JPS61106581A - Novel cephem compound and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<3> is amino, or protected amino; X and Y are H, or halogen; R<1> is tetrazolopyridazinylthio, and R<2> is carboxy, or protected carboxy, or R<1> is 1-dihydropyridinio, etc. and R<2> is COO<->) or its salt. EXAMPLE:7[(Z)-2-Chloromethylene-2-(2-aminothiazol-4-yl)acetamido]-3-[1 -(6,7-di hydro-5H-1-pyridinio)methyl]-3-cephem-4-carboxylate. USE:A preventive and remedy for microbism. PREPARATION:A compound shown by the formula II or a reactive derivative at its carboxy group or its salt is reacted with a compound shown by the formula III or a reactive derivative at its amino group or its salt to give a compound shown by the formula I. The reaction is usually carried out in the presence of an organic base or an inorganic base in a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel cephem compounds and salts thereof.

More specifically, the present invention relates to a novel cephem compound having antibacterial activity and its salts, a method for producing the same, and a prophylactic and therapeutic agent for bacterial infections containing the same as an active ingredient.

That is, one object of the present invention is to provide a novel cephem compound and its salts that have strong antibacterial activity against many pathogenic bacteria.

Another object of this invention is to provide a method for producing novel cephem compounds and their salts.

Yet another object of the present invention is to provide a preventive and therapeutic agent for bacterial infections containing the novel cephem compounds and their salts as active ingredients.

For example, the following compounds are well known in the technical field to which this invention pertains.

c in the formula, R1 is an aromatic group; 2 is represented by the formula: (wherein R2 is hydrogen, a salt-forming cation or a protecting group for a carboxylic acid; R3 means hydrogen or a residue of a nucleophilic compound) means a group; X and X2 each mean a hydrogen atom or a halogen atom, provided that Xl and x2 cannot both represent hydrogen at the same time] (European Patent Publication No. 004)
No. 8954).

The target novel cephem compound is a new compound and can be represented by the following general formula (1).

(wherein, R3 is an amine group or a protected amino group; X and Y each represent hydrogen or a halogen; R1 represents a tetracylopyridazinylthio group, and R
2 means a carboxy group or a protected carboxy group; or R1 means a 1-dihydropyridinio group or a 1-pyridinio group with a suitable substituent, and R is -C0o
(means O).

The novel cephem compound (I) of this invention can be produced by various production methods shown in the following reaction formula.

A reactive derivative or a salt thereof (lλ or a salt thereof or a salt thereof (in the formula, R1, R2, R3 , X and Y each have the same meaning as before and R3 means a protected amino group).

Regarding the target compounds (I), (Ia) and (Ib) and the starting material (■), 2 isomers, E isomers and mixtures thereof exist, all of which can be used as the target compound and starting material of this invention. shall be included within the scope of compounds.

Suitable salts of the target compound (I) are pharmaceutically acceptable conventional non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, and alkaline earth metal salts such as calcium salts, magnesium salts, etc. Metal salts, ammonium salts such as trimethylamine salts, triethylamine salts, pyridine salts1. Organic base salts such as bifrin salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate Examples thereof include organic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, and salts with amino acids such as arginine, aspartic acid, and glutamic acid.

In the foregoing and following description of this specification, preferred examples and explanations of various definitions that fall within the scope of this invention are set forth in detail below.

r-lower means 1 to 6 carbon atoms, unless otherwise specified.
shall mean an individual.

Suitable 1-protected amino groups for R3 and R3 include acylamino groups or alkyl groups optionally having at least one suitable substituent, such as conventional 1-protected amino groups such as benzyl, trityl, etc. Examples include amine groups substituted with protective groups.

Suitable acyl moieties of the "acylamino group" include carbamoyl groups, aliphatic acyl groups, and acyl groups containing aromatic rings or heterocycles. Suitable examples of such acyl groups include carbamoyl groups such as formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl,
Isovaleryl, oxalinosuccinyl, succinyl, pivaloyl hexanoyl, heptanoyl, suftanoyl, nonaninoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl,
Alkanoyl having 1 to 18 carbon atoms such as heptadecanoyl, octadecanoyl, methacryloyl, crotonoyl, isocrotonoyl, pentenoyl, hexenoyl,
Alkenoyl groups having 3 to 20 carbon atoms such as heptenoyl, dodecanoyl, tetradecenoyl, hexadecenoyl, oleoyl, elidoyl; for example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, 1-cyclopropylethoxycarbonyl, imbropoxycarbonyl 1, butoxy tertiary butoxycarbo 1; =
,,,,Tsuke,,Oyauka,,□． ，I,heyau，，
Lower alkoxycarbonyl having 2 to 7 carbon atoms such as oyashicarbonyl; lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, phthanesulfonyl; allenesulfonyl groups such as benzenesulfonyl and tosyl; Aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.; Al(lower) alkanoyl groups such as phenylacetyl, phenylpropionyl; Al(lower) alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, etc. can be mentioned.

Examples of suitable protected carboxy groups include the following mono-esterified carboxy groups.

Suitable examples of the ester moiety of the esterified carboxy group include methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester,
Lower alkyl esters which may have at least one suitable substituent, such as pentyl ester, hexyl ester, 1-cyclopropylethyl nitride, etc., such as acetoxymethyl ester, propionyloxymethyl ester, etc. Lyloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1
(or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester,
1 (or 2) propionyloxyethyl ester, 1
(or 2 or 3)-propionyloxypropylene ester, 1 (or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester, 1 (or 2)-pivaloyl Oxymethyl esters 1 (or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryl ester, 1 (or 2)-pentanoyloxyethyl Lower alkanoyloxy (lower) alkyl esters such as esters, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, mono (or di- or tri)-halo(lower) alkyl esters, such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester,
Lower alkoxycarbonyloxy (lower) alkyl esters such as 1-impropoxycarbonyloxyethyl ester, phthalidylidene (lower) alkyl esters, or e.g. Ester mutter (5-ethyl-
(5-lower alkyl-2-year-old xo-1,3-dioxo-4-yl) methyl ester, (5-propyl-2-year-old 1.3-dioxol-4-yl) lower alkyl ester; Examples include lower alkenyl esters such as evavinyl ester and allyl ester; Lower alkynyl esters such as ethynyl ester & propynyl ester; Examples include benzyl ester and 4-methoxybenzyl ester , 4-nitrobenzyl ester, phenetel ester, trityl ester, benzhydryl ester, bis(
Al(lower) which may have at least one suitable substituent such as methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Alkyl estyl; (9) having at least one suitable substituent such as phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiary butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc. Aryl esters that may be used include phthalidyl esters and the like.

Preferred halogens are chlorine, bromine, fluorine and iodine.

Preferred “1-pyridinio group having a suitable substituent”
Examples of "substituents" include methyl, ethyl, propyl,
Examples include lower alkyl groups such as isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl, and the aforementioned halogens.

The method for producing the object compound (I) of the present invention will be explained in detail below.

Compound (I) or a salt thereof can be prepared by reacting compound (n) or a reactive derivative at the amino group or a salt thereof with compound (III> or a reactive derivative at the carboxyl group thereof or a salt thereof). can be manufactured.

Suitable salts of starting materials compounds (II) and (III) include the same salts as exemplified for compound (I).

Suitable reactive derivatives at the amino group of compound (I[) include conventional derivatives, such as compound (Wataru)
Silyl derivatives formed by reaction with silyl compounds such as dobis(trimethylsilyl)acetamide, trimethylsilylacetamide, etc.; isocyanates; isothiocyanates: amyle groups and e.g. acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, Aldehyde compounds such as p-nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthaldehyde, furfuraldehyde, or for example acetone,
Examples thereof include Schiff's base or its enamine-type tautomer, which is produced by reaction with a carbonyl compound such as a ketone compound such as methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, ethyl acetoacetate, and the like.

Suitable reactive derivatives at the carboxy group of compound (I[I) include, for example, acid halides, acid anhydrides, activated amides, and activated ester derivatives. but preferably acid chlorides, acid bromides; for example, substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, such as carbonic acid. Methyl, ethyl carbonate,
Mixed acid anhydrides with acids such as alkyl carbonates such as propyl carbonate, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, impentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, aromatic carboxylic acids such as benzoic acid, etc. symmetrical acid anhydrides; activated acid amides with heterocyclic compounds containing imino functions such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole: e.g. lfp-nitrophenyl ester, 2.4- dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,
Phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-talesylthioester, carboxymethylthioester, pyridyl ester, piperidinyl ester, 8-quinolylthioester, or N,N-dimethylhydroxylamine, esters with N-hydroxy compounds such as l-hydroxyl 2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc. activated esters, etc.

Suitable reactive derivatives can be arbitrarily selected from the above-mentioned compounds depending on the types of compounds (I[) and (III) actually used.

This reaction is carried out using alkali metals such as lithium, sodium, potassium, etc., alkaline metals such as calcium, alkali metal hydrides such as sodium hydride, etc.
For example, alkaline earth metal hydrides such as calcium hydride,
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate; e.g. sodium methoxide; Alkali metal alkoxides such as sodium methoxide, potassium tert-butoxide, alkali metal salts of alkanoates such as sodium acetate, trialkylamines such as triethylamine, pyridine compounds such as pyridine, lutidine, picoline, quinoline, etc. This can be carried out in the presence of an organic or inorganic base.

When compound (III) is used in this reaction in the form of free acid or salt, for example N,N'-dicyclohexylcarbodiimide-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N. N'-diisopropylcarbodiimide, N-ethyl-N'-(3
Carbodiimide compounds such as -dimethylaminepropyl)carbodiimide; Ketenimine compounds such as N,N'-carbonylbisole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine; olefinic or acetylene-based Ether compounds such as ethoxyacetylene, β-chlorovinylethyl ether, e.g.
Sulfonic acid esters of N-hydroxybenzotriazole derivatives such as (4-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole; trialkyl phosphorous acid or triphenylphosphine and carbon tetrachloride;
Combinations with carbon disulfide or diazenedicarboxylic acid esters such as diethyl azenedicarboxylate; phosphorus compounds such as phosphoryl chloride, thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-
Ethyl-5-phenylisoxazolium-3-sulfonate, such as N. N-dimethylformamide etc. c7)
Amide compounds such as N,N-cy(lower)alkylformamide, N-methylformamide, etc. and thionyl chloride,
Preferably, the reaction is carried out in the presence of a condensing agent, such as the so-called Vilsmeier reagent, which is produced by reaction with a halogen compound such as phosgene chloride or the like.

The reaction is usually carried out using water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N. It is carried out in conventional solvents that do not adversely affect the reaction, such as N-dimethylformamide, pyridine, hexamethylphosphoramide, etc., or mixtures thereof.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

A compound (Ib) or a salt thereof can be produced by subjecting a compound (Ia) or a salt thereof to an elimination reaction of the amine protecting group of R3.

Suitable methods for this elimination reaction include conventional methods such as hydrolysis, reduction, and the like.

(i) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid or a base.

Suitable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-
Examples include organic acids such as toluenesulfonic acid, acidic ion exchange resins, and the like. When organic acids such as trifluoroacetic acid and p-1-luenesulfonic acid are used in this reaction,
For example, it is preferable to carry out the reaction in the presence of a cation scavenger such as anisole.

Suitable bases include those exemplified in Production Method 1 and 1. f
The same 0 organic base 3W inorganic base is listed as Formula 6. The acid or base suitable for this hydrolysis can be selected depending on the type of protecting group to be removed. For example, this hydrolysis can be carried out using It is preferably applied to the removal of amino protecting groups of R3 such as carbonyl groups, substituted or unsubstituted lower alkanoyl groups.

The hydrolysis is usually carried out in a conventional solvent that does not adversely affect the reaction, such as water, methane, ethanol, I-fluorocarbon, tert-butyl alcohol, tetrahydrofuran, N,N-dimethylformamide, dioxane, etc. , or mixtures thereof, but the acids mentioned above can also be used as solvents if they are liquid.

Although the reaction temperature for this hydrolysis cannot be particularly limited, the reaction is usually carried out in a temperature range of from cooling to slightly warming.

(i) Reduction Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and for example formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid,
It is a combination with an organic acid such as hydrochloric acid or hydrobromic acid or an alt-free acid.

Suitable catalysts used for the catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, platinum catalysts such as palladium, sponges, palladium black, palladium oxide, palladium-carbon, colloids. Palladium catalysts such as palladium, palladium-barium sulfate and palladium barium carbonate; nickel catalysts such as reduced nickel, nickel oxide and Raney nickel; cobalt catalysts such as reduced cobalt and Raney cobalt; iron catalysts such as reduced iron and Raney iron; Commonly used catalysts include copper catalysts such as reduced copper, Raney copper, Ullmann rust, and the like.

The reduction method can be selected depending on the type of protecting group to be removed. For example, chemical reduction is preferably applied to remove an amino protecting group of R3 such as a halo (lower) alkyl dicarbonyl group, Catalytic reduction is preferably applied to remove amino protecting groups such as substituted or unsubstituted alkoxycarbonyl groups and the like.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, or mixtures thereof. Furthermore, when the acids used in the chemical reduction are liquids, they can also be used as solvents. Suitable solvents used in the catalytic reduction are also the above-mentioned solvents, as well as conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating.

The method explained above may be selected depending on the type of protecting group to be removed.

Compound (I) and its salts are novel compounds, exhibit strong antibacterial activity, inhibit the growth of a wide range of pathogenic bacteria including Durum-positive bacteria and Durum-negative bacteria, and are useful as preventive and therapeutic agents for bacterial infections. be.

For therapeutic use of the compounds of this invention, pharmaceutically acceptable excipients, such as organic or inorganic solid or liquid excipients, containing said compounds as active ingredients and suitable for oral, parenteral or topical administration. It can be mixed with a carrier and used in the form of a conventional pharmaceutical formulation. Pharmaceutical formulations may be in solid form, such as capsules, tablets, dragees, ointments, or suppositories, or liquid, such as solutions, suspensions, or emulsions. If desired, auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other agents such as lactose, fumaric acid, citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, terra alba, etc. may be added to the above formulation. Conventional additives such as sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc. may be included.

Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds of this invention have an average single dose of about 10 mg;
50mg, 100mg, 250mg, 500mg,
1000mg is effective in treating pathogenic bacterial infections. In addition, generally 1 mg/solid to about 5000 mg/day
Solid or larger doses may be administered.

In order to demonstrate the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below.

[1 test compound (1) 7-[:(Z)-2-chloromethylene-2-(2
-aminothiazol-4-yl)acetamide]-3-
[(tetracylo[1,5-bcopyridazin-6-yl)
thiomethyl]-3-cephemu-4-carboxylic acid.

(2) 7-[(Z)-2-chloromethylene-2-(2-
aminothiazol-4-yl)acetamitoco-3-[
1-(6,7-cyhydro 5H-1-pyrindinio)methylrho 3-cephemu 4-carboxylate.

[2]! Otori: Standing J and Hi 1 Rin ■! The in vitro antibacterial activity was measured by the agar plate dilution method described below.

Each test strain was added to Tryptocase soy broth (1 viable cell count).
08 cells/ml) was cultured overnight, and a loopful of the same was inoculated onto heart infusion agar (HI-agar) containing representative test compounds at each concentration level, and after culturing at 37°C for 20 hours, The minimum inhibitory concentration (MIC) was expressed in μg/ml.

■Pod! MIC (μg/ml) Higashi'u'tech (1) Phosphorous oxychloride (49 μg/ml) was added to a solution of N,N-dimethylformamide (0.5 g) in tetrahydrofuran (8 ml).
5 mg) is added and the mixture is stirred at room temperature for 30 minutes and then cooled to -20°C. (Z)-2-chloromethylene-2-(2-formamidothiazol-4-yl)acetic acid (0,5 g) was added to this and the reaction mixture was
Stir for 30 minutes at 0°C. On the other hand, 7-amino-3-
[(Tetrazolo-1-1.5-b]pyridazin-6-yl)thiomethylcou-3-cephem-4-carboxylic acid (9
A mixture of 10a+g), mono(trimethylsilyl)acetamide (4,5g) and tetrahydrofuran (15ml) was stirred at 35°C for 30 minutes, then at -15°C.
Cool to This solution is added all at once to the activated acid solution obtained above at -15°C. The mixture is stirred at -15 to -10°C for 30 minutes.

The reaction mixture was mixed with sodium bicarbonate (840 mg) in water (
20 ml) solution and stir for 30 minutes at room temperature.

Tetrahydrofuran was distilled off and ethyl acetate (20ml)
and then ethyl acetate (20 ml) is added to the aqueous solution. The mixture was adjusted to pH 2.0 with 10% hydrochloric acid, the organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off. The residue was triturated with diisopropyl ether to give 7-
[(Z)-2-chloromethylene-2-(2-formamidodeazol-4-yl)acetamitoco-3-[(tetracylo[1,5-b]pyridazin-6-yl)thiomethyl]-3-cephemu 4 -Carboxylic acid (690mg)
powder is obtained.

NMR (DMSO-ds, S)' 3-77 (2
H9br s), 4,27 and 4.63 (2H,A
Bq, J=14Hz>, 5.23 (IH.

d, J=5Hz), 5.83 <IH, ddJ=5H
z, 8Hz>, 7.0 (2H, s), 7.77
(1)1. d, J=9Hz), 8.50 (I
H,s).

, 8.60 (LH, d, J=9Hz), 9.6
3 (LH, d, J = 8 Hz) (2) 1 L of phosphorus oxychloride was added to a solution of N,N-dimethylformamide (1.0 g) in trahydrofuran (15 ml).

(8139 mg) was added, stirred at room temperature for 30 minutes, and then cooled to -20°C. (Z)-2-chloromethylene-2-(2-formamidothiazol-4-yl)acetic acid (Lag) was added to this and the reaction mixture was
Stir for 30 minutes at °C. -1 separately 7-amino-3-[1
-(6,7-cyhydro-5H-1-pyrindinio)methyl-3-cephem-4-carboxylate monohydrochloride (2,29 g), mono(trimethylsilyl)acetamide (7,5 g) and tetrahydrofuran (42 ml
) was stirred at 35°C for 5 minutes, then at -15°C.
Cool to C. This solution is added all at once to the activated acid solution obtained above at -15°C. -15 to -1 reaction mixture
Stir at 0°C for 30 minutes, add sodium hydrogen carbonate (2.4g
) in water (50 ml) and stirred at room temperature for 30 minutes.

Tetrahydrofuran is distilled off. Add ethyl acetate to the aqueous solution, adjust the mixture to pH 2 and O with 10% hydrochloric acid, separate the aqueous solution, and add it to the nonionic adsorption resin Diaion' HP
-20'' (commercial d: manufactured by Mitsubishi Chemical Corporation) (60 ml).The column was subjected to column chromatography using water (50 ml).
After washing with water with 0ml), add 30% methanol aqueous solution (700ml).
m1). Fractions containing the desired compound were combined, methanol was distilled off, and lyophilized to give 7-[(Z)-
2-(2-formamidothiazol-4-yl)acetamitoco-3-[1-(6,7
-Sihydro5H-1-pyrindinio)methyl]-3-
Cephemu 4-carboxylate (1,07 g) is obtained as a powder.

NMR (DMSO-da, S)' 2-00-2-
40 (2H1m).

2.70-3.80 (6H, m), 5.08 (I
H, d, J = 5Hz).

5.22.5.45 (2H, ABq, J=14Hz>
, 5.66 (IH, dd, J=5Hz, 8Hz),
6.98 (IH, s), 7.02 (LH, s),
7.85 (IH, t, J=7Hz), 8.30 (
LH, d.

J=7Hz), 8.48 (IH,s), 9.20
(IH, d, J=7Hz>.

9.55 (11(,d,J=8Hz)(3)!New U
The following compound is obtained in the same manner as above.

7-C(Z)-2-chloromethylene-2-(2-formamidothiazol-4-yl)acetamide]-3-
(3-Ethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate.

NMR (DMSO-da-8): 1.25 (3H1
tJ=7Hz>, 2,80(2H,q, J=7Hz>
, 3.12 and 3.52 (2H, ABq.

J=18Hz), 5.10 (IH, d, J=5Hz
>, 5.10 and 5.62 (2H, ABq, J=
14Hz), 5.66 (IH, dd.

J=5Hz, 8Hz>, 6.99. (LH,s),
7.02 (IH,s).

8.06 (LH, t, J=7Hz>, 8.45 (
IH, d, J = 7H2).

8.48 (LH, s), 9.30 (tH,
s), 9.36 (IH, d.

J-7Hz>, 9.54 (IH, d, J=13H
z >
Formamidothiazol-4-yl)acetamitoco-
3-[(tetrazolow[1,5-b cobyridazine-6-
yl)thiomethyl]-3-cephemu-4-carvone H(
Concentrated hydrochloric acid (0.22 ml) is added to a mixture of 650 mg ) and methanol (7 ml), the mixture is stirred at room temperature for 1 hour, and then an aqueous sodium bicarbonate solution is added thereto to adjust the pH to 7.0. The mixture is concentrated under reduced pressure to remove methanol, washed with ethyl acetate, and the aqueous solution is then adjusted to pH 2.0 with 10% hydrochloric acid. Filter the precipitate,
7-C(Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[(tetracylo(1,5-bcopyridazin-6-yl)thiomethyl2-3-cephem-4 - Carboxylic acid (0.42 g) is obtained as a powder.

mp, decomposed at 170-175℃) NMR (DMSO-d6.S): 9.5o (LH
, d, J=8Hz'), 8.55(IH, d, J=9
Hz), 7.71 (1B, d, J=9Hz), 6
．． 80 (LH, s), 6.36 (IH, s), 5
．． 76 (IH, dd, J=5Hz.

8Hz), 5.15 (IH, d, J=5Hz>,
4.56 and 4.20 (21(, ABq, J=14
Hz), 3.76 and 3.66 (2H, ABq, J
= 18Hz) (2) 7-[(Z)-z-chloromethylene-2-(2-
formamidothiazol-4-yl)acetamide]-
Salted Ha (0.72 ml) is added to a mixture of 3-[:1-(6,7-cyhydro-5H-1-pyrindinio)methyl-3-cephem-4-carboxylate (1.0 g) and methanol (10 ml). The mixture is stirred at room temperature for 1 hour and then adjusted to $) H7,0 by adding aqueous sodium bicarbonate solution. fj liquid was concentrated under reduced pressure to remove methanol, adjusted to pH 3.0, non-ion absorbing,
After washing the column with water (50 ml), the column was eluted with 30% methanol aqueous solution (500 ml). Fractions containing the desired compound were combined, methanol was distilled off, and lyophilized to yield 7
-[(Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[1-(6
,7-sihydro-5H-1-pyrindinio)methyl-3-cephem-4-carboxylate (650 mg) is obtained as a powder.

mp, 150-155°C (decomposition) NMR (DtjSO-ds, 8-); 9. as (
1)1. d, J=8Hz”), 9.20(LH, d,
J=7Hz), 8.30 (LH,d,,C7Hz>
, 7.85 (IH, t, J=7Hz), 7.08
(2H, br s), 6.78 (IH, s), 6.
34 (LH, s), 5.63 (IH, dd, J=
5Hz.

8Hz), 5.43 and s, 20 (21(,AB
q, J=14Hz>.

5.05 (IH, d, J=5Hz), 3.80-
2.70 (4H+2H, m).

2.4(1-2,0(2H,m) <3) The following compound is obtained in the same manner as in Example 2-(1).

7-[(Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(3-ethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate.

NMR (DMSO-ds, l; ): 1-26 (3
H, t, J = 7Hz), 2.83 (2H, q, J = 7
Hz>, 3. LO and 3.53 (21,ABq.

J=18Hz), 5.10 (IH, d, J-5Hz
>, 5.10 and 5.63 (2H, ABq, J=
14Hz), 5.66 (LH, dd.

J=5Hz, 8Hz>, 6.35 (IH,s),
6.80 (LH,s).

7.10 (2H, br s), 13.05 (IH
, t, J=7Hz), 8.45(LH, d, J near H
z>, 9.30 (LH,s), 9.35 (IH
,d.

Claims (1)

[Claims] 1) General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^3 is an amino group or a protected amino group; X and Y each mean hydrogen or halogen; R^1 means a tetrazolopyridazinylthio group, and
R^2 means a carboxy group or a protected carboxy group; or R^1 means a 1-dihydropyridinio group or a 1-pyridinio group with a suitable substituent, and R^2 is -
A novel cephem compound and its salts represented by COO^■. 2) R^3 is amino or lower alkanoylamino; R^1 is tetrazolopyridazinylthio and R is carboxy; or R^1 is 1-dihydropyridinio or 1-pyridinio with lower alkyl, and R The compound according to claim 1, wherein ^2 is -COO^■. 3) R^3 is amino or formamide; X and Y are each hydrogen or chloro; R^1 is tetrazolopyridazinylthio and R^2 is carboxy; or R^1 is 1-dihydropyridinio or 3) -Ethyl-
The compound according to claim 2, which is 1-pyridinio and R^2 is -COO^■. 4) 7-[(Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[(
4. The compound according to claim 3, which is tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid. 5) 7-[(Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[1
The compound according to claim 3, which is -(6,7-dihydro-5H-1-pyrindinio)methyl]-3-cephem-4-carboxylate. 6) 7-[(Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(3
-ethyl-1-pyridiniomethyl)-3-cephem-4
3. The compound according to claim 3, which is a -carboxylate. 7) Formula (A): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is an amino group or a protected amino group; X and Y each mean hydrogen or halogen) Compounds represented by or its reactive derivatives or salts at the carboxy group have the formula: ▲Mathematical formula, chemical formula, table, etc.▼ (wherein, R^1 means a tetrazolopyridazinylthio group, and R^2 is represents a carboxy group or a protected carboxy group; or R^1 represents a 1-dihydropyridinio group or a 1-pyridinio group with a suitable substituent, and R^2 represents a C
(means OO^■) or its reactive derivative at the amino group or its salt is reacted to form the formula: ▲mathematical formula, chemical formula,
There are tables, etc. ▼ (In the formula, R^1, R^2, R^3, X and Y each have the same meaning as before) Or obtain the compound or its salt represented by (b) Formula: ▲Math. , chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, X and Y each have the same meaning as before, and R^3_a means a protected amino group) or The salt is subjected to the elimination reaction of the amino protecting group, and the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, X and Y each have the same meaning as before). A general formula characterized by obtaining the compound shown or its salt: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R^1, R^2, R^3, X and Y are respectively the preceding and (same meaning) A method for producing a novel cephem compound or its salts. 8) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is an amino group or a protected amino group; X and Y each mean hydrogen or halogen; R^1 is tetrazolo means a pyridazinylthio group, and
R^2 means a carboxy group or a protected carboxy group; or R^1 means a 1-dihydropyridinio group or a 1-pyridinio group with a suitable substituent, and R^2 is -
A prophylactic and therapeutic agent for bacterial infections containing a novel cephem compound represented by COO^■ or its salts as an active ingredient.