JPH05222058A - New cephem compound and its salt - Google Patents

Abstract

PURPOSE:To obtain a new compound capable of preventing growth of diffuse pathogenic bacteria including Gram-negative bacteria, Gram-positive bacteria and useful as antimicrobial agents, etc. CONSTITUTION:A compound of formula I [R<1> is (protected)amino; R<2> is H or organic group; R<3> is (substituted)pyrrolopyridium; R<4> is (protected)carboxy or COO<->; X is N or CH; Y<-> is anion; n is 0 or 1], e.g. 7-beta-[2-(2-aminothiazol-4- yl)-2-methoxyimino-acetamido]-3-[4-)1H-pyrrolo[3,2--4]pyridinio)]methy l-3- cephem-4-carboxylate. Furthermore, the compound of formula I is obtained by reacting a compound of formula II with a compound of formula III in an organic solvent such as acetonitrile in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephem compound having high antibacterial activity and a salt thereof, which is used in the medical field.

[0002]

BACKGROUND OF THE INVENTION Many cephem compounds are known, but no cephem compound represented by the following general formula (I) of the present invention is known.

[0003]

Although many cephem compounds having antibacterial activity and useful as medical treatment are known,
This invention was made with the intention of developing even more excellent pharmaceutical products.

[0004]

The cephem compound for this purpose is novel and can be represented by the following general formula (I).

[0005]

[Chemical 2] [Wherein R ¹ is an amino group or a protected amino group, R 1
² is hydrogen or an organic group, R ³ is a pyrrolopyridinium group which may have an appropriate substituent, R ⁴ is a protected carboxy group or a group represented by the formula: —COO ⁻ , X is N or CH. , Y ^- means an anion, and n means 0 or 1. However, n is 0 when R ⁴ is a group represented by the formula: —COO ⁻ , and n is 1 when R ⁴ is a protected carboxy group. ]

The novel cephem compound (I) of the present invention can be produced by the production method described below. Manufacturing method 1

[Chemical 3] Alternatively, a reactive derivative of a carboxyl group or an amino group, a reactive derivative thereof, a salt thereof, or a salt thereof.

[Chemical 4]

Manufacturing method 2

[Chemical 5]

Manufacturing method 3

[Chemical 6] [Wherein R ¹ a is a protected amino group, R ⁴ a is a carboxy group or a protected carboxy group, R ⁵ is a pyrroloviridine which may have an appropriate substituent, Q is a leaving group. means group, ^{respectively, R 1, R 2, R} 3, R 4, X, Y -
And n each have the same meaning as before]

The raw material compound (III) is novel and can be produced by the production method described below. Manufacturing method A

[Chemical 7] [In the formula, R ⁶ represents a protected amino group, and R ³ , R
⁴ , R ⁴ a, R ⁵ , Q, Y ⁻ and n each have the same meaning as above]

A part of the compound (II) is novel and can be produced by the method disclosed in the production examples described below or in a manner similar thereto. Compounds (I), (Ia), (Ib), (I
With respect to I) and (IV), it is readily understood that those compounds include syn isomers, anti isomers and mixtures thereof. For example, referring to the object compound (I), the syn isomer means one geometrical isomer having a partial structure represented by the following formula,

[Chemical 8] (In the formula, R ¹ , R ² and X have the same meanings as described above.)
The anti isomer means another geometric isomer having a partial structure represented by the following formula.

[0011]

[Chemical 9] (In the formula, R ¹ , R ² and X have the same meanings as described above). Regarding the other compounds other than the above compound (I), the same geometrical isomer as described for the compound (I) may be referred to for the syn isomer and the anti isomer.

Further, the pyrrolopyridinium group which may have an appropriate substituent of R ^{3 in} the compound (I) can also exist in a tautomeric form, and such a tautomeric equilibrium is For example, when R ³ is a 1H-pyrrolo [3,2-b] pyridinium group which may have an appropriate substituent at the N-position, it can be represented by the following formula.

[Chemical 10] (In the formula, R means hydrogen or a suitable substituent.) When R is hydrogen in the above formulas, formulas (B) and (D) are 1H-pyrrolo [3,2-b] pyridyl groups. R ⁴ in compound (I) in that case is a carboxy group or a protected carboxy group, and n is 0. However, including such cases, all tautomers are within the scope of the present invention. include.

Suitable salts of the target compound (I) include conventional pharmaceutically acceptable non-toxic salts, ie salts with various bases and acid addition salts. More specifically, a salt with an inorganic base such as an alkali metal salt (eg, sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), an ammonium salt, Salts with organic bases such as organic amine salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.), inorganic acids Addition salts (eg hydrochloride,
Hydrobromide, sulfate, phosphate, etc.), organic carboxylic acid addition salt or organic sulfonic acid addition salt (eg formate,
Acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-
Toluenesulfonate, etc.), salts with basic amino acids or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) and the like.

In the above and subsequent descriptions of the present specification, suitable examples and explanations of the various definitions included within the scope of the present invention are explained in detail below.

The term "lower" means 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) unless otherwise specified.

"Lower alkyl group" and "acyl (lower) alkyl group", "carboxy (lower) alkyl group", "protected carboxy (lower) alkyl group",
Suitable “lower alkyl” moiety of “hydroxy (lower) alkyl group”, “protected hydroxy (lower) alkyl group”, “halo (lower) alkyl group” is methyl,
A straight or branched chain carbon number 1 to 6 such as ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, hexyl, etc.
Is a residue of an alkane of which C is preferable.
₁ -C ₄ alkyl group.

Suitable "protected amino group" includes:
Examples thereof include an amino group substituted with a conventional protecting group such as an acylamino group or an ar (lower) alkyl group which may have a suitable substituent such as benzyl and trityl.

Suitable "acyl" moieties of "acyl group" and "acyl (lower) alkyl group", "acyloxy group", "acylamino group" include carbamoyl group, substituted carbamoyl group, aliphatic acyl group and An acyl group containing an aromatic ring or a heterocycle can be mentioned. Suitable examples of the acyl group include mono- or di (lower) alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl and dimethylcarbamoyl; for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like. Lower alkanoyl group: for example, lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarponyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc .: for example mesyl. Lower alkanesulfonyl groups such as ethanesulfonyl, propanesulfonyl, propanesulfonyl, isopropanesulfonyl and butanesulfonyl: eg benzene Arenesulfonyl groups such as rufonyl and tosyl: aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc .: al (lower) alkanoyl groups such as phenylacetyl, phenylpropionyl: benzyloxycarbonyl, phenethyloxycarbonyl And an ar (lower) alkoxycarbonyl group and the like. The acyl moieties may have suitable substituents such as halogen such as chlorine, bromine, iodine or fluorine and the like.

Suitable "organic groups" include lower alkyl groups, halo (lower) alkyl groups such as vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or Lower alkenyl groups such as 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, eg ethynyl, 1-provinyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4 −
Lower alkynyl groups such as pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, for example aryl groups such as phenyl, naphthyl, etc., ar (lower) such as phenyl (lower) alkyl groups such as benzyl, phenethyl, phenyl propyl ) Alkyl group, carboxy (lower) alkyl group, protected carboxy (lower) alkyl group, hydroxy (lower) alkyl group, protected hydroxy (lower) alkyl group, hydroxy protecting group and the like. Suitable "halo (lower) alkyl group" includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, trichloroethyl, fluoropropyl, pentafluoropropyl and the like. Is mentioned.

Suitable "protected carboxy" moieties of the "protected carboxy group" and "protected carboxy (lower) alkyl group" include esterified carboxy groups and the like. Preferable examples of the ester include, for example, methyl ester, ethyl ester,
Lower alkyl ester such as propyl ester, isoprobyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester; for example, vinyl ester, allyl ester, etc. Lower alkenyl ester of, for example, lower alkynyl ester such as ethynyl ester and propynyl ester;
Lower alkoxyalkyl esters such as methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester; for example, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylomethyl. Lower alkylthioalkyl ester such as ester; mono- (or di- or tri) halo (lower) alkyl ester such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester; eg acetoxymethyl ester, propionyloxymethyl ester, Butyryloxymethyl ester,
Valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-
Lower alkanoyloxy (lower) alkyl ester such as acetoxyethyl ester and 2-propionyloxyethyl ester; lower alkanesulfonyl (lower) such as mesylmethyl ester and 2-mesylethyl ester
Alkyl ester; for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,
Suitable 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3.5-ditertiary butylbenzyl ester, etc. Ar (lower) alkyl ester such as phenyl (lower) alkyl ester optionally having one or more substituents; for example, phenyl ester, tolyl ester, tertiary butylphenyl ester, xylyl ester, mesityl ester, Aryl ester optionally having one or more suitable substituents such as substituted or unsubstituted phenyl ester such as cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester; tri (lower) alkylsilyl Esters; eg methyl Oesuteru include those such as the lower alkyl thio esters, such as ethyl thioester.

Suitable "hydroxy-protecting group" may be an acyl group as exemplified above. Suitable "protected hydroxy" moiety of "protected hydroxy (lower) alkyl group" includes acyloxy group and the like.

Suitable leaving groups include, for example, halogen such as chlorine, bromine, iodine, etc., sulfonyloxy group such as benzenesulfonyloxy, tosyloxy, mesyloxy, etc., lower alkanoyloxy group such as acetyloxy, propionyloxy, etc. Acid residues such as acyloxy groups.

Suitable "pyrrolopyridinium group" is 1H-pyrrolo [2,3-b] pyridinium, 1H-
Pyrrolo [2,3-c] pyridinium, 1H-pyrrolo [3,2-b] pyridinium, 1H-pyrrolo [3,2-
c] pyridinium, 1H-pyrrolo [3,4-b] pyridinium, 1H-pyrrolo- [3,4-c] pyridinium and the like. The pyrrolopyridinium group and the pyrrolopyridine of the compound (V) may have one or more suitable substituents, and preferable examples of the “suitable substituent” are, for example, a lower alkyl group and an acyl (lower) group. Alkyl group, carboxy (lower) alkyl group, protected carboxy (lower) alkyl group, hydroxy (lower) alkyl group, protected hydroxy (lower) alkyl group, halo (lower) alkyl group, acyl group, carboxy group, A protected carboxy group and the like can be mentioned.

Suitable "anions" include formate ion, acetate ion, trifluoroacetate ion, maleate ion, tartrate ion, methanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion, chlorine ion, bromine ion, Examples thereof include iodine ion, sulfate ion, and phosphate ion.

More preferable examples of the compound (I) include R ¹ : amino group, for example, acylamino group [eg lower alkanoylamino group such as formylamino, acetylamino and the like], ar (lower) alkylamino group [eg tritylamino]. protected amino group such as and the like], and the like, R ^2: hydrogen, a lower alkyl group [e.g., methyl, ethyl,
Propyl, etc.], a halo (lower) alkyl group [eg, fluoromethyl, difluoromethyl, trifluoromethyl,
Fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, pentafluoropropyl, chloromethyl, chloroethyl, bromomethyl, etc.], carboxy (lower) alkyl [eg, carboxymethyl, carboxyethyl, carboxypropyl, etc.], etc., R ³ : Lower alkyl groups [eg methyl, ethyl,
Propyl etc.], halo (lower) alkyl group [eg fluoromethyl, fluoroethyl, difluoroethyl, chloromethyl, chloroethyl etc.], acyl (lower) alkyl group [eg carbamoylmethyl etc.], carboxy group, esterified carboxy Groups [eg carboxy groups esterified with lower alkyl groups such as methyl, ethyl, acyl groups [eg carbamoyl groups, methylcarbamoyl,
A mono- or di (lower) alkylcarbamoyl group such as dimethylcarbamoyl], a hydroxy (lower) alkyl group [eg, hydroxymethyl, hydroxyethyl, etc.] or an optionally substituted pyrrolopyridinium group, R ⁴ : : -COO ^- group represented by and, X: N or CH and the like.

The method for producing the object compound of the present invention will be described in detail below. Production Method 1 Compound (I) or a salt thereof is prepared by reacting compound (II) or a reactive derivative thereof at a carboxy group or a salt thereof with compound (III) or a reactive derivative thereof at an amino group or a salt thereof. Can be manufactured by.

Suitable reactive derivatives at the carboxy group of compound (II) include acid halides, acid anhydrides,
Examples thereof include activated amides and activated esters. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, and the like. Sulfurous acid, thiosulfuric acid, sulfuric acid, for example, sulfonic acid such as methanesulfonic acid, for example, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, tricarboxylic acetic acid such as trichloroacetic acid or Mixed acid anhydrides with acids such as aromatic carboxylic acids such as benzoic acid; symmetrical acid anhydrides; activity with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, 1-hydroxy-1H-benzotriazole or tetrazole Amide; or, for example, cyanomethyl ester, methoxymethyl ester, Methyl imino-methyl [(CH _{3) 2} N ⁺
= CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl Thioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester,
Activated esters such as 8-quinolylthioester, or for example N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzo. Examples thereof include esters with N-hydroxy compounds such as triazole. These reactive derivatives can be arbitrarily selected according to the type of compound (II) to be used.

Suitable salts of the compound (II) and its reactive reactive derivative may be referred to those exemplified for the compound (I). Suitable reactive derivative at the amino group of compound (III) is compound (III)
Schiff's base-type imino or its enamine-type tautomer formed by the reaction of carbonyl compounds such as aldehydes, ketones, etc .; Compound (III) with bis (trimethylsilyl) acetamide, such as N- (trimethylsilyl) acetimide Namono (trimethylsilyl)
Examples thereof include a silyl derivative formed by a reaction with a silyl compound such as acetamide, bis (trimethylsilyl) urea; and a derivative formed by a reaction between compound (III) and phosphorus trichloride or phosgene.

Suitable salts of the compound (III) and its reactive derivative may be referred to those exemplified for the compound (I). The reaction is usually carried out with water, for example, alcohol such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N.
The reaction is carried out in a conventional solvent such as dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent as long as it does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.

When compound (II) is used in this reaction in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-
N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl)
Carbodiimide; N, N'-diethylcarbodiimide,
N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene- N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; Lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2
-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N-dimethylformamide and thionyl chloride, It is desirable to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by reaction with phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like.

The reaction may also be performed with an inorganic or organic base such as an alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. May be performed in the presence of. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 2 Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to an elimination reaction of an amino-protecting group. For the suitable salts of the compounds (Ia) and (Ib), those exemplified for the compound (I) may be referred to. Suitable methods for this elimination reaction include conventional methods such as hydrolysis and reduction.

(I) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, alkali metals such as sodium and potassium, such as magnesium,
Alkaline earth metals such as calcium Hydroxides or carbonates or bicarbonates of these metals, for example trialkylamines such as trimethylamine, triethylamine, picoline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undeca-
Inorganic and organic bases such as 7-ene and the like can be mentioned. Suitable acids include, for example, organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, hydrogen chloride and hydrogen bromide. The elimination using a Lewis acid such as trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid is preferably carried out in the presence of a cation scavenger such as anisole or phenol. The reaction is usually water,
The reaction is carried out in a solvent such as an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction can be carried out in any other solvent as long as it does not adversely influence the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but usually the reaction is performed under cooling or heating.

(Ii) Reduction Reduction is carried out by a conventional method including chemical reduction and catalytic reduction. Suitable reducing agents used for chemical reduction are, for example, metals such as tin, zinc, iron or metal compounds such as chromium chloride, chromium acetate, and formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluene. Sulfonic acid,
It is a combination with an organic acid such as hydrochloric acid or hydrobromic acid, or an inorganic acid. Suitable catalysts used for catalytic reduction are, for example, platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxides, platinum wires, and other platinum catalysts, such as palladium sponge, palladium black, palladium oxide, palladium-carbon, colloids. Palladium catalysts such as palladium, palladium-barium sulfate, 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. , Conventional copper catalysts such as reduced copper, Raney copper, and Ullmann copper. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Furthermore, if the acids used for the chemical reduction are liquids, they can also be used as solvents. Furthermore, suitable solvents used for catalytic reduction include the above solvents, as well as other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran and the like, or mixtures thereof. The reaction temperature of this reaction is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 3 Compound (I) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof. For the suitable salts of the compounds (IV) and (V), those exemplified for the compound (I) may be referred to. The reaction is water, phosphate buffer,
Acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide,
The reaction may be carried out in a solvent such as N, N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, but the reaction is carried out in any other solvent as long as it does not adversely affect the reaction. May be. The reaction temperature is not particularly limited, but the reaction is usually performed at room temperature, under heating or under heating.

The method for producing the starting compound will be described below. Production Method A- Compound (VII) or a salt thereof can be produced by reacting compound (VI) or a salt thereof with compound (V) or a salt thereof. For suitable salts of the compound (VI), the salts with various bases exemplified for the compound (I) may be referred to. For the suitable salts of compound (VII), those exemplified for compound (I) may be referred to. This reaction can be carried out in the same manner as in the above Production Method 3, and therefore, for the reagents to be used and the reaction conditions such as the solvent and the reaction temperature, refer to the description of Production Method 3 .

Production Method A- Compound (III) or a salt thereof can be produced by subjecting compound (VII) or a salt thereof to elimination reaction of the amino protecting group of R ⁶ . This reaction can be carried out in the same manner as in the above Production Method 2, and therefore the reagents to be used and the reaction conditions such as the solvent and the reaction temperature are the same as in Production Method 2.
Refer to the description of.

The object compound (I) and its salts are novel, exhibit a strong antibacterial action, inhibit growth of a wide variety of pathogenic bacteria including Gram-positive bacteria and Gram-negative bacteria, and are useful as antibacterial agents.

[0039]

In order to show the usefulness of the objective compound (I), the test results for the MIC (minimum inhibitory concentration) of representative compounds of the present invention are shown below. Test method: In vitro antibacterial activity was measured by the following agar plate multiple dilution method. Each test strain was cultured overnight in tryptocase-soy broth, and 1 platinum loop (10 ⁶ viable cells / m 2)
l) was inoculated into heart infusion agar (HI-agar) containing a representative test compound at each concentration step, and 37 ° C, 2
After incubating for 0 hours, the minimum inhibitory concentration (MI
C) was expressed in μg / ml. Test compound: (1) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [4- (1H-pyrrolo [3,2- b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (2) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyimino Acetamide] -3- [1-methyl-4- (1H-pyrrolo [3,2
-B] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (3) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxy Iminoacetamide] -3- [1- (2,2-difluoroethyl) -4-
(1H-pyrrolo [3,2-b] pyridinio)] methyl-
3-Cephem-4-carboxylate (syn isomer) (4) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamide] -3- [ 4- (1H-pyrrolo [3,2-
b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (5) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2 , 2-Difluoroethoxyimino) acetamido] -3- [4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (6) 7β- [ 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (2-fluoroethoxyimino) acetamido] -3- [4- (1H-pyrrolo [3,2-b] pyridinio) ] Methyl-3-cephem-
4-carboxylate (syn isomer)

[0040]

For administration as a therapeutic, the object compound (I) of the present invention and its salts are organic or inorganic solid or liquid excipients suitable for oral administration, parenteral administration and external (topical) administration. It is used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient in admixture with such a pharmaceutically acceptable carrier. The pharmaceutical preparation may be in a solid form such as tablets, granules, powders and capsules, or a liquid form such as a solution, suspension, syrup, emulsion and lemonade. If necessary, auxiliary agents, stabilizers, wetting agents and other lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay in the above formulation,
Additives commonly used such as sucrose, corn starch, talc, gelatin, agar, peanut oil, olive oil, cocoa butter, ethylene glycol and the like may be included.

The dose of the compound (I) will vary depending on the patient's age, condition, type of disease, type of the compound (I) used, etc., but it is generally between 1 mg and about 4000 mg or more. The above may be administered per day. The object compound (I) of the present invention is an average single dose drug 50 mg,
100 mg, 250 mg, 500 mg, 1000 mg may be used for the treatment of pathogenic infections.

[0043]

The present invention will be described in more detail below with reference to production examples and examples.

Production Example 1 Ice-cooled 1H-pyrrolo [3,2-b] pyridine (2.0
To a solution of g) in N, N-dimethylformamide (10 ml) is added 60% sodium hydride (812 mg) under ice cooling. After stirring at the same temperature for 1 hour, iodomethane (2.88
g) is added. After stirring the mixture at 5-8 ° C. for 2 hours,
Pour into a mixture of ethyl acetate (50 ml) and water (50 ml). After adjusting the pH of the aqueous layer to 10.5 with potassium carbonate, the aqueous layer is extracted 5 times with ethyl acetate (50 ml). The extracts are combined, dried over potassium sulfate and magnesium sulfate, and the solvent is evaporated under reduced pressure. Residue with chloroform 4
The residue was distilled off three times with toluene to give 1-methyl-1H-pyrrolo [3,2-b] pyridine (1.40 g) as an oil. NMR (DMSO-d ₆ δ): 3.82 (3H, s), 6.54 (1H, d, J = 3.2Hz), 7.13
(1H, dd, J = 4.6Hz, J = 8.3Hz), 7.61 (1H, d, J = 3.2Hz), 7.86 (1
H, d, 8.3Hz), 8.33 (1H, dd, J = 4.6Hz)

Production Example 2 The following compound was obtained in the same manner as in Production Example 1. (1) 1-Methyl-1H-pyrrolo [2,3-b] pyridine NMR (DMSO-d ₆ , δ): 3.83 (3H, s), 6.46 (1H, d, J = 3.4Hz), 7.08
(1H, dd, J = 4.6Hz, 7.8Hz), 7.51 (1H, d, J = 3.4Hz), 7.96 (1H,
d, J = 7.8Hz), 8.27 (1H, d, J = 4.6Hz) (2) 1-methyl-1H-pyrrolo [3,2-c] pyridine NMR (DMSO-d ₆ , δ): 4.10 (3H , s), 6.56 (1H, d, J = 3.5Hz), 7.49
(1H, d, J = 5.7Hz), 7.78 (1H, d, J = 3.5Hz), 8.27 (1H, d, J = 5.7H
z), 8.86 (1H, s) (3) 1-carbamoylmethyl-1H-pyrrolo [3,2
-B] Pyridine NMR (DMSO-d ₆ , δ): 4.84 (2H, s), 6.55 (1H, d, J = 3.2Hz), 7.12
(1H, dd, J = 4.6Hz, J = 8.3Hz), 7.27 (2H, s), 7.60 (1H, d, J = 3.2
Hz), 7.77 (1H, dd, J = 1.2Hz, J = 8.3Hz), 8.33 (1H, dd, J = 1.2H
z, J = 4.6Hz) (4) 1-carbamoylmethyl-1H-pyrrolo [3,2
-C] Pyridine IR (nuclear): 3400,1772 cm ^-1 NMR (DMSO-d ₆ , δ): 4.74 (2H, s), 6.50 (1H, d, J = 3.5Hz), 7.45
(2H, br, s), 7.58 (1H, d, J = 7.5Hz), 7.75 (1H, d, J = 3.5Hz), 8.
27 (1H, d, J = 7.5Hz), 8.84 (1H, s) (5) 1- (2,2-difluoroethyl) -1H-pyrrolo [3,2-b] pyridine NMR (DMSO-d ₆ , δ): 4.75 (2H, dt, J = 3.4Hz, J = 15.9Hz), 6.40
(1H, tt, J = 3.4Hz, J = 54.9Hz), 6.65 (1H, d, J = 3.3Hz), 7.17 (1
H, dd, J = 4.6Hz, J = 8.3Hz), 7.67 (1H, d, J = 3.3Hz), 7.98 (1H,
d, J = 8.3Hz), 8.38 (1H, d, J = 4.6Hz) (6) 1- (2,2-difluoroethyl) -1H-pyrrolo [3,2-c] pyridine NMR (CDCl ₃ , δ ): 4.45 (2H, dt, J = 3.9Hz, J = 13.2Hz), 6.09 (1
H, tt, J = 3.9Hz, J = 54.3Hz), 6.51 (1H, d, J = 3.5Hz), 7.30 (1H,
d, J = 3.5Hz), 7.36 (1H, d, J = 5.8Hz), 8.38 (1H, d, J = 5.8Hz),
8.89 (1H, s)

Production Example 3 Ice-cooled 1H-pyrrolo [3,2-b] pyridine (1.0
g) and diisopropylethylamine (1.47 m
l) N, N-dimethylformamide (11.6 ml)
To the solution, 7β-formamide-3-chloromethyl-3-
Cephem-4-carboxylic acid (2.33 g) is added with stirring under ice cooling. After stirring for 100 minutes at the same temperature, the mixture is poured into ethyl acetate (100 ml) and stirred for 30 minutes. The precipitate formed is filtered off, washed with ethyl acetate and dried under reduced pressure, 7β-formamido-3- [4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-.
4-carboxylate is obtained. The compound (3.0 g) was suspended in methanol (30 ml), and concentrated hydrochloric acid (7.7 m) was added.
l) is added. After stirring for 2 hours, the resulting mixture is poured into a mixture of acetone (75 ml) and ethyl acetate (75 ml). The resulting precipitate is collected by filtration, washed with acetone, and dried under reduced pressure to obtain the crude target compound (2.0 g). This crude compound was dissolved in water and the aqueous solution was adjusted to pH 1.0 with 6N hydrochloric acid.
And column chromatography using Diaion HP-20 (trademark: manufactured by Mitsubishi Kasei) (20 ml) and eluting with water. Fraction containing target compound (45m
l) was collected and diisopropyl alcohol (450 ml)
Gradually dilute under ice-cooling with stirring. The precipitate formed is collected by filtration, washed with diisopropyl alcohol, and dried over phosphorus pentoxide under reduced pressure to give 7β-amino-3- [4- (1H-
Pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate dihydrochloride (0.88 g)
To get IR (Nugeol): 3350,1790,1632,1580cm ^-1 NMR (DMSO-d ₆ , δ): 3.30,3.42 (2H, ABq, J = 17.6Hz), 5.19,5.
24 (2H, ABq, J = 5Hz), 5.56,5.75 (2H, ABq, J = 15.0Hz), 6.98 (1
H, d, J = 3.5Hz), 7.66 (1H, dd, J = 6.2Hz, 8.2Hz), 8.13 (1H, d, J
= 3.5Hz), 8.53 (1H, d, J = 8.2Hz), 8.60 (1H, d, J = 6.2Hz).

Production Example 4 To a solution of dimethyl hydroxyiminomalonate (258 mg) in N, N-dimethylformamide (3 ml) was added 1-
Bromo-2-fluoroethane (203 mg) and triethylamine (162 mg) are added. After stirring at 60 ° C. for 2.5 hours, the solution was mixed with ethyl acetate (10 ml) and water (10 m).
Pour into a mixture with l). The separated organic layer is washed with saturated brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with a mixed liquid of n-hexane and ethyl acetate (3: 1) to obtain dimethyl 2-fluoroethoxyiminomalonate (150 mg). IR (neat): 2960, 1760, 1700, 1610, 1440 cm ^-1 NMR (CDCl ₃ , δ): 3.90 (3H, s), 3.91 (3H, s), 4.45-4.50 (1H,
m), 4.50-4.70 (2H, m), 4.75-4.85 (1H, m)

Production Example 5 Dimethyl 2-fluoroethoxyiminomalonate (122
28% aqueous ammonia (140 ml) is added to a solution of (mg) in methanol (0.5 ml) under ice cooling. After stirring at the same temperature for 30 minutes, the solution was poured into a mixture of ethyl acetate and water,
Adjust to pH 7.0 with concentrated hydrochloric acid. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (Z) -2-carbamoyl-2-
Methyl (2-fluoroethoxyimino) acetate (94m
g) is obtained. IR (Nugeol): 3450, 3200, 1740, 1690 cm ^-1 NMR (CDCl ₃ , δ): 3.92 (3H, s), 4.40-4.45 (1H, m), 4.50-4.60
(2H, m), 4.75-4.80 (1H, m), 5.93 (1H, br s), 6.45 (1H, br s)

Production Example 6 Methyl (Z) -2-carbamoyl-2- (2-fluoroethoxyimino) acetate (60 mg) in pyridine (600
ml) solution, trifluoroacetic anhydride (120 ml)
Is added under ice cooling. After stirring for 40 minutes at room temperature, the solution is poured into a mixture of ethyl acetate and water. Separate the organic layer and
It was washed with N hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give methyl (Z) -2-cyano-2- (2-fluoroethoxyimino) acetate (8
8 mg) is obtained. IR (neat): 2980, 2260, 1750, 1560, 1450 cm ^-1 NMR (CDCl ₃ , δ): 3.92 (3H, s), 4.59 (2H, s), 4.70-4.75 (1H,
m), 4.80-4.85 (1H, m)

Production Example 7 Methanol (44 m) of methyl (Z) -2-cyano-2- (2-fluoroethoxyimino) acetate (1.74 g)
l) To the solution is added 28% sodium methoxide in methanol (965 ml). After stirring for 30 minutes at room temperature,
The methanol is distilled off and the residue is poured into a mixture of ethyl acetate and water. The organic layer is separated, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with a mixed liquid of n-hexane and ethyl acetate (3: 1) to obtain (Z) -3-
Methyl imino-3-methoxy-2- (2-fluoroethoxyimino) propionate (0.80 g) is obtained. IR (neat): 3320, 2960, 1740, 1660 cm ^-1 NMR (CDCl ₃ , δ): 3.90 (3H, s), 3.91 (3H, s), 4.35-4.40 (1H,
m), 4.45-4.55 (2H, m), 4.75-4.80 (1H, m), 8.26 (1H, br s)

Production Example 8 Methyl (Z) -3-imino-3-methoxy-2- (2-fluoroethoxyimino) propionate (790 mg)
Ammonium chloride (615 mg) was added to the methanol solution (17.4 ml). After stirring under reflux for 5 hours, the mixture is poured into ethyl acetate. The precipitate formed was filtered off, the solvent of the filtrate was distilled off under reduced pressure, and the residue was crushed with diethyl ether and pulverized with (Z) -2-amidino-2- (2-fluoroethoxyimino) acetic acid methyl hydrochloride (660 mg). ) Get. IR (Nugeol): 3100, 1750, 1680, 1605 cm ^-1 NMR (DMSO-d ₆ , δ): 3.87 (3H, s), 4.50-4.55 (1H, m), 4.60-4.
70 (2H, m), 4.85-4.90 (1H, m), 9.66 (3H, br s)

Production Example 9 A solution of methyl (Z) -2-amidino-2- (2-fluoroethoxyimino) acetate hydrochloride (640 mg) in methanol (8.0 ml) was added with triethylamine (654 m).
g) and bromine (449 mg) are added at -15 ° C. After stirring for 15 minutes at the same temperature, a solution of potassium thiocyanate (273 mg) in methanol (3.0 ml) was added to the mixture at -1.
Add at 5 ° C. with stirring. After stirring for 2 hours at -5 ° C, the methanol is distilled off and the residue is poured into a mixture of ethyl acetate and water. The organic layer is separated, washed with saturated brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel,
Elute with a mixture of n-hexane and ethyl acetate (1: 1) to give 2- (5-amino-1,2,4-thiadiazol-
Methyl 3-yl) -2- (2-fluoroethoxyimino) acetate (syn isomer) (320 mg) is obtained. IR (Nugeol): 3400, 3250, 3100, 1740, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 3.83 (3H, s), 4.35-4.40 (1H, m), 4.50-4.
55 (2H, m), 4.75-4.80 (1H, m), 8.26 (2H, s)

Production Example 10 2- (5-amino-1,2,4-thiadiazol-3-
(Methyl) -2- (2-fluoroethoxyimino) acetate (syn isomer) (12.1 g) in methanol (350
ml) solution, 1N sodium hydroxide solution (195 m
l) is added. After stirring for 30 minutes at 50 ° C, the methanol is distilled off. The residue is poured into a mixture of ethyl acetate, tetrahydrofuran and water and adjusted to pH 2.0 with 1N hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with diisopropyl ether to give 2- (5-amino-1,2,4-thiadiazol-
3-yl) -2- (2-Fluoroethoxyimino) acetic acid (syn isomer) (9.31 g) is obtained. IR (Nugeol): 3400, 3150, 1700, 1620, 1540 cm ^-1 NMR (DMSO-d ₆ , δ): 4.30-4.35 (1H, m), 4.45-4.55 (2H, m), 4.
75-4.80 (1H, m), 8.22 (1H, s)

Production Example 11 Phosphorus pentoxide (2.80 g) in methylene chloride (30 ml)
The solution is stirred at room temperature for 20 minutes. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- in solution
(2-Fluoroethoxyimino) acetic acid (syn isomer)
(3.0 g) is added with stirring at -5 ° C. 1.5 at the same temperature
After stirring for an hour, the mixture was mixed with diisopropyl ether (90 m).
l) was added and crushed to give 2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2- (2-fluoroethoxyimino) acetyl chloride hydrochloride (syn isomer) (2.22 g) is obtained. IR (Nugeol): 3250, 1780, 1635 cm ^-1 NMR (DMSO-d ₆ , δ): 4.30-4.35 (1H, m), 4.45-4.55 (2H, m), 4.
75-4.80 (1H, m), 11.4 (2H, br s)

Preparation Example 12 2.2-Difluoroethanol (10.0 g) and sodium hydroxide (5.8 g) were added to a mixture of P-toluenesulfonyl chloride (25.56 g) and water (42.7 ml).
5 g) in water (23.2 ml) is added. After stirring for 1.5 hours at 50 ° C., the solution is poured into ethyl acetate (100 ml). The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,2-difluoroethyl P-toluenesulfonate (25.8).
4 g) are obtained. IR (Nugeol): 1595, 1180 cm ^-1 NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 4.35 (2H, dt, J = 2.8Hz, 15.1
Hz), 6.25 (1H, tt, J = 2.8Hz, 53.3Hz), 7.51 (2H, d, J = 8Hz), 7.
83 (2H, J = 8.0Hz)

Production Example 13 N-hydroxyphthalimide (163 mg) and 1,8-diazabicyclo [5.4.0] undec-7-
A solution of ene (167 mg) in N, N-dimethylformamide (2.0 ml) was added with P-toluenesulfonic acid 2,2.
-Add difluoroethyl (260 mg). After stirring at 90 ° C. for 3 hours, the solution was mixed with water (10 ml) and ethyl acetate (1
Pour into a mixture with 0 ml). The organic layer is separated, washed twice with saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from diisopropyl ether to give N- (2,2-difluoroethoxy) phthalimide (141 mg). IR (Nugeol): 1800, 1740, 1720 cm ^-1 NMR (CDCl ₃ , δ): 4.38 (2H, dt, J = 4.2Hz, 12.7Hz), 6.23 (1H, t
t, J = 4.2Hz, 54.5Hz), 7.7-8.0 (4H, m)

Production Example 14 N- (2,2-difluoroethoxy) phthalimide (5
To a solution of 45 mg) in ethanol (2.4 ml) is added hydrazine hydrate (120 mg). After stirring the mixture under reflux for 5 minutes, the resulting precipitate was filtered off and the O- (2,2
-Difluoroethyl) hydroxylamine (Compound A)
To get On the other hand, in a solution of sodium hydroxide (240 mg) in water (3.0 ml), 2- (5-formamide-1,
2,4-Thiadiazol-3-yl) -2-oxothioacetate S-methyl (776 mg) is added. After stirring for 1 hour at room temperature, the solution is adjusted to pH 7.0 with 6N hydrochloric acid under ice cooling. To this cold solution is added the ethanolic solution of Compound A obtained above. After adjusting the pH to 3.5 with 6N hydrochloric acid, the mixture is stirred at room temperature for 3.5 hours. After filtering off the formed precipitate,
Ethanol was distilled off under reduced pressure, and the resulting solution was adjusted to pH 7.
Wash with ethyl acetate at 0. The solution was adjusted to pH 0.9 with 6N hydrochloric acid under ice cooling, the precipitate formed was collected by filtration and washed with cold water to give 2- (5-formamide-1,2,4-thiadiazol-3-yl). ) -2- (2,2-Difluoroethoxyimino) acetic acid (syn isomer) (220 mg) is obtained. IR (Nugeol): 3400, 1720, 1685 cm ^-1 NMR (DMSO-d ₆ , δ): 3.50 (1H, br s), 4.53 (2H, dt, J = 3.6Hz, 1
4.7Hz), 6.29 (1H, tt, J = 3.6Hz, 54.3Hz), 8.85 (1H, s), 13.57
(1H, s)

Production Example 15 2- (5-formamido-1,2,4-thiadiazol-3-yl) -2- (2,2-difluoroethoxy) was added to a solution of sodium hydroxide (240 mg) in water (3 ml). Imino) acetic acid (syn isomer) (560 mg) is added. Fifty
After stirring for 30 minutes at ℃, the solution is cooled to room temperature, adjusted to pH 7.0 with 1N hydrochloric acid, and washed with ethyl acetate. The solution was diluted with 1N hydrochloric acid to PHO. Adjust to 9 and oil out with ethyl acetate. The oily liquid was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to give 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2,2-difluoro). Ethoxyimino) acetic acid (syn isomer) (370 mg) is obtained. IR (Nugeol): 3400, 1720, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 4.46 (2H, dt, J = 3.6Hz, 14.7Hz), 6.24 (1
H, tt, J = 3.6Hz, 54.4Hz), 8.24 (2H, s)

Production Example 16 In the same manner as in Production Example 11, the following compound was obtained. 2- (5-
Amino-1,2,4-thiadiazol-3-yl) -2
-(2,2-Difluoroethoxyimino) acetyl chloride hydrochloride (syn isomer).

Example 1 7β-Amino-3- [4- (1H-pyrrolo [3,2-
b] pyridinio)] methyl-3-cephem-4-carboxylate dihydrochloride (0.19 g) in water (10 ml)
5- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl chloride hydrochloride (syn isomer) (0.16 g) was added to a solution of acetone and acetone (10 ml).
% Sodium hydrogencarbonate aqueous solution while slowly maintaining the pH at 5-6. The mixture obtained is diluted with water (50 ml) and the acetone is distilled off under reduced pressure. The aqueous solution is adjusted to pH 2.0 with 1N hydrochloric acid, subjected to column chromatography using Diaion HP-20, and eluted with 25% aqueous methanol solution. Combine the fractions containing the target compound,
Lyophilized to give 7β- [2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (0.13 g) is obtained. IR (Nugeol): 1760,1652,1603,1525 cm ^-1 NMR (D ₂ O, δ): 3.21,3.34 (2H, ABq, J = 17.6Hz), 3.97 (3H, s),
5.17 (1H, d, J = 5Hz), 5.51,5.74 (2H, ABq, J = 14.7Hz), 5.83 (1
H, d, J = 5Hz), 6.98 (1H, s), 6.99 (1H, d, J = 3.4Hz), 7.65 (1H, d
d, J = 6.2Hz, 8.2Hz), 8.13 (1H, d, J = 3.4Hz), 8.52 (1H, d, J = 8.
2Hz), 8.59 (1H, d, J = 6.2Hz)

Example 2 In the same manner as in Example 1, the following compound is obtained. (1) 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (2,2-difluoroethoxyimino) acetamido] -3- [4- (1H- Pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 1767,1660,1610,1523 cm ^-1 NMR (D ₂ O-DCl, δ): 3.24,3.57 (2H, ABq, J = 18.3Hz), 4.56 (2
H, dt, J = 3.7Hz, 11Hz), 5.29 (1H, d, J = 5Hz), 5.71,5.91 (2H, A
Bq, J = 14.8Hz), 5.90 (1H, d, J = 5Hz), 6.17 (1H, tt, J = 3.7Hz, 5
3.6Hz), 6.98 (1H, d, J = 3.5Hz), 7.66 (1H, dd, J = 6.2Hz, 8.2H
z), 8.14 (1H, d, J = 3.5Hz), 8.54 (1H, d, J = 8.2Hz), 8.57 (1H,
(2) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-fluoroethoxyimino) acetamide] -3- [4- (1H-Pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-
4-carboxylate (syn isomer). IR (Nugeol): 1770, 1660, 1608, 1512 cm ^-1 NMR (DMSO-d ₆ ,, δ): 2.97, 3.32 (2H, ABq, J = 17.4Hz), 4.32 (2
H, dt, J = 29.7Hz, 3.2Hz), 4.61 (2H, dt, J = 47.9Hz, 4.1Hz), 5.
01 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5Hz, 8Hz), 5.69 (2H, s), 7.
38 (1H, d, J = 3.1Hz), 7.70 (1H, dd, J = 6.1Hz, 8.1Hz), 8.18 (2
H, br s), 8.29 (1H, d, J = 3.1Hz), 8.63 (1H, d, J = 8.1Hz), 9.10
(1H, d, J = 6.1Hz), 9.56 (1H, d, J = 8Hz). (3) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)- 2- (1-Carboxy-1-methylethoxyimino) acetamide] -3- [4- (1
H-pyrrolo [3,2-b] pyridinio)] methyl-3-
Cephem-4-carboxylate (syn isomer). IR (Nujol): 1770, 1658, 1600, 1515 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 1.51 (6H, s), 3.17, 3.33 (2H, ABq, J =
17.7Hz), 5.19 (1H, d, J = 5Hz), 5.51,5.71 (2H, ABq, J = 14.9H
z), 5.87 (1H, d, J = 5Hz), 6.94 (1H, d, J = 3.2Hz), 7.57 (1H, dd,
J = 6.0Hz, 8.2Hz), 8.11 (1H, d, J = 3.2Hz), 8.46 (1H, d, J = 8.2H
z), 8.55 (1H, d, J = 6.0Hz). (4) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamide] -3- [4- (1H-pyrrolo [3,2-
b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 1770, 1668, 1610, 1522 cm ^-1 NMR (DMSO-d ₆ , δ): 2.99, 3.34 (2H, ABq, J = 17.3Hz), 5.04 (1
H, d, J = 5Hz), 5.71 (1H, dd, J = 5Hz, 8Hz), 5.72 (2H, br s), 5.7
2 (2H, d, J = 54.9Hz), 7.34 (1H, d, J = 3.2Hz), 7.70 (1H, dd, J =
6.0Hz, 8.1Hz), 8.23 (2H, br s), 8.29 (1H, d, J = 3.2Hz), 8.63
(1H, d, J = 8.1Hz), 9.05 (1H, d, J = 6.0Hz), 9.73 (1H, d, J = 8H
z).

Example 3 A suspension of Vilsmeier reagent in tetrahydrofuran (6.8 ml) adjusted with phosphorus oxychloride (0.114 ml) and N, N-dimethylformamide (0.105 ml) was added to 2- (2- Tritylaminothiazol-4-yl) -2- (2,2-difluoroethoxyimino) acetic acid (syn isomer) (0.51 g) is added under ice cooling with stirring.
After stirring at the same temperature for 40 minutes, the resulting activated acid solution was treated with 7β-
Amino-3- [4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxyla-
Toni hydrochloride (0.35 g) in acetone (10 ml) and water (10 ml) was added dropwise under ice cooling. During dripping,
The pH of the reaction mixture was adjusted to pH with 5% aqueous sodium hydrogen carbonate solution.
Maintain between H5 and H6. The resulting mixture was mixed with water (40 m
It is diluted with 1), adjusted to pH 2.0 with 1N hydrochloric acid, and extracted twice with a mixture of ethyl acetate (30 ml) and tetrahydrofuran (20 ml). The organic layers are combined and dried over magnesium sulfate. The solvent was evaporated and the residue was washed with ethyl acetate (15
(ml) and diisopropyl ether (30 ml). Insoluble matter is filtered off and dried under reduced pressure to give 7β
-[2- (2-Tritylaminothiazol-4-yl)
-2- (2,2-Difluoroethoxyimino) acetamide] -3- [4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxyla-
To give the (syn isomer) (0.3 g). NMR (DMSO-d ₆ , δ): 3.02, 3.31 (2H, ABq, J = 17.2Hz), 4.28 (2
H, dt, J = 3.7Hz, 11Hz), 5.02 (1H, d, J = 5.0Hz), 5.65 (1H, dd, J
= 5.0Hz, 8.0Hz), 5.70 (2H, s), 6.14 (1H, tt, J = 3.7Hz, 53.6H
z), 6.82 (1H, s), 7.2-7.5 (17H, m), 7.71 (1H, dd, J = 6.2Hz, 8.
2Hz), 8.31 (1H, d, J = 3.5Hz), 8.61 (1H, d, J = 8.2Hz), 9.01 (1
H, d, J = 6.2Hz), 9.60 (1H, d, J = 8.0Hz).

Example 4 7β- [2- (2-Tritylaminothiazol-4-yl) -2- (2,2-difluoroethoxyimino) acetamido] -3- [4- (1H-pyrrolo [ 3,2-b]
Pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (0.30 g) and anisole (0.5 ml) in methylene chloride (1.5 ml),
Trifluoroacetic acid (2.0 ml) is added under ice-cooled stirring. After stirring for 2 hours at the same temperature, the reaction mixture is poured into diisopropyl ether (50 ml). The precipitate formed is filtered off and dissolved in water (50 ml). After adjusting the pH of the aqueous solution to 2.0, it is subjected to column chromatography using Diaion HP-20 and eluted with a 40% aqueous methanol solution. Fractions containing the target compound are combined, lyophilized,
7β- [2- (2-aminothiazol-4-yl) -2
-(2,2-Difluoroethoxyimino) acetamido] -3- [4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) ( 66 mg) is obtained. IR (Nugeol): 1770, 1661 (sh), 1605 cm ^-1 NMR (D ₂ O, δ): 3.21, 3.36 (2H, ABq, J = 17.4Hz), 4.44 (2H, dt,
J = 3.7Hz, 14.4Hz), 5.18 (1H, d, J = 5.0Hz), 5.52,5.75 (2H, AB
q, J = 15.0Hz), 5.84 (1H, d, J = 5.0Hz), 6.16 (1H, tt, J = 3.7Hz,
54.6Hz), 6.98 (1H, d, J = 3.5Hz), 7.03 (1H, s), 7.65 (1H, dd, J
= 6.0Hz, 8.1Hz), 8.83 (1H, d, J = 3.5Hz), 8.51 (1H, d, J = 6.0H
z), 8.59 (1H, d, J = 8.1Hz).

Example 5 Ice-cooled 1H-pyrrolo [3,2-b] pyridine (1.0
g) and sodium 2-ethylhexanoate (0.92
4 g) in N, N-dimethylformamide (9 ml) was added to 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3-chloro. Methyl-3-cephem-4-carboxylic acid / monotrifluoroacetic acid salt (syn isomer) (1.89)
g) is added under ice cooling. After stirring for 2 hours at the same temperature, the reaction mixture is poured into ethyl acetate (300 ml). The precipitate formed is filtered off, washed with ethyl acetate and dried under reduced pressure. The precipitate is dissolved in water (100 ml) at pH 3.0. The insoluble matter is filtered off, the aqueous solution is subjected to column chromatography using Diaion HP-20, and eluted with a 30% aqueous methanol solution. Combine the fractions containing the target compound, 1
Concentrate to 00 ml, lyophilize to 7β- [2- (5
-Amino-1,2,4-thiadiazol-3-yl)-
2-Ethoxyiminoacetamide] -3- [4- (1H
-Pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer) (0.4
33 g) are obtained. IR (Nugeol): 1760, 1660, 1600 cm ^-1 NMR (D ₂ O-DCl, δ): 1.30 (3H, t, J = 7.1Hz), 3.27,3.59 (2H, AB
q, J = 18.5Hz), 4.40 (2H, q, J = 7.1Hz), 5.32 (overlaps with 1H, DOH), 5.71,5.93 (2H, ABq, J = 15.4Hz), 5.91 (1H, d, J = 4.8Hz),
7.01 (1H, d, J = 3.4Hz), 7.67 (1H, dd, J = 6.2Hz, 8.1Hz), 8.16
(1H, d, J = 3.4Hz), 8.56 (1H, d, J = 8.1Hz), 8.60 (1H, d, J = 6.2H
z).

Example 6 The following compound was obtained in the same manner as in Example 5. (1) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [4- (1H-pyrrolo [2,3-b ] Pyridinio)] Methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 1770, 1665, 1620, 1512 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 1.27 (3H, t, J = 7Hz), 3.15, 3.51 (2H,
ABq, J = 17.8Hz), 4.30 (2H, q, J = 7Hz), 5.24 (1H, d, J = 5Hz), 5.
20,5.33 (2H, ABq, J = 14.6Hz), 5.88 (1H, d, J = 5Hz), 6.79 (1H,
d, J = 3.4Hz), 7.57 (1H, d, J = 3.4Hz), 7.61 (1H, d, J = 7.2Hz),
8.00 (1H, d, J = 7.2Hz), 8.84 (1H, s).

(2) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [4- (1H-pyrrolo [3,3
2-c] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nujol): 1750, 1665, 1620 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 1.27 (3H, t, J = 7.0Hz), 3.14, 3.51 (2
H, ABq, J = 17.7Hz), 4.29 (2H, q, J = 7.0Hz), 5.24 (1H, d, J = 5H
z), 5.11,5.33 (2H, ABq, J = 16.5Hz), 5.88 (1H, d, J = 5Hz), 6.7
9 (1H, d, J = 3.4Hz), 7.56 (1H, d, J = 3.4Hz), 7.61 (1H, d, J = 7.2
Hz), 8.01 (1H, d, J = 7.2Hz), 8.83 (1H, s).

(3) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [1-methyl-4- (1H-
Pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 3300, 1750, 1665, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.19 (3H, t, J = 7.0Hz), 2.93,3.27 (2H, AB
q, J = 17.4Hz), 4.03 (3H, s) 4.11 (2H, q, J = 7.0Hz), 4.97 (1H,
d, J = 4.9Hz), 5.61-5.66 (3H, m), 7.40 (1H, d, J = 3.2Hz), 7.78
(1H, dd, J = 6.1Hz, 8.2Hz), 8.16 (2H, s), 8.29 (1H, d, J = 3.2H
z), 8.74 (1H, d, J = 8.2Hz), 9.19 (1H, d, J = 6.1Hz), 9.48 (1H,
d, J = 8.5Hz).

(4) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [1-methyl-4- (1H-
Pyrrolo [2,3-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 3250, 1760, 1650, 1610 cm ^-1 NMR (D ₂ O, δ): 1.30 (3H, t, J = 7.1Hz), 3.29, 3.73 (2H, ABq, J =
17.7Hz), 4.24 (3H, s) 4.35 (2H, q, J = 7.1Hz), 5.35 (1H, d, J =
5.0Hz), 5.93 (1H, d, J = 5.0Hz), 5.95,6.18 (2H, ABq, J = 15.4H
z), 6.91 (1H, d, J = 3.6Hz), 7.52 (1H, d, J = 3.6Hz), 7.58 (1H, d
d, J = 7.7Hz, J = 6.1Hz), 8.28 (1H, d, J = 6.1Hz), 8.61 (1H, d, J =
7.7 Hz).

(5) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [1-methyl-4- (1H-
Pyrrolo [3,2-c] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 1760,1668,1612,1590 cm ^-1 NMR (DMSO-d ₆ ,, δ): 2.99,3.51 (2H, ABq, J = 17.5Hz), 3.84 (3
H, s), 4.22 (3H, s), 5.06 (1H, d, J = 5Hz), 5.66 (1H, dd, J = 5Hz,
8Hz), 5.12,5.71 (2H, ABq, J = 16.6Hz), 7.10 (1H, d, J = 3.5H
z), 8.21 (1H, d, J = 7.5Hz), 8.23 (2H, br s), 8.34 (1H, d, J = 3.
5Hz), 9.17 (1H, d, J = 7.5Hz), 9.51 (1H, d, J = 8Hz), 9.83 (1H,
s)

(6) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [1-carbamoylmethyl-
4- (1H-pyrrolo [3,2-b] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 3300, 1760, 1650, 1600 cm ^-1 NMR (D ₂ O-DCl, δ): 1.05 (3H, t, J = 7.1Hz), 3.03, 3.37 (2H, AB
q, J = 18.5Hz), 4.12 (2H, q, J = 7.1Hz), 5.05 (1H, d, J = 4.8Hz),
5.07 (2H, s), 5.48,5.71 (2H, ABq, J = 15.9Hz), 5.63 (1H, d, J =
4.8Hz), 6.86 (1H, d, J = 3.3Hz), 7.49 (1H, dd, J = 6.2Hz, J = 8.2
Hz), 7.89 (1H, d, J = 3.3Hz), 8.32 (1H, d, J = 8.2Hz), 8.43 (1H,
(d, J = 6.2Hz)

(7) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [1-carbamoylmethyl-
4- (1H-pyrrolo [3,2-c] pyridinio)] methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 1770, 1670, 1602 cm ^-1 NMR (D ₂ O, δ): 1.28 (3H, t, J = 7Hz), 3.19, 3.59 (2H, ABq, J = 1
7.8Hz), 4.30 (2H, q, J = 7Hz), 5.02 (2H, s), 5.26 (1H, d, J = 5H
z), 5.34,5.51 (2H, ABq, J = 14.6Hz), 5.87 (1H, d, J = 5Hz), 7.0
0 (1H, d, J = 3.5Hz), 8.00 (1H, d, J = 3.5Hz), 8.07 (1H, d, J = 7.5
Hz), 8.50 (1H, d, J = 7.5Hz), 9.24 (1H, s).

(8) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [1- (2,2-difluoroethyl) -4- (1H-pyrrolo [3,2-b] pyridinio)] Methyl-3-cephem-4-carboxylate (syn isomer). IR (Nugeol): 1760, 1660, 1600 cm ^-1 NMR (D ₂ O, δ): 1.31 (3H, t, J = 7.1Hz), 3.29, 3.64 (2H, ABq, J =
18.6Hz), 4.42 (2H, q, J = 7.1Hz), 4.97 (1H, dt, J = 3.0Hz, J = 1
3.9Hz), 5.32 (1H, d, J = 4.9Hz), 5.73,5.96 (2H, ABq, J = 15.4H
z), 5.89 (1H, d, J = 4.9Hz), 6.40 (1H, tt, J = 3.0Hz, J = 54.1H
z), 7.13 (1H, d, J = 3.4Hz), 7.78 (1H, dd, J = 6.3Hz, J = 8.3Hz),
8.21 (1H, d, J = 3.4Hz), 8.68 (1H, d, J = 8.3Hz), 8.71 (1H, d, J =
6.3 Hz).

(9) 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [1- (2,2-difluoroethyl) -4- (1H-pyrrolo [3,2-c] pyridinio)]] Methyl-3-cepham-4-carboxylate (syn isomer). IR (Nugeol): 1770, 1668, 1610 cm ^-1 NMR (D ₂ O-DCl, δ): 3.06, 3.49 (2H, ABq, J = 18.9Hz), 3.83 (3
H, s), 4.60 (2H, dt, J = 1.5Hz, J = 14.6Hz), 5.09 (1H, d, J = 5H
z), 5.65 (1H, d, J = 5Hz), 5.14,5.63 (2H, ABq, J = 16.5Hz), 6.0
9 (1H, tt, J = 1.5Hz, 53.3Hz), 6.78 (1H, d, J = 3.5Hz), 7.79 (1
H, d, J = 3.5Hz), 7.80 (1H, d, J = 7.5Hz), 8.28 (1H, d, J = 7.5H
z), 8.99 (1H, s).

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ is an amino group or a protected amino group, R ² is hydrogen or an organic group, R ³ is a pyrrolopyridinium group which may have an appropriate substituent, and R ⁴ is a protected carboxy group. Alternatively, a group represented by the formula: —COO ⁻ , X represents N or CH, Y ⁻ represents an anion, and n represents 0 or 1. However, when R ⁴ is a group represented by the formula: —COO ⁻ , n is 0,
N is 1 when R ⁴ is a protected carboxy group. ] The novel cephem compound shown by these, and its salt.