JPS62123189A - Cephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [n is 1 or 2; Y represents CH or N; R1 represents lower hydrocarbon, carboxyl-substituted lower alkyl, carbamoyl-substituted lower alkyl or cyclopropyl-substituted lower alkyl; R2 represents OH, (hydroxyl-substituted) lower alkyl or carbamoyl] and salt thereof. EXAMPLE:7beta-[( Z )-2-( 2-Aminothiazol-4-yl )-2-methoxyiminoacetamido)-3-(4-hydro xy-1,4-methylene-1-pyperidinio)methyl-3-cephem-4-carboxylate expressed by formu la II. USE:An antimicrobial agent against Gram-positive and Gram-negative bacteria. PREPARATION:A compound expressed by formula III (X is halogen atom), a derivative thereof wherein amino group and carboxyl group are protected or a salt thereof is reacted with a compound expressed by formula IV or a salt thereof, and, as necessary, followed by elimination of the protecting group.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel cephem derivatives useful as antibacterial agents.

Conventionally, many compounds are known as compounds having a substituted thiadiazolyl acetamide group or a substituted thiazolyl acetamide group at the 7-position of the cephem skeleton. for example,
JP-A-55-11600, JP-A-55-105689
No., JP-A-57-24389, JP-A-57-8149
No. 3, JP-A-58-4789, JP-A-58-4188
No. 7, JP-A-58-59992, JP-A-51-149
No. 296, JP-A-52-102293, JP-A-52-
116492, JP 52-125190, JP 54-154786, JP 57-192394,
JP-A-59-219292, JP-A-60-97982
No., JP-A-60-197693, JP-A-60-231
Examples include compounds described in publications such as No. 683. In particular, JP-A-59-219292, JP-A-60-197693
7β-((
Z) -2-(2-aminothiazol-4-yl)-2
-methoxyiminoacetamide]-3-(1-quinuclidinio)methyl-3-cephem-4-carboxylate is described.

This compound has an acute toxicity value (LDso (intravenous injection))
It is a compound that has extremely high toxicity of less than 100 mg/hrt and cannot be used clinically.

The present inventors have discovered that compounds having a group represented by a group, a lower alkyl group, a hydroxy-substituted lower alkyl group, or a carbamoyl group at the 3-position of the cephem skeleton have excellent antibacterial activity. It is completed.

Therefore, an object of the present invention is to provide a novel compound useful as an antibacterial agent, a method for producing the same, and its use as an antibacterial agent.

[Structure of the invention]

The compound of the present invention is represented as follows.

General formula: [In the formula, n is 1 or 2. Y is CH or nitrogen atom.

R1 is a lower hydrocarbon group, a carboxy-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, or a cyclopropyl-substituted lower alkyl group, and Rx is a hydroxyl group.

lower alkyl group, hydroxy-substituted lower alkyl group or carbamoyl group] and non-toxic salts thereof.The lower hydrocarbon group for R1 in the above general formula (I) is as follows:

Methyl, ethyl, n-propyl, i-propyl.

Lower alkyl groups such as n-butyl, t-butyl, and 5ec-butyl; lower alkenyl groups such as vinyl and allyl;
Examples include lower alkynyl groups such as propargyl. Further, carboxy-substituted lower alkyl group of Rs includes carboxymethyl, 2-carboxyethyl, 3-carboxyethyl,
Examples include carboxypropyl, 1-carboxyethyl, 1-carboxy-1-methylethyl, and the like. Examples of the carbamoyl-substituted lower alkyl group for R1 include carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl, 1-carbamoyl-1-methylethyl, and 1-carbamoylethyl. Examples of the cyclopropyl-substituted lower alkyl group for R1 include cyclopropylmethyl and 2-cyclopropylethyl.

As the hydroxy-substituted lower alkyl group for R2.

Examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl. The lower alkyl group for R2 is methyl, ethyl, n
-propyl, 1'-propyl, n-butyl, t-butyl and the like.

Non-toxic salts of the compound of general formula (I) include pharmaceutically acceptable salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; hydrochlorides.

Hydrobromide, hydroiodide, sulfate, carbonate.

Inorganic acid salts such as bicarbonate; maleate, lactate.

Organic carboxylates such as tartrate; organic sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate; arginine salt.

Amino acid salts such as lysine salts, serine salts, aspartate salts, glutamate salts; trimethylamine salts.

Triethylamine salt, pyridine salt, brocaine salt.

Amines such as picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzylamine salt Examples include salt.

Concerning the steric coordination of the following moieties of the compound of the present invention of general formula (I).

C- SuOR・ There is a syn isomer (Z) and an anti isomer (E).

Although both isomers are included in the present invention, the syn isomer is preferred from the standpoint of antibacterial activity.

The compound of the present invention can be produced by the method shown below.

Production method I A compound represented by the general formula: [In the formula, Y and R+ are the same as defined above, and X represents a halogen atom], a compound whose amino group and/or carboxyl group is protected with a protecting group,
or a salt thereof is reacted with a compound represented by the general formula: [In the formula, n and R2 are the same as defined above] or a salt thereof, and if necessary, the protecting group is removed to form the compound of the general formula (I) and its salt. Non-toxic salts can be obtained.

The halogen atom of X in the above general formula (n) is:

Examples include iodine atom, bromine atom, and chlorine atom.

Particularly desirable are iodine atoms and bromine atoms.

The above reaction can be carried out at a reaction temperature of -10'C to 60C, preferably 0C to 40C. Further, as the reaction solvent, an anhydrous organic solvent is preferable. Organic solvents that can be used include lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl halides such as chloromethane, methylene chloride, and chloroform; ethers such as tetrahydrofuran and dioxane;
, amides such as N-dimethylformamide; esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene, or mixed solvents thereof.

As protecting groups for the salts of the compounds of general formulas (II) and (III) and the amine group and carboxyl group of the compound of general formula (II), commonly used ones may be used as long as they do not interfere with the above reaction. can be used.

For example, a formyl group is a protecting group for an amino group.

Acetyl group, chloroacetyl group, dichloroacetyl group,
t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p-methoxybenzyl group, diphenylmethyl group, etc.; Protecting groups for Calhoki A include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, Methyl group.

2.2.2-t+) chloroethyl group, diphenylmethyl group, pivaloyloxymethyl group, etc.

Also, bis(trimethylsilyl)acetamide, N-methyl-N-(trimethylsilyl)acetamide.

If a silylating agent such as N-methyl-N-)limethylsilyrutrifluoroacetamide is used.

This is convenient because the amino group and the carboxy group can be protected at the same time.

As salts of compounds of general formulas (I[) and (III).

Alkali metal salts such as sodium salts and potassium salts;
Alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochlorides, hydrobromides, sulfates,
Inorganic acid salts such as carbonates, hydroiodides, bicarbonates; acetates, maleates, lactates.

Organic carboxylates such as tartrates; methanesulfonates,
Organic sulfonates such as benzenesulfonate and toluenesulfonate; trimethylamine salt.

Triethylamine salt, pyridine salt, propyroine salt.

Amines such as picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzylamine salt, etc. Salt: Arginine salt, aspartate, lysine salt.

It can be appropriately selected from salts such as amino acid salts such as glutamate and serine salts.

Removal of protecting groups depends on the type of protecting group used.

This can be carried out by conventional methods such as hydrolysis and reduction.

Manufacturing method ■ A compound represented by the general formula: [In the formula, n and R1 are the same as defined above], a compound whose -000- is protected with a protecting group, or a salt thereof, the general formula: [In the formula, Rte Y is the same as the above formula a], a compound whose amino group is protected with a protecting group,
The compound of general formula (I) and its non-toxic salt can be obtained by reacting reactive derivatives at the carboxyl group or salts of those compounds and, if necessary, removing the protecting group.

This method can be carried out according to conventional N-acylation reaction conditions. For example, in an inert solvent, in the presence or absence of a base, at -50°C to 50°C9, preferably -20°C.
The reaction can be carried out at ~30°C. Inert solvents include acetone and tetrahydrofuran.

N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, dichloromethane, chloroform, benzene, toluene, acetonitrile.

Alternatively, a mixed solvent thereof may be used. As the base, N,N-dimethylaniline, triethylamine,
Examples include pyridine and N-methylmorpholine.

In the method of the present invention, when a carboxylic acid (-〇〇〇H) represented by the general formula (■) is used, for example, 9.

N,N'-dicyclohexylcarbodiimide, N,N'
-diethylcarbodiimide, N-cyclohexyl-N'
- The reaction is preferably carried out in the presence of a condensing agent such as morpholinoethylcarbodiimide, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, p-toluenesulfonic acid chloride. In addition, when using a reactive derivative at the carboxyl group of general formula (V), examples of the 9-reactive derivative include acid halides such as acid chlorides and acid bromides; symmetric acids! ! [Water; mixed acid anhydrides with carboxylic acids such as ethyl chlorocarbonate, trimethylacetic acid, thioacetic acid, and diphenylacetic acid; 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2.4-dinitrophenol, pentachlorophenol Active esters of sea lion; active acid amides with saccharin, etc. are used.

As the protecting group for 1000- in the compound of general formula (IV), the groups listed above as the protecting group for the carboxyl group of the compound of general formula (If) can be used. Also, the general formula (
As a protecting group for the amino group of the compound (2), the above general formula (I
This can be achieved by using the groups listed above as the protecting group for the amino group of the compound [). These protecting groups can be hydrolyzed depending on the type of protecting group used.

It can be removed by conventional methods such as reduction.

As salts of the compounds of general formulas (IV) and (to).

For example, the salts of general formulas (II) and (II) mentioned above can be appropriately selected and used.

The following general formula including the compound of the general formula (IV) and intermediates thereof: [wherein n, R2 are as defined above, a is 0 or 1. R3 is a hydrogen atom or a protecting group for an amine group, A is an anion, and when Ra is 1000-, bi'i
o.

The compound represented by R4 is -COORa (when Ra is a carboxyl protecting group, b represents 1) and its salt are new compounds.

This compound is an intermediate for the compound of the present invention represented by the above general formula (I), and is used in producing the compound of the present invention by the above-mentioned production method ①.

As the protecting group for the amino group of R3 in the compound of the above general formula (VD), 9 are commonly used 2, such as formyl,
Acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl, 2-f enylacetyl, 2
- Substituted or unsubstituted lower alkanoyl groups such as furylacetyl, phenoxyacetyl; substituted or unsubstituted lower alkoxycarbonyl groups such as benzyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl; trityl, p Examples include substituted lower alkyl groups such as -methoxybenzyl and diphenylmethyl; substituted silyl groups such as trimethylsilyl and t-butyldimethylsilyl.

Protecting groups for the carboxyl group of R5 include those commonly used, such as methyl, ethyl, and propyl.

Substituted or unsubstituted lower alkyl groups such as t-methyl, 2,2.2-trichloroethyl, valeryloxymethyl, pivaloyloxymethyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl; trimethylsilyl, t Examples include substituted silyl groups such as -butyldimethylsilyl.

Examples of anions of A include chlor ion, glome ion,
Examples include halogen ions such as iodine ions; inorganic acid ions such as sulfate ions and nitrate ions.

Examples of the salt of the compound of the general formula (VI) include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and carbonic salt 9 bicarbonate; acetate and maleate.

Organic carboxylates such as lactate, tartrate, trifluoroacetate; organic sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate; amino acid salts such as aspartate, glutamate, etc. can give.

The compound of general formula (VI) can be produced by the method shown below.

General formula: [In the formula, a and R3 are the same as defined above, Rs is a hydrogen atom or a protecting group for a carboxyl group, and Z is a halogen atom or a lower alkanoyloxy group] or a salt thereof is given the general formula : [In the formula, n and R2 are the same as defined above] or a salt thereof is reacted, and if necessary, the protecting group is removed and/or the sulfoxide is reduced to form the compound of the general formula (VI) or its salt. Get the salt.

When Z in the general formula (■) is a halogen atom, the above reaction is 9 For example, acetone, tetrahydrofuran, N,
N-dimethylformamide, methylene chloride.

The reaction can be carried out in an inert solvent such as chloroform or acetonitrile at a reaction temperature of -10°C to 50°C.

In addition, when 2 in the general formula (■) is a lower alkanoyloxy group, the above reaction is carried out in an inert solvent such as chloroform, methylene chloride, tetrahydro7rane, N,N-dimethylformamide, dioxane, acetone, etc.
2 reaction temperature in the presence of iodotrimethylsilane -20°C
It can be carried out at ~60°C. The protecting group can be removed by conventional methods such as hydrolysis and reduction depending on the type of protecting group used. Further, the reduction of sulfoxide can also be carried out by a conventional method, such as by reacting with phosphorus trichloride.

Examples of the halogen atom of Z in the compound of general formula (■) include a chlorine atom, a bromine atom and an iodine atom. Also,
Examples of the lower alkanoyloxy group for Z include acetyloxy and propionyloxy. Examples of the protecting group for the carboxyl group of R6 include the groups mentioned above in the explanation of R5. Also.

As the salt of the compound of general formula (Shu and general formula (III)), any salt can be used as long as it does not interfere with the above reaction. For example, alkali metal salts such as sodium salts and potassium salts; calcium salts, magnesium salts, etc. alkaline earth metal salts; ammonium salts; inorganic acid salts such as hydrochlorides, sulfates, carbonates monobicarbonates, hydrobromides, hydroiodides; acetates, maleates, lactates, Organic carboxylic acid salts such as tartrate and trifluoroacetate; methanesulfonate, benzenesulfonate, ) organic sulfonate of luenesulfonate; trimethylamine salt.

Triethylamine salt, pyridine salt, propyroine salt.

Amine salts such as picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt; arginine salt, It can be appropriately selected from salts such as amino acid salts such as aspartate, lysine salt, glutamate, and serine salt.

The compound of the present invention exhibits strong antibacterial activity against Duram positive and negative bacteria. In addition, acute toxicity value (LID).

(mouse, intravenous injection)] is 3g/k for each of the following compounds.
rt or higher.

7β-"(Z')-2-(2-aminothiazole-4
-yl)-2-methoxyiminoacetamide)-3-(
4-Hydroxy-1,4-methylene-1-piperidinio)methyl-3-cephem-4-carboxylate 7β-C(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide]-3-(4-hydroxy-1,4-methylene-1
-piperidinio)methyl-3-cephem-4=carboxylate 7β-((Z) -2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(4
-hydroxy-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-[(Z) -2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide) -3-(4-hydroxy-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-((Z) -2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide)-3-(4
-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-[:(Z) -2
-(5-amino-1,2,4-thiadiazol-4-yl)-2-methoxyiminoacetamide)-3-(4-
Carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate Dosage when using the compound of the present invention as an antibacterial agent
2-300 mg/kg/day, preferably (10-100 mg/hg/day).

This antibacterial agent is administered orally in the form of powder, granules, capsules, etc., or parenterally in the form of injections, suppositories, etc. These preparations can be manufactured by conventional methods using pharmaceutically acceptable carriers.

2 In the present invention, a 9-order nomenclature system is adopted.

Next, the present invention will be explained in more detail by showing experimental examples and examples.

Experimental Example 1 Production of 4-hydroxy-1,4-methylenepiperidine 1) 1-benzyl-4-ethoxycarbonyl-4-
Hydroxypiperidine l-benzyl-4-cyano-4-hydroxypiperidine hydrochloride Log solution of 50rnL of ethanol with concentrated sulfuric acid 12
rILt was added and heated in a sealed tube at 130°C for 24 hours.

After concentrating the reaction solution, ice water was added. Add hydrogen carbonate to this)
After the solution was adjusted to pH 7.0 by adding an aqueous solution of IJum, it was extracted with diethyl ether. The extract was washed with saturated brine and dried by adding anhydrous sodium sulfate. The solvent was distilled off to obtain 9.7 g of the target product.

2) 1-benzyl-4-hydroxymethyl-4-hydroxypiperidine lithium aluminum hydride 19.4 Q of diethyl ether 0.5 was suspended under water cooling, and the compound 44.6 y obtained in 1) above was added to the diethyl ether. A 0.51 solution of ether was added dropwise. After the dropwise addition was completed, the mixture was stirred for 1 hour and 30 minutes.

Add 100 mL of ethyl acetate and saturated sulfuric acid to the reaction solution)
After adding 100+aL of Jium aqueous solution, it was filtered through Celite. The residue was washed with tetrahydrofuran. The P solution and the washing solution were combined and concentrated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent: chloroform, 596 methanol-chloroform and 20% methanol-chloroform) to obtain the desired product 31.5.

3) 1-benzyl-4-hydroxy-1,4-methylenepiperidine p-) luenesulfonate To a solution of 11.3 g of the compound obtained in 2) above in 120 zL of pyridine,
at -30°C I)-) luenesulfonyl chloride 10.7
g was added. The mixture was heated to 4°C and stirred at the same temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in a small amount of ice water. Add 82% of 2N potassium hydroxide aqueous solution to this solution.
After adding rat, it was extracted with benzene. Anhydrous potassium carbonate was added to the extract to dry it. The solution was refluxed for 9 hours and then cooled to room temperature. The resulting precipitate was collected and washed with anhydrous benzene to obtain 16.5 g of the desired product.

4) 4-Hydroxy-1,4-methylenepiperidine Compound obtained in 3) above 16.5 y methanol 300
10% palladium-carbon (50% quartz crystals) in mL solution
3.3 g was added and stirred for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, and the P solution was concentrated under reduced pressure. A saturated aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with chloroform. After adding anhydrous potassium carbonate to the extract and drying.

It was concentrated under reduced pressure to obtain 4.0 g of the target product.

Melting point: 124.0-124.5°C Mass spectrum (M”): 113 NMR spectrum (CDCl2; δ): 1.70 (4H
, m), 2.41 (2H,S).

2.75 (2H, m), 3.16 (2H, m) Example 1 7β-C(Z') -2-(2-aminothiazole-4
-yl)-2-methoxyiminoacetamide]-3-(
4-Hydroxy-1,4-methylene-1-piperidinio)methyl-3-cephem-4-carboxylate 7β-C(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide] -240 ml of -3-acetoxymethyl-3-cephem-4-carboxylic acid was suspended in 4 trtl of methylene chloride, and N-methyl-N-
0-lymethylsilyl) trifluoroacetamide 330μ
and stirred at room temperature for 30 minutes.

After cooling with water, 200 μl of iodotrimethylsilane was added.

Stirred at room temperature for 15 minutes. Concentrate the reaction solution under reduced pressure.

7β-C(,Z)-2-(2-aminothiazole-4
A silylated product of -yl)-2-methoxyiminoacetamide)-3-iodomethyl-3-cephem-4-carboxylic acid was obtained.

This was dissolved in 3rrLL of acetonitrile, and 60μt of tetrahydrofuran was further added. Add 4- to the resulting solution
72 mg of hydroxy-1,4-methylenepiperidine was added, and the mixture was stirred at room temperature for 2 hours. Add 0.3 methanol to the reaction solution.
ml and stirred for 15 minutes. The resulting precipitate was fixed and washed with acetonitrile. After dissolving this in 30% ethanol and concentrating under reduced pressure, the residue was dissolved in acetone-water (7:
1). This solution was subjected to silica gel column chromatography (developing solvent: acetone-water 9:1 and 7
: Purified by 1).

39 mg of the target product was obtained.

Example 2 7β-C(Z)-2-(5-amino-1,2,4-thiadiazol-'-3-yl)-2-methoxyiminoacetamide E-3-(4-hydroxy-1,4- Methylene-
1-piperidinio)methyl-3-cephem-4-carboxylate 7β-[(Z)-2-(s-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacet
319 mg of [doamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid was suspended in 4 rnL of methylene chloride, 877 μL of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added, and the mixture was stirred at room temperature for 1 hour. After cooling with water, 268 μL of iodotrimethylsilane was added, and after stirring for 15 minutes, the 9 reaction solutions were concentrated under reduced pressure.

Silylated product of 7β-((Z)-2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid I got it.

This was dissolved in 3.5 mL of acetonitrile. 71 mg of 4-hydroxy-1,4-methylenepiperidine was added to the obtained solution, and the mixture was stirred for 1 hour under water cooling. 0.3 ttd of methanol was added to the reaction solution, and the mixture was further stirred for 15 minutes. The resulting precipitate was collected and washed with acetonate. This was dissolved in 30% ethanol and concentrated under reduced pressure, and then the residue was dissolved in acetone-water (7:1). This solution was purified by silica gel column chromatography (developing solvent: acetone-water 7:1 and 5:1) to obtain 29 mg of the target product.

Example 3 7βCC2)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3=(4-hydroxy-1-quinuclidine-o)methyl-3-cefime-,! l--/Furuze book/Solace h7β-((Z)-2
-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid (977 mg) was added to methylene chloride 1
The suspension was suspended in 6 mL, 350 μt of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added, and the mixture was stirred at room temperature for 1 hour.

After cooling with water, add 810 μl of iodotrimethylsilane and
After stirring for 5 minutes, the two reaction solutions were concentrated under reduced pressure to give 7β-[(Z)-
A silylated product of 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid was obtained.

This was dissolved in 12 mL of acetonitrile, and 240 μt of tetrahydrofuran was further added. Add 4- to the resulting solution
Add 300 mg of hydroxyquinuclidine and incubate at room temperature for 1
The mixture was stirred for 30 minutes. 1.2 ounces of methanol was added to the reaction solution, and the mixture was washed with 1 liter of methanol and 1 liter of acetonitrile for 15 minutes. After dissolving this in 36% ethanol and concentrating under reduced pressure, the residue was dissolved in acetone-water (
7:1). This solution was purified by silica gel column chromatography (developing solvent: acetone-water 7:1) to obtain 38 mg of the target product.

Example 4 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-C4-hydroxy-1-quinuclidinio)
Methyl-3-cephem-4-carboxylate 7β-C(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-acetoxymethyl-3 - 486 mg of cephem-4-carboxylic acid was suspended in 9 ml of methylene chloride,
980 μt of N-methyl-N-()limethylsilyl)trifluoroacetamide was added, and the mixture was stirred at room temperature for 1 hour. After cooling with water, 410 μl of iodotrimethylsilane was added, and after stirring for 15 minutes, one reaction solution was concentrated.

Silylated product of 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid I got it.

This was dissolved in 6-proof acetonitrile, and 130 μL of tetrahydrofuran was further added. 150 m47 of 4-hydroxyquinuclidine was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. Add 0.6 trtt of methanol to the reaction solution,
Stir for 15 minutes. The resulting precipitate was fixed and washed with acetonitrile. After dissolving this in 30% ethanol and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: acetone-water 9:1).
13 mg of the target product was obtained.

Example 5 7β-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide 1-3- and 4-
Carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-[(Z)-2-(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid (240+ ng) was suspended in 4 ml of methylene chloride, and N-methyl-N-(trimethylsilyl)trifluoroacetamide was suspended in 4 ml of methylene chloride. 330 μL was added and stirred at room temperature for 30 minutes.

After cooling with water, add 200 μL of iodotrimethylsilane and
After stirring for 5 minutes, one reaction solution was concentrated under reduced pressure to obtain 7β-((2)-
A silylated product of 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid was obtained.

This was dissolved in 3 mL of acetonitrile, and 60 μl of tetrahydrofuran was further added. 98 tons of 4-carbamoylquiscridine was added to the resulting solution, and the mixture was stirred at room temperature for 2 hours. 0.3+nL of methanol was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Count the resulting sediment.

Washed with acetonitrile. After dissolving this in 3096 ethanol and concentrating under reduced pressure, the residue was dissolved in acetone-water (7:
1). This solution was purified by silica gel column chromatography (developing solvent: acetone-water 7:1) to obtain 53 mg of the target product.

Example 6 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide)-3-(4-carbamoyl-1-quinuclidinio)methyl- 3-cephem-4-carboxylate 7β-((Z)-2-(s-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-acetoxymethyl-3-cepheny 4-
790 mg of carboxylic acid was suspended in 10 ml of methylene chloride, 2.1 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added, and the mixture was stirred at room temperature for 1 hour. After cooling with water, 660 μl of iodotrimethylsilane was added, and after stirring for 15 minutes, the 9 reaction mixture was concentrated under reduced pressure to obtain 7β-((Z
)-2-(5-amino-1,2,4-thiadiazole-
3-yl)-2-methoxyiminoacetamide]-3-
A silylated product of iodomethyl-3-cephem-4-carboxylic acid was obtained.

This was dissolved in 9 mL of acetonitrile, 240 rny of 4-carbamoylquinuclidine was added, and the mixture was stirred for 1 hour under water cooling. Add 0.6 mL of methanol to the reaction solution.

Stir for 15 minutes. The resulting precipitate was collected and washed with acetonitrile. This was dissolved in 30% ethanol and concentrated under reduced pressure, and then the residue was dissolved in acetone-water (7:1). This solution was purified by silica gel column chromatography (developing solvent: acetone-water 7:1 and 5:1) to obtain the target product 326 TrLg.

Example 7 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamide)-3-(4-hydroxy-1°4-
7β-[(Z)-2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-Carboxymethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid soo
my* 7β((Z) −2=(5-
Amino-1,2,4-thiadiazol-3-yl)-2
-Carboxymethoxyiminoacetamide] A silylated product of -3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and this was reacted with 90 mg of 4-hydroxy-1,4-methylenepiperidine to obtain the target product 113+B. .

Example 8 7β-((Z)-2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide)-3-(4
-Hydroxymethyl-1-quinuclidinio)methyl-3
-Cephem-4-carboxylate 7β-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3 in the same manner as in Examples 1 to 6)
-acetoxymethyl-3-cephem-4-carboxylic acid 2
40 mg, N-methyl-N-0-limethylsilyl)
7β-((Z)-2-(2-
aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-
Obtain a silylated carboxylic acid and react it with 89 mg of 4-hydroxymethylquinuclidine to obtain 6 mg of the target product.
I got it.

Example 9 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamide)-
3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-((Z)-2-(2
-aminothiazol-4-yl)-2-propargyloxyiminoacetamide]-3-acetoxymethyl-3
7β-((Z)-2-(2-aminothiazole-4-
yl)-2-propargyloxyiminoacetamide]
A silylated product of -3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and this was reacted with 4-carbamoylquinuclidine 112+++,y to obtain 10 mg of the target product.

Example 10 7β-[(Z)-2-(2-aminothiazole-4-
yl)-2-carbamoylmethoxyiminoacetamide)-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate Similarly to Examples 1 to 6, 7β-C(Z)-2 −(2
-aminothiazol-4-yl)-2-carbamoylmethoxyiminoacetamide]-3-acetoxymethyl-
7 from 110 mg of 3-cephem-4-carboxylic acid, 140 μL of N-methyl-N-(trimethylsilyl)trifluoroacetamide, and 180 μt of iodotrimethylsilane.
β-((Z)-2-(2-aminothiazol-4-yl)-2-carbamoylmethoxyiminoacetamide]
A silylated product of -3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and this was reacted with 41 mg of 4-carbamoylquinuclidine to obtain the target product 5+n47.

Example 11 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide)-3-(4-carbamoyl-1-quinuclidinio)methyl- 3-cephem-4-carboxylate Similarly to Examples 1 to 6, 7β-[:(Z) −2=
(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid 300 ml
7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxy from 600 μl of N-methyl-N-(trimethylsilyl)trifluoroacetamide and 500 μl of iodotrimethylsilane) [iminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and this and 4-
118 mg of carbamoylquiscridine was reacted to obtain the target product 62.71!9.

Example 12 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1
-methylethoxy)iminoacetamide)-3-(4-
Carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-((Z)-2-(5-amino-1,2,4-thiadiazole-3- yl)-2-(1-carboxy-1
-methylethoxy)iminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid 530 m
gm 7β-[(Z)-2-(s-amino-
1,2,4-thiadiazol-3-yl)-2-(1-
A silylated product of carboxy-1-methylethoxy)iminoacetamide)-3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and this was reacted with 186 mg of 4-carbamoylquinuclidine to obtain 100 mg of the target product.

Example 13 7β-((Z)-2-(s-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamide)-3-(4-carbamoyl-1-quinuclidinio)methyl -3-cephem-4-carboxylate 7β-[(Z) -2-(
5-amino-1,2,4-thiadiazol-3-yl)
=2-carboxymethoxyiminoacetamide]-3-
Acetoxymethyl-3-cephem-4-carboxylic acid 50
0 my + N-methyl-N-(trimethylsilyl)trifluoroacetamide 1.23 rrLl,
780μl of iodotrimethylsilane? )7β−[(Z
) -2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and this was reacted with 142 mg of 4-carbamoylquinuclidine to obtain 36 ml of the target product.

Example 14 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide)-3-C4- and droxymethyl-1-quinuclidinio]methyl-3 -Cephem-4-carboxylate 7β-[(Z)-2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-Methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid (7β-CCZ) -2-( 5-amino-1,2,4-
A silylated product of thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylic acid was obtained, and 142 mg of 4-hydroxymethylquinuclidine was reacted with this to obtain 8 mg of the target product. I got it.

Example 15 7β-((Z)-2-(s-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(4-methyl-1-quinuclidinio)methyl- 3-cephem-4-carboxylate p-methoxybenzyl 7β-((Z)-2-(s-amino-1,2,4-thiadiazol-3-yl)-2-
Methoxyiminoacetamide]-3-iodomethyl-3
-Cephem-4-carboxylate 700m! J was dissolved in a mixture of 50 ml of ethyl acetate and 1 rILL of methanol. After cooling with water, a solution of 114 mg of 4-methylquinuclidine in 2.8 ml of ethyl acetate was added and stirred for 15 minutes. The resulting precipitate was purified and washed with ethyl acetate to give p-methoxybenzyl 7β-((Z)-2-(5-amino-1,2
, 4thiadiazol-3-yl)-2-methoxyiminoacetamido)-3-(4-methyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodite (770 my) was obtained.

770 my of this compound was suspended in 8 rrtL of methylene chloride.

After cooling on ice, 510 μL of anisole and 730 μL of trifluoroacetic acid were added, stirred for 4 hours, and further stirred at room temperature for 2 hours.
Stirred for 0 minutes. Diisopropyl ether 30% of the reaction solution
It was added dropwise into RNL, and the resulting precipitate was collected. Add this to 5 liters of water.
The solution was dissolved in rrLL and the pH of the solution was adjusted to 5 with sodium bicarbonate. This was purified by reverse phase silica gel column chromatography (elution: water → 5% methanol water),
27 mg of the target product was obtained.

Example 16 7β-((Z)-2-(s-amino-1,2,4-thiadiazol-3-yl)-2-cyclopropylmethoxyiminoacetamide)-3-(4-carbamoyl-1-
quinuclidinio)methyl-3-cephem-4-carboxylate p-methoxybenzyl 7β-((Z)-2-(5-t-
Butoxycarboxamide-1,2,4-thiadiazol-3-yl)-2-cyclopropylmethoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylate 450 m! 7 Ethyl acetate 30++
+j and after cooling with water, 80 mg of 4-carbamoylquinuclidine in methanol 1+! LL-ethyl acetate 5 m
A solution of L was added and stirred for 30 minutes. The resulting precipitate was purified and washed with ethyl acetate to form p-methoxybenzyl 7β-
((Z) -2-(5-t-butoxycarboxamide-
1,2,4-thiadiazol-3-yl)-2-cyclopropylmethoxyiminoacetami)')-3-(4-
290 mg of carbamoyl-1-quinuclidine-o)methyl-3-cephem-4-carboxylate iodite was obtained.

290 my of this compound was dissolved in 6 mL of formic acid and stirred at room temperature for 1 day. 10rnL of acetone, 30rrLt of diisopropyl ether, and 50ml of n-hexane were added to the reaction solution. The resulting precipitate was removed from the furnace, and the furnace liquid was concentrated under reduced pressure.

The residue was dissolved in 10 rrtl of water-methanol solution, and the pH of the solution was adjusted to 5.5 with sodium hydrogen carbonate. This solution Example 17 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopropylmethoxyiminoacetamide)-3-(4-hydroxymethyl-1 -quinuclidinio)methyl-3-cephem-4-carboxylate p-methoxybenzyl 7β-
[(Z) -2-(5-t-butoxycarboxamide-
1,2,4-thiadiazol-3-yl)-2-cyclopropylmethoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylate 45011
1 g was reacted with 73 nLg of 4-hydroxymethylquinuclidine to produce p-methoxybenzyl 7β-[(Z)-2-
(s-t-butoxycarboxamido-1,2,4-thiadiazol-3-yl)-2-cyclopropylmethoxyiminoacetamide]-3-(4-hydroxymethyl-
1-quinuclidinio)methyl-3-cephem-4-carboxylei) was obtained, and then the protecting group was removed with formic acid to obtain 23 mg of the desired product.

Experimental Example 2 7β-formamide-3-(4-carbamoyl-1-quinuclidine)methyl-3-cephem-4-carboxylate 7β-formamide-3-acetoxymethyl-3-cephem-4-carboxylic acid 1.2 y Methylene chloride 12m
815 μL of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added and stirred for 30 minutes. After cooling with water, 1.25 t of iodotrimethylsilane
nt, stirred for 5 minutes, returned to room temperature, and further stirred for 15 minutes.
Stir for a minute. The solvent was removed under reduced pressure.

The residue was dissolved in 12-proof acetonitrile, and 616 mg of 4-carbamoylquinuclidine was added under water cooling, followed by stirring for 1 hour. 3rrL of methanol and 300ml of ethyl ether were added to the reaction solution, and the resulting precipitate was collected.

This precipitate was subjected to silica gel column chromatography1)
] to obtain 140 my of the target product.

Experimental example 3 7β-tritylamino-3-(4-carbamoyl-1-
Quinuclidinio)methyl-3-cephem-4-carboxylate 2.4 g of 7β-tritylamino-3-acetoxymethyl-3-cephem-4-carboxylic acid was added to 24 I of methylene chloride.
Dissolved in Ll, N-methyl-N=(trimethylsilyl)
960 μL of trifluoroacetamide was added and stirred for 30 minutes. After cooling with water, 720 μl of iodotrimethylsilane
was added and stirred for 5 minutes, then returned to room temperature and further stirred for 15 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 24 rrtl of acetonitrile and cooled with water.

Add 756 mg of 4-carbamoylquinuclidine to I
Fl'! Add 1nNt4'' to 1f-ErJdomechano-nt2') ml and then add 240 ml of diethyl ether.
rnL was added and the resulting precipitate was poured to the bottom of the furnace. This precipitate was subjected to silica gel column chromatography [developing solvent: acetone-water (7:1).

(5: 1) and (3: 1)) to obtain the target product 2.
07m was obtained.

Experimental Example 4 7β-(2-chenylacetamide)-3-(4-nonorbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-(2-chenylacetamide)-3-acetoxymethyl-3- 6.0 g of cephem-4-carboxylic acid was suspended in 60 ml of methylene chloride, and 3.08 mL of N-methyl-N-()limethylsilyl)trifluoroacetamide was added.
was added and stirred for 30 minutes. After cooling with water, 4.73 rILL of iodotrimethylsilane was added and stirred for 5 minutes.

The mixture was further stirred at room temperature for 15 minutes. The solution was concentrated under reduced pressure and the residue was dissolved in 60 ml of acetonitrile. After water cooling.

2.3g of 4-carrenoquinuclidine
B! Stir for f. 6 ml of methanol was added to the reaction solution, and then 600 rrLl of diethyl ether was added dropwise. After stirring for 1 hour, the resulting precipitate was collected at the bottom of the furnace and subjected to silica gel column chromatography [Developing solvent: acetone-water (
Purify with 7: 1) and (5: 1)) to obtain the target product 70
0 wtg was obtained.

Clidinio) methyl-3-cephem-4-carboxylate hydrochloride 130+ng of the compound obtained in Experimental Example 2 was added with 5 ng of methanol.
ml, added 0.52 ml of concentrated hydrochloric acid at room temperature, and stirred for 4 hours. The reaction solution was concentrated under reduced pressure and crystallized from diethyl ether-methanol to obtain 115 mg of the desired product.

Experimental Example 6 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride 100 mg of the compound obtained in Experimental Example 3 was mixed with 50% formic acid 5
rnL and stirred at room temperature for 3 hours and 30 minutes. 20 ml of water was added to this, insoluble matter was removed in an oven, and the P solution was concentrated under reduced pressure. The residue was dissolved in IN hydrochloric acid, and to this were added 51 rLL of Improper Tool and 10 TILL of diethyl ether. The precipitated crystals were poured into the bottom of a furnace, washed with n-hexane, and then dried to obtain 45 mg of the desired product.

Experimental Example 7 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride 600 mg of the compound obtained in Experimental Example 4 was dissolved in methylene chloride 3
1.24 m of N,N-dimethylaniline suspended in 0.0 m
1 and 465 μL of chlorotrimethylsilane, and
Stirred at 0°C for 3 hours. After cooling the reaction solution to -25° C., 1.27 y of phosphorus pentachloride was added and stirred for 1 hour.

To this, 1.3 rnL of 1.3-butanediol and 25 rnL of methylene chloride were added hot and cold, and the mixture was stirred at the same temperature for 10 minutes.

After heating the reaction solution to 0° C. and stirring for an additional 40 minutes, the resulting precipitate was constant. This was dissolved in 7 rnL of methanol, and after removing insoluble matter, 20 mL of methylene chloride and 20 rnL of diethyl ether were added to the furnace solution to constant the precipitated crystals, yielding 30 mg of the desired product.

Experimental Example 8 t-Butyl 7β-amino-3-(4-carnocumoyl-1-quinuclidinio)methyl-3-cepheny 4-carboxylate l-oxide Bromide t-butyl 7β-amino-3-bromomethyl-3-cephem -4-carboxylate 1-oxide hydrobromide 600 mg N,N-dimethylformamide 6
Dissolve 456 mL of 4-carbamoylquinuclidine
mg was added thereto, and the mixture was stirred at room temperature for 14 hours in an argon gas stream. Add 120 mL of diethyl ether to the reaction solution, stabilize the resulting precipitate, wash it with n-hexane,
580 mg of the target product was obtained.

Experimental Example 9 t-7'Til 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate bromide hydrochloride Compound obtained in Experimental Example 8 570W! Dissolve g in 10 rIL of N,N-dimethylformamide and add 500 μl of phosphorus trichloride at -25°C.
1 was added and stirred for 30 minutes. Add 50 rnL of diethyl ether to the reaction solution, and separate the liberated oil.

After washing with 10 ml of diethyl ether, the mixture was dried under reduced pressure to obtain 164 mg of the desired product.

Experimental Example 10 7β-Amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate To 150 mg of the compound obtained in Experimental Example 9 was added 1 formic acid under water cooling.
．． Add 5 rttL and 0.15yaL of concentrated hydrochloric acid,
After stirring for an hour, it was concentrated under reduced pressure. Add the residue to ice water for 5 rn
The solution was dissolved in L and neutralized with double sodium bicarbonate. This was subjected to reverse phase silica gel column chromatography (developing solvent: water).
Purification was performed to obtain 60 mg of the target product.

Experimental Example 11 p-methoxybenzyl 7β-phenylacetamide
3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodite p-methoxybenzyl 7β-phenylacetamide-
980 mg of 3-chloromethyl-3-cephem-4-carboxylate was suspended in 20 mL of acetone.

362 mg of sodium iodide was added and stirred at room temperature for 1 hour. To this, 313 ma of 4-carbamoylquinuclidine was added under water cooling, stirred for 2 hours, the reaction solution was filtered, and 70 ml of diethyl ether was added to the filtrate.

The precipitated crystals were quantified to obtain 500+xg of the target product.

Experimental Example 12 p-methoxybenzyl 7β-formamide-3-(4
-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodite p-methoxybenzyl 7β-formamide-3-iodomethyl-3-cephem-4-carboxylate) 9.
To 465 mL of a solution of 3 g of ethyl acetate, add 4
- A solution of 2.94 y of carbamoylquinuclidine in 176 rnL of methanol and ethyl acetate (1:4 V/V) was added dropwise over 1 hour. After stirring for 30 minutes, the resulting precipitate was poured into the bottom of the furnace and washed with ethyl acetate and then diisopropyl ether to obtain 12.0 g of the desired product.

Infrared absorption spectrum (cm-', Nujol):
178ONMR spectrum (δ, D2o-acetone-d
6): 1.9-2.4 (m), 3.50 (8H
, m), 3.70 (3H.

S), 4.16 (IH, d, J=15Hz),
4.54 (IH.

d, J=15Hz), 5.24 (2H, m),
5.78 (IH.

d, J=5±), 6.87 (2H, d, J=1
07).

7.33 (2H, d, J=10±) Experimental Example 13 7β-Formamido-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate Compound 11 obtained in Experimental Example 12 After dissolving .8 g in 50 ml of ice-cooled formic acid, the solution was stirred at room temperature for 10 hours. The reaction solution was filtered, and the P solution was dropped into acetone 100+++j. Furthermore, 200 μl of diisopropyl ether was added dropwise to the same solution, and the resulting precipitate was made constant and washed with acetone.

The precipitate was dissolved in 30 ml of dimethylformamide and the solution was added dropwise into 150++ iL of acetone. The resulting precipitate was poured into the bottom of the furnace, washed with acetone and diisopropylethyl, and then dried under reduced pressure to obtain the desired product 6.66.

Infrared absorption spectrum (Cm-1, Nujol):
177ONMR spectrum (δ, D20): 2.30 (6H, m), 3.2-5.0 (m)
, 5.39 (IH.

d, J=6Hz), 5.89 (IH, d, J
=6Hz).

8.35 (IH,S) Example 18 7β-[(Z) -2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide)-3-(4- Carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 2-(5-amino-1,2,4-thiadiazole-35
mg, N,N'-dicyclohexylcarbodiimide 5
2m9 and N,N-dimethylformamide 1rnL,
ki) The mixture is stirred at room temperature for 3 hours and then filtered;
The P solution was cooled to 0°C. This solution was added to 7β-amino-3
-(4-carbamoyl-1-quinuclidinio)methyl-
3-cephem-4-carboxylic acid hydrochloride 100mg,
N,N-dimethylformamide 2 utL and N,
It was added to a water-cooled solution of 72 μt of N-dimethylaniline.

The deposited precipitate was poured into a furnace and washed with diethyl ether.

Add 10rrtL of water to this and remove the insoluble matter in the oven.

The reaction solution was purified by reverse-phase silica gel column chromatography to obtain 3 mg of the target product.

Infrared absorption spectrum (cm-', Nujol): 17
75 Koden spectrum (δ, D20) 2.30 (6H, m), 3.1-4.0 (m)
, 4.16 (3H.

s), 5.43 (IH, d, J=6Hz),
5.97 (IH.

d, J=6 Hz) Example 19 7β-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide)-3-(4-carbamoyl -1-quinuclidinio)methyl-3-cephem-4-carboxylate 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylic acid hydrochloride 2 g was mixed with acetonitrile-water (1: 1) mixed solvent 40
mL and added 2.08 ml of triethylamine. This solution was cooled on ice and 2-(5-amino-1,2,4
-Thiadiazol-3-yl)-(Z)-2-methoxyiminoacetyl chloride 2.55, and 50
Stir for a minute. Add the reaction solution to 200 ml of ethanol,
The precipitated crystals were filtered and washed with ethanol and isopropyl ether to obtain 450 mg of the desired product.

The infrared absorption spectrum and NMR spectrum were consistent with those of the compound of Example 18.

The following compounds of Examples 20 to 28 were synthesized in the same manner as Examples 18 and 19.

Claims (13)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n is 1 or 2, Y is CH or nitrogen atom, R
_1 is a lower hydrocarbon group, a carboxy-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, or a cyclopropyl-substituted lower alkyl group; R_2 is a hydroxyl group, a lower alkyl group, a hydroxy-substituted lower alkyl group, or a carbamoyl group] Derivatives and their non-toxic salts. (2) The compound according to claim 1, wherein Y is a nitrogen atom. (3) The compound according to claim 1 or 2, wherein R_1 is a lower alkyl group. (4) The compound according to claim 1, wherein R_1 is a methyl group or an ethyl group, and R_2 is a hydroxyl group or a carbamoyl group. (5) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]
The compound according to claim 1, which is -3-(4-hydroxy-1,4-methylene-1-piperidinio)methyl-3-cephem-4-carboxylate and its non-toxic salt. (6) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7β-[(Z)-2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(4-hydroxy-1,4-
Methylene-1-piperidinio)methyl-3-cephem-
4-Carboxylate and its non-toxic salts. (7) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]
The compound according to claim 1, which is -3-(4-hydroxy-1-quinuclidinio)methyl-3-cephem-4-carboxylate and its non-toxic salt. (8) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7β-[(Z)-2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(4-hydroxy-1-quinuclidinio)methyl-3-cephem-4-carboxylate and its non-toxic salts A compound according to item 1. (9) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]
The compound according to claim 1, which is -3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate and its non-toxic salt. (10) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7β-[(Z)-2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate and its non-toxic salts A compound according to item 1. (11) General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Y is CH or a nitrogen atom, R_1 is a lower hydrocarbon group, a carboxy-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, or a cyclopropyl-substituted lower a compound represented by an alkyl group, X represents a halogen atom],
General formulas for compounds with protected amino and/or carboxyl groups, or salts thereof: ▲Mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n is 1 or 2, R_2 is a hydroxyl group, lower alkyl group, hydroxy-substituted A general formula characterized by reacting a compound represented by [representing a lower alkyl group or a carbamoyl group] or a salt thereof, and removing a protecting group if necessary: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n, Y, R_1 and R_2 are the same as defined above] or a non-toxic salt thereof. (12) General formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n is 1 or 2, and R_2 represents a hydroxyl group, a lower alkyl group, a hydroxy-substituted lower alkyl group, or a carbamoyl group]. The general formula for a compound whose -COO^- is protected with a protecting group, or a salt thereof: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Y is CH or a nitrogen atom, R_1 is a lower hydrocarbon group, a carboxy Substituted lower alkyl group, carbamoyl-substituted lower alkyl group, or cyclopropyl-substituted lower alkyl group], compounds whose amino groups are protected with protecting groups, reactive derivatives of their carboxyl groups, or salts of these compounds. A general formula characterized by reacting and removing a protecting group if necessary: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n, Y, R_1 and R_2 are the same as defined above] A method for producing a compound or a non-toxic salt thereof. (13) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n is 1 or 2, Y is CH or nitrogen atom, R
_1 is a lower hydrocarbon group, a carboxy-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, or a cyclopropyl-substituted lower alkyl group, and R_2 is a hydroxyl group, a lower alkyl group, a hydroxy-substituted lower alkyl group, or a carbamoyl group] or Antibacterial agent consisting of its non-toxic salts.