WO1998058933A1 - Cephalosporin compounds, use thereof and intermediate compounds of the same - Google Patents

Abstract

Cephalosporin compounds (I) represented by general formula (I) or pharmaceutically acceptable salts thereof: wherein R1 represents hydrogen or an amino-protective group; R2 represents hydrogen, lower alkyl or a hydroxy-protective group; R3 represents optionally esterified carboxy; and R4 represents optionally substituted thiazolyl. These compounds (I) or their pharmaceutically acceptable salts are excellent in absorbability via the digestive tracts when administered orally and have a sufficient antimicrobial activity over a broad range of bacteria, which makes them highly useful as preventives and remedies for infectious diseases (in particular, microbisms).

Description

 Specification

 Cephalosporin compounds, their uses and intermediate compounds

 "Technical field"

 The present invention relates to a novel cephalosporin compound or a pharmaceutically acceptable salt thereof useful as an agent for preventing or treating bacterial infections, a pharmaceutical composition containing the compound as an active ingredient, and the cephalosporin compound. The present invention relates to an intermediate compound for production or a salt thereof.

 "Background technology"

 To date, research on cephalosporin compounds has been remarkable, and various cephalosporin compounds having a strong antibacterial activity and a broad antibacterial spectrum have been developed as therapeutic agents for infectious diseases. However, the emergence of new resistant bacteria and the emergence of cephalosporin compounds having antibacterial properties and antibacterial spectrum according to disease conditions are expected. In addition, conventional cephalosporin compounds have poor absorption from the digestive tract and are only administered clinically as injections. Oral preparations are easier and easier to administer than injections, and their clinical utility is extremely high. Therefore, the development of a cephalosporin compound having a strong antibacterial activity and a broad antibacterial spectrum and having excellent gastrointestinal absorption properties and suitable for oral administration has been strongly desired.

 "Disclosure of the invention"

 The present inventors have conducted intensive studies to find an injectable and oral cephalosporin compound having a strong antibacterial activity and a broad antibacterial spectrum.

The novel cephalosporin compound represented by (I) or a pharmaceutically acceptable salt thereof has a sufficiently strong antibacterial property, is extremely useful as an antibacterial agent for injection, and a prodrugized compound is excellent. It has a good gastrointestinal absorption and is extremely useful as an oral antibacterial agent. Furthermore, they have found a novel intermediate compound to be used for producing the compound, and have completed the present invention.

That is, the cephalosporin compound and the pharmaceutically acceptable salt thereof of the present invention are as described below. (1) — General formula (I)

(Wherein, R ¹ represents a hydrogen atom or an amino protecting group, R ² represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group, R ³ represents a carboxyl group which may be esterified, and R ⁴ represents a substituent. A thiazolyl group which may be present), or a pharmaceutically acceptable salt thereof.

(2) The cephalosporin compound or a pharmaceutically acceptable salt thereof according to the above (1), wherein R ³ is an esterified carboxyl group.

 (3) 7; 8— [(Z) — 2— (2-aminothiazoyl 4-yl) -1-2-hydroxyiminoacetamide] 1-3— [(Ζ) -2-(4-methylthiazolyl) 1-5-yl) vinylthio] 1-3-Cefm-4

 1 β- [(Ζ)-2-(2-aminothiazoyl 4-yl) 1-2-methoxyminoacetamide] 1 3- [(Ζ) — 2— (4-methylthiazoyl 5-yl) Vinylthio] —3-Cefem—4-carboxylic acid,

 Bivaloyloxymethyl 7 iS — [(Ζ) —2— (2-aminothiazolyl 4-—yl) -1-2-Methoxyiminoacetamide] —3 — [(Z) —2— (4 1-methylthiazoyl 5-yl) vinylthio] 1-3-cefumo 4-carboxylate,

1-Isopropoxycarbonyloxyshetyl Ί β— [(Ζ) — 2— (2-Aminothiazolu-l 4-yl) 1 2-Methoxyiminoacetamide] — 3— [(Ζ) — 2- (4-methylthiazol-5-yl) vinylthio] —3-cef-14-carboxylate, 1-acetoxityl Ί β- [(Ζ) -2-(2-aminothiazoyl 4-yl) 1-2-methoxyiminoacetamide] 1 3-[(Ζ)-2-(4-methylthio) Azoyl-5-yl) vinylthio] — 3-sefume 4-carboxylate,

(5-Methyl-1-oxo-1, 3-dioxolen-41-yl) Methyl Ί β-[(-)-2--(2-aminothiazol-1-41) 1-2-Methoxyiminoacetamide] 3-([Ζ) —2 -— (4-Methylthiazoyl 5-yl) vinylthio] _3-Sebum-4-carboxylate,

 7 β-[(Ζ) -2- (2-aminothiazoyl 4-yl) -1-2-methoxyminoacetamide] — 3 — [(Ζ) -2-((thiazoyl 5-yl) vinylthio] — 3—Cefem—4—Carboxylic acid,

 Bivaloyloxymethyl Ί β— [(Ζ) — 2— (2-Aminothiazol 4-l) -1 2-Methoxyiminoacetamide] — 3— [(Ζ)-2-(Thiazol — 5-yl) vinylthio] — 3-sefm — 4-carboxylate,

 Ί β— [(Ζ)-2-(2-aminothiazole-4-yl) -1-2-methoxyminoacetamide] — 3— C (Ζ)-2-(2-methylthiazoyl 5-yl) Vinylthio] — 3-cef — 4-carboxylic acid, and

 7 β-[(Ζ) — 2— (2-aminothiazoyl 4-yl) 1-2-methoxyminoacetamide] — 3— [(Ζ)-2-(thiazoyl 4-yl) vinylthio] — The cephalosporin compound or a pharmaceutically acceptable salt thereof according to the above (1), which is selected from the group consisting of 3-cefum-4-carboxylic acid.

 (4) The cephalosporin compound according to (3), which is in the form of a sodium salt or a hydrochloride.

 (5) A pharmaceutical composition comprising the cephalosporin compound of (1) or a pharmaceutically acceptable salt thereof.

 (6) The pharmaceutical composition according to the above (5), which is a prophylactic or therapeutic drug for infectious diseases.

(7) A pharmaceutical composition comprising the cephalosporin compound of the above (1), wherein R ³ is an esterified carboxyl group, or a pharmaceutically acceptable salt thereof. (8) The pharmaceutical composition _c of the above (7), which is a preventive / therapeutic agent for infectious disease

 (9) General formula (I I)

(Wherein, R ³ represents a carboxyl group which may be esterified, and R ⁴ represents a thiazolyl group which may have a substituent) or a salt thereof.

 (10) diphenylmethyl 7) 5-amino-1 3-[(Z)-2- (4-methylthiazol-5-yl) vinylthio] 13-cefmu 4- 4-carboxylate, bivaloyloxymethylamino-3 — [(Ζ) 1 2— (4-Methylthiazolyl 5-yl) vinylthio] 1-3-Cefem-4 1-carboxylate,

 1-Isopropoxycarbonyloxyshetyl 7 S-amino-3-([Ζ) —2- (4-Methylthiazoyl 5-yl) vinylthio] -13-Sebum-4

 1-acetoxityl—amino-3 — [(Z) -2- (4-methylthiazol-5-yl) vinylthio] —0.3 rcebum—4-carboxylate,

 (5-Methyl-2-oxo-1, 3-dioxolen-1-yl) methyl Ίβ-amino-3-[(Ζ) —2- (4-methylthiazol-5-yl) vinylthio] — 3-sefumu 4 monocarboxylate,

 Diphenylmethyl ΊjS-amino-3-([Z) —2- (thiazolyl-5-yl) vinylthio] —3-cefume-4-carboxylate, and

Pivaloyloxymethyl 7 yS-Amino-3-([Z) -2- (thiazolyl-5-yl) vinylthio] —3-Cephem—4-Carboxylate The selected 7-aminocephalosporin compound of the above (9) or a salt thereof.

 Hereinafter, each definition used in the present specification will be described.

As the “amino protecting group” for R ^1, those used in the field of S-lactam synthesis and peptide synthesis are conveniently used. Specifically, a phthaloyl group, a formyl group, a monochloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, and a p-nitrobenzene Benzyloxycarbonyl group, diphenylmethyloxycarbonyl group, methoxymethylcarbonyl group, methoxymethyloxycarbonyl group, trimethylsilyl group, 2,2,2-trichloroethoxycarbonyl group, 2-methylsulfonylethyl Methoxycarbonyl group, t-butoxycarbonyl group (hereinafter, referred to as “BOC”), trityl group and the like, preferably formyl group, B 0 C and trityl group.

The “lower alkyl group” for R ² is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group Group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, isohexyl group, neohexyl group, and the like. A methyl group, an ethyl group, a propyl group and a butyl group.

As the “hydroxy protecting group” for R ^2, those used in the field of / S-lactam synthesis and peptide synthesis are conveniently used. Specifically, formyl, acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2- Ethoxycarbonyl group, benzoyl group, trityl group, trimethylsilyl group, tetrahydrovinylyl group, 1-methyl-1-methoxyl group, etc., and preferably acetyl group, trityl group, tetrahydroviranyl group and It is a methyl-1-methoxyl group.

The ester of the "optionally esterified carboxyl group" in R ³ is- Carboxyl-protecting group, or an ester that is hydrolyzed in vivo (which is easily hydrolyzed in vivo to give a free carboxylic acid group and is hydrolyzed in blood), etc. .

In the general formula (I), those in which R ³ is an ester hydrolyzed in vivo are so-called prodrugs, which are easily absorbed from the gastrointestinal tract by oral administration and are excellent after being hydrolyzed. Demonstrates antibacterial properties.

 The “protecting group for carboxyl group” includes, for example, t-butyl group, t_amyl group, benzyl group, p-methoxybenzyl group, p-methoxybenzyl group, benzhydryl group, p-nitrophenyl group, A methoxymethyl group, an ethoxymethyl group, a benzyloxymethyl group, a methylthiomethyl group, a trityl group, a 2,2,2-trichloroethyl group, a trimethylsilyl group, a diphenylmethoxybenzenesulfonylmethyl group, and a dimethylaminoethyl group. Preferred are a p-nitrobenzyl group, a p-methoxybenzyl group and a benzylhydryl group.

 “Esters that are hydrolyzed in vivo” include aryl groups which may have a substituent (eg, phenyl, tolyl, xylyl, indanyl, etc.), 1-alkanoyl A xyalkyl group, a monoalkoxycarbonyloxyalkyl group, a phthalidyl group and a 5-methyl-2-oxo-1,3-dioxolen-14-ylmethyl group, and preferably a monoalkanoyloxyalkyl group A 1-alkoxycarbonyloxyalkyl group and a 5-methyl-2-oxo-1,3-dioxolen-14-ylmethyl group.

 The “optionally substituted aryl group” is preferably an unsubstituted or substituted aryl group which may be substituted with 1 to 3 substituents, and the substituents may be the same or different. Is also good. Specific examples of the substituent include an alkyl group having 1 to 6 carbon atoms such as a methyl group and an ethyl group.

The number of carbon atoms of the alkanoyl moiety in the “1-alkanoyloxyalkyl group” is preferably 2 to 10, more preferably 2 to 7, and may be any of linear, branched or cyclic. The number of carbon atoms in the alkyl moiety is preferably 1 to 3, More preferably, it is one or two.

 Specific examples of the “1-alkanoyloxyalkyl group” include an acetyloxymethyl group, a propionyloxymethyl group, an n-butylyloxymethyl group, an isoptyryloxymethyl group, a bivaloyloxymethyl group, and a Valeryloxymethyl group, 2-methylbutyryloxymethyl group, isovaleryloxymethyl group, n-hexanoyloxymethyl group, 3-methylvaleryloxymethyl group, neohexanoyloxymethyl group, 2- Methylhexanoyloxymethyl group, 2,2-dimethylvaleryloxymethyl group, neoheptanyloxymethyl group, cyclohexanecarbonyloxymethyl group, cyclohexylacetoxymethyl group, 1-acetoxethyl Group, 1-propionyloxyxetyl group, 1-n-butyryloxethyl group, 1-isobutyryl Kisechyl group, 1-n-Valeryloxyl, 1-Vivaloyloxyl, 1-Isovaleryloxyl, 1n-Hexanoyloxetyl and 1-Cyclohexanecarbonyl And a shetyl group.

 The number of carbon atoms in the alkoxy moiety in the “1-alkoxycarbonyloxyalkyl group” is preferably 1 to 10, more preferably 1 to 7, and may be any of linear, branched or cyclic. The number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1 or 2.

 The term “1-alkoxycarbonyloxyalkyl group” specifically refers to a 1-methoxycarbonyloxyl, a 1-ethoxycarbonyloxyl, a 1-n-propoxycarbonylloxyl group. , 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxy, 1-sec-butoxycarbonyloxy, 1-t-butoxycarbonyloxy, and 1-pentyl Oxycarbonyloxyl and 1-cyclohexyloxycarbonyloxyl and the like.

The `` thiazolyl group optionally having substituent (s) '' for R ⁴ is preferably a thiazolyl group which may be unsubstituted or optionally substituted by 1 to 2 substituents, wherein the substituents are the same or different. You may. Specific examples of the substituent include carbon atoms of 1 to 6 And a straight-chain or branched-chain alkyl group and the like, preferably a methyl group and an ethyl group.

 —7-side chain of cephalosporin compound (I) represented by general formula (I I I)

(Wherein R ¹ and R ² have the same meanings as described above), there are Z-isomer and E-isomer, both of which are included in the scope of the present invention. Preferably, it is Z-shaped.

 In addition, cis- and trans-forms, or Z-form and E-form geometric isomers exist for the double bond of the vinyl group in the 3-position side chain of the cephalosporin compounds (I) and (II), Both isomers are included in the scope of the present invention.

 The cephalosporin compound (I) can form a pharmaceutically acceptable salt at its amino group or carboxyl group by a method known per se. Further, various isomers of the compound (I) can also be produced by a known method.

 The cephalosporin compound (I) can form an acid addition salt at its amino group, and the acid for forming the acid addition salt is not particularly limited as long as it is a pharmaceutically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid and methanesulfonic acid.

The cephalosporin compound (I) can form a salt at its carboxyl group. Examples of the salt in the carboxyl group include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, potassium salt, magnesium salt, etc.), organic base salts (eg, triethylamine salt, Dicyclohexylamine salt, pyridine salt, etc.).

 Examples of the salt of the 7-aminocephalosporin compound (II) include salts similar to those of the cephalosporin compound (I).

 Among the cephalosporin compounds (I), preferred are 7yS — [(Z) —2— (2-aminothiazo-l-41-yl) -1-2-hydroxyiminoacetamide] —3 — [( Z) — 2 — (4-Methylthiazol-5-yl) vinylthio] 1-3-cefm 14-sodium rubonate, 、 β-[(Ζ)-2-(2-aminothiazole 1-4-) 1) 2-Methoxyiminoacetamide] — 3— [(Ζ) — 2— (4-methylthiazolyl-5-yl) vinylthio] 13-cef-14-force Sodium rubonate, Bivaloyloxymethyl Ί β— [(Ζ) — 2— (2-Aminothiazoyl 4-41) 1 2-Methoxyiminoacetamide] 1 3— [(Ζ)-2-(4— Methylthiazole-5-yl) vinylthio] —3-cef-4-1carboxylate hydrochloride, 1-isopropoxycarbonyloxy Chill Ί β-

C (Ζ) — 2- (2-aminothiazol-1-yl) -1-2-methoxyiminoacetamide] — 3-— ((Ζ) — 2 -— (4-methylthiazol-5-yl) vinylthio] 1-3-Cefem-4-carboxylate hydrochloride, 1-acetoxityl Ίβ 1 [(Ζ) -2- (2-aminothiazol-4-yl) 1-2-methoxyiminoacetamide] — 3— [(Ζ) -2- (4-Methylthiazol-5-yl) vinylthio] -1-cefum-4-carboxylate hydrochloride, (5-methyl-2-oxo-1 1,3-dioxolen-1 4 —Yl) Methyl Ί β— [(Ζ) — 2— (2—aminotinazoyl 4-yl) 1 2—Methoxyiminoacetamide] 1 3— [(Ζ)-2-(4— Methylthiazol-5-yl) vinylthio] —3-Sefm—4—force Rupoxylate hydrochloride, Ίβ — [(Ζ) -2- (2-Aminothiazol-4-yl) I 2—Methoxyiminoacetamide] — 3— [(Ζ) — 2— (Thiazoyl 5-yl) vinylthio] — 3-Cepham— 4 [(Ζ) — 2— (2-aminothiazol-1-yl) 1-2-methoxyiminoacetamide] — 3— [(Ζ)-2-(thiazol-1-5-yl) Vinylthio] — 3-Cefem-4-carboxylate hydrochloride, 7 / 3— [(Z) —

2- (2-aminothiazole-41-yl) -1-2-Methoxyiminoacetamide] ―

3-[(Z) -2- (2-Methylthiazolyl-5-yl) vinylthio] 1-3-cefume 4-sodium carboxylate and 7yS—C (Z) -2- (2-aminothiazole 1—41) — 2—Methoxyiminoacetamide) — 3— [(Z)-2-

(Thiazolyl-4-yl) vinylthio] -3-sodium-1-carboxylate.

 Above all, Ίβ — [(Ζ) —2— (2-aminothiazoyl 4-yl) -1-2-hydroxyhydroxyminoacetamide] -3-C (Ζ) —2 -— (4-methylthiazole -5-yl) vinylthio] — 3-Cefem-4 monosodium rubonate, 7 — [

(Ζ)-2-(2-Aminothiazol-1-41) 1 2-Methoxyiminoacetamide] — 3— [(Ζ) -2-(4-Methylthiazol-5-yl) Vinylthio] — 3-Cefem-4-Sodium carboxylate, Bivaloyloxymethyl 71

[(Ζ) — 2— (2-aminothiazoyl 4-yl) 1-2-methoxyiminoacetamide] 1-3— [(Ζ) — 2— (4-methylthiazoyl-5-yl) vinylthio

1-3-Cephem-4-carboxylate hydrochloride, 1-isopropoxycarboxyloxyshetyl [(ζ) —2- (2-aminothiazol-41-yl)-

2-Methoxyximinoacetamide] — 3 — [(Z) -2- (4-Methylthiazolyl-5-yl) vinylthio] —3-Cefem-4-carboxylate hydrochloride, ββ [(Ζ) — 2— (2-aminothiazole-4-yl) -1-2-methoxyiminoacetamide] — 3— [(Ζ) -1-2- (thiazole-5-yl) vinylthio] — 3— Cefum—sodium 4-carboxylate and bivaloyoxymethyl 7 S—

(Z) — 2— (2-Aminothiazoyl 4-yl) 1 2-Methoxyiminoacetamide] 1 3 — [(Z) -2- (thiazole-5-yl) vinylthio] — 3 —Sephem— 4-carboxylate hydrochloride is particularly preferred.

The cephalosporin compound (I) of the present invention can be produced by any one of the following production methods 1 to 3.

(Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, respectively, and Y is a halogen atom such as chlorine, bromine or iodine, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and butanesulfonyl. And a leaving group such as an arylsulfonyloxy group such as ethoxy, and an arylsulfonyloxy group such as phenylsulfonyloxy and tolylsulfonyloxy.

Compound (IV) is described in Literature. Antibiotics. 44, 1422-1431, 1991 and J. Antibiotics. 43, 1160-1168, 1990) or a compound prepared by a conventional method based on these documents. Similarly, compound (V) is also prepared by a conventional method based on the above two documents.

 In the production method 1, the compound (IV) or a salt thereof is added in an amount of about 1 to 5 moles, preferably about 1 to 5 moles.

By reacting 1 to 3 times the molar amount of compound (V) or a salt thereof, the compound (V)

I) or a method for producing a salt thereof.

 In this reaction, a solvent that does not inhibit the reaction (eg, water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethyl acetate, dimethyl sulfoxide, etc., or a mixture thereof). When the compound (V) is subjected to the reaction in a free form, the reaction is preferably performed in the presence of a base.

 The base to be used is not particularly limited. Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal carbonates such as sodium hydrogen carbonate. Metal bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, alkali metal alkoxide such as potassium t-butoxide, and organic bases such as pyridine, triethylamine, disopropylethylamine and the like. No.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 120 to 80 ° C, preferably at 120 to 30 ° C. The reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.

(In the formula, R ¹ , R ² , R ³ and R ⁴ are as defined above.)

 Compound (VI) is described in the literature (J. Antibiotics. 44, 1422-1431, 1991 and J. Antibiotics.

Antibiotics. 43, 1160-1168, 1990) or a compound prepared by a conventional method based on these documents. Similarly, the compound (VI

I) is also prepared by a conventional method based on the above two documents. In the production method 2, the compound (VI) or a salt thereof is added in an amount of about 1 to 5 moles, preferably about This is a method for producing the compound (I) or a salt thereof by reacting the compound (VII) in an amount of 1 to 3 moles.

 In this reaction, a solvent that does not inhibit the reaction (eg, water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc., or a mixture thereof). When the compound (VI) is subjected to the reaction in a free form, the reaction is preferably performed in the presence of a base.

 The base to be used is not particularly limited. Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal carbonates such as sodium hydrogen carbonate. Metal bicarbonate, sodium methoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium t—Alkali metal alkoxide such as butoxide, pyridine, triethylamine, diisopropylethylamine, and other organic bases Is mentioned.

 This reaction may be carried out in the presence of sodium iodide, sodium thiocyanate and the like.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 120 to 80 ° C, preferably at −20 to 30 ° C. The reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.

OS

) (I

You

(In the formula, R ¹ , R ² , R ³ and R ⁴ are as defined above.)

The compound (VIII) is _c Preparation 3 are those prepared according to per se known methods, the compound (II) or a salt thereof, about 1 to 3 molar equivalents, preferably about 1 to 1. This is a method for producing a compound (I) or a salt thereof by reacting a 5-fold molar amount of the compound (VIII) or a reactive derivative at a carboxyl group or a salt thereof. In the reaction, the compound (VIII) is used as a free carboxylic acid or as a reactive derivative thereof. That is, as a free acid or a salt thereof such as sodium, potassium, calcium, triethylamine, pyridine or the like; an acid halide (eg, acid chloride, acid bromide, etc.); an acid anhydride; a mixed acid anhydride [eg, Substituted phosphoric acid (eg, dialkyl phosphoric acid), alkyl carbonate (eg, ethyl ethyl carbonate), active amide (eg, amide with imidazole), ester (eg, cyanomethyl ester, 412-trophy) , Etc.) as a reactive derivative.

 When the compound (VIII) is used in the reaction as a free acid or a salt thereof, the reaction is preferably performed in the presence of a condensing agent. Examples of the condensing agent used include Ν, N'-disubstituted carbodiimides such as Ν, Ν'-dicyclohexyl carbodiimide, and 1-ethyl-3--3- (3-dimethylaminopropyl) carbodiimide. Carbodiimid compounds such as imido, Ν-cyclohexylΝ, morpholinoethylcarbodiimide, Ν-cyclohexyl mono-, mono (4-ethylethylcyclohexyl) carbodiimid, Ν, N Dehydrating agents such as azolide compounds such as' -carbonyldiimidazole, Ν, N'-thionyldiimidazole. When these condensing agents are used, the reaction is considered to proceed via a reactive derivative of the carboxylic acid.

 This reaction is usually performed in an inert solvent. Examples of the solvent include water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, Ν, Ν-dimethylformamide, Ν, ジ メ チ ル -dimethyla. Cetamide, dimethyl sulfoxide, etc., or a mixture thereof).

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually at 120 to 20 ° C, preferably at 120 to 0 ° C. The reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours. Further, the 7-aminocephalosporin compound (II) can be produced by the following production method 4 or 5.

 5¾

(Wherein, R ³ R ⁴ and Y have the same meanings as described above, and R ⁷ represents a hydrogen atom or an amino protecting group.)

 Compound (IX) is described in the literature (J. Antibiotics. 44, 1422-1431, 1991 and J.

Antibiotics. 43, 1160-1168, 1990) or a compound prepared by a conventional method based on these documents. In production method 4, compound (IX) or a salt thereof is reacted with about 1 to 5 moles, preferably about 1 to 3 moles of compound (V) or a salt thereof, and R ⁷ is removed if necessary. A compound (II) or a salt thereof.

The reaction of compound (IX) or a salt thereof with compound (V) or a salt thereof can be carried out in the same manner under the conditions described in Production method 1. In this reaction, R ⁷ of compound (IX) is an amino protecting group It is preferred that In this case, a compound in which the amino group at the 7-position in the general formula (II) is protected is obtained, and the protecting group can be eliminated by a method known per se.

As the amino protecting group for R ^7, a protecting group generally used in the art can be used. Examples thereof include phenylacetyl, phenyloxyacetyl, 2-ceenylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl, BOC, trityl, phthaloyl, and 0-hydroxybenzylidene.

As a method for removing the amino protecting group, a method known per se is used. For example, when the amino-protecting group is phenylacetyl, phenyloxyacetyl, 2-phenylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl, etc., it is possible to obtain methanol through iminochlorination with phosphorus pentoxide. When the amino-protecting group is BOC, trityl, 0-hydroxybenzylidene, etc., a method of treating with an acid (for example, hydrochloric acid, formic acid, trifluoroacetic acid, etc.), etc., and an amino-protecting group When is phthaloyl or the like, an Ing-Manske method using hydrazine and the like can be mentioned.

 in

(Wherein, R ³ , R ⁴ and R ⁷ have the same meanings as described above.)

 Compound (X) is a compound described in the literature (L Antibiotics. 44, 1422-1431, 1991 and J. Antibiotics. 43, 1160-1168, 1990), or is a conventional compound based on these documents. It is prepared by a technique.

 In the production method 5, the compound (X) or a salt thereof is added in a molar amount of about 1 to 5 times, preferably about 1 to 5 times.

Reacting up to 3 times the molar amount of compound (VII) or a salt thereof, and converting R ⁷ if necessary This is a method for producing compound (II) or a salt thereof by elimination.

The reaction between compound (X) or a salt thereof and compound (VII) or a salt thereof can be carried out in the same manner under the conditions described in Production method 2, but R ⁷ of compound (X) is an amino protecting group Is preferred. In this case, a compound in which the amino group at the 7-position in the general formula (II) is protected is obtained, and the protecting group can be removed by a method known per se.

 The amino protecting group to be used and the method for elimination thereof are the same as those described in the above-mentioned Production method 4.

 Among the 7-aminocephalosporin compounds (II), preferred is diphenylmethyl 75-amino-3-([Ζ] -12- (4-methylthiazolyl-5-yl) vinylthio] —3-cefm — 4-Carboxylate hydrochloride, Vivaloyloxymethyl 7) 6-Amino-3-C (Ζ) -2- (4-Methylthiazoyl 5-yl) vinylthio] — 3-Cefem-4-carboxylate hydrochloride , 1-Isopropoxycarbonyloxyshetyl 7 ^ -Amino-3-([—) — 2- (4-Methylthiazolyl-5-yl) vinylthio] —3-Cefumeu 4-carboxyxylate hydrochloride , 1-acetoxitytyl 7 ^-amino-3-[(2)-2-(4-methylthiazolyl-5-yl) vinylthio] 13-cefm-4-carboxylate hydrochloride, (5-methyl One 2-oxo-1, 3-dioxolen 4-yl) Methyl 7 / 3-amino-3-([Ζ) -2- (4-methylthiazol-5-yl) vinylthio] -13-cefm-4-carboxylate hydrochloride, diphenylmethyl 75 —Amino _ 3— [(Ζ) — 2— (thiazolyl-5-yl) vinylthio] — 3-cephum-4-monocarboxylate hydrochloride and bivaloyoxymethyl 7 ^ 3—amino-3 — [(Z) —2- (thiazol-15-yl) vinylthio] -13-cefm-4-carboxylate hydrochloride.

Among them, diphenylmethyl 7; 6-amino-3-([Z) -2- (4-methylthiazo-1-yl-5-yl) vinylthio] —3-cefum-4-carboxylate hydrochloride, bivaloyloxymethyl 7 / 3—amino 3 — [(Z) —2— (4—me Thithiazol-5-yl) vinylthio] -13-cebum-4-carboxylate hydrochloride, 1-isopropoxycarbonyloxyshethyl 7) δ-amino-3-[(Ζ) -2-( 4 —Methylthiazol-5-yl) vinylthio] —3-cefm —4-carboxylate hydrochloride, diphenylmethyl 7; 6-—amino-3 -— [(Ζ) —2 — (thiazotyl-5-yl) ) Vinylthio] 1-3-Cepum 4 —Carboxylate hydrochloride and Bivaloyloxymethyl 7 iS—Amino-3 -— [(Z) -2- (thiazolyl-5-yl) vinylthio] — 3 —Sebum—4 —Carboxylate hydrochloride is particularly preferred.

 The cephalosporin compound (I) thus synthesized can be converted to an arbitrary purity by appropriately performing known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, and recrystallization. Can be collected.

In the cephalosporin compound (I) obtained by the above method, when R ³ is a lipoxyl group or a salt thereof, a reactive derivative thereof (for example, an alkali metal salt such as a sodium salt or a potassium salt) may be used if necessary. Salt, an alkaline earth metal salt such as calcium, an organic base salt such as triethylamine salt, pyridine salt, etc.), and R ³ is esterified with a ester of a prodrug that is easily hydrolyzed in vivo by a known method. The cephalosporin compound (I) obtained by the above-mentioned method usually has a protecting group, and the elimination of the protecting group. Decomposes with an acid depending on the type of the protecting group (for example, formyl, BOC, trityl, tetrahydroviranyl, etc. Decomposition by acid such as chloroacetic acid), decomposition by hydrazine (for example, phthaloyl is decomposed by hydrazine), decomposition by catalytic reduction (for example, benzyl, benzyloxycarbonyl, etc. is decomposed by palladium-carbon etc.), etc. These can be carried out by appropriately selecting a conventional method used in lactam synthesis, peptide synthesis and the like.

Cephalosporin compound (I) and its pharmaceutically acceptable salts are In addition, it is useful as a prophylactic / therapeutic agent for bacterial infections. For example, diseases caused by bacteria in mammals (eg, humans, dogs, cats, dogs, dogs, rats, mice, etc.) (for example, It can be used parenterally (intravenously or intramuscularly) and orally as a preventive and therapeutic agent for suppurative diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.

 When the cephalosporin compound (I) and a pharmaceutically acceptable salt thereof are used as a pharmaceutical preparation, usually a pharmaceutically acceptable carrier and excipient (eg, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.) Binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.), disintegrants (eg, calcium carboxymethylcellulose, talc, etc.) Or the like to form a pharmaceutical composition, which can be orally administered in the form of capsules, tablets, fine granules, granules, dry syrups and the like into a formulation suitable for oral administration.

 Further, it is preferable to further add an organic acid to the pharmaceutical composition from the viewpoint that solubility in the digestive tract is increased and absorption into the blood becomes easier.

 The organic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid, and benzoic acid. And organic carboxylic acids. The amount of the organic acid is usually 0.01 to 20 mol, preferably 0.02 to 2 mol, per 1 mol of the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof. .

 The dosage of the cephalosporin compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the subject to be administered, the condition, and the like. Administer parenterally or orally about 1 to 40 mg / kg body weight about 1 to 4 times a day.

In particular, R ³ is an esterified carboxyl group that is hydrolyzed in vivo The orally administered cephalosporin compound (I) and its pharmaceutically acceptable salts are rapidly absorbed into the blood from the gastrointestinal tract, and the metabolite R ³ is a cephalosporin whose lipoxyl group is It becomes compound (I) and its pharmaceutically acceptable salt, shows a high blood concentration, and maintains this high blood concentration.

Further, the cephalosporin compound (I) wherein R ³ is a carboxyl group and a pharmaceutically acceptable salt thereof can be administered rectally, for example, after being formulated in a suppository or a storage enema or the like. Alternatively, the compound or a salt thereof can be formulated as an injection.

 The cephalosporin compound (I) and a pharmaceutically acceptable salt thereof may be used for treating other systemic symptoms caused by other antibacterial active substances, such as antibacterial agents (benicillins, aminoglycosides, cephalosporins, etc.) or bacterial infection. May be used in combination with drugs (eg, antipyretics, analgesics, anti-inflammatory agents).

 Hereinafter, the physical properties and production methods of the cephalosporin compound (I) and the amino cephalosporin compound (II) of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. Absent.

Example 1

 1 β-[(Ζ) -2- (2-aminothiazoyl 4-yl) 1-2-hydroxyiminoacetamide] 1-3-[(Ζ) -2- (4-methylthiazol-5-yl) Vinylthio] — 3-Cefem — Sodium 4-carboxylate

 (1) 4.5 g of 4-methyl-5-thiazolcarboxaldehyde and 23.5 g of carbon tetrabromide were dissolved in 27 Om1 of methylene chloride and cooled to 5 ° C. Triphenylphosphine 23.28 was added in portions at 5 to 10 ° C, and after stirring at the same temperature for 20 minutes, methylene chloride was distilled off under reduced pressure. To the residue was added 200 ml of a mixed solution of ethyl acetate-methylene chloride (3: 1), and the precipitated crystals were collected by filtration. Crystals of 4-monomethyl-5- (2,2-dibromovinyl) thiazole 12.5 g was obtained.

Ή-NMR (DMS 0- d ₆ ):

_{2.45 (s, 3H, -CH 3} ), 7.90 (s, 1H, - CH =), 9.16 (s, 1H, C 2 -H). (2) 11.5 g of 4-methyl-5- (2,2-dibromovinyl) thiazol obtained in (1) of Example 1 was dissolved in 22 ml of tetrahydrofuran, and the solution was heated to 140 ° C. Then, 83.5 ml of 1.6 M n-butyllithium hexane solution was added dropwise, and the mixture was stirred at the same temperature for 25 minutes. Add 300 ml of ethyl acetate and add 100% aqueous citric acid 300 m

After washing with 1, the aqueous layer was extracted with 100 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 300 ml of a saturated saline solution, dried (Glauber's salt), and the ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate), and the solvent of the desired fraction was distilled off under reduced pressure to obtain 1.63 g of 4-methyl-5-ethenylthiazol. .

IRV (N ujor) cm " ¹ : 3305, 1655.

^ -NMR (DMS 0- d ₆ ):

_{2.45 (s, 3H, -CH 3} ), 4.75 (s, 1H, - C three CH), 8.98 (s, 1H , C 2 - H).

 (3) 1.6 g of 4-methyl-5-ethenylthiazol obtained in (2) of Example 1 was dissolved in 41 ml of tetrahydrofuran, and 4.67 g of triphenylmethyl mercaptan and potassium tertiary salt were dissolved. 1.89 g of grade butoxide was added, and the mixture was stirred at 60 to 70 ° C for 1.5 hours. After adding 200 ml of chloroform, washing with 200 ml of a saturated saline solution, and drying (glauberinite), the form of chloroform was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform), and the solvent of the target fraction was distilled off under reduced pressure. 40 ml of a mixture of n-hexane-isopropyl ether (1: 1) was added, and the precipitate was collected by filtration. Crystals of 4-methyl-5-[(Z) -2-tritylthiovinyl] thiazole 1.5 5 g were obtained.

IRV (Nu j 0 r) cm- ¹ : 1595.

^ -NMR (DMS 0-d ₆ ):

2.37 (s, 3H, - CH 3), 5.83 (d, J = 10.5Hz, 1H, - CH =),

 6.74 (d, J = 10.5Hz, 1H,-SCH =), 7.00-7.70 (m, 15H, Ph),

_{8.95 (s, 1H, C 2} -H).

(4) 4-methyl-5-[(Z) -2-tritylthio obtained in (3) of Example 1 Ovinyl] 1.45 g of thiazole was dissolved in 14.5 ml of methylene chloride, 14.5 ml of chloroform and 14.5 ml of methanol, and 0.3 ml of pyridine and 925 mg of silver nitrate were dissolved. A solution of 46 ml of water was added dropwise at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The precipitate was collected by filtration, washed successively with methanol and methylene chloride, and crystallized with 4-methyl-5-[(Z) -2-mercaptovinyl] thiazol silver salt 1.33 g (purity 72%) I got

 (5) 8-29 mg (purity: 72%) of 4-methyl-5-[(Z) -12-mercaptovinyl] thiazol silver salt obtained in (4) of Example 1 was added to acetonitrile (19 ml). After suspending, adding 1.35 g of sodium iodide and stirring at room temperature for 30 minutes, diphenylmethyl 、 β-[(Ζ) -2- (2—tritylaminothiazoyl-1-yl) was added under ice-cooling. L) -1-Trityloxyiminoacetamide] -13-Methanesulfonyloxy-13-cef-4-carboxylate 1.99 g was added, and the mixture was stirred at the same temperature for 1.5 hours. 10% aqueous citric acid was added, and acetonitrile was distilled off under reduced pressure. Add 200 ml of ethyl acetate, wash twice with 100 ml of 10% aqueous solution of citric acid and 100 ml of saturated saline solution in that order, dry (Glauber's salt) and distill the ethyl acetate under reduced pressure. I left. The residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate), the solvent of the target fraction was distilled off under reduced pressure, and difuunylmethyl Ίβ-[(Ζ) 1-2- (2-tritylaminothia) Zol _ 4 -yl) 1-2-trityloxyiminoacetamide] 1-3-((Ζ)-2-(4-methylthiazoyl-5 -yl) vinylthio) 1-3-cefm- 1.53 g of 4-carboxylate was obtained.

IRV (N ujor) cm— ¹ : 1786, 1728, 1678, 1528.

iH—NMR (DMS 0- d ₆ ):

2.44 (s, 3H, -CH ₃ ), 3.80-4.00 (m, 2H, C ₂ -H ₂ ),

5.31 (d, J = 5.0Hz, 1H, C 6 - H), 5.90 (dxd, J = 5.0, 8.0Hz, 1H, C 7 -H),

6.60 (d, J = 10.0Hz, 1H, = CH-). 6.66 (s, 1H, aminothiazole C ₅ — H),

 6.96 (s, 1H, -CO 2 CH), 6.80-7.80 (m, pole, Ph),

7.01 (d, J = 10.0Hz, 1H, - SCH =), 8.72 (b- s, 1H, aminothiazole C 2 - NH-), 8.98 (s, 1H, thiazole C ₂ -H), 9.89 (d, J = 8.0Hz, 1H, -CONH-).

 (6) Diphenylmethyl 7 iS — ((Z) —2- (2-tritylaminothiazo-1-yl 4-yl) —2_trityloxyminose obtained in Example 1, (5) Evening mid) 1 3-[(Z)-2- (4-methylthiazol-5-yl) vinylthio]-3-cefm-4-carboxylate 1.5 g to 1.5 ml of anisol Trifluoroacetic acid (4.5 ml) was added, and the mixture was stirred for 1 hour under ice cooling. After adding n-hexane and separating the separated oily substance by decantation, a mixed solution of n-hexane-isopropyl ether was added, and the precipitate was collected by filtration. 4.96 ml of 80% formic acid was added to 1.24 g of the obtained powder, and the mixture was stirred at 20 to 30 ° C. for 1 hour. A mixed solution of isopropyl ether-jetilether (2: 1) was added, and the precipitate was collected by filtration. The obtained powder (578 mg) was suspended in water (58 ml), and the suspension was adjusted to pH 7.5 with saturated sodium bicarbonate water and dissolved. And eluted). The desired fraction was concentrated under reduced pressure to about 2.4 g, and then freeze-dried to obtain 346 mg of a powder of the title compound.

IRV (N ujor) cm " ¹ : 1762, 1611, 1529.

^ -NMR (DMS 0- d ₆ ):

2.42 (s, 3H, -CH _S ), 3.00-4.00 (m, 2H, C ₂ -H ₂ ),

5.09 (d, J = 5.0Hz, 1H, C ₆ -H), 5.65 (dxd, J = 5.0, 8.0Hz, 1H, C ₇ _H),

6.55 (d, J = 10.0Hz, 1H, = CH_). 6.64 (s, 1H, aminothiazole C ₅ -H),

6.83 (d, J = 10.0Hz, 1H, -SCH =), 7.10 (b ~ s, 2H, -NH ₂ ),

8.93 (s, 1H, thiazole C ₂ — H), 9.41 (d, J = 8.0Hz, 1H, — C0NH—),

 11.10-12.00 (br, 1H, -OH).

Example 2

 7 β-[(Z) 1 2— (2-aminothiazoyl 4-yl) 1-2-methoxyminoacetamide] 1 3 — [(Z) —2— (4-methylthiazol-5-yl ) Vinylthio] — 3-cefume 4-sodium carboxylate

(1) 4-methyl-5-[(Z) —2-mercapto obtained in (4) of Example 1 Vinyl) thiazol silver salt 539 mg was suspended in acetonitrile 11 ml, sodium iodide 895 mg was added, and after stirring at room temperature for 30 minutes, diphenylmethyl 1β-[(Ζ) was added under ice cooling. -2--(2-tritylaminothiazolyl-4-yl) -1-2-methoxyiminoacetamide] -1-3-methanesulfonylooxy-3-3-cefm-14-carboxylate 1.10 g Was added and stirred at the same temperature for 1 hour. 10% aqueous citric acid was added, and acetonitrile was distilled off under reduced pressure, 200 ml of ethyl acetate was added, and the mixture was washed sequentially with 100% aqueous citric acid 200 ml and saturated saline 100 ml. Thereafter, it was dried (Glauber's salt) and ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl benzene monoacetate), and the solvent of the target fraction was distilled off under reduced pressure to obtain diphenylmethyl Ίβ-[(Ζ) -2- (2-tritylaminothia. Zol — 4-yl) 1 2-Methoxyiminoacetamide]-3-((Ζ)-2-(4-Methylthiazo 1 -5-yl) vinylthio)-3-Cefem-41 1.17 g of carboxylate was obtained.

IRV (N ujor) cm " ¹ : 1780, 1715.

! H-NMR (DMS 0- d ₆ ):

2.44 (s, 3H, -CH ₃ ), 3.50-4.10 (m, 2H, C ₂ -H ₂ ), 3.83 (s, 3H,-0CH ₃ ),

5.23 (d, J = 5.0Hz, 1H, C 6 - H), 5.76 (dxd, J = 5.0, 8.0Hz, 1H, C 7 -H),

6.56 (d, J = 10.0Hz, 1H, = CH_). 6.76 (s, 1H, aminothiazole C ₅ -H),

 6.93 (s, 1H, -CO 2 CH <), 7.10 (d, J = 10.0Hz, 1H,-SCH =),

7.10-7.80 (m, 25H, Ph), 8.60-9.00 (br, 1H, aminothiazole C ₂ -H),

8.98 (s, 1H, thiazole C ₃ -H), 9.59 (d, J = 8.0Hz, 1H, -CONH-).

(2) difuunylmethyl 1 β-[(Ζ) —2- (2-tritylaminothiazo-1-yl-4-yl) -12-methoxyiminoacetamide obtained in (1) of Example 2 ] — 3— [(Ζ) — 2— (4-Methylthiazoyl 5-yl) vinylthio] — 3—Cefem-4-carboxylate 1.13, 1.1 ml of anisol and 3 ml of trifluoroacetic acid 3 3 ml was added, and the mixture was stirred for 1 hour under ice cooling. n-Hexane was added, and the separated oil was separated by decantation. A mixture of ter was added, and the precipitate was collected by filtration. To 80 mg of the obtained powder, 3.2 ml of 80% formic acid was added, and the mixture was stirred at 20 to 30 ° C for 1 hour. A mixed solution of isopropyl ether and ethyl ether (2: 1) was added, and the precipitate was collected by filtration. The obtained powder (60 mg) was suspended in water (60 ml), dissolved in saturated aqueous sodium hydrogen carbonate to adjust the pH to 7.5, and then dissolved in column chromatography (diaion HP-216 ml, aqueous acetonitrile solution). (Elution). The desired fraction was concentrated under reduced pressure to about 80 Omg, and then lyophilized to obtain 26 Omg of a powder of the title compound.

IRV (N uj 0 r) cm— ¹ : 1765, 1655, 1620.

^ -NMR (DMS 0- d ₆ ):

2.42 (s, 3H, -CH ₃ ), 3.20-4.00 (m, 2H, C ₂ -H ₂ ), 3.84 (s, 3H, -0CH ₃ ), 5.11 (d, J = 5. OHz, 1H, C _{6 - H), 5.65 (dxd} , J = 5.0, 8.0Hz, 1H, C 7 -. H), 6.56 (d, J = 10.5Hz, 1H, = CH-) 6.73 (s, 1H, aminothiazole C 5 _H ),

6.88 (d, J = 10.5Hz, 1H, -SCH =), 7.19 (bs, 2H, - NH 2),

8.94 (s, 1H, thiazole C ₃ -H), 9.55 (d, J = 8. OHz, 1H,-C0NH-).

Example 3

Diphenylmethyl 7) 5-amino-3-([(Z) -12- (4-methylthiazo-l-5-yl) vinylthio] —3-cefm-4-carboxylate hydrochloride (1) Example 1 (4) Dissolve 1.97 g of the 4-methyl-5-[(Z) -2-mercaptovinyl] thiazol silver salt obtained in Step 4 in 45 ml of acetonitrile, and add 4.83 g of sodium iodide. The mixture was stirred at room temperature for 30 minutes. At 5 ° C., 4.66 g of diphenylmethyl 7 yS-phenylacetamide-3-methanesulfonyloxy-1-cephem-4-carboxylate was added, and the mixture was stirred at the same temperature for 45 minutes. 50 ml of 10% aqueous solution of citrate was added thereto, and after acetonitrile was distilled off under reduced pressure, 150 ml of ethyl acetate was added, and the insoluble matter was filtered. After the ethyl acetate layer was separated, it was washed with 150 ml of a saturated saline solution and dried (glauberin). The ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with ethyl benzene monoacetate). The solvent of the target fraction was distilled off under reduced pressure to obtain diphenylmethyl 7-phenylacetamido 3 — 4.0 g of a foamy powder of [(Z) —2- (4-methylthiazol-5-yl) vinylthio] -13-cephe-4-carboxylate was obtained.

IRV (N ujor) cm- ¹ : 1780, 1665.

 — NMR (DMSO-de):

2.44 (s, 3H, -CH ₃ ), 3.55 (s, 2H, -CH ₂ CO-),

3.70,4.00 (ABq, J = 16.0Hz, 2H, C 2H 2), 5.19 (d, J = 5.0Hz, 1H, C 6 - H),

5.75 (dxd, J = 5.0, 8.0Hz, 1H, C ₇ -H), 6.57 (d, J = 10.5Hz, 1H, = CH-),

6.94 (s, 1H, -CO 2 CH <), 7.09 (d, J = 10.5Hz, 1H, -SCH =),

7.10-7.70 (m, 15H, Ph), 8.98 (s, 1H, thiazole C ₂ -H),

 9.14 (d, J-8.0Hz, 1H, —COM—).

 (2) 68 Omg of phosphorus pentachloride was suspended in 20 ml of methylene chloride, 0.26 ml of pyridine was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Diphenylmethyl 7-phenylacetamide-3-([Z] -2- (4-methylthiazolyl-5-yl) vinylthio] -13-cefm-4-carboxylate obtained in (1) of Example 3 70 Omg was added, and the mixture was further stirred at the same temperature for 1 hour. — After cooling to 40 ° C, 4.4 ml of methanol was added dropwise, and the mixture was stirred at 130 to 120 ° C for 20 minutes. Water 4.4m

Add 1 and stir at 0 ° C for 20 minutes, then add methylene chloride (30 ml), wash twice with 10% saline (50 ml), dry (Glauber's salt), and then add 8.68 N 0.07 ml of a hydrogen chloride isopropanol solution was added, and methylene chloride was distilled off under reduced pressure. Ethyl ether was added to the residue, and the precipitate was collected by filtration to obtain 47 Omg of a powder of the title compound.

IRV (Nu jor) cm— ¹ : 1785, 1760.

 'H-NMR (DMSO-de):

2.43 (s, 3H, -CH ₃ ), 3.97 (b-s, 2H, C ₂ -H ₂ ), 5.10-5.40 (m, 2H, C ₆ .i-H),

6.56 (d, J = 10.5Hz, 1H, = CH-). 6.95 (s, 1H,-C0 ₂ CH <),

 7.09 (d, J = 10.5Hz, 1H,-SCH =), 7.10-7.70 (m, 10H, Ph),

8.97 (s, 1H, thiazole C ₂ -H), 8.00-10.50 (br, 3H,-N + H ₃ ).

Example 4 7 β-[(Z) -2- (2-Aminothiazol-4-yl) -1-2-Methoxyxyminoacetamide] — 3 — [(Z) —2— (4-Methylthiazol-5-yl) (Vinylthio) — 3-Cefem — 4 Sodium rubonate

 (1) diphenylmethyl 7 δ-amino-3-[(Z) -2- (4-methylthiazolyl-5-yl) vinylthio] —3-cef-4-1carboxy obtained in Example 3 (2) 40 mg of hydrochloride hydrochloride and 47 mg of (Z) -2- (2-tritylaminothiazol-1-yl) -12-methoxyiminoacetate dicyclohexylamine were suspended in 30 ml of methylene chloride, At −10 ° C., 0.12 ml of pyridine and 0.09 ml of phosphorus oxychloride were sequentially added, and the mixture was stirred at the same temperature for 15 minutes. 100 ml of ethyl acetate was added, and the mixture was washed successively with 100% citric acid aqueous solution and 100 ml of a saturated saline solution, dried (Glauber's salt), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate), the solvent of the desired fraction was distilled off under reduced pressure, and diphenylmethyl Ίβ-[(Ζ) —2- (2-tritylaminothiazole- 4-yl) 1 2-Methoxyiminoacetamide] 1-3-[(Ζ)-2--(4-methylthiazo-l-yl 5-yl) vinylthio]-3- cefm-4-carboxyl 59 Omg was obtained.

 IR and iH-NMR data were consistent with the compound obtained in Example 2, (1).

 (2) The title compound was obtained in the same manner as in Example 2, (2).

 IR and 'H-NMR data were consistent with the compound obtained in Example 2, (2). Example 5

 Bivaloyloxymethyl 7; δ-amino-3-[(Ζ) -2- (4-methylthiazol-5-yl) vinylthio] —3-cef-14-carboxylate hydrochloride

(1) diphenylmethyl Ίβ-phenyl obtained in Example 3 (1) —3 -— [(Ζ) -2- (4-methylthiazo-1-yl 5-yl) vinylthio] —3 —Sefm—4-carboxylate 4.0 ml of anisol and 12.2 ml of trifluoroacetic acid were added to 4.Og, and the mixture was stirred for 1 hour under ice cooling. Isopropyl ether 100 ml was added, and the precipitate was collected by filtration, and Ί ^ -phenylacetamide_3 — [(Z) -12- (4-methylthiazo-1-yl-5-yl) vinylthio] —3-sefm-4-1carbon 2.42 g of acid powder was obtained.

IRV (N ujor) cm— ¹ : 3260, 1770, 1700, 1645.

 »H-NMR (DMSO-de):

2.45 (s, 3H, -CHs) , 3.53 (s, 2H, - CH 2 CO-),

3.62, 4.01 (ABq, J = 17.5Hz, 2H, C 2H 2), 5.14 (d, J = 5.0Hz, 1H, C 6 -H), 5.67 (dxd, J = 5.0, 8.0Hz, 1H, C ₇ — H), 6.57 (d, J = 10.0 Hz, 1H, = CH—),

 7.08 (d, J = 10.0Hz, 1H, -SCH =), 7.10-7.40 (m.5H, Ph),

9.00 (s, 1H, thiazole C ₂ -H), 9.10 (d, J = 8.0Hz, 1H, -CONH-).

 (2) 7 ^ -phenylacetamido 3 _ [(Z) -2- (4-methylthiazo-1-yl 5-yl) vinylthio] obtained in (1) of Example 5—3-cefume 4-carboxylic acid Dissolve 500 mg in 2.5 ml of N, N-dimethylformamide, add 106 mg of potassium acetate and 380 mg of bivaloyloxymethyl peroxide at —5 and add the solution. Stirred at temperature for 1 hour. After adding 150 ml of ethyl acetate, the mixture was washed successively with 10% aqueous citric acid, 2% saline, saturated aqueous sodium bicarbonate and 100 ml of saturated saline, and dried (glauberium salt), followed by acetic acid under reduced pressure. The ethyl was distilled off. 50 ml of isopropyl ether was added to the residue, and the precipitate was collected by filtration. Bivaloyloxymethyl 7 yS-phenylacetamide 3-! : (Z) —2- (4-Methylthiazoyl 5-yl) vinylthio] —3-Sefm-4-carboxylate powder 525 mg was obtained.

IRV (Nu jor) cm— ¹ : 3275, 1780, 1755, 1650.

 ^ -NMR (DMSO-de):

1.14 (s, 9H, - C (CH 3) a), 2.46 (s, 3H, - CH 3), 3.53 (s, 2H, - CH 2 CO-), 3.70, 4.05 (ABq, J = 16.0Hz, 2H, C ₂ -H ₂ ), 5.17 (d, J = 5, 0Hz, 1H, C ₆ -H), 5.60-6.00 (m, 3H, C ₇ -H,-C0 ₂ CH _2- ), 6.58 ( d, J = 10.0Hz, 1H, = CH-),

7.00-7.40 (m, 6H, -SCH =, Ph), 9.02 (s, 1H, thiazole C ₂ -H),

9.10 (d, J = 8.0Hz, 1H,-CONH-). (3) Phosphorus pentachloride (53 2 mg) was suspended in methylene chloride (10 ml), pyridine (0.21 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Bivaloyloxymethyl 7 jS-phenylacetamido 3 -— ((Z) -2- (4-methylthiazol-5-yl) vinylthio) —3-cefum—4—obtained in (5) of Example 5 500 mg of carboxylate was added, and the mixture was further stirred at the same temperature for 1 hour. — After cooling to 40 ° C, 3.4 ml of methanol was added dropwise, and the mixture was stirred at 130 to 120 ° C for 20 minutes. Add 3.4 ml of water, stir at 0 ° C for 20 minutes, add 50 ml of methylene chloride, wash twice with 50 ml of 10% saline solution, dry (Glauber's salt) and add 8 ml of water. 0.65 N hydrogen isopropanol solution (0.05 ml) was added, and methylene chloride was distilled off under reduced pressure. 30 ml of ethyl acetate was added to the residue, and the precipitate was collected by filtration to obtain 365 mg of a powder of the title compound.

IRV (N ujor) cm— ¹ : 1785, 1755.

'H-NMR (DMS 0- d ₆ ):

1.15 (s, 9H, -C (CH ₃ ) ₃ ), 2.48 (s, 3H, -CH ₃ ), 3.96 (s, 2H, C ₂ — H ₂ ),

4.20-6.00 (br, 3H, -N + H 3), 5.10-5.40 (m, 2H, C 6 7 -. H),

5.80, 5.94 (ABq, J = 6.0Hz, 2H, -C0 2 CH 2), 6.63 (d, J = 10.0Hz, 1H, = CH -), 7.28 (d, J = 10.0Hz, 1H, - SCH = ), 9.08 (s, 1H, thiazole C ₂ -H).

Example 6

 1-Isopropoxycarbonyloxyshetyl 7 ^ -Amino-3-([(Z) —2- (4-Methylthiazo-1-yl-5-yl) vinylthio] —3-Cefem-4—force ruboxyl hydrochloride

(1) The diphenylmethyl 7 / 3-phenylacetamide obtained in (1) of Example 3-3-[(Z) -2- (4-Methylthiazo-1-yl 5-yl) vinylthio] —3-Sefm 1.3 g of 4-carboxylate was dissolved in 6.5 ml of N, N-dimethylformamide, and 276 mg of potassium acetate and 1-ethyl isopropyl carbonate were added at 15 ° C. 57 g was added, and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate 150 ml was added, and the mixture was washed successively with 10% aqueous citric acid, 2% saline, saturated aqueous sodium bicarbonate, and 100 ml of saturated saline, dried (glauberin), and then dried under reduced pressure. Stay I left. To the residue was added 100 ml of a mixed solution of n-hexane-isopropyl ether (2: 1), and the precipitate was collected by filtration. 1-Isopropoxycarbonyloxexetyl Ίβ-phenylacetamide-3 3 [(Ζ 1.2 g of a powder of) _ 2-(4-methylthiazoyl 5-yl) vinylthio] 13-cefmue 4-carboxylate was obtained.

IRV (N uj 0 r) cm " ¹ : 1759, 1665, 1535.

'H-NMR (DMS 0- d ₆ ):

1.23 (d, J = 6 ΟΗζ , 6H, -. CH (CH 3) 2), 1.50 (d, J = 5.5Hz, 3H, - CH 3),

2.46 (s, 3H, thiazole C ₄ ― CH ₃ ), 3.00-4.20 (m, 2H, C ₂ -H ₂ ),

3.53 (s, 2H, -CH ₂ CO-), 4.40-5.00 (m, 1H, -CH_ (CH ₃ ) ₂ ),

_{5.00-5.30 (m, lH, C 6} - H), 5.50-5.90 (m, 1H, C 7 - H),

6.40-7.00 (m, lH, - C0 2 CH rather), 6.60 (d, J = 10.0Hz, 1H, _SCH =),

7.00-7.60 (m, 6H, = CH- , Ph), 9.01 (s, 1H, thiazole C 2 - H),

 9.10 (d, J = 8.0Hz, 1H,-C0NH-).

 (2) 1.25 g of phosphorus pentachloride was suspended in 24 ml of methylene chloride, 0.49 ml of pyridine was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. 1-Isopropoxycarbonyloxyshethyl 7- (phenylacetamide 13-) obtained in (1) of Example 6

[(Z) -2- (4-Methylthiazol-5-yl) vinylthio] —3-cefum-4-carboxylate 1.18 g was added, and the mixture was stirred at the same temperature for 1 hour. After cooling to _c -40 ° C, 8.1 ml of methanol was added dropwise, and the mixture was stirred at 130 to 120 ° C for 50 minutes. After adding 8.1 ml of water and stirring at 0 ° C for 20 minutes, 10% saline 40 m

1 was added, the pH was adjusted to 2.5 with saturated aqueous sodium hydrogen carbonate, and the two layers were separated. The aqueous layer was extracted with methylene chloride (30 ml), combined with the methylene chloride layer, washed with 10% saline (50 ml), and dried (glauberic acid). 8.68 N Hydrogen chloride isopropanol solution 0.

12 ml was added, and methylene chloride was distilled off under reduced pressure. Getyl ether was added to the residue, and the precipitate was collected by filtration to obtain 964 mg of crystals of the title compound.

IRV (N ujor) cm— ¹ : 1786, 1759. ^-MR (DMS 0- d ₆ ):

1.23 (d, J = 6 OHz , 6H, -CH (CH 3) 2.), 1.50 (d, J = 5.5Hz, 3H, - CH 3),

2.48 (s, 3H, thiazole C ₄ -CH ₃ ), 3.00-4.40 (m, 2H, C ₂ -H ₂ ),

4.50-5.00 (m, 1H, -CH_ (CH 3) 2), 5.00-5.40 (m, 2fl, C ₆ -H, C ₇ -H),

6.40-7.60. (M, 3H, - SCH =, = CH-, - C0 2 CH <), 9.01 (s, 1H, thiazole C 2 -H) Example 7

 1-acetoxitytyl 7 ^ -amino-3-([(Z) —2- (4-methylthiazol-5-yl) vinylthio] —3-cefm-14-carboxylate hydrochloride (1) Example 1 (1) )) Diphenylmethyl 7 ^ -phenylacetamide-3-([(Z) -12- (4-methylthiazol-5-yl) vinylthio] -13-cefm-4-carboxylate 1.2 g of N, After dissolving in 6.0 ml of N-dimethylformamide, 255 mg of potassium acetate and 84 mg of 1-acetoxetyl chloride were added at 5 ° C., and the mixture was stirred at the same temperature for 1 hour. Add 200 ml of ethyl acetate, wash successively with 100 ml of 10% aqueous citric acid, 2% saline, saturated aqueous sodium bicarbonate and 100 ml of saturated saline, dry (Glauber's salt) and remove ethyl acetate under reduced pressure. Distilled off. 100 ml of a mixed solution of n-hexane-isopropyl ether (1: 1) was added to the residue, and the precipitate was collected by filtration. 1-acetoxityl 7 iS-phenylacetamide 3-([Z) 12- (4 —Methylthiazol-5-yl) vinylthio] —3-cef-4-carboxylate powder (960 mg) was obtained.

IRV (Nu jor) cm- ¹ : 3281, 1771, 1647, 1539.

iH—NMR (DMS 0- d ₆ ):

1.48 (d, J = 5.5Hz, 3H,> CHCH 3), 2.03 (d, J = 5.0Hz, 3H, -CH ₃ ),

2.46 (s, 3H, thiazole C ₄ -CH ₃ ), 3.53 (s, 2H, Ph- CH _2- ),

3.70, 4.05 (ABq, J = 18Hz, 2H, C ₂ -H ₂ ), 5.00-5.30 (m, 1H, C ₆ -H),

_{5.50-5.90 (m, 1H, C 7H} ), 6.40-7.60 (m, 7H, - C0 2 CI rather, - SCH =, Ph- H) ,

6.59 (d, J = 10Hz, 1H, = CH_), 9.02 (s, 1H, thiazole C ₂ -H),

9.10 (d, J = 8.0Hz, 1H,-C0NH-). (2) 1.0 g of phosphorus pentachloride was suspended in 20 ml of methylene chloride, 0.39 ml of pyridine was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. 1-acetoxitytyl 7 yS-phenylacetamide obtained in (1) of Example 7 3-[(Z) -2- (4-methylthiazolyl-5-yl) vinylthio] -3-cefume 90 mg of 4-carboxylate was added, and the mixture was further stirred at the same temperature for 1 hour. After cooling to −10 ° C., 1.1 ml of isobutanol was added dropwise, and the mixture was stirred at 110 to 10 ° C. for 50 minutes. After adding 1.1 ml of water and stirring at 0 ° C for 20 minutes, 40 ml of 10% saline was added, the pH was adjusted to 2.5 with saturated aqueous sodium hydrogen carbonate, and the two layers were separated. The aqueous layer was extracted with methylene chloride (30 ml), combined with the previous methylene chloride layer, washed with 10% saline (5 Oml), and dried (glauberite). 8.68 N hydrogen chloride isopropanol solution (0.19 ml) was added, and methylene chloride was distilled off under reduced pressure. Getyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 595 mg of crystals of the title compound.

IRV (N uj 0 r) cm— ¹ : 1782, 1717.

'Η—NMR (DMS 0— d ₆ ):

1.48 (d, J = 5.5Hz, 3H,> CHCH_ 3), 2.04 (d, J = 5. OHz, 3H, -CH 3),

2.48 (s, 3H, thiazole C ₄ -CH _S ), 3.95 (s, 2H, C ₂ -H ₂ ),

_{5.00-5.40 (m, 2H, C 6} - H, C 7 - H), 6.60 (d, J = 10Hz, 1H, - SCH =),

6.80-7.10 (m, 1H,-C0 ₂ C H_ <), 7.25 (d, J = 10Hz, 1H, = CH-),

9.04 (s, 1H, thiazole C ₂ -H).

Example 8

 (5-Methyl-1-oxo-1, 3-dioxolen-1-yl) Methyl Ίβ-amino-3 〔[(Ζ) 2 2- (4-Methylthiazo-l-5 yl) vinylthio] 33— Septum-4-carboxylate hydrochloride

(1) Diphenylmethyl 7β-phenyl obtained from Example 3 (1) 3- (3- (4-Methylthiazoyl-5-yl) vinylthio) — Dissolve 7-12 mg of 3-cef-4-carboxylate in 3.5 ml of Ν, Ν-dimethylformamide, and add 135 mg of potassium acetate and (5-methyl-2- Oxo-1,3-dioxolen-41-yl) methylpromide (509 mg) was added, and the mixture was stirred at the same temperature for 1.5 hours. Ethyl acetate 15 Om1 was added, and the mixture was washed successively with 10% aqueous citric acid, 2% saline, saturated aqueous sodium bicarbonate and 100 ml of saturated saline, dried (malt salt), and then dried under reduced pressure. Was distilled off. Isopropyl ether was added to the residue, the precipitate was collected by filtration, and (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl 7 ^ -phenylacetamide- 1-((Z)-2- (4-Methylthiazole-5-yl) vinylthio] —3-cefume-4-carboxylate powder (717 mg) was obtained.

IRV (N uj 0 r) cm " ¹ : 1821, 1774, 1645, 1531.

^ -NMR (DMS 0- d ₆ ):

2.16 (s, 3H, -CH ₃ ), 2.46 (s, 3H, thiazole C ₄ -CH ₃ ),

3.53 (s, 2H, Ph-CH _2- ), 3.65, 4.05 (ABq, J = 18Hz, 2H, C ₂ -H ₂ ),

5.18 (br-s, 3H, C ₆ — H, _C0 ₂ CH _2- ), 5.50-6.00 (m, 1H, C ₇ -H),

 6.55 (d, J = 10Hz, 1H, -SCH =), 6.80-7.80 (m, 6H '= CH-, Ph),

9.00 (s, 1H, thiazole C ₂ -H), 9.10 (d, J = 8.0Hz, 1H,-C0NH-).

(2) 736 mg of phosphorus pentachloride was suspended in 14 ml of methylene chloride, and 0.29 ml of pyridine was added under ice cooling, followed by stirring at the same temperature for 1 hour. (5-Methyl_2-oxo- 1,3-dioxolen-41-yl) methyl Ίβ-phenylacetamide obtained in (1) of Example 8 — 3 — ((Ζ) — 2 — (4— Methylthiazol-5-yl) vinylthio] -3-cef-4-carboxylate (690 mg) was added, and the mixture was further stirred at the same temperature for 1 hour. The mixture was cooled to −40 ° C., 4.77 ml of methanol was added dropwise, and the mixture was stirred at −40 to −30 for 25 minutes. After adding 4.77 ml of water and stirring at 0 ° C for 35 minutes, 50 ml of methylene chloride and 50 ml of 10% saline were added, and the pH was adjusted to 3.0 with 5% aqueous sodium hydrogen carbonate. And the two layers were separated. The aqueous layer was extracted with methylene chloride (30 ml), combined with the methylene chloride layer, washed with 50 ml of 10% saline, and dried (glauberin). 8.68 N hydrogen chloride isopropanol solution (0.07 ml) was added, and methylene chloride was distilled off under reduced pressure. Ethyl acetate and getyl ether were added to the residue, The precipitate was collected by filtration to obtain 284 mg of the title compound as crystals.

IRV (Nu jor) cm— ¹ : 1819, 1773.

^ -NMR (DMS 0- d ₆ ):

2.16 (s, 3H,-CH ₃ ), 2.45 (s, 3H, thiazole C ₄ -CH ₃ ),

_{3.00-4.20 (m, 2H, C 2H} 2), 4.60-5.60 (m, 4H, C 6 -H, C 7 - H, - C0 2 CH 2 -), 6.55 (d, J = 10Hz, 1H ,-SCH =), 7.05 (d, J = 10Hz, 1H, = CH-),

8.99 (s, 1H, thiazole C ₂ -H).

Example 9

 Bivaloyloxymethyl Ίβ— ((Ζ) -2-(2-aminothiazol-1-41) -1 2-Methoxyiminoacetamide) 1 3— ((Ζ) -2-(4— Methyl thiazol-5-yl) vinylthio] 13-cephum-4-carboxylate hydrochloride

 (1) Bivaloyloxymethyl 7; 8-amino-31 [(Z) -2- (4-methylthiazo-1-yl-5-yl) vinylthio] —3-cef obtained in Example 5, (3) Pem-4-carboxylate hydrochloride 33 Omg and (Z) -2- (2-tritylaminothiazo-1-yl 4-yl) -1-dicyclohexylamine 2-methoxyiminoacetate 48 mg to methylene chloride 1 The mixture was suspended in 0 ml, 0.12 ml of pyridine and 0.110 ml of phosphorus oxychloride were sequentially added at 110 ° C, and the mixture was stirred at the same temperature for 15 minutes. 100 ml of ethyl acetate was added, and the mixture was washed successively with 100% aqueous citric acid and 100 ml of saturated saline, dried (mirror salt), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with benzene monoacetate), and the solvent of the target fraction was distilled off under reduced pressure to give bivaloyloxymethyl Ίβ-[(Ζ) -2-(2- Trimethylaminothiazolu-l 4-yl) 1 2- methoxyiminoacetamide] 1 3 _

[(Ζ) -2- (4-Methylthiazol-5-yl) vinylthio] —3-cefm-4-carboxylate (470 mg) was obtained.

IRV (N uj 0 r) cm— ¹ : 1790, 1755, 1680.

^ -NMR (DMS O— d ₆ ): 1.14 (s, 9H, -C (CH ₃ ) 3), 2.45 (s, 3H, -CH ₃ ),

3.00-3.80 (m, 2H, C ₂ -H ₂ ), 3.81 (s, 3H,-0CH ₃ ),

5.21 (d, J = 5.0Hz, 1H, C 6 - H), 5.73 (dxd, J = 5.0, 8.0Hz, 1H, C 7 one H),

5.80, 5.91 (ABq, J = 6.0Hz, 2H,-C0 ₂ CH _2- ), 6.57 (d, J = 10.0Hz, 1H, = CH—),

6.73 (s, 1H, aminothiazole C ₅ -H), 7.10-7.50 (m, 16H, -SCH =, Ph),

8.74 (bs, 1H, aminothiazole C ₂ -NH-), 9.01 (s, 1H, thiazole C ₂ -H),

9.54 (d, J = 8.0Hz, 1H, -C0NH-).

 (2) Bivaloyloxymethyl 7 jS — ((Z) —2- (2-tritylaminothiazo-1-yl-4-yl) — 2—methoximinoa obtained in Example 9 (1) Cetamide] — 3— ((Z) — 2- (4-Methylthiazol-5-yl) vinylthio) — 3-Cefem-4-carboxylate 80% 80% formic acid 1.7% m 1 was added, and the mixture was stirred at room temperature for 1.5 hours. 50 ml of ethyl acetate was added, and the mixture was washed with 50 ml of 10% saline, and the aqueous layer was further extracted with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 50% aqueous 5% sodium bicarbonate solution and saturated saline solution each for 50 ml, dried (Glauber's salt), and evaporated to remove ethyl acetate under reduced pressure. To the obtained residue, 1 Oml of getyl ether and 50 ml of isopropyl ether were added, and the precipitate was collected by filtration to obtain 245 mg of powder. The obtained powder was dissolved in 1.5 ml of methylene chloride, and 0.068 ml of 8.68 N isopropanolic hydrogen chloride solution was added at −10 ° C., and the mixture was immediately poured into 70 ml of isopropyl ether. The precipitate was collected by filtration to give 195 mg of powder of the title compound.

IRV (ujor) cm- ¹ : 1785, 1750, 1655.

'H-NMR (DMS O-d ₆ ):

1.14 (s, 9H, -CCCHs) 3), 2.46 (s, 3H, - CH 3),

3.00-4.50 (br, 5H, C ₂ — H ₂ , -N ⁺ H ₃ ), 3.90 (s, 3H, -0CH ₃ ),

5.26 (d, J = 5.0Hz, 1H, C 6 _H), 5.70-6.00 (m, 3H, C 7 one H, - C0 ₂ CH ₂ one), 6.59 (d, J = 10.0Hz, 1H, = CH -), 6.89 (s, 1H, aminothiazole C ₅ — H),

7.18 (d, J = 10.0Hz, 1H, -SCH =), 9.03 (s, 1H, thiazole C ₂ -H),

9.70 (d, J = 8.0Hz, 1H, -C0NH-). Example 10

 1-Isopropoxycarbonyloxyshetyl Ίβ- ((Ζ) -2-(2-aminothiazolu-l 4-yl) 2 1-2-Methoxyiminoacetamide) 1 3-〔((Ζ) — 2 — (4-Methylthiazol-5-yl) vinylthio] 1-3-Cephem — 41-carboxylate hydrochloride

 (1) 1-isopropoxycarbonyloxhetyl obtained in (2) of Example 6

7 i8-Amino-3-([(Z) -2- (4-methylthiazol-5-yl) vinylthio] -13-cefm-4-carboxylate hydrochloride 840 mg and (Z) — 2— (2—Tritylaminothiazoyl-41-yl) — Suspension of 1.09 g of 2-cyclohexylamine dimethoxyaminoacetate in 22 ml of methylene chloride and — 10 0.28 ml of pyridine and 21 ml of phosphorus oxychloride were sequentially added, and the mixture was stirred at the same temperature for 15 minutes. 100 ml of ethyl acetate was added, and the mixture was washed successively with 100% aqueous citric acid solution and 100 ml of saturated saline, dried (Glauber's salt), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate), the solvent of the target fraction was distilled off under reduced pressure, and 1-isopropoxycarbonyloxyethyl チ ル β-[(Ζ) —2- (2-tritylaminothiazolyl-41-yl)-2-methoxyiminoacetamide] 1-3-[(Ζ) -2- (4-methylthiazolyl-5-yl) vinylthio] 960 mg of —3-cef—4-carboxylate was obtained.

IRV (N ujor) cm " ¹ : 1786, 1761, 1684, 1529.

^ -NMR (DMS 0- d ₆ ):

1.21 (d, J = 6 ΟΗζ , 6H, -. CH (CH 3) z), 1.50 (d, J = 5.5Hz, 3H, - CH 3), 2.46 (s, 3H, thiazole C 4 -CH 3) , 2.90-4.30 (m, 2H, C ₂ -H ₂ ),

3.81 (s, 3H, -0CH ₈ ), 4.50-5.00 (m, 1H, -CiL (CH 3) 2),

5.00-5.30 (m, lH, C ₆ -H), 5.50-5.90 (m, lH, C ₇ -H),

6.30-7.80 (m, 17H, -C0 ₂ CH, = CH-, Ph), 6.60 (d, J = 10.0Hz, 1H, -SCH =), 6.72 (s, 1H, thiazole C ₅ — H), 8.75 (br- s, 1H, thiazole C ₂ -NH-), 9.01 (s, 1H, thiazole C ₂ -H), 9.55 (d, J = 8.0Hz, 1H, -CONH-).

 (2) 1-Isopropoxycarboxyloxyshetyl 7 iS — ((Z) —2— (2-tritylaminothiazole-4-yl) 1-2—obtained in Example 10 (1) Methoxyiminoacetamide] — 3— ((Z) — 2— (4-methylthiazolyl-1-yl) vinylthio) -1,3-cefum-4-carboxylate 80% formic acid in 90% Omg 3.6 ml was added, and the mixture was stirred at room temperature for 1.5 hours. 50 ml of ethyl acetate was added, and the mixture was washed with 50 ml of 10% saline, and the aqueous layer was further extracted with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 5% aqueous sodium bicarbonate solution and 50 ml of a saturated saline solution, dried (Glauber's salt), and ethyl acetate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (4.0 ml), and 0.168 ml of 8.68Νisopropanol solution of hydrogen chloride was added at —1OT, and the mixture was immediately poured into 70 ml of ethyl ether. The precipitate was collected by filtration to give 48 O mg of the title compound as a powder.

IRV (N uj 0 r) cm " ¹ : 1786, 1763, 1676, 1638, 1541.

'Η—NMR (DMS 0- d ₆ ):

1.23 (d, J = 6.0Hz, 6H, -CH (CH ₃ ) ₂ ), 1.50 (d, J = 5.5Hz, 3H, one CH ₃ ), 2.47 (s, 3H, thiazole C ₄ -CH ₃ ), 3.00-4.40 (m, 2H, C ₂ -H ₂ ),

_{3.96 (s, 3H, -0CH 3} ), 4.40-5.00 (m, 1H, -CH_ (CH 3) 2),

_{5.00-5.40 (m, 1H, C 6} - H), 5.40-8.00 (m, 2H, C 7 - H, - C0 2 CH rather)

6.60 (d, J = 10.0Hz, 1H, -SCH =), 6.98 (s, 1H, thiazole C ₅ -H),

7.20 (d, J = 10.0Hz, 1H, = CH-), 9.08 (s, 1H, thiazole C 2 - H),

 9.84 (d, J = 8.0Hz, 1H, -C0NH-).

Example 1 1

 1-acetoxityl Ί β— [(Ζ) — 2— (2—aminothiazoyl 4-yl) -1- 2-methoxyethoxyaminoacetamide] 1 3— [(Ζ)-2-(4— Methylthiazole-5-yl) vinylthio] 1-3-cef-4-carboxylate hydrochloride

(1) 1-acetoxityl 7 ^ -amino-3- obtained in (2) of Example 7 [(Z) -2- (4-Methylthiazol-5-yl) vinylthio] — 3-cefume-4-carboxylate hydrochloride 599.4 mg and (Z) — 2 -— (2-tritylaminothiazo 8-15 mg of dicyclohexylamine 2-methoxyiminoacetate was suspended in 16 m1 of methylene chloride, and 0.21 m1 of pyridine and phosphorus oxychloride were added at 110 ° C. .16 ml were sequentially added, and the mixture was stirred at the same temperature for 20 minutes. 100 ml of ethyl sulphate was added, washed successively with 100 ml of 10% aqueous solution of citric acid and 100 ml of a saturated saline solution, and dried (Glauber's salt), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl benzene monoacetate), and the solvent of the target fraction was distilled off under reduced pressure to give 1-acetoxityl 7) 8 — [(Z) — 2— (2-tritylaminothiazolyl—4-yl) _2—Methoxyoximinoacetamide] 1-3 — ((Z) —2— (4-methylthiazolyl-5-yl) [Vinylthio] 1-3-Cef-4-carboxylate (1.08 g) was obtained.

IRV (N ujor) cm— ¹ : 1786, 1684, 1528.

^ -NMR (DMS 0- d ₆ ):

1.47 (d, J = 5, 5Hz, 3H,> CHCH ₃ ), 2.02 (d, J = 5.0Hz, 3H, -CH ₃ ),

2.46 (s, 3H, thiazole C ₄ -CH ₃ ), 3.00-4.30 (m, 2H, C ₂ -H ₂ ),

3.81 (s, 3H, -0CH ₃ ), 5.00-5.30 (m, 1H, C ₆ -H),

5.00-5.30. (M, 1H, C 6 - H) 5.50-5.90 (m, 1H, C 7 -H),

_{6.40-7.80 (m, 17H, _C0 2} CH rather, = CH-, Ph), 6.55 (, d, J = 10.0Hz, 1H - SCH =), 6.71 (s, 1H, thiazole C 5 - H), 8.70 (br- s, 1H, thiazole C ₂ — NH-), 9.01 (s, 1H, thiazole C ₂ -H), 9.50 (d, J = 8.0Hz, 1H,-C0NH-).

(2) Example 11 1-acetoxityl 7 / S — ((Z) —2- (2-tritylaminothiazo-1-yl 4-yl) obtained in 1) (1) 1-2-Methoxyiminoacetone ) —3 — [(Z) —2- (4-methylthiazol-5-yl) vinylthio] —3-cefem-4-carboxylate To 1.06 g, add 4.3 ml of 80% formic acid Then, the mixture was stirred at 25 to 30 for 1.5 hours. 50 ml of ethyl acetate was added, and the mixture was washed with 50 ml of 10% saline, and the aqueous layer was further extracted with 50 ml of ethyl acetate. vinegar The acid ethyl layers were combined, washed with 5% aqueous sodium bicarbonate and saturated saline (5 Oml each), dried (glauberin), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was dissolved in 4.0 ml of methylene chloride, and 0.18 ml of a 8.68 N hydrogen chloride isopropanol solution was added at −10, and the mixture was immediately poured into 70 ml of ethyl ether. The precipitate was collected by filtration to obtain 62 Omg of a powder of the title compound.

IRV (Nu j 0 r) cm— ¹ : 1782, 1676, 1630, 1545.

— NMR (DMS 0- d ₆ ):

1.48 (d, J = 5.5Hz, 3H,> CHCH ₃ ), 2.03 (d, J = 5.0Hz, 3H, -CH ₃ ),

2.47 (s, 3H, thiazole C ₄ _CH ₃ ),

_{3.00-6.00 (m, 4H, C 2} - H 2, C 6 - H, C 7 -H),

3.95 (s, 3H, -OCHs) , 6.30-7.50 (m, 1H, rather _C0 ₂ CH),

6.60 (d, J = 10Hz, 1H, - SCH =), 6.96 (s, 1H, thiazole C 5 - H),

7.20 (d, J = 10Hz, 1H, = CH), 9.06 (s, 1H, thiazole C ₂ _H),

 9.80 (d, J = 8.0Hz, 1H,-C0NH-).

Example 1 2

 (5-Methyl-1-oxo-1, 3-dioxolen-4-yl) Methyl-1β-[(Ζ) -2- (2-aminothiazo-l-4-1yl) 1-2-Methoxyiminoacetamide ] — 3— ((Ζ) -2- (4-Methylthiazoyl 5-yl) vinylthio) — 3-Sefm-14-carboxylate hydrochloride

(1) (5-Methyl-oxo-1,3-dioxolen-4-yl) methyl 7 jS-amino-1 3 -— ((Ζ) —2— (4) obtained in Example 8 (2) —Methylthiazole—5-yl) vinylthio] 1-3-Cefem-4 monocarboxylate hydrochloride 264 mg and (Z) —2_ (2-tritylaminothiazol) -4-yl )-Suspension of 36 Omg of dicyclohexylamine 2-methoxyimino diacid in 7.2 ml of methylene chloride, and-at 10 ° C, 0.09 ml of pyridine and 0.07 ml of phosphorus oxychloride are successively added. In addition, the mixture was stirred at the same temperature for 20 minutes. Add 100 ml of ethyl acetate, wash with 100 ml of 10% aqueous solution of citric acid and 100 ml of saturated saline solution in turn, and after drying (Glauber's salt), The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (benzene

—Eluted with ethyl acetate), and the solvent of the desired fraction is distilled off under reduced pressure to give (5-methyl-1-oxo-1,3-dioxolen-4-yl) methyl 7 jS— [ (Z) I 2-(2-tritylaminothiazole 14-yl) 12-methoxyiminoacetamide] 13-[(Z)-2-(4-methylthiazo 1-5-yl) vinylthio] There were obtained 410 mg of 1-3-carboxy-4-carboxylate.

IRV (N uj 0 r) cm— ¹ : 1821, 1784, 1734, 1676, 1533.

^ -NMR (DMS 0- d ₆ ):

2.16 (s, 3H, -CH ₃ ), 2.45 (s, 3H, thiazole C ₄ -CH ₃ ),

2.80-4.40 (m, 2H, C ₂ -H ₂ ), 3.81 (s, 3H, -0CH ₃ ),

4.80-5.40 (m, 3H, C ₆ _H,-C0 ₂ CH _2- ), 5.50-5.90 (m, 1H, C ₇ -H),

6.55 (d, J = 10.0Hz, 1H, - SCH =), 6.71 (s, 1H, thiazole C 5 - H),

6.90-7.80 (m, 16H, = CH ~, Ph), 8.75 (br- s, 1H, thiazole C ₂ -NH),

8.99 (s, 1H, thiazole C ₂ -H), 9.55 (d, J = 8.0Hz, 1H, -C0NH-).

 (2) (5-Methyl-2-oxo-1,3-dioxolen-14-yl) methyl 1 β — [(Ζ) -2- (2-) obtained in Example 1 (2) Tritylaminothiazol-4-yl) 1-2-Methoxyiminoacetamide] 1-3-((Ζ) —2— (4-Methylthiazo-1-yl 5-yl) vinylthio) -13-Sebum—4 —1.56 ml of 80% formic acid was added to 39 mg of carboxylate, and the mixture was stirred at 25 to 30 ° C. for 1.5 hours. 50 ml of ethyl acetate was added, and the mixture was washed with 50 ml of 10% saline, and the aqueous layer was further extracted with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 5% aqueous sodium bicarbonate and 50 ml each of a saturated saline solution, dried (Glauber's salt), and ethyl acetate was distilled off under reduced pressure. The obtained residue is dissolved in methylene chloride (2.0 ml), and-at 10 ° C, 8.68 N isopropanol solution (0.07 ml) is added, and the mixture is immediately poured into 70 ml of ethyl acetate. did. The precipitate was collected by filtration to obtain 195 mg of a powder of the title compound.

IRV (N ujor) cm— ¹ : 1819, 1785, 1672, 1632, 1560. 'H-NMR (DMS 0— d ₆ ):

2.17 (s, 3H,-CH ₃ ), 2.46 (s, 3H, thiazole C ₄ -CH ₃ ),

_{3.00-6.00 (m, 6H, C 2} -H 2, C 6H, C 7 -H, -C0 2 CH 2 -),

_{3.92 (s, 3H, -0CH 3} ), 6.55 (d, J = 10 OHz, 1H, -. SCH =),

6.90 (s, 1H, thiazole C ₅ -H), 7.15 (d, J = 10. OHz, IH, = CH-),

9.01 (s, 1H, thiazole C ₂ -H), 9.74 (d, J = 8. OHz, 1H, -C0NH-).

 The following compounds were obtained in the same manner as described in any of Examples 1 to 5.

Example 13

 Ί β— [(Ζ) -2-(2-aminothiazol-1-yl) -1-2-methoxyminoacetamide] — 3— [(Ζ) — 2— (thiazol-5-yl) Vinylthio] —3-Cefum 4-sodium carboxylate

IRV (N ujor) cm " ¹ : 1763, 1609.

^ -NMR (DMS O-d ₆ ):

3.53 (bs, 2H, C ₂ -H ₂ ), 3.84 (s, 3H, -0CH ₃ ),

5.09 (d, J = 5.0Hz, IH, C 6 - 10, 5.64 (dxd, J = 5.0, 8. OHz, IH, C 7 - H),

6.63 (d, J = 10.5Hz, IH, = CH-), 6.73 (s, IH, aminothiazole C ₅ -H),

6.95 (d, J = 10.5Hz, IH, -SCH =), 7.26 (b- s, 2H, -NH ₂ ),

7.96 (s, IH, thiazole C ₂ -H), 9.04 (s, IH, thiazole C ₄ _H),

 9.55 (d, J = 8.0Hz, 1H,-C0NH-).

Example 14

 7 j8—! (Z) — 2— (2-Aminothiazol-1-yl) -1-2-Methoxyxyminoacetamide] 1—3 ([(Z) —2— (2-Methylthiazol-1-yl)) Nilthio] — 3-Cefem — Sodium 4-carboxylate

IRV (N uj 0 r) cm— ¹ : 1767, 1668, 1614.

— NMR (DMSO— d ₆ ):

2.64 (s, 3H, -CH ₃ ), 3.36, 3.88 (ABq, J = 17. OHz, 2H, C ₂ -H ₂ ),

3.84 (s, 3H, -OCH3), 5.09 (d, J = 5. OHz, IH, C ₆ — H), 5.63 (dxd, J = 5.0, 8. OHz, IH, C ₇ -H), 6.51 (d, J-10.5Hz, IH, = CH-),

6.73 (s, 1H, aminothiazole C 5 -H), 6.86 (d, J = 10.5Hz, IH, - SCH =),

7.19 (bs, 2H, -NH ₂ ), 7.66 (s, IH, thiazole C ₄ -H),

 9.53 (d, J = 8. OHz, lfl, -CONH-),

Example 15

 7 β-[(Z) -2- (2-aminothiazole-4-yl) -12-methoxyminoacetamide] 13-[(Z) -2- (thiazole-4-yl) vinylthio] — 3-Cefem-1-Sodium carboxylate

IRV (Nu j 0 r) cm- ¹ : 3350, 1767, 1616.

rH-NMR (DMS 0— d ₆ ):

3.54 (bs, 2H, C ₂ -H ₂ ), 3.84 (s, 3H, -0CH ₃ ),

5.09 (d, J = 5 OHz, 1H, C ₆ -H), 5.62 (dxd, J = 5.0, 8. OHz, IH, C ₇ -H),

6.64 (bs, 2H, -SCH = CH-), 6.73 (s, IH, aminothiazole C 5 - H),

7.17 (bs, 2H, -NH ₂ ), 7.57 (s, 1H, thiazole C ₂ -H),

9.08 (s, IH, thiazole C ₅ -H), 9.54 (d, J = 8.0Hz, 1H, -CONH-),

Example 16

 Bivaloyloxymethyl 1 β — ((Ζ) -2-(2-aminothiazole 14-yl) 1-2-methoxyiminoacetamide) 1 3-[(-)-2-(thiazole — 5-yl) Vinylthio] 1- 3-cefum — 4-carboxylate hydrochloride

IRV (N uj 0 r) cm— ¹ : 1786, 1753, 1676, 1630.

'H-NMR (DMS O-d ₆ ):

1.15 (s, 9H, - C (CH 3) 3), 3.70, 4.09 (. ABq, J = 18 OHz, C 2 -H 2),

3.80 (s, 3H, -OCHs) , 5.27 (d, J = 5. OHz, IH, C 6 -H),

_{5.66-6.03 (m, 3H, C 7} - H, -C0 2 CH 2 -), 6.60-9.00 (br, 3H, -N + H 3),

6.68 (d, J = 10. OHz, IH, = CH_), 6.98 (s, IH, aminothiazole C ₅ -H),

7.28 (d, J = 10.5Hz, IH, -SCH =), 8.08 (s, IH, thiazole C ₄ -H),

9.12 (s, IH, thiazole C ₂ — H), 9.83 (d, J = 8.0Hz, 1H, -CONH-). Example 17

 Bivaloyloxymethyl Ίβ-rymino — — ((Ζ) -2- (thiazolyl-5-yl) vinylthio) — 3-cefem-4 monocarboxylate hydrochloride

IRV (Nu jor) cm ' ¹ : 3400, 1782, 1753, 1720.

 JH-NMR (DMS O-de):

1.15 (s, 9H, -C (CH ₃ ) 3), 2.48 (s, 3H, -CH ₃ ), 3.96 (s, 2fl, C ₂ — H ₂ ), 4.20-6.00 (br, 3H, -N + H _{3), 5.10-5.40 (m, 2H} , C 6 7 -. H),

5.81, 5.95 (ABq, J = 6.0Hz, 2H, -C0 ₂ CH _2- ), 6.72 (d, J = 10.5Hz, 1H, = CH-),

7.36 (d, J = 10.5Hz, 1H, - SCH =), 8.12 (s, 1H, thiazole C 4 - H),

9.15 (s, 1H, thiazole C ₂ -H).

Example 18

 Diphenylmethyl 7 δ-amino-13-[(Z) 12- (thiazolyl-5-yl) vinylthio] — 3-cebum-4-carboxylate hydrochloride

IRV (N ujor) cm— ¹ : 1783, 1755.

 One NMR (DMS O-de):

3.98 (b - s, 2H, C 2H 2), 5.07-5.30 (. M, 2H, C 6 7 -H),

6.73 (d, J = 10.5Hz, 1H, = CH-), 6.94 (s, 1H, -C0 ₂ CH =),

 7.12 (d, J = 10.5Hz, 1H,-SCH =), 7.10-7.70 (m, 10H, Ph),

8.10 (s, 1H, thiazole C ₄ -H), 9.04 (s, 1H, thiazole C ₂ -H)

^{8.00-10.30 (br, 3H, -N +} H 3).

Experimental example 1 (antibacterial test)

 The minimum inhibitory concentrations (M I C) of the cephalosporin compound (I) of the present invention (compounds of Examples 1, 2 and 13) and the control compound (cefpodoxime) against various bacteria were measured.

Table 1 shows the results. The unit in the table is ^ g / m1. table 1

As is evident from Table 1, cephalosporin compounds (I) include Staphylococcus aureus, Staphylococcus aureus, Gram-yang bacteria such as Staphylococcus epidermides, and Escherichia coli. (Escherichia Coli) ヽ Crab sill ♦ Has excellent antibacterial activity against gram-negative bacteria such as Klebsiella pneumon iae, Proteus vulgaris, and Proteus mirabillis Things.

 That is, the cephalosporin compound (I) and a pharmaceutically acceptable salt thereof are valuable antibacterial agents that have significantly improved antibacterial activity against Gram-positive bacteria while maintaining their antibacterial activity against Gram-negative bacteria. These compounds are extremely low-toxic.

 "Industrial applicability"

The cephalosporin compound (I) or a pharmaceutically acceptable salt thereof is excellent in gastrointestinal absorption by oral administration and has sufficient antibacterial properties against a wide variety of bacterial species, and is useful for infectious diseases ( In particular, it is extremely useful as a prophylactic and therapeutic agent for bacterial infections. The infectious disease preventive and therapeutic agents include, for example, warm-blooded animals including humans (dogs, cats, cattle, horses, Parenteral (intravenous or intramuscular) as a prophylactic / therapeutic agent for diseases caused by bacteria (eg, mouse, mouse, etc.) (eg, purulent diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.) Injection) and orally. This application is based on Japanese Patent Application No. 1666275 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

 1. General formula (I)

(Wherein, R ¹ represents a hydrogen atom or an amino protecting group, R ² represents a hydrogen atom, a lower alkyl group or a hydroxy protecting group, R ³ represents a carboxyl group which may be esterified, and R ⁴ represents a substituent. A thiazolyl group which may be present) or a pharmaceutically acceptable salt thereof.

2. The cephalosporin compound according to claim 1, wherein R ³ is an esterified carboxyl group, or a pharmaceutically acceptable salt thereof.

 3.7 iS — [(Z) —2— (2-aminothiazoyl 4-yl) -1-2-hydroxyiminoacetamide] —3 — [(Z) -2- (4-methylthiazol-5-yl) ) Vinylthio] 1-cefum-4 rubonic acid,

 7 β- [(Ζ) 1 2— (2-aminothiazoyl 4-yl) 1 2—Methoxyxyminoacetamide] — 3— [(Ζ)-2-(4-methylthiazoyl 1-5-yl) [Vinylthio] —3-Cefem—4 rubonic acid,

 Bivaloyloxymethyl Ί β— [(Ζ) — 2— (2-Aminothiazoyl 4- 4-yl) 1 2-Methoxyiminoacetamide] 1 3— [(Ζ)-2-(4-methyl Thiazole-5-yl) vinylthio] -1-3-dimethyl 4-carboxylate,

1-Isopropoxycarbonyloxyshetyl Ί β-[(Ζ) -2-(2-aminothiazole 4-1yl) 22-methoxyiminoacetamide] 33-[(Ζ) — 2- (4-Methylthiazoyl 5-yl) vinylthio] -1-3-Sefm— 4— Carboxylates,

 1-acetoxityl Ί β— [(Ζ) — 2— (2-aminothiazoyl-41-yl) 1 2-methoxyiminoacetamide] 1 3— [(Ζ) 1 2— (4 -Methylthiazol-5-yl) vinylthio] -3-cef-4-1-carboxylate,

(5-Methyl-1-oxo-1, 3-dioxolen-1-yl) Methyl Ί β — [(Ζ) — 2 _ (2-aminothiazo-1-ru 4-yl) 1-2-Methoxyiminoacetamide] — 3— [(Ζ) — 2— (4-Methylthiazol-5-yl) vinylthio] — 3—Semumo 4 _carboxylate,

 7 β- [(Ζ) — 2— (2-aminothiazoyl 4-yl) 1 2-methoxyminoacetamide] — 3— [(Ζ) — 2— (thiazoyl 5-yl) vinylthio] — 3-Cefem-4 monocarboxylic acid,

 Bivaloyloxymethyl 1 β- [(Ζ)-2-(2-aminothiazoyl 4- 1-yl) 1-2-methoxyiminoacetamide] — 3— [(Ζ) — 2— (thiazolyl 1-5-yl) vinylthio] — 3-serum-14-carboxylate,

 Ί β— [(Ζ) — 2— (2-Aminothiazoyl 4-yl) -1-2-Methoxyxyminoacetamide] — 3— [(Ζ) — 2— (2-Methylthiazol-5-yl) Vinylthio] — 3-cef — 4-carboxylic acid, and

 7 β-[(Ζ)-2-(2-Aminothiazoyl 4-yl) 1-2-Methoxyxyminoacetamide] — 3-[(Ζ)-2-(Thiazole-4-yl) vinylthio] 1 3. The cephalosporin compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the cephalosporin compound is selected from the group consisting of 3-cefuma-4 rubonic acid.

 4. The cephalosporin compound according to claim 3, which is in the form of a sodium salt or a hydrochloride.

 5. A pharmaceutical composition comprising the cephalosporin compound according to claim 1 or a pharmaceutically acceptable salt thereof.

 6. The pharmaceutical composition according to claim 5, which is a prophylactic or therapeutic drug for infectious disease.

7. The cephalo according to claim 1, wherein R ³ is an esterified carboxyl group. A pharmaceutical composition comprising a sporin compound or a pharmaceutically acceptable salt thereof.

 8. The pharmaceutical composition according to claim 7, which is a prophylactic or therapeutic drug for infectious disease.

9 · General formula (II)

(Wherein, R ³ represents a carboxyl group which may be esterified, and R ⁴ represents a thiazolyl group which may have a substituent) or a salt thereof.

 1 0. Diphenylmethyl 7 ^ -amino-1-3-[(Z) -2- (4-methylthiazol-5-yl) vinylthio] -13-cefm-4-carboxylate, vivaloyloxymethyl 7 / S—Amino-3 -— [(Z) -2- (4-Methylthiazol-5-yl) vinylthio] —3-Cefem—4-Carboxylate,

1-Isopropoxycarbonyloxyshethyl 7 / S-amino-3-([Z) —2- (4-methylthiazol-5-yl) vinylthio] -1-3-cefem-4—force ruboxylate

 1-acetoxitytyl 7 yS-amino-3 — [(Z) -1-2- (4-methylthiazol-5-yl) vinylthio] —3-cefuma-4-carboxylate,

 (5-Methyl-1-oxo-1,3-dioxolen-4-yl) Methyl Ίβ-amino-3-([3) —2- (4-Methylthiazol-5-yl) vinylthio] 1-3 SEFM 4-carboxylate,

 Diphenylmethyl 7 jS-amino-3 — [(Ζ) —2— (thiazolyl-5-yl) vinylthio] 13-cefuma-4-carboxylate, and

Bivaloyloxymethyl 75-amino-3-[[(Z) -2- (thiazol-5-yl) vinylthio] -13-cephum-4-carboxylate Chosen claims 9 wherein the 7-amino cephalosporin compound or a salt thereof _c