropyl, butyl, respectively.

The term "esterified carboxyl group" represented by R [high] 4 in the formula means a group which is useful in improving absorbability upon oral administration of the cephem compound and in which in vivo hydrolysis of the esterified moiety advantageously occurs after oral administration developing high antibacterial activity. Compounds capable of forming esters with the carboxylic acid group include, for example, the compounds represented by the general formulas (VI), (VII) and (VIII).

Typical examples of the aryl group represented by A include phenyl and phenoxy groups, and further may include a group which is commonly used as a substituent at the 7-position of the small beta-lactam compound.

The amino protective group represented by B can be any group which can optionally be converted back into an amino group. Groups which are widely used for this purpose are, for example, 2,2,2-trichloroethoxycarbonyl group, 2-methylsulfonylethyloxycarbonyl group, t-butoxycarbonyl group, chloroacetyl group and trityl group.

The protective group for the carboxyl group represented by R [high] 4 'is a group which is generally used in reactions of small beta-lactam compounds and includes, for example, diphenylmethyl group, p-nitrobenzyl group, trichloroethyl group, p-methoxybenzyl group or the like

Pharmaceutically acceptable salts of the compounds of formula (I) according to the present invention include acid addition salts. All salts that are commonly used in the known small beta-lactam compounds can be used, for example salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts with organic acids such as maleic acid, acetic acid, citric acid, malic acid, malonic acid, lactic acid, methanesulfonic acid and the like.

The aimed compounds (I) and the starting materials (IV) and (V) according to the present invention may exist in two tautomeric forms according to the following formulas: n

In the present specification, these compounds are represented by the thiazole type formula. In addition, the compounds occur as syn and anti isomers and mixtures thereof. The syn isomer has a partial structure according to the following formula where R [high] 2, X and B are as defined above.

The anti isomer is a geometric isomer having a partial structure according to the following formula where R [high] 2, X and B are as defined above.

The compounds of formula (I) obtained in the manner described above and their salts are novel compounds. Their absorbability upon oral administration is 4 to 5 times that of compounds of the type having a free carboxyl group in the 4-position.

In a test for curing an infectious disease, the following results were obtained.

Test procedure

Groups of ICR-JCL mice (4 weeks old, weight 20 ± 0.5 g), each group consisting of 10 mice, were used as test animals. The strain used for the infection is Escherichia coli No. 29 fungi. This strain was precultured in Heart infusion agar at 37 ° C. for 20 hours. Then it was suspended in a physiological saline solution and mixed with mucin at a concentration of 2.5%. The suspension was injected intraperitoneally into the mouse. Immediately after infection with the strain, the drug samples were administered orally in various concentrations. 7 days after the administration, the number of surviving mice is determined and an ED [low] 50 value is calculated using the Litchfield-Wilcoxon method. The results obtained are shown in Table 1.

Table 1

Results of the test of cure for an infectious disease (oral administration)

Compound ED [low] 50 value (mg / mouse)

Products according to the invention

Compound of Ex. 8 0.0234

Compound of Ex. 9 0.0216

Comparison products

non-esterified prod. d. Ex 8 0.094

non-esterified prod. d. Ex. 9 0.095

Cephloxadine 0.24

pathogenic bacteria (Escherichia coli No. 29)

From the above results it is clear that the compounds of the present invention can be extracted from the digestive tract are absorbed much more easily than the free acid compounds, considering the molecular weight.

The esters obtained according to the invention can be used for curing infectious diseases which are triggered by gram-positive and gram-negative bacteria, including resistant bacteria. For this purpose, the compounds can be administered in the form of capsules, dry syrup or suppositories, both as a free amino acid and as a salt thereof. In the case of these esters, the dose is 2 to 4 dose units / day, each dose unit comprising 200 to 1000 mg / dose.

The invention is explained in more detail below with the aid of examples, without the invention being intended to restrict the invention by the examples.

example 1 n

7-Amino-3-methylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl hydrochloride (small alpha form):

481 mg (0.001 mol) of 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester (small alpha form) (melting point 157 to 158 ° C.) are dissolved in 20 ml of methylene chloride, and 0.40 ml of pyridine is added and then cools to -20 ° C. 440 mg of phosphorus pentachloride are added to the mixture. The mixture is gradually heated with stirring and reacted at a temperature of +5 to +10 ° C for about 90 minutes (the reaction is continued for 30 minutes after the disappearance of phosphorus pentachloride). The reaction solution is cooled to -30 ° C. and 5 ml of a methylene chloride solution of 2.0 ml of isobutanol are added dropwise with stirring. The mixture is then gradually heated for reaction at a temperature of +5 to +10 ° C. for 2 hours (the course of the reaction is followed by thin layer chromatography (TLC)). After completion of the reaction, the reaction system is cooled to 0 ° C. and poured into 5 ml of cold water containing 2 ml of brine with stirring. Stirring is then continued for about 60 minutes while cooling with ice, and 10 ml of diisopropyl ether and 10 ml of ethyl ether are added. After a short time, the amount of white crystals increased. The crystals were collected, washed with diisopropyl ether and then with ether and dried; Yield 360 mg; M.p. 148-150 ° C (dec.).

UV small lambda [deep] max: 321 nm (95% ethanol)

IR (Nujol): 1781, 1762, 1700 cm [high] -1.

Example 2

7-Amino-3-ethylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester hydrochloride:

990 mg (0.002 mol) of 7-phenylacetamido-3-ethylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester (melting point 130 ° to 131 ° C.) are used and treated in the same way as in Example 1. 750 mg (90.8%) of the desired compound are obtained; M.p. 188-190 ° C (dec.).

UV small lambda [deep] max: 320 nm (95% ethanol)

IR (Nujol): 1780, 1763, 1710 cm [high] -1.

Examples 3 to 7

In the same way as in Example 1, the compounds listed in Table 2 are prepared.

Table 2

Example 8

7- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-methylthio-3-cephem-4-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester:

399 mg (1 mmol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl hydrochloride (compound of Example 1) are dissolved in a small amount of water and ethyl acetate is added while cooling with ice. An aqueous NaHCO [deep] 3 solution is added to the mixture in order to make it weakly alkaline. An aqueous NaCl solution is then added to the mixture and it is extracted several times. The ethyl acetate extracts are combined and dried, and the solvent is distilled off under reduced pressure. The residue is then dissolved in CH [deep] 2Cl [deep] 2.

On the other hand, 139 mg of phosgene dimer, which has been cooled to -10 ° C., are added to 10 ml of CH [deep] 2Cl [deep] 2 containing 117 mg of dimethylformamide. The mixture is then gradually heated to +10 ° C while stirring. After 30 min the mixture is cooled to -30 ° C. To this cooled solution, a solution containing 361 mg of 2-chloroacetamido-thiazol-2-methoxyimino-2-acetic acid and 132 mg of triethylamine is added, and the whole is reacted at a temperature of -30 to -20 ° C. for 30 minutes. The resulting solution is treated with the amino-carboxylic acid ester solution with stirring and reacted for 60 min at a temperature of -20 to -10 ° C. Ice-cold water is then added to the reaction mixture, the pH is adjusted to 1.5 and the amino products are removed in this way. The organic phase is washed with water and adjusted to pH 6.8 using an aqueous NaHCO [deep] 3 solution. The acidic components are removed from the organic phase and the residue is dried. The solvent is distilled off under reduced pressure and the resulting residue is purified using a silica gel column (benzene + ethyl acetate). 340 mg of 7- (2-chloroacetaminothiazole-2-methoxyimino-2-acetamido) -3-methylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester are obtained; Mp 127-129 ° C.

312 mg of the chloroacetylamide product obtained are dissolved in 2 ml of dimethylacetamide and then mixed with 46 mg of thiourea while cooling with ice and reacted for about 2 to 3 hours, the course of the reaction being followed by TLC. Ice-water and ethyl acetate are added to the reaction solution, the pH is adjusted to 7.0 using NaHCO [deep] 3 and extracted several times. The organic phase is dried and then the solvent is removed by distillation under reduced pressure. The resulting residue is treated with n-hexane, whereupon it solidifies.

The product is purified using silica gel column chromatography (ethyl acetate: benzene = 2: 1). 180 mg of the abovementioned compound are obtained.

Example 11

Small alpha-ethoxycarbonyloxyethyl-7- [2- (2-tritylaminothiazol-4-yl) -2-ethoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylate:

(1) 0.031 ml of DMF is dissolved in 2 ml of methylene chloride, cooled to -10 ° C., then 0.03 g of Cl [deep] 3CCOCl is added dropwise and the mixture is stirred at 0 ° C. for 15 min. The mixture is then cooled to -30 ° C. and 5 ml of a methylene chloride solution containing 0.1 g of (2-tritylaminothiazol-4-yl) -2-ethoxyiminoacetic acid and 0.032 ml of triethylamine are added dropwise. The mixture is stirred for 30 minutes at the same temperature. Separately, 0.0825 g of small alpha-ethoxycarbonyloxyethyl-7-amino-3-ethylthio-3-cephem-4-carboxylate.hydrochloride is adjusted to pH 7.5 using sodium bicarbonate.

The methylene chloride solution of ethoxycarbonyloxyethyl 7-amino-3-ethylthio-3-cephem-4-carboxylate is then added dropwise to the mixture. After 30 minutes of reaction, the solution is poured into a cold, aqueous sodium bicarbonate solution. An organic phase is collected and washed with saturated brine, then dried over magnesium sulfate and the solvent removed by distillation under reduced pressure. The resulting residue is treated by chromatography, whereby 0.12 g of crystalline powder of the above-identified compound is obtained; Mp. 118 to 120 ° C (decomposition with foaming).

Small alpha-ethoxycarbonyloxyethyl-7- [2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamido] -3-ethylthio-3-cephem-4-carboxylate:

(2) Treating 0.1 g of the compound obtained in step (1) with anisole and trifluoroacetic acid while cooling with ice, and then adjusting to pH 7.5 using aqueous sodium bicarbonate. The solution is then extracted with ethyl acetate and dried over magnesium sulfate, followed by distilling off the solvent and solidifying with isopropyl ether. A crystalline powder of the abovementioned compound is obtained in almost quantitative yield; Mp 110-112 ° C (dec.).

Example 16

7- (2-Amino-thiazol-4-yl-2-methoxyimino-2-acetamido) -3-methylthio-3-cephem-4-carboxylic acid- (5-methyl-2-oxo-1,3-dioxolen-4 -yl) methyl ester (syn isomer):

415 mg of 7- (2-amino-thiazol-4-yl) -2-methoxyimino-2-acetamido) -3-methylthio-3-cephem-4-carboxylic acid and 93 mg of sodium bicarbonate become a small amount to form a transparent solution Given water. The solution is concentrated under reduced pressure and evaporated to dryness. The residue is with

Ethyl ether mixed and solidified. The resulting solid is dried under reduced pressure. To dissolve it, 5 ml of dimethylformamide are added to the sodium salt and a further 232 mg of (5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide. The mixture is stirred at room temperature for about 30 to 40 min When TLC confirmed that the reaction was complete, 30 ml of water was added to the reaction solution to thereby precipitate solids, the precipitate was collected, washed with water, dissolved in ethyl acetate and adjusted to pH 7 using an aqueous sodium bicarbonate solution , 5. The resulting organic phase is separated, washed with brine and dried over magnesium sulfate, the solvent is concentrated under reduced pressure and the resulting residue is treated with diisopropyl ether to give 460 mg of the crude product. The product is purified by silica gel chromatography; receives 340 mg of the compound given above.

Example 17

7- (2-Amino-thiazol-4-yl-2-methoxyimino-2-acetamido) -3-methylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer):

A sodium salt derived from 208 mg of 7- (2-amino-thiazol-4-yl-2-methoxyimino-2-acetamido) -3-methylthio-3-cephem-4-carboxylic acid and 47 mg of NaHCO [deep] 3 is used in 5 ml of dimethyl sulfoxide dissolved to form a solution. 117 mg of pivaloyloxymethyl bromide are added to the solution at room temperature and the reaction is then monitored by TLC. When the reaction has ended (after about 60 to 80 minutes), 30 ml of water are added in order to precipitate solid materials. The precipitate is collected, washed with water, dissolved in 30 ml of ethyl acetate, washed with brine containing a small amount of sodium bicarbonate, and the organic phase is dried. The ethyl acetate solution is subjected to distillation under reduced pressure and treated with diisopropyl ether to solidify. This gives 220 mg of crude product. The product is purified by silica gel chromatography (benzene: ethyl acetate = 1: 2); 140 mg of the abovementioned compound are obtained.

Examples 9-20

In the same manner as in Examples 8, 11, 16 and 17, the compounds and intermediates shown in Tables 3 and 4 are obtained. The compounds obtained in Examples 8, 11, 16 and 17 are also listed in the tables.

Table 3

Tabel

Table 4

Tabel

Reference example 1

7-Phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid:

(1) The 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (melting point 169 to 170 ° C.) is treated with anisole and trifluoroacetic acid while cooling with ice, then the trifluoroacetic acid is distilled off under reduced pressure and the solidified resulting residue with ether. The solid product is dissolved in ethyl acetate, the pH of the solution is adjusted to 7.5 using aqueous NaHCO [deep] 3 solution, the aqueous phase is separated and its pH is adjusted to 2.0 using 20% hydrochloric acid 2.5 had been set, then add NaCl and collect the organic phase. The organic phase is washed with aqueous NaCl solution and dried. The solvent is distilled off and the residue is treated with diisopropyl ether; the large delta [high] 3-carboxylic acid given above is obtained in a yield of about 90%; M.p. 192 to 193 ° C (dec.).

UV small lambda [deep] max: 302 nm (95% ethanol)

IR (Nujol): 1767, 1690, 1642 cm [high] -1.

7-Phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester:

(2) 93 mg of NaHCO [deep] 3 and 1 ml of water are dissolved in 376 mg of the 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid obtained in step (1) and the resulting mixture is evaporated to dryness. The residue obtained is washed with ethyl ether to give a powder. 3 ml of dimethyl sulfoxide are added to this powder to dissolve it. 205 mg of pivaloyloxymethyl bromide are then added to the solution and the mixture is then stirred. The implementation is followed by TLC. After 10 to 20 minutes, 30 ml of ice-water are added and the mixture is then extracted with ethyl acetate. The ethyl acetate phases are combined and aqueous NaCl solution is added. After adjusting the pH to 7.5, the organic phase is collected and dried, after which the solvent is distilled off. The resulting residue is treated first with n-hexane and then with diisopropyl ether to solidify. 440 mg of crude product of the abovementioned ester are obtained. The product is purified by silica gel chromatography (benzene + ethyl acetate); Yield 360 mg; Mp 122-123 ° C.

UV (in ethanol): 324 nm

NMR (CDCl [deep] 3) small delta: 1.17 (9H, s), 2.31 (3H, s), 3.5 (2H, s), 3.58 (2H, s), 4.91 ( 1H, d, J = 5Hz), 5.55-5.97 (3H, m), 6.48 (1H, d, J = 9Hz), 7.28 (5H, s).

Reference Examples 2 to 9

In the same manner as in Referential Example 1, compounds shown in Table 5 are obtained.

Table 5

Claims (3)

1. Cephem compound represented by the following general formula where R [high] 1 represents an amino-substituted thiazolyl group which may or may not have a halogen atom; R [high] 2 represents a lower alkyl group; R [high] 3 represents a lower alkyl group; and R [high] 4 represents an esterified carboxyl group; or pharmaceutically acceptable salts thereof. 2. A syn isomer of the compound of claim 1. 3. Compound and pharmaceutically acceptable salts thereof according to claim 1, characterized in that in the formula R [high] 1 denotes a 2-aminothiazol-4-yl group, R [high] 2 denotes a lower alkyl group, R [high] 3 represents a lower alkyl group and R [high] 4 represents an esterified carboxyl group.