WO1991007413A1 - 3-(bicyclic hetero ring thiomethyl)cephem derivatives - Google Patents

Abstract

The invention relates to compounds represented by general formula (I) (wherein R1 represents hydrogen or an optionally substituted lower alkyl, lower alkynyl, lower alkynyl or aralkyl, A represents a single bond or a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, m represents an integer of 0 to 3, and n represents an integer of 2 or 3, provided that the bicyclic hetero ring group formed by the pyridine ring and its cyclic side chain may be substituted by 1 to 3 substituents which may be the same or different) medicinally acceptable salts or esters thereof, a process for their preparation, and the use thereof.

Description

 Specification

3- (bicyclic heterocyclic thiomethyl) septum rust conductor Technical field

 The present invention relates to a novel cephalosporin compound useful in the field of medicine, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient. Background art

 Conventionally, a large number of compounds having a 2- (2-aminothiazol-4-yl) -2- (substituted oxyimino) acetoamide group at the 7-position side chain of the cefm nucleus have been synthesized in an extremely large number. Published technologies include, for example, British Patent No. 2051788, European Patent No. 29557, US Patent No. 4399132, US Patent No. 4489072, European Patent No. 64740; US Patent No. 446899, European Patent No. 153709, U.S. Pat.No. 4,495,182 and Japanese Patent Application Laid-Open No. 62-234087, etc., have excellent antibacterial activity against cephalosporin-resistant gram-negative bacteria including gram-positive bacteria and Pseudomonas aeruginosa (Pseu-domonas aeruginosa). It has been suggested to have a broad antibacterial spectrum.

 Among the above-mentioned prior documents, the one similar to the present invention is Japanese Patent Application Laid-Open No. 622-234087 (A publication). However, although the substituent at the 3-position of the nucleus of C in the A publication forms a bicyclic thioalkyl group with the pyridine nucleus, it is thio-bonded at the α-position of the pyridine nucleus. It is a compound with a completely different structure.

In addition, the antibacterial activity of these compounds is gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Pseudomonas cepa-cia, Pseudomonas maltophilia, and Pseudomonas maltophilia. It is not sufficient for glucose non-fermen-iative gram-negative rods such as Acinetobacter calcoaceticus.

 Since S-lactam antibiotics are selective toxic to bacteria only and do not affect animal cells, they are widely used as antibiotics with few side effects for the treatment of bacterial infections, and are highly useful drugs. It is.

 However, in recent years, non-glucose non-fermentative gram-negative bacilli, especially Pseudomonas aeruginosa, and even methicillin-resistant Staphylococcus aureus have often been isolated as infectious disease-causing bacteria from patients with reduced immunity. Has been raised. Therefore, development of an antibacterial agent having improved antibacterial activity against these bacteria has been desired. The present inventors have conducted intensive studies to create a cephalosporin derivative having strong antibacterial activity against gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and Gram-negative bacteria such as Pseudomonas aeruginosa. It has been found that the novel cephalosporin derivative represented by the general formula (I) described below exhibits excellent antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa. Thus, the present invention has been completed. Disclosure of the invention

 The present invention has the general formula

Wherein R ¹ is a hydrogen atom or an optionally substituted lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group, and A is a single bond or a nitrogen atom, an oxygen atom and a sulfur atom. A heteroatom selected from the group consisting of: m is an integer of 0 to 3, n is an integer of 2 or 3) or a pharmaceutically acceptable salt or ester thereof, a process for producing the compound or an antibacterial agent of the compound General formula useful as a production intermediate

(in)

Wherein A, m and n have the above-mentioned meaning. However, the bicyclic group formed by the pyridine ring and its cyclic side chain may be replaced by the same or different 1 to 3 substituents which may be protected as appropriate.) The present invention relates to a method for producing a compound or a salt thereof and a production intermediate thereof.

 The definitions of various terms referred to in the description of this specification and appropriate examples thereof will be described.

A lower alkyl group which may have a substituent is, for example, a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group. A lower alkanoyloxy group having 2 to 4 carbon atoms such as an acetyloxy group, a propionyloxy group or a butyryloxy group; a hydroxyl group; a carboxyl group; a rubamoyl group; a sulfo group and, for example, a chlorine atom, a bromine atom or A linear, branched or cyclic lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms such as elemental atoms. I do. Specific examples of the alkyl group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, Isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, 2-chloroethyl, 2 -Fluoroethyl, 2,2-difluoromethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, carboxymethyl, 1-carboxyethyl, 1-carbamoylmethyl, 1-butyl Moylethyl group, 1-potassyloxy-1-methylethyl group, 1-potumbyl-1-methylethyl group, 2-carboxyethyl group, 2-potyl group Moylethyl group, 3-carboxypropyl group, 2-carboxypropyl group, 1-carboxypropyl group, 3-carbamoylpropyl group, 2-l-rubamoylpropyl group, 1-l-rubamoylpropyl group, 1-carboxycyclopropyl Group, 1-forcerubamoylcyclopropyl, 1-carboxycyclobutyl, 1-forcerubamoylcyclobutyl, 1-carboxycyclopentyl, 1-forcerubamoylcyclopentyl, 1-carboxycyclohexyl, 1 -Balmoylcyclohexyl, 1-sulfocyclohexyl, 1-sulfocyclopentyl, trisulfocyclobutyl, 1-sulfocyclopropyl, sulfomethyl, 2-sulfoethyl, 1-sulfoethyl, 3-sulfoyl A propyl group, a 2-sulfopropyl group or a 1-sulfopropyl group. The lower alkenyl group which may have a substituent means a lower alkenyl group having 2 or 6 carbon atoms which may be substituted with an S substituent such as a carboxyl group, a carbamoyl group or a sulfo group. I do. Specific examples of the alkenyl group include, for example, vinyl group, 1-propenyl group, aryl group, 1-methylvinyl group, 2-methyl -Topropropenyl group, 1,3-butadienyl group, 1,1-dimethylaryl group, 2-butenyl group, 3-butenyl group, 3-methylbutenyl group, 1-carboxyvinyl group, 2-carboxyvinyl group, 1 -Carboxy-1-propenyl group, 2-carboxy-1-propenyl group, 3-carboxy-1-propenyl group, 1-carboxy-2-methyl-1-propyl group, 1 -Carboxyaryl, 2-carboxyaryl, 3-carboxyaryl, 1-carboxy-3-butenyl, 1-carboxy-3-methyl-2-butenyl, 1-sulfovinyl, 1-force Rubamoyl vinyl group, 1-sulfoallyl group, 1-force rubamoylaryl group, 3-carboxy-1,1-dimethylaryl group, 3_sulfo-1,1-dimethylaryl group or 3-force rubamoyl-1,1-dimethylaryl group, etc. Is mentioned. The lower alkynyl group which may have a substituent is, for example, a alkynyl group or a sulfo group which may be substituted with, for example, an ethynyl group, a 1-propyl group, a 2-propynyl group or It means a lower alkynyl group having 2 to 6 carbon atoms such as a 1-dimethyl-2-propynyl group. Specific examples of the alkynyl group include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1,1-dimethyl-2-propynyl group, 2-carboxyethynyl group, 2-sulfethynyl group, 1-propynyl group, Carboxy-2-propynyl group, 1-sulfo-2-propynyl group, 3-carboxy-1,1-dimethyl-2-propynyl group or 3-sulfo-1,1-dimethyl-2-propynyl group. I can do it.

The aralkyl group which may have a substituent is, for example, one to four selected from the group consisting of a hydroxyl group, an acetyl group, a propionyloxy group, a carboxy group, a sulfo group, a carboxymethyl group or a sulfomethyl group. may be substituted with substituents such base Njiru group, phenethyl group, 3-full C 7 carbon atoms such as phenylpropyl group or naphthylmethyl group _t which means eleven Ararukiru groups Specific examples of the aralkyl group include, for example, benzyl, phenethyl, β-carboxyphenethyl, tricarboxy-3-phenylpropyl, α-carboxy-1-naphthylmethyl, α-carboxynaphthyl Methyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 3-acetoxybenzyl, 4-acetoxybenzyl, 2-carboxybenzyl, 3-carboxybenzyl, 4-carboxybenzyl, 2-carboxy Methylbenzyl, 3-carboxymethylbenzyl, 4-carboxymethylbenzyl, 2-sulfobenzyl, 3-sulfobenzyl, 4-sulfobenzyl, 2-sulfomethylbenzyl, 3-sulfomethylbenzyl, 4-sulfomethylbenzyl group, 3-carboxy-4-hydroxybenzyl group, 3,4-dihydroxybenzyl group, 3,4- Acetoxybenzyl group, 3,4,5-trihydroxybenzyl group, 3,4,5-triacetoxybenzyl group, α-carboxybenzyl group, ct-carboxy-3-hydroxybenzyl group, o-force ruboxoxy- 4-hydroxybenzyl group, α-carboxy-3-acetoxybenzyl group, α-carboxy-4-acetoxybenzyl group, α-carboxy_3,4-dihydroxybenzyl group, α-carboxy-3,4-di Examples include an acetoxybenzyl group, an α-carboxy-3,4,5-trihydroxybenzyl group or an α, carboxy-3,4,5-triacetoxybenzyl group.

Cyclic side chains Sefuwemu nuclear position 3 of Pirijiniumu nuclei formula _{- (CH 2) mA- (CH} 2) n - ( in the formula, A barrel selected from the group consisting of a single bond or a nitrogen atom, an oxygen atom and a sulfur atom A heteroatom, m represents an integer of 0 to 3, and n represents an integer of 2 or 3.) -Suitable cyclic side chains include those in the following table. One (CH ₂ ) m-A— (CH ₂ ) n-

No m A n

 1 0 0 2

 2 0 〇 3

 3 0 s 2

 4 0 s 3

 5 0 s → 〇 2

 6 0 s → o 3

7 0 s〇 ₂ 2

8 0 s 0 ₂ 3

 9 1 〇 2

 10 1 s 2

 11 1 s → 〇 2

12 1 s〇 ₂ 2

 13 1 N H 2

 14 1 N- (bone alkyl) 2

 15 1 N-(Alkaliyl) 2

 16 1 Single bond 2

 17 1 'Single bond 3

Among the above-mentioned 璟 -shaped side chains, more preferred are the 9, 10, 13, 14, 16 and 17 side chains. The lower alkyl group in the table refers to an alkyl group having 1 to 4 carbon atoms such as a methyl group or an ethyl group, and the lower alkanol group refers to a carbon atom having 1 carbon atom such as a formyl group, an acetyl group, or a propionyl group. Or 4 alkanoyl groups. The bicyclic heterocyclic group formed by the pyridine ring and its cyclic side chain is, for example, a group having 1 carbon atom such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group. Or 4 lower alkyl groups, for example, a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an izpropoxy group, a butoxy group, an isobutoxy group or a tert-butoxy group, a formyl group, It may have 1 to 3 identical or different substituents selected from the group consisting of a carboxyl group, a carbamoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an N-methylcarbamoyl group, a hydroxyl group and the like. Specific examples of the bicyclic heterocyclic group include, for example, a 2,3-dihydro-1H-indolizindium-7-yl group, a 2,3-dihydro-3-methyl-1H-indolizinium_7-yl group, 2,3-dihydro-6-methoxy-3-methyl-1H-indolizinum-7-yl group, 5-force ruboxylate-2,3-dihydro-3-methyl-1H-indolizinium-7-yl group, 6 , 7,8,9-Tetrahydroquinolinidin-2-yl group, 3,4-dihydro-1H-pyrido [2,1-c] [1,4] oxazidin-8-yl group, 2 2,3-dihydro-7H-oxazolo [3,2-a] pyridinium-7-yl group, 2,3-dihydro-7H-thiazolo [3,2-a] pyridinium-7-yl group, 2 , 3-Dihydro-7H-thiazolo [3,2-a] pyridinium-7-yl Toloxide group, 2,3-dihydro-7H-thiazolo [3,2-a] pyridinium-7-yl 1,1 -Dioxide group, 3,4-dihydro-2H-pyrido [2, lb] [l, 3] oxazidinium-8- 3,4-dihydro-2H-pyrido [2, lb] [1,3] thiazinium-8-yl, 3,4-dihydro-2H-pyrido [2,1-b] [1 , 3] thiazinium-8-yl toloxide group, 3,4-dihydro-2H-pyrido [2, trib] [1,3] thiadinin-8-yl 1,1-dioxide group, 3,4 -Dihydro-1H-pyrido c] [1,4] thiazinium-8-yl group, 3,4-dihydro-1H-pyrido [2, lc] [l, 4] thiazinium-8-ylethoxy Group, 3,4-dihydro-1H-pyrido [2 JC] [1,4] thiazinium-8-yl 1,1-dioxide group, 3,4-dihydro-1H, 2H-pyrido [l, 2- a] pyrazin-8-yl group, 3,4-dihydro-2-methyl-1H, 2H-pyrido [l, 2-a] pyrazin-2-yl group, 2-ethyl-3, 4-dihydro_1H, 2H-pyrido [1,2-a] pyrazidum-8-yl group, 2-forminole-3,4-dihydro-1H, 2H-pyrido [l, 2-a A pyrazinum-8-yl group or a 2-acetyl-3,4-dihydro-1H, 2H-pyrido [l, 2-a] pyrazinum-8-yl group can be used. Particularly preferred examples include a 2,3-dihydro-1H-indolizindium-7-yl group, a 6,7,8,9-tetrahydroquinolizinidine-2-yl group and a 3,4-dihydro-1H group. -Pyrid [2, tric] [1,4] oxazinium-8-yl group and the like. The non-toxic salt of the compound of the general formula (I) means a pharmaceutically acceptable conventional salt, and is a carboxyl group at the 4-position of the cefm nucleus, a bicyclic heterocyclic group or a carboxyl group substituted with R ¹ . And salts of an acidic residue such as a sulfo group, or a basic residue such as a 2-aminothiazole group or a quaternary ammonium group at the 7-position of the nucleus. The salts of the compound may be mono-, di- or tri-salts.

Examples of bases that form addition salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, such as trimethylamine salts and triethylamine salts. Aliphatic amines such as dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, glucamine, N-methyldalcamine or procaine; for example, Ν, Ν'-dibenzylethylenediamine Aralkylamine salts such as pyridine salts, picoline salts, heterocyclic aromatic amine salts such as quinoline salts or isoquinoline salts; For example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt or tetrabutylammonium salt A quaternary ammonium salt such as a dimethyl salt or a basic amino acid salt such as an arginine salt or a lysine salt is exemplified.

 Examples of the acid forming an addition salt include an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate or perchlorate, for example, acetate. Organic salts such as propionate, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate, for example, methanesulfonate, isethionate, benzenesulfonate Salts or sulfonates, such as P-toluenesulfonate, or acidic amino acid salts, such as, for example, aspartate or glutamate.

 The compound of the general formula (I) can be converted into its pharmaceutically acceptable non-toxic ester by a conventional method. The non-toxic ester, which can be hydrolyzed in vivo, is formed by the carboxyl group at the 4-position of the cefm nucleus. In that case, an externally added anion paired with the pyridinium group is required. Examples of the anion include a halogen ion such as a chloride ion, a bromide ion, and an iodine ion.

Examples of the ester residue capable of forming a nontoxic ester that can be hydrolyzed in a living body include, for example, an alkanoloxymethyl group such as an acetooxymethyl group and a bivaloyloxymethyl group, a 1- (ethoxycarbonyloxy) ethyl group, and a 1- (isopropoate). Alkoxycarbonyloxyalkyl group such as ethyl group, phthalidyl group, for example, (5-methyl-2-oxo-1,3-dioxo-1-yl) And (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl groups such as methyl group.

The partial structure of the oxyimino group of the general formula (I) includes a syn isomer (Z configuration) and an anti isomer (E configuration). In general, the syn isomer (Z configuration) exhibits excellent antibacterial activity. In, all OR ¹ groups are syn isomers (Z configuration). The EZZ nomenclature is described in the Journal of the American Chemical Society (J. Am. Cheni. So), Vol. 90, p. 509 (1968).

(Hereinafter the margin)

The method for producing the compound of the present invention will be described. The compound of the present invention has the general formula

(Π)

[Wherein, R ³ is a hydrogen atom or an amino-protecting group, R ⁴ is a hydrogen atom, which may have a protected substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or an aralkyl. R ⁵ is a hydrogen atom or a carboxyl protecting group, and X is a leaving group.)

[In the formula, A represents a single bond or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, fn represents an integer of 0 to 3, and n represents an integer of 2 or 3. However, the bicyclic heterocyclic ring formed by the pyridine ring and the cyclic side chain thereof may be replaced with the same or different 1 to 3 appropriately protected substituents. Reacting the compound with the general formula

[Wherein, R ³ , RR ⁵ , A, m and n have the above-mentioned meanings, and ΧΘ means a yion. However, the bicyclic heterocyclic group formed by the pyridine ring and the cyclic side chain thereof may be substituted with the same or different 1 to 3 substituents which may be protected as appropriate.) With and without, if necessary,

 (i) Step of removing a protecting group

 (ii) a step of converting the free acid to its non-toxic salt

 (iii) converting the free acid into a non-toxic ester that can be hydrolyzed in vivo

It can be manufactured by performing one or more of the above steps.

 X in the general formula (II) represents a leaving group, specifically, a halogen atom such as chlorine, bromine or iodine, or an acetyl group.

 の in the general formula (IV) represents an anion of a leaving group.

 The production method of the compound (I) of the present invention will be described in detail.

 The compound represented by the general formula (IV) is obtained by converting the compound represented by the general formula (Π) and the bicyclic heterocyclic pyridothione derivative (ΙΠ) into methylene chloride, chloroform, dimethyl ether, ethyl acetate, butyl acetate, and tetrahydrofuran. , Acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or a mixed solvent thereof in the presence or absence of a deoxidizing agent. Examples of the deoxidizing agent include metal salts such as sodium carbonate, potassium carbonate and magnesium carbonate, and, for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine or N, N-dimethylaniline. And the like. Bicyclic heterocyclic thione derivative

(II) can be used after being silylated with a silylating agent such as N, 0-bis (trimethylsilyl) acetamide. The reaction is based on 1 mole of the compound of the general formula (Π). The reaction temperature and reaction time are 0 to 40 ° C and 0.5 to 5 hours using 1 to 2 mol of the bicyclic heterocyclic thione derivative (II).

 When X in the general formula (Π) is an acetyl group, the reaction with the bicyclic heterocyclic thione derivative (ΙΠ) is performed, for example, with water, phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, N, N -Dimethylformamide, dimethylsulfoxide or a mixed solvent thereof. The reaction is preferably performed near neutrality, the reaction temperature is from room temperature to 90 ° C, and the reaction time is 1 to 15 hours. The reaction is carried out with 1 to 20 moles of iodide such as sodium iodide or potassium iodide, thiocyanate such as sodium thiocyanate or potassium thiocyanate or trimethylbenzyl ammonium per 1 mole of compound (II). It is promoted by conducting in the presence of a quaternary ammonium salt such as bromide.

 The reaction between the compound (Π) and the pyridothione derivative (ΙΠ) is carried out, for example, by reacting the compound (Π) in acetic acid, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. 1 to 50 mol of an acid such as sulfuric acid, P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, boron trifluoride or boron trifluoride getyl ether complex, etc. Compound (IV) can be produced even in the presence at room temperature to 60 ° C for 1 to 10 hours.

 The cefm compound (I) of the present invention can be produced, if necessary, by removing the protecting group from the compound of the general formula (IV).

The method for protecting the carboxyl group, amino group or hydroxyl group in the above general formula and removing the same is selected from methods commonly used in the field of lactam synthesis. Can be used. Methods for introducing and removing protecting groups include, for example,

FeJ.FW published in 1973 by Protective Groups in Organic Synthesis and Plenum Press by TW Green published by Wiley in 1981. It is carried out according to the method described in Protective Groups in Organic Chemistry by Mcomie and the like.

 Examples of the carboxyl-protecting group include lower alkyl groups such as tert-butyl group; halo-substituted lower alkyl groups such as 2,2,2-trichloroethyl group; acetomethyl group, propionyloxymethyl group, and vivaloyl A lower alkanoyloxyalkyl group such as an oxymethyl group, a 1-acetoxyl group or a propionyloxyl group; for example, a 1- (methoxycarbonyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group Or a lower alkoxycarbonyloxyalkyl group such as 1- (isopropoxycarbonyloxy) ethyl group; for example, a benzyl group, a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-nitrobenzyl group, a benzhydryl group or An aralkyl group such as bis (4-methoxyphenyl) methyl group; for example, (5-methyl (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl groups such as -2 -oxo-1,3-dioxol-4-yl) methyl group; for example, trimethylsilyl group or tert- Examples thereof include a lower alkylsilyl group such as a butyldimethylsilyl group and a phthalidyl group, and particularly preferred are a benzhydryl group, a tert-butyl group, a trimethylsilyl group and a tert: -butyldimethylsilyl group.

Examples of the amino protecting group include benzyl, 4-methoxybenzyl, and 3,4- Aralkyl groups such as dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group or bis (4-methoxyphenyl) methyl group; for example, formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group Or a lower alkanoyl group such as a pivaloyl group; a halogen-substituted lower alkanol group such as a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group or a trifluoroacetyl group; a phenylacetyl group or a phenoxyacetyl group; Arylalkanol group; for example, lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group or tert-butoxycarbonyl group; for example, benzyloxycarbonyl group, p-nitrobenzyloxy group I And an aralkyloxycarbonyl group such as a phenethyloxycarbonyl group or a lower alkylsilyl group such as a trimethylsilyl group or a tert-butyldimethylsilyl group.

 Examples of hydroxyl-protecting groups include 2-methoxyethoxymethyl, methoxymethyl, methylthiomethyl, tetrahydroviranyl, phenacyl, isopropyl, tert-butyl, benzyl, 4-methoxybenzyl, -Nitrobenzyl, acetyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, trimethylsilyl, tert-butyldimethylsilyl, methylene acetal, ethylene acetal, benzylidene acetal Cyclic ortho-esters such as methoxymethylidene or methoxyethylidene; and cyclic ketals or cyclic carbonates such as isopropylidene ketal.

For the method of removing the protecting group, a commonly used method is appropriately selected according to the type of the protecting group. You can do it. For example, removal of protecting groups such as trityl group, formyl group, tert-butoxycarbonyl group, benzhydryl group or tert-butyl group, 2-methoxyethoxymethyl group is performed by removing hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid or P- The reaction can be carried out with an inorganic acid such as toluenesulfonic acid or an organic acid, and trifluoroacetic acid is particularly preferred. When trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisol, and side reactions are also suppressed. The reaction can be performed in a solvent that does not adversely affect the reaction, such as water, methylene chloride, chloroform, ethylene chloride or benzene, or a mixed solvent thereof. The reaction temperature and the reaction time are appropriately selected according to the chemical properties of the compound (IV) and the cefm compound (I) of the present invention, and the type of the protecting group, and the reaction temperature is a moderate condition of about -10 to 60 ° C. It is preferred to do so.

 The step of converting the free form of the cefm compound (I) of the present invention into its non-toxic salt can be carried out, for example, by applying a technique commonly used in the art to the free form produced by the above-mentioned production method. .

 The step of converting a free form of the cefm compound (I) of the present invention into a physiologically hydrolyzable non-toxic ester can be carried out, for example, by the method described in US Pat. No. 4,388,460 and US Pat. No. 4,260,607. It can be easily implemented by an equivalent method.

 Isolation and purification of the cefm compound (I) of the present invention and the nontoxic salt or ester thereof produced by the above steps can be carried out by a known method, for example, crystallization or column chromatography.

The method for producing the starting compound used for producing the compound of the present invention will be described below. The compound represented by the general formula (Π) is represented by the general formula

Η ₂

Wherein X and R ^s have the above-mentioned meaning.

One _NH

[Wherein R ³ and R ⁴ have the above-mentioned meanings] or a reactive derivative of a carboxyl group thereof.

The acylation reaction is carried out, for example, in water, acetone, dioxane, getyl ether, tetrahydrofuran, ethyl methyl ketone, chloroform, methylene chloride, dichloroethane, ethyl acetate, ethyl formate, Ν, Ν-dimethylformamide, dimethyl sulfoxide or The reaction is completed in a solvent that does not adversely affect the reaction, such as a mixed solvent thereof, under water cooling or at room temperature for 1 to 10 hours. Reactive derivatives of the carboxyl group of the compound (VI) include, for example, a condensing agent such as Ν, Ν-dicyclohexylcarbodiimide and a compound formed by 縮合 -hydroxysuccinimide or 1-hydroxybenzotriazole. Acid esters formed with halogenating agents such as, for example, thionyl chloride, phosphorus pentachloride or oxalyl chloride; in the presence of a deoxidizing agent such as, for example, triethylamine or Ν-methylmorpholine, for example, methyl chloroform Ichito or Isobuchirukuro port Hol Ma, _c in which one preparative black hole mixed acid anhydride by being re formed formate such as and the like When an acid halide is used for the acylation reaction, it may be preferable to carry out the reaction in the presence of a base, in order to allow the reaction to proceed smoothly. Examples of such bases include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or carbonated lime, and organic bases such as trimethylamine, triethylamine, N, N-dimethylaniline or pyridine. Is mentioned. When a free carboxylic acid is used for the acylation reaction, it is preferable to use a condensing agent such as N, N-dicyclohexylcarpoimide or N, N-getylcarpoimide.

 Separation and purification of the starting compound (Π) produced in the above step is carried out by a conventional method such as crystallization or column chromatography, but may be used as a starting material in the next step without separation and purification. It is possible.

 —The compound represented by the general formula (V) can be prepared by a known method such as British Patent No. 1459212, European Patent No. 29557, Journal of Antibiotics

(J. Antibiotics), 38, 1738 (1985) and Tetrahedron Letters

(Tetrahedron Lett.), Vol. 22, p. 3915 (1981) and the like.

 General formula which is an intermediate for producing the compound of the present invention

W

Wherein A, m and n have the above-mentioned meaning. Provided that the pyridine ring and the bicyclic heterocyclic ring formed by the cyclic side chain thereof are the same or different, and may be substituted with 1 to 3 appropriately protected protecting groups. The compound is a novel compound not described in the literature.

 The bicyclic pyridothiones represented by the general formula (ΙΠ) are, for example, tetrahedrons

(Tetrahedron) Vol. 39, p. 2571 (1983), and Synthesis (p. 1) (1981).

 (ΥΠ) (W) (m)

1: wherein A, m and n have the above-mentioned meaning. However, the bicyclic heterocyclic ring formed by the pyridine ring and its cyclic side chain may be substituted by the same or different 1 to 3 optionally protected substituents.)

 The reaction for converting the compound (W) into the compound (VI) is carried out in an inert organic solvent such as tetrahydrofuran, dimethyl ether or dioxane, for example, phosphine such as triphenylphosphine and dimethyl ester or azodicarboxylic acid azodicarboxylate. The reaction is completed by reacting compound (W) at 0 to 80 ° C for 0.5 to 10 hours in the presence of an azodicarboxylic acid ester such as an acid getyl ester. The amount of phosphine and azodicarboxylic acid ester used is

(W) 1 to 3 mol per 1 mol. The reaction for converting the compound (νπι) into the compound (m) is carried out in an organic base such as pyridine, colizine or lutidine, for example, phosphorus pentasulfide or loetzone.

 Compound (VI) at 20 to 150 ° C, preferably 20 to 80 in the presence of a phosphorus sulfide compound such as (Lawesson) reagent (see Tetrahedron, Vol. 35, p. 2433 (1979)). Complete by reacting at ° C for 1 to 15 hours. This reaction can be carried out by diluting with an inert solvent such as toluene, benzene or tetrahydrofuran.

 The compound (II) produced by the above reaction can be subjected to the next reaction step, without purification, or purified by appropriately combining purification methods such as solvent extraction, crystallization or chromatography.

 Compound (W) has an equilibrium as described above due to tautomerism. Further, on the pyridine nucleus or the side chain at the 2-position of the compound (YD), 1 to 3 substituents which are the same or different and are optionally protected are present.

 Compound (VI), which is a raw material for producing compound (ΙΠ), is obtained by reacting 4-hydroxy-2,6-pyridinedicarboxylic acid or 2-carboxy-4-hydroxy-5-methoxypyridine [Acta Chem. Scand. Vol. 16, page 78 to page 82 (1962)] from the picoline derivative (VI, XII, W) obtained by a known synthesis reaction and further extending the side chain at the 2-position of the pyridine ring. It is produced by functional group conversion and cyclization reaction.

For example, the production of picolinaldehyde derivative (XE) using 2-carboxy-4-hydroxy-5-methoxypyridine as a raw material is carried out by the following production route. Introduction of protecting groups

 H00C C00H R "00C

1) Deesterification

 2) Decarboxylation

C00R ¹¹

Wherein R ^{1 D} is a protecting group for a hydroxyl group such as a benzyl group, a P-methoxybenzyl group, a 2-methoxyethoxymethyl group or a tert-butyldimethylsilyl group, and R ¹¹ is a methyl group or a Indicates a carboxyl-protecting group such as a benzhydryl group. However, on the pyridine nucleus, there is a substituent which may be appropriately protected and is a substituent of the compound (ΙΠ).)

 The reaction for converting 4-hydroxy-2,6-pyridinedicarboxylic acid (K) to the compound (X) is carried out by reacting the compound (K) with the disulfide in an inert solvent such as, for example, diethyl ether, ethyl acetate or methanol. Nyldiazomethane or diazomethane is reacted at 20 to 80 ° C. for 1 to 10 hours to obtain a diester (X), and the diester (X) is further reacted with, for example, N, N-dimethylformamide, dimethyl In an inert solvent such as sulfoxide or tetrahydrofuran, for example, in the presence of carbon dioxide or a base such as N, N-diisopropylethylamine, an alkylating agent such as benzyl or benzyl bromide is added. The reaction is completed by reacting at 20-80 ° C for 1-10 hours. The simultaneous protection of the hydroxyl group and the carboxyl group is carried out by changing the required amount of the alkylating agent.

The step of converting the compound (X) into the compound (XI) may be performed, for example, using methanol or te. The compound (X) is treated with an aqueous solution containing 1 equivalent of a base such as carbonated sodium carbonate or sodium hydroxide in an inert solvent such as trahydrofuran to form a monoester. In a high boiling inert solvent such as diphenyl ether, trichlorobenzene or quinoline, a catalyst such as copper powder may be added if necessary, followed by heating at 160 to 200 ° C for 1 to 20 hours. You.

 The step of converting the compound (XI) into the compound (XH) is carried out in an inert solvent such as benzene, toluene, methylene chloride or tetrahydrofuran at a low temperature, preferably in the range of -70 to -50 ° C. (XI) is carried out by operating 1 to 3 equivalents of a metal hydride such as lithium aluminum hydride or diisopropyl aluminum hydride.

 Using 2-carboxy-4-hydroxy-5-methoxypyridine as a starting material instead of 4-hydroxy-2,6-pyridine'dical, bonic acid, the above reaction is carried out to obtain picoline aldehyde (XH).

 The production of compounds (VE) using picolinaldehyde derivative (XE) as a raw material is carried out by the following production route.

(Hereinafter the margin)

Wherein R ^{1 (>} , R ¹¹ , A, m and n have the above-mentioned meanings, X is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, and Y is an oxygen atom, a nitrogen atom Or a sulfur atom, and R ¹² represents a hydrogen atom or a protecting group for a hydroxyl group such as a benzyl group, a P-methoxybenzyl group, a 2-methoxyethoxymethyl group or a tert-butyldimethylsilyl group, provided that a pyridine nucleus is present. On the side chain or on the 2-position side, there is a substituent which may be appropriately protected and is a substituent for compound (ΙΠ).)

The reaction of converting compound (M) to compound 01) by subjecting it to a carbon enrichment reaction is carried out by adding a compound (M) to a phosphorus ylide compound in an inert solvent such as dioxane, tetrahydrofuran, N, N-dimethylformamide or methanol. The reaction is completed at 10-80 ° C for 1-10 hours. The phosphorus ylide compound used in the carbon-enrichment reaction can also be obtained by reacting a phosphonium salt with a base such as sodium hydride, butyllithium, sodium methoxide or sodium hydrogen carbonate. You.

 When an ester group or a carbonyl group is present in the side chain of the compound (XI) obtained by the above carbon-enrichment reaction, these compounds are, for example, sodium borohydride in methanol and hydrogen in tetrahydrofuran. It is converted to compound (W) by a metal reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in methylene chloride. The reaction is completed at -70 to 80 ° C for 1 to 20 hours.

The removal of the protecting group of compound (M) can be performed by a known method. For example, when R "is a P-methoxybenzyl group or a 2-methoxyethoxymethyl group, treatment with an acid such as hydrochloric acid or trifluoroacetic acid in an inert solvent such as, for example, diethyl ether or tetrahydrofuran, When R ^{1 D} is a tert-butyldimethyl group, it is treated with an inert solvent such as tetrahydrofuran, for example, with potassium fluoride, tetrabutylammonium fluoride, etc. When R "is a benzyl group, for example, in an inert solvent such as methanol, tetrahydrofuran or N, N-dimethylformamide, for example, 10% palladium Using a metal catalyst such as carbon, palladium black or platinum oxide, add water for 1 to 10 hours at 20 to 80 ° C under normal temperature and normal pressure of hydrogen gas. Protecting groups can be removed by elementary decomposition. Further, as the phosphorus compound or the phosphonium compound used in the carbon increasing reaction, a commercially available or known compound is appropriately used.

The step of converting the compound (XH) into the compound (W) includes, for example, sodium borohydride in a methanol solvent and lithium hydride in a tetrahydrofuran solvent. The reaction is performed under conditions such as sodium aluminum borohydride in a solvent of aluminum or acetic acid, and particularly preferred is sodium borohydride sodium in an acetic acid solvent.

 The starting compound in the case where m = 1 in the compound of the general formula (ΙΠ) is also produced by the following method.

 The step of converting the compound (XI) into the compound () /) is carried out by treating the compound (XI) with a reducing agent such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran.

 The step of converting compound (HV) into compound (XV) is carried out by converting compound (XIV) in the presence of an organic base such as, for example, pyridin, triethylamine, N, N-dimethylaniline, for example, for example, thionyl chloride or phosphorus pentachloride or the like. This is carried out by treating with a halogenating agent of 1 to 5 equivalents for 1 to 10 hours at 0 to 80 ° C. This step may be performed, if necessary, with an inert solvent such as methylene chloride, benzene or tetrahydrofuran. It can be carried out by diluting with a solvent.

The step of converting the compound (XV) to the compound () is performed by the general formula HA- (CH ₂ ) n-0R ¹² [wherein, Y, Α, η and R ¹² have the same meaning as described above. However, a substituent which may be appropriately protected and which is a substituent of the compound (IE) may be optionally substituted.) With a base such as sodium hydride or butyllithium. After the treatment, the reaction is carried out by reacting the compound (XV) in an inert solvent such as N, N-dimethylformamide, tetrahydrofuran or dioxane at -70 to 80 ° C for 1 to 20 hours. Compound (W) is produced by removing the hydroxyl-protecting group of compound ().

The compound represented by the general formula (VI) can be produced by a known method such as a chemical and According to the method described in Pharmaceutical Bulletin (Chem. Pharm. Bull), Vol. 25, pp. 3115-3119 (1977), and the Chemical Society of Japan, 785-801 (1981), etc. It is produced using a diaminothiazol-4-yl) glyoxylic acid derivative or a 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetic acid ester derivative.

 The in vitro antibacterial activity of the cefm compound of the present invention against various bacteria was measured by the following agar plate dilution method [The standard method of the Japanese Society of Chemotherapy: Chemoterapy, Vol. 29, pp. 76-79. (1981)]. One platinum loop of each test strain cultured overnight in Mueller Hinton broth

(Inoculation amount: 10 ⁶ CFU / m fi) was inoculated into Muller Hinton agar. This medium contained antimicrobial agents at various concentrations. After culturing at 37 ° C for 16 hours, the minimum growth inhibitory concentration (MlO g / n) was measured. Cefotaxime and ceftazidime were used as comparative compounds. The results are shown in the following table.

(Hereinafter the margin)

Table 1 // concentration of growth inhibition

 Note 1) -Lactamase producing bacteria

 2) CA Z: Ceftazidium

3) C Τ X: Cefotaxime

Therefore, the compound of the present invention represented by the general formula (I) is useful as an antibacterial agent, especially for the treatment of bacterial infections in humans caused by Gram-negative bacteria including Gram-positive bacteria and non-glucose non-fermentative Gram-negative bacilli such as S. aeruginosa. Can be used for

 The cefm compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration. Examples of the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, these preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters and surfactants, if necessary. Additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

 When the cefm compound of the present invention is used as an antibacterial agent, the dosage varies depending on the age, sex, etc. of the patient, but is generally used in the range of l to 100 mg / kg per day, and is preferably 5 to 100 mg / kg per day. It is preferable to administer the drug at a dose of 30 m 2/2 to 4 times.

 The present invention will be described in more detail with reference to the following Examples and Reference Examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed.

Examples and Kieselgel 60F _{2 6 4} thin layer click port Matogurafi one (TLC) is a TLC plate Merck (Merck) manufactured in Reference Example, using UV detector as a detection method. Silica gel for the column is Wako Pure Chemical Industries Co., Ltd.'s Co-Gel C-300® or Chemco's LC-SORB® RP-18, The rate used was Merck Art 5717 manufactured by Merck. The NMR spectrum is used as an internal standard for deuterated dimethyl sulfoxide (DMS0-d _e ) or deuterated chloroform (tetramethylsilane for measurement with CDC1J solution).

(TMS), heavy water (D ₂ 0) when measured in solution 2,2 - dimethyl - 2-silapentane - 5 - Suruhona using an bets (DSS), Varian (Vrian) manufactured by XL- 200 (200 MHz) or R-40 (90 MHz) spectrometer manufactured by Hitachi, Ltd., and all δ values are shown in ppm. The symbols in the NMR measurement have the following meanings.

 s: singlet

 d: doublet

 t: triplet

 q: Quartetet ·

 ABq: AB type quartet

 dd: double doublet

 dt: double triplet

 m: multiplet

 br ： broad

 J: Coupling constant

 Hz: Herz

DMS0-d _B : heavy dimethyl sulfoxide

CDC1 _3: heavy black hole Holm

D ₂₀ : Heavy water Example 1

 7β-[(Ζ) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(6,7,8,9-tetrahydroquinolidinium-2- Thiol) thiomethyl] -3-cef-4-carboxylate

 (1) Diphenylmethyl 3-hydroxymethyl-7 / 3-[(Ζ) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cefem-4- Dissolve 250 mg (0.27 mmol) of carboxylate and 53 mg (0.32 mmol) of 6,7,8,9-tetrahydro-2 (2H) -quinolidinethione in 2.0 m of Ν, ίί-dimethylformamide. The mixture is stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and diphenylmethyl 3_ (6,7,8,9-tetrahydroquinolidinin-2-yl) thiomethyl-7 / 3-[(Z) -2-methoxyimino-2- (2-Trityl minothiazole-4-yl) acetoamide] -3-Cef-4-carboxylate A residue containing iodide was obtained and used in the next step without purification.

 (2) Dissolve the residue obtained in the above reaction (1) in methylene chloride (1.2mβ), and add anisol 0.25ιηβ and trifluoroacetic acid 1.2ιηβ under water cooling. The reaction mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, getyl ether is added to the residue, and the precipitate is collected by filtration. Suspend the precipitate in 10 IDJ water and sonicate for 15 minutes. The filtrate is subjected to reverse phase silica gel column chromatography (LC-SORB® RP-18, Chemco, eluted with 20% methanol-water), and the fractions containing the target compound are collected and concentrated under reduced pressure to about 2 mJ2 . Lyophilize the concentrate to obtain 46 mg of the title compound.

(Yield 31%).

NMR (DMS0-d ₆ ) δ: 1.86 (2H, m), 2.00 (2Η, πι), 3.16 (2H, m), 3.3 to 3.7 (2H, m), 3.86 (3H, s), 4.40 (2H, m), 4.50 (2H, ni), 5.02 (lH, d, J = 4Hz), 5.60 (lH, dd, J = 4.8Hz), 6.78 (lH, s), 7.30 (2H, brs), 8.06 (1 (, πι), 8.22 (lH, brs), 8.34 (lH, d, J = 6Hz), 9.58 (lH, br d, J = 8Hz)

IR (KBr) cm: 3400,1760,1660,1620,1530 Example 2

 Sodium Ίβ-C (Z) -2- (2-aminothiazol-1-yl) -2- (1-carboxylate-trimethylethoxyimino) acetoamide] -3-[(6,7,8 , 9-Tetrahydroquinolinidin-2-yl) thiomethyl] -3-cefm-4-carboxylate

 (1) Diphenylmethyl 3-odomethyl-7-[(Z) -2- (methyl-1-diphenylmethyloxycarbonylethoxyimino) '-2- (2-tritylaminonothiazol-4-yl) acetamide ] -3-Cefem 4-carboxylate 300 mg (0.26 mmol) and 6,7,8,9-tetrahydro-2 (2H) -ki J lysinethione 53 mg

(0.32 mmol) in N, N-dimethylformamide 2.0 · ηηβ, and stir the mixture at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and diphenylmethyl 3- (6,7,8,9-tetrahydroquinolidinium-2-yl) thiomethyl-7 / 3-[(Ζ) -2- (1-methyl -1-diphenylmethyloxycarbonylethoxyimino) -1-(2-tritylaminothiazolyl-4-yl) acetamide] -3-cephem-4-carboxylate A residue containing iodide was obtained. Use for the next step without purification.

(2) The residue obtained in the above reaction (1) is dissolved in methylene chloride (1.5 mfi), and 0.3 ml of anisol and 1.5 ml of trifluoroacetic acid are added under ice cooling. The reaction mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, getyl ether is added to the residue, and the precipitate is collected by filtration. The precipitate is suspended in 10 mJU of water, dissolved in saturated aqueous sodium hydrogen carbonate, and the filtrate Is subjected to reverse phase silica gel column chromatography (LC-SORB®, Chemco, eluted with 10% methanol-water), and the fraction containing the desired product is collected and concentrated under reduced pressure to about 2πι. The concentrate is lyophilized to give 51 mg (30% yield) of the title compound.

麵 (DMS0-d ₆ ) δ: 1.36 (3H, s), 1.38 (3H, s), 1.85 (2H, jn), 1.95 (2H, m), 3.12 (2H, m), 3.3 to 3.6 (2H, ni), 4.22 (lH, ni), 4.50 (2H, ni), 4.82 (lH, in), 5.00 (lH, d, 4 ^), 5.62 (111, (101, 4 and ぴ 8} 12), 6.72 (111,5), 7.20 (2 ^ s), 8.10 (lH, πι), 8.36 (2Η, πι)

IR (KBr) cm ¹ : 3400, 1760, 1620, 1530 Example 3

 7 / 3- C (Z) -2- (2-aminothiazole-4-yl) -2-hydroxyiminoacetamide] -3--[(6,7,8,9-tetrahydroquinolidinium) -2-yl) thiomethyl]-3-cef-4-carboxylate

 Diphenylmethyl 3-iodomethyl-7; 5-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamide] -3-cef-4-carboxy The same reaction as in (1) and (2) of Example 1 was carried out from 300 mg (0.28 mmol) of the compound and 50 ing (0.3 mmol) of 6,7,8,9-tetrahydro-2 (2H) quinolidinethione to obtain 46 mg of the title compound. Rate 30%).

Haze (DMS0-d ₆ ) δ: 1.82 (2H, m), 2.00 (2H, m), 3.10 (2H, m), 3.30 (2H, m), 4.40 (38,111), 4.56 (111, (1 , 14), 5.00 (111, (1, 4¾), 5.58 (1) 1, 01 (1, 4, and 8), 6.64 (lH, s), 7.16 (2H, br s), 8.02 (lH, br d , J = 6Hz), 8.22 (lH, br s), 8.50 (lH, d, J = 6Hz), 9.38 (lH, br d, J = 8Hz) IR (KBr) cm: 3400, 1765, 1620, 1530 Example 4

 Sodium 73-[(Z) -2- (2-Aminothiazol-4-yl) -1-2-[(1S) -tricarboxylateethoxyimino] acetamide] -3-[(6,7, 8,9-tetrahydroquinolinidin-2-yl) thiomethyl] -3-cefm-4-carboxylate

 Diphenylmethyl 3-chloromethyl-7jS-[(Z) -2-[(1S) -todiphenylmethyloxycarbonylethoxyimino] acetamide] -2-[(2-tritylaminothiazol-4-4-y ) Acetoamide] -3-cef-4-carboxylate 354ing (0.33 mmol) and 6,7,8,9-tetrahydro-2 (2H) -quinolidinethione 501½ (0.30 mmol) from Example 2 ( Perform the same reaction as in 1) and (2) to obtain 113 mg (yield 58%) of the title compound.

(DMS0-d _e ) δ: 1.30 (3H, d, J = 6Hz), 1.86 (2H, m), 2.00 (2H, ni), 3.12 (2H, ni), 3.30 (2H, in), 4.22 ( lH, d, J = 16Hz), 4.35 (lH, m), 4.46 (2H, m), 4.80 (lH, d, J = 16), 5.00 (111, (1,4112), 5.70 (111,0 ^ , 』= 4 and ぴ 8112), 6.78 (^, 5), 7.20 (211, br s), 8.12 (lH, br d, J = 6Hz), 8.44 (lH, br s), 8.60 (lH, d, (J = 6Hz)

 IR (KBr) cm: 3400,1760,1620,1590,1530 Example 5

Sodium Ίβ-C (Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxylatevinyloxyimino) acetamide] -3-[(6,7, 8,9-tetrahydroquinolinidin-2-yl) thiomethyl] -3-cefm-4-carboxyla Up

 Diphenylmethyl Ίβ-[(Ζ) -2- (1-tert-butoxycarbonylvinyloxy) -2- (2-tritylaminothiazol-1-yl) acetamide] -3-c -Same as (1) and (2) in Example 2 from 317 mg (0.33 mmol) of 3-cef-4-carboxylate and 50 mg (0.30 mmol) of 6,7,8,9-tetrahydro-2 (2H) -quinolidinethione The above reaction is carried out to obtain 97 mg (yield 50%) of the title compound.

NMR (DMS0-d _B ) δ: 1.88 (2H, m), 2.00 (2H, m), 3.12 (2H, m), 3.40 (2H, m), 4.30 (lH, d, J = 14Hz), 4.44 ( 2H, m), 4.76 (lH, d, J = 14Hz), 4.88 (lH, s), 5.00 (lH, d, J = 4Hz), 5.18 (lH, s), 5.60 (lH, m), 6.95 ( lH, s), 7.30 (2H, br s), 8.08 (lH, br d, J = 6Hz), 8.46 (lH, br s), 8.50 (lH, d, J = 6Hz)

 IR (KBr) cm: 3400, 1760, 1620, 1530 Example 6

 Sodium 7/3-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxylate methoxyimino) acetamide]-3-[(6,7,8,9- Tetrahydroquinolinidin-2-yl) thiomethyl] -3-cef-4-carboxylate

Diphenylmethyl 3-iodomethyl -7 / 3- [(Z) -2- (1-diphenylmethyloxymethoxyethoxyimino) -2- (2-tritylaminothiazole-4-yl) acetamide]-3 The same as (1) and (2) of Example 2 from 300 mg (0.26 mmol) of -cef-4-carboxylate and 50 mg (0.30 mmol) of 6,7,8,9-tetrahydro-2 (2H) -quinolidinethione The reaction is carried out to obtain the title compound 102nig (yield 62%). NMR (DMS0-d _B ) δ: 1.82 (2Η, πι), 1.98 (2Η, πι), 3.10 (2Η, ι), 3.30 (2Η, πι), 4.18 (2H, br s), 4.22 (lH, d , J = 16Hz), 4.40 (lH, m), 4.60 (lH, in), 4.75 (lH, d, J = 16¾), 4.98 (111, (1,4112), 5.60 (111,0 (1, 4 and 8), 6.82 (1} 1,5), 7.20 (211, brs), 8.02 (lH, d, J = 6Hz), 8.44 (lH, s), 8.48 (lH, d, J = 6Hz)

IR (KBr) cm ¹ : 3400,1760,1620,1530 Example 7

 Ίβ-C (Z) -2- (2-aminothiazole-4-yl) —2-methoxyiminoacetamide] -3-[(3,4-dihydro-1H-pyrido [2, tric] [ 1,4] oxazinidine-8-yl) thiomethyl] -3-sephem-4-carboxylate

 Diphenylmethyl 3-iodomethyl-7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cefm-4-force ruboxylate lOOmg (0.11 mmol) And 3,4-dihydro-8 (1H) -pyrido [2,1-c] [1,4] oxazinethione 20 mg (0.12 mmol) were reacted in the same manner as (1) and (2) in Example 1. This gives 29 mg (48% yield) of the title compound.

Thigh _{(DMS0-d 6) δ:} 3.3~3.6 (2H, m), 3.82 (3H, s), 4.20 (2H, m), 4.50 (4H, ni), 5.00 (211, (1 (1, 4及{16}), 5.12 (111, 01, = 16), 5.58 (111, (1 (1, 4, and 8)), 6.78 (lH, s), 7.28 (2H, br s), 8.18 (lH, br d, J = 6Hz), 8.30 (lH, br s), 8.56 (lH, d, J = 6Hz), 9.55 (lH, br d, J = 8Hz)

IR (KBr) cm: 3400, 1765, 1620, 1530 Example 8

Sodium 7 / 3- [(Z) -2-(2-Aminothiazol-4-yl) -2-(Tocal 7 Boxylate-1-methylethoxyimid J) acetoamide] -3- [(3,4-dihydrido- (1H) -pyrido [2,1-c] [1,4] oxazidin-8-yl) thiomethyl] -3- Cefm-4 4-Rubixylate

 Diphenylmethyl 3-hydroxymethyl-7) S- [(Z) -2-(trimethyl-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4- Yl) acetoamide] -3-cef-4-carboxylate 210 mg (0.18 mmol) and 3,4-dihydro-8 (1H) -pyrido [2, tric] [1,4] oxazine thione 30 mg (0.18 Mmol) to give 21 mg (yield 18%) of the title compound by the same reaction as in (1) and (2) of Example 2.

NMR (DMS0-d _e ) δ: 1.38 (6H, s), 3.30 (2H, m), 4.22 (2Η, πι), 4.24 (lH, d, J = 14 Hz), 4.56 (2H, m), 4.76 ( lH, d, J = 14Hz), 5.00 (3H, in), 5.60 (lH, m), 6.70 (lH, s), 7.18 (2H, br s), 8.15 (lH, br d, J = 4Hz), 8.48 (lH, brs), 8.55 (lH, d, J = 4Hz)

IR (KBr) cm: 3400,1760,1685,1620,1530 Example 9

 Sodium 7j3-[(Z) —2- (2-Aminothiazol-4-yl) -2-[(1S) -tricarboxylateethoxyimino] acetamide] -3-[(3,4-dihydro -1H-pyrido [2, lc] [l, 4] oxazinium-8-yl) thiomethyl] -3-cef-4-carboxylate

Diphenylmethyl 3-chloromethyl-7; 3- [(Z) -2-[(1 S)-1-diphenylmethyloxycarbonylethoxyimino] -2-(2-tritylami J thiazol- 4-yl) acetoamide]-3-cef-4-carboxylate 200mg (0.19mmol) and 3,4-dihydro-8 (1H) -pyrido [2, lc] [1,4] oxazine The same reaction as in (1) and (2) of Example 2 was carried out from 50 nig (0.30 mmol) of thione to obtain 53 mg (44% yield) of the title compound.

Orchid (DMS0-d _e ) δ: 1.30 (3H, d, J = 6Hz), 4.20 (2H, m), 4.30 (lH, ni), 4.58 (2H, m), 4.74 (lH, d, J = 12Hz ), 5.00 (lH, d, J = 4 Hz), 5.02 (2H, m), 5.64 (lH, dd, J-4 and 8 Hz), 6.78 (lH, s), 7.20 (2H, brs), 8.22 ( lH, br d, J = 6Hz), 8.40 (lH, br s), 8.60 (lH, d, J = 6Hz)

 IR (KBr) cm: 3400, 1760, 1620, 1590, 1530 Example 10

 Sodium 7-[(Z) -2- (2-Aminothiazol-4-yl) -2- (1-carboxylatevinyloxyimino) acetamide] -3-[(3,4-dihydro- 1H-pyrido [2,; ic] [1,4] oxazinium-8-yl) thiomethyl] -3-cefum-4-carboxylate

 Diphenylmethyl 3-chloromethyl-7 ^ 3-[(Z) -2- (1-tert-butoxycarbonylcarbonylvinyloximino) -2- (2-tritylaminothiazole-4-yl) acetamide] -3 From 171 mg (0.18 mmol) of 3-cef-4-carboxylate and 30 rag (0.18 mmol) of 3,4-dihydro-8 (1H) -pyrido [2,1-c] [1,4] oxazinethione, The same reaction as in (1) and (2) is carried out to obtain 46 mg (40% yield) of the title compound.

 NMR (DMS0 −) δ: 3.20 (2H, ra), 4.0 to 4.8 (6H, ra), 4.82 (1H, s), 5.00 (1H, d, J = 4 Hz), 5.02 (2H, m), 5.12 ( lH, s), 5.56 (lH, ni), 6.90 (lH, s), 6.22 (2H, br s), 8.10 (lH, br d, J = 6Hz), 8.50 (lH, d, J = 6Hz), 8.62 (lH, s)

IR (KBr) cm: 3400,1760,1620,1530 Example 11

 7 / 3-C (Z) -2- (2-amidothiazol-4-yl) -2 -methoxyiminoacetamide] -3-[(2,3-dihydro-1H-indolizinium- A-yl) Thiomethyl] -1-Cefem-4-carboxylate

 Diphenylmethyl 3-odomethyl-7; 3-[(Z) -2 -Methoxyimino-2- '

(2-Tritylaminothiazole-4-yl) acetamide] -3-cef-4-force ruboxylate 200 mg (0.21 mmol) and 2,3-dihydro-7 (1H) -indolizinethione 38 mg (0.26 mmol) Thus, the same reaction as in (1) and (2) of Example 1 was carried out to obtain 30 mg (yield 26%) of the title compound.

(DMS0-d _e ) δ: 2.36 (2H, ra), 3.20 ~ 3.62 (4H, m), 3.82 (3H, s), 4.52 (2H, m), 4.62 (211,111), 5.00 (111, [1, 4¾), 5.56 (111, 011, 4 and 8), 6.76 (111, 5), 7.24 (2H, br s), 8.10 (lH, br d, J = 6 Hz), 8.34 (lH, br s) ) 、 8.68 (lH, d, J = 8Hz): 9.52 (lH, br d, J = 8Hz)

 IR (KBr) cm: 3400, 1765, 1620, 1530 Example 12

 Sodium 7/3-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide] -3-[(2, 3-Dihydro-1H-indolizinid-7-yl) thiomethyl] -3-cef-4-carboxylate

Diphenylmethyl 3-hydroxymethyl-7β-[(Ζ) -2- (trimethyl-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl) ) Acetoamide] -3-cef-4-carboxylate 250mg (0.21 mmol) and 38 mg (0.26 mmol) of 2,3-dihydro-7 (1H) -indolizinethione were reacted in the same manner as (1) and (2) in Example 2 to give 53 mg (yield) of the title compound. Rate 39%).

NMR (DMS0-d _B ) δ: 1.36 (3H, s), 1.38 (3H, s), 2.38 (2H, ra), 3.20-3.60 (4H, m), 4.28 (lH, d, J = 12 Hz), 4.68 (2H, ra), 4.78 (lH, d, J = 12Hz), 5.00 (lH, d, J = 4Hz), 5.64 (111,0 (1,4 and 8¾), 6.74 (111,5), 7.20 (211, 1 ^ s), 8.12 (lH, br d, J = 6Hz), 8.60 (lH, br s), 8.72 (lH, d, J = 6Hz)

 IR (KBr) o¾ 3400, 1760, 1620, 1590, 1530 Example 13

 Sodium Ίβ-C (Z) -2- (2-aminothiazole-4-yl) -2-[(1S) carboxylateethoxyimino] acetamide] -3-[(2,3-dihydro- 1H-indolizinum-7-yl) thiomethyl] -3-cef-4-carboxylar

 Diphenylmethyl 3-chloromethyl-7 / 3-[(Z) -2-[(1S) -1-diphenylmethyloxycarbonylethoxyimino] acetamide] -3-cef-4-carboxylate 250 mg ( 0.23 mmol) and 50 nig (0.33 mmol) of 2,3-dihydro-7 (1H) -indolizinthione were reacted in the same manner as (1) and (2) in Example 2 to give 58 mg of the title compound (40% yield) Get.

Image _{(DMS0-d 8) δ:} 1.30 (3H, d, J = 6Hz), 2.38 (2H, m), 2.60 (2H, m), 3.40 (2H, ni), 4.30 (2H, m), 4.70 ( 3H, m), 5.00 (lH, d, J = 4 Hz), 5.64 (lH, dd, J = 4 and 8 Hz), 6.78 (lH, s), 7.20 (2H, br s), 8.18 (lH, m) , 8.52 (lH, br s), 8.72 (lH, d, J = 6 Hz) IR (KBr) cm: 3400, 1760, 1620, 1530 Example 14

 Sodium 7/3-[(Z) -2- (2-Aminothiazol-4-yl) -2- (1-carboxylatevinyloximino) acetamide] -3-[ (2,3-dihydro-: LH-indolizinid-7-yl) thiomethyl] -3-cephem-4-carboxylate diphenylmethyl Ίβ-[(Ζ) -2- (1-tert-butoxycarbonylvinyloxyimino)- 2- (2-tritylaminothiazol-4-yl) acetamide] -3-chloromethyl-3-cephem-4-carboxylate 200nig (0.21 mmol) and 2,3-dihydro-7 (1H From 50 mg (0.33 mmol) of) -indolizinethione, the same reaction as in (1) and (2) of Example 2 was carried out to obtain 5 g (yield 41%) of the title compound.

NMR (DMS0-d _B ) δ: 2.38 (2H, m), 3.3 to 3.7 (4Η, πι), 4.22 (lH, m), 4.5 to 4.8 (3Η, ra), 4.82 (lH, s ), 5.00 (lH, d, J = 4Hz), 5.15 (lH, s), 5.60 (lH, m), 6.92 (lH, s), 7.26 (2H, br s), 8.08 (lH, br d, J = 6Hz), 8.54 (lH, br s), 8.66 (lH, br d, J = 6Hz)

 IR (KBr) cm: 3400, 1760, 1620, 1530 Example 15

 7j3- [(Z) -2- (2-aminothiazole-4-yl) -2-hydroxyiminoacetamide] -3-[(2,3-dihydro-3-methyl-1H-indolizinium-7 -Yl) thiomethyl] -3-cef-4-carboxylate

Diphenylmethyl 3-chloromethyl-7 / 3-[(Z) -2- (2-tritylamino Thiazole-4-yl) -2-trityloxyiminoacetamide] -3-Cefem-4-carboxylate and 2,3-dihydro-3-methyl-7 (1H) -indolizinethione The title compound is obtained in the same manner as in Jeong example 1.

MR (DMS0-d ₆ ) δ: 1.58 (3H, d, J = 6 Hz), 1.98 (2H, ra), 2.40 (2H, ni), 3.38 (2H, m), 4.50 (2H, br 5), 4.90 (111,111), 5.00 (111, (1, = 4¾), 5.8 (111, (^, 4 and 8112), 6.70 (lH, s), 7.16 (2H, brs), 8.18 (lH, brd , J = 6Hz), 8.30 (lH, brs), 8.72 (lH, d, J = 6Hz), 9.38 (lH, d, J = 8Hz)

 IR (KBr) cm: 3400, 1765, 1620, 1525 Example 16

 7β-C (Z) -2- (2-aminothiazol-41-yl) -2-methoxyimi Jacet amide] -3--[(2,3-dihydro-3-methyl-1H-indolizinium) -7-yl) thiomethyl] -3-cef-4-carboxylate

 Diphenylmethyl 3-hydroxymethyl -7/3 _ [(Z) -2-methoxyimino-2- 2- (2-tritylaminothiazol-4-yl) acetamide] -3-cefem-4-force The title compound is obtained from ruboxylate and 2,3-dihydro-3-methyl-7 (1Ή) -indolizinethione in the same manner as in Example 1.

Thigh (DMS0-d _E ) δ: 1.56 (3H, d, J = 6 Hz), 2.00 (2H, ni), 3.30 to 3.60 (4H, m), 3.84 (3H, s), 4.52 (2H, m), 4.92 (lH, m), 5.00 (lH, d, J = 4 Hz), 5.56 (lH, dd, J = 4 and 8 Hz), 6.76 (lH, s), 7.22 (2H, br s), 8.16 (lH, br d, J = 6Hz), 8.32 (lH, br s), 8.72 (lH, d, J = 6Hz), 9.54 (lH, br d, J = 8Hz)

IR (KBr) cm: 3400,1765,1670,1620,1530 Example 17

 Sodium Ί β-C (Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxylate-trimethylethoxyimino) acetoamide] -3-[(2,3- Dihydric mouth-3-Methyl-1H-indolizinum-7-yl) Thiomethyl] -3-Cefem-4 4-Ruboxylate

 Diphenylmethyl 3-iodomethyl-7 / 3-[(Z) -2- (1-methyl-1-diphenylmethyloxycarbonylethoxyimino) -2- (2-tritylaminothiazol-4-yl) [Acetamide] -3-cef-4-carboxylate and 2,3-dihydro-3-methyl-7 (1H) -indolizinethione to give the title compound in the same manner as in Example 2.

 NMR (DMSO-de) δ: 1.36 (3H, s), l. 38 (1.5H, s), l. 40 (1.5H, s), 1.98 (2H, m), 3.1 to 3, 6 (4H, m), 4.30 (0.5H, d, J = 16Hz), 4.36 (0.5H, d, J-16Hz), 4.66 (0.5H, d, J = 16Hz), 4.76 (0.5H, d, J = 16Hz) , 5.00 (lH, d, J = 4Hz), 5.02 (lH, ni), 5.64 (111, (1 (1,4 and 8112), 6.74 (111,5), 7.20 (2} 1,1 ^ s) , 8.06 (0.5H, br d, J = 8 Hz), 8.24 (0.5H, br d, J = 8 Hz), 8.32 (0.5H, br s), 8.58 (0.5H, br s), 8.76 (lH, d, J = 8Hz), 8.80 (0.5H, d, J = 8Hz)

 IR (KBr) cm: 3400,1760,1620,1535 Example 18

Sodium 7 / 3- [(Z) -2-(2-Aminothiazole-4-yl) -2-[(1 S) -1-carboxylateethoxyimino] acetamide] -3- [(2,3-dihydro-3-methyl-1H-indolizinum-7-yl) thiomethyl] -3-cef-4-carboxylate Diphenylmethyl 3-chloromethyl-7 jS- [(Z) -2-[(1S) ~ l-diphenylmethyloxycarbonylethoxyimino)]-2- (2-tritylaminothiazole-l- 4-yl) acetoamide] -3-cefnium-4-carboxylate and 2,3-dihydro-3-methyl-7 (1H) -indolizionthion, the title compound as in Example 2 Get.

Haze (DMS0-d _B ) δ: 1.30 (3H, d, J = 6 Hz), 1.58 (3H, d, J = 6 Hz), 2.00 (2H, m), 2.50 (2H, m), 3.40 (2H, iD ), 4.20 to 4.60 (3H, ni), 4.80 (lH, ra), 5.00 (lH, 1, J = 4 Hz), 5.68 (111 (1, 4, and 8112), 6,80 (111, 5), 7.22 (211,1 ^ s), 7.8 ~ 8.9 (3H, m)

IR (KBr) cm: 3400, 1760, 1620, 1530 Example 19

 Sodium Ίβ-C (Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxylatevinyloxyimino) acetoamide] -3-[(2,3-dihydro -3-Methyl-1H-indolizinum-7-yl) thiomethyl]-3-Cefem-4-carboxylate

Diphenylmethyl Ίβ-[(Ζ) -2- (1-tert-butoxycarbonylvinyloxyimino)-2- (2-tritylaminothiazol-4-yl) acetamide] -3-chloromethyl-3-cephem The title compound is obtained in the same manner as in Example 2 from -4-carboxylate and 2,3-dihydro-3-tyl-7 (1H) -indolizionthione. (DMS0-d _B ) δ: 1.56 (3H, d, J = 6Hz), 2.00 (2H, m), 2.62 (2H, ni), 3.25 (2H, m), 4.2 ~ 4.8 (3H, m), 4.86 (lH, s), 5.00 (lH, d, J = 4 Hz), 5.16 (lH, s), 5.60 (lH, m), 6.92 (lH, s), 7.28 (2H, brs), 8.08 (0.5 H, br d, J = 6Hz), 8.26 (0.5H, br d, J = 6Hz), 8.36 (0.5H, br s), 8.60 (0.5H, br s), 8.76 (0.5H, d, J = 6Hz), 8.78 (0.5H, br d, J = 6Hz)

IR (KBr) cni: 3400,1760,1620,1535 Example 20

 Sodium 7/3-[(Z) -2- (2-aminothiazole-4-yl) -2-carboxylatomethoximininoacetamide] -3-[(2,3-dihydro-3- Methyl-1H-indolizindium-7-yl) thiomethyl] -3-cefm-4_carboxylate diphenylmethyl 3-hydrodmethyl-7 jS- [(Z) -2-diphenylmethyloxycarbonylmethoxyimino- 2- (2-tritylaminothiazol-4-yl) acetamide] -3-cef-4-carboxylate and 2,3-dihydro-7 (1H) -di. The title compound is obtained in a similar manner.

Image (DMS0-d ₆ ) δ: 1.55 (3H, d, J = 6 Hz), 2.00 (2H, m), 2.60 (2H, m), 3.40 (2H, Di), 4.20 (2H, s), 4.25 ( 2H, m), 4.80 (lH, m), 5.00 (lH, d, J = 4Hz), 5.60 (lH, m), 6.82 (lH, s), 7.22 '(2H, brs), 8.04 (0.5H , Br d, J = 6Hz), 8.28 (0.5H, br d, J = 6Hz), 8.36 (0.5H, br s), 8.68 (0.5H, d, J = 6Hz), 8.70 (0.5H, br s ), 8.72 (0.5H, br d, J = 6Hz)

IR (KBr) cm ¹ : 3400,1760,1620,1530 Example 21

Sodium 7; 3-[(Z) -2- (2-aminothiazol-4-yl) -2- (a-force ruvoxylate benzyloxyimino) acetamide] -3-[(2, 3-dihydro-3-methyl-1H-indolizindium-aryl) thiomethyl] -3-cef-4-carboxylate Diphenylmethyl 3-hydromethyl-73-[(Z) -2- {α- (diphenylmethyloxycarbonyl) benzyloxyimino]-2- (2-tritylaminothiazol-4-yl) acetamide] The title compound is obtained in the same manner as in Example 2 from -3-cef-4-carboxylate and 2,3-dihydro-7 (1H) -indridinethione.

Awake (DMS0-d _e ) δ: 1.50 (3Η, πι), 1.96 (2Η, ι), 2.50 (2Η, πι), 3.30 (2Η, πι), 4.28 (2H, m), 4.90-5.10 (2H, ni), 5.18 (0.5H, s), 5.24 (0.5H, s), 5.72 (lH, m), 6.80 (0.5H, s), 6.90 (0.5H, s), 7.1 to 7.8 (5H, m) , 8.0 to 8.9 (3H, ni)

 IR (KBr) cm: 3400, 1760, 1620, 1530 Example 22

 Nato_rium 7/3-[(Z) -2- (2-Aminothiazol-1-yl)-2--force ruboxylate-3,4-dihydroxybenzyloxyimino) acetamide]-3- [ (2,3-dihydro-3-methyl-1H-indolizinum-7-yl) thiomethyl] -3-cef-4-carboxylate

 Diphenylmethyl 3-iodomethyl-7-[(Ζ) -2- [3,4-di (2-methoxyshethoxymethoxy) -a-diphenylmethyloxycarbonylbenzyloxysimino] -2--2- (2-trityl Aminothiazole-4-yl) acetoamide] -3-Cefem-4-carboxylate and 2,3-dihydro-7 (1Η) -indolinidinethione, the title compound was obtained in the same manner as in Example 2. .

NMR (DMS0-d _e ) δ: 1.50 (3H, m), 2.00 (2H, m), 2.40 (2H, m), 3.40 (2Η, πι), 4.2-

5.8 (4H, ni), 6.6 to 7.1 (4H, m), 7.1 to 7.5 (2H, in), 8.0 to 8.9 (3H, in)

IR (KBr) cm: 3400,1760,1600,1530 Example 23

Sodium 7; g-[(Z) -2- (2-aminothiazole-4-yl) -2-methoxyiminoacetamide] -3-[(5-carboxylate-2,3-dihydro-3-methyl -1 H-indolizinum-7-yl) thiomethyl] -3-cef-4-carboxylar diphenylmethyl 3-hydromethyl-7S- [(Z) -2-methoxyimino-2- (2-tritylamino) Zol-4-yl) acetamide] -3-Cefem-4 -force ruboxilate and 2,3-dihydro-3-methyl-5-diphenyloxycarbonyl-7 (1H) -indridinethione First, the title compound is obtained in the same manner as in Example 2. NMR (DMS0-d _e ) δ: 1.40 (3H, d, J = 6 Hz), 2.00 (2Η, πι), 2.44 (2H, m), 3.3 to 3.7 (2H, m), 3.90 (3H, s), 4.32 (0.5H, d, J-12Hz), 4.38 (0.5H, d, J = 12Hz), 4.74 (0.5H, d, J = 12Hz), 4.80 (0.5H, d, J = 12Hz), 5.02 ( lH, d, J = 4Hz), 5.58 (lH, m), 5.90 (111, (1 (1, = 4 and 81 {2), 6.76 (111,3), 7.28 (211,1) s), 7.76 (0.5H, s), 7.80 (0.5H, s), 8.00 (0.5H, s), 8.10 (0.5H, s), 9.56 (lH, br d, J = 8Hz)

IR (KBr) cm: 3400, 1760, 1605, 1530 Example 24

 Disodium 7/3-[(Z) -2- (2-Aminothiazol-4-yl) -2- (1-force ruvoxylate-1-methylethoxyimino) acetoamide] -3-[(5 -Carboxylate-2,3-dihydro-3-methyl-1H-indolizinum-7-yl) thiomethyl] -3-cef-4-carboxylate

Diphenylmethyl 3-hydroxymethyl-7 / 3-[(Z) -2- (1-methyl-1-diphenylmethyloxycarbonylethoxyimino) -2- (2-tritylaminothia) /6eA.llodrGd 9 ει

00 inch

Example 26

 Sodium 7/3-[(Z) -2- (2-Aminothiazol-4-yl) -2- (tetracarboxylate-1-methylethoxyimino) acetamide]-3-[( 2,3-Dihydrido-6-Methoxy-3-methyl-1H-indolizindium-7-yl) thiomethyl] -3-cefm-4-carboxylate

 Diphenylmethyl 3-odomethyl-7 / 3-[(Z) -2- (trimethyl-1-diphenylmethyloxycarbonylethoxyoximino) -2- (2-tritylaminothiazol-4-yl) acetami C] -3-cef-4-carboxylate and 2,3-dihydro-6-methoxy-3-methyl-7 (1Η) -indolizinethione to give the title compound in the same manner as in Example 2. obtain.

NMR (DMS0-d _e ) δ: 1.34 (6H, s), 1.60 (3H, d, J = 6 Hz), 2.00 (2H, m), 3.05 (2H, m), 3.3 to 3.6 (2H, m), 4.00 (3H, s), 4.1 to 4.8 (2H, ni), 5.00 (0.5H, d, J = 4Hz), 5.02 (0.5H, d, J = 4Hz), 5.02 (0.5H, ra), 5.15 ( 0.5H, m), 5.62 (lH, ra), 6.76 (lH, s), 7.20 (2H, brs), 8.50 (lH, brs), 8.72 (lH, brs), 8.96 (lH, brs) )

 IR (KBr) cm: 3400, 1765, 1610, 1530, 1500 Example 27

 6,7,8,9-tetrahydro-2 (2H) -quinolidinethione

(1) Dissolve 1.71 g (4.26 mmol) of (3-hydroxypropyl) triphenylphosphonium bromide in 17 ratetrahydrofuran. The solution is cooled to −78 ° C., and 5.32 mL (8.51 mmol) of a 1.6 M butyllithium hexane solution is added dropwise. After the reaction mixture was warmed to room temperature and further stirred for 2 hours, 700 ing (3.28 mmol) of 4-benzyloxy-2-pyridinecarboxaldehyde was added to tetrahydrofuran. Add the solution dissolved in Run 3.5. After stirring overnight at room temperature, the reaction solution is poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ヮ Ko-Igel ® C-300, eluted with ethyl acetate) to give 670uig of 4- (4-benzyloxy-2-pyridyl) -3-butene-toluol (80% yield) ).

 NMR (CDCla) δ: 2.50 (2H, m), 3.80 (2H, t, J = 6 Hz), 5.08 (2H, s), 6.55 (1H, d, J = 16), 6.74 (111, (1 (1 (1 , '' = 2 and 6112), 6.75 (111, (11 :, 16 and 7¾), 6.86 (111, 1, J = 2 Hz), 7.40 (5H, m), 8.35 (lH, d, J = 6 Hz)

 (2) Dissolve 1.18 g (4.62 mmol) of the compound obtained in the above reaction (1) in 22 mj of methanol, add 120 nig of 10% palladium on carbon catalyst, and perform catalytic reduction at room temperature. After 2 hours, add 120mg of the same catalyst and reduce for another 3 hours. After filtering off the catalyst, the solvent is distilled off under reduced pressure. The residue is dissolved in tetrahydrofuran Kkfi, and 2.42 g (9.23 mmol) of triphenylphosphine is added. Under ice cooling, 1.46 mJ2 (9.23 mmol) of acetyl dicarboxylate was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography-(ヮ Ko-gel ® C-300, eluted with 10% methanol) to give 6,7,8,9-tetrahydro-2 (2H) -To obtain 509 mg (74% yield) of quinolidinone.

NMR CD S0-d ₈ ) δ: 1.70 (2H, m), 1.84 (2H, m), 2.68 (2H, t, J = 5Hz), 3.88 (2H, t, J = 6Hz), 5.98 (lH, d , J = 2Hz), 6.02 (lH, dd, J = 2 and 6Hz), 7.54 (lH, d, J = 6Hz)

(3) Dissolve 509 mg (3.42 mmol) of the compound obtained in the above reaction (2) in 5 mβ of pyridine, add 564 mg (2.54 mmol) of phosphorus pentasulfide, and stir the reaction mixture at 80 ° C for 1 hour. Pour the reaction mixture into water and extract three times with methylene chloride. Organic layer Dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The residue is washed with getyl ether-methanol to obtain 6,7,8,9-tetrahydro-2 (2H) -quinolidinethione (yield 52%).

NMR (DMS0-d ₆ ) δ: 1.72 (2H, m), 1.90 (2H, m), 2.72 (2H, t, J = 6Hz), 4.00 (2H, t, «1 = 6¾), 7.04 (111, 111) (1 (1, 2 and 6112), 7.12 (111, 1, 2112), 7.50 (11 {, (1, ₁ 1 = 6112) IR (KBr) cm: 3400,1620,1530,1460,1080

UV (MeOH) λ nm: 204,240,339 Example 28

 2,3-dihydro-7 (1H) -indolizinethione

 (1) Dissolve 1.23 g (5.77 mmol) of 4-benzyloxy-2-pyridinecarbaldehyde in dioxane 20raJ2, and add 1.55 g (6.23 mmol) of getyl ethoxycarbonylmethylphosphonate and 0.41 g of 50% oily sodium hydride at room temperature. (8.65 mmol) and the reaction mixture is stirred for 15 minutes. Pour the reaction solution into water and extract with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Ecogel ® C-300, eluted with ethyl acetate-hexane = 3: 1), and ethyl 3- (4-benzyloxy-2-pyridyl) acrylate 0.90 g ( Yield 57%). NMR (CDC1J δ: 1.35 (3H, t, J = 6 Hz), 4.32 (2H, t, J = 6 Hz), 5.16 (2H, s), 6.90 (111, (1 (1, 2, and 6), 6.95 ( 11 ^, 16} 12), 7.06 (111, € 1, 2¾), 7.46 (511,111), 7.66 (lH, d, J = 16), 8.50 (lH, d, J = 6Hz)

(2) Dissolve 3.0 g (11.1 mmol) of the compound obtained in the above reaction (1) in methylene chloride 60π ^. 1.5M diisobutylaluminum hydride at -78 ° C Liquid) 22m (33.3 mmol) is added. After stirring at the same temperature for 30 minutes, 2'm of acetic acid is added, and the reaction mixture is further stirred at room temperature for 10 minutes. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ヮ Kogel® C-300, eluted with ethyl acetate) to give 3- (4-benzyloxy-2-pyridyl) -2-propen-1-ol 2.11 g (yield 83 %).

Ran _{(CDC1 3) δ: 4.42 (} 2H, d, J = 4Hz), 5.12 (2H, s), 6.68 (lH, d, J = 16Hz), 6.78

(1 (1 (1, 2, and 6), 6.88 (^,, ₁ 1 = 16 and 41 ^), 6.92 (111, (1, = 2¾), 8.42

(lH, d, J = 6Hz)

(3) Using 2.11 g (9.21 mmol) of the compound obtained in the above reaction (2), a reaction similar to that of Example 27- (2) was carried out to give 2,3-dihydro-7 (1H) -indolidinone 1.09 (yield Rate of 88 ° / ₀ ).

Awakening: _{(DMS0-d 8) δ:} 2.15 (2H, m), 2.95 (2H, t, J = 6Hz), 4.08 (2H, t, J = 6Hz), 6.03

(lH, d, J = 6Hz), 6.05 (lH, s), 7.72 (lH, d, J = 6Hz)

IR (KBr) cm: 3400,1640,1540

UV (βΟΗ) ληπι: 204,258

 (4) Using 1.09 g (8.07 mmol) of the compound obtained in the above reaction (3), the same reaction as in Example 27- (3) was performed, and 2,3-dihydro-7 (1H) -indolizinethione 300ing (Yield 25%) and raw material 320mg (recovery 26%).

Awake (DMSO-de) δ: 2.20 (2H, ra), 3.04 (2H, t, J = 6Hz), 4.20 (2H, t, J = 6Hz), 7.12 (lH, br d, J = 6Hz), 7.22 (lH, brs), 7.74 (lH, brs, J = 6Hz) 2,3-dihydro-3-methyl-7 (1H) -indolizinethione

 (1) Dissolve 10 g (54.6 mmol) of 4-hydroxy-2,6-pyridinedicarboxylic acid in 100 mL of N-dimethylformamide and add 19.5 mJ2 of benzyl bromide at room temperature.

(164 mmol) and 28.5πι (164 mmol) of N, N-diisopropylethylamine. After stirring for 2 hours, further add 6.5 ιπ (54.6 mmol) of benzyl bromide and 7.5 g (54.6 mmol) of potassium carbonate. The reaction mixture is heated and stirred at 80 ° C for 30 minutes. After allowing the reaction solution to cool to room temperature, pour into water and extract with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ヮ Ko-gel ® C-300, eluted with ethyl acetate-hexane-1: 1) to give 19.3 g of dibenzyl 4-benzyloxy-2,6-pyridinedicarboxylate crystals. 78%).

Noodles _{(CDC1 3) δ: 5.24 (} 2H, s), 5.48 (4H, s), 7.2~7.7 (15H, m), 7.88 (2H, s) IR (KBr) cm: 1720,1590,1350,1240, 1110

 (2) 5.0 g (11.0 mmol) of the compound obtained in the above reaction (1) was dissolved in a mixed solution of 50 mβ of tetrahydrofuran and 50 mJ of meth] phenol, and 5.5 tn £ (11.0 mmol) of 2N sodium hydroxide was added at room temperature. Add. After stirring for 15 minutes, the solvent is distilled off under reduced pressure, and the residue is diluted with water. Wash the mixture with ethyl acetate. Adjust the aqueous layer to pH 4.0 with dilute hydrochloric acid and extract with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.39 g of 4-benzyloxy-6-methoxycarbonylpicolinic acid solid residue.

(3) To the residue obtained in the above reaction (2), add 6.0 m of diphenyl ether, and heat the mixture in an oil bath preheated to 18 CTC for 30 minutes. After allowing to cool to room temperature, the reaction mixture is diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. Extract the organic layer three times with IN hydrochloric acid Put out. Collect the aqueous layer, adjust to ρΗΙΟ.Ο by adding 20% sodium hydroxide, and extract with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.07 g (yield 77%) of methyl 4-benzyloxypicolinate.

_{NMR (CDC1 3) δ: 4.04} (311,5), 5.22 (211,5), 7.08 (111, (11, 1 1 = 2 and 6112), 7.44 (511, in ), 7.80 (lH, d, J = 2Hz), 8.80 (lH, d, J = 6Hz)

IR (KBr) cm ¹ : 1730,1580,1300,1220

 (4) Dissolve 2.62 g (10.8 mmol) of the compound obtained in the above reaction (3) in 52 m of methylene chloride, and dropwise add -1.5 M diisobutylaluminum hydride (toluene solution) 21.6niJ2 (32.4 mmol) at -78 ° C. . After stirring for 1 hour, add 4.6mJ2 of acetic acid. The reaction mixture is warmed to room temperature, then poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After the organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to obtain 2.28 g (yield 99%) of 4-benzyloxy-2-pyridinecarboxaldehyde solid residue.

Testimony _{(CDC1 3) δ: 5.20 (} 2 5), 7.10 (111, (1 (1, 2 and 6112), 7.44 (511, [ 11), 7.60 (111, d, J = 2Hz), 8.62 (lH, (d, J = 6Hz)

IR (KBr) αϊί: 1700, 1580, 1480, 1360, 1300

(5) Dissolve 1.0 g (4.69 mmol) of the compound obtained in the above reaction (4) in dioxane 10ιηβ, and add 1.50 g (4.71 mmol) of acetylmethylene (triphenyl) phosphorane. The reaction solution is stirred at 8 CTC for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ヮ Ko-gel ® C-300, eluted with ethyl acetate-hexane = 1: 3) to give 4- (4-benzyloxy-2-pyridyl) ) 3-buten-2-one 1.76 g (triphenylphosphinoxide Including).

_{NMR (CDC1 3) δ: 2.40} (311,5), 5.16 (211,5), 6.88 (111, (1 (1, 2 and 6¾), 7.10 (lH, d , J = 2Hz), 7.15 (lH, d, J = 16Hz), 7.44 (5H, m), 7.48 (lH, d, J = 16Hz), 8.48 (lH, d, J = 6Hz)

 (6) Dissolve 1.76 g of the compound obtained in the above reaction (5) in 20 m of methanol, and add 0.18 g (4.73 mmol) of sodium borohydride at 0 ° C. After stirring for 1 hour, add 0.5m of acetic acid. Pour the reaction mixture into saturated aqueous sodium bicarbonate and extract with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.90 g of a crude product of 4- (4-benzyl-2-pyridyl) -3-buten-2-ol.

Kasumi _{(CDC1 3) δ: 1.40 (} 3H, d, J = 6Hz), 4.56 (lH, m), 5.12 (2H, s), 6.62 (lH, d, J = 16112), 6.78 (111, (1 ( 1, '' = 2 and 6¾), 6.70 (11 ^ (1, 6 and 16112), 6.90 (111, (1, J = 2 Hz), 7.3 to 7.6 (5H, ni), 8.40 (lH, d, J = 6Hz)

 (7) The same reaction as in Example 27- (2) was carried out from 2.72 g (10.7 mmol) of the compound obtained in the above reaction (6), and 478 mg of 2,3-dihydro-3-methyl-7 (1H) -indolidinone was obtained. (Yield from 4-benzyloxy-2-pyridinecarboxaldehyde in step (4) above: 48%).

_{NMR (DMS0-d 8) 6} : 1.38 (3H, d, J = 6Hz), 1.78 (lH, in), 2.38 (lH, m), 2.9o (2H, m), 4.38 (lH, m), 6.02 (lH, br s), 6.06 (lH, br d, J = 6Hz), 7.76 (lH, d, J = 6Hz)

(8) The same reaction as in Example 27- (3) was carried out using 0.78 g (5.23 mmol) of the compound obtained in the above reaction (7), and 2,3-dihydro-3-methyl-7 (1H)- Obtain 0.44 g (51% yield) of indolizinthion.

Haze (DMS0-d _e ) 6: 1.40 (3H, d, J = 6Hz), 1.90 (lH, m), 2.40 (lH, m), 3.00 (2H, m), 4.35 (111, 111), 7.16 (111, (12 and 6), 7.20 (111, (1, << 1 = 2112), 7.78 (111, 1, 6 Hz) Example 30

 2,3-dihydro-3-methyl-5-diphenylmethyloxycarbonyl-7 (1H) -indridinethione

 (1) Dissolve 5.0 g (27.3 mmol) of 4-hydroxy-2,6-pyridinedicarboxylic acid in a mixture of 50 m12 of methanol and 50 mβ of ethyl acetate, and divide 20 g (0.10 mmol) of diphenyldiazomethane into several portions at room temperature. Add. After stirring for 2 hours, the reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer is dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Ecogel® C-300, eluted with ethyl acetate-hexane = 1: 1) to give 2,6-di (diphenylmethyl). 9.1 g (yield 64%) of crystals of (oxycarbonyl) -4-hydroxypyridine are obtained.

_{NMR (CDC1 3) δ: 7.06} (2H, s), 7.2~7.6 (22H, ra)

(2) Dissolve 3.0 g (5.82 mmol) of the compound obtained in the above reaction (1) in 30 mJ2 of N, N-dimethylformamide, and add 804 mg (5.82 mmol) of potassium carbonate and 1.0 mL (8.8 mmol) of benzyl chloride. . Stir the mixture at 80 ° C for 1 hour. After cooling to room temperature, pour the reaction mixture into water and extract with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Eco-gel ® C-300, eluted with ethyl acetate-hexane = 1: 1) to give di (diphenylmethyl) 4-benzyloxy-2,6-pyridinedicarboxylate. This gives 3.03 g (74% yield) of a solid of the latet. MR (CDCI3) δ: 5.20 (2H, s), 7.16 (2H, s), 7.2 to 7.6 (20H, m), 7.88 (2H, s)

(3) Dissolve 6.Og (9.92 mmol) of the compound obtained in the above reaction (2) in 120 m of methylene chloride, and dropwise add 1.5 M diisobutylaluminum hydride (toluene solution) 19.8πιβ (29.7 mmol) at -78 ° C. I do. After stirring for 30 minutes, add 6 mJ2 of acetic acid. The reaction mixture is allowed to warm to room temperature, then poured into saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in dioxane 40DIJU, acetylmethylene (triphenyl) phosphorane 3.15 g (9.90 mmol) is added, and the mixture is stirred at 80 ° C for 30 minutes. The reaction solution is concentrated under reduced pressure, and the precipitated crystals are washed with a mixed solution of methylene chloride-ethyl acetate, and washed with 4- (4-benzyloxy-6-diphenylmethyloxycarbonyl-2-pyridyl) -3-butene- 2.17 g of 2-one (47% yield) are obtained.

 (4) 830 mg (1.79 mmol) of the compound obtained in the above reaction (3) is suspended in a mixture of methanol 10 mH and methylene chloride 4πι £, and 150 mg (3.95 mmol) of sodium borohydride is added at room temperature. After stirring for 1 hour, add 0.5 ml of acetic acid. Pour the reaction mixture into saturated aqueous sodium bicarbonate and extract with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, and the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ヮ Ko-gel ® C-300, eluted with ethyl acetate-hexane = 1: 2) to give 4- (4-benzyloxy-6-diphenylmethyloxycarbonyl-2 -Pyridyl) -3-buten-2-ol (321 mg, yield 38%) was obtained.

Haze (CDC1J δ: 1.42 (3H, d, J = 6Hz), 4.60 (lH, m), 5.20 (2H, s), 6.76 (lH, d, J = 16 ^), 6.94 (111, (11,5 16), 7.05 (111, (1, 2), 7.18 (111, 5), 7.2 to 7.6 (15H, m), 7.62 (lH, d, J = 2Hz)

(5) 780 mg (1.68 mmol) of the compound obtained in the above reaction (4) was added to methanol 16 Dissolve mJH, add 70 nig of 10% palladium on carbon catalyst and carry out catalytic reduction at room temperature for 30 minutes. After filtering off the catalyst, add 326 nig (1.68 mmol) of diphenyldiazomethane to the filtrate and stir the mixture for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ヮ Ko-gel ® C-300, eluted with 5% methanol-methylene monochloride) to give 6- (3-hydroxybutyl) -2 This gives 512 mg (81% yield) of -diphenylmethyloxycarbonyl-4-hydroxypyridine.

_{NMR (CDC1 3) δ: 1.22} (3H, d, J = 6Hz), 1.6~2.0 (2H, ni), 2.78 (2H, ni), 3.92

 (lH, m), 6.48 (lH, d, J = 2Hz), 7.02 (lH, s), 7.1 to 7.8 (lH, m)

 (6) Dissolve 512 mg (1.36 mmol) of the compound obtained in the above reaction (5) in 10 ml of tetrahydrofuran, and add 356 mg (1.36 mmol) of triphenylphosphine and 236 mg (1.36 mmol) of getyl azodicarboxylate under eternal cooling. After stirring at room temperature for 10 minutes, the same amounts of triphenylphosphine and acetyldicarboxylate are added again under water cooling, and the reaction solution is stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Pelcogel ® C — 300, eluted with 5% methanol-methylene monochloride) to give 2,3-dihydro-3-methyl- 5-diphenylmethyloxycarbonyl-7 (1H) -indolidinone 363mg

(74% yield).

Awake (CDCla) δ: 1.20 (3H, d, J = 6 Hz), 1.96 (lH, m), 2.32 (lH, m), 3.00 (2H, m), 5.42 (lH, m), 6.46 (lH, br s), 7.04 (lH, s), 7.2 to 7.6 (10H, m)

(7) Dissolve 350 mg (0.97 mmol) of the compound obtained in the above reaction (6) in 3.6 m fi of pyridine, and add 449 mg (2.02 mmol) of phosphorus pentasulfide. Stir the mixture at 100 ° C for 30 minutes. After allowing the reaction mixture to cool, the solvent was distilled off under reduced pressure. 2,3-dihydro-3-methyl-5-diphenylmethyloxycarbonyl -7 (1H) -India by thin-layer chromatography (Merk Art 5717, developed with 5% methanol-methylene chloride) 235 mg (65% yield) of lysine thione are obtained.

囊_{(CDC1 3) δ: 1.22 (} 3H, d, J = 6Hz), 1.98 (lH, m), 2.38 (lH, m), 3.04 (2H, m), 5.54 (lH, m), 7.06 (lH, s), 7.2 to 7.6 (llH, m), 8.16 (lH, br s) Example 31

 2,3-dihydro-6-methoxy-3-methyl-7 (1H) -indolizinethione

 (1) 9.2 g (5.4 mmol) of 2-carboxy-5-methoxy-4-pyrone is stirred with 30 ml of concentrated ammonia water at 100 ° C. overnight. After allowing to cool, the solvent is distilled off under reduced pressure. The residue is washed with a mixed solution of ethyl acetate-methanol to obtain 4.73 g (yield: 52%) of 2-carboxy-5-methoxy-4-pyridone solid.

NR (DMS0-d ₆ ) δ: 3.66 (3H, s), 6.52 (lH, s), 7.16 (lH, br s)

 (2) Dissolve 2.73 g (1.6 mmol) of the compound obtained in the above reaction (1) in 27 mL of N, N-dimethylformamide, and add 6.6 g (4.8 mmol) of potassium carbonate and 5.6 mfi (4.8 mmol) of benzyl chloride. . Stir the mixture at 80 ° C for 1 hour. After cooling, pour the reaction mixture into water and extract with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue was washed with ethyl acetate and benzyl 4-benzyloxy-5-methoxypicolinate 2.45 g

(43% yield).

NMR (D S0-d _B ) δ: 4.02 (3H, s), 5.22 (2H, s), 5.42 (2H, s), 7.2 to 7.6 (10H, m), 7.76 (lH, s), 8.28 (lH , S)

(3) The same reaction as in Example 30- (3) was performed using 2.45 g of the compound obtained in the above reaction (2). The reaction yields 2.24 g of 4- (4-benzyloxy-5-methoxy-2-pyridyl) -3-buten-2-one (containing a small amount of triphenylphosphinoxide).

Orchid (CDCla) δ: 2.38 (3H, s), 4.00 (3H, s), 5.22

 (2H, s), 6.g4 (lH, d, J = 16Hz), 7.08 (lH, s), 7.3 to 7.6 (6H, m), 8.20 (lH, s)

(4) The same reaction as in Example 30- (4) was carried out from 2.24 g of the crude product obtained in the above reaction (3) to give 4- (4-benzyloxy-5-methoxy-2-pyridyl) -3- 0.83 g of butene-2-ol (yield from 2-carboxy-5-methoxy-4-pyridone in step (2) above: 37%) is obtained.

Flame _{(CDC1 3) 5: 1.35 (} 3H, d, J = 6Hz), 3.94 (3H, s), 4.50 (lH, m), 5.20 (2H, s), 6.54 (2H, m), 6.8 (lH, s), 7.3 to 7.6 (5H, m), 8.08 (lH, s)

 (5) 0.83 g of the compound obtained in the above reaction (4) The same reaction as in Example 29- (7) was performed, and 2,3-dihydro-6-methoxy-3-methyl-7 (1H)- Indolidinone 481 rag (93% yield) is obtained.

Negation _{(CD 3 0D + CDC1 3)} δ: 2.55 (3H, d, J = 6Hz), 2.00 (lH, m), 2.56 (lH, ni), 3.10 (2H, m), 3.86 (3H, s), 4.56 (lH, m), 6.42 (lH, br s), 7.36 (lH, s)

 (6) The same reaction as in Example 27- (3) was carried out from 481 mg of the compound obtained in the above reaction (5), and 2,3-dihydro-6-methoxy-3-methyl-7 (1H) -indolizinethione was obtained. 294 mg (56% yield) are obtained.

Thigh _{(CD 3 0D + CDC1 3)} δ: 1.60 (3H, d, J = 6Hz), 2.05 (lH, m), 2.58 (lH, ni), 3.16 (! 2H m), 3.92 (3H, s), 4.62 (lH, m), 7.32 (lH, s), 7.70 (lH, s) Example 32

 3,4-dihydro-8 (1H) -pyrido [2,1-c] [1,4] oxazinethione

 (1) To 20 ml of a tetrahydrofuran solution containing 156 mg (4.10 mmol) of lithium aluminum hydride was added 1.0 g (4.11 mmol) of methyl 4-benzyloxypicolinate at -78 ° C, and the reaction mixture was stirred for 15 minutes. Stir. Add ethyl acetate to the reaction mixture. After the mixture is warmed to room temperature, it is washed with saturated aqueous sodium hydrogen carbonate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Dissolve the residue in acetic acid 5.0πι, and add sodium cyanoborohydride 0.26g (4.14mmol) at room temperature. After stirring the reaction mixture for 30 minutes, the solvent is distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate are added to the residue, and the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.85 g (yield: 96%) of 4-benzyl-2-hydroxymethylpyridin solid.

_{MR (CDC1 3) a: 4.72} (2H, br s), 5.12 (2H, s), 6.82 (lH, br d, J = 6Hz), 6.86 (1H, br s), 7.42 (5H, m), 8.38 (lH, d, J = 6Hz)

IR (KBr) cm ¹ : 3200,1600,1310,1010

 (2) Dissolve 1.92 g (8.93 mmol) of the compound obtained in the above reaction (1) in 20 m of methylene chloride, and add 1.0 ml of thionyl chloride (13.7 mmol). Under water cooling, 0.70 mJ2 (8.86 mmol) of pyridine is added dropwise, and the mixture is stirred for 30 minutes. The reaction solution is poured into a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.54 g (yield: 74%) of crude 4-benzyl-2-chloromethylpyridine.

(3) 1.2 g (5.14 mmol) of the crude product obtained in the above reaction (2) and 1.0 g (6.6 mmol) of sodium iodide are suspended in 3.0 mJ2 of N, N-dimethylformamide. Dissolve 1.2 g (7.89 mmol) of 2-benzyloxyethanol in 24πιβ of N, N-dimethylformamide, add 1.90 g (39.6 mmol) of 50% sodium hydride at room temperature, and add this mixture to the above mixture. Add the suspension. After stirring at room temperature for 30 minutes, pour the reaction solution into water and extract with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ヮ Ko-gel ® C-300, eluted with ethyl acetate-hexane = 1: 1) to give 4-benzyloxy-2- (2-benzyloxyethoxymethyl) pyridine 1.56 g (87% yield).

_{MR (CDC1 3) δ: 3.75} (2H, m), 3.78 (2H, m), 4.62 (2H, s), 4.70 (2H, s), 5.10 (2H, 5), 6.80 (111, (1 [1 , = 2 and 6), 7.16 (111, (1,) = 2112), 7.2 ~ 7.6 (1011,111), 8.38 (lH, d, J = 6Hz)

 (4) Dissolve 200 mg (0.57 mmol) of the compound obtained in the above reaction (3) in 4.0 mfi of ethanol, and add 40 nig of 10% palladium on carbon catalyst. Perform catalytic reduction at 80 ° C for 3 hours. The catalyst is removed by filtration, and the solvent is distilled off under reduced pressure to obtain a residue of 2- (2-hydroxyethoxymethyl) -4-pyridone.

 (5) Dissolve the residue obtained in the above reaction (4) and 264 mg (1.41 mmol) of triphenylphosphine in 2.0 mL of tetrahydrofuran, and add dropwise 10 nig (1.03 mmol) of getyl azodicarboxylate at room temperature. After stirring for 1 hour, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (MerkArt5717, developed with 10% methanol in methylene monochloride) to give 70 mg of 3,4-dihydro-8 (1H) -pyrido [2, lc] [1,4] oxazinone. .

_{NMR (DMS0-d 6) δ} : 3.98 (2H, m), 4.02 (2H, m), 4.64 (2H, s), 5.96 (lH, d, J = 2Hz), 6.10 (111, ^, 2 and 6¾ ), 7.58 (111, (1, 6¾) (6) The same reaction as in Example 27- (3) was carried out on 0.74 g (4.90 mmol) of the compound obtained in the above reaction (5), and 3,4-dihydro-8 (1H) -pyrido [2,1 -c] [1,4] oxazine thione 470mg (57% yield).

NMR (DMS0-d _B ) δ 4.04 (4H, s), 4.70 (2H, s), 7.06 (lH, d, J = 2 Hz), 7.10 (lH, dd, J = 2 and 6 Hz), 7.54 (lH, d, J = 6Hz) Industrial applicability

 The compound of the present invention is a novel compound that has not been described in the literature. It has unexpectedly strong antibacterial activity, has excellent stability against lactamase, and is effective as an antibacterial agent.

(Hereinafter the margin)

Claims

The scope of the claims

 (1) General formula

H ₂ N

(In the formula, R ¹ may have a hydrogen atom or a substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group, A is a single bond or a nitrogen atom, an oxygen atom and a sulfur atom. A hetero atom selected from the group consisting of: m represents an integer of 0 to 3; n represents an integer of 2 or 3; Provided that the pyridine ring and the bicyclic heterocyclic group formed by the cyclic side chain thereof may be replaced by the same or different 1 to 3 substituents.) Salt or ester.

(2) R ¹ may have a substituent selected from the group consisting of a hydrogen atom or a lower alkoxy group, a lower alkanoyloxy group, a hydroxyl group, a carboxyl group, a carbamoyl group, a sulfo group and a halogen atom. A lower alkenyl group optionally having a substituent selected from the group consisting of an alkyl group, a carboxy group, a carbamoyl group and a sulfo group, a lower alkynyl group optionally having a carboxyl group or a sulfo group, a hydroxyl group, 2. The compound according to claim 1, which is an aralkyl group which may have a substituent selected from the group consisting of a lower alkanoyloxy group, a carboxyl group, a sulfo group and a sulfo lower alkyl group.

(3) R ¹ is hydrogen atom or methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, Isopentyl group, hexyl group, isohexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, 2 -Chloroethyl group, 2-Fluoroethyl group, 2,2-Difluoroethyl group, 2,2,2-Trifluoroethyl group, 2-Bromoethyl group, Carboxymethyl group, 1-force Ruboxexetyl group, Forcebamoylmethyl group, 1 -Rubamoylethyl group, 1-Rupoxy-1-methylethyl group, 1-Rubamoyl-1-methylethyl group, 2-carboxyshetyl group, 2-Lumbamoylethyl group, 3-carboxypropyl group, 2-carboxypropyl group, 1- Carboxypropyl group, 3-force rubamoyl propyl group, 2-force rubamoyl propyl group, 1-force rubamoyl 1-carboxycyclopropyl, 1-carbamoylcyclopropyl, 1-carboxycyclobutyl, 1-carbamoylcyclobutyl, 1-carboxycyclopentyl, 1-carbamoylcyclopentyl, 1 -Carboxycyclohexyl group, 1-carbamoylcyclohexyl group, 1-sulfocyclohexyl group, 1-sulfocyclopentyl group, 1-sulfocyclobutyl group, 1-sulfocyclopropyl group, sulfomethyl group, 2 A lower alkyl group which may have a substituent selected from the group consisting of -sulfoethyl group, 1-sulfoethyl group, 3-sulfopropyl group, 2-sulfopropyl group and 1-sulfopropyl group, vinyl group, Propenyl group, aryl group, 1-methylvinyl group, 2-methyl-1-propenyl group, 1,3-butadienyl group, 1,1-dimethylaryl Group, 2-butenyl group, 3-butenyl group, 3-methylbutenyl group, 1-force propyloxyvinyl group, 2-carboxyvinyl group, 1-carboxy-topropenyl group, 2-carboxy-1-propenyl group, 3-carboxy-1-propenyl, 1-carboxy-2-methyl-1-propenyl, tricarboxyaryl, 2-carboxyaryl Group, 3-carboxyaryl group, tricarboxy-3-butenyl group, tricarboxy-3-methyl-2-butenyl group, 1-sulfovinyl group, 1-rubumboylvinyl group, trisulfoallyl group, tricarbamoylaryl group, It may have a substituent selected from the group consisting of 3-carboxy-1, tridimethylaryl, 3-sulfo-1,1-dimethylaryl and 3-carbamyl-1,1-dimethylaryl. Lower alkenyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1, tridimethyl-2-propynyl group, 2-carboxyethynyl group, 2-sulfethynyl group, 1-carboxy-2-propynyl group, Having a substituent selected from the group consisting of 1-sulfo-2-propynyl, 3-carboxy-1,1-dimethyl-2-propynyl and 3-sulfo-1,1-dimethyl-2-propynyl Low-grade alky Or benzyl group, phenethyl group, 3-carboxyphenethyl group, 1-carboxy-3-phenylpropyl group, α-carboxy-1-naphthylmethyl group, α-carboxynaphthylmethyl group, 3-hydroxy Benzyl group, 4-hydroxybenzyl group, 3-acetoxybenzyl group, 4-acetoxybenzyl group, 2-carboxybenzyl group, 3-carboxybenzyl group, 4-carboxybenzyl group, 2-carboxymethylbenzyl group , 3-carboxymethylbenzyl, 4-carboxymethylbenzyl, 2-sulfobenzyl, 3-sulfobenzyl, 4-sulfobenzyl, 2-sulfomethylbenzyl, 3-sulfomethylbenzyl, 4 -Sulfomethylbenzyl group, 3-carboxy-4-hydroxybenzyl group, 3,4-dihydroxybenzyl group, 3,4-diacetoxybenzyl group, 3,4,5- Rehydroxybenzyl group, 3,4,5-triacetoxybenzyl group, α-carboxybenzyl group, α-carboxy-3-hydroxybenzyl group, carboxy-4-hydroxybenzyl group, α-carboxy-3-acetoxybenzyl group Α-carboxy-4-acetoxybenzyl group, α-carboxy-3, 4-dihydroxybenzyl group, α-carboxy-3,4-diacetoxybenzyl group, α-carboxy-3,4,5-trihydroxybenzyl group and α-carboxy-3,4,5-triacetoxybenzyl group The compound according to claim 1, which is an aralkyl group which may have a substituent selected from the group consisting of:

 (4) The compound according to claim 1, wherein Α is a single bond or an oxygen atom.

 (5) The compound according to claim 1, wherein m is 1 and n is 2.

 (6) The compound according to claim 1, wherein A is a single bond or an oxygen atom, m is 1, and n is 2.

 (7) 7β-[(Ζ) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(6,7,8,9-Tetrahydroquinolidinium-2 -Yl) thiomethyl] -3-cef-4-carboxylate,

Ίβ-ί (Ζ) -2- (2-Aminothiazole-4-yl) -2- (1-carboxy-1-methylethoxyimid J) acetamide] -3-[(6,7,8,9- Tetrahydroquinolidinium-2-yl) thiomethyl] -3-cefm-4-carboxylate,

7β-[(Ζ) -2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3--[(6,7,8,9-tetrahydroquinolidinium-2- Yl) thiomethyl] -3-cef-4-carboxylate,

Ίβ-[(Ζ) -2- (2-Aminothiazol-4-yl) -2-[(1S) -1-Carboxy shetoxyimino] acetamide] -3-[(6,7,8,9 -Tetrahydroxy J-Ridinidium-2-yl) thiomethyl] -3-cefm-4-carboxylate,

7β-C (Z) -2- (2-aminothiazole-4-yl) -2-carboxyvinyl Oxyimino) acetamide] -3- [(6,7,3,9-tetrahydroquinolizindium-2-yl) thiomethyl] -3-cefm-4-carboxylate,

7β-[(Ζ) -2- (2-Aminothiazole-4-yl) -2- (1-carboxymethoximino) acetamide] -3-[(6,7,8,9-tetrahydroquinolizini) M-2-yl) thiomethyl] -3-cef-4-carboxylate,

7β-[(Ζ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(3,4-dihydro-1H-pyrido [2,: L-c ] [1,4] oxazinium-8-yl) thiomethyl] -3-cefm-4-carboxylate,

7β-C (Z) -2- (2-aminothiazole-4-yl) -2- (tricarboxy-1-methyl ethoxyimino) acetamide] -3-[(3,4-dihydro- ( 1H) -pyrido [2, 1-c] [1,4] oxazinidine -8-yl) thiomethyl] -3-cefm -4-carboxylate,

 , Β-[(Ζ) -2- (2-Aminothiazol-4-yl) -2-[(1S) -tricarboxyethoxyimino] acetamide] -3--[(3,4 dihydro-1H- Pyrido [2,; LC] [1,4] oxazinium-8-yl) thiomethyl] -3-cefm-4-carboxyla

Ίβ-[(Ζ) -2- (2-aminothiazol-4-yl) -2-carboxyvinyloxyimino) acetamide] -3-[(3,4-dihydro-1H-pyrido [2 ,; Lc] [1,4] oxazidin-8-yl) thiomethyl] -3-cef-4-carboxylate,

7jS-[(Z) -2- (2-aminothiazole-4-yl) -2-methoxyiminoaceto Amide] -3-[(2,3-dihydro-1H-indolizinid-7-yl) thiomethyl] -3-cef-4-carboxylate,

7β-Ε (Ζ) -2- (2-aminothiazol-4-yl) -1-(tricarboxy-1-methylethoxyimino) acetoamide] -3- [(2,3-dihydro-1H -Indolizindium-7-yl) thiomethyl] -3-cef-4-carboxylate,

7 / 3- [(Ζ) -2- (2-Aminothiazol-4-yl) -2-[(1S)-: i-Rolepoxyethoxyimino] acetamide] -3-[(2,3 -Dihydro-1H-indolizinium-7-yl) thiomethyl] -3-cef-4-carboxylate,

1 β-C (Z) -2- (2-Aminothiazol-4-yl) -2-α-carboxyvinyloxyimino) acetoamide] —3-[(2,3-Dihydro-1H-indolizinium-7) -Yl) thiomethyl] -3 -sefm-4-carboxylate,

Ίβ-[(Ζ) —2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(2,3-dihydro-3-methyl-1Η-indolizinium-7- Yl) thiomethyl] -3-sefm-4-carboxylate,

7jS- C (Z) -2-(2-Aminothiazole-4-yl) -2-methoxyiminoacetoamide] -3-[(2,3-dihydro-3-methyl-1H-indolizinium-7 -Yl) thiomethyl] -3-cef-4-carboxylate,

7 / S-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3-[(2,3 -Dihydro-3-methyl-1H-indridinium-7-yl) thiomethyl] -3-cef-4-carboxylate, Ίβ-[(Ζ) -2- (2-Aminothiazol-4-yl) -2-[(1S) -l-Hydroxy shetoxyimino] acetamide] -3-[(2,3-dihydro- 3-methyl-1H-indridinium-7-yl) thiomethyl] -3-cef-4_carboxylate,

7/3-[(Z) -2- (2-Aminothiazol-4-yl) -2-α-carboxyvinyloxyimino) acetamide] -3-[(2,3-dihydro-3-methyl- 1Η-indolinidin-7-yl) thiomethyl] -3-cef-4-carboxylate,

7 / S- [(Ζ)-2- (2-Aminothiazole-4-yl) -2-carboxymethoxyminoacetamide] -3-[(2,3-dihydro-3-methyl-1H-indolizinium -Aryl) thiomethyl] _3-cef-4-carboxylate,

7 / S-[(Ζ) -2- (2-Aminothiazole-4-yl) -2- (α-carboxybenziloximino) acetamide] -3-([2,3-dihydro-3-methyl) -1Η-Indridinium-7-yl) thiomethyl] -3-cef-4-carboxylate,

7 / 3- [(Ζ) -2-(2-Aminothiazol-4-yl) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) acetamide] -3- [( 2,3-dihydro-3-methyl-1Η-indolizinid-7-yl) thiomethyl] -3-cefem-4-hexyloxylate,

Ίβ-[(Ζ) -2- (2-Aminothiazol-4-yl) —2-methoxyiminoacetamide] -3- (5-carboxy-2,3-dihydro-3-methyl- 1H-indolizinum-7-yl) thiomethyl] -3-cef-4-carboxylate,

7β-[(Ζ) -2- (2-aminothiazol-1-yl) -2--2- (carboxy-1-methyl) Tylethoxyimino) acetoamide] -3-[(5-carboxy-2,3-dihydro-3-methyl-1H-indolizinum-7-yl) thiomethyl] -3-cefum-4-carboxylate

Ίβ-[(Ζ) -2- (2-aminothiazoyl-4-yl) -2--2-methoxyiminoacetamide] -3-[(2,3-dihydro-6-methoxy-3-methyl-1H- Indolidin-7-yl) thiomethyl] -3-cef-4-carboxylate and β-[(Ζ) -2- (2-aminothiazol-4-yl) -2-bi-carboxy-1-meth Tylethoxyimino) acetamide] -3-[(2,3-dihydro-6-methoxy-3-methyl-1Η-indolizinum-7-yl) thiomethyl] -3-cefem-4-carboxylate A compound according to claim 1.

(Hereinafter the margin)

(8) General formula

(H)

[Wherein, R ³ is a hydrogen atom or an amino-protecting group, R ⁴ is a hydrogen atom, which may have a protected substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or an aralkyl. R ⁵ is a hydrogen atom or a carboxyl protecting group, and X is a leaving group.)

[In the formula, A represents a single bond or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, m represents an integer of 0 to 3, and n represents an integer of 2 or 3. Provided that the pyridine ring and the bicyclic heterocyclic ring formed by the cyclic side chain thereof may be the same or different, and may be substituted with 1 to 3 appropriately protected protecting groups. Reacting the compound with the general formula

(IV)

[Wherein, R ³ , RRA, m and n have the above-mentioned meanings, and ΧΘ means an yion. However, a bicyclic heterocyclic ring formed by a pyridine ring and its cyclic side chain May be substituted with the same or different 1 to 3 substituents which may be protected as appropriate.)

 (i) Step of removing a protecting group

 (ii) converting the free acid to its non-toxic salt

 (iii) a step of converting a free acid into a non-toxic ester hydrolyzable in the living body, characterized by performing one or more of the above steps;

(I)

[In the formula, R ¹ may have a hydrogen atom or a substituent, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group, and A, m and n have the above-mentioned meanings. However, the bicyclic complex formed by the pyridine ring and its cyclic side chain may be substituted by the same or different 1 to 3 substituents.) A method for producing a salt or ester.

(Hereinafter the margin)

(9) General formula

Wherein R ¹ is a hydrogen atom or an optionally substituted lower alkyl group, a lower alkenyl group, a lower alkynyl group or an aralkyl group, and A is a single bond or a nitrogen atom, an oxygen atom and a sulfur atom. A heteroatom selected from the group consisting of: m represents an integer of 0 to 3; n represents an integer of 2 or 3; Provided that the pyridine ring and the bicyclic heterocyclic group formed by the cyclic side chain thereof may be substituted with the same or different 1 to 3 substituents.) Or a pharmaceutically acceptable salt thereof. Or, an antibacterial agent containing ester as an active ingredient.

(10) — General formula

[In the formula, A represents a single bond or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, m represents an integer of 0 to 3, and n represents an integer of 2 or 3. Provided that the pyridine ring and the bicyclic heterocyclic ring formed by the cyclic side chain thereof may be substituted with the same or different 1 to 3 substituents which may be appropriately protected.) Or a salt thereof.