JPH01290683A - Dicyclic heterocyclic thiomethylcephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is H, (substituted) lower alkyl, (substituted) alkenyl, etc.; R<2> is H, negative charge or ester residue; A alkylene which may contain unsaturated bond; dicyclic hetero ring formed from pyridine ring and group A may contain 1-3 substituent groups]. EXAMPLE:7beta-[(Z)-2-(2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (6, 7, 8, 9-tetrahydroquinolizinium-2-yl) thiomethyl-3-cephem-4-carboxylate. USE:An antibacterial agent against Gram-positive bacteria including Staphylococcus aureus having methicillin resistanceand Gram-negative bacteria including Pseudomonas aeruginosa. PREPARATION:A compound shown by formula II (R<3> is N or amino-protecting group; R<4> is H, lower alkyl, etc.; R<5> is H, carboxyl-protecting group, etc.; X is eliminable group) is reacted with a compound shown by formula III (ring B is alkylene) to give a compound shown by formula IV (X<-> is anion).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel cephalosporin derivative useful in the pharmaceutical field, a method for producing the same, an intermediate for producing the same, and an antibacterial agent containing the compound as an active ingredient. It is.

Prior Art Conventionally, 2-(2-aminothiazol-4-yl)-2-f! is attached to the 7-position side chain of the cephem nucleus. A large number of compounds having a substituted oxyiminoacetamide group have been synthesized, and published techniques describing them include, for example, JP-A-52-10
No. 2293, No. 52-116492, No. 53-137
No. 988, No. 54-9296, No. 54-154786
No. 54-157596, No. 55-154980, No. 56-86187, No. 57-59895, No. 5
No. 7-99592, No. 57-192394 and No. 58
-174387, etc., and includes Gram-negative bacteria and Pseudomonas asruginos.
It also shows activity against cephalosporin-resistant Gram-negative bacteria, including a), and is suggested to have excellent antibacterial activity and a broad antibacterial spectrum.

However, the antibacterial activity of these compounds is limited to Gram-negative bacteria such as methicillin-resistant Staphylococcus aureus, as well as Pseudomonas aeruginosa and Pseudomonas cepacia.
cepacia), Pseudomonas maltophilia
and Acinetobacter calcoaceticus (Acfne
glucose non-fermenting Durham-negative rods such as Tobacterium tobacterium
-fermentative grand-negat
iverods).

Problems to be Solved by the Invention β-lactam antibiotics exhibit selective toxicity only to bacteria;
Since it does not affect animal cells, it is a highly useful antibiotic that is widely used in the treatment of bacterial infections with few side effects.

However, in recent years, glucose non-fermenting Durum-negative bacilli,
In particular, Pseudomonas aeruginosa and, moreover, methicillin-resistant Staphylococcus aureus are often isolated from immunocompromised patients as causative agents of refractory infections, posing various problems. Therefore, it is desired to develop an antibacterial agent having improved antibacterial activity against these bacteria.

Means for Solving the Problem The present inventors aimed to create a cephalosporin derivative that has strong antibacterial activity against Gram-negative bacteria such as methicillin-resistant Staphylococcus aureus and Gram-negative bacteria such as Pseudomonas aeruginosa. As a result of extensive research, we have found that a new cephalosporin derivative, indicated by the symbol (r) below, has excellent antibacterial activity against Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. The present invention was completed by discovering that

That is, the present invention provides a novel general formula, [wherein R1 is a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, R' is a hydrogen atom, a negative charge, or an ester residue that forms a nontoxic ester that can be hydrolyzed in the living body. A represents an alkylene group that may contain an unsaturated bond (the carbon atom of the alkylene group may be replaced with at least one of an oxygen atom, a sulfur atom, or a nitrogen atom), and The bicyclic heterocycle formed by the pyridine ring and group A may have the same or different substituents or 3 substituents, or a non-toxic salt thereof, a method for producing the same, and The use of the compound as an antibacterial agent, and the new general formula [wherein R1 is a hydrogen atom, a protecting group for an amino group, or a lower alkyl group that may have a substituent, a lower alkenyl group that may have a protected substituent, a lower alkynyl group that may have a protected substituent, or a protected substituent. (respectively represents an aralkyl group which may have a group), R' is a hydrogen atom, a negative charge or a protecting group for a carboxyl group, and group B is an alkylene group which may contain an unsaturated bond. group (in addition, the carbon atom of the alkylene group is an oxygen atom,
The bicyclic heterocycle formed by the pyridine ring and Group B has the same or different groups or three substituents. (The substituent may be protected)] or a non-toxic salt thereof; and a new general formula [wherein group B has the above meaning]; It concerns the compounds represented and their use as production intermediates.

Next, definitions of various terms mentioned in the description of this specification and appropriate examples thereof will be explained.

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, e.g. a lower alkanoyloxy group having 2 to 4 carbon atoms such as an acetoxy group, a propionyloxy group or a butyryloxy group,
Optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a carboxyl group, a carbamoyl group, a sulfo group, and a halogen atom such as a chlorine atom, a bromine atom, or a fluorine atom, and has 1 to 3 carbon atoms. It means 6 straight chain, branched or cyclic lower alkyl groups. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec-butyl group, tert-butyl group, pentyl group, impentyl 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-carboxyethyl group, carbamoylmethyl group, 1-carbamoylethyl group, l-carboxy-
1-methylethyl group, ■-carbamoyl-1-methylethyl group, 2-carboxyethyl group.

2-carbamoylethyl group, 3-carboxypropyl group, 2-carboxypropyl group, l-carboxypropyl group, 3-carbamoylpropyl group, 2-carbamoylpropyl group, ■-carbamoyl°propyl group, l-carboxycyclopropyl group , 1-carbamoylcyclopropyl group, 1-carboxycyclobutyl group, 1-carbamoylcyclobutyl group, 1-carboxycyclopentyl group,
l-carbamoylcyclopentyl group, 1-carboxycyclohexyl group, 1-carbamoylcyclohexyl group,
l-sulfocyclohexyl group, l-sulfocyclopentyl group, 1-sulfocyclobutyl group, 1-sulfocyclopropyl group, sulfomethyl group, 2-sulfoethyl group, 1-
Sulfoethyl group.

3-sulfopropyl group, 2-sulfopropyl group or i-
Examples include sulfopropyl group.

The lower alkenyl group which may have a substituent means, for example, a lower alkenyl group having 2 to 6 carbon atoms which may be substituted with a substituent such as a carboxyl group, a carbamoyl group or a sulfo group.

Specific examples of the alkenyl group include vinyl group, l
-propenyl group, allyl group, 1-methylvinyl group, 2-
Methyl-1-propenyl group, 1,3-butadienyl group,
■, 1-dimethylallyl group, 2-butenyl group, 3-butenyl group, 3-methylbutenyl group, 1-carboxyvinyl group, 2-carboxyvinyl group, l-carboxy-1-propenyl group, 2-carboxy-1- Propenyl group.

3-carboxy-1-propenyl group, l-carboxy-
2-methyl-1-propenyl group, l-carboxyallyl group, 2-carboxyallyl group, 3-carboxyallyl group, 1-carboxy-3-butenyl group, ■-carboxy-3-methyl-2-butenyl group, 1-sulfovinyl base, 1
-Carbamoyl vinyl group, l-sulfoallyl group, l-carbamoylallyl group, 3-carboxy-1,1-dimethylallyl group, 3-sulfo-1,1-dimethylallyl group or 3-carbamoyl-1,1-dimethylallyl group Examples include groups.

The lower alkynyl group which may have a substituent is, for example, an ethynyl group which may be substituted with a substituent such as a carboxyl group or a sulfo group.

It means a lower alkynyl group having 2 to 6 carbon atoms such as 1-propynyl group, 2-propynyl group, or 1,1-dimethyl-2-propynyl group. Specific examples of the alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl group, 1,1-dimethyl-2-propynyl group, 2-
Carboxyethynyl group, 2-sulfoethynyl group, ■-carboxy2-propynyl group, ■-sulfo-2-propynyl group, 3-carboxy-1,1-dimethyl-2-propynyl group or 3-sulfo-1,1-dimethyl -2-propynyl group and the like.

The aralkyl group which may have a substituent is, for example, one to four substituents selected from the group consisting of a hydroxyl group, an acetoxy group, a propionyloxy group, a carboxy group, a sulfo group, a carboxymethyl group, a sulfomethyl group, etc. means an aralkyl group having 7 to 11 carbon atoms, such as a benzyl group, a phenethyl group, a 3-phenylpropyl group, or a naphthylmethyl group, which may be substituted with . Specific examples of the aralkyl group include benzyl group, phenethyl group, β-carboxyphenethyl group, l-carboxy-3-phenylpropyl group, α-carboxy-1-naphthylmethyl group, α-carboxynaphthylmethyl group, −
Hydroxybenzyl group, 4-hydroxybenzyl group, 3
-acetoxybenzyl group, 4-acetoxybenzyl group,
2-carboxybenzyl group, 3-carboxybenzyl group, 4-carboxybenzyl group, 2-carboxymethylbenzyl group, 3-carboxymethylbenzyl group, 4-carboxymethylbenzyl group, 2-sulfobenzyl group, 3-
Sulfobenzyl group, 4-sulfobenzyl group, 2-sulfomethylbenzyl group, 3-sulfomethylbenzyl group, 4-
Sulfomethylbenzyl group, 3-carboxy-4-hydroxybenzyl group, 3,4-dihydroxybenzyl group, 3
, 4-diacetoxybenzyl group, 3,4.5-trihydroxybenzyl group, 3.4.5-triacetoxypencyl group, α-carboxybenzyl group, α-carboxy-3
-hydroxybenzyl group, α-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-
Examples include carboxy-3,4,5-trihydroxybenzyl group and α-carboxy-3,4,5-triacetoxybenzyl group.

Examples of ester residues that form nontoxic esters that can be hydrolyzed in vivo include alkanoyloxymethyl groups such as acetoxymethyl groups and pivaloyloxymethyl groups;
Alkoxycarbonyloxyalkyl groups such as 1-(ethoxycarbonyloxy)ethyl group and 1-(isopropoxycarbonyloxy)ethyl group, phthalidyl group, such as (5-methyl-2-oxo-1,3-oxol-4-
(5-substituted-2-oxo-1,3-
Examples include dioxol-4-yl)methyl group.

What is the alkylene group that may contain an unsaturated bond represented by group A (the carbon atom of the alkylene group may be replaced with at least one of an oxygen atom, a sulfur atom, or a nitrogen atom)? .

It is an alkylene group containing 3 to 5 carbon atoms, and the carbon atom of the alkylene group is substituted with at least one of oxygen atom, sulfur atom, or nitrogen atom, and the single bond between carbon atoms of the alkylene group A specific example of the alkylene group which may be substituted with an unsaturated bond such as a double bond is shown as a bicyclic heterocyclic group formed by group A and a pyridine ring.

Further, the bicyclic heterocyclic group includes, for example, a methyl group, an ethyl group,
Lower alkyl groups having 1 to 4 carbon atoms such as propyl group, isopropyl group, butyl group, isobutyl group or term-butyl group, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group or a lower alkoxy group having 1 to 4 carbon atoms such as a tert-butoxy group, a formyl group, a carboxyl group, a carbamoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an N-methylcarbamoyl group, or a hydroxyl group. - or may have 1 to 3 different substituents.

Specific examples of the bicyclic heterocyclic group include IH-indolizinium-7-yl group, 2,3-dihydro-IH-
indolizinium-7-yl group, 2,3-dihydro-3
-methyl-IH-indolizinium-7-yl group, 2,
3-dihydro-6-medoxy-3-methyl-IH-indolizinium-7-yl group, 5-carboxy-2,3-
dihydro-3-methyl-IH-indolizinium-7-
yl group, quinolidinium-3-yl group, 6,7,8.9
-tetrahydroquinolidinium-2-yl group, 3,4-
dihydro-IH-pyrido(2,1-cl (1,4)oxazinium-8-yl group, 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 1-oxide group, 2 ,3-dihydro-7H-oxazoO(3,
2-a) Pyridinium-7-yl 1,1-dioxide group, 3,4-dihydro-2H-pyrido(2,1-b) (
1,3) Oxazinium-8-yl group, 3,4-dihydro-21! -pyrido(24-bl (1,3)thiazinium-8-yl group, 3,4-dihydro-2H-pyrido(
2,1-b) (1,3)thiazinium-8-yl 1
-oxide group, 3,4-dihydro-2H-pyrido (2,
1-b) (1,3)thiazinium-8-yl 1,1
-dioxide group, 3,4-dihydro-IH-pyrido (2
,1-c](1,4)thiazinium-8-yl group, 3.
4-dihydro-IH-pyrido (2,1-cl(1,4)
Thiazinium-8-yl 1-oxide group, 3,4-dihydro-IH-pyrido(2,1-c) (1,4) Thiazinium-8-yl 1,1-dioxide group, 3,4-
Dihydro-IH92H-pyrido(1,2-a) pyrazinium-8-yl group, 3,4-dihydro-2-methyl-I
H,2H-pyrido[1,2-a] pyrazinium-8-
yl group, 2-ethyl-3,4-dihydro-IH.

2H-pyrido(1,2-a) pyrazinium-8-yl group, 2-formyl-3,4-dihydro-IH, 2H-pyrido(1,2-a) pyrazinium-8-yl group or 2-acetyl- 3,4-dihydro-11(,2H-pyrido(1
, 2-a) pyrazinium-8-yl group, and the like.

Particularly preferred examples include 2,3-dihydro-IH-indolizinium-7-yl group, 6.7,8.9-tetrahydroquinolidinium-2-yl group, or 3,4-dihydro-111-pyrido group. (2,1-cl (1,4)oxazinium-8-yl group, etc.).

- The non-toxic salt of the compound of Monena (1) refers to a conventional pharmaceutically acceptable salt, and refers to a carboxyl group, a bicyclic heterocyclic group, or a carboxyl substituted with R at the 4-position of the cephem nucleus. Examples include salts of acidic residues such as groups or sulfo groups, basic residues such as the 2-aminothiazole group or quaternary ammonium group at the 7-position of the cephem nucleus. Salts of the compounds may be mono-, di- or tri-salts.

Bases forming addition salts include, for example, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts,
Aliphatic amine salts such as ammonium salts, e.g. trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, jetanolamine salts, triethanolamine salts or brocaine salts, e.g.
.

Aralkylamine salts such as N-dibenzylethylenediamine salts, such as heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts, such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyl Examples include quaternary ammonium salts such as triethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt, or basic amino acid salts such as arginine salt or lysine salt.

Acids that form addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, carbonates, bicarbonates or perchlorates, such as acetates, propionates, etc. salts, organic acid salts such as lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate, such as methanesulfonate, isethionate, benzenesulfonate or p- Examples include sulfonic acid salts such as toluene sulfonate, or acidic amino acid salts such as, for example, aspartate or glutamate.

In addition, the partial structure of the oximino group in general formula (I) has a syn isomer (Z configuration) and an anti isomer (E configuration), and in general, the syn isomer (Z configuration r!l) has excellent antibacterial activity. In this specification, all ○R'' groups are syn isomers (Z configuration).

The E/Z nomenclature is based on the Journal of the American
Chemical Society 1' (Journal of
theAIIlerican Chemical 5o
90, p. 509 (1968).

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention has the general formula [wherein, R1 is a hydrogen atom or a protecting group for an amino group, R4
is a hydrogen atom, a lower alkyl group which may have a protected substituent, a lower alkenyl group which may have a protected substituent, a lower alkynyl group which may have a protected substituent. or an aralkyl group which may have a protected substituent.

R'' represents a hydrogen atom, a negative charge, or a protecting group for a carboxyl group, and X represents a leaving group, respectively. (note that the carbon atom of the alkylene group may be replaced with at least one or more of oxygen atom, sulfur atom, or nitrogen atom), which may be formed by the pyridine ring and the B. The bicyclic heterocycle may be substituted with the same or different groups or three substituents (the substituents may be protected).

A compound represented by the general formula [wherein R'', R'', R'' and group B have the above-mentioned meanings, and xo means an anion], and then, if necessary, (+> Step of removing the protecting group (ii) Step of converting the free acid into its nontoxic salt (■)
It can be produced by performing one or more steps of converting the free acid into its in vivo hydrolyzable non-toxic ester.

or a leaving group in general formula (n), specifically chlorine,
Examples include halogen atoms such as bromine and iodine, and acetoxy groups.

Xo in the general formula (IV) represents an anion of a leaving group. Next, the method for producing the compound (1) of the present invention will be explained in detail.

The compound of general formula (IV) can be prepared by combining a compound of general formula ([+) and a bicyclic heterocyclic pyridothione derivative (I [[)] with methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N , N-
It can be produced in dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof in the presence or absence of a deoxidizing agent.

Examples of deoxidizers include metal salts such as sodium carbonate, potassium carbonate or magnesium carbonate, and triethylamine, N,N-diisopropylethylamine, N
- Organic amines such as methylmorpholine or N,N-dimethylaniline. The bicyclic heterocyclic thione derivative (m) can also be used by silylating it with a silylating agent such as N,O-bistrimethylsilylacetamide.
The reaction was carried out using 1 to 2 moles of the bicyclic heterocyclic thione derivative (III) per mole of the compound of general formula (If), and the reaction temperature and reaction time were 0 to 40°C for 0.5 to 5 hours. be.

Further, when X in general formula (II) is an acetoxy group, the reaction with the bicyclic heterocyclic thione derivative (III) can be carried out using, for example, water, phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, acetonitrile. , N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof. The reaction is preferably carried out near neutrality, the reaction temperature is from room temperature to 90°C, and the reaction time is 1 to 15 hours. In one reaction, 1 to 20 mol of an iodide such as sodium iodide or potassium iodide, a thiocyanate such as sodium thiocyanate or potassium thiocyanate, or trimethylbenzylammonium bromide is added to 1 mol of compound (■). This is promoted by carrying out the reaction in the presence of a quaternary ammonium salt such as.゛Also, the reaction between the compound (n) and the pyridothione derivative (III) can be carried out using, for example, acetic acid, acetone,
1 to 50 moles of an acid, such as sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, based on compound (U) in acetonitrile, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof. , trifluoromethanesulfonic acid, chlorosulfonic acid, trifluoride, or trifluoride methyl ether complex, etc., from room temperature to 60°C.
Compound (TV) can be produced even if the reaction is carried out for 1 to 10 hours.

The cephem compound (+) of the present invention can optionally be prepared by the general formula (I
It can be produced by removing the protecting group from the compound V).

As a method for protecting a carboxyl group, an amino group, or a hydroxyl group in the above general formula and for removing the same, methods commonly used in the field of β-lactam synthesis can be appropriately selected and used. Methods for introducing and removing protecting groups are described, for example, in the T.I.
Double Knee Green (T.

Protective Groups in Organic Synthesis (Ij, Greene)
veGroups in Organic 5ynth
esis) and Blenheim Press (Plenum Pr
G.F. Ess), published in 1973
W McComiy (J, Flw.

ni cal! 1ie) by Protective Groups.
In Organic Chemistry (Protecti)
ve Groupsin Organic Chemi
This can be carried out using the method described in Str.

Examples of carboxyl protecting groups include 1, for example, lower alkyl groups such as tert-butyl group; halo-substituted lower alkyl groups such as 2,2.2-)lichloroethyl group; for example, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group; group, 1-acetoxyethyl group or 1-
Lower alkanoyloxyalkyl groups such as propionyloxyethyl; for example, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, or 1-(isopropoxycarbonyloxy)
Lower alkoxycarbonyloxyalkyl groups such as ethyl; for example, benzyl, 4-methoxybenzyl, 3,
4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group or bis(4-methoxyphenyl)
Aralkyl groups such as methyl groups; for example (5-methyl-2-
(5-substituted-2-oxo-1,3-dioxo-4-yl) such as oxo-1,3-dioxo-4-yl)methyl group
-yl)methyl group: for example lower alkylsilyl groups such as trimethylsilyl group or tert-butyldimethylsilyl group or phthalidyl group, in particular benzhydryl group, tert-butyl group, trimethylsilyl group or tert-butyldimethylsilyl group:
An ert-butyldimethylsilyl group is preferred.

Examples of amino-protecting groups include aralkylidene groups such as benzylidene, p-chlorobenzylidene, p-nitrobenzylidene, salicylidene, α-naphthylidene, and β-naphthylidene; for example, benzyl, 4-
methoxybenzyl group, 3,4-dimethoxybenzyl group,
Aralkyl groups such as 4-nitrobenzyl group, benzhydryl group or bis(4-methoxyphenyl)methyl group;
Lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, oxalyl, succinyl or pivaloyl; halogen-substituted lower alkanoyl such as chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl groups; e.g. arylalkanoyl groups such as phenylacetyl or phenoxyacetyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or tert-butoxycarbonyl; e.g. benzyloxycarbonyl, p-nitro an aralkyloxycarbonyl group such as a benzyloxy group or a phenethyloxycarbonyl group, or for example a trimethylsilyl group or a ter
Examples include lower alkylsilyl groups such as t-butyldimethylsilyl group.

Examples of protecting groups for hydroxyl groups include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, terc-butyl group, benzyl group, 4-methoxybenzyl group, 4- Nitrobenzyl group, acetyl group, 2,2.
Cyclic acetals such as 2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, trimethylsilyl group, tert-butyldimethylsilyl group, methylene acetal, ethylene acetal, benzylidene acetal,
Examples include orthoesters such as methoxymethylidene or methoxyethylidene, cyclic ketals such as isopropylidene ketal, or cyclic carbonate esters.

The protecting group can be removed by appropriately selecting a commonly used method depending on the type of the protecting group.

For example, protective groups such as trityl, formyl, tert-butoxycarbonyl, benzhydryl or tert-butyl, 2-methoxyethoxymethyl can be removed using hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid or P-toluene. The reaction can be carried out with an inorganic acid such as sulfonic acid or an organic acid, and trifluoroacetic acid is particularly preferred. When trifluoroacetic acid is used as the acid, the reaction is accelerated and side reactions are suppressed by adding anisole.

The reaction can be carried out in a solvent that does not adversely affect the reaction, such as water, methylene chloride, chloroform, ethylene chloride, or benzene, or in a mixed solvent thereof.The reaction temperature and reaction time are the same as those of the compound (rV) and the present invention. It is preferable to select the reaction temperature appropriately depending on the chemical properties of the cephem compound (1) and the type of protecting group, and to conduct the reaction at mild conditions of about 0°C to 60°C.

The step of converting the educt of the cephem compound (1) of the present invention into a non-toxic salt thereof is 1. For example, the educt can be produced by applying a technique commonly used in the art to the educt produced by the above-mentioned production method. can.

The step of converting the free form of the cephem compound (1) of the present invention into its physiologically hydrolyzable non-toxic, ester form is 1.
For example, JP-A-56-160782, JP-A-56-1477
It can be easily carried out by the method described in No. 89 and No. 53-21192, or a method based thereon.

The cephem compound of the present invention produced by the above steps (
Isolation and purification of 1) and its non-toxic salts can be carried out by known methods such as crystallization or column chromatography.

The method for producing the raw material compound used for producing the compound of the present invention will be explained below.

The compound represented by the general formula ([1)] is -Momon [wherein, X
and R' have the above meanings],
- 0 which can be produced by reacting with a compound represented by the formula [wherein R' and R4 have the above-mentioned meanings] or a reactive derivative of its carboxyl group, such as water, acetone, dioxane, and ether. , tetrahydrofuran,
In a solvent that does not adversely affect the reaction, such as ethyl methyl ketone, chloroform, methylene chloride, dichloroethane, ethyl acetate, ethyl formate, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof, and at a reaction temperature of water cooling or room temperature. The reaction can be carried out under the conditions that the reaction time is 1 hour to 10 hours. Examples of reactive derivatives of the carboxyl group of compound (■) include active esters formed from a condensing agent such as N,N-dicyclohexylcarbodiimide and, for example, N-hydroxysuccinimide or 1-hydroxybenzotriazole; for example, thionyl chloride; .

Acid halides formed with halogenating agents such as phosphorus pentachloride or oxalyl chloride; chloroformates such as methyl chloroformate or isobutyl chloroformate in the presence of acid scavengers such as triethylamine or N-methylmorpholine; Examples include mixed acid anhydrides formed by.

Further, depending on the type of the reactive derivative of the carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the reaction to proceed smoothly.

Such bases include, for example, inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, or organic bases such as trimethylamine, triethylamine, N,N-dimethylaniline or pyridine. In addition, when using the compound represented by the Ikki formula (■) in the form of a free carboxylic acid, N,
Preference is given to using condensing agents such as N-dicyclohexylcarbodiimide or N,N-diethylcarbodiimide.

The raw material compound (b) produced in the above step can be separated and purified by known methods such as crystallization or column chromatography, but in some cases it may be used as a raw material for the next step without separation and purification. It is also possible to provide

- The compound represented by Monka (Vl) can be prepared by known methods such as JP-A-50-76089, JP-A-56-86187, Journal of Antibiotics (J.

Antibiotics), Volume 38, Page 1738 (
1985) and Tetrahedron Letters (Tetr
ahedron Lett, ), vol. 22, 3915
(1981) and others.

This is an intermediate for producing the compound of the present invention. - Monna [in the formula, base B
has the above-mentioned meaning] is a novel compound that has not been described in any literature, and is the first compound produced by the present inventors.

- Bicyclic pyridothiones represented by Monka (III) are:
It is manufactured in two steps as shown below.

(+01, CII)
(Ill) [wherein group B has the above-mentioned meaning 6] The step of producing compound (IX) by subjecting compound (■) to a cyclization reaction is, for example, a step of producing compound (IX) using tetrahedron (Tetrahedron).
n) The cyclization reaction can be carried out by appropriately carrying out the Mitsunobu reaction described in Vol. 39, p. 2571 (1983) and Synthesis, p. 1 (1981). That is, the step of converting compound (1o) to compound (11) is 1. A phosphine such as triphenylphosphine and azodicarboxylic acid dimethyl ester or azodicarboxylic acid in an inert organic solvent such as tetrahydrofuran, ether or dioxane. This can be carried out by treating the compound (]O) with an azodicarboxylic acid ester such as diethyl ester at 0°C to 80°C for 30 minutes to 10 hours. The amount of the phosphine and the azodicarboxylic acid ester used is 1 to 3 mol, respectively, per 1 mol of compound (10).

Next, the step of converting compound (11) to compound (III) is carried out using a compound such as pyridine, collidine or lutidine.
In the base, for example, phosphorous trisulfide compounds or
Lawesson reagent [Tetrahedron (Tetra
compound (11) at 20°C to 1% with a phosphorus sulfide compound such as
50°C, preferably 20°C to 80°C for 1 hour to 15
This can be done by time processing. This step can optionally be carried out by diluting with an inert solvent such as toluene, benzene or tetrahydrofuran.

Compound (I) produced by performing the above two steps
[I) can be purified by an appropriate combination of purification methods such as solvent extraction, crystallization, or chromatography, or can be used as a raw material for producing the cephem compound of the present invention without being purified.

Compound (11) used as a raw material for producing compound (nl)
For example, commercially available chelidamic acid (4-hydroxy-2,6
-pyridine dicarboxylic acid) or 2-carboxy-4-hydroxy-5-methoxy-pyridine [from kojic acid, Acta Chemical
aScandinavica) Volume 16, Pages 78-82
(1962)] using a picoline derivative easily derived by a known synthetic reaction as a common intermediate, and further elongation of the side chain at the 2-position of the pyridine ring, functional group conversion, and cyclization reaction. Manufactured by.

For example, the picolinaldehyde derivative (4) using chelidamic acid as a raw material can be produced by the following production route.

[In the formula, R10 is a hydroxyl-protecting group such as a benzyl group, p-methoxybenzyl group, 2-methoxyethoxymethyl group, or di-butyldimethylsilyl group, and RI1 is a carboxyl group such as a methyl group or a benzhydryl group. chelidamic acid (1) is converted into a compound (
In the step of converting into 2), compound (1) is heated at 20°C to 80°C with diphenyldiazomethane or diazomethane in an inert solvent such as ether, ethyl acetate, or methanol.
C. for 1 to 10 hours to form a diester, the diester is dissolved in an inert solvent such as N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran, for example, potassium carbonate or N,N.
- It can be carried out by treating with an alkylating agent such as benzyl chloride or benzyl bromide at 20°C to 80°C for 1 to 10 hours in the presence of a base such as diisopropylethylamine.

Note that protection of hydroxyl groups and protection of carboxyl groups can be carried out at the same time by simply changing the amount of the alkylating agent used.

The step of converting compound (2) to compound (3) is carried out, for example, in an inert solvent such as methanol or tetrahydrofuran,
1 of a base such as potassium carbonate or sodium hydroxide
After compound (2) is treated with an aqueous solution containing an equivalent amount to form a half ester, the half ester is dissolved in a high boiling point inert organic solvent such as diphenyl ether, trichlorobenzene or quinoline, or in some cases with copper powder etc. This can be carried out by adding a catalyst and heating at 160°C to 200°C for 1 hour to 20 hours.

The step of converting compound (3) to compound (4) is carried out in an inert solvent such as benzene, toluene, methylene chloride or tetrahydrofuran at a low temperature, preferably from -70°C to -
This can be carried out by treating compound (3) at a temperature of 50° C. using 1 to 3 equivalents of a metal hydride such as lithium aluminum hydride or diisopropylaluminium hydride.

Incidentally, if the same procedure as described above is carried out using 2-carboxy-4-hydroxy-5-methoxy-pyridine as a starting material instead of chelidamic acid, the corresponding picolinaldehyde can be obtained.

Compound made from picolinaldehyde derivative (4) (
Type V) can be produced by the following production route.

[In the formula, R1, R1 and B have the above-mentioned meanings, and X is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom,
Y is an oxygen atom, nitrogen atom or sulfur atom, R'' is a hydrogen atom or, for example, a benzyl group, p-methoxybenzyl group, 2
- represents a hydroxyl group-protecting group such as a methoxyethoxymethyl group or a tert-butyldimethylsilyl group] The step of converting compound (4) into compound (5) by subjecting it to a carbonization reaction involves adding a phosphorus ylide to compound (4). The compound is prepared in an inert solvent such as dioxane, tetrahydrofuran, N,N-dimethylformamide or methanol at 10°C to
This can be carried out by reacting at 80° C. for 1 hour to 10 hours. Alternatively, the same carbonization reaction as described above can be carried out by treating the phosphonium salt with a base such as sodium hydride, butyllithium, sodium methoxide, or sodium bicarbonate to generate the phosphorus ylide compound in the reaction system. be able to.

When an ester group or a carbonyl group exists in the side chain of the precursor of compound (5) produced by the above carbonization reaction, for example, sodium borohydride in methanol,
-70'C to 80' by combination with a solvent and metal hydride such as lithium aluminum hydride in tetrahydrofuran or diisobutyl hydride in methylene chloride.
By treating at °C for 1 to 20 hours, the ester group or the carbonyl group is converted into the hydroxyl group necessary for the ring-closing reaction.

The step of producing compound (10) by 1 deprotection reaction of compound (5) can be carried out by a known method for removing a hydroxyl protecting group.6 For example, when Rlo is p-methoxybenzyl group or 2-methoxyethoxymethyl In the case of a group, the deprotection step can be carried out by treatment with an acid such as hydrochloric acid or trifluoroacetic acid in an inert solvent such as ether or tetrahydrofuran.

Also, R″.

When is a tert-butyldimethyl group, the deprotection step can be carried out by treatment with, for example, potassium fluoride, tetrabutylammonium fluoride, etc. in an inert solvent such as tetrahydrofuran.

Furthermore, when Rlo represents a benzyl group, using a metal catalyst such as 10% palladium on carbon, palladium black or platinum oxide in an inert solvent such as methanol, tetrahydrofuran or N,N-dimethylformamide,
The deprotection step can be carried out by performing hydrogenolysis at room temperature and hydrogen atmosphere at 20° C. to 80° C. for 1 hour to 10 hours. In addition, during this deprotection step by reduction, if a double bond or triple bond is present in the side chain of the pyridine ring, the group group is also hydrogenated. Therefore, it is necessary to appropriately select the hydroxyl protecting group or reaction reagent depending on the compound to be produced. Further, as the phosphorus ylide compound or the phosphonium compound used in the carbonization reaction, commercially available or known compounds can be used as appropriate.

The step of converting compound (4) to compound (6) is carried out using a solvent-reducing agent such as sodium borohydride in methanol, lithium aluminum hydride in tetrahydrofuran or sodium cyanoborohydride in acetic acid. Combinations of conditions can be carried out, a particularly preferred combination being sodium cyanoborohydride in acetic acid.

The step of converting compound (3) to compound (6) can be carried out, for example, by treating compound (3) with a reducing agent such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran.

The step of converting compound (6) into compound (7) is the step of converting compound (6) into compound (7).
) for example pyridine, triethylamine.

This can be carried out by treating with 1 to 5 equivalents of a halogenating agent such as thionyl chloride or phosphorus pentachloride in an organic base such as N,N-dimethylaniline at 0°C to 80°C for 1 to 10 hours. . Note that this step can also be carried out by diluting with an inert solvent such as methylene chloride, benzene, or tetrahydrofuran, if necessary.

The step of converting compound (7) to compound (9) is to convert compound (8) represented by -Momonena HY-B-○R11 [in the formula, Y, B and Rl 1 have the above-mentioned meanings] , after treatment with a base such as sodium hydride or butyllithium,
-70°C to 80°C in an inert solvent such as N,N-dimethylformamide, tetrahydrofuran or dioxane.
℃, for 1 to 20 hours to react with compound (7). 1. Next, compound (10) can be produced by removing the hydroxyl protecting group of compound (8). can. Moreover, a commercially available product or a known compound can be used as the compound (8).

The compound represented by the general formula (■) can be prepared by known methods such as Chemical and Pharmaceutical Bulletin (
Chem, Pharm, Bull), Volume 25.

2-(2-aminothiazol-4-yl)glyoxyl m derivative or 2-(2- Aminothiazole-4-
yl)-2-hydroxyiminoacetic acid ester derivative.

Next, the in vitro antibacterial activity of the cephem compounds of the present invention against various bacteria was measured by the agar plate dilution method described below [
Japanese Society of Chemotherapy Standard Method: Chemotherapy
therapy), Vol. 29, pp. 76-79 (1981
), Mueller-Hinton Bross (Muel)
One loopful of each test strain (inoculum 11: 10' CF) cultured overnight in lerllington broth)
U/mQ) to Mueller-Hinton-Agar (MHa
gar). This medium contained antibacterial agents at various concentrations, and after culturing at 37° C. for 16 hours, the minimum inhibitory concentration (MIC: μg/Uafl) was measured. Cefotaxime and ceftazidime were used as comparison compounds.

The results are shown in the table below.

Therefore, the compound of the present invention of general formula (1) can be used as an antibacterial agent, particularly for the treatment of human bacterial infections caused by Durum-positive bacteria and Durum-negative bacteria, including glucose non-fermenting Durum-negative rods such as Pseudomonas aeruginosa. It can be used for.

The cephem compounds of the present invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical formulations suitable for parenteral, oral or external administration.

Pharmaceutical preparations include injections.

Liquid preparations such as syrups and emulsions, tablets, and capsules.

Examples include solid preparations such as 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 enhancers, surfactants, etc., as necessary. Distilled water, Ringer's solution, glucose, sucrose syrup, gelatin.

Examples include edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

When using the cephem compound of the present invention as an antibacterial agent,
The dosage varies depending on the condition of the patient, such as age, sex, etc.1 Usually, it is used in the range of 1 to loo+++g/electrode per day, and is administered in 2 to 4 doses at 5 to 30 mg/- per day. is preferable.

The present invention will be further explained in 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. You may change it by

Thin layer chromatography (TLC) of Examples and Reference Examples
K manufactured by Merck is used as a TLC plate.
ieselgel 60F, , and UV as the detection method.
using a detector. The silica gel for the column is Wakogel C-300 manufactured by Wako Pure Chemical Industries, Ltd. or Kemco.
The preparative plate was Merck Art (Merck).
Merck Art) 5717 was used. The NMR spectrum contains deuterated dimethyl sulfoxide (D
When measuring with MSO-d, ) or deuterated chloroform (CDC1,) solution, use tetramethylsilane (TMS),
When measuring with a heavy water (D, O) solution, 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) is used, and XL-200 manufactured by Vrian is used.
(200N11z) or R-40 (9
0 Hz) type spectrometer, and all δ values were expressed as pp
Indicated by m.

Symbols in NMR measurement have the following meanings.

S: Singlet d: Doublet t Triplet q: Quartet ABq: AB type
quartet) dd: double doublet
le doubleL) dt: double triplet (d
double triplelm multi bullet (a+
u 1 t i p le t )br nibroad (b
road) j: coupling constant (coupling constant
nt) tlz: Hertz D? 15O-d, : heavy dimethyl sulfoxide CDC
l, : Deuterated chloroform D, O/deuterated water Example 1 (1) Diphenylmethyl 3-iodomethyl-7β-
((Z)-2-methoxyimino-2-(2-)su° thylaminothiazol-4-yl)acetamidogo 3-cephem-4-carboxilade 250II 1 g (0,
27 mmol) and 6.7,8.9-tetrahydro-2 (
531 g (0.32 mmol) of 2H)-quinolidinethione were mixed with 2.5 g of N,N-dimethylformamide. Dissolve in OmQ and stir the mixture for 1 hour at room temperature.

Diphenylmethyl 3-(6,
7,8,9-tetrahydroquinolidinium-2-yl)
Thiomethyl-7β-[(Z)-2-methoxyimino-2
-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-4-carboxylade A residue containing iodide is obtained and used in the next step without purification.

(2) The residue obtained in the above reaction (1) was mixed with 1.2 methylene chloride.
Dissolve in mΩ and add 0.25 mA of anisole and 1.2 + afl of trifluoroacetic acid while cooling with water. The reaction mixture is stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitate was collected. Precipitate in 1 part water
0IIIQ and subjected to ultrasonication for 15 minutes. The reaction solution was subjected to reverse phase silica gel column chromatography (LC-
5ORB RP-18, Kewc.

Both fractions containing the target product were collected and condensed under reduced pressure to approximately 2a+fl. Freeze-dry the concentrated solution to obtain 46 mg of the listed compound (Collection 3
1%).

Nl'lR (DMSO-d,) δ: 1.86 (2H
, n+), 2.00 (2H, m).

3.16 (211, m), 3.3-3.7 (2) 1. +
n), 3.86(3)1. s).

4.40 (2H, m), 4.50 (2) 1. m), 5.
02 (IH, d, J=4Hz).

5.60 (LH, dd, J=4.8Hz), 6.78 (
IH, s), 7.30 (2H, br s), 8.06 (
il+, +o), 8.22 (IH, br s), 8.3
4 (111, d, J = 611z), 9.58 (IH, b
r d,, I:8)1z)IR(KBr) cm-'
: 3400,1760. +660.1620.153
0 Example 2 (1) Diphenylmethyl 3-iodomethyl-7β-
((Z) -2-(1-methyl-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl)acetamidogo 3
-cephem-4-carboxilade 300mg (0,
26 mmol) and 6.7,8.9-tetrahydro-2(
211)-quinolidinethione 53 mg (0.32 mmol) were dissolved in N,N-dimethylformamide 2. Dissolve in OmQ and stir the mixture for 1 hour at room temperature. The solvent was distilled off under reduced pressure to give diphenylmethyl 3-(6,7,8,9-tetrahydroquinolidinium-2-yl)thiomethyl-7β.
-((Z) -2-(t-methyl-1-diphenylmethyloxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamidogo 3
-Cephem-4-carboxilade A residue containing iodide is obtained and used in the next step without purification.

(2) The residue obtained in the above reaction (1) was mixed with 1.5 methylene chloride.
mD, and add 0.3+nQ of anisole and 1.5 mA of trifluoroacetic acid while cooling with water. The reaction mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitate was collected.

The precipitate was suspended in 10 mQ of water, dissolved in saturated sodium bicarbonate solution,
The reaction solution was subjected to reverse phase silica gel column chromatography (LC).
-5ORB: Kemco, eluted with 10% methanol-water), the fractions containing the target product were collected, and the
Concentrate to IIIQ. The concentrate was freeze-dried to obtain 51 mg (yield 30%) of the title compound.

NMR (DMSO-d,) δ: 1.36 (3H, s
), 1.38 (3H, s), 1.85 (2H, m), 1
．． 95 (2H, m), 3.12 (211, m), 3.3
〜3.6(2)1, m), 4.22(ill, m
), 4.50 (21+, m ), 4.82 (I
II, m).

5.00 (IH, d, J = 4tlz), 5.62 (IH
, dd, J = 4 and 8 Hz).

6.72 (III, s), 7.20 (2H, br s)
, 8.10 (IH, m), 8.36 (211, m) IR (KBr) cm-': 3400,1760,
1620.1530 Example 3 Diphenylmethyl 3-iodomethyl-7β- [(2)
-2-(2-tritylaminothiazol-4-yl)-
Example 1 from 300 mg (0.28 mmol) of 2-trityloxyiminoacetamide]-3-cephem-4-carboxilade and 50 mg (0.3 mmol) of 6.7,8.9-tetrahydro-2(2H)quinolidinethione. The same reactions as (1) and (2) were carried out to obtain 46 mg (yield 30%) of the title compound.

NMR (DMSO-d,) δ: 1.82 (2H,
m), 2.00 (2H, m), 3.10 (2H, m),
3.30 (2H, m), 4.40 (3H, m), 4.5
6 (LH, d.

J=14Hz), 5.00(11(,d, J=4Hz)
, 5.58 (18, dd, J = 4 and 8 Hz), 6.6
4 (IH, s), 7.16 (28, br s), 8.0
2 (LH, br d, J=6Hz), 8.22 (IH,
br s), 8.50 (IH, d.

J=6Hz), 9.38(1)1. br d, J=8t
lz)IR(KBr) am-': 3400,17
65,1620.1530 Example 4 Diphenylmethyl 3-chloromethyl-7β-((Z)
-2-((I5)-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl)acetamide)-3-cephem-4-carboxilade 354 mg (0,33 mmol) The same reaction as in Example 2 (1) and (2) was carried out using 50 mg (0.30 mmol) of 6.7,8°9-tetrahydro-2(2H)-quinolidinethione to obtain 3 mg of the title compound (yield 58%). ).

NMR (DMSO-d,) δ: 1.30 (3H, d,
J=6Hz), 1.86 (2H, m).

2.00 (211, m), 3.12 (2H, m), 3.
30 (2H, m), 4.22 (IH.

d, J=1611z), 4.35(Ill, m)
, 4.46 (211, m), 4.80 (1) 1.

d, J=1611z), 5.00(IH, d, J=4H
z), 5.70 (IH, dd, J=4 and 811z),
6.78 (111, s), 7.20 (21+, br s
), 8.12 (IH, br d, J=6Hz), 8.4
4 (IH, br s), 8.60 (LH, d.

J=6Hz) IR (KBr) cIll-': 3400,176
0,1620,1590.1530 Example 5 Diphenylmethyl 7β-((Z) -2-(1-te
rt-butoxycarbonylvinyloxy') -2-(
317 mg (0.33 mmol) of 2-tritylaminothiazol-4-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxylade and 6.7,
Example 2 (1) from 50 mg (0.30 mmol) of 8.9-tetrahydro-2(2H)-quinolidinethione
And the same reaction as (2) was carried out to obtain 97 mg of the title compound.
(yield 50%).

NMR (DMSO-d,) δ: 1.88 (2H, m)
, 2.00 (2H, m), 3.12 (2H, m), 3.
40 (2H, m), 4.30 (III, d, J = 14H
z), 4.44 (2H, l11), 4.76 (18, d
, J=14Hz), 4.88(LH,s), 5.00(
Ill, d, J=4Hz), 5.18 (LH, s), 5
．． 60 (LH, m), 6.95 (IH, s), 7.30
(2H, br s), 8.08 (IH, br d, J=
6Hz).

8.46 (IH, br s), 8.50 (IH, d, J
=6Hz) [R(KBr) am-': 3400,
1760,1620.1530 Example 6 Diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-(1-diphenylmethyloxymethoxyimino)
-2-(2-tritylaminothiazol-4-yl)acetamidocou 3-cephem-4-carboxilade 3
00 mg (0,26 mmol) and 50 mg of 6,7,8,9-tetrahydro-2(211)-quinolidinethione
(0.30 mmol), (1) and (2 of Example 2)
) to obtain 102 mg (yield 62%) of the title compound.

NMR (DMSO-d,) δ: 1.82 (2+1.l
11), 1.98(2)1. m), 3.10 (2H, m
), 3.30 (2H, m), 4.18 (2H, br s
), 4.22(1)1°d, J=16Hz), 4.40
(IH, m), 4.60 (IH, m), 4.75 (il
l.

d, J=16Hz), 4.98(1B, d, J
:=4Hz), 5.60 (IH, dd,, b4 and 8
Hz), 6.82 (ltl, s), 7.20 (2H, b
r s), 8.02 (111, d, J"6Hz), 8.
44 (IH, s), 8.48 (IH, d, J=6Hz)
IR(KBr)cIll-': 3400,176
0,1620.1530 Example 7 No. 25 diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamidocou-3-cephem-4
- 100 mg (0.11 mmol) of carboxilade and 3,4-dihydro-8(IH)-pyrido (2,1-c)
(1,4)oxazinethione 20Il1g (0,1
2 mmol) was subjected to the same reaction as in (1) and (2) of Example 1 to obtain 29 mg (yield: 48%) of the title compound.

N? IR(DMSO-d,) δ: 3.3-3.6(
2H, IO), 3.82 (3tl, s).

4.20 (2tl, m), 4.50 (41 (, a+),
5.0O (2H, dd, J=4 and 16Hz), 5.1
2 (IH, d, J = 16Hz), 5.58 (IH, dd
, J = 4 and 8 Hz), 6.78 (1) (, s), 7.
28 (21, br s), 8.18 (IH, brd, J
:6Hz), 8.30(IH, br s), 8.56(
II (, d.

J=6Hz), 9.55(IH, br d, J=8Hz
)IR(KBr) cm'': 3400,1765
, 1620.1530 Example 8 Xylard diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-(1-methyl-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl)acetamidocou 3-cephem-4-carboxilade 210 mg (0,18 mmol) and 3 ,4-dihydro-8(IH)-pyrido(2,1
-c) (1,4)oxazinethione 30mg (0,
18 mmol), 21 mg (yield 18%) of the title compound was obtained by the same reaction as in (1) and (2) of Example 2. 6 HMR (DNSO-d,) δ: 1.38 (6H, s)
, 3.30 (2H, +n), 4', 22 (2H, 11)
,4.24(11(,d,J=14Hz),4.56(
2H, +o), 4.76 (IH, d, J=14)1z)
, 5.00 (3H, m), 5.60 (18, l11),
6.70 (IH, s), 7.18 (2H, br s),
8.15 (18,br d, J=411z).

8.48 (IH, br s), 8.55 (IH, d, J
=4Hz) IR (KBr) cm-': 3400,
1760,1685,1620.1530Example 9 diphenylmethyl 3-chloromethyl-7β-((Z)
-2-((IS)-1-diphenylmethyloxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-cephem-4-carboxilade 200 mg (0,19 mmol) and 3,4-dihydro-8(LH)-pyrido (2,
1-c) (1,4)oxazinethione 5-axis g (0,
30 mmol), the same reaction as in (1) and (2) of Example 2 was carried out to obtain 53 mg (yield 44%) of the title compound.
get.

NMR (DMSO-d,) δ・1.30 (3H, d, J
=6Hz), 4.20 (2H, a+).

4.30(ltl+m)+4-4-58(289+4-
74(1)1. d+J=12Hz)+5.00(18,
d, J=4Hz), 5.02 (2H, m), 5.64 (
LH, dd.

J=4 and 811z), 6.78 (IH, s), 7.2
0 (2H, br s).

8.22 (IH, br d, J=6Hz), 8.40 (
IH, br s), 8.60 (LH, d, J=6Hz) IR (KBr) aIll-': 3400,176
0. +620.1590.1530 Example 1O Sodium 7β-((Z) -2-(2-aminothiazol-4-yl)-2-(1-carboxylade vinyloxyimino)acetamide) -3-(3,4- Dihydrodiphenylmethyl 3-chloromethyl-7β-[
(Z)-2-(1-tert-butoxycarbonylvinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-4-
Carboxilade 171+ng (0.18 mmol)
and 3,4-dihydro-8(IH)-pyrido(2,1-c
) From 30 mg (0.18 mmol) of (1,4) oxazinethione, the same reaction as in (1) and (2) of Example 2 was carried out to obtain 46 mg (yield 40%) of the title compound.

N) IR (DMSO-d,) δ: 3.20 (2H, m
), 4.0-4.8 (6H, +n).

4.82 (IH, s), 5.00 (1) 1. d, J=4
Hz), 5.02 (2H, m).

5, 12 (IH, s), 5.56 (LH, m), 6.9
0 (IH, s), 6.22 (2H, br s), 8.1
0(IH, br d, J=61(z), 8.50(IH
,d.

J=6Hz), 8.62 (IH, 5) IR (KBr) am-': 3400, 1760,
1620.1530 Example 11 Diphenylmethyl 3-iodomethyl-7β- [(2)
-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-4
-carboxilade 200 mg (0.21 mmol)
and 38 mg (0.26 mmol) of 2,3-dihydro-7(IH)-indolizinethione, (1
) and (2) to obtain 30 mg of the indicated compound.
(yield 26%).

NMR (DMSO-d,) δ: 2.36 (211
, +n), 3.20-3.62 (4H, m).

3.82 (3H, s), 4.52 (21+, m), 4.
62 (2H, m), 5.00 (Itl, d, J=
411z), 5.56 (ill, dd, J=4 and 8Hz), 6.76 (IH, s), 7.24 (21!
, br s), 8.10 (IH, br d, J=611
z).

8.34 (III, br s), 8.68 (111, d
, J=811z), 9.52 (IH.

br d, J=811z) IR (KBr) am-': 3400,1765,
1620.1530 Example 12 Diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-(1-methyl-1-diphenylmethyloxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-
Example 2 (
The same reaction as 1) and (2) was carried out to obtain the title compound 53m.
g (yield 39%) is obtained.

NMR (DMSO-d,) δ: 1.36(3)1
．． s), 1.38 (3H, s), 2.38 (2H, m
), 3.20-3.60 (4t(, l11), 4.
28 (IH, d,, J'12tlz).

4.68 (2H, m), 4.78 (111, d, JJ2
tlz), 5.00 (IH, d.

J=4Hz), 5.64(IH, dd, J=4 and 81
1z), 6.74 (III, s).

7.20 (211, br s), 8.12 (ill, b
r d, J=6Hz), 8.60 (IH, br s),
8.72(1)1. d, J=6Hz) IR (KBr)
cIll-' + 3400.1760,1620,1
590.1530 Example 13 Diphenylmethyl 3-chloromethyl-7β-((Z)
-2-((lS)-1-diphenylmethyloxycarbonylethoxyimino)acetamide)-3-cephem-4-carboxilade 250 mg (0,23 mmol) and 2,3-dihydro-7(IH)-indolizine Using 50 mg (0.33 mmol) of thione, the same reaction as in Example 2 (1) and (2) was carried out to obtain the title compound 58.
mg (yield 40%).

NMR (DMSO-d,) δ: 1.30 (3H, d,
J=6Hz), 2.38 (2H, m).

2.60 (2H, m)', 3.40 (2H, m), 4
．． 30 (2H, m), 4.70 (3H.

m), 5.00 (III, d,, J'4Hz), 5.
64 (III, dd, J = 4 and 8 Hz), 6.78 (
IH, s), 7.20 (2H, br s), 8.18 (
IH, l11).

8.52 (LH, br s), 8.72 (IH, d, J
=6Hz)IR(KBr) cIll-': 340
0,1760,1620.1530 Example 14 Diphenylmethyl 7β-((Z) -2-(1-te
rt-butoxycarbonylvinyloxyimino)-2-
(2-tritylaminothiazol-4-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxilade 200 mg (0.21 mmol) and 2,3
-dihydro-7(LH)-indolizinethione 50mg
(0.33 mmol), (1) and (
The same reaction as in 2) was carried out to obtain 54 mg (yield 41%) of the title compound.

NMR (DMSO-d,) δ: 2.38 (2H, m)
, 3.3-3.7 (4H, m).

4.22 (Ill, m), 4.5-4.8 (3H, m)
, 4.82 (18,s).

5.00 (111, d, J=4Hz), 5.15 (II
, s), 5.60 (18, In).

6.92 (Ill, s), 7.26 (2H, br s)
, 8.08 (Ill, br d, J:611z), 8.
54(Hl,br s), 8.66(l[l,br d
, J=6Hz) IR (KBr) c+n-' + 34
00.1760,1620.1530 Example 15 Diphenylmethyl 3-chloromethyl-7β-[(Z)
-2-(2-tritylaminothiazol-4-yl)-
The title compound is obtained in the same manner as in Example 1 from 2-trityloxyiminoacetamide]-3-cephem-4-carboxylad and 2,3-dihydro-3-methyl-7(III)-indolizinethione.

NMR (DMSO-d,) δ: 1.58 (311, d
, J=6tlz), 1.98(2)1. m).

2.40 (2H, m), 3.38 (2H, m), 4.5
0 (211, br s), 4.90 (IH, m), 5.
00(ill, d, J=411z), 5.8(IH,
dd, J=4 and 811z), 6.70(1!I,s)
, 7.16 (211, br s), 8.18 (LH, b
r d, J: 6Hz), 8.30 (IH, br s),
8.72 (IH, d.

J=6Hz), 9.38 (IH, d, J=8Hz)IR
(KBr) c+n-': 3400,1765,1
620.1525 Example 16 Diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamidogo-3-cephem-4
-carboxilade and 2,3-dihydro-3-methyl-
The title compound is obtained from 7(IH)-indolizinethione in the same manner as in Example 1.

NMR (DMSO-d,) δ: 1.56 (3H, d,
J=6Hz), 2.00 (2H, m).

3.30-3.60 (4H, m), 3.8/+ (3tl
, s ), 4.52 (2H, m).

4.92 (IH, In), 5.00 (IH, d, J=4
Hz), 5.56 (18, dd.

J=4 and 811z), 6.76(LH,s), 7.2
2 (211, br s).

8.16 (III, br d, J=6!lz), 8.3
2 (III, br s), 8.72 (18, d, J=6
11z), 9.54 (Iff, br d, J=811z
)IR(KBr) cm-': 3400,1765
, 1670, 1620.1530 Example 17 Diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-(1-Methyl-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl)acetamido-3-cephem=4-carboxylade and 2,3-dihydro-3- From methyl-7(III)-indolizinethione, Example 2
The title compound is obtained in the same manner as above.

NMR (DMSO-d,) δ: 1.36 (311,s
), 1.38 (1,5H,s).

1.40 (1.5H, s), 1.98 (211, m),
3.1-3.6 (4H, m).

4.30 (0,511, d., J=16Hz), 4.
36 (0,5H, d, J=1611z).

4.66 (0,511, d, J=16Hz), 4.
76 (0,51!, d, J=16tlz)+5.
00 (18, d, J=4Hz), 5.02 (IH, m)
, 5.64 (III, dd.

J=4 and 8Hz), 6.74(LH,s), 7.20
(211, br s).

8.06 (0.5H, br d, J=8Hz), 8.2
4 (0,5H, br d, J=8Hz), 8.32 (0
,5H,br s), 8.58(0,5H,br s)
.

8.76 (IH, d, J = 8Hz), 8.80 (0,5
H, d, J=8Hz) IR (KBr) cm-' +
3400.1760, 1620.1535 Example 18 Diphenylmethyl 3-chloromethyl-7β-((Z)
-2-((IS)-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl)acetamide)-3-cephem-4-carboxilade and 2,3-dihydro- From 3-methyl-7(IH)-indolizinethione, Example 2
The title compound is obtained in the same manner as above.

NMR (DMSO-d,) δ: 1.30 (31
1, d, J=611z), 1.58 (3H, d.

J=611z), 2.00 (211, m), 2.
50 (2H, m), 3.40 (211, m).

4.20-4.60 (311, m), 4.80 (lft
, m) , 5.00 (LH, d, J: 41!z), 5.
68 (111, dd, J = 4 and 8 Hz), 6.80 (
IH,s).

7.22 (211, br s), 7.8-8.9 (3H
, m) IR(KBr) am-': 3400,17
60,1620.1530 Example 19 Diphenylmethyl 7β-((Z) -2-(1-te
rt-butoxycarbonylvinyloxy) -2-(2
-tritylaminothiazol-4-yl)acetamido-3-chloromethyl-3-cephem-4-carboxilade and 2,3-dihydro-3-methyl-7 (111)
-The title compound is obtained from indolizinethione in the same manner as in Example 2.

NMR (DMSO-d,) δ: 1.56 (3H, d,
, J=6Hz), 2.00(2H,+n).

2.62 (2H, +n), 3.25 (2H, m), 4.
2-4.8 (3H, m).

4.86 (IH, s), 5.00 (18, d, J=4)
1z), 5.16 (1B, s).

5.60 (ill, m), 6.92 (IH, s), 7.
28 (2H, br s), 8.08 (0.5H, br s)
d, J=6Hz), 8.26(0,511,br d,
J=6)1z).

8.36 (0,5■, br s), 8.60 (0,5H
,br s), 8.76(0,511,d, J:6Hz
), 8.78 (0,5H,br d,J:6Hz)IR
(KBr) Cl11-': 3400,1760,
1620.1535 Example 20 Diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-diphenylmethyloxycarbonylmethoxyimino-2-(2-tritylaminothiazol-4-yl)
The title compound is obtained in the same manner as in Example 2 from acetamido-3-cephem-4-carboxilade and 2,3-dihydro-7(III)-indolizinethione.

NMR (DMSO-d,) δ: 1.55 (3H, d,
6Hz), 2.0O (2H, m).

2.60 (2H, m), 3.40 (211, m), 4.
20 (2H, s), 4.25 (211, m), 4.80
(IH, m), 5.00 (IH, d, J=4Hz), 5
．． 60 (18, m), 6.82 (III, s), 7.2
2 (2H, br s), 8.04 (0,5H, br d
, J=611z), 8.28(0,5H,br d,,
I=6tlz).

8.36 (0,511,br s), 8.68 (0,5
11,d, J=6Hz), 8.70(0,511,br
s), 8.72 (0,5H,br d,,J'6Hz
)IR(KBr) c+nn': 3400,176
0,1620.1530 Example 21 Diphenylmethyl 3-iodomethyl-7β-((Z)
-2-[α-(diphenylmethyloxycarbonyl)benzyloxyimino) -2-(2-tritylaminothiazol-4-yl)acetamide)-3-cephem-
4-carboxilade and 2,3-dihydro-7(il+
)-indolizinethione to obtain the title compound in the same manner as in Example 2.

NMR (DMSO-d,) δ: 1.50 (3H, m)
, 1.96 (21 (, m), 2.50 (2H, m), 3
．． 30 (211, m), 4.28 (21 (, m), 4
．． 90-5.10 (211, m), 5.18 (0,5
11, s ), 5.24 (0,5H, s ), 5.72
(IH'.

m), 6.80 (0,511, s ), 6.90 (0
, 511, s), 7, 1-7.8 (5H.

m), 8.0-8.9 (3H, m) IR (KBr) cml'V': 3400,176
0,1620.1530 Example 22 Silate diphenylmethyl 3-iodomethyl-7β-((2)
-2-(3,4-di(2-methoxyethoxymethoxy)
-α-diphenylmethyloxycarbonylbenzyloxyimino) -2-(2-tritylaminothiazole-
The title compound is obtained in the same manner as in Example 2 from 4-yl)acetamido)-3-cephem-4-carboxilade and 2,3-dihydro-7(IH)-indolizinethione.

NMR (DMSO-d,) δ: 1.50 (311, m
), 2.00 (2H, m), 2.40 (2H, m), 3
．． 40 (211, m), 4.2-5.8 (4H, m),
6.6-7.1 (4tl, m), 7.1-7.5 (2H
, m), 8.0 to 8.9 (3H, +n) IR (KBr)
cm-': 3400,1?60,1600.15
30 Example 23 Diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-methoxyimino-2-(2-)lytylaminothiazol-4-yl)acetamide]-3-cephem-4
-carboxilade and 2,3-dihydro-3-methyl-
The title compound is obtained in the same manner as in Example 2 from 5-diphenyloxycarbonyl-7(III)-indolizinethione.

N) IR (DMSO-d,) δ: 1.40 (311,
d, J=6tlz), 2.00 (2!l,m).

2.44 (28, m), 3.3~3.7 (21!, +
n), 3.90 (38, s).

4.32 (0.5H, d, J=12Hz), 4.38 (
0.5H, d, J=12Hz).

4.74 (0.5H, d, J=12Hz), 4.8
0 (0,511, d, J=12Hz).

5.02 (111,d,, I'4Hz), 5.58 (I
H, m), 5.90 (IH, dd.

J=4 and 8Hz), 6.76 (IH, s), 7.28
(2H, br s).

7.76 (0,5H,s), 7.80 (0,5H,s)
, 8.00 (0,5H,s).

8.10 (0,5H, s), 9.56 (ltl, br
d, J=8)1z)IR(KBr) cmrV':
3400,1760,1605.1530Example 24 4diphenylmethyl 3-iodomethyl-7β-[(2
)-2-(1-methyl-1-diphenylmethyloxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-4-carboxilade and 2,3-dihydro- 3-Methyl-5-diphenylmethyloxycarbonyl-7(I
The title compound is obtained in the same manner as in Example 2 from H)-indolizinethione.

NMR (DMSO-d,) δ: 1.40 (6H, s)
, 1.44 (3H, d, J-6Hz).

2.00 (IH, m), 2.40 (IH, m), 3.2
2-3.60 (2H, m).

4.22 (0,511, d, J=14Hz), 4.32
(0,5H,d, J44Hz).

4.78 (0,51!, d, J=14tlz), 4.8
0(0,5!(,d,J44Hz).

5.00 (IH, d, J=4Hz), 5.64 (LH,
m)', 5.90 (IH, m).

6.72 (IH, s), 7.18 (2H, br s),
7.76 (IH, br s).

8.08 (IH, br 5) IR (KBr) alW-': 3400,1760
, 1605.1530 Example 25 17-yl)thiomethyl-3-cephem-4-carboxyladiphenylmethyl 3-iodomethyl-7β-[(Z)
-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-4
The title compound is obtained in the same manner as in Example 1 from -carboxilard and 2,3-dihydro-6-medoxy-3-methyl-7(lI()-indolizinethione.

NMR (D!'150-d,) δ: 1.32 (3tl
, d, J=6Hz), 2.04 (2H, m).

3.00 (2H, m), 3.3-3.6 (21 (, m)
, 3.83 (3H, s).

4.04 (3H, s), 4.46 (2H, m), 5.0
0 (mountain m), 5.02 (IH,'d, J=4Hz), 5
．． 60 (IH, dd, J = 4 and 8 Hz), 6.76 (
IH.

s), 7.26 (2H, br s), 8.50 (2H,
m), 9.55 (IH, br d.

J=8Hz) IR (KBr) cm-': 3400,1760,
1665,1615,1530.1500 Example 26 Hydro6-methoxy3-methyl-1■-indoliziniusylate diphenylmethyl 3-iodomethyl-7β-[(Z)
-2-(1-methyl-1-diphenylmethyloxycarbonylethoxyimino) -2-(2-tritylaminothiazol-4-yl)acetamide]-3-cephem-4-carboxilade and 2,3-dihydro-6 -Medoxy-3-methyl-7(1)1)-Indolizinethione to obtain the title compound in the same manner as in Example 2.

NMR (DMSO-d,) δ: 1.34 (6H, s)
, 1.60 (3H, d, J=6Hz).

2.00 (2H, m), 3.05 (211, l11),
3.3-3.6 (211, m).

4.00 (3H, s), 4.1-4.8 (2H, m),
5.00 (0.5H, d, J=411z), 5.02 (
0,5H,d, J=411z), 5.02(0,5H,
+a).

5.15 (0.5H, m), 5.62 (IH, +o)
, 6.76 (IH, s), 7.20 (2H, br s)
, 8.50(1)1. br s), 8.72 (LH, b
rs).

8.96 (ill, br 5) rR (KBr) c+n-': 3400,1765
．． +610. ．． 1530.1500 Example 27 6.7,8.9-tetrahydro-2(2H)-quinolidinethione (1) 1.71 g (4.26 mmol) of (3-hydroxypropyl)triphenylphosphonium bromide was dissolved in 17 m Q of tetrahydrofuran. The solution was cooled to -78°C, and 1.6N butyllithium hexane solution was added dropwise.The reaction mixture was warmed to room temperature, and then cooled to 78°C.
After stirring for an hour, a solution of 700 mg (3.28 mmol) of 4-benzyloxy-2-pyridinecarbaldehyde in 3.5 o+Q of tetrahydrofuran is added.

After stirring at room temperature overnight, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (Wakogel C-300, eluted with ethyl acetate) to give 4-(
4-Benzyloxy-2-pyridyl)-3-butene-1
670 mg (yield 80%) of -ol are obtained.

NMR (CDCI,) δ: 2.50 (211, m
), 3.80 (6 Hz at 211,t) + 5.08 (2
11, s), 6.55 (1) 1. d, J”1611z)
, 6.74 (IH, dd.

J=2 and 611z), 6.75(111,dt,,J
= 16 and 7Hz), 6.86 (IH, d, J = 2Hz
), 7.40 (511, m), 8.35 (IH, d, J
"6Hz) (2) Compound 1.18 obtained in the above reaction (1)
g (4.62 mmol) was dissolved in 22 mΩ of methanol, 120 mg of 1O% palladium on carbon catalyst was added, and catalytic reduction was carried out at room temperature. After 2 hours, 120 mg of the same catalyst was added and further reduced for 3 hours. After the catalyst is removed from the furnace, the solvent is distilled off under reduced pressure. The residue was dissolved in 10 m of tetrahydrofuran.
Dissolved in R, 2.42 g of triphenylphosphine (
9°23 mmol). 1.46 mΩ (9.23 mmol) of diethyl azodicarboxylate was added dropwise under water cooling and stirred at room temperature for 30 minutes. 1. The reaction solution was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (Wakogel C-300, eluted with 10% methanol), and 6
, 509 mg (yield 74%) of 7,8.9-tetrahydro-2(2H)-quinolidinone are obtained.

NMR (DMSO-d,) δ: 1.70 (211
, m), 1.84 (2H, m), 2.68 (211, t
, J=5Hz), 3.88 (211, L, J=6
tlz), 5.98 (IH, d.

J=211z), 6.02 (Ill, dd, J=2 and 611z), 7.54 (IH, d.

J=611z) (3) Compound 509+ng obtained in the above reaction (2) (3
, 42 mmol) in 5 mfl of pyridine, add 564+ng (2,54 mmol) of niline pentasulfide, and stir the reaction mixture at 80°C for 1 hour.Pour the reaction solution into water.
Extract three times with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is washed with ether-methanol to obtain 6,7,8.9-tetrahydro-2(2H)-quinolidinethione (yield 52%).

NMR (DMSO-d,) δ: 1.72 (2fl
, m), 1.90 (2H, m), 2.72 (2H, t,
J=6Hz), 4.00 (2tl, t, J=6tlz)
, 7.04 (IH, dd.

J = 2 and 6Hz), 7.12 (IH, d, J = 2tl
z), 7.50 (IH, d.

J=611z) IR(KBr) ci-' + 3400.1620,
1530,1460.1080UV (MeOIl)λ
nm: 204,240,339 Example 28 2.3-dihydro-7(IH)-indolizinethione (
1) 1.23 g (5.77 mmol) of 4-benzyloxy-2-pyridinecarbaldehyde was added to 20 g of dioxane.
1.55 g (6.23 mmol) of triethylphosphonoacetate and 0.41 g (8.65 mmol) of 50% oily sodium hydride are added at room temperature and the reaction mixture is stirred for 15 minutes. Pour the reaction solution into water,
Extract with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Woccogel C-300
, ethyl acetate-hexane=3:1) to obtain 0.90 g (yield 57%) of ethyl 3-(4-benzyloxy-2-pyridyl)acrylate.

NMR (CDC1,) δ: 1.35 (3H, t, J
=6H2), 4.32(2H,t.

611z), 5.16 (211,s), 6.90 (I
H, dd, J = 2 and 6 Hz).

6, 95 (Ift, d, J=1611z), 7.
06 (III, d, J=211z), 7.46 (
511,+n), 7.66(It(,d, J=16),
8.50 (lH, d, J=611z) (2) The above reaction (
Dissolve 3.0 g (11.1 mmol) of the compound obtained in 1) in 60 mQ of methylene chloride to make 1.5 M at -78'C.
Diisobutylaluminum hydride (toluene solution) 2
Add 2 mΩ (33.3 mmol). After stirring at the same temperature for 30 minutes, 2 mQ of acetic acid is added, and the reaction mixture is further stirred at room temperature for 10 minutes. The reaction solution was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, eluted with ethyl acetate) to give 3-(4-benzyloxy-
2-pyridyl)-2-propen-1-olz, ug(
Yield: 83%).

NMR (CDCl2) δ: 4.42 (2H, d, J
=4)1z), 5.12(2H,s).

6.68 (LH, d, J=16tlz), 6.78
(IH, dd, J=2 and 6Hz).

6.88 (LH, dtj=16 and 4Hz), 6.92
(IH, d, J=2Hz).

8.42 (IH, d, J = 6Hz) (3) 2.11 g of the compound obtained in the above reaction (2) (9
, 21 mmol) in the same manner as in Example 27-(2) to obtain 1.09 g (yield: 88%) of 2,3-dihydro-7(IH)-indolizinone.

NMR (DMSO-d,) δ: 2.15 (2H, m)
, 2.95 (2H, t, J: 6) 1z).

4.08 (2B, L, J=6Hz), 6.03 (IH,
d, 6 Hz), 6.05 (ill, s), 7.72 (
IH, d, 6Hz) IR (KBr) cmn':
3400,1640.1540LIV (MeOII)
λnm: 204,258 (4) Using 1.09 g (8,07 mmol) of the compound obtained in reaction (3) above, the same reaction as in Example 27-(3) was carried out to obtain 2,3-dihydro- 7(Ill)-Indolizinethione 300mg
(yield 25%) and raw material 320mg (recovery rate 26%)
).

NMR (DMSO-d,) δ: 2.20 (2B, l
11), 3.04 (2H, t, J=6Hz).

4.20 (211,t, J=6Hz), 7.12 (II
I, br d, J = 6Hz).

7.22 (IH, br s), 7.74 (IH, br s)
s, 641z) Example 29 2.3-dihydro-3-methyl-711I)-indolizinethione (1) 10 g (54.6 mmol) of 4-hydroxy-2,6-pyridinedicarboxylic acid was reacted with N,N- 19.5 taQ (164 mmol) of benzyl bromide and N,N-
Diisopropylethylamine 28.5m Q (164
mmol). After stirring for 2 hours, a further 6.511 IQ (54.6 mmol) of benzyl bromide and 7.5 g (54.6 mmol) of potassium carbonate are added. The reaction mixture is heated and stirred at 80° C. for 30 minutes. 1. The reaction mixture is allowed to cool to room temperature, then poured into water 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 (Wakogel C-300, eluted with ethyl acetate-hexane = 1:1) to obtain 19.3 g (78%) of crystals of dibenzyl 4-benzyloxy-2,6-biricine dicarboxylate. ).

NMR (cDcl,) δ: 5.24 (2H, s)
, 5.48 (4H, s), 7.2-7.7 (15■, +
a), 7.88 (21(,5)IR(KBr) cra
-': 1720, 1590, 1350, 1240.
1110 (2) 5.0 g of the compound obtained in the above reaction (1) (
11,.

5.5 mQ (11.0 mmol) of 2N sodium hydroxide was added at room temperature. 15
After stirring for a minute, the solvent is evaporated under reduced pressure and the residue is diluted with water. Wash the mixture with ethyl acetate. The aqueous layer was adjusted to pH 4.0 with dilute hydrochloric acid and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.39 g of a solid residue of 4-benzyloxy-6-methoxycarbonylpicolinic acid.

(3) Add diphenyl ether 6 and OmQ to the residue obtained in reaction (2) above, and heat the mixture for 30 minutes in an oil bath preheated to 180°C. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. IN organic layer
Extract three times with hydrochloric acid. The aqueous layer is collected, adjusted to ptno, o by adding 20% sodium hydroxide, and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.07 g (yield 77%) of methyl 4-penzyloxybicolinate as a solid.

NMR (CDCI,) δ: 4.04 (3H, s),
5.22 (2H, s), 7.08 (IH, dd, J=
2 and 6 Hz), 7.44 (58, m), 7.80 (I
H,d.

J=2■Z), 8.80 (IH, d, J=6Hz)IR
(KBr) cm-': +730.1580,13
00.1220 (4) Compound 2 obtained in the above reaction (3).
62 g (10,8 mmol) of methylene chloride 52 m
1.5M diisobutylaluminum hydride (toluene solution) 21.6n+Q(32
, 4 mmol) was added dropwise.

After stirring for 1 hour, 4.6 rnQ of acetic acid is added. The reaction mixture was allowed to warm up to room temperature, then poured into saturated sodium bicarbonate solution,
Extract with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to leave a solid residue of 4-benzyloxy-2-pyridinecarbaldehyde (2.28 g).
g (yield 99%).

NMR (CDCI,) δ: 5.20 (2H, s),
7.10 (ill, dd, 'J'2 and 6Hz), 7.
44 (5H, m), 7.60 (IH, d, J=2) 1z
), 8.62 (IH, d, J=6Hz) IR (KBr) cm-': 1700, 1580,
1480,1360.1300 (5) 1.0 g (4,69 mmol) of the compound obtained in reaction (4) above was dissolved in dioxane 10IIIQ, and 1.50 g (4,71 0 Stir the reaction solution at 80°C for 30 minutes. 6 Condense the reaction solution under reduced pressure and collect the residue by silica gel column chromatography (Wakogel C-300, ethyl acetate)
4-(4-benzyloxy-2-pyridyl)-3=buten-2-one 1.7
6 g (containing triphenylphosphine oxyto) are obtained.

NMR (DCI3) δ: 2.40 (311,s
), 5.16 (2B, s), 6.88 (III, dd,
J=2 and 6Hz), 7.10 (IH, d, , J'2H
z), 7.15 (III, d, J=16) 1z), 7
．． 44 (5H, l11), 7.48 (IH, d, J=1
611Z), 8.48 (IH, d, J = 6) IZ) (6
) 1.76 g of the compound obtained in reaction (5) above was dissolved in 20 mΩ of methanol, and 0.0 g of sodium borohydride was dissolved at 0°C.
Add 18 g (4.73 mmol). After stirring for 1 hour, 0.5 mQ of acetic acid was added. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 4-(
6HMR (CDCIj) to obtain 1.90 g of crude product of 4-benzyl-2-pyridyl)-3-puten-2-ol.
δ: 1.40 (3H, d, J=6Hz), 4.56
(LH, m).

5.12 (2H, s), 6.62 (IH, d, J=16
Hz), 6.78 (IH, dd.

J = 2 and 6 Hz), 6.70 (111, dd, J = 6
and 1611Z), 6.90 (Ill, d, J=2Hz
), 7.3-7.6 (5) 1. +n), 8.40(
IH, d, J = 611z) (7) 2.72 g of the compound obtained in the above reaction (6) (1
0.7 mmol) was subjected to the same reaction as in Example 27-(2) to obtain 2,3-dihydro-3-methyl-7 (III
)-indolizinone 478II (yield from 4-benzyloxy-2-pyridinecarbaldehyde in step (4): 48%) is obtained.

NMR(DNSO-d,)δ: 1.38(31(,d
, 6Hz), 1.78 (IH, m).

2.38 (IH, m), 2.95 (2H, +o), 4.
38 (IH, m), 6.02 (IH.

br s), 6.06(1)1. br d, J'6Hz
), 7.76 (IH, d, J = 6H2) (8) 0.78 g of the compound obtained in the above reaction (7) (5
, 23 mmol) was carried out in the same manner as in Example 27-(3) to produce 2,3-dihydro-3-methyl-7(I
H)-indolizinethione 0.44 g (yield 51%
).

NMR (DMSO-d,) δ: 1.40 (3H, d,
J=6Hz), 1.90 (IH, m).

2.40 (IH, m), 3.00 (2) 1. m), 4.
35 (IH, m), 7.16 (III.

dd, J = 2 and 6 Hz), 7.20 (IH, d, J =
2Hz), 7.78 (IH.

d, J = 6 Hz) Example 30 (1) 5.0 g (27.3 mmol) of 4-hydroxy-2,6-pyridinedicarboxylic acid was dissolved in a mixture of 5 methanol ρ and 50 m (l) of ethyl acetate, and diphenyldiazomethane was added. Add 20 g (0.10 mmol) several times at room temperature. After stirring for 2 hours, the reaction mixture is poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate. Reduced pressure. The solvent was distilled off and the residue was subjected to silica gel column chromatography (Wako gel).
C-300, eluted with ethyl acetate-hexane=1=1) to give 9.1 g of crystals of 2,6-di(diphenylmethyloxycarbonyl)-4-hydroxypyridine (yield: 6
4%).

NMR (CDCI,) δ: 7.06 (24+, s),
7.2-7.6 (22)1. m) (2) The above reaction (1)
3.0 g (5.82 mmol) of the compound obtained in N,
Dissolved in 30+n Q of N-dimethylformamide, 804 mg (5.82 mmol) of potassium carbonate and 1. Add OmQ (8.8 mmol).

Stir the mixture at 80° C. for 1 hour. After cooling to room temperature,
Pour the reaction mixture into water and extract with mr1i ethyl.

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 (Wakogel C-300, ethyl acetate-hexane =
1:1) to give a solid of di(diphenylmethyl)4-benzyloxy-2,6-pyricinedicarboxylate 3. o3g (yield 74%) is obtained.

NMR (CDCI,) δ: 5.20 (2M, s)
, 7.16(2)1. s), 7.2-7.6 (2011
, m), 7.88 (2H,5) (3) Dissolve 6.0 g (9.92 mmol) of the compound obtained in the above reaction (2) in 120 mQ of methylene chloride, and add 1.5 M diisobutyl hydride at -78°C. Aluminum (toluene solution') 19.8+
n 12 (29.7 mmol) is added dropwise. After stirring for 30 minutes, add 6 mfl of acetic acid. The reaction mixture is warmed to room temperature, then poured into saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. Dioxane the residue at 40mf
), add 3.15 g (9.90 mmol) of triphenylphosphoranylidene-2-propanone,
Stir the mixture at 80°C for 30 minutes. 1. Stir the reaction mixture under reduced pressure.
! :41H, the precipitated crystals were washed with a mixture of methylene chloride and ethyl acetate to obtain 2.17 g of 4-(4-penzyloxy-6-cyphenylmethyloxycarbonyl-2-pyridyl)-3-buten-2-one ( yield of 47%).

(4) Compound 83 axis g (1,7
9 mmol) was suspended in a mixture of 10+11 Q methanol and 4 mfl methylene chloride, and 150 mg (3.95 mmol) of sodium borohydride was added at room temperature. 1
After stirring for an hour, add 0.5 mn of acetic acid. The reaction mixture is poured into saturated sodium bicarbonate solution and extracted 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 (
Wakogel C-300, ethyl acetate-hexane = 1:
4-(4-benzyloxy-6-diphenylmethyloxycarbonyl-2-pyridyl)-3
321 mg (yield 38%) of -buten-2-ol are obtained.

NMR (CDCI, ) δ: 1.42 (3H, d
, J=6Hz), 4.60(LH, m).

5.20 (211, s), 6.76 (IH, d, J: 1
6Hz), 6.94 (IH, dd.

J=5 and 16tlz), 7.05(IH,d, J=2
11z), 7.18(III, s).

7.2-7.6 (+5H, m), 7.62 (Iff, d
, J: 2Hz) (5) Compound 78 obtained in the above reaction (4)
0 mg (1,68 mmol) in methanol 16 m n
Add 70 rng of 10% palladium on carbon catalyst and carry out indirect contact light for 30 minutes at room temperature. After removing the catalyst from the furnace, add 326 mg of diphenyldiazomethane (1,
68 mmol) is added and the mixture is stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300, 5% methanol).
6-(3-hydroxybutyl)-2-diphenylmethyloxycarbonyl-4-
512 mg (81% yield) of hydroxypyridine are obtained.

Nl'lR(CDC1,) δ: 122(3tl, d
, J=6tlz), 1.6-2.0 (2H, l11),
2.78 (2H, m), 3.92 (LH, m), 6.4
8 (IH, d.

J=2Hz), 7.02 (IH, s), 7.1-7.8
(IH, l11) (6) Compound 5 obtained in the above reaction (5)
12 mg (1.36 mmol) is dissolved in 10 mfl of tetrahydrofuran, and 356 mg (1.36 mmol) of triphenylphosphine and 236+ ng (1.36 mmol) of diethyl azodicarboxylate are added while cooling with water.

After stirring at room temperature for 10 minutes, the same amounts of triphenylphosphine and diethyl azodicarboxylate are added again while cooling with water, 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 (Wakogel C-300, eluted with 5% methanol-methylene chloride) to obtain 2,3-dihydro-3-methyl-5-diphenylmethyloxycarbonyl. −7(t++
)-indolizinone 363 mg (yield 74%) is obtained.

NMR (CDCI,) δ: 1.20 (3H, d, J
=6Hz), 1.96 (IH, m).

2.32 (IH, a+), 3.00 (2H, m), 5.
42 (IH, m), 6.46 (IH.

br s), 7.04 (IH, s), 7.2-7.6 (
101(,m)(7) Compound 35 obtained in the above reaction (6)
0 mg (0.97 mmol) dissolved in 3.6 m Q of pyridine, 449 mg (2.02 mmol) of phosphorus trisulfide
Add. Stir the mixture at 100°C for 30 minutes. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography (Merk Art 571
7. (developed with 5% methanol-methylene chloride),
235 mg (yield: 65%) of 2,3-dihydro-3-methyl-5-diphenylmethyloxycarbonyl-7(III)-indolysinthione is obtained.

NMR (CDC1,,) δ: 1.22 (3H, d
, J=6Hz), 1.98 (IH, m).

2.38 (11 (, m), 3.04 (2H, m), 5.
54(it(,m), 7.06(IH,s), 7.2
~7.6 (IIH, l11), 8.16 (IH, br
s) Example 31 (1) 2-carboxy-5-methoxy-4-pyrone9.
2g (5.4 mmol) in concentrated ammonia water 30IIlΩ
Heat and stir at 100°C overnight. After cooling, the solvent is distilled off under reduced pressure. The residue was washed with a mixture of ethyl acetate and methanol to obtain 4.73 g (yield: 52%) of 2-carboxy-5-methoxy-4-pyridone as a solid.

NMR (1)! ! 5o-d, ) δ: 3.66 (3L
s), 6.52 (ILs), 7.16 (LH, br 5
) (2) 2.73 g (1,6
mmol) to N,N-dimethylformamide 27 m 1
2, and add 6.6 g (4.8 mmol) of potassium carbonate and 5.6 mQ (4.8 mmol) of benzyl chloride.

Stir the mixture at 80° C. for 1 hour. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue is washed with ethyl acetate to obtain 2.45 g (43% yield) of benzyl 4-benzyloxy-5-methoxybicolinate.

NMR (DNSO-d,) δ: 4.02 (3H,
S), 5.22 (2H, S), 5.42 (211, s)
, 7.2-7.6 (1011, m), 7.76 (IHl
s), 8.28 (LH, 5) (3) The same reaction as in Example 30-(3) was carried out using 2.45 g of the compound obtained in the above reaction (2), and 4-(4-benzyloxy- 2.24 g of 5-methoxy-2-pyridyl)-3-buten-2-one (containing a small amount of triphenylphosphine oxide) are obtained.

NMR (CDCI,) δ: 2.38 (3H, s), 4
．． 00 (3H, s), 5.22 (2) 1. s), 6.9
4 (IH, d, J = 16 Hz), 7.08 (III, s
), 7.3-7.6 (6H, l11), 8.20 (IH
, 5) (4) 2.24 g of the crude product obtained in the above reaction (3)
Then, the same reaction as in Example 30-(4) was carried out to obtain 4-(
4-benzyloxy-5-methoxy-2-pyridyl)-
0.83 g of 3-buten-2-ol (yield from 2-carboxy-5-methoxy-4-pyridone in step (2) above: 37%) is obtained.

NMR (CDCI,) δ: 1.35 (3H, d,
J=6H2), 3.94 (38,S).

4-4-50(IH4+5.20(211,s)+6.
54 (2H9m), 6.8 (IH9s), 7.3-7.
6 (5H, m), 8.08 (IH, 5) (5) Example 29-(7) from 0.83 g of the compound obtained in the above reaction (4)
2,3-dihydro-6-medoxy-3-methyl-7(IH)-indolizinone 481a
+g (93% yield) is obtained.

NMR (CD, OD+CDC1,) δ: 2.55
(311, d, J=611z), 2.00 (III,
l11), 2.56(ill, m), 3.10(
2H, m), 3.86 (3tl, s).

4.56 (IH, m), 6.42 (18, br s),
7.36 (III, 5) (6) Using 481 mg of the compound obtained in the above reaction (5), the same reaction as in Example 27-(3) was carried out to obtain 2.3-dihydro-6-medoxy-3-methyl-7. 294 mg (yield 56%) of (III)-indolizinethione are obtained.

NMR (CD, OD+CDC1,) δ: 1.60 (
3B, d, J=6Hz), 2.05 (IH, m), 2.
58 (ltl, m), 3.16 (211, m), 3
．． 92 (311, s).

4.62 (ill, m), 7.32 (IH, s), 7.
70(II!,s) Example 32 3.4-dihydro-8(ill)-pyrido(2,1-c
) [1,4) Oxazinethione (1) Lithium aluminum hydride 156mg (4,
20ml of tetrahydrofuran solution containing 10mmol)
1.0 g (4.11 mmol) of methyl 4-penzyloxybicolinate is added to Q at -78 DEG C. and the reaction mixture is stirred for 15 minutes. Add ethyl acetate to the reaction solution. After the mixture is heated to room temperature, it is washed with saturated sodium bicarbonate solution.

The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was dissolved in 5.0 m Q of acetic acid, and 0.26 g of sodium cyanoborohydride (4,
14 mmol). After stirring the reaction mixture for 30 minutes, the solvent is distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate 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 of 4-benzyl-2-hydroxymethylpyridine as a solid (yield: 96%).
).

NMR (CDCI,) δ: 4.72 (211, br
s), 5.12 (2H, s), 6.82 (III, br
d, J=611z), 6.86 (III, br s)
, 7.42 (511, m).

8.38 (IH, d, J=611Z) IR (KBr) cm-': 3200, 1600,
1310.1010 (2) 1.92 g (8.93 mmol) of the compound obtained in the above reaction (1) was dissolved in methylene chloride 2
Dissolve in 1.0 mO of thionyl chloride. Add axis Q (13,7 mmol). Pyridine 0.70m under water cooling Q
(8.86 mmol) was added dropwise and the mixture was stirred for 30 minutes. The reaction solution was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.54 g (yield: 74%) of a crude product of 4-benzyl-2-chloromethylpyridine.

(3) 1.2 g of the crude product obtained in reaction (2) above (5,1
4 mmol) and 1.0 g (6.6 mmol) of sodium iodide in 3.0 m of N,N-dimethylformamide Q
Suspend in 2-benzyloxyethanol 1.2 g
(7.89 mmol) is dissolved in 24 mQ of N,N-dimethylformamide, 1.90 g (39.6 mmol) of 50% sodium hydride is added at room temperature, and the suspension prepared above is added to this mixture. After stirring for 30 minutes at room temperature, the reaction solution is poured into water 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 (
Wakogel C-300, Ml'acid ethyl hexane=
4-benzyloxy-2-(2
-benzyloxyethoxymethyl)pyridine 1.56g
(yield 87%).

NMR (CDCI,) δ: 3.75 (21+, m),
3.78 (211, m), 4.62 (2H, s), 4.
70 (2H, s), 5.10 (2H, s), 6.80 (
IH, dd.

J = 2 and 611z), 7, 16 (IH, d, J
=2Hz), 7.2~? , 6 (108, m), 8.38
(l) l, d, J = 611z) (4) Dissolve 200 mg (0.57 mmol) of the compound obtained in the above reaction (3) in ethanol (4.0 mf), and add 40 mg of 10% palladium on carbon catalyst. Catalytic reduction is carried out at 80° C. for 3 hours. The catalyst is separated from the furnace and the solvent is distilled off under reduced pressure to obtain a residue of 2-(2- and droxyethoxymethyl)-4-pyridone.

(5) The residue obtained in reaction (4) above and 264 mg (1.41 mmol) of triphenylphosphine are dissolved in 2.0 mQ of tetrahydrofuran, and diethyl azodicarboxylate long (1.03 mmol) is added dropwise at room temperature.

After stirring for 1 hour, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (MerkArt57
17. Developed with 10% methanol-methylene chloride) to give 3,4-dihydro-8(IH)-pyrido[2,1-c
] (1,4) Oxazinone 70n+g is obtained.

NMR (DMSO-d,) δ: 3.98 (2H1m
), 4.02 (2H, Ill), 4-64 (2H
, s), 5.96 (IH, d, J=211z), 6.1
0 (LH, dd, , C2 and 6H2), 7.58 (IH
, d, J = 6) IZ) (6) 0.74 g (4.90 mmol) of the compound obtained in the above reaction (5) was added to Example 27-
A reaction similar to (3) was carried out, and 3,4-dihydro-8(
470 mg (yield 57%) of IH)-pyrido(2,1-c)(1,4)oxazinethione are obtained.

NMR (DMSO-d,) δ: 4.04 (4H, s)
, 4.70(211,s), 7.06(11(,d,J
= 2Hz), 7.10 (IH, dd, J = 2 and 6tl
z), 7.54 (III, d, J = 6 Hz) The compound of the present invention is a new compound that has not been described in any literature, and is effective against sensitive and resistant Durum-positive and Durum-negative bacteria, especially methicillin-resistant It has unexpectedly strong antibacterial activity against glucose non-fermenting Durum-negative bacilli including Staphylococcus aureus and Pseudomonas aeruginosa, has excellent stability against β-lactamase, and is effective as an antibacterial agent.

Claims (5)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 is a hydrogen atom, a lower alkyl group that may have a substituent, or a lower alkyl group that may have a substituent. A lower alkenyl group, a lower alkynyl group that may have a substituent, or an aralkyl group that may have a substituent, R^2 is a hydrogen atom, a negative charge, or a nontoxic group that can be hydrolyzed in the living body. Group A is an alkylene group which may contain an unsaturated bond (where the carbon atom of the alkylene group is at least one of an oxygen atom, a sulfur atom, or a nitrogen atom). The bicyclic heterocycle formed by the pyridine ring and the group A may have the same or different 1 to 3 substituents. or a non-toxic salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^3 is a hydrogen atom or a protecting group for an amino group, R
^4 is a hydrogen atom, a lower alkyl group that may have a protected substituent, a lower alkenyl group that may have a protected substituent, or a protected substituent. A lower alkynyl group or an aralkyl group which may have a protected substituent, R^5 represents a hydrogen atom, a negative charge or a carboxyl group protecting group, and X represents a leaving group, respectively] The compound or its salt has a general formula▲mathematical formula, chemical formula, table, etc.▼(III) [In the formula, group B is an alkylene group that may contain an unsaturated bond (in addition, if the carbon atom of the alkylene group is oxygen atom, sulfur atom, or nitrogen atom), and the bicyclic heterocycle formed by the pyridine ring and the group B has 1 to 3 atoms that are the same or different. A compound represented by the general formula ▲ includes a mathematical formula, a chemical formula, a table, etc. ▼ (IV) [in the formula , R^3, R^4, R^5 and group B have the above-mentioned meanings, and X^■ means an anion], and then, if necessary, (i) step (ii) of removing the protecting group; step (iii) of converting the free acid into its non-toxic salt;
) A general formula that is characterized by performing one or more steps beyond the step of converting a free acid into its nontoxic ester that can be hydrolyzed in vivo ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) , R^1 represents a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, a lower alkynyl group that may have a substituent, or a substituent. R^2 is a hydrogen atom, a negative charge, or an ester residue capable of forming a nontoxic ester that can be hydrolyzed in vivo, and group A is an aralkyl group that may contain an unsaturated bond. a good alkylene group (the carbon atom of the alkylene group may be replaced with at least one of oxygen atom, sulfur atom or nitrogen atom), and is formed by the pyridine ring and the group A. The bicyclic heterocycle may have 1 to 3 substituents that are the same or different.] or a non-toxic salt thereof. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) [In the formula, R^6 is a hydrogen atom, a protecting group for an amino group, or general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula , R^3 is a hydrogen atom or a protecting group for an amino group, R^4 is a hydrogen atom, a protecting group for a hydroxyl group, a lower alkyl group that may have a protected substituent, or a protecting group for a protected substituent. a lower alkenyl group that may have an optionally protected substituent, a lower alkynyl group that may have a protected substituent, or an aralkyl group that may have a protected substituent, respectively. R^5 is a hydrogen atom, a negative charge, or a carboxyl group protecting group, and group B is an alkylene group that may contain an unsaturated bond (the carbon atom of the alkylene group is an oxygen atom, a sulfur atom, or a nitrogen atom). at least one of
The bicyclic heterocycle formed by the pyridine ring and the group B has 1 to 3 substituents that are the same or different (the substituents may be protected). ) or a non-toxic salt thereof. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) [In the formula, group B is an alkylene group that may contain an unsaturated bond (in addition, the carbon atom of the alkylene group is an oxygen atom, a sulfur The bicyclic heterocycle formed by the pyridine ring and the group B may be substituted with at least one atom or nitrogen atom), and the bicyclic heterocycle formed by the pyridine ring and the group B may be substituted with 1 to 3 same or different substituents ( A compound represented by the above formula, which may be protected by the substituent. (5) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 is a hydrogen atom, a lower alkyl group that may have a substituent, or a lower alkyl group that may have a substituent. A lower alkenyl group, a lower alkynyl group that may have a substituent, or an aralkyl group that may have a substituent, R^2 is a hydrogen atom, a negative charge, or a nontoxic group that can be hydrolyzed in the living body. Group A is an alkylene group which may contain an unsaturated bond (the carbon atom of the alkylene group is at least one of an oxygen atom, a sulfur atom, or a nitrogen atom). and the bicyclic heterocycle formed by the pyridine ring and the group A may have 1 to 3 substituents that are the same or different. or an antibacterial agent containing its non-toxic salt as an active ingredient.