GB2131799A

GB2131799A - Cephalosporin compounds

Info

Publication number: GB2131799A
Application number: GB08329387A
Authority: GB
Inventors: Toshiyasu Ishimaru; Kenji Sakagami; Hajime Nitta
Original assignee: Meiji Seika Kaisha Ltd
Current assignee: Meiji Seika Kaisha Ltd
Priority date: 1982-11-05
Filing date: 1983-11-03
Publication date: 1984-06-27
Also published as: GB2131799B; DE3339667A1; GB8329387D0; JPS5984890A

Abstract

Cephem compounds represented by the general formula (I), <IMAGE> in which R<1> represents an amino- substituted thiazolyl group with or without a halogen atom, R<2> represents a lower alkyl group, R<3> represents a lower alkyl group, and R<4> represents an esterified carboxyl group and pharmaceutically acceptable salts thereof show improved absorptivity from digestive organs when orally administered. Compounds of formulae <IMAGE> where R1 is lower alkyl and R2 completes an ester group, are disclosed.

Description

SPECIFICATION Cephalosporin compounds for oral administration i) Field of the invention: This invention relates to 7-[2-(2-substituted amino-thiazole-4-yl-2-alkyloxyiminoacetamido]-3alkylthio-3-cephem-4-carboxylic acid ester derivatives and pharmaceutically acceptable salts thereof.

More specifically, it relates to cephem compounds represented by the following general formula (1),

in which R1 represents an amino-substituted thiazolyl group with or without a halogen atom, R2 represents a lower alkyl group, R3 represents a lower alkyl group, and R4 represents an esterified carboxyl group, and pharmaceutically acceptable salts thereof.

ii) Description of the prior art: As is well known in the art, a number of 3-substituted (or unsubstituted) 3-cephem-4-carboxylic acids having at a side chain of the 7 position a 2-amino-thiazole-4-yl-2-substituted (or unsubstituted) alkylimino-2-acetamido group have already been prepared. However, these compounds have the drawback that they are active against gram-negative bacteria and are effective against resistant bacteria, but their antibiotic action on gram-positive bacteria is rather poor (see The Journal of Antibiotics Vol. 35, page 585, (1982).

With cephem compounds having an unsubstituted hydrogen atem at the 3 position, they are poor in absorptivity from digestive organs when orally administered, and thus only injections of these compounds are known. Accordingly, efforts have been made to improve the absorptivity by oral administration (Japanese Laid-open Application No. 57--139015).

Mentioned as the prior art of the present invention are processes of preparing cephem compounds having a methylthio group, an aromatic thio group or a heterocyclic thio group at the 3 position such as described in Japanese Laid-open Application No. 53--48690 (Ciba Geigy A.G.), Hellveticha Chimica Acta Vol. 58, p. 2437 and P. 2450 (1 975), Japanese Laid-open Application No. 51-82292, and Japanese Laid-Application Nos. 53-119888, 53-103493 and 57-145883 (Roussel-UCLAF).Of these, compounds which have side chains at the 3 and 7 positions of cephalosporin similar to the compounds of the invention are 4-carboxylic acid compounds having a combination of 2-aminothiazole-4-yl-2-methoxyimino-2-acetamido group at the 7 position and methylthio group at the 3 position as disclosed in Japanese Laid-open Application No. 53-11 9888.

In this application, however, there is described use of a lower alkylthio group as a substituent at the 3 position but neither experimental examples nor physical properties of compounds having C2 or a larger number of carbon atoms are described. This is considered partly due to the fact that a compound having a methylthio group of C, or larger carbon atoms has been advantageously effected from the viewpoint of yield by a process of our copending Japanese Patent Application No. 56-135759.

On the other hand, as for the alkyloxyimino group, methoxyimino group is predominantly used. In recent years, there are proposed ethyloxyimino group (Japanese Laid-open Application No. 57-59894 in which a methoxymethyl group is used at the 3 position), carboxypropyloxyimino group (Japanese Laid-open Application No. 53-119887 and Japanese Laid-open Application No. 55-89289 (Glaxo)), and carboxymethylimino group (ditto). Accordingly, cephem compounds comprising any combinations of alkylthio groups having C2 or larger carbon atoms at the 3 position and alkyloxyimino groups at the side chain of the 7 position except that both alkyl moieties are, respectively,-a methyl group are believed to be novel compounds.In addition, esterified cephem compounds which are improved in absorptivity upon oral administration are certainly novel.

SUMMARY OF THE INVENTION In order to overcome the drawbacks of the prior art, we have made extensive studies in which there were prepared a great number of compound having at the side chain of the 7 position 2-aminothiazole-4-yl-2-alkyloxyimino-2-acetamides while changing the number of carbon atoms in the alkyl group of the alkyloxyimino group of the 3-cephem compounds and the type of substituent at the 3 position along with 4-carboxylic acid ester derivatives. These compounds were evaluated by 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 of the 7 position showed excellent efficacy.

Accordingly, an object of the invention is to provide cephem compounds of the afore-indicated formula (I) and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Specific examples of the compounds according to the invention are mentioned below.

1.7-[2-(2-amino-thiazole-4-yl)-2-methoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylic acid-(5-methyl-2-oxo- 1 ,3-dioxolene-4-yl)methyl ester.

2. 7-[2-(2-amino-thiazole-4-yl)-2-methoxyi minoacetamido]-3-methylthio-3-cephem-4-ca rboxylic acid pivaloyloxymethyl ester.

3.7-[2-(2-a mino-thiazole-4-yl)-2-methoxyiminoaceta mido]-3-methylthio-3-cephem-4-carboxylic acid-2-(ethoxycarbonyloxy)ethyl ester.

4.7-[2-(2-amino-thiazole-4-yl)-2-methoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylic acid-(2-oxo- 1 ,3-dioxolene-4-yl)methyl ester.

5. 7-[2-(2-amino-thiazole-4-yl)-2 -ethoxyiminoaceta mido]-3-ethylthio-3-cephem-4-carboxylic acid privaloxymethyl ester.

6.7-[2-(2-amino-thiazole-4-yl)-2-ethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid-1-(ethoxycarbonyloxy)ethyl ester.

7. 7-[2-(2-a mino-thiazole-4-yl) -2-ethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid-(5-methyl-2-oxo- 1 ,3-dioxolene-4-yl)-methylester.

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

9.7-[2-(2-a mino-thiazole-4-yl)-2-methoxyiminoaceta mido] -3-ethylthio-3-cephem-4-carboxylic acid-(5-methyl -2-oxo-1 ,3-dioxolene-4-yl)-methyl ester.

10. 7-[2-(2-a mino-thiazole-4-yl)-2-methoxyiminoacetamido] -3-ethylthio-3-cephem-4- carboxylic acid-(2-oxo- 1 ,3-dioxolene-4-yl)-methylester.

11. 7-[2-(2-a mino-thiazole-4-yl)-2-methoxyiminoacetamido] -3-ethylthio-3-cephem-4- carboxylic acid pivaloyloxymethyl ester.

12. 7-[2-(2-a mino-thiazole-4-yl) -2-ethoxyimi noacetamido]-3-methylthio-3-cephem-4- carboxylic acid piva loyloxymethyl ester.

13. 7-[2-(2-a mino-th iazole-4-yl)-2-ethoxyiminoacetamido]-3-methylthio-3-cephem-4- carboxylic acid-(5-methyl-2-oxo- 1 ,3-dioxolene-4-yl)methyl ester.

14.7-[2-(2-amino-thiazole-4-yl)-2-ethoxyiminoacetamido]-3-methylthio-3-cephem-4carboxylic acid-(2-oxo- 1 ,3-dioxolene-4-yl) methyl ester.

1 5. 7-[2-(2-a mino-thiazole-4-yl) -2-ethoxyiminoacetamido]-3-methylthio-3-cephem-4- carboxylic acid- 1 -(ethoxywarbonyloxy)ethyl ester.

16.7-[2-(2-amino-thiazole-4-yl)-2-ethoxyiminoacetamido]-3-methylthio-3-cephem-4carboxylic acid phthalidyl ester.

17.7-[2-(2-amino-thiazole-4-yl)-2-methoxyiminoacetamido]-3-propylthio-3-cephem-4 carboxylic acid phthalidyl ester.

1 8. 7-[2-(2-amino-thiazole-4-yl)-2-methoxyim carboxylic acid-(5-methyl-2-oxo- 1,3-dioxolene-4-yl) methyl ester.

19.7-[2-(2-amino-thiazole-4-yl)-2-methoxyiminoacetamido]-3-propylthio-3-cephem-4 carboxylic acid pivaloyloxyethyl ester.

20. 7-[2-(2-a mino-thiazole-4-yl) -2-ethoxyiminoacetamido]-3-propylthio-3-cephem-4 carboxyl ic acid- 1 -(ethoxyca rbonyloxy)ethyl ester.

21.7-[2-(2-amino-thiazole-4-yl)-2-ethoxyiminoacetamido]-3-propylthio-3-cephem-4 carboxylic acid-(5-methyl-2-oxo- 1,3-dioxolene-4-yl) methyl ester.

22. 7-[2-(2-a mino-th iazole-4-yl) -2-ethoxyiminoacetamido]-3-propylthio-3-cephem-4 ca rboxylic acid-(2-oxo- 1 ,3-dioxolene-4-yl)methyl ester.

23. 7-[2-(2-a mino-thiazole-4-yl) -2-ethoxyiminoaceta mido]-3-propylthio-3-cephem-4 carboxylic acid piva loyloxymethyl ester.

24.7-[2-(2-amino-thiazole-4-yl)-2-ethoxyiminoacetamido]-3-propylthio-3-cephem-4 carboxylic acid phthalidyl ester.

25.7-[2-(2-amino-thiazole-4-yl)-2-propoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid- 1 -(ethoxycarbonyloxy)ethyl ester.

26.7-[2-(2-amino-thiazole-4-yl)-2-propoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

27. 7-[2-(2-a mino-thiazole-4-yl)-2-propoxyiminoaceta mido]acid-(5-methyl-2-oxo- 1 ,3-dioxolene- 4-yl)methyl ester.

28.7-[2-(2-amino-thiazole-4-yl)-2-propoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid phthalidyl ester.

29.7-[2-(2-amino-thiazole-4-yl)-2-propoxyiminoacetamido]-3-methylthio-3-cephem-4 ca rboxylic acid-5-methyl-2-oxo- 1 ,3-dioxolene-4-yl) methyl ester.

30.7-[2-(2-amino-thiazole-4-yl)-2-propoxyiminoacetamido]-3-methylthio-3-cephem-4 ca rboxylic acid- 1 -(ethoxycarbonyloxy)ethyl ester.

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

32.7-[2-(2-a mino-thiazole-4-yl)-2-propoxyiminoaceta mido]-3-methylthio-3-cephem-4- carboxylic acid phthalidyl ester.

33. 7-[2-(2-a mino-thiazole-4-yl)-2-methoxyiminoaceta mido]-3-propylthio-3-cephem-4- carboxylic acid- 1 -(ethoxyca rbonyloxy)ethyl ester.

34. 7-[2-(2-amino-thiazole-4-yI)-2-methoxyiminoacetamidoj-3-propylthio-3-cephem-4- carboxylic acid-(2-oxo-1,3-dioxolene-4-yl)methyl ester.

35. 7-[2-(2-a mino-thiazole-4-yl)-2-propoxyiminoacetamido]-3-methylthio-3-cephem-4- ca rboxylic acid-(2-oxo- 1 ,3-dioxolene-4-yI) methyl ester.

36. 7-[2-(2-a mino-thiazole-4-yl)-2-propoxyi minoacetamido]-3-ethylthio-3-cephe m-4-carboxylic acid-2-oxo-l ,3-dioxolene-4-yl)methyl ester.

37. 7-[2-(2-a mino-thiazole-4-yl)-2-ethoxyi minoaceta mido]-3-ethylthio-3-cephem-4-carboxylic acid-(2-oxo- 1 ,3-dioxolene-4-yl)methyl ester.

38. 7-[2-(2-amino-thiazole-4-yI)-2-ethoxyiminoacetamido]-3-propylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

Preparation of these compounds of the present invention is described.

A first method comprises the steps of subjecting a starting compound represented by the following general formula (II) which is obtained by our method (see Japanese Patent Application No.

56-135759)

(in which A represents an aryl group, R3 represents a lower alkyl group, and R4' has the same meaning as R4 defined before or a protected carboxyl group), to deacylation reaction of the cephem nucleus at the 7 position by any known technique such as, for example, the iminohalide or imino ether method, thereby obtaining a 7-amino-cephem compound of the following general formula (III) or a salt thereof

(in which R3 and R4' have the same meanings as defined above, respectively.

The thus obtained compound is subsequently acylated, by a usual manner, with a known compound represented by the following general formula (IV) or a derivative thereof which has a reactive substituent in the carboxyl group thereof

(in which B represents a hydrogen atom or an amino-protecting group, X represents a halogen atom or a hydrogen atom, and R2 has the same meaning as defined before), thereby forming an amido bond. If desired, the 7 position-substituent or protecting group is removed to obtain a compound of the formula (I) of the present invention.

A second method is as follows: a compound of the following general formula (V) or a reactive derivative thereof

(in which R2, R3, and B have the same meanings as defined before, respectively) is reacted with a compound of the general formula (VI), (VII) or (VIII)

(in which 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),

(in which X represents a halogen atom, and Rc represents a hydrogen atom, a lower alkyl group or an unsubstituted or substituted phenyl group), or

(in which X represents a halogen atom, and Rd represents a hydrogen atom or a lower alkyl group), thereby obtaining a compound of the general formula (I).The above reaction is known per se and a procedure used for ordinary esterification reactions can be used, after which protecting groups can be removed by any known method, thereby obtaining an intended compound.

The compound of the general formula (V) is obtained, for example, by subjecting a compound, which is obtained by reaction between the compounds of the general formulas (III) and (IV) and whose carboxyl group at the 4 position of the cephem nucleus is protected, to a known method, i.e. a reaction of removing a protecting group for the carboxylic acid of the beta-lactam compound.

The substituents and protecting groups for the compounds of the general formulas (I) to (VIII) will now be described. The term "lower alkoxy and lower alkyl groups" used herein is intended to mean alkoxy and alkyl groups having 1 to 4 carbon atoms, respectively, unless otherwise indicated.

The term "esterified carbonyl group" represented by R4 means a group which is useful in improving the absorptivity by oral administration of cephem compound and which has an advantage of undergoing hydrolysis in vivo in the esterified moiety after oral absorption, developing high antibacterial activity. Compounds capabie of forming esters with the carboxylic acid include, for example, those represented by the general formulas (Vl), (VII) and (VIII).

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

The amino-protecting group represented by B may be any group which can be re-converted into an amino group, if desired. For the above purpose, there are widely used, for example, 2,2,2- trichloroethoxycarbonyl group, 2-methylsulfonylethyloxycarbonyl group, t-butoxycarbonyl group, chloroacetyl group, and trityl group.

The protecting group for the carboxyl group represented by R4' is a group which is usually employed for reaction of beta-lactam compound and includes, for example, diphenylmethyl group, pnitrobenzyl group, trichloroethyl group, p-methoxybenzyl group, or the like.

Pharmaceutically acceptable salts of the general formula (I) according to the invention include acid addition salts. Salts ordinarily employed in existing beta-lactam compounds may also be used including.

for example, inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, and organic acid salts such as maleic acid, acetic acid, citric acid, malonic acid, malic acid, lactic acid, methanesulfonic acid and the like.

The intended compounds (I) and starting materials (IV) and (V) of the invention may take two tautomeric forms as shown by the following formulas

Here, these compounds are indicated by the thiazole type. Moreover, the compounds involve syn and anti isomers and mixtures thereof. The syn isomer has a partial structure represented by the following formula

(in which R2, X and B have the same meanings as defined before, respectively).

The anti isomer means a geometrical isomer having a partial structure represented by the following formula

(in which R2, X and B have the same meanings as defined before, respectively).

The thus obtained compounds of the formula (I) and salts thereof are novel compounds and have an absorptivity at the time of oral administration by 4 to 5 times as great as compounds of the type which has a free carboxyl group at the 4 position.

An infectious disease-curing test was effected with the results shown below.

Test Method Groups of ICR-JCL mice (4 weeks old, weight 20 + 0.5 g), each group consisting of 10 mice, were used as test animals. A strain used for the infection was fungi of Escherichia Coli No. 29. This strain was precultivated in a heart infusion agar at 37CC for 20 hours, after which it was suspended in a physiological saline solution and admixed with mucin in a concentration of 2.5%. The suspension was intraperitoneally injected into the mice. Drug samples were orally administered in different concentrations immediateiy after the infection of the strain. Seven days after the administration, the number of surviving mice was checked and an ED50 value was calculated according to the Litchfield Wilcoxon method. The results are shown in Table 1.

TABLE 1 Results of infected Disease-Curing Test (Oral Administration)

Compound EDso Value mg/mouse m . Compound of Example 8 0.0234 0 , Hz Compound of Example 9 0.0216 Non-esterified Non-esterified product of Example 8 0.094 '00 m O Non-esterified product of Example 9 0.095 Cephloxadin 0.24 0 Pathogenic bacteria (Escherichia coli No. 29) As will be apparent from the above results, the compounds of the invention are much more readily absorbed from digestive organs than free acid compounds upon due consideration of molecular weight.

The esters obtained according to the invention can be used to cure infectious diseases brought about by gram-positive and gram-negative bacteria including resistant bacteria by administering them in the form of capsules, dry syrup or suppository as a free amino acid or a salt thereof. These esters should take 2 to 4 doses a day in an amount of 200 to 1000 mg per dose.

The present invention is described in more detail by way of examples, which should not be construed as limiting the present invention thereto.

EXAMPLE 1

7-Amino-3 -ethylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl hydrochloride (alpha-form): 481 mg (0.001 mole) of 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester (alpha-form) (m.p. 1 57 to 1 580C) was dissolved in 20 ml of methylene chloride, to which was added 0.40 ml of pyridine, followed by cooling to -200C. To the mixture was added 440 mg of phosphorus pentachloride, which was gradually heated under agitation for reaction at a temperature of +5 to +1 00C for about 90 minutes (reaction for 30 minutes after disappearance of.

phosphorus pentachloride). The reaction solution was cooled down to 300 C, into which was dropped 5 ml of a methylene chloride solution of 2.0 ml of isobutanol with agitation. The mixture was subsequently heated gradually for reaction at a temperature of +50C to +1 00C for 2 hours (the reaction being checked by TLC). After completion of the reaction, the reaction system was cooled to 0 C and poured into 5 ml of cold water containing 2 ml of saline solution under agitation, followed by further agitation under ice-cooling conditions for about 60 minutes and adding 10 ml of diisopropyl ether and 10 ml of ethyl ether. Shortly, white crystals increased in amount. The crystals were collected, washed with diisopropyl ether and then ether, and dried. Yield: 360 mg.

M.P.: 148 to 1 500C (decomposed) UVmax: 321 nm (95% ethanol) IR (nujol): 1781,1762,1700cm-1 EXAMPLE 2

7-Amino-3-ethylthio-3-cephe m-4-carboxylic acid-ethoxycarbonyloxyethyl ester hydrochloride: 990 mg (0.002 mole) of 7-phenyiacetamido-3-ethylthio-3-cephem-4-carboxylic acidethoxycarbonyloxyethyl ester (m.p. 1 30 to 1 31 0C) was used and treated in the same manner as in Example 1. As a result, the indicated compound was obtained in 750 mg (90.8%).

M.P.: 188 to 1900C (decomposed) UV;lmaX: 320 nm (95% ethanol) IR (nujol): 1780,1763,1710 cm~' EXAMPLES 3-7 In the same manner as in Example 1, compounds indicated in Table 2 were prepared.

TABLE 2

l R2 | NMR Example 3 -CH3 CH20CBu+ 1.19(9H, s), 1.94 (2H, br-s), 2.31 (3H, s), 3.56 (2H, s).

4.68 (1H, d, J=5.0 Hz), 4.91(1 H, d, J=5.0 Hz), 5.85 0 (2H,s) Example 4 -C2H5 -CH2OCBu+ 1.28 (9H, 5), 1.30 (3 H, t, J=7 Hz), 1.99 (2H, br-s), 2.84 (2H, q, J=7 Hz), 3.62 (2H, s), 4.79 (1H, d, J=5.0 O Hz), 5.01(1 H, d, J=5.0 Hz), 5.97 (2H, s) Example 5 -CH3 CH3 1.80 CH3 br-s), 2.15 (3H, 5), 2.31 (3H, 5), 3.56 (2H 5) 4.67 (1H,d,J=5.0 Hz),4.874.97 (3H, m) 0 Hz 0 0 Example 6 --C,HS CH 1.30(3H,t,J=7 Hz),1.95(2H,br-s),2.24(3H,s), - CH2 w 3 2.84 (2H, q, J=7 Hz), 3.63 (2H, s), 4.80 (1H, d, J=5 Hz), 5.03 (1H, d, J=5 Hz), 5.09 (2H, s) U Example 7 -CH3 -(H- 2.10 (2H, br-s), 2.38 (3H, 5)3.67 (2H, 5), 4.77 (1H, d, J=5.0 Hz), 4.99 (1H, d, J=5.0 Hz), 5.07 (2H, s), 7.36 0 0 (1H,s) Y 0 EXAMPLE 8

7-[2-(2-aminothiazole-4-yl)-2-methoxyiminoacetamido]-3-methylthio-3-cephem-carboxylic acid-1 - (ethoxycarbonyloxy)ethyl ester: 399 mg (1 mmole) of 7-amino-3-methyl-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl hydrochloride (compound of Example 1) was dissolved in a small amount of water, to which was added ethyl acetate under ice-cooling conditions. To the mixture was added an aqueous NaHCO3 solution to render it weakly alkaline. Thereafter, an aqueous NaCI solution was added to the mixture, followed by extraction several times. The ethyl acetate solution was combined and dried, and the solvent was distilled off under reduced pressure, followed by dissolution in CH2CI2.

On the other hand, 139 mg of phosgene dimer which was cooled down to -1 00C was added to 10 ml of CH2CI2 containing 117 mg of dimethylformamide, followed by gradually heating up to + 1 00C under agitation. After 30 minutes, the mixture was cooled down to --300C. To the thus cooled solution was added a solution containing 361 mg of 2-chloroacetamido-thiazole-2-methoxyimino-2-acetic acid and 132 mg of triethylamine for reaction at a temperature of -30 to -200C for 30 minutes. To the resulting solution was added the amino-carboxylic acid ester solution under agitation, followed by reaction at a temperature of -20 to -1 00C for 60 minutes.Thereafter, iced water was added to the reaction, which was adjusted to pH to 1.5, thereby removing amino products therefrom. The organic phase was washed with water and adjusted in pH to 6.8 using an aqueous NaHCO3 solution, from which acidic components were removed and the residue was dried. The solvent was distilled off under reduced pressure and the resulting residue was purified using a silica gel column (benzene + ethyl acetate). As a result, there was obtained 340 mg of 7-(2 -chloroacetaminothiazole-2-methoxyimino-2-acetamido)-3- methylthio-3-cephem-4-carboxylic acid ethoxycarbonyloxyethyl ester. M.P. 127 to 1 2 9 OC.

312 mg of the thus obtained chloroacetylamide product was dissolved in 2 ml of dimethylacetamide and then admixed with 46 mg of thiourea under ice-cooling conditions for reaction for about 2 to 3 hours while tracing the reaction by TLC. Iced water and ethyl acetate were added to the reaction solution, followed by adjusting its pH to 7.0 using NaHCO3 and extraction several times. The organic phase was dried, after which the solvent was removed by distillation under reduced pressure.

The resulting residue was treated with n-hexane, by which it was solidified.

The product was purified using a silica gel column chromatogram (ethyl acetate:benzen = 2:1), thereby obtaining 180 mg of the above-indicated compound.

EXAMPLE 11

Al pha-ethoxywarbonyloxyethyl 7-[2-(2-trityla m inothiazole-4-yl)-2-ethoxyi minoacetamidoj-3-ethylthio- 3-cephem-4-carboxylate: (1) 0.031 ml of DMF was dissolved in 2 ml of methylene chloride and cooled to-I 00C, followed by dropping 0.03 g of Cl3COCOCI and agitating at OOC for 1 5 minutes. Thereafter, the mixture was cooled down to -300C, into which was dropped 5 ml of a methylene chloride solution containing 0.1 g of (2-tritylaminothiazole-4-yl)-2-ethoxyiminoacetic acid and 0.032 ml of triethylamine. At the same temperature, the mixture was agitated for 30 minutes.Separately, 0.0825 g of alpha ethoxycarbonyloxyethyl-7-am ino-3-ethylthio-3-cephem-4-carboxylate.hyd rochloride was adjusted to pH 7.5 using sodium bicarbonate.

Then the methylene chloride solution of ethoxycarbonyloxyethyl-7-amino-3-ethylthio-3-cephem4-carboxylate was dropped into the mixture. After reaction for 30 minutes, the solution was added to a cold aqueous sodium bicarbonate solution. An organic phase was collected and washed with a saturated saline solution, followed by drying over magnesium sulfate and removing the solvent by distillation under reduced pressure. The resulting residue was chromatographically treated to obtain 0.12 g of crystalline powder of the above-indicated compound.

M.P.: 118 to 1 200C (foamed and decomposed).

Alpha-ethoxycarbonyloxyethyl 7-[2-(2-aminothiazole-4-yl)-2-ethoxyiminoacetamidoj-3-ethylthio-3- cephem-4-carboxylate: (2) 0.1 g of the compound obtained in (1) was treated with anisoie and trifluoroacetic acid under ice-cooling conditions, after which it was adjusted to pH to 7.5 using an aqueous sodium bicarbonate.

Thereafter, the solution was extracted with ethyl acetate and dried over magnesium sulfate, followed by distilling off the solvent and solidifying with isopropyl ether, thereby obtaining crystalline powder of the above-indicated compound almost quantitatively.

M.P.: 110 to 112 C (decomposed).

EXAMPLE 16 7-(2-a mino-thiazole-4-yl-2-methoxyi mi no-2-acetamido)-3-methylthio-3-cephem-4-carboxylic acid-(5- methyl-2-oxo-1 ,3-dioxolene-4-yl)-methyl ester (syn isomer): 41 5 mg of 7-(2-amino-thiazole-4-yl-2-methoxyimino-2-acetamido)-3-methylthio-3-cephem-4- carboxylic acid and 93 mg of sodium bicarbonate were added to a small amount of water to obtain a transparent solution. The solution was concentrated under reduced pressure and evaporated to dryness.

The residue was admixed with ethyl ether and solidified. The resulting solid was dried under reduced pressure. To the sodium salt was added 5 ml of dimethylformamide for dissolution, to which was further added 232 g of (5-methyi-2-oxo-l ,3-dioxole-4-yl-methyl bromide. The mixture was agitated at room temperature for about 30 to 40 minutes. After confirmation by TLC that the reaction was complete, 30 ml of water was added to the reaction solution, thereby permitting solid matters to precipitate. The precipitate was collected, washed with water, dissolved in ethyl acetate, and adjusted in pH to 7.5 by the use of an aqueous sodium bicarbonate solution. The resulting organic phase was separated, washed with a saline solution, and dried over magnesium sulfate.The solvent was concentrated under reduced pressure and the resulting residue was treated with diisopropyl ether to obtain 460 mg of a crude product. The product was purified by the silica gel chromatography to obtain 340 mg of the aboveindicated compound.

EXAMPLE 17 7-(2-amino-thiazole-4-yl-2-methoxyi mino-2-aceta mido)-3-methylthio-3-cephem-4-ca rboxylic acid pivaloyloxymethyl ester (syn isomer): A sodium salt which was derived from 208 mg of 7-(2-amino-thiazole-4-yl-2-methoxyimino-2 acetamido)-3-methyithio-3-cephem-4-carboxylic acid and 47 mg of NaHCO3 was dissolved in 5 ml of dimethylsulfoxide to obtain a solution. To the solution was added 11 7 mg of pivalyloxymethyl bromide at room temperature, followed by tracing the reaction by TLC. After confirming completion of the reaction after about 60 to 80 minutes, 30 ml of water was added in order to permit solid matters to precipitate. The precipitate was collected, washed with water, dissolved in 30 ml of ethyl acetate, washed with a saline solution containing a small amount of sodium bicarbonate, and the organic phase was dried. The ethyl acetate solution was subjected to distillation under reduced pressure and treated for solidification with diisopropyl ether, thereby obtaining 220 mg of a crude product. The product was purified by the silica gel chromatography (benzene:ethyl acetate = 1 :2) to obtain 140 mg of the aboveindicated compound.

EXAMPLES 9-20 .n the same manner as in Examples 8, 11, 1 6 and 17, compound and intermediates indicated in Tables 3 and 4 were obtained. In the tables, the compound obtained in Examples 8, 11, 1 6 and 1 7 are also shown.

TABLE 3

UV (#max) IR 95% Nujol Ethanol Example R1 R2 R3 (cm-1) (nm) NMR 8 -CH3 # -CH3 1.30 (3H, t), 1.60 (3H, d), 2.40 (3H, s), 3.65 (2H, s), 4.10 (3H, 2), 4.25 (2H, q), 5.16 (1H, d), 5.63 (2H, 2), 5.98 (1H, d, d), 6,82 (1H, s), 7.0 (1H, m) 8.04 (1H, d) 9 -C2H5 # -CH3 1780 301~ 1.32 (6H, m), 1.59 (3H, d, J=5.5 Hz), 2.91 (2H, q, 1764 302 J=4 Hz), 3.50 (2H, m), 4.07 (3H, s), 4.24 (2H, q, J=4 Hz), 5.12 (1H, d, J=5 Hz), 5.28 (2H, br-s), 5.90 (1H, d, d, J=5.9 Hz), 6.89 (1H, s), 7.0 (1H, m, 7.47 (1H, d, J=9 Hz) 10 -CH3 # -C2H5 1789 209 1.18~1.63 (9H, m), 2.35 (3H, s), 3.6 (2H, s), 4.2 1775 308 (4H, q), 5.07 (1H, d, J=4.5 Hz), 5.3 (2H, br-s), 1768 5.85 (1H, d, d, J=4.5, 9 Hz), 6.91 (1H, s), 6.83~7.12 (1H, m), 7.30 (1H, d, J=9 Hz) 11 -C2H5 # -C2H5 1775 301 1.04~1.39 (9H, m), 1.54 (3H, d), 2.80 (2H, q), 1760 231 3.56 (2H, br-s), 4.01~4.46 (4H, m), 5.09 (1H, d), 1680 5.83 (1H, d, d), 6.85 (1H, s), 6.79~7.07 (1H, m), 7.58 (1H, d) 12 -CH3 # -C2H5 1780 302 1.17 (9H, s), 1.27 (3H, t), 2.33 (3H, s) 3.58 (2H, 1760 s), 4.29 (2H, q), 5.07 (1H, d, J=4.5 Hz), 1680 5.75~5.95 (3H, m), 6.85 (1H, s), 7.58 (1H, d, J=9 Hz) 13 -C2H5 # -C2H5 1780 301 1.17 (9H, s), 1.26 (6H, t), 2.80 (2H, q). 3.56 (2H, 1680 s), 4.29 (2H, q), 5.09 (1H, d, J=4.5 Hz), 5.75~5.97 (3H, m), 6.81 (1H, s), 7.61 (1H, d, J=9 Hz) TABLE 3 (Continued)

UV (#max) IR 95% Nujol Ethanol Example R1 R2 R3 (cm-1) (nm) NMR 14 -CH3 # -C2H5 1820 295 1.29 (3H, t), 2.15 (3H, s), 2.33 (3H, s), 3.6 (2H, 1780 s), 4.31 (2H, q), 4.97 (2H, s), 5.08 (1H, d, J=4.5 1680 Hz), 5.78 (1H, d, d, J=4.5, 9 Hz), 6.87 (1H, s), 7.41 (1H, d, J=9 Hz) 15 -C2H5 # -C2H5 1820 295 1.15 (3H, t), 1.27 (3H, t), 2.15 (3H, s), 2.81 (2H, 1785 q), 3.58 (2H, s), 4.28 (2H, q), 4.97 (2H, s), 5.10 1775 (1H, d, J=5 Hz), 5.84 (1H, d, d, J=5, 10 Hz), 6,81 1680 (1H, s), 7.59 (1H, d, J=10Hz) 16 -CH3 # -CH3 1820 304 2.25 (3H, s), 2.40 (3H, s), 3.66 (2H, s), 4.10 (3H, 1780 s), 5.06 (2H, br-s), 5.17 (1H, d, J=4.5 Hz), 5.66 1680 (2H, br-s), 6.02 (1H, d, d, J=4.8 Hz), 6.76 (1H, s), 1620 8.20 (1H, d, J=8 Hz) 17 -CH3 # -CH3 1780 306 1.25 (9H, s), 2.38 (3H, s), 3.65 (2H, s), 4.09 (3H, 1760 s), 5.16 (1H, d, J=4.0 Hz), 5.49 (2H, br-s), 5.93 1730 (2H, br-s), 5.95 (1H, d, d, J=4.0, 8.0 Hz), 6.87 1680 (1H, s), 7.90 (1H, d, J=8.0 Hz) 18 -CH3 # -C2H5 1825 300 1.34 (3H, t), 2.38 (3H, s), 3.65 (2H, s), 4.31 (2H, 1775 q), 5.03 (2H, br-s), 5.11 (1H, d, J=4.5 Hz), 5.68 1670 (2H, br-s), 5.91 (1H, d, d, J=4.5, 9 Hz), 6.84 (1H, s), 7.23 (1H, s), 7.63 (1H, d, J=9 Hz) TABLE 3 (Continued)

UV (#max) IR 95% Nujol Ethanol Example R1 R2 R3 (cm-1) (nm) NMR 19 1830 305 2.39 (3H, s), 3.67 (2H, s), 3.99 (3H, s), 5.07 (2H, 1778 s), 5.13 (1H, d, J=4.5 Hz), 5.75 (1H, d, d, J=4.5, 1710 9 Hz), 6.32 (2H, s), 6.84 (1H, s), 7.41 (1H, s), 1675 9.24 (1H, d, J=9 Hz) 20 1780 303 0.91~1.86 (11H, m). 2.83 (2H, t), 3.65 (2H, s).

1785 4.10 (3H, s), 4.29 (2h, q), 5.18 (1H, d, J=4.5 Hz), 1690 5.90 (1H, d, d, J=4.5 Hz, 9.0 Hz), 6,85~7.1 (1H, 1673 m), 6.95 (1H, s), 8.15 (1H, d, J=9.0 Hz) TABLE 4

UV(#max) IR 95% Nujol Ethanol Example R1 R2 R3 R4 (cm-1) (nm) NMR 8 -CH3 # -C2H5 C@CH2CONH- 1.30 (3H, t), 1.60 (3H, d), 2.40 (3H, s), 3.62 (2H, s), 4.06 (3H, s), 4.20 (2H, q), 4.26 (2H, s), 5.10 (1H, d), 5.82 (1H, d, d), 6.94 (1H, m), 7.22 (1H, s), 7.70 (1H, d) 10 -CH3 # -C2H5 C@CH2CONH- 1778 276 1.08~1.65 (9H, m), 2.40 (3H, s), 3.67 (2H, s), 1764 4.28 (4H, q), 4.33 (2H, s), 5.14 (1H, d, J=4.5Hz), 5.90 (1H, d, d, J=4.5, 9 Hz), 7.06 (1H, q), 7.44 1H, s), 7.46 (1H, d, J=9.0 Hz) 11 -C2H5 # -C2H5 PH3CNH- 301 1.18~1.37 (9H, m), 1.54 (3H, d), 2.78 (2H, q), 3.54 (2H, m), 4.05~4.5 (4H, m), 5.03 (1H, d, J=4.5 Hz), 5.79 (1H, d, d, J=4.5, 9.0 Hz), 6.73 (1H, s), 6.95 (1H, m). 7.26 (2H, s), 7.75 (1H, br-s) 12 -CH3 # -C2H5 C@CH2CONH- 1785 230 1.14 (9H, s), 1.28 (3H, t), 2.33 (3H, s), 3.54 (2H, 1755 276 s), 4.23 (2H, s), 4.30 (2H, q), 5.05 (1H, d, J=4.5 1680 Hz), 5.63~5.95 (3H, m), 7.30 (1H, s), 7.77 (1H, d, J=9 Hz) 13 -C2H5 # -C2H5 C@CH2CONH- 1785 228 1.19 (9H, s), 1.30 (3H, t). 1.35 (3H, t), 2.80 (2H, 1765 278 q), 3.54 (2H, br-s), 4.23 (2H, s), 4.33 (2H, q), 1680 5.09 (1H, d, J=5 Hz), 5.67~5.97 (3H, m), 7.38 (1H, s). 7.50 (1H, d, J=9.0 Hz) TABLE 4 (continued)

UV (#max) IR 95% Nujol Ethanol Example R1 R2 R3 R4 (cm-1) (nm) NMR 14 -CH3 # -C2H5 C@CH2CONH- 1820 229 1.31 (3H, t), 2.17 (3H, s), 2.33 (3H, s), 3.60 (2H, 1780 276 s), 4.21 (2H, s), 4.33 (2H, q), 4.97 (2H, s), 5.08 1680 (1H, d, J=4.5 Hz), 5.86 (1H, d, d, J=4.5, 9.0 Hz), 7.32 (1H, s), 7.50 (1H, d, J=9.0 Hz) 15 -C2H5 # -C2H5 C@CH2CONH- 1820 278 1.00 (3H, t), 1.04 (3H, t), 1.90 (3H, s), 2.54 (2H, 1780 q), 3.30 (2H, s), 3.97 (2H, s), 4.07 (2H, q), 4.72 1680 (2H, s), 4.85 (1H, d, J=4.5 Hz), 5.60 (1H, d, d, J=4.5, 9.0 Hz), 7.10 (1H, s), 7.26 (1H, d, J=9.0 Hz) 19 -CH3 # -CH3 PH3CNH- 1835 310 2.35 (3H, s), 3.61 (2H, s), 4.05 (3H, s), 5.01~5.09 1780 (3H, m), 5.77 (1H, d, d, J=5.0, 9.0 Hz), 6.70 (1H, 1680 s), 7.18 (1H, s), 7.29 (15H, s) 18 -CH3 # -C2H5 C@CH2CONH- 1825 277 1.36 (3H, t), 2.39 (3H, s), 3.66 (2H, s), 4.27 (2H, 1775 322 s), 4.33 (2H, q), 5.05 (2H, s), 5.09 (1H, d, J=5.0 1680 Hz), 5.83 (1H, d, d, J=5.0, 9.0 Hz), 7.22 (1H, s), 7.36 (1H, s), 7.67 (1H, d, J=9.0 Hz) 20 -CH2CH2CH3 # -CH3 PH3CNH- 1778 308 0.91~1.86 (11H, m), 2.81 (2H, t), 3.64 (2H, s), 1763 4.12 (3H, s), 4.30 (2H, q), 5.15 (1H, d, J=4.5 Hz), 1738 5.89 (1H, d, d, J=4.5, 9.0Hz), 6.88 (1H, s), 6.95~7.25 (2H, m), 7.43 (15H, s), 7.72 (1H, d, J=9.0 Hz) Reference 1

7-Phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid: (1) 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid diphenyl methyl ester (m.p.

169--1700C) was treated with anisole and trifluoroacetic acid under ice-cooling conditions, after which the trifluoroacetic acid was distilled off under reduced pressure and the resulting residue was solidified with ether. The solid product was dissolved in ethyl acetate, which was adjusted in pH to 7.5 by the use of an aqueous Na HCO3 solution followed by separating the aqueous phase, whose pH was adjusted to 2.0 to 2.5 with use of 20% hydrochloric acid, followed by adding NaCI and collecting an organic phase. The organic phase was washed with an aqueous NaCI solution and dried. The solvent was distilled off and the residue was treated with diisopropyl ether to obtain the above-indicated A3carboxylic acid in a yield of about 90%.

M.P:: 192 to 1 930c (decomposed) UV AmaX: 302 nm (95% ethanol) IR (nujol): 1767, 1690, 1 642 cm-l

7-Phenylacetamido-3-methylthio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester: (2) 93 mg of NaHCO3 and 1 ml of water were dissolved in 376 mg of the 7-phenylacetamido-3methylthio-3-cephem-4-carboxylic acid obtained in (1), and the resulting mixture was evaporated to dryness. The thus obtained residue was washed with ethylether to give a powder. To said powder was added 3 ml of dimethylsulfoxide for dissolution, to which was subsequently added 205 mg of pivaloyloxymethyl bromide, followed by agitation. The reaction was traced by TLC. After 10 to 20 minutes, 30 ml of iced water was added, followed by extraction with ethyl acetate.The ethyl acetate phases were combined, to which was added an aqueous NaCI solution. After adjustment of pH to 7.5, the organic phase was collected and dried, after which the solvent was distilled off. The resulting residue was treated first with n-hexane and then with diisopropyl ether for solidification. As a result, there was obtained 440 mg of a crude product of the above-indicated ester. The product was purified by the silica gel chromatography (benzene + ethyl acetate). Yield: 360 mg.

UV (in ethanol): 324 nm NMR (8value in CDCI3): 1.17 (9H. 5). 2.31 (3H, s), 3.5 (2H. 5), 3.58 (2H, s), 4.91(1 H, d, J=5Hz), 5.55-5.97 (3H, m), 6.48 (1 H, d, J=9Hz), 7.28 (5H, s) M.P.:122to1230C References 2-9 In the same manner as in Reference 1, there were obtained compounds indicated in Table 5.

TABLE 5

UV(#max) Refer- IR 95% ence Nujol Ethanol R1 R2 mp( C) (cm-1) (nm) NMR 2 -C2H5 # 130~131 1780 320 1.30 (6H, m), 1.58 (3H, d, J=5 Hz), 2.84 (2H, q, 1768 J=8 Hz), 3.54 (2H, m), 3.67 (2H, s), 4.26 (2H, m, J=7 Hz), 5.00 (1H, d, J=5 Hz), 5.69 (1H, d, d, J=5, 8 Hz), 6.28 (1H, d, J=8 Hz), 7.00 (1H, q, J=5 Hz), 7.37 (5H, s) 3 -C2H5 # 99~102 1775 316 1.22 (9H, s), 1.29 (3H, t, J=7 Hz), 2.85 (2H, q, 1750 J=7 Hz), 3.54 (2H, s), 3.67 (2H, s), 5.01 (1H, d, 1720 J=4 Hz), 5.75 (1H, d, d, J=4.8 Hz), 5.94 (2H, 1660 br-s), 6.48 (1H, d, J=8 Hz), 7.39 (5H, s) 4 -C2H5 # 129~133 1820 321 1.30 (3H, t. J=7 Hz), 2.21 (3H, s), 2.83 (2H, q, 1785 J=7 Hz), 3.57 (2H, s), 3.69 (2H, s), 5.04 (1H, d, 1710 J=4 Hz), 5.04 (2H, s), 5.79 (1H, d, d, J=4, 8 Hz), 1640 6.19 (1H, d, J=8 Hz), 7.39 (5H, s) 5 -CH3 # 191~194 1847 321 2.38 (3H, s), 3.61 (2H, s), 3.65 (2H, s), 5.07~5.11 1780 (3H, m). 5.63 (1H, d, d, J=4.5, 9 Hz), 7.29 (5H, 1708 s), 7.42 (1H, t), 8.71 (1H, d, J=9 Hz) TABLe 5 (continued)

UV (#max) IR 95% Nujol Ethanol Example R1 R2 mp( C) (cm-1) (nm) NMR 6 -CH3 # 175~188 1820 319 2.15 (3H, s), 2.33 (3H, s), 3.52 (2H, s), 3.68 (2H, 1870 s), 4.97~5,50 (3H, m), 5.57 (1H, d, d, J=5 Hz), 1700 7.24 (5H, s), 9.0 (1H, d, J=9 Hz) 7 -CH3 # 157~158 1784 321 1.30 (3H, t), 1.55 (3H, d), 2.37 (3H, s), 3.55 (2H, 1774 s), 3.62 (2H, s), 4.23 (2H, q), 4.96 (1H, d), 5.66 (1H, d, d), 6.67 (1H, d), 6.97 (1H, q), 7.33 (5H, s) 8 -CH3 # 122~123 1775 324 1.17 (9H, s), 2.31 (3H, s), 3.5 (2H, s), 3.58 (2H, 1750 s), 4.91 (1H, d, J=5 Hz), 5.55~ 5.97 (3H, m), 1220 6.48 (1H, d, J=9 Hz), 7.28 (5H, s) 9 -CH2CH2CH3 # 134~137 1778 320 0.90~1.84 (11H, m), 2.83 (2H, t), 3.56 (2H, s), 1756 3.64 (2H, s), 4.26 (2H, q), 5.03 (1H, d, J=4.5 Hz) 1740 5.68 (1H, d, d, J=4.5, 9 Hz), 6.85 (1H, d, J=9 1726 Hz), 7.01 (1H, q), 7.40 (5h, S)

Claims

1. A cephem compound represented by the following general formula,

(in which R' represents an amino-substituted thiazolyl group with or without a halogen atom, R2 represents a lower alkyl group, R3 represents a lower alkyl group, and R4 represents an esterified carboxyl group), or pharmaceutically acceptable salts thereof.

2. A syn isomer of the compound of Claim 1.

3. The compound and pharmaceutically acceptable salts thereof according to Claim 1, wherein in the formula, R' represents a 2-aminothiazole-4-yl group, R2 represents a lower alkyl group, R3 represents a lower alkyl group, and R4 represents an esterified carboxyl group.

4. A cephem compound substantially as described in any one of the specific examples hereinbefore set forth.