KR0143534B1 - New cephalosporins and processes for proparation thereof - Google Patents

Abstract

The present invention relates to a novel cephalosporin-based compound represented by the following structural formula (I), a pharmaceutically acceptable salt thereof, and a preparation method thereof.

Wherein R ¹ is a hydrogen atom or an amino protecting group and R ² is a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a lower alkyl group of 1 to 3 carbon atoms substituted by one or more halogen atoms, or (Wherein R ⁴ and R ⁵ are the same as or different from each other, a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ⁶ is a hydrogen atom, an alkali metal such as sodium or lithium, or a carboxy protecting group).

R ³ is a hydrogen atom, a halogen atom, an amino group, a hydroxy group or a lower alkyl group having 1 to 4 carbon atoms, A is an oxygen atom, a sulfur atom or NR ^a [wherein R ^a is a hydrogen atom, a hydroxyl group,-(CH ₂ ) NR ^b (n = 1-2, R ^b is a hydrogen atom, a hydroxy group, or a carboxy group)], and Q is a carbon or nitrogen atom.

Description

Novel cephalosporin compounds and preparation method thereof

The present invention relates to a novel cephalosporin-based compound represented by the following structural formula (I), a pharmaceutically acceptable salt thereof, and a preparation method thereof.

Wherein R ¹ is a hydrogen atom or an amino protecting group, R ² is a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a lower alkyl group of 1 to 3 carbon atoms substituted with one or more halogen atoms, or (Wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ⁶ is a hydrogen atom, an alkali metal such as sodium or lithium, or a carboxy protecting group).

R ³ is a hydrogen atom, a halogen atom, an amino group, a hydroxy group or a lower alkyl group having 1 to 4 carbon atoms, A is an oxygen atom, a sulfur atom or NR ^a [wherein R ^a is a hydrogen atom, a hydroxyl group,-(CH ₂ ) _N -R ^b (n = 1 to 2, R ^b is a hydrogen atom, a hydroxy group, or a carboxy group)], and Q is a carbon or nitrogen atom.

Currently known cephalosporin-based antibiotics are substituted with various functional groups at positions 3 and 7 using the following structural formula (a) as the mother nucleus, and are active against various gram-positive and negative bacteria, and are useful for treating various infectious diseases. .

(a)

In particular, in the cephalosporin antibiotics, the 3-position was substituted with the quaternary ammonium methyl group, and the 7-position was substituted with various acylamino groups, which showed good efficacy in the activity against anti-Staphylococcus aureus and Pseudomonas aeruginosa. Cephalosporin-based antibiotics having a Zwieter ion structure include ceftazidime (US Pat. Nos. 4,250,041 and 4,328,453), cefepime [Journal of Antibiotics, 1988. p86], Sepyrom [ EP 64,740, ME 1228 (Journal of Antibiotics, 1990. p62) and the like. Ceftazidime shows an excellent anti-pneumococcal activity, but the activity against glucose cocci is shown to be relatively lower than that of other cefem compounds, and cepirom shows a broad and excellent antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria.

In addition, cephalosporin-based antibiotics include Cytotaxin [US Pat. Nos. 4,152,432 and 4,098,888], Ceftriaxone [US Pat. No. 4,327,210], and the like. When compared with the anti-stool fungal activity is known to be relatively weak activity.

Accordingly, the inventors of the present invention have studied new cephalosporin-based antibiotics excellent in both anti-pseudomonas aeruginosa activity and antiseptic aureus activity, and the 3 position of the cepam nucleus has a substituted pyridinium thiomethyl group represented by the following structural formula (b). At the same time, the present invention is realized by the fact that the cephalosporin-based compound having several groups specific to position 7 shows high activity in anti-pneumococcal and anti-apocotic action, and particularly shows strong potency against a wide range of pathogens in systemic infection treatment tests. Was completed.

(b)

An object of the present invention is to provide a novel cephalosporin-based compound represented by Structural Formula (I) and a preparation method thereof.

Hereinafter, the present invention will be described in detail.

The present invention is characterized by the cephalosporin-based compound represented by the following structural formula (I) and pharmaceutically acceptable salts thereof useful as antibiotics.

Wherein R ¹ , R ² , R ³ , Q and A are as defined above.

Referring to the present invention in more detail as follows.

The present invention relates to a cephalosporin-based compound represented by the formula (I) and a method for preparing the compound, wherein the compound (I) may have two isomers as shown in the following partial structural formulas. (Z) -isomer] is known to be pharmaceutically more useful.

In addition, the cephalosporin-based compound represented by the above formula (I), which is the target compound of the present invention, may be prepared with various pharmaceutically acceptable salts. As such salts, inorganic acid salts include sulfates, hydrochlorides, bromates, Iodide, phosphate, and the like, and organic carboxylates include acetates, maleates, tartarates, fumarates, citrates, succinates, lactates, oxylates, and the like. and p-toluenesulfonic acid salts, and the like, and salts with basic or acidic amino acids include arginine salts, asparagine salts, glutamate salts, and lysine salts. Inorganic salts include alkali metal salts such as sodium salts and potassium salts, or metal salts and ammonium salts such as alkaline earth metal salts such as calcium salts and magnesium salts. Organic salts include trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, Picoline salt, dicyclohexylamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, phenylethylbenzylamine salt, dibenzylethylenediamine salt and the like.

Preferred among these are sulfates, hydrochlorides, maleates or fumarates.

As a method for preparing a cephalosporin-based compound of the present invention as described above, the first method may be represented by the following scheme 1.

Wherein R ¹ , R ² , R ³ , Q and A are as defined above, L is a leaving group or a halogen atom such as chlorine, bromine or iodine or an acetoxy group, and R ⁹ is a hydrogen atom or an alkali metal Or a carboxy protecting group.

In the compound of the above formula (II), a compound in which L is a halogen atom is easily prepared by Japanese Patent Application Laid-Open No. 81-13159, No. 83-90590, No. 84-10593 or EP 251,299. Substituted reaction with the compound of III) to prepare a compound represented by the formula (I) of the target compound of the present invention.

The compound of formula (II), wherein L is an acetoxy group, is prepared according to European Patent No. 318.552 and reacted with the compound of formula (III) to prepare a compound represented by formula (I), which is the target compound of the present invention. In this case, the solvent used may be water, phosphate buffer, acetone, acetonitrile, N, N-dimethylformumamide, N, N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, dioxane, methol or ethanol. It is preferable to use a polar solvent or a mixed solvent with water. The reaction is preferably carried out under neutral conditions, and the reaction temperature is not particularly limited, but the preferable temperature range is 0 to 50 ° C. The time required for the reaction varies depending on the reaction conditions, but is generally 30 minutes to 10 hours. In addition, this reaction can be promoted by adding alkali metal halides such as sodium iodide, lithium iodide and potassium iodide.

In the second method, the acylation reaction of a compound represented by the following structural formula (IV) or an active derivative thereof with the compound represented by the following structural formula (V) is carried out by removing the protecting group, if necessary, as shown in the following Scheme 2. The cephalosporin-based compound is prepared.

Wherein R ¹ , R ² , R ³ , R ⁹ , Q and A are as defined above and X is a halogen atom or an acid residue.

The acylation reaction is prepared by reacting 1 mole of the compound represented by the above formula (V) with 1 to 3 moles of the compound represented by the above formula (IV) or an activated derivative thereof.

In this case, examples of the active derivatives of the compound of formula (IV) include acid halides, active amides, active esters, and the like, and acid chlorides, acid bromide, pivalic acid acetate, isopyvalic acid or trichloroacetic acid. Mixed acid anhydrides such as; active amides such as pyrazole, imidazole, dimethyl pyrazole or benzotriazole; p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-1H And active esters such as 2-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.

In the reaction step, when the compound represented by the formula (IV) is used in the form of a free acid, a condensing agent is added. Examples of the condensing agent include N, N-dicyclohexylcarbodiimide and N-cyclohexyl-N. Carbodiimide compounds such as ′ -morpholinoethylcarbodiimide or N-cyclohexyl-N ′-(4-dimethylaminocyclohexyl) carbodiimide, or N-methylformamide or N, N-dimethylformum Reagents formed by reacting amide compounds such as amides with halides such as thionyl chloride, phosphorus oxychloride or phosgene are used so-called vilsmeier reagents.

When the active derivative of the compound represented by the above formula (IV) is an acid halide or an acid anhydride, the reaction proceeds in the presence of an acid condensation agent. Examples of such acid condensing agents include organic bases such as triethylamine, trimethylamine, ethyldiisopropylamine, N, N-dimethylamine, N-methylmorpholine or pyridine; hydroxides of sodium, potassium or calcium, carbonate Or alkali metal compounds such as bicarbonate; oxiranes such as ethylene oxide or propylene oxide.

In addition, the acylation reaction is carried out in a solvent that does not generally adversely affect the reaction, such solvents are water, acetone, acetonitrile, dioxane, tetrahydroxyfuran, methylene chloride, chloroform, dichloroethane, N, N -Dimethylformamide or a mixed solvent thereof is used.

As other acylation reaction conditions, the reaction temperature is not particularly limited, but is generally reacted at -30 to 40 ° C, and the reaction time is 30 minutes to 10 hours to complete the reaction.

The compound represented by the structural formula (IV) used as a raw material in Scheme 2 is a known compound, Journal of Antibiotics Vol. 36 No. 8 p1020 (1983), Journal of Antibiotics Vol. 43 No. 12 p1564 (1990) or European Patent No. 536,900, wherein the compound represented by formula (V) is a novel compound, or a salt thereof and a new compound represented by the following formula (VI): The compound represented by can be prepared by substitution reaction.

Wherein R ³ , R ⁹ , A, L and X are as defined above.

In the above two reaction processes, various kinds of amino protecting groups and carboxy protecting groups are introduced to prepare the final compound (I), which is a final target compound, and those protecting groups are used for the same purpose in the field of β-lactam and peptide synthesis. to be. For example, amino group protecting groups include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyl Oxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, trityl or trimethylsilyl and the like. And protecting groups for carboxyl groups include t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methuxibenzyl, benzhydryl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, Acetoxymethyl, methylthiomethyl, trityl, trichloroethyl, trimethylsilyl, dimethylsilyl or dimethylaminoethyl and the like.

In addition, these protecting groups need to be appropriately removed according to the manufacturing method, and methods for removing the protecting group include a method of using an acid, a method of using a base, or a method of using hydrazine, depending on the type of the protecting group. . These methods can be carried out by appropriately selecting general methods used in the field of β-lactam and peptide synthesis.

The compound represented by the said structural formula (III) which comprises a substituent at the 3-position of the cephalosporin type compound represented by the said structural formula (I) of this invention is synthesize | combined by the following method.

The compound of formula (III), that is, the compound represented by formula (4), wherein R ³ = H, is substituted with position 2 by using the compound of formula (1) as a starting material, thereby replacing the compound of formula (2) It is prepared by treating the hydroxy group of the compound of formula (2) with tetrabromomethane and triphenylphosphine, or by substituting with halogen and then ring closure to treat with NaSH.

Wherein X and A are as defined above.

In addition, the compound of formula (III), ie, the compound represented by formula (10), wherein R ³ = NH ₂ is substituted with position 2 using the compound of formula (5) as a starting material, and the compound of formula (6) To prepare a compound of formula (6) by the known method (J. Chem, Soc., P1390, 1948) to prepare a compound of formula (7), and then to the hydroxyl group of the compound of formula (7) Prepared by treatment with mommethane and triphenylphosphine or by substitution with halogen followed by ring closure and treatment with NaSH.

Wherein X and A are as defined above and R ¹⁰ is an amino protecting group.

In addition, the compound represented by the above formula (III) wherein R ³ = halogen atom, hydroxy group or lower alkyl group having 1 to 3 carbon atoms, that is, the compound represented by the following formula (13), is selected as NaOH starting from the compound of formula (8) Treatment and known methods [J. Org, Chem, Vol. 46, p2153, 1981; Org, Chem, Vol. 42, p 2426, 1977; Org, Chem, Vol. 48, p1333, 1983; Adv. Fluorine Chem., Vol. 4 pp. 1 to 30, 1965; Helv. Chim. Acta., Vol. 64, p488, 1981] to prepare a compound (12) and treatment with phosphorus pentasulphide (P ₂ S ₅ ) or Lawson's reagent represented by the following structural formula (c).

(c)

Wherein R ³ , X and A are as defined above.

Specific examples of the compound represented by the above formula (I) which is the target compound of the present invention as described above are listed below. However, the present invention is not limited to the following description.

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (imidazolidino [1,2 -a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (1,3-oxazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2 (methoxyimino) acetamido] -3-thiazolidino [1,2-a] Pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [8-aminoimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (N-methylamidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [8-methylimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (N-hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (1,2-oxazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (thiazolidino [1,2- a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (8-aminoimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (N-methylimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- [8-methylimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (N-hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-imida Zolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1 , 3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2 (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-thiazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- [8 -Fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- [N -Methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- [8 -Methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamino] -3- [N- Hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-ylmethoxyimino) acet Amido] -3- [imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-ylmethoxyimino) acet Amido] -3- [1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1.5-dihydroxy-4-pyridone-2-ylmethoxyimino) acetamido ] -3- [thiazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-ylmethoxyimino) acet Amido] -3- [8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1.5-dihydroxy-4-pyridone-2-ylmethoxyimino) acetamido ] -3- [N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-ylmethoxyimino) acet Amido) acetamino] -3- [N-hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3- [ Imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3- [ 1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3- [ Thiazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3- ( 8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) -thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (hydroxyimino) acetamido] -3- (N -Methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino1,2,4-thiadiazol-3-yl) -2- (hygeshiimino) acetamino] -3- (N- Hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Thiazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 8-aminoimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 8-aminoimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( N-hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( Imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (2-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( 1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( Thiazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( 8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( 8-aminoimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( 8-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( N-hydroxyimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (carboxyprop-2-oxyimino) acetamido ] -3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate,

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

Reference Example 1

Synthesis of Imidazolidino [1,2-a] -5-thiopyridone

29.6 g of 2,6-dichloropyridine is dissolved in 48.8 ml of amino ethanol, heated to reflux for 1 hour, and the reaction solution is cooled to room temperature. 6N hydrochloric acid solution was adjusted to pH 7-8, 200 ml of dichloromethane was added, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 33.6 g of oily 6-close-2- (2-hydroxyethylamino) pyridine. .

NMR (DMSO-d ₆ , δ): 3.78 (4H, m), 4.91 (1H, s), 6.91 (1H, d), 7.21 (1H, t), 8.51 (1H, d) ,.

33.6 g of 6-chloro-2- (2-hydroxyethylamino) pyridine is dissolved in dichloromethane, and 56.9 ml of thionyl chloride (SOCl ₂ ) is added and heated to reflux for 8 hours. The resulting solid was filtered and dried to obtain 11.1 g of white solid 5-chloroimidazolidino [1,2-a] pyridinium chloride.

NMR (DMSO-d ₆ , δ): 3.95 (2H, t), 4.72 (2H, t), 7.01 (1H, d), 7.10 (1H, d), 7.90 (1H, t) ,. 10.4 (1 H, s).

11.1 g of 5-chloroimidazolidino [1,2-a] pyridinium chloride was dissolved in 140 ml of N, N-dimethylformamide, followed by adding 9.7 g of sodium hydrosulfide hydrate (NaSH.XH ₂ O) for 1 hour. Stir while. 300 ml of dichloromethane was added to the reaction solution to remove the insoluble substance, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) and concentrated under reduced pressure. 7.3 g of dazolidino [1,2-a] -5-thiopyridone was weighed out.

NMR (DMSO-d ₆ , δ): 3.69 (2H, t), 4.35 (2H, t), 5.90 (1H, d), 6.51 (1H, d), 7.11 (1H, t). 7.76 (1 H, s).

Reference Example 2

Synthesis of 1,3-oxazolidino [1,2-a] -5-thiopyridone

7.4 g of 2,6-dichloropyridine is dissolved in 14 ml of ethylene glycol, and 2 g of sodium hydroxide is added and heated to reflux for 1 hour. 50 ml of ethyl acetate and 50 ml of water are added to the reaction solution, and the organic layer is separated and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1), and then concentrated under reduced pressure to obtain 6.2 g of 6-chloro-2- (2-hydroxyethoxy) pyridine as an oil.

NMR (DMSO-d ₆ , δ): 3.72 (4H, m), 3.75 (1H, s), 6.46 (2H, q), 7.34 (1H, t), 8 ,.

After dissolving 2 g of 6-chloro-2- (2-hydroxyethoxy) pyridine in 220 ml of tetrahydrofuran, 3.1 g of triphenylphosphine and 4.6 g of tetrabromethane were added thereto, followed by heating and circulating for 1 hour. The resulting crystals were filtered and dried to obtain 1.1 g of white solid 5-cholo-1,3-oxazolidino [1,2-a] pyridinium bromide.

NMR (DMSO-d ₆ , δ): 5.08 (4H, m), 7.85 (2H, q), 8.44 (1H, q)

1.1 g of 5-chloro-1,3-oxazolidino [1,2-a] pyridinium bromide was dissolved in 5 ml of N, N-dimethylformamide, and 0.7 g of sodium hydrosulfide hydrate (NaSH.XH ₂ O). Was added and stirred for 1 hour. 50 ml of dichloromethane was added to the reaction solution to remove the insoluble substance, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1), and concentrated under reduced pressure. 0.4 g of, 3-oxazolidino [1,2-a] -5-thiopyridone was obtained.

NMR (DMSO-d ₆ , δ): 4.73 (4H, m), 6.09 (1H, q), 7.15 (2H, q).

Reference Example 3

Synthesis of Thiazolidino [1,2-a] -5-thiopyridone

2-propane was added to 30 ml of 3.0 g of 2,6-dichloropyridine, 1.7 ml of 2-hoxyethylthiol and 0.8 g of sodium hydroxide and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 100 mL of dichloromethane and 100 mL of water were added to the residue, and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6-closed-2- (2-hydroxyethylthio) pyridine as an oil. g was obtained.

NMR (DMSO-d ₆ , δ): 3.35 (2H, t), 3.95 (2H, t), 7.41 (3H, m).

After dissolving 1.9 g of 6-chloro-2- (2-hydroxyethylthio) pyridine in 30 ml of dichloromethane, 2.2 ml of thionyl chloride (SOCl2) was added and heated and quenched for 2 hours. The resulting crystals were filtered and dried to obtain 1.9 g of 5-chlorothiazolidino [1,2-a] pyridinium chloride.

NMR (DMSO-d ₆ , δ): 3.66 (2H, t), 5.20 (2H, t), 8.21 (3H, m)

1.7 g of 5-chlorothiazolidino [1,2-a] pyridinium chloride was dissolved in 20 ml of N, N-dimethylformamide, 0.9 g of sodium hydrosulfide hydrate (NaSH.XH ₂ O) was added, followed by stirring for 3 hours. Let's do it. The reaction solution was added to 300 ml of water, and the resulting crystals were filtered and dried to obtain 1.2 g of thiazolidino [1,2-a] -5-thiopyridone, which is a target compound of white crystals.

NMR (acetone-d ₆ , δ): 3.66 (2H, t), 4.90 (2H, t), 6.72 (1H, t), 7.15 (2H, d).

Reference Example 4

Synthesis of 8- (t-butoxycarbonylamino) imidazolidino [1,2-a] -5-thiopyridone

To 100 ml of methanol, 9 g of 2,6-dichloro-3-nitropyridine and 3 ml of aminoethanol were added thereto, dissolved, and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 200 ml of water and 200 ml of ethyl acetate were added to the residue, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6-closed-2- (2-hydroxyethylamino) as a yellow needle. 10 g of) -3-nitropyridine was obtained.

NMR (DMSO-d ₆ , δ): 3.62 (4H, m), 4.91 (1H, s), 4.82 (1H, d), 8.51 (1H, d)

10 g of 6-chloro-2- (2-hydroxyethylamino) -3-nitropyridine is dissolved in 200 ml of ethanol and 50 ml of water, 20 g of mixed iron and 3 ml of concentrated hydrochloric acid are added, followed by heating to reflux for 2 hours. The reaction solution was cooled to room temperature, the insoluble matter was removed, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) and concentrated under reduced pressure to obtain crystalline 3-amino-6-chloro-. 3.2 g of 2- (2-hydroxyethylamino) pyridi were obtained.

NMR (DMSO-d ₆ , δ): 3.49 (4H, m), 4.71 (1H, s), 4.81 (2H, s), 5.90 (1H, s)

, 6.40 (1 H, d), 6.75 (1 H, d).

3.2 g of 3-amino-6-chloro-2- (2-hydroxyethylamino) pyridine is dissolved in 100 ml of dichloromethane, 3 ml of thionyl chloride (SOC12) is added and heated to reflux for 4 hours. The resulting solid was filtered, washed with 20 mL dichloromethane and dried to give 3.63 g of 8-amino-5-chloro-imidazolidino [1,2-a] pyridinium chloride.

NMR (DMSO-d ₆ , δ): 3.98 (2H, t), 4.67 (2H, t), 6.38 (2H, s), 6.90 (2H, d), 9.85 (1H, s).

3.6 g of 8-amino-5-chloro-imidazolidino [1,2-a]) pyridinium chloride was dissolved in 20 ml of N, N-dimethylformamide, 3 ml of triethylamine and di-t-butyldi Add 3.6 g of carbonate and stir for 3 hours. 4 ml of dichloromethane was added to the reaction solution, and the resulting solid was filtered and dried to obtain 3.5 g of 5-chloro-8- (t-butoxycarbonylamino) imidazolidino [1,2-a] pyridinium chloride. Got it.

NMR (DMSOd ₆ , δ): 1.59 (9H, s), 4.33 (2H, t), 4.76 (2H, t), 6.48 (2H, s), 7.73 (2H, d).

3.5 g of 5-chloro-8- (t-butoxycarbonylamino) imidazolidino [1,2-a] pyridinium chloride was dissolved in 20 ml of N, N-dimethylformamide, followed by sodium hydrosulfide hydrate ( NaSH.XH ₂ O) was added and stirred for 1 hour. 50 ml of water was added to the reaction mixture, and the resulting solid was filtered and dried to yield 3 g of 8- (t-butoxycarbonylamino) imidazolidino [1,2-a] -5-thiopyridone as a target compound. Got it.

NMR (acetone-d ₆ , δ): 1.53 (9H, s), 4.12 (4H, m), 4.92 (2H, s), 7.05 (2H, d).

Reference Example 5

Synthesis of 8-chloroimidazolidino [1,2-a] -5-thiopyridone

2.1 g of 8-amino-5-chloroimidazolidino [1,2-a]) pyridinium chloride and 1.2 g of sodium hydroxide were dissolved in 10 ml of water and 10 ml of methanol and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 6: 1) and concentrated under reduced pressure to give 0.5 g of 8-aminoimidazolidino [1,2-a] -5-pyridone. Got.

NMR (DMSO-d ₆ , δ): 3.93 (2H, t), 4.69 (2H, t), 6.34 (2H, br), 6.85 (2H, dd), 10.06 (1H, br).

0.5 g of 8-aminoimidazolidino [1,2-a] -5-pyridone is dissolved in 4 ml of tetrahydrofuran, 0.4 g of t-butyl nitrile and tetrabutylammonium fluoride (10 M in tetrahydrofuran). Solution) 4 ml are added and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (acetonitrile: water = 4: 1) and concentrated under reduced pressure to give 8-fluoroimidazolidino [1,2-a] -5-pyridine. Got 0.2 g of money.

NMR (DMSO-d ₆ , δ): 4.52 (2H, t), 5.01 (2H, t), 6.12 (1H, br), 6.68 (2H, dd).

0.2 g of 8-fluoroimidazolidino [1,2-a] -5-pyridone is dissolved in 5 ml of tetrahydrofuran, and 0.4 g of Lawesson's reagent is added and heated to reflux for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) and concentrated under reduced pressure to give 8-chloroimidazolidino [1,2-a] -5-thiopyridone 0.1. g was obtained.

NMR (DMSO-d ₆ , δ): 3.81 (2H, t), 4.58 (2H, t), 5.48 (1H, br), 7.01 (2H, m).

Reference Example 6

Synthesis of N-methylimidazolidino [1,2-a])-5-thiopyridone

29.6 g of 2,6-dichloropyridine is dissolved in 10.9 ml of 2- (methylamino) ethanol, heated to reflux for 1 hour, and the reaction solution is cooled to room temperature. Adjust the pH to 7-8 with 6N hydrochloric acid solution, add 200 ml of dichloromethane, separate the organic layer, dry with anhydrous magnesium sulfate, and concentrate under reduced pressure to give 6-closed-2- [N- (2-hydroxyethyl) -N-methylamino ] 5.3 g of pyridine.

NMR (DMSO-d ₆ , δ): 3.03 (3H, s), 3.70 (4H, m), 3.84 (1H, s), 6.43 (2H, q), 7.34 (1H, t).

5.3 g of 6-chloro-2- [N- (2-hydroxyethyl) -N-methylamino] pyridine was dissolved in 500 ml of tatrahydrofuran, followed by 11.17 g of triphenylphosphine and 9.42 g of tetrabromoethane. Heated to reflux for 1 hour. The resulting crystals were filtered and dried to obtain 10.5 g of 5-chloro-N-methylimidazolidino [1,2-a] pyridinium bromide as a white solid.

NMR (DMSO-d ₆ , δ): 3.10 (3H, s), 4.23 (4H, m), 7.05 (2H, q), 7.89 (1H, t).

1.8 g of 5-chloro-N-methylimidazolidino [1,2-a] pyridinium bromide was dissolved in 10 ml of N, N-dimethylformamide and 1.21 g of sodium hydrosulfide hydrate (NaSHXH ₂ O). Was added and stirred for 1 hour. 50 ml of dichloromethane was added to the reaction solution to remove the insoluble substance, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) and concentrated under reduced pressure to obtain N-methyl as a target compound. 0.6 g of imidazolidino [1,2-a] -5-thiopyridone was obtained.

NMR (DMSOd ₆ , δ): 2.88 (3H, s), 3.67 (2H, t), 4.21 (2H, t), 5.99 (1H, d), 6.60 (1H, d)., 7.19 (1H, t).

Production Example 1

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-chloromethyl Synthesis of 3-Cefem-4-carboxylate

19.6 g of phosphorus pentachloride is suspended in 440 mL of dichloromethane and the temperature is cooled to -30 ° C. 41.3 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetic acid hydrochloride was slowly added thereto, and the solution was stirred at -20 ° C to -15 ° C for 2 hours. Manufacture. 34.9 g of 7β-amino-3-chloromethyl-3-cepem-4-carboxylic acid-p-methoxybenzylester hydrochloride is added to 850 ml of acetonitrile and 69.7 ml of N, O-bistrimethylsilyl acetamide is added. It stirs at -15 degreeC for 1.5 hours. The prepared solution was added to the reaction solution at −30 ° C. to −15 ° C., stirred for 1.5 hours, and then 2 l of water and 2 l of ethyl acetate were added thereto to separate an organic layer and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was concentrated under reduced pressure, and then the resulting solid was filtered using diethyl ether to give 62.5 g of the target compound.

NMR (DMSO-d ₆ , δ): 3.65 (2H, q), 3.78 (1H, s), 3.85 (3H, s), 4.54 (2H, bs), 5.20 (2H, d) ,. 5.80 (1 H, dd)., 6.75 (1 H, s), 7.10-7.70 (19 H, m).

Production Example 2

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (trityloxyimino) acetamido] -3-chloromethyl- Synthesis of 3-Cefem-4-carboxylate

After dissolving 3.4 g of (Z) -2- (2-aminothiazol-4-yl) -2- (trityloxyimino) acetic acid in 16 ml of N, N-dimethylformumamide, 1-hydroxybenzotriazole was dissolved. 1.3 g and 2.0 g of dicyclohexyldiimide were added, stirred for 30 minutes and the insoluble material was removed to prepare a solution.

Suspend 3.3 g of methoxybenzyl 7β-amino-3-chloromethyl-3-cepem-4-carboxylate 40 ml [tetrahydrofuran], cool to 10 ° C., 2.5 ml triethylamine and 1.5 ml trimethylsilyl chloride. Was added and stirred at the same temperature for 2 hours. The prepared solution was slowly added to the reaction solution at 10 ° C., followed by stirring for 15 hours. The reaction solution was concentrated under reduced pressure, 200 ml of water was added, and the resulting solid was filtered and dried to yield 6.0 g of the target compound.

NWR (DMSO-d ₆ , δ): 3.34 (2H, ABq), 3.78 (3H, s), 4.57 (2H, s), 5.31 (3H, m), 6.01 (1H, dd), 6.63 (1H, s ), 7.37 (19 H, m).

Production Example 3

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-triaminothiazol-4-yl) -2- (1,5-dibenzhydryloxy-4-pyridone 2-ylmethoxyimino)] acetamido-3-chloromethyl-3-cepem-4-carboxylate

8.1 g of (Z) -2- (2-triaminothiazol-4-yl) -2- (1,5-dibenzhydryloxy-4-pyridone-2-ylmethoxyimino) acetic acid and p-meth After dissolving 4.1 g of oxybenzyl 7β-amino-3-chloromethyl-3-cepem-4-carboxylate in 100 ml of dichloromethane, it was cooled to -30 ° C and 2.3 ml of N, N-dimethylaniline and 2,6- Add 2.1 ml of Lutidine to prepare a solution. 1.1 ml of phosphorus oxychloride was dissolved in 10 ml of dichloromethane and the solution prepared above was added at -30 ° C for 30 minutes and then stirred for 2 hours. Pyridine was added to the reaction solution to adjust the pH to 6-7, 300 ml of ethyl acetate and 200 ml of saturated brine were added thereto. It was purified by 2: 1) and concentrated under reduced pressure to obtain 5.8 g of the target compound.

NMR (CDCl ₃ , δ): 3.42 (2H, d), 3.75 (1H, s), 4.32-4.69 (2H, ABq), 4.89 (1H, d), 4.94 (2H, s). 5.21 (2H, s)., 5.34 (1 H, dd), 6.05 (1 H, s), 6.71 (1 H, s) 6.77 (1 H, s), 7.31 (35 H, m).

Production Example 4

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (trityloxyimino) acetami Fig.] Synthesis of 3-chloromethyl-3-cepem-4-carboxylate

(Z) -2- (5-amino-1,2,4-thiadiazole- instead of (Z) -2- (2-aminothiazol-4-yl) -2- (trityloxyimino) acetic acid By using 3.5 g of 3-yl) -2- (trityloxyimino) acetic acid, 5.2 g of the target compound was obtained by the same method as in Preparation Example 2.

NMR (DMSO-d ₆ , δ): 3.40 (2H, ABq), 3.78 (3H, s), 4.60 (2H, bs), 5.30 (3H, m)., 6.00 (1H, dd), 7.38 (19H) , s)

Production Example 5

Synthesis of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodo salt

2.9 g of p-methoxybenzyl 7β-amino-3-chloromethyl-3-cepem-4-carboxylate hydrochloride and the imidazolidino [1,2-a] -5-thio prepared in Reference Example 1 above 1.1 g of pyridone and 1.2 g of potassium iodide are dissolved in 7 ml of N, N-dimethylformamide and stirred for 3 hours. 5 ml of water is added to the reaction solution, and this solution is added to acetone 3, and the resulting solid is filtered and dried to obtain 1.8 g of a solid compound. A mixed solution of 4 ml of trifluoroacetic acid and 2 ml of anisole was added to the compound, and the mixture was stirred for 4 hours. The reaction solution was adjusted to pH7.0 with 27% aqueous ammonia solution, and added to 1 l of diethyl ether. The resulting solid was filtered and dried to obtain 1.2 g of the target compound.

TLC (acetonitrile: water = 4: 1): Rf = 0.1

NMR (DMSO-d ₆ , δ): 3.41 (2H, ABq), 3.81 (2H, m), 4.20-4.71 (4H, m), 5.00 (2H, dd), 5.81 (1H, dd), 6.50 (1H , d).

Production Example 6

Synthesis of 7β-amino-3- (1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodo salt

Instead of imidazolidino [1,2-a] -5-thiopyridone, 1.2 g of 1,3-oxyzolidino [1,2-a] -5-thiopyridone prepared in Reference Example 2 was prepared. 1.3 g of the target compound was obtained by the same method as in Preparation Example 5 above.

NMR (DMSO-d ₆ , δ): 3.40 (2H, ABq), 4.50-4.79 (4H, m), 4.90-5.31 (4H, m), 6.20 (1H, dd), 7.01 (1H, d), 7.51 (1H, d).

Production Example 7

Synthesis of 7β-amino-3- (8-poloroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodo salt

1.2 g of 8-poloroimidazolidino [1,2-a] pyridinium-thiopyridone prepared in Reference Example 5, instead of imidazolidino [1, 2-a] -5-thiopyridone 1.0 g of the target compound was obtained in the same manner as in Preparation Example 5 using

NMR (DMSO-d6, δ): 3.51 (2H, ABq), 3.80 (2H, m), 4.21-4.80 (4H, m), 5.10 (2H, dd), 6.49 (1H, m), 7.51 (1H, m).

Preparation Example 8 Synthesis of 7β-amino-3- (N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodo salt

Instead of imidazolidino [1,2-a] -5-thiopyridone, 1.2 g of N-methylimidazolidino [1,2-a] -5-thiopyridone prepared in Reference Example 6 was prepared. 1.5 g of the target compound was obtained by the same method as in Preparation Example 5 above.

NWF (DMSO-d ₆ , δ): 3.49 (2H, ABq), 3.60 (3H, s), 4.11-4.90 (4H, m), 5.10 (2H, dd), 6.01 (1H, dd), 6.61 (1H , d), 7.11 (1 H, d).

Example 1

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [imidazolidino [1,2 -a] Synthesis of Pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

P-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetate synthesized in Preparation Example 1 5.6 g of amido] -3-chloromethyl-3-cepem-4-carboxylate, 1.1 g of imidazolidino [1,2-a] -5-thiopyridone and 1.7 g of potassium iodide were added N, N- It is dissolved in 20 ml of dimethyl formumamide and stirred for 2 hours. The reaction solution was added to 500 ml of diethyl ether, and the resulting solid was filtered and dried to obtain 5.4 g of a solid compound, which was used in the next reaction without purification. To 5.4 g of this solid compound, 6 ml of anisole and 8 ml of trichloroacetic acid were added and stirred for 4 hours. The reaction solution was adjusted to pH 7.0 with 27% aqueous ammonia solution, 500 ml of diethyl ether was added, and the resulting solid was filtered and dried. A small amount of water was added to the obtained solid, and the mixture was separated by silica gel column chromatography (80% aqueous acetonitrile solution). The liquid obtained is concentrated under reduced pressure. The solution was dissolved in a small amount of water, purified by diion Hp-20 (Mitsubishi Chemical) column chromatography (15% aqueous acetonitrile solution), and concentrated under reduced pressure and lyophilized to give 1.1 g of a white solid target compound.

NMR (DMSO-d ₆ , δ): 3.74 (2H, ABq), 3.89 (2H, t), 3.92 (3H, s), 4.35 (2H, ABq), 4.60 (2H, t), 5.22 (1H, d ), 5.80 (1 H, m). 6.85 (2H, m). 6.91 (1H, s), 7.20 (2H, bs), 7.70 (1H, t), 9.74 (1H, t), 9.80 (1H, d)

Example 2

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [1,3-oxazoladino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

1.2 g of 1,3-oxazoladino [1,2-a] -5-thiopyridone was used instead of imidazolidino [1,2-a] -5-thiopyridone, and was used in the same manner as in Example 1. By the method, 1.1 g of a pale white solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.70 (2H, ABq), 3.95 (3H, t), 4.47 (2H, ABq), 4.85 (2H, t), 5.02 (3H, t), 5.21 (1H, d ), 5.79 (1H, dd), 6.921 (1H, s), 7.49 (2H, m). 8.31 (1H, t), 9.51 (2H, bs), 9.82 (1H, d).

Example 3

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (thiazolidino [1,2- a] Synthesis of Pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

In the same manner as in Example 1, using 1.2 g of thiazole [1,2-a] -5-thiopyridone instead of imidazolidino [1,2-a] -5-thiopyridone, 1.1 g of a solid target compound were obtained.

NMR (DMSO-d ₆ , δ): 3.51 (2H, ABq), 3.82 (2H, t), 3.91 (3H, s), 4.26 (2H, ABq), 5.05 (2H, t), 5.13 (1H, d ), 5.72 (1H, dd), 6.84 (1H, s), 7.61 (2H, m). 8.05 (1H, t), 9.50 (2H, bs), 9.81 (1H, d).

Example 4

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [8-iminozolidino [1 Synthesis of, 2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

1.4 g of 8- (t-butoxycarbonylimino) imidazolidino [1,2-a] -5-thiopyridone instead of imidazolidino [1,2-a] -5-thiopyridone In the same manner as in Example 1 using to give 1.0g of a pale yellow solid target compound.

NMR (DMSOd ₆ , δ): 3.59 (2H, ABq), 3.89 (2H, t), 3.96 (3H, s), 4.35 (2H, ABq), 4.69 (2H, t), 5.10 (1H, d ), 5.67 (1 H, m). 6.63 (2H, s), 6.77 (1H, s), 6.85 (2H, bs), 7.18 (2H, bs), 9.51 (1H, d).

Example 5

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [8-fluoroimidazolidino Synthesis of [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

Example 1 above, using 1.2 g of 8-fluoroimidazolidino [1,2-a] -5-thiopyridone instead of imidazolidino [1,2-a] -5-thiopyridone In the same manner, 0.9 g of an off-white solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.60 (2H, ABq), 3.91 (3H, s), 4.01 (2H, m). 4.45 (2H, m). 4.80 (2H, t). 5.11 (1H, d), 5.82 (1H, dd), 6.80 (1H, s), 7.52 (1H, m), 8.30 (1H, m)

Example 6

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [N-methylimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

1.2 g of N-methylimidazolidino [1,2-a] -5-thiopyridone, instead of imidazolidino [1,2-a] -5-thiopyridone, was used as in Example 1 above. By the method, 1.2 g of a pale yellow solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.10 (3H, s), 3.68 (2H, ABq), 3.95 (3H, s), 4.09 (2H, ABq), 4.32-4.60 (6H, m), 5.23 (1H , d), 5.77 (1H, dd), 7.00 (1H, s), 6.87 to 7.08 (2H, m), 7,95 (1H, t), 9.10 (2H, bs), 9.80 (1H., d)

Example 7

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [imidazolidino [1,2 -a] Synthesis of Pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-chloromethyl P-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (tri instead of 5.0 g of 3-cefe-4-carboxylate 1.0 g of a white solid target compound was obtained in the same manner as in Example 1 using 5.0 g of methyloxyamino) acetamido] -3-chloromethyl-3-cepem-4-carboxylate.

NMR (DMSO-d ₆ , δ): 3.61 (2H, ABq), 3.80 (2H, m), 4.45 (2H, m), 4.60 (2H, t), 5.01 (1H, d), 5.98 (1H, dd ), 6.81 (1H, s), 7.91 (1H, t)

Example 8

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- [imidazoli Synthesis of Dino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

1.0 g of 2-mercaptobenzothiazolyl (Z) -2- (2-aminothiazol-4-yl) -2- (t-butoxycarbonylprop-2-oxyimino) acetate and Preparation Example 5 1.0 g of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt obtained in It is dissolved in 10 ml of amide and stirred for 3 hours. The reaction solution was added to 500 ml of diethyl ether, and the resulting solid was filtered and dried to obtain 1.1 g of a solid compound, which was used in the next reaction without purification. To 1.1 g of this solid compound, 1 ml of anisole and 1 ml of trichloroacetic acid were added and stirred for 12 hours. The reaction solution was adjusted to pH 7.0 with 27% aqueous ammonia solution, added to 400 ml of diethyl ether, and the resulting solid was filtered and dried. A small amount of water was added to the obtained solid, and the mixture was separated by silica gel column chromatography (80% aqueous acetonitrile solution). The obtained liquid was concentrated under reduced pressure and lyophilized to obtain 0.2 g of a pale yellow solid target compound.

NMR (DMSOd ₆ , δ): 2.11 (6H, s), 3.49 (2H, ABq), 3.99 (2H, m), 4.29 (2H, ABq), 4.63 (2H, m), 5.24 (1H, d ), 5.83 (2H, m), 6.91 (1H, s), 6.99 (2H, m), 7.78 (1H, m), 8.90 (2H, bs), 9.46 (1H, t), 9.56 (1H, d) .

Example 9

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- [1,3 Synthesis of -oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

7β- obtained in Preparation Example 6 instead of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt Example 8 above using 1.3 g of amino-3- (1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt In the same manner, 0.3 g of a pale yellow solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.70 (2H, d), 3.86-4.10 (2.11 (2H, ABq), 4.45 (2H, d), 4.82 (1H, dd), 5.02 (1H, dd), 5.21 (1H, d), 5.79 (1H, dd), 6.92 (1H, s), 7.49 (2H, t), 8.31 (1H, t), 9.51 (1H, s), 9.82 (1H, d).

Example 10

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihixishi-4-pyridone-2-yl-methoxyimino Synthesis of acetamido] -3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-chloromethyl P-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (1 instead of 3-cefem-4-carboxylate In the same manner as in Example 1, using 1.0 g of 5,5-dibenzhydryloxy-4-pyridone-2-ylmethoxyimino) acetamido] -3-chloromethyl-cefe-4-carboxylate 0.2 g of a white solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.65 (2H, ABq), 3.95 (2H, m). 4.23 (2H, ABq), 4.52 (2H, m). 5.20 (1 H, m). 5.39 (2H, s), 5.85 (1H, dd), 6.80 (1H, s), 6.92 (1H, s), 7.31 (1H, s), 7.78 (2H, m)., 8.40 (1H, s).

Example 11

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihixishi-4-pyridone-2-ylmethoxyimino) acet Synthesis of Amido] -3- (1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

Example 10 using 0.5 g of 1,3-oxazolidino [1,2-a] pyridinium-5-thiopyridone instead of imidazolidino [1,2-a] -5-thiopyridone 0.2 g of a slightly yellow solid target compound was obtained in the same manner as the method described above.

NMR (DMSO-d ₆ , δ): 3.71 (2H, ABq), 3.94 (2H, m). 4.43 (2H, ABq), 4.54 (2H, m). 5.20 (1 H, m). 5.21 (1H, d), 5.41 (2H, s), 5.83 (1H, dd), 6.81 (1H, s), 6.93 (1H, s), 7.30 (1H, s), 7.76 (2H, m)., 8.41 (1 H, s).

Example 12

(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihixishi-4-pyridone-2-yl-methoxyimino Synthesis of acetamido] -3- (1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

Example 10 using 0.5 g of 8-pololimidazolidino [1,2-a] -5-thiopyridone instead of imidazolidino [1,2-a] -5-thiopyridone In the same manner, 0.2 g of a pale yellow solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.45 (2H, ABq), 3.90 (2H, m). 4.43 (2H, ABq), 4.58 (2H, m). 5.12 (1H, d), 5.43 (2H, s), 5.82 (1H, dd), 6.83 (1H, s), 6.98-8.37 (1H, s).

Example 13

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,3-thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3- ( Synthesis of imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

p-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (trityloxyimino) acetamido] -3-chloromethyl- P-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-thiadiazol-3-yl) -2 obtained in Example 4 above in place of 3-cefe-4-carboxylate 0.2 g of a pale yellow solid target compound was obtained in the same manner as in Example 7 using 1.6 g of-(trityloxyimino) acetamido] -3-chloromethyl-3-cepem-4-carboxylate.

NMR (DMSO-d ₆ , δ): 3.65 (2H, ABq), 3.90 (3H, s), 4.35 (2H, ABq), 4.77 (2H, t), 4.99 (2H, t), 5.19 (1H, d ), 5.78 (1H, doublet), 7.44 (2H, m). 8.31 (1H, t), 9.51 (2H, bs), 9.88 (1H, d),

Example 14

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

0.4 g of (Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetic acid and 1-hydride in 5 ml of N, N-dimethylformamide 0.4 g of oxybenzotriazole and 0.5 g of dicyclohexyl diimide are added thereto, dissolved, stirred for 1 hour, and the insoluble material is filtered off to prepare a solution. 1.1 g of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt synthesized in Preparation Example 5 was prepared. It is suspended in 2 ml of N, N-dimethylformamide and then the solution prepared above is added and stirred for 3 hours. The reaction solution was added to 300 ml of diethyl ether, and the resulting solid was filtered and dried. A small amount of water was added to the obtained solid, and the resulting liquid was separated by silica gel column chromatography (80% aqueous acetonitrile solution) and concentrated under reduced pressure. The solution was dissolved in a small amount of water, purified by diion Hp-20 (Mitsubishi Chemical) column chromatography (12% aqueous acetonitrile solution), and the resulting liquid was concentrated under reduced pressure and lyophilized to obtain 0.3 g of a white solid target compound.

NMR (DMSO-d ₆ , δ): 3.65 (2H, ABq), 3.81 (2H, t), 3.99 (3H, d), 4.23 (2H, ABq), 4.58 (2H, t), 5.18 (1H, d ), 5.82 (1H, doublet), 6.85 (2H, m). 7.76 (1H, t), 8.21 (2H, bs), 9.60 (1H, t), 9.63 (1H, d).

Example 15

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of 1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

7β- obtained in Preparation Example 6 instead of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt Example 14 above using 1.2 g of amino-3- (1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt In the same manner, 0.3 g of a pale yellow solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.70 (2H, d), 3.90 (3H, s), 4.41 (2H, ABq), 4.81-5.02 (4H, m), 5.21 (1H, d), 5.80 (1H , dd), 7.51 (2H, m), 8.30 (1H, t).

Example 16

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of 8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

7β synthesized in Preparation Example 7 instead of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt Example above using 1.4 g of -amino-3- (8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt In the same manner as in 14, 0.2 g of a pale yellow solid target compound was obtained.

NMR (DMSO-d ₆ , δ): 3.60 (2H, ABq), 3.91 (3H, s), 4.01 (2H, m), 4.43 (2H, m), 4.80 (2H, t), 5.10 (1H, d ), 5.82 (1 H, dd), 6.80 (1 H, s), 7.50 (1 H, m), 8.32 (1 H, m).

Example 17

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate

7β- obtained in Preparation Example 8, instead of 7β-amino-3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt Example 14 above using 1.4 g of amino-3- (N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate iodine salt In the same manner, 0.3 g of a pale yellow solid target compound was obtained.

NMR (DMSOd ₆ , δ): 3.11 (3H, s), 3.75 (2H, ABq), 3.90 (3H, s), 4.01 (2H, m), 4.40 (2H, ABq), 4.65 (2H, m ), 5.10 (1H, d), 5.81 (1H, dd), 7.05 (2H, m), 7.91 (1H, t).

Experimental Example 1

Antibacterial activity test for the compound represented by the above formula (I) of the present invention was carried out using agar plate dilution method for the standard test strain. That is, the compound of the formula (I) of the present invention was prepared in a 2-fold dilution method at 1,000 µg / ml, and then 100-0.002 µg / ml of Muller Hinton Agar and antibiotics were mixed in Petridish. It was prepared so that the test culture culture stock was used to adjust to 10 ⁷ CFU / ml. After incubation at 37 ° C. for 18 hours, the concentration of antibiotics that inhibited growth was determined as the minimum growth inhibition concentration (MIC), and the results are shown in Table 1 below.

[Test Example 2]

In vivo pharmacokinetic experiments, systemic infection treatment experiments and toxicity experiments were carried out on the compounds prepared by Examples 1 and 14 among the compounds represented by the above formula (I) according to the present invention.

In vivo pharmacokinetic experiments were performed by intravenously injecting 40 mg / kg of compound using 4 mice (average body weight 29 g) in each group, and then bleeding timely. Streptococcus pyogenes 77A was used to measure compound concentration. ) Was measured by microbiological bioassay using the test bacteria. The results are shown in Table 2 below.

In addition, systemic infection treatment experiments on the compounds prepared in Examples 1 and 14 were carried out as follows. Six strains containing Gram-positive and Gram-negative bacteria were inoculated with each strain intraperitoneally using 10 mice (average body weight 24g) in each group, and subcutaneously administered the sample compound by concentration at 1 hour after infection, and then the residual water was collected. Observed after one week. The results are shown in Table 3 below.

In addition, acute toxicity experiments were conducted for the compounds prepared in Examples 1 and 14. Representative compounds are dissolved in physiological saline and phosphate buffer (pH 7.0), and the poorly dissolved compounds are suspended in carboxymethyl cellulose (CMC) or Arabian gum and mixed in phosphate buffer to intravenous and subcutaneous injection. The residual water was observed after one week, and the acute toxicity test results are shown in Table 4 below.

The compound represented by the structural formula (I) of the present invention as described above exhibits excellent antimicrobial activity that inhibits the development of a wide range of pathogenic microorganisms, including Gram-positive and negative bacteria, as a new compound, in particular pharmacokinetic experiments and systemic infection treatment experiments The results clearly show the usefulness of the compound of formula (I) of the present invention. For example, Example 1 and Example 14 compounds used in the above Experimental Example showed a superior therapeutic effect than the control compound Cefpirome in systemic infection treatment against six strains including Gram-positive and negative bacteria. It is clearly proved. In addition, pharmacokinetic experiments showed much better results than the control compound, cepirom. In addition, the compounds of Examples 1 and 14 exhibited an LD50 value of 3000 mg / kg or more in the intravenous injection and 5000 mg / kg or more in the subcutaneous injection, thus demonstrating the high stability as a medicine.

As described above, the compound of the present invention is a cephalosporin-based compound having excellent antibacterial activity, very high blood concentration, and particularly high systemic infection treatment effect on animals. Therefore, antibiotics using this compound as an active ingredient can be usefully used for the treatment of human and animal diseases. When used as an antibiotic, the cephalosporin-based compound of the present invention may be administered parenterally 50 to 1000 mg, preferably 100 to 500 mg, once or twice a day, based on an adult, for human bacterial infection. It can be administered orally.

The antibiotic of the present invention is composed of the compound of the present invention and an excipient of a solid or liquid, and examples of the formulation include solid preparations such as tablets, capsules and powders, or liquid preparations such as injection solutions, suspensions, and syrups. Is to use. As the solid or liquid excipient, known excipients widely used in the antibiotic field may be used.

Claims (7)

A cephalosporin-based compound represented by the following structural formula (I) and a pharmaceutically acceptable salt thereof useful as an antibiotic. Wherein R ¹ is a hydrogen atom or an amino protecting group, R ² is a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a lower alkyl group of 1 to 3 carbon atoms substituted by one or more halogen atoms, or Wherein R ⁴ and R ⁵ are the same as or different from each other and are hydrogen atoms or lower alkyl groups having 1 to 3 carbon atoms, and R ⁶ is a hydrogen atom, an alkali metal such as sodium or lithium, or a carboxy protecting group. R ³ is a hydrogen atom, a halogen atom, an amino group, a hydroxy group or a lower alkyl group having 1 to 4 carbon atoms, A is an oxygen atom, a sulfur atom or NR ^a [where R ^a is a hydrogen atom, a hydroxyl group, (CH ₂ ) n R ^b (n = 1-2, R ^b is a hydrogen atom, a hydroxy group or a carboxy group)], and Q is a carbon or nitrogen atom. The compound of claim 1, wherein R ¹ is a hydrogen atom; R ² is a hydrogen atom, a methyl group or Q is CH or N; R ³ is H, F, or NH ₂ ; A is O, S, NH or NOH, the cephalosporin-based compound represented by the above formula (I), and Pharmaceutically acceptable salts. According to claim 1, The cephalosporin-based compound represented by the formula (I) is (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (imidazolidino [1,2 -a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (1,3-oxazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (thiazolidino [1,2- a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (8-aminoimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (N-methylimidazolidino [ 1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyino) acetamido] -3- (imidazolidino [1,2 -a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (already Dazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (1 , 3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-ylmethoxyimino) acet Amido] -3- (imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-ylmethoxyimino) acet Amido] -3- (1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetamido] -3- ( Imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Imidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 1,3-oxazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 8-fluoroimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( N-methylimidazolidino [1,2-a] pyridinium-5-yl) thiomethyl-3-cepem-4-carboxylate and pharmaceutically acceptable salts thereof. A method for producing a cephalosporin-based compound represented by the following structural formula (I) by substitution reaction of a compound represented by the following structural formula (II) and a compound represented by the following structural formula (III). Wherein R ¹ , R ² , R ³ , Q and A are as defined in claim 1, L is a halogen atom or an acetoxy group as leaving group, and R ⁹ is a hydrogen atom, an alkali metal or a carboxy protecting group Indicates. After acylating the compound represented by the following structural formula (IV) or an active derivative thereof and the compound represented by the following structural formula (V), the protecting group is removed if necessary to remove the cephalosporin-based compound represented by the following structural formula (I) How to prepare. Wherein R ¹ , R ² , R ³ , R ⁹ , Q and A are as defined in claim 1 and X is a halogen atom or an acid residue. According to claim 5, The active derivative is acid chloride, acid bromide, acetic acid pivalic acid, isopyvalic acid, trichloroacetic acid, pyrazole, imidazole, dimethylpyrazole, benzotriazole, p-nitrophenyl ester, Structural formula (I) characterized in that 2,4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide Method for producing a cephalosporin-based compound represented by. A compound represented by the following structural formula (III) useful for the preparation of a cephalosporin-based compound represented by the following structural formula (I). Wherein R ¹ , R ² , R ³ , Q and A are as defined in claim 1, 4 or 5 above.