JPH05213971A - Novel cephem compounds - Google Patents

Abstract

PURPOSE:To provide a novel compound which is useful as an antimicrobial agent because it inhibits pathogenic microorganisms over a wide range including gram-positive and gram-negative bacteria from growing. CONSTITUTION:A compound of formula I [R<1> is amino, acylamino; R<2> is hydroxy (which may be protected); A is lower alkylene], for example, 7beta- amino-3-[1-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2yl) methyl}-5-(1H-imidazo[1,2 b]pyrazolio)]methyl-3-cephem-4-carboxylate dihydrochloride. The compound of formula I is given by the reaction between compounds of formula II (X<1> is a leaving group) and formula III.

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 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 medicines are known,
This invention was made with the intention of developing even more excellent pharmaceutical products.

[0004]

The target compound, the cephem compound, is novel and is represented by the following general formula (I).

[Chemical 2] [Wherein, R ¹ represents amino or acylamino, R ² represents hydroxy or protected hydroxy, and A represents lower alkylene] The object compound (I) of the present invention can be produced by the following methods.

Manufacturing method (1)

[Chemical 3]

Manufacturing method (2)

[Chemical 4]

Manufacturing method (3)

[Chemical 5]

Manufacturing method (4)

[Chemical 6]

Manufacturing method (5)

[Chemical 7] [In the above formulas, R ¹ , R ² and A are as defined above, R ¹ _a is acylamino, R ² _a is protected hydroxy, R ¹ _b is protected carboxy (lower) alkyl. Having acylamino, R ¹ _c represents acylamino having carboxy (lower) alkyl, and X ¹ represents a leaving group.] The starting compound (III) can be produced by the following methods.

Manufacturing method (A)

[Chemical 8]

Manufacturing method (B)

[Chemical 9] [In the above formulas, R ² and A are respectively as defined above, and X ² represents a leaving group.] In the description above and below in the present specification, various definitions included in the scope of the present invention Preferred examples and explanations of are described in detail below.

The term "lower" means 1 to 6 carbon atoms unless otherwise specified. Unless otherwise specified, the term "luxury" means
It means 7 to 20 carbon atoms. Suitable "acyl" in "acylamino", "acylamino having a protected carboxy (lower) alkyl group" and "acylamino having a carboxy (lower) alkyl group"
As the part, carbamoyl derived from organic carboxylic acid, organic carbonic acid, organic sulfonic acid or organic carbamic acid,
Examples thereof include an aliphatic acyl group and an acyl group having an aromatic ring (which is referred to as an aromatic ring acyl), an acyl having a heterocycle (which is referred to as a heterocyclic acyl), and the like.

Preferable examples of the acyl include aliphatic acyl such as lower or higher alkanoyl (eg formyl, acetyl, succinyl, hexanoyl, heptanoyl, valeryl, stearoyl etc.); lower or higher alkoxycarbonyl (eg methoxycarbonyl, ethoxy). Carbonyl, t-butoxycarbonyl, t
-Pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkanesulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.);

Aromatic acyls such as aroyl (eg benzoyl, toluoyl, naphthoyl etc.); phenyl (lower) alkanoyls (eg phenylacetyl,
Phenyl (propionyl, etc.) and the like, al (lower) alkanoyl; aryloxycarbonyl (eg, phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy (lower) alkanoyl (eg, phenoxyacetyl, phenoxypropionyl, etc.); Oxyloyl,
Naphthylglyoxyloyl etc.); arenesulfonyl (eg benzenesulfonyl, p-toluenesulfonyl etc.);

Heterocyclic acyl, such as heterocyclic carbonyl (eg, tenoyl, furoyl, nicotinoyl, etc.); Heterocyclic (lower) alkanoyl (eg, thienylacetyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.); Heterocyclic glyoxyloyl (for example, thiazolyl glyoxyloyl, thienyl glyoxyloyl, etc.); and the like, and the above "heterocyclic carbonyl", "heterocyclic (lower) alkanoyl" and "heterocyclic glyoxyloyl". The preferable heterocyclic moiety in the above means a saturated or unsaturated monocyclic or polycyclic heterocyclic group having at least one hetero atom such as an oxygen atom, a sulfur atom or a nitrogen atom.

Particularly preferred heterocyclic groups are 3- to 8-membered ones having 1 to 4 nitrogen atoms, more preferably 5 members.
Or a 6-membered unsaturated heteromonocyclic group such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl,
Pyrazinyl, pyridazinyl, triazolyl (eg 4
H-1,2,3-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),
Tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.) and the like; 3 to 8-membered (more preferably 5 or 6-membered) saturated heteromonocyclic group having 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl,
Piperidino, piperazinyl and the like; unsaturated condensed heterocyclic groups having 1 to 4 nitrogen atoms, for example, indolyl, isoindolyl, indoridinyl, benzimidazolyl,
Quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc .;

3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,
Isoxazolyl, oxadiazolyl (eg 1,
2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like); 3 to 8-membered having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (more preferably 5 or 6-membered) saturated heterocyclic groups such as morpholinyl, sydnonyl, etc .; unsaturated fused heterocyclic groups having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl,
Benzoxazodiazolyl and the like;

A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl (for example, 1,2). , 3-
Thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc .; sulfur atom 1 or 2
3 to 8-membered (more preferably 5 or 6-membered) saturated heteromonocyclic group having 1 to 3 nitrogen atoms and 1 to 3 nitrogen atoms, for example, thiazolidinyl; A 5- or 6-membered) unsaturated heteromonocyclic group such as thienyl, dihydrodithynyl, dihydrodithionyl, etc .; an unsaturated fused heterocyclic group having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl , Benzothiadiazolyl, etc .;

3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having one oxygen atom, such as furyl; one oxygen atom and one or two sulfur atom.
Having 3 to 8 members (more preferably 5 or 6)
Members) unsaturated heteromonocyclic groups such as dihydrooxathiynyl; unsaturated condensed heterocyclic groups having 1 or 2 sulfur atoms, such as benzothienyl, benzodithynyl; 1 oxygen atom and 1 or 2 sulfur atoms. Unsaturated fused heterocyclic groups having, for example, a heterocyclic group such as benzoxathiynyl and the like.

Regarding the above-mentioned heterocyclic group, the following points should be noted. That is, for example, when the heterocyclic group is a thiazolyl or thiadiazolyl group having an amino group or a protected amino group as a substituent, such a thiazolyl or thiadiazolyl group includes a tautomer derived from the behavior of the thiazole or thiadiazole ring. .. That is, such an amino or protected amino thiazolyl or thiadiazolyl group is represented by the formula:

[Chemical 10] (Wherein R ³ is amino or protected amino, Z is C
H or N respectively). However, the group represented by the formula Q is specifically

[Chemical 11] (Wherein R ³ and Z are as defined above) or

[Chemical 12] (In the formula, Z is as defined above, and R ^{3 ′} represents imino or protected imino). That is, the two groups represented by the formulas (Q ′) and (Q ″) are in a tautomeric equilibrium state which can be represented by the following equilibrium formula.

[Chemical 13] (In the formula, R ³ , Z, and R ^{3 ′} are as defined above.)

2-aminothiazole or 5-aminothiadiazole compound and 2-iminothiazoline or 5-
Such tautomerism with an iminothiadiazoline compound is a phenomenon well known in the art, and it is obvious to those skilled in the art that these tautomers are in equilibrium and can be converted into each other. That is. Therefore, it will be understood that these isomers belong to the same category as the compound itself. That is, it is clear that these tautomers are included in the scope of the present invention. In the present specification, for the sake of convenience, the target compound and the starting compound containing such a tautomeric group are described in the above-mentioned 2
-Amino (or protected amino) thiazolyl or 5-amino (or protected amino) thiadiazolyl

[Chemical 14] It is written with.

The acyl moiety is 1 to 10 identical or different suitable substituents, eg lower alkyl;
Lower alkoxy (eg methoxy, ethoxy, propoxy etc.); lower alkylthio (eg methylthio,
Ethylthio etc.); lower alkylamino (eg methylamino etc.); cyclo (lower) alkyl (eg cyclopentyl, cyclohexyl etc.); cyclo (lower)
Alkenyl (eg, cyclohexenyl, cyclohexadienyl, etc.); halogen; amino; protected amino; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; amino (lower ) Alkyl (eg aminomethyl, aminoethyl, etc.); Carbamoyloxy; Hydroxy (lower) alkyl (eg hydroxymethyl, 1- or 2-hydroxyethyl, 1
Or 2 or 3-hydroxypropyl, etc.); cyano (lower) alkenylthio (eg, cyanovinylthio, etc.); a group represented by the formula: N—OR ⁴ (wherein R ⁴ represents hydrogen or an organic group described later). And so on. Here, the acyl moiety has the formula = N-OR ⁴ (wherein
R ⁴ has the same meaning as defined above) as a substituent, geometric isomers (syn isomer and anti isomer) exist due to the presence of a double bond. For example, the syn isomer has the formula

[Chemical 15] A geometrical isomer having a group represented by, and the corresponding anti-isomer is the following formula

[Chemical 16] It is a geometric isomer having a group represented by.

Preferable examples of "lower alkyl" and "lower alkyl moiety" in "carboxy (lower) alkyl" and "protected carboxy (lower) alkyl" include methyl, ethyl, propyl, isopropyl, butyl, t. - butyl, pentyl, mention may be made of linear or branched alkyl such as hexyl, the preferred than among them is a C ₁ -C ₄ alkyl. Suitable "protected amino" includes acylamino or an amino group substituted with a conventional protecting group such as ar (lower) alkyl which may have a suitable substituent (eg, benzyl, trityl and the like). Can be mentioned.

Suitable "organic groups" include lower alkyl (eg methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), mono (or di or tri) halo (lower) alkyl (eg chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, Trichloroethyl, fluoroethyl, trifluoroethyl, etc.), lower alkenyl (eg vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc., lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or Or 4 or 5-hexynyl etc.), aryl (eg phenyl, naphthyl etc.), ar (lower) alkyl, eg phenyl (lower) alkyl (eg benzyl, phenethyl, phenylpropyl etc.), lower alkyl moiety as indicated above. Carboxy (lower) alkyl which is a kimono, a protected carboxy (lower) alkyl in which a lower alkyl part is as shown above and a protected carboxy part is as shown below, and the like can be mentioned. ..

Suitable examples of "protected carboxy moiety" in "protected carboxy" and "protected carboxy (lower) alkyl" include esterified carboxy and the like. Preferable examples of the ester include lower alkyl ester (for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester,
t-pentyl ester, hexyl ester and the like); lower alkenyl ester (eg vinyl ester, allyl ester etc.); lower alkynyl ester (eg ethynyl ester, propynyl ester etc.); lower alkoxyalkyl ester (eg methoxymethyl ester, ethoxymethyl ester, Isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); Lower alkylthioalkyl ester (eg, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); Mono (or di Or tri) halo (lower) alkyl ester (eg, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); low Alkanoyloxy (lower) alkyl ester (eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2 -Propionyloxyethyl ester, etc.); lower alkanesulfonyl (lower) alkyl ester (eg, mesylmethyl ester, 2-mesylethyl ester, etc.); ar (lower) alkyl ester, eg, having one or more suitable substituents Optionally a phenyl (lower) alkyl ester (for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, Lens benzhydryl ester, bis (methoxyphenyl) methyl ester,
3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); Aryl ester optionally having one or more suitable substituents, eg, substituted or unsubstituted Phenyl ester (eg phenyl ester, tolyl ester, t
-Butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri (lower) alkylsilyl ester; lower alkylthioester (eg, methylthioester, ethylthioester, etc.), etc. Can be mentioned.

Suitable "protecting group" in "protected hydroxy" is the above-mentioned acyl or suitable substituent.
Examples thereof include phenyl (lower) alkyl (eg, benzyl, 4-methoxybenzyl etc.) which may have one or more, tetrahydropyranyl and the like. Suitable "lower alkylene" may include straight chain or branched alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene and propylene, and among them, more preferable. is a C ₁ -C ₄ alkylene, most preferred is methylene. Suitable “leaving group” includes acyloxy such as halogen (eg chlorine, bromine, iodine etc.), sulfonyloxy (eg benzenesulfonyloxy, tosyloxy, mesyloxy etc.), lower alkanoyloxy (eg acetyloxy, propionyloxy etc.). And so on.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts, such as alkali metal salts (eg sodium salt, potassium salt etc.) and alkaline earth metal salts (eg calcium salt). Salt, magnesium salt, etc.), ammonium salt, salt with organic base (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.),
Salts with organic acids (eg formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), salts with inorganic acids (eg hydrochloric acid) Salt, hydrobromide,
(Sulfate, phosphate, etc.), salts with amino acids (eg, arginine salt, aspartate, glutamate, etc.) and the like.

Preferred examples of the target compound (I) are as follows. R ¹ is amino, lower alkanoylamino or a formula

[Chemical 17] [Wherein R ³ is amino or protected amino, R ⁴ is hydrogen or an organic group (more preferably lower alkyl, carboxy (lower) alkyl or protected carboxy (lower) alkyl; most preferably lower alkyl, carboxy) (Lower) alkyl or lower alkoxycarbonyl (lower) alkyl), Z represents CH or N, respectively, and R ² is hydroxy or ar (lower) alkoxy which may have a suitable substituent. (More preferably phenyl (lower) alkoxy which may have a suitable substituent; most preferably phenyl (lower) alkoxy having lower alkoxy, A is lower alkylene. Object compound and starting compound of the present invention The manufacturing method of is described in detail below.

Production Method (1) Compound (I) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof. The reaction is usually carried out with water, an alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), a common solvent such as tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylacetamide, N, N-dimethylformamide, and other reactions. It is carried out in a solvent such as an organic solvent that does not adversely affect. Of these solvents, the hydrophilic solvent can also be used as a mixture with water. The reaction is
Also, alkali metal bicarbonates, tri (lower) alkylamines, pyridines, alkali metal lower alkanes, N-
It is carried out in the presence of an inorganic or organic base such as (lower) alkylmorpholine or N, N-di (lower) alkylbenzylamine. Further, when the bases are liquid, they can be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Process (2) Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to a deacylation reaction. Suitable methods for this reaction include hydrolysis,
A conventional method such as reduction can be mentioned.

(I) Hydrolysis This hydrolysis is preferably carried out in the presence of a base or an acid containing a Lewis acid. Suitable bases include alkali metals (eg sodium, potassium etc.), alkaline earth metals (eg magnesium, calcium etc.), their hydroxides or carbonates or bicarbonates, trialkylamines (eg trimethylamine, triethylamine etc.). ), Picoline, 1,5-diazabicyclo [4.
3.0] Nonene-5,1,4-diazabicyclo [2.
2.2] Octane, 1,8-diazabicyclo [5.4.
0] Inorganic bases such as undecene-7 and organic bases can be mentioned. Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). You can Elimination with Lewis acids such as trihaloacetic acid (eg trichloroacetic acid, trifluoroacetic acid, etc.) can be achieved by cation trapping agents (eg anisole, phenol)
Is preferably carried out in the presence of This reaction is usually carried out with water,
Alcohol (eg methanol, ethanol, etc.),
Methylene chloride, tetrahydrofuran, mixtures thereof,
The reaction is carried out in a solvent such as a solvent that does not adversely affect the reaction. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually 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 in the chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid, propionic acid, triacetic acid). Fluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts used for catalytic reduction include platinum catalysts (eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg palladium sponge, palladium black, palladium oxide, palladium charcoal). , Colloidal palladium, palladium-barium sulfate,
Palladium-barium carbonate etc.), nickel catalyst (eg reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalyst (eg reduced cobalt, Raney cobalt etc.), iron catalyst (eg reduced iron, Raney iron etc.), copper catalyst (eg reduction) Copper, Raney copper, Ullmann copper, etc.) and the like. The reduction is usually carried out in a solvent such as water, methanol, ethanol, propanol, N, N-dimethylformamide, a conventional solvent which does not adversely influence the reaction or a mixture thereof. Further, when the acid used for the chemical reduction is liquid, these can be used as a solvent. Further, suitable solvents used for catalytic reduction include the above-mentioned solvents and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran and the like, or a mixture thereof. The reaction temperature for the main reduction is not particularly limited, and the reaction is usually performed under cooling or heating.

Process (3) Compound (Ia) or its salt can be produced by subjecting compound (Ib) or its reactive derivative at the amino group or its salt to an acylation reaction. Preferable examples of the reactive derivative at the amino group of the compound (Ib) include Schiff base type imino compounds obtained by reacting the compound (Ib) with carbonyl compounds such as aldehydes and ketones, or tautomeric enamine type compounds thereof. Isomer: silyl derivative obtained by reacting compound (Ib) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; compound (Ib) with phosphorus trichloride or phosgene Examples thereof include derivatives obtained by the reaction, and others. Suitable acylating agents used in the present acylation reaction may include conventional ones, those represented by the formula R ⁵ —OH (VIII) (wherein R ⁵ is acyl) or the reaction thereof. It is a sex derivative or its salt.

Suitable reactive derivatives of compound (VIII) include acid halides, acid anhydrides, active amides, active esters and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid (for example, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, Sulfonic acid (such as methanesulfonic acid), aliphatic carboxylic acid (such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid) or aromatic carboxylic acid (For example, benzoic acid)
Mixed acid anhydrides with acids such as; symmetrical acid anhydrides; active amides with imidazole, 4-substituted imidazole, 1-hydroxy-1H-benzotriazole, dimethylpyrazole, triazole, or tetrazole; or active esters (eg cyanomethyl Ester, methoxymethyl ester, dimethyliminomethyl [(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-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, benzothiazolylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc.) or N-hydroxy Compounds [eg N, N
-Dimethylhydroxylamine, 1-hydroxy-2-
(1H) -pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-1H-
Benzotriazole etc.] and the like. These reactive derivatives may be appropriately selected depending on the type of compound (VIII) used.

This reaction is usually carried out with water, alcohol (eg methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N.
A conventional solvent such as dimethylformamide, pyridine,
Alternatively, it is carried out in a solvent such as an organic solvent that does not adversely influence the reaction. These conventional solvents can also be used as a mixture with water. When compound (VIII) is used in the form of a free acid or a salt thereof in this reaction, the reaction is carried out by a conventional condensing agent such as 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;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformates (eg chloro) Ethyl formate, isopropyl chloroformate, etc.); triphenylphosphine; 2
-Ethyl-7-hydroxybenzoisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H -Benzotriazole; preferably performed in the presence of a so-called Vilsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like.

This reaction is carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine. You can also do it below. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Production Method (4) Compound (Id) or a salt thereof can be produced by subjecting compound (Ic) or a salt thereof to a hydroxy protecting group elimination reaction. Since this reaction can be carried out in the same manner as in the above-mentioned production method (2), the reagents and reaction conditions (for example, solvent, reaction temperature, etc.) to be used are the same as those explained in the production method (2). be able to.

Production Method (5) Compound (If) or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to a reaction for eliminating a carboxy protecting group. This reaction is based on the above-mentioned production method (2).
As described above, the reagents and reaction conditions (for example, solvent, reaction temperature, etc.) to be used can be the same as those described in the production method (2).

Process (A) Compound (VI) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof. This reaction can be carried out in the same manner as in Production Example 2.

Process (B) Compound (III) or a salt thereof can be produced by reacting compound (VI) or a salt thereof with compound (VII) or a salt thereof. This reaction can be carried out in the same manner as in Production Example 3. Manufacturing method (1)-
Suitable salts of the target compound, the starting compound and the reactive derivative thereof in (5), (A) and (B) may be the same as those exemplified for the compound (I). The object compound (I) and its pharmaceutically acceptable salts are novel and have high antibacterial activity,
It inhibits the growth of a wide range of pathogenic bacteria including Gram-positive and Gram-negative bacteria and is useful as an antibacterial agent. Now, in order to show the usefulness of the target compound (I), the minimum inhibitory concentration (MIC) test data of a representative compound belonging to the compound (I) is shown below.

Test method In vitro antibacterial activity was measured by the following agar plate multiple dilution method. Each test strain was cultivated overnight in tryptocase-soy-broth, and 1 platinum loop (viable cell count: 10 ⁸ cells / ml) was
Heart infusion agar (HI-agar) containing representative test compounds at each concentration step was inoculated and incubated at 37 ° C. for 20 hours, after which the minimum inhibitory concentration (MIC) was expressed in μg / ml.

Test Compound 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide]-
3- [1-{(5-hydroxy-4-oxo-1,4-
Dihydropyridin-2-yl) methyl} -5- (1H-
Imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4-carboxylate (syn isomer)

Test results

[Table 1] When the object compound (I) of the present invention and a pharmaceutically acceptable salt thereof are used for therapeutic purposes, an organic or inorganic solid or liquid suitable for oral administration, parenteral administration or external use is used as the active ingredient. It is administered as a usual preparation mixed with a pharmaceutically acceptable carrier such as an excipient. These formulations may be solid dosage forms such as tablets, granules, powders, capsules, or solutions,
It may be a liquid dosage form such as a suspension, syrup, emulsion or lemonade. If necessary, various auxiliaries, stabilizers, wetting agents, and other commonly used additives in the above-mentioned preparations such as lactose, citric acid, tartaric acid, stearic acid,
Magnesium stearate, white clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil,
Olive oil, cocoa butter, ethylene glycol and the like can be added. The dose of compound (I) will vary depending on the age and other conditions of the patient, the type of disease, the type of compound used, etc., but generally, about 1 mg to about 4,000 mg or more per day is administered to each patient. be able to. For the treatment of infectious diseases caused by pathogenic bacteria, the target compound (I) has an average dose of about 50 mg,
100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg can be administered. The following Manufacturing Examples and Examples are provided to illustrate the present invention.

Production Example 1 2-Hydroxymethyl-4-oxo-5- (4-methoxybenzyloxy) -4H-pyran (262 g) and 2,
Thionyl chloride is added dropwise at 7 ° C. to a suspension of 6-lutidine (127.3 ml) in acetonitrile (2.6 l). After stirring for 1 hour at 45-50 ° C, the resulting solution is poured into a mixture of ethyl acetate (7.81) and saturated aqueous sodium hydrogen carbonate solution (7.81). Separate the organic layer to 0.1
It is washed with N hydrochloric acid (7.8 l × 2), saturated aqueous sodium hydrogen carbonate solution (7.8 l) and brine (7.8 l), dried over magnesium sulfate and then evaporated. The residue was triturated with isopropyl ether (1.3 l), and the obtained powder was collected by filtration and dried under reduced pressure to give 2-chloromethyl-4-.
Oxo-5- (4-methoxybenzyloxy) -4H-
Pyran (217.2 g) is obtained. IR (nujor): 1635, 1610, 1580 cm ^-1 NMR (DMSO-d ₆ , δ): 3.76 (3H, s), 4.67 (2H, s), 4.87
(2H, s), 6.56 (1H, s), 6.95 (2H, d, J = 8.7Hz), 7.35 (2H,
d, J = 8.7Hz), 8.27 (1H, s)

Production Example 2 1H-imidazo [1,2-b] pyrazole (82.42)
g) in N, N-dimethylformamide (824 ml) solution with potassium t-butoxide (103.58 g) at 5 ° C.
Add in. After the mixture was stirred at 5 ° C. for 20 minutes, it was mixed with 2-
Chloromethyl-4-oxo-5- (4-methoxybenzyloxy-4H-pyran (216g) was added.After stirring at 5 ° C for 1 hour, the reaction mixture was added with ethyl acetate (2.05g).
p) into a mixture of 1), tetrahydrofuran (2.05 l) and brine (4.1 l). The precipitate obtained is filtered off, the organic layer is separated, washed twice with brine (4.1 l), dried over magnesium sulphate and then evaporated. The residue was subjected to silica gel (1.28 kg) column chromatography to give 1-[{5- (4-methoxybenzyloxy) -4-oxo-4H-pyran-2-yl} methyl] -1H-imidazo [. 1,2-b] pyrazole (13
3.75 g) is isolated. IR (nujor): 1640, 1620, 1595 cm ^-1 NMR (DMSO-d ₆ , δ): 3.75 (3H, s), 4.18 (3H, s), 5.12
(3H, s), 5.71 (1H, dd, J = 0.6Hz & 2.2Hz), 6.32 (1H, s),
6.93 (2H, d, J = 8.7Hz), 7.26 (1H, dd, J = 1.3Hz & 2.2H
z), 7.32 (2H, d, J = 8.7Hz), 7.49 (1H, dd, J = 1.3Hz & 2.2H
z), 7.61 (1H, dd, J = 0.6Hz & 2.2Hz), 8.18 (1H, s)

Production Example 3 1-[{5- (4-methoxybenzyloxy) -4-oxo-4H-pyran-2-yl} methyl] -1H-imidazo [1,2-b] pyrazole (133.75 g) 28% aqueous ammonia (1.31) is added to a suspension of 1) in ethanol (670 ml). After stirring at 60-70 ° C for 3 hours,
The reaction mixture is subjected to evaporation. The residue was powdered with 50% ethanol aqueous solution (470 ml), the obtained powder was collected by filtration, washed with 50% ethanol aqueous solution (100 ml) and ethanol (100 ml, 2 times), dried, and 1-
[{5- (4-Methoxybenzyloxy) -4-oxo-1,4-dihydropyridin-2-yl} methyl] -1
H-imidazo [1,2-b] pyrazole (120.54
g) is obtained. IR (nujor): 1660, 1635, 1610, 1585 cm ^-1 NMR (DMSO-d ₆ , δ): 3.74 (3H, s), 4.99 (2H, s), 5.03
(2H, s), 5.58 (1H, dd, J = 0.6Hz & 2.1Hz), 6.39 (1H, br
s), 6.92 (2H, d, J = 8.6Hz), 7.24 (1H, dd, J = 1.2Hz & 2.2H
z), 7.34 (2H, d, J = 8.6Hz), 7.45 (1H, dd, J = 1.2Hz & 2.1H
z), 7.57 (1H, dd, J = 0.6Hz & 2.2Hz), 7.84 (1H, br s)

Example 1 1-[{5- (4-methoxybenzyloxy) -4-oxo-1,4-dihydropyridin-2-yl} methyl]
-1H-imidazo [1,2-b] pyrazole (35.0
4g) and diisopropylethylamine (12.68m)
7β-Formamide-3-chloromethyl-3-cephem-4-carboxylic acid (27.67 g) was added to a solution of 1) in N, N-dimethylformamide (350 ml) at 5 ° C. After stirring at 5 ° C. for 5 hours, the reaction mixture is poured into a mixture of ethyl acetate (1.75 l), acetone (1.75 l) and diisopropylethylamine (26.13 ml). The obtained precipitate was collected by filtration, and ethyl acetate (350 m
After washing with a mixture of 1) and acetone (350 ml), it is dried under reduced pressure. The dried powder was pulverized with N, N-dimethylformamide (276 ml), and the obtained powder was collected by filtration, washed with N, N-dimethylformamide (35 ml) and acetone (70 ml), and dried under reduced pressure to give 7β. -Formamide-3- [1-[{5- (4-methoxybenzyloxy) -4-oxo-1,4-dihydropyridin-2-yl} methyl] -5- (1H-imidazo [1,2-b] Pyrazolio)] methyl-3-cephem-4-carboxylate (16.90 g) is obtained. Obtained compound (16.
90 g) was added to dichloromethane (33.8 ml), anisole (16.9 ml) and trifluoroacetic acid (33.8 ml).
ml) in an ice-cold mixture. The reaction mixture is stirred under ice cooling for 2 hours and then at 15 ° C. for 1 hour. The solution obtained is poured into diisopropyl ether (507 ml). The precipitate was collected by filtration, and diisopropyl ether (100
(ml) and then dried under reduced pressure to give 7β-formamide-
3- [1-{(5-hydroxy-4-oxo-1,4-
Dihydropyridin-2-yl) methyl} -5- (1H-
Imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4-carboxylate trifluoroacetate salt (16.60 g) is obtained. Obtained compound (16.60)
g) in methanol (166 ml) in concentrated hydrochloric acid (27.
9 ml) is added under ice cooling. The solution is stirred at 22 ° C. for 3 hours. The resulting solution is poured into a mixture of ethyl acetate (625ml) and acetone (625ml). The precipitate is filtered off,
After washing with a mixture of ethyl acetate (125 ml) and acetone (125 ml), it was dried under reduced pressure to give 7β-amino-3-.
[1-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl} -5- (1H-imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4- Carboxylate dihydrochloride (11.33g)
To get IR (Nujol): 1775, 1585 cm ^-1 NMR (D ₂ O, δ): 3.36, 3.59 (2H, ABq, J = 17.9Hz), 5.20
(1H, d, J = 5.1Hz), 5.30 (1H, d, J = 5.1Hz), 5.44 (2H, s),
5.65 (2H, s), 6.44 (1H, d, J = 3.6Hz), 7.15 (1H, s), 7.6
1 (1H, d, J = 2.5Hz), 8.05 (1H, d, J = 2.4Hz), 8.09 (1H, s),
8.13 (1H, d, J = 3.6Hz)

Example 2 1-[{5- (4-methoxybenzyloxy) -4-oxo-1,4-dihydropyridin-2-yl} methyl]
-1H-imidazo [1,2-b] pyrazole (58.6
0 g) and N, N-diisopropylethylamine (175
ml) N, N-dimethylformamide (1.04 l)
7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3-chloromethyl-3-cephem-in solution. 4-Carboxylic acid trifluoroacetate salt (syn isomer) (207 g) is added. 1.5 at 5 ° C
After stirring for an hour, the reaction mixture is poured into ethyl acetate (10.4 l). The powder obtained is filtered and dried under reduced pressure. 8 powder
Dissolve in 0% aqueous acetone (2.56 l) and subject the solution to silica gel (2.56 kg) column chromatography. The column is washed with 80% acetone water (20 l), and the target compound is eluted with 50% acetone water. Lyophilize the eluate. The obtained compound (76.8 g) was converted into formic acid (38
4%) solution was added dropwise with 35% hydrochloric acid (29.5 ml) at room temperature. After stirring at room temperature for 3 hours, the solution was diluted with ethyl acetate (2.
Pour into a mixture of 56 l) and acetone (1.28 l). The powder obtained is filtered and dried under reduced pressure. The pH was adjusted to 10 with 1N sodium hydroxide, the powder (74.6 g) was dissolved in water (3.36 l), and immediately the pH of the solution was adjusted with 6N hydrochloric acid.
The precipitate was adjusted to 0.9 and the resulting precipitate was filtered off, and the filtrate was used as Diaion HP-20 (trademark, Mitsubishi Kasei Co., Ltd.) (1.
Column chromatography using 68 l). After washing the column with water (8.4 l), the target compound was eluted with a 35% aqueous methanol solution, and the eluate (6.72 l) was added with 750
After concentrating to ml, cool to 6 ° C. The obtained powder was collected by filtration and dried under reduced pressure to obtain 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide]-
3- [1-{(5-hydroxy-4-oxo-1,4-
Dihydropyridin-2-yl) methyl} -5- (1H-
Imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4-carboxylate (syn isomer) (11.
68 g) are obtained. IR (nujor): 1770 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 1.49 (6H, s), 3.13, 3.37 (2H,
ABq, J = 17.6Hz), 5.19 (1H, d, J = 4.8Hz), 5.21 (2H, s), 5.
29 (2H, br s), 5.84 (1H, d, J = 4.8Hz), 6.17 (1H, d, J = 3.5
Hz), 6.59 (1H, s), 7.51 (1H, d, J = 2.2Hz), 7.51 (1H,
s), 7.94 (1H, d, J = 2.2Hz), 8.00 (1H, d, J = 3.5Hz)

Example 3 7β-Amino-3- [1-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl}
-5- (1H-imidazo [1,2-b] pyrazolio)]
To a suspension of methyl-3-cephem-4-carboxylate dihydrochloride (1.55 g) in tetrahydrofuran (31 ml) was added N- (trimethylsilyl) acetamide (7.
94 g) are added and the mixture is warmed to 40 ° C. 2- (2-aminothiazol-4-yl) -2- was added to the resulting solution.
Methoxyiminoacetyl chloride hydrochloride (syn isomer) (807 mg) is added at 5 ° C. After stirring for 2 hours at 5 ° C., the reaction mixture is poured into a mixture of ethyl acetate (250 ml) and acetic acid (3.78 ml). 30 at room temperature
After stirring for a minute, the obtained powder was collected by filtration and washed with ethyl acetate (10
(0 ml) and then dried under reduced pressure. Powder (2.86g)
Is dissolved in water (30 ml), and the solution is Diaion HP-
Subject to 20 (55 ml) column chromatography. Wash the column with water (275 ml). Target compound 25%
Elute with an aqueous solution of methanol and freeze-dry the eluate (275 ml) to obtain 7β- [2- (2-aminothiazole-4).
-Yl) -2-methoxyiminoacetamide] -3-
[1-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl} -5- (1H-imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4- Carboxylate (syn isomer) (605m
g) is obtained. IR (nujol): 1770, 1595 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 3.12, 3.37 (2H, ABq, J = 17.7H
z), 3.96 (3H, s), 5.17 (1H, d, J = 4.7Hz), 5.18 (2H, s),
5.29 (2H, br s), 5.79 (1H, d, J = 4.7Hz), 6.14 (1H, d, J =
3.6Hz), 6.59 (1H, s), 6.96 (1H, s), 7.51 (2H, br s),
7.94 (1H, d, J = 2.2Hz), 7.98 (1H, d, J = 3.6Hz)

Example 4 7β-Amino-3- [1-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl}
-5- (1H-imidazo [1,2-b] pyrazolio)]
To a suspension of methyl-3-cephem-4-carboxylate dihydrochloride (1.55 g) in tetrahydrofuran (31 ml) was added N- (trimethylsilyl) acetamide (7.
94 g) are added and the mixture is warmed to 40 ° C. S-2-Benzothiazolyl 2- (2-aminothiazol-4-yl) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) ethanethionate (syn isomer) (1. 72 g) is added at 5 ° C. After stirring for 1 hour at 5 ° C. and then 1 hour at room temperature, the reaction mixture is poured into a mixture of ethyl acetate (250 ml) and acetic acid (3.78 ml). The mixture was stirred at room temperature for 1 hour, the resulting powder was filtered off and dried under reduced pressure to give 7β- [2- (2-aminothiazol-4-yl) -2- (1-t-butoxycarbonyl-1). -Methylethoxyimino) acetamide] -3-
[1-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl} -5- (1H-imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4- Carboxylate (syn isomer) (1.90
g) is obtained. The obtained compound (1.90 g) was mixed with anisole (3.74 ml) and trifluoroacetic acid (9.35 m).
Add little by little to the ice-cooled mixture of l). The reaction mixture is stirred at room temperature for 2 hours. The solution obtained is poured into diisopropyl ether (150 ml). The precipitate is collected by filtration, washed with diisopropyl ether (30 ml), and dried under reduced pressure.
A solution of powder (1.91 g) in water (30 ml) was adjusted to pH 1 with 6N hydrochloric acid, and Diaion HP-20 (51 ml).
Subject to column chromatography. Column with water (255
ml) wash. The target compound was eluted with a 35% aqueous methanol solution, and the eluate (204 ml) was lyophilized to give 7β-
[2- (2-aminothiazol-4-yl) -2- (1
-Carboxy-1-methylethoxyimino) acetamide] -3- [1-{(5-hydroxy-4-oxo-
1,4-dihydropyridin-2-yl) methyl} -5-
(1H-imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4-carboxylate (syn isomer)
(407 mg) is obtained. IR (nujor): 1770 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 1.46 (6H, s), 3.12, 3.39 (2H,
ABq, J = 17.6Hz), 5.20 (1H, d, J = 4.8Hz), 5.26 (2H, s), 5.
30 (2H, s), 5.81 (1H, d, J = 4.8Hz), 6.22 (1H, d, J = 3.4H
z), 6.59 (1H, s), 6.93 (1H, s), 7.52 (1H, d, J = 2.4Hz),
7.55 (1H, s), 7.98 (1H, d, J = 2.4Hz), 8.02 (1H, d, J = 3.
4Hz)

Example 5 1-[{5- (4-methoxybenzyloxy) -4-oxo-1,4-dihydropyridin-2-yl} methyl]
-1H-imidazo [1,2-b] pyrazole (0.35
g) and sodium 2-ethylhexanoate (0.66 g)
7β in N, N-dimethylformamide (5 ml) solution of
-[2- (5-amino-1,2,4-thiadiazole-
3-yl) -2-ethoxyiminoacetamide] -3-
Chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate salt (syn isomer) (1.12 g) is added at 5 ° C. After stirring at 5 ° C. for 4 hours, the reaction mixture was diluted with ethyl acetate (5
0 ml). The resulting precipitate was collected by filtration and dried under reduced pressure to give 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [1- [{5- (4-Methoxybenzyloxy) -4-oxo-1,4-dihydropyridine-2-
Il} methyl] -5- (1H-imidazo [1,2-b]
Pyrazolio)] methyl-3-cephem-4-carboxylate (syn isomer) (1.23 g) is obtained. Trifluoroacetic acid (5 ml) is added to a suspension of this compound (1.23 g) in anisole (5 ml) under ice cooling. After stirring at 5 ° C. for 1.5 hours, the resulting solution was diluted with ethyl acetate (50 m
Pour into a mixture of l) and diisopropyl ether (50 ml). The powder obtained is filtered and dried under reduced pressure. The pH was adjusted to 9 with 1N sodium hydroxide solution and the powder was mixed with water (38 m
1), the solution was adjusted to pH 1 with 6N hydrochloric acid, the resulting precipitate was filtered off, and the filtrate was used as Diaion HP-20.
(20 ml) Subject to column chromatography. Wash the column with water (100 ml). The target compound was eluted with a 30% aqueous methanol solution, and the eluate (60 ml) was lyophilized to give 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide. ] -3- [1-{(5-hydroxy-4-oxo-
1,4-dihydropyridin-2-yl) methyl} -5-
(1H-imidazo [1,2-b] pyrazolio)] methyl-3-cephem-4-carboxylate (syn isomer)
(0.12 g) is obtained. IR (Nujol): 1770 cm ^-1 NMR (D ₂ O-NaHCO ₃ , δ): 1.28 (3H, t, J = 7.1H), 3.10, 3.
37 (2H, ABq, J = 17.8Hz), 4.31 (2H, q, J = 7.1Hz), 5.18 (1
H, d, J = 4.8Hz), 5.21 (2H, s), 5.28 (2H, s), 5.84 (1H, d,
J = 4.8Hz), 6.19 (1H, d, J = 3.5Hz), 5.59 (1H, s), 7.43
(1H, d, J = 2.2Hz), 7.52 (1H, s), 7.96 (1H, d, J = 2.2Hz),
7.99 (1H, d, J = 3.5Hz)

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents amino or acylamino, R ² represents hydroxy or protected hydroxy, and A represents lower alkylene, respectively] A novel cephem compound and a pharmaceutically acceptable salt thereof.