JPS6117589A - Novel cephalosporin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R<1> is 1-5C alkyl, 3-6C cycloalkanomethyl (the above groups may be substituted with halogen), or group of formula II [m is 0-3; A is -COR<6> (R<6> is 1-5C alkyl, alkenyl, O, or -(CH2)pB (p is 0-3; B is amino, alkyl-substituted amino, OH, COOH, CN, etc.); n is 3-5}. EXAMPLE:Syn-7-[2-( 2-aminothiazol-4-yl )2-methoxyiminoacetamido]-3-( 2,3-cyclopenteno-1-carboxymethylpyridinium-4-yl )thiomethyl-3-cephem-4-carboxylic acid sodium salt. USE:Antibacterial agent effective to Gram-negative and Gram-positive bacteria. PREPARATION:The objective compound can be prepared by reacting the compound of formula IV with the 2-(2aminothiazol-4-yl) 2-syn-substituted-oxyiminoacetatic acid of formula V (R<9> is H or aminoprotecting group; R<10> is same as R<1>), etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel cephalosporin compound having a broad antibacterial spectrum and a method for producing the same.

C. Prior Art and Problems] Conventionally, a large number of cephalosporin antibiotics have been obtained. The antibacterial activity of these cephalosporin antibiotics is largely influenced by the type of substituent at the 3-position in addition to the acyl group at the 7-position of the cephem nucleus.

Some cephem antibiotics having a substituted pyridinium thio group at the 3-position are known (for example,
4-154787), none of which have been used clinically to date.

Furthermore, as the amount of so-called third-generation cephem antibiotics used has increased in recent years, the frequency of isolation of plum-positive bacteria including staphylococci has been increasing, and this is becoming a major clinical problem.

[Purpose of the invention]

The present invention was developed as a result of various studies on cephalosporin compounds in which a substituted pyridinium thio group was substituted as a substituent at the 3-position of the cephem nucleus. It has been discovered that a new cephalosporin compound having a group of 100 to 100% has a strong antibacterial activity against not only Durum-negative bacteria but also Gram-positive bacteria, and the present invention has developed a new cephalosporin compound having strong antibacterial activity against Gram-positive bacteria as well as Durham-negative bacteria, and has developed a new cephalosporin compound that overcomes the drawbacks of the third-generation cephalosporin antibiotics mentioned above and its pharmacological properties. It is an object of the present invention to provide acceptable salts and methods for their production.

[Structure of the invention]

The present invention provides a general formula in which R1 is a straight chain or a numbered chain having 1 to 5 carbon atoms.
a branched alkyl group, a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with a halogen atom), or [m represents an integer of 0 or 1 to 3, °yo group -COR6 (R" represents a hydroxyl group, a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), a 5- to 6-membered heterocyclic group, R4 and R5 are a hydrogen atom, a carbon number an alkyl group having 1 to 5 carbon atoms or a cycloalkylidene group having 3 to 5 carbon atoms when R4 and R5 are bonded], and R3 is a hydrogen atom or a cycloalkylidene group having 1 to 5 carbon atoms. R2 is an alkyl group having 1 to 5 carbon atoms, an alkenyl group, an oxygen atom or (CH2) B (1) is 0 or an integer of 1 to 3, B is an amino group, an alkyl substituted Amino group, hydroxyl group, alkoxy group, carboxyl group, carbamoyl group, sulfonic acid group, sulfonic acid amide group, cyano group, thiol group, alkylthio group, methanesulfonylaminocarbonyl group,
or an acetamidosulfonyl group), and n is an integer of 3 to 5, and a pharmacologically acceptable salt thereof, and
In the formula, R2, R3, n have the same meanings as above, or a salt thereof or a protected form of a carboxyl group, where R9 represents a hydrogen atom or a protecting group for an amino group, and RI
G is a straight or branched alkyl group having 1 to 5 carbon atoms, a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with a halogen atom), or a formula Indicates an integer from to 3, A' is the group -COR"(R" is OR
” (R11 represents a carboxyl group protecting group), a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R
12 is a protecting group for an amino group or a carbon number of 1 to 5 (indicates an alkyl group having 1)), R12 is a protecting group for an amino group), or a 5- to 6-membered heterocycle containing nitrogen and sulfur 2-(2-aminothiazol-4-yl)2- having a group represented by "indicates a group, and R4 and R5 have the same meanings as above."
Syn-substituted oximinoacetic acid or its reactive derivative at the carboxyl group is reacted, and if necessary, the protecting group for the amino group and the protecting group for the carboxyl group are removed to obtain A method for obtaining a compound having the same meaning and a pharmacologically acceptable salt thereof, and in the formula, X represents a substitutable residue of a nucleophile, R9 has the same meaning as above, RI3 is a carbon A linear or branched alkyl group having 1 to 5 carbon atoms, a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with halogen atoms), or represents an integer, A" is a group -COR6'(R8' is O
RIP (RIY indicates a protecting group for a hydroxyl group or carboxyl group), a hydrogen atom or an alkyl group having 1 to 5 carbon atoms)) or a 5- to 6-membered complex containing nitrogen or sulfur (having the same meaning) A compound having the formula, in which R2, R3, and n have the same meanings as above, is reacted with a compound having the following formula, in which R2, R3, and n have the same meanings as above. By removing the protecting group for the carboxyl group, a compound having the formula R', in which R', R'', , R3-, n have the same meanings as above, and a pharmacologically acceptable salt thereof are obtained. It's a method.

The R1 substituent of the compound represented by the above formula (I) of the present invention includes a straight or branched alkyl group such as methyl, ethyl, propyl, butyl, isopropyl, and isobutyl;
Groups in which these groups are substituted with halogen atoms such as 2-fluoroethyl and 2゜2.2-trifluoroethyl, cycloalkanomethyl groups such as cyclopropylmethyl and cyclohexylmethyl, carboxymethyl, 2-carboxyethyl, 2- Carboxypropyl, 1-methyl-2-carboxyethyl, 1-methyl-1-carboxyethyl, carbamoylmethyl, N-methylcarbamoylmethyl, N
, N-dimethylcarbamoylmethyl, 2-amino-2-
Carboxyethyl, 3-amino-3-carboxypropyl, 1-methyl-2-amino-2-carboxyethyl,
3-amino-3-carboxypropyl, (pyridine-2
-yl)methyl, (imidazol-4-yl)methyl,
(5-methyl-imidazol-4-yl)methyl, (2
-methyl-imidazol-4-yl)methyl, (5-methyl-imidazol-4-yl)methyl, (2-aminothiazol-4-yl)methyl, and the like.

Further, as the substituent at the 3-position of formula (I), (2,3-cyclopenteno-1-methylpyridinium-4-yl)thiomethyl, [2,3-cyclopenteno-1-(2-dimethylaminoethyl)pyridinium- 4-ylkothiomethyl,
(2,3-cyclopenteno-1-(2-hydroxyethyl)pyridinium-4-ylcothiomethyl, (2,3
-Cyclopenteno-1-methoxymethylpyridinium-
4-yl)thiomethyl, (2,3-cyclopenteno-1
-carboxymethylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-2-carboxyethylpyridinium-4)
-yl)thiomethyl, (2,3-cyclopenteno-1-
Carboxyethylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-1-cyanomethylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl, (2 ,3-cyclopenteno-1-sulfamoylmethylpyridinium-4-yl)thiomethyl, [2,
3-Cyclopenteno-1-(2-sulfoethyl)pyridinium-4-ylcothiomethyl, (2,3-cyclopenteno-1-methylthiomethylpyridinium-4-yl)
Thiomethyl, (2,3-cyclopenteno-1-acetamidosulfonylmethylpyridinium-4-yl)thiomethyl, [2,3-cyclopenteno-1-(methanesulfonylaminocarbonylmethyl5pyridinium-4-yl)thiomethyl, (2 ,3-cyclopentenopyridine-
N-oxide-4-yl)thiomethyl, '(2,3-cyclopenteno-1-(2-hydroxyethyl)pyridinium-4-ylcothiomethyl, (2,3-cyclohexeno-1-carboxymethylpyridinium-4-yl)
Thiomethyl, (2,3-cyclohexeno-1-sulfomethylpyridinium-4-yl)thiomethyl, (3,4-
cyclopenteno-1-carboxymethylpyridinium-
2-yl)thiomethyl, (3,4-cyclopenteno-1
-sulfomethylpyridinium-2-yl)thiomethyl,
(3,4-cyclopenteno-1-methylpyridinium-
2-yl)thiomethyl, etc.

The compound of formula (I) of the present invention exhibits strong antibacterial activity against Gram-positive bacteria as well as Durham-negative bacteria including opportunistic bacteria, and is clinically useful.

The pharmacologically acceptable salts of formula (I) of the present invention include medically acceptable salts, particularly conventional non-toxic salts, such as inorganic, salts with bases, For example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, salts with organic bases, such as triethylamine salts, pyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexyl Examples include organic amine salts such as amine salts and basic amino acid salts such as lysine and arginine.

The compound of formula (I) is a syn isomer, and if an asymmetric carbon is present in the 7-position side chain, the 0-isomer and the L-isomer can exist, but the present invention includes both of them and the DL-isomer. .

Examples of the compounds of the present invention include the compounds shown below. However, the present invention is not limited to the following description.

Syn-7-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-('2.3
~cyclopenteno 1-carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-” (2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3 −(2,
3-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-(2,3-
Cyclopenteno-1-(2-carboxyethyl)pyridinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide) ]−
3-(2,3-cyclopenteno-1-cyanomethylpyridinium-4-yl)thiomethyl-3-cephem-4-
Carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-(2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cefemu 4-carboxylate, syn-7-(1-(2-amino thiazol-4-yl)
-2-methoxyiminoacetamide]-3-(2,3-cyclopenteno-1-sulfamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4c carboxylate, syn-7-[22 -aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[2,3-
Cyclopenteno-1-(2-sulfoethyl)vinidinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-(2,3-cyclopenteno-1-methylthiomethylvinidinium-4
-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-[2,3-cyclopenteno-1-(2-hydroxyethyl)vinidinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-( 2-aminothiazol(d4-yl)-2-methoxyiminoacetamide]
-3-(2,3-cyclopenteno-1-(2-dimethylaminoethyl)pyridinium-4-ylcothiomethyl-
3-cephem-4-carboxylate, syn-7-(2
-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2,'3-cyclopenteno 1-acetamidosulfonylmethylpyridinium-
4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazole-4
-yl)-2-methoxyiminoacetamide]-3-(
2,3-cyclopenteno-1-methanesulfonylaminocarbonylmethylpyridinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Ethoxyiminoacetamide]-3-(2,3-
cyclopenteno-1-carboxymethylpyridinium-
4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(1-(2-aminothiazol-4-yl)
-2-ethoxyiminoacetamide]-3-(2',
3-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Ethoxyiminoacetamide]-3-(2,3-
Cyclopenteno-1-(2-carboxyethyl)pyridinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide)
-3-(2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cephem-4
-carboxylate, syn-7-[2-(2-aminothiazol-4-yl)
-2-Ethoxyiminoacetamide]-3-(2,3-
C') Lopenteno 1-sulfamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide) ]−
3-(2,3-cyclopenteno-1-(2-sulfoethyl)pyridinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2 -(2-fluoroethoxyimino)acetamide)-3-(2,' 3-cyclopenteno-1-carboxymethylpyridinium-4
-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2-fluoroethoxyimino)acetamide)
-3-(2,3-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2-fluoroethoxyimino)acetamide)
-3-(2,3-cyclopenteno-1-(2-carboxyethyl)pyridinium-4-ylcothiomethyl-3-
Cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2-fluoroethoxyimino)acetamide)
-3-(2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cephem-4
-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamide)-3-(2,3-cyclopenteno-1-sulfamoylmethylpyridinium -4-yl)
Thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2-fluoroethoxyimino)acetamide)
-3-(2,3-cyclopenteno-1-(2-sulfoethyl)pyridinium-4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2'-(2-aminothiazol-4-yl) ~2-(2,2,2-)lifluoroethoxyimino)acetamide)-3-(2,3-cyclopenteno-1
-carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-cal arrestoxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2,2,1-1-lifluoroethoxyimino)
acetamido)-1-(2,3-cyclopenteno-1-
Sulfomethylpyridinium-4-yl)thiomethyl-3
-cephem-4-carboxylate, syn-7-(1-(2-aminothiazol-4-yl)
Syn-7-(2-( 2-aminothiazol-4-yl)
-2-(cyclopropylmethoxyimino)acetamide)-a-(2,a-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-( 2-aminothiazol-4-yl)
-2-(cyclopropylmethoxyimino)acetamide)-3-(2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cephem-
4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-(cyclopropylmethoxyimino)acetamide)-3-(2,3-cyclopenteno-1-(2-sulfoethyl) Pyridinium-4-ylkothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(cyclopropylmethoxyiminoacetamide)
-3-(2,3-cyclopenteno-1-'sulfamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl) )
-2-(carboxymethoxyimino)acetamide]
-3-(2,3-cyclopenteno-1-carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl')- Syn-7-(2-( 2-aminothiazol-4-yl)
-2-(carboxymethoxyimino)acetamide)-
3-(2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cephem-4-
Carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamide)-3-(2,3-cyclopenteno-■
-(2-sulfoethyl)pyridinium-4-ylkothiomethyl-3-cephem-4-carboxylate, syn-7-[2-(2-aminothiazol-4-yl)
-2-(carbamoylmethoxyimino)acetamide)
-3-(2,3-cyclopenteno-1-carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(carbamoylmethoxyimino)acetamide]
-a-(2,s-cyclopenteno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cephem-4
-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-(carbamoylmethoxyimino)acetamide)-3-(2,3-cyclopenteno-1-(2-sulfomethyl)pyridinium- 4-ylcothiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(carbamoylmethoxyimino)acetamide)
-3-(2,3-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(carbamoylmethoxyimino)acetamide)
-3-<2.3-cyclopenteno-1-sulfamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(1-methyl-1-carboxyethoxyimino)
acetamido)-3-(2,3-cyclopenteno-1-
Carboxymethylvinidinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(1-methyl-1-carboxyethoxyimino)
acetamido)-3-(2,3-cyclopenteno-1-
Sulfomethylpyridinium-4-yl)thiomethyl-3
-cephem-4-carboxylate, syn-7-C2-(2-aminothiazol-4-yl)
~2-methoxyiminoacetamide]-3-(2,3-
cyclohexeno-1-carboxymethylpyridinium-
4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-(2,3-
Cyclohexeno-1-sulfomethylpyridinium-4-
yl)thiomethyl-3-cephem-4-carboxylate, syn-7-C2-(2-aminothiazol-4-yl)
-2-Ethoxyiminoacetamide]-3-(2,3-
cyclohexeno-1-carboxymethylpyridinium-
4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-('2-aminothiazole-4-y,
)-2-ethoxyiminoacetamide]-3-(2,
3-Cyclohexeno-1-sulfomethylpyridinium-
4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2-fluoroethoxyimino)acetamide)
-3-, (2,3-cyclohexeno-1-carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-? -(2'-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acedoamide)-3-(2,3-cyclohexeno-1-sulfomethylpyridinium-4-yl)thiomethyl- 3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)-2-(cyclopropylmethoxyimino)acetamide)-3-(2,3-cyclohexeno-1- Carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(cyclopropylmethoxyimino)acetamide)-3-(2,3-cyclohexeno-1-sulfomethylpyridinium-4-yl)thiomethyl-3-cephem-
4-carboxylate, syn-7-(2-'(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(3,4-cyclopenteno-1-methylpyridinium-2-yl)thiomethyl -3-Cephem-
64-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-(3,4-
cyclopenteno-1-carboxymethylpyridinium-
2-yl)thiomethyl-3-, cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-(3,4-
Cyclopenteno-1-sulfomethylpyridinium-2-
yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2= (2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3-(3,4
-cyclopenteno-1-carboxymethylpyridinium-2-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-ethoxyiminoacetamide]-3-'(3,4
-cyclopenteno-1-sulfomethylpyridinium-2
-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-1-((pyridin-2-yl)methoxyimino)acetamide)-3-(2,3-cyclopenteno-1-methylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7- (2-(2-aminothiazol-4-yl)
-2-((pyridin-2-yl)methoxyimino)acetamide)-3-(2,3-cyclopenteno-1-carboxymethylpyridinium-4-yl)thiomethyl-3
-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-((imidazol-4-yl)methoxyimino)
acetamido)-3-(2,3-cyclopenteno-1-
methylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-((5-methylimidazol-4-yl)methoxyimino)acetamide]-3-(2,3-cyclopenteno-1-methylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn -7-(2-(2-aminothiazol-4-yl)
-2-((2-methylimidazol-4-yl)methoxyimino)acetamide]-3-(2,3-cyclopenteno-1-methylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn -7-(2-(2-aminothiazol-4-yl)
-2-((imidazol-4-yl)methoxyimino)
acetamido)-3-(2,3-cyclopenteno-1-
Carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-((imidazol-4-yl)methoxyimino)
acetamido)-3-(2,3-cyclopenteno-1-
Sulfomethylpyridinium-4-yl)thiomethyl-3
-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(N-methylcarbamoylmethoxyimino)acetamide)-3-(2,3-cyclopenteno-1-methylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylesin-7-(2-(2 -aminothiazol-4-yl)-2-(N-methylcarbamoylmethoxy□ imino)acetamide)-3-(2,3
-cyclopenteno-1-carboxymethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxyethoxyimino)acetamide)-3-'(2゜3-cyclopenteno-1-carboxymethylpyridinium-4-yl)
Thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxyethoxyimino)acetamide) -3-(2,,.

3-Cyclopenteno-1-sulfomethylpyridinium-
4-yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2= (3DL-3-amino-3-carboxypropyloxyimino)acetamide]-3-(2,3-cyclopenteno-1-carboxymethylpyridinium-4-
yl)thiomethyl-3-cephem-4-carboxylate, syn-7-(1-(2-aminothiazol-4-yl)
-2-(3DL-3-amino-3-carboxypropyloxyimino)acetamide)-3-(2,3-cyclopenteno-1-sulfomethylpyridinium-4-yl)
Thiomethyl-3-cephem-4-carboxylate, syn-7-(2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxyethoxyimino)acetamide)-3-(2゜3-cyclopenteno-1-carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate, syn -7-(2-(2-aminothiazol-4-yl)
-2-(2D-2-amino-2-carboxyethoxyimino)acetamide)-3-(2゜3-cyclopenteno-1-sulfamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate , The compound of general formula CI) is produced by either method A) or B) shown below. That is, A) a compound represented by the general formula (n) z (I[) (wherein R'l , R3, and n have the same meanings as above) or a salt thereof or a protected form of a carboxyl group, Reacting a compound represented by formula (III) (wherein R9 and RIG have the same meanings as above) or a reactive derivative of carboxylic acid,
After that, the amino group-protecting group and the carboxyl group-protecting group, if any, are removed to produce the product.

B) Reacting a compound represented by general formula (IV) (wherein R9, R+9.X have the same meanings as above) with a compound represented by (R2, Ra, n have the same meanings as above) Then, the compound of general formula (I) is obtained by removing the protecting group for the amino group or, if there is a protecting group for the carboxyl group.

As the protecting group for the amino group and carboxyl group in the above general formula, those used for this purpose in the field of β-lactam and peptide synthesis can be appropriately employed.

Examples of protecting groups for amino groups include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and diphenyl. Methyloxycarbonyl, methoxymethyloxycarbonyl, trityl, trimethylsilyl, etc., and protecting groups for carboxyl groups include, for example, t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, Phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl.

Methylthiomethyl, trityl, trichloroethyl.

Examples include trimethylsilyl, dimethylsilyl, dimethylaminoethyl and the like.

The acylation reaction in production method A) is carried out by reacting 1 to 3 moles of the carboxylic acid-reactive derivative of the compound (III) with 1 mole of the compound (II).

Examples of the reactive derivative include acid halides, acid anhydrides, active amides, and active esters. Preferred examples include acid chlorides, acid bromides, mixed acid anhydrides such as acetic acid, pivalic acid, isovaleric acid, and trichloroacetic acid, activated amides with pyrazole, imidazole, dimethylpyrazole, benzotriazole, etc., and p-nitrophenyl esters. .

2, 4-'; Examples include active esters with nitrophenyl ester, trichlorophenyl ester, 1-hydroxy-IH-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and the like.

In addition, in this reaction, when the compound of CI[[ ] is used in the form of a free acid, it is preferable to carry out the reaction in the presence of a condensing agent. Hexylcarbodiimide.

Carbodiimide compounds such as N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4°-diethylaminocyclohexyl)carbodiimide, amide compounds such as N-methylformamide, N,N-dimethylformamide, and thionyl chloride; This can be carried out in the presence of a reagent (so-called Vilsmeier reagent) produced by reaction with a halide such as phosphorus oxychloride or phosgene.

Among the reactive derivatives in this reaction, acid halides,
The reaction with an acid anhydride requires the presence of an acid condensing agent, and examples of the acid binding agent include organic bases such as triethylamine, trimethylamine, ethyldiisopropylamine, N,N-dimethylamine, N-methylmorpholine, and pyridine. Examples include alkali metal substances such as sodium, potassium, or calcium hydroxides, carbonates and bicarbonates, and oxiranes such as ethylene oxide and propylene oxide.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, and solvents include water, acetone, acetonitrile,
dioxane, tetrahydrofuran.

Methylene chloride, chloroform, dichloroethane.

N,N-dimethylformamide or a mixed solvent thereof is used.

Although the reaction temperature is not particularly limited, it is usually carried out at -30 to 40°C, and the reaction time is 30 minutes to 10 hours to complete the reaction.

If the acylated product thus obtained has a protecting group, removal of the protecting group will be necessary. Methods for removing protecting groups include methods using acids, bases, and hydrazine, depending on the type of the protecting group. It can be selected and carried out as appropriate.

The substitutable residue X of the nucleophile of the compound of general formula [■] used in production method B) is, for example, an acetoxy group, chlorine,
Halogen atoms such as bromine and iodine are preferred.

In production method B), the reaction between a compound of general formula (IV) in which X is an acetoxy group and general formula (V) ``'' (V ) (wherein R2, B3 and n have the same meanings as above) is , usually a polar solvent such as water, phosphate buffer, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethylsulfoxide, dioxane, methanol, ethanol, or a mixture with water. Preferably, it is carried out in a solvent. The reaction is preferably carried out near neutrality, and although the reaction temperature is not particularly limited, it is usually suitable to carry out the reaction from room temperature to around 70°C.

The time required for this reaction varies depending on the reaction conditions, but is usually 1 to 10 hours. Further, this reaction is promoted by performing it in the presence of an alkali metal halide such as sodium iodide or potassium iodide.

In addition, when the desired compound (1) is produced from a compound in which X in the general formula (IV) is a halogen, examples of the halogen include chlorine, bromine, and iodine, but iodine is generally preferred in view of its reactivity.

The compound in which X in the general formula (IV) is iodine can be easily prepared from the protected form of the amino group or carboxyl group of the compound in which X is an acetoxy group according to a known method (for example, JP-A-56-131590). Ru.

This reaction usually involves acetone, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, and N.

It is preferable to carry out the reaction under non-aqueous conditions in a solvent such as N-dimethylformamide or N,N-dimethylacetamide. The reaction is generally preferably carried out at 0 to 50°C, and is completed in 1 to 5 hours. The protecting group can be removed from the reaction product thus obtained by a conventional method to obtain a compound of general formula CI).

The compound represented by general formula (III) can be prepared by a known method (
For example, according to JP-A-55-149289), potassium carbonate is added to the compound represented by the general formula (Vl) N'' (VI) (wherein R9 and R11 have the same meanings as above). , in the presence of a base such as sodium hydride, in an organic solvent (e.g., N,N-dimethylformamide, tetrahydrofuran, dioxane), general formula [■] RIOY (■) (in the formula R1
G has the same meaning as above. Y is chlorine.

It is produced by reacting a compound represented by a halogen such as bromine or iodine, or a nucleophilic leaving group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group.

Furthermore, the compound represented by the general formula (Iff) is a compound represented by the general formula [■] 0 [■] (wherein R9 has the same meaning as above), and the general formula (IX) H2NORIO(IX) ( It can also be produced by reacting a compound represented by (where RIG has the same meaning as above).

This reaction usually involves N,N-dimethylformamide.

N,N-dimethylacetamide, acetonitrile.

The reaction is carried out in a solvent such as dioxane, tetrahydrofuran, alcohol or other solvents that do not affect the reaction or a mixture thereof with water. The time required for the reaction is usually 30 minutes to 10-odd hours. The reaction temperature is not particularly limited, but is usually carried out between room temperature and 60°C.

The time required for the reaction is usually 30 minutes to 10-odd hours.・
Although the reaction temperature is not particularly limited, it is usually carried out between room temperature and 6q°C.

The compound of general formula (IX) is prepared according to a known method (for example, JP-A-57-131758 and JP-A-55-149289), that is, in the presence of a base, N-hydroxyphthalimide and the corresponding active halide are prepared. After the reaction with
It can be produced by hydrazine decomposition.

Further, among the compounds represented by the general formula (IX), the general formula (X) having an amine group and a carboxyl group (wherein R
The compound represented by 4, R'', m, R'' and R12 have the same meanings as above can be produced using triphenylphosphine and diethyl azodicarboxylate under mild conditions.

That is, a compound represented by the general formula (, N-hydroxyphthalimide is reacted in the presence of (where R4r R
" , R", R12,m have the same meanings as above) was obtained, and this was decomposed with hydrazine to form (X
) can be obtained.

The reaction to produce the general formula (XI[) is carried out by reacting triphenylphosphine and 1 to 2 moles of diethyl azodicarboxylate per mole of (XI). This reaction usually uses dioxane.

Tetrahydrofuran, acetonitrile, methylene chloride,
The reaction is carried out in an inert solvent such as benzene or ether, preferably under non-aqueous conditions. Although the reaction temperature is not particularly limited, it is usually carried out at θ to 30°C, and the reaction time is 1 to 10 hours to complete the reaction.

Compound (XI[) thus obtained can be subjected to hydrazine decomposition by a conventional method to obtain the target compound (X).

In addition, by subjecting cycloserine to a hydrolysis reaction according to the method of C.H. Stammer et al. (J.O.C., vol. 27, p. 2957, 1962), and then protecting the carboxyl group, it can be easily Obtainable.

The compound of general formula (V) constituting the 3-position substituent of the compound of the present invention can be synthesized by the following method.
1-substituted cycloalkano(,b)4-thiopyridones are described by S., Hunig et al. (Chem, Be
r, 94+486, 1961) and G, J't;g
Cycloalkano [b] 4-pyrones such as er (Ann, Chem, 1689+1976) are expressed by the general formula (Vla) R2N (CH2)FB (Vla)
(CB, p have the same meanings as above)) After reacting with the amino compound represented by
08, Abramovich et al. (J, 8m, Ch
em, Soc.

1525, 1981) or by halogen substitution of the cycloalkano [b] 4-pyrones after treatment with ammonia. 3. -Cyclopentinoviridine (X is a halogen atom, R3 and n have the same meanings as above) with the general formula v+b X (CH2)p B (■b)(
After reacting with a halide represented by (X, B, P have the same meanings as above), it is synthesized by KSFI treatment.

(X, R3, n, p, B have the same meanings as above) 1-
Substituted-cyclopentano [C] 2-thiopyridones can be obtained by the following method. That is, S, YAMAMUR
Methods such as A (Bull, Chem, Soc, Ja
panvol, 42.1766 (1969)
(c) When 2-pyrone is treated with ammonia, cyclopentano CC)-2-pyridone is obtained. [C] Can be led to 2-thiopyridone.

(X, P, B have the same meanings as above) In addition, the intermediate cyclopentano [c] 2-pyridone is G, Simc
(Chern, Ber-103+ 3-89
It can also be easily prepared by reduction treatment (dehalogenation) of 6-chloro-cyclopentano[C]2-pyridone obtained by the method of +1970).

The compound of general formula CI) obtained as described above is collected from the reaction mixture by a conventional method. For example, Amberlite X A D-2 (manufactured by Rohm & Hass),
It can be purified by adsorption onto an adsorbent resin such as Diaion HP-20 (Mitsubishi Kasei side part) and elution with a water-containing organic solvent.

〔Effect of the invention〕

The object compound (I) of the present invention or its salts is a new compound and exhibits high antibacterial activity that inhibits the growth of a wide range of pathogenic microorganisms, including Durham-positive and -negative bacteria. In order to demonstrate the usefulness of the target compound (I), the compound (I) of this invention
) The antibacterial activity measured for representative ones among them is shown below.

Minimum Inhibitory Concentration (MIC) in nag/m (4) The compounds of the present invention are useful as pharmaceuticals for treating bacterial diseases, and the dosage forms for this purpose generally include intravenous injection, intramuscular injection. Alternatively, it can be administered parenterally using suppositories, or orally using tablets, powders, capsules, syrups, and the like.

The present invention will be further explained in detail in the following examples, but these examples are merely illustrative and do not limit the present invention, and various changes and modifications can be made without departing from the scope of the present invention. Needless to say, it is.

In addition, the N'MR data in the examples is 100MHz or 4
Unless otherwise specified, in the case of heavy water, the δ value is shown when the peak of water is set to 4.65, and for other heavy solvents, TMS is used as the standard. did.

〔Example〕

Reference example 1 fa) cyclopentano (b)-4-pyrone (5,
5g) and concentrated ammonia (50mj2), and put it in a sealed tube.
The mixture was heated at 00°C for 3 hours. After cooling, the crystals were collected by filtration, washed with a small amount of water, and after drying, cyclopentano (b) -4-
5.23 g (95%) of pyridone was obtained. Next, phosphorus oxychloride (7ml) was added to this cyclopentano(b)-4-pyridone (6.3g), and the mixture was heated at 135°C for 1 hour. After cooling, the reaction product was dissolved in 10% hydrochloric acid (60 mL) and washed with diethyl ether (60 mL).

The ether layer was extracted with 10% hydrochloric acid (30 mβ), and the aqueous layers were combined and made alkaline with 20% caustic soda. Extract with ethyl ether (150 ml x 3), rinse with magnesium sulfate, distill off the ether, and extract 6.25 g of 4-chloro-cyclopentano(b)-pyridine (90%
)Obtained.

(b) 4-Chloro-cyclopentano (b)-Pyridine (1.2 g) and ethyl bromoacetate <1.2 mJ) were mixed and stirred at 60°C for 1 hour.

The solidified reaction solution was slurried with ether, the crystals were collected by filtration, and 1-ethoxycarbonylmethyl-4-chloro-cyclopentano (b)-pyridinium bromide 2.2
7g (92%) was obtained.

NMR (D20) δ, 1.28 (t, 3H), 2.15-2.6
2 (m, 2H), 3.05-3.55 (m, 4H)
, 4.32 (q, 2H), 5.43 (s, 2H)
, 7.90 (d, IH) , 8.47 (d, 1■
) This 1-ethoxycarbonylmethyl-4-chloro-cyclopent [b] hyridinium bromide salt (1,
'6g) in a KSH solution (1.8g of caustic potassium in 25ml of water)
j! (prepared by introducing hydrogen sulfide gas into a solution dissolved in phenolphthalein until the red color of phenolphthalein fades)
was added under water cooling. After stirring for 15 minutes at room temperature, the resulting crystals were collected by filtration, dried, and converted into niethoxycarbonylmethyl-cyclopentano (b)-4-thiopyridone L, 03 g (8
7%).

NMR (CDCIa) 1.26 (t, 3f(), 1.8-2.3 (m
, 21() , 2.8-3.3 (m, 4H) , 4
．． 28 (q, 2H), 4.65 (s, 2H), 7
．． 05 (d, II (), 7.24 (d, In) (
C) 1-ethoxycarbonylmethyl-cyclopentano
(b) -4-thiopyridone, (712w) surrounded by F 4m
ff, 4 ml of IN caustic soda was added thereto, and the mixture was stirred at room temperature for 1 hour. After adding 10 m4 of water and acidifying with IN' acid, the mixture was concentrated and the crystals were collected by filtration. Further crystals were collected by filtration from the mother liquor, and after drying, 1-carboxymethyl-cyclopencuts (b)-4-thiopyridone 505■ (80%
) was obtained.

NMR (CD30D) δ, 1.95-2.4 (m, 2H), 2.8-
3.3 (m, 4H), 4.90 (s, 2■), 7
．． 30 (d, IH), 7.56 (d, 18) Reference example 2 1-ethoxycarbonylmethyl-cyclopentano (b
)-4-thiopyridone 240■ in concentrated ammonia water 2mβ
and react for 1 hour under water cooling.

After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain 200 portions of 1-carbamoylmethyl-cyclopentano(b)-4-thiopyridone.

NMR(d a −DM3Q)δ, 2
．． 03 (m, 2H), 2.76 (t, 2H),
2.92 (t, 2H), 4.68 (s, 2H)
, 7.05 (d, IH) , 7.26 (d, IH
) Compounds of Reference Examples 3 and 4 were obtained by treating in the same manner as in Reference Example 1(b), using reagent (A) instead of ethyl bromoacetate.

Reference example 3 1-cyanomethyl-cyclopentano (b) 4-thiopyridone (A) Bumuloacetonitrile NMR (CDC1a + CDa OD) δ, 2.2
2 (m, 2H) , 3.04 (t, 2H) , 3.
18 (t, 2H), 3.85 (s, 2H), 7.
36 (d, IH), 7.40 (d, IH) Reference Example 4 (A) Chlormethyl methyl sulfide NMR (CDC1a) δ, 2.15 (s, 3N), 2.17 (m, 2
H), 3.04 (t, 2H), 3.09 (t, 2
H), 4.84 (s, 2H), 7.14 (d,
IH), 7.34 (d, LH) Reference Example 5 (a) 4-chloro-cyclopentano (b)-pyridine927 Q? and 0.6 mA of 2-bromoethanol were mixed and stirred at 50°C for 30 minutes and then at 80°C for 1 hour. After concentration under reduced pressure, the residue was dissolved in water and washed with ether.

The ether layers were combined and extracted with a small amount of water.

The aqueous layers were combined and concentrated to dryness. The residue was soaked in silica gel (40
The product was subjected to column chromatography (g) and eluted with chloroform:methanol (2:1). Fractions containing 1-(2-hydroxyethyl)-4-chloro-cyclopentano (b)-4-pyridinium bromide were collected, the solvent was distilled off, and crystallized from acetone to give 536 mg (32
%) was obtained as crystals.

NMR (D20) δ, 2.15-2.65 (m, 2) 1), 3.1
~3.7 (m, 4H), 3.9~4.21 (m,
2H), 4.5-4.8 (m, 2H), 7.82
(d, IH) , 8.46 (d, 2) 1) (bll
-(2-Hydroxyethyl)-4-chloro-cyclopentano (b) Phenolphthalein discolors 520 μl of -4-pyridinium bromide by adding hydrogen sulfide gas to a KSH solution (0.66 g of caustic potassium dissolved in 1° mJ of water). ) and stirred at room temperature for 2 hours. After adding sodium chloride after the reaction, the mixture was extracted 10 times with dichloromethane, dehydrated with magnesium sulfate, and dichloromethane was distilled off. The residue was crystallized from acetone-ether, collected by filtration, and dried to obtain 279 ml (77%) of 1-(2-hydroxyethyl)-cyclopentano(b)-4-thiopyridone.

N M R (D 20 10 D a OD ) δ,
1.88-2.35 (m, 2H), 2.67-3
．． 2 (m, 4H), 3.83 (t, 2■), 4
．． 17 (t, 2■), 7.28 (d, 1■), 7
．． 59 (d,,IH) Reference example 6 (al cyclopentano (b)-4-thiopyridone 680 ml and N,N-dimethylethylenediamine 1 ml
The mixture was mixed, heated and stirred at 120° C. for 7 hours, the reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (40 g). Chloroform: methanol (3:
The target product was obtained by elution in step 1).

This product crystallized when left at room temperature. Ethyl ether was added, the slurry was collected by filtration, and 1-(2-dimethylaminoethyl)-cyclopentano (b)-4-pyridone
I got 4 ■.

NMR (CDC13) δ, 2.20 (s, 68), 1.95-2.30
(m, 2H), 2.54 (t, 2H), 2.7~
3.2 (m, 4H), 3.81 (t, 2H), 6
．． 26 (d, in), 7.24 (d, LH) (b
)1-(2-dimethylaminoethyl)cyclopentano
(b) 515 cm of -4-pyridone and 555 cm of phosphorus trisulfide were thoroughly mixed and heated at 140°C for 20 minutes.

After cooling, the mixture was made alkaline by adding water and IN-caustic soda, crushed well, and extracted four times with chloroform.

After washing with saline and dehydrating with magnesium sulfate, chloroform was distilled off. The resulting crystals were slurried with ethyl acetate, collected by filtration, and 1-(2-dimethylaminoethyl)-cyclopentano(b)-4-thiopyridone 331 (6
0%) was obtained.

NMR (CDC1a) δ, 2.22 (s, 6B), 1.95-2.3
(m, 28), 2.60 (t, 2H), 2.85
~2.25 (m, 4H), 3.92 (t, 2u)
, 7.14 (d, In), 7.28 (d, IH)
-Reference Example 7 1-Hydroxy-cyclopentano (b)-4-thiopyridone (a) 4-chloro-cyclopentano (b)-Pyridine 920 ml was dissolved in acetic acid 4 m j! Melt it and heat it to 90℃.

Add 30% hydrogen peroxide to this and stir for 4 hours.

Water 4m7! was added, diluted, and an aqueous solution of sodium thiosulfate was added until the iodopotash starch paper no longer appeared blue. After concentrating this reaction solution, an aqueous sodium hydrogen carbonate solution and brine were added, and the mixture was extracted three times with chloroform. After dehydration with magnesium sulfate, chloroform is distilled off. The resulting crystals were made into a slurry with ethyl ether, collected by filtration, and after drying, 4-chloro-cyclopentano (b)-pyridine-N
-Oxyto 700 μm (67%) was obtained.

NMR (CDCIa) δ, 1.95-2.45 (m, 2H), 2.
9 (1~3.45 (m, 41 (), 7, .10
(d, IH), 8.10 (d, LH) (b)
4-chloro-cyclopencts [b], -pyridine-N
- Oxide 340 ■ in KSH solution (made of steel by blowing hydrogen sulfide gas into a solution of caustic potassium 717 ■ dissolved in water 1.0 ml until the red color of phenolphthalein fades)
and heated overnight at 100°C in a sealed tube. After cooling, the mixture was concentrated under reduced pressure, 10 mj2 of water was added, and the mixture was made acidic with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, dried, and 1-human'roxycyclopentano (b)-4-thiopyridone 229 μ (32
%) was obtained.

NMR (CDC13+CD30D) δ, 2.1-2.45 (m, 2H), 2.9-3
．． 4 (m, 4H), 7.28 (d, IH), 7
．． 73 (d, 10) Reference Example 8 4-chloro-2,3-cyclopentenopyridine 765
470 μ of N and 2-bromoethanesulfonic acid were reacted at 80° C. for 2 hours.

After the reaction is complete, dichloromethane and water are added to remove the water layer.
was adjusted to 8 with a saturated aqueous sodium bicarbonate solution, the aqueous layer was separated, washed with dichloromethane, and then concentrated to dryness under reduced pressure at a pi of 6°5. This was dissolved in methanol and purified by Sephadex L H-20 column chromatography (packed with methanol) to obtain 110 μl of 1-(2-sulfoethyl)-3-chloro-cyclopentenopyridinium.

This is 2m7 of water! The pH was adjusted to 7 with IN sodium hydroxide solution, and 1 ml of 20% potassium sulfide aqueous solution was added under water cooling. After the reaction is completed, the pH of the reaction solution is adjusted to 1.5 with 5N hydrochloric acid, concentrated under reduced pressure, and dried. This was dissolved in methanol, the insoluble portion was filtered off, and purified using Sephadex L H-20 column chromatography (filled with methanol) to obtain 65 μl of 1-(2-sulfoethyl)-cyclopentano[b]-4-thiopyridone. Obtained.

NMR (d4 MeOH) δ, 2.39 (m, 2H), 3.08 (t
, 2H) , 3.45 (t, 2H) , 3.54
(t, 2H) , 4.79 (t, 20) , 7
．． 77 (d, IH) , 8.43 (d, IH) Reference Example 9 1-Methyl-cyclopentano [CD 2-thiopyridone (a) 5-methoxycarbonyl-cyclopentano [CD
20 ml of concentrated ammonia water was added to 2 g of 2-pyrone, and the mixture was reacted by heating at 100° C. for 10 hours in a sealed tube. The reaction solution was concentrated and then subjected to silica gel chromatography using chloroform-methanol (
5:1) to obtain 1.5 g of a decarboxylated pyridone compound, cyclopents [CD2-pyridone.

fb) Then cyclopentano [CD 2-pyridone 1g was dissolved in phosphorus oxychloride lQmA at 100°C, 1.
After treatment for 5 hours, it was concentrated to dryness. The residue was diluted with 50% ethyl acetate.
After washing with 10% aqueous sodium bicarbonate and saturated brine, the solution was concentrated under reduced pressure to obtain 950 ml of 2-chloro-3°4-cyclopentenopyridine.

(C) 750 μl of the thus obtained 2-chloro-3,4-cyclopentenopyridine was mixed with 8 m I methyl iodide.
When the mixture was dissolved at t and left at room temperature for 10 hours, a precipitate was formed. Remove the supernatant and add 5ml of 20% potassium sulfide aqueous solution to the residue.
After dilution with 10 ml of water, extraction with 59 mA of chloroform and concentration to dryness, 680 ml of -methyl-cyclopentano[CD2-thiopyridone] was obtained.

NMR (CDC1a) δ, 2.10 (m, 2H), 2.96 (t, 2
■) , 3.04 (t, 2H), 4.03 (s, 3
8), 6.60 (d, IFI), 7.65 (d
, 1 ■) Reference example 10 1-Methyl-cyclopentano CC)-2-thiopyridone (a) 6-chloro-cyclopentano (c) -2-pyridone 420 ■ was dissolved in benzene 3Qml and 10% Pd
40 μ of /C was added, and hydrogenation was carried out at room temperature and at 2 atm for 2 hours. The catalyst was filtered off and the solvent was distilled off to give cyclopentano (
C)-2-pyridone was obtained quantitatively.

(b) Cyclopentano (c)-2-pyridone 35
0 ml was dissolved in 5 ml of dimethylformamide, 150 ml of 55% sodium hydride was added, and the mixture was stirred at room temperature for 15 minutes. Then, 1.2 mA of methyl iodide was added, and the mixture was allowed to react at room temperature for 2 hours. It was concentrated, dichloromethane was added to dissolve it, and the mixture was washed with a small amount of water. The dichloromethane layer was dried over magnesium sulfate and concentrated to give 1-methyl-cyclopentano.
(c)-2-pyridone 330 ml was obtained.

(C) 1-Methyl-cyclopentano (c) -2-Pyridone 250 ■ and phosphorus trisulfide 355 ■ are mixed well and 1
The reaction was carried out at 40°C for 2 hours. The resulting black solid was dissolved in dichloromethane and IN caustic Zoda solution and extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate, passed through 5 g of silica gel for columns, and washed with dichloromethane. The solvent was concentrated to obtain 150 ml of 1-methyl-cyclopentano CC)2-thiopyridone. The spectral data of this compound matched that of Reference Example 9.

Example 1 Syn-7-[2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide] -3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt 720 μm was mixed with 5 mA of water and 6 mA of acetonitrile!
To this, 350 g of 1-carboxymethyl-cyclopentano (b)-4-thiopyridone and 2.25 g of sodium iodide were added, and the reaction solution was diluted with a saturated aqueous sodium bicarbonate solution for 6.5-7. Adjust to 0, 70
React at ℃ for 8 hours.

After the reaction was completed, the reaction solution was concentrated to a small amount under reduced pressure, and poured into 70 mjt of acetone under water cooling, and the resulting precipitate was collected by filtration. This was dissolved in water and purified using HPIO column chromatography (eluted with 15% acetone water containing the desired product), and the fraction containing the desired product was concentrated and freeze-dried to obtain the title compound 560.

NMR (D20) δ, 2.16 (n+, 28), 2.85 (t, 2
H), 3.03 (t, 2H), 3.48 (AB
q, 2H), 3.86 (s, 3H),
4.18 (8BQ+2■), 4.81 (s, 2
8), 5.07 (d, IH), 5.63 (d, I
H), 6.83 (s, IH), 7.52 (d,
IH), 8.05 (d, IH) Treated in the same manner as in Example 1, except that each reagent (B) was used instead of 1-carboxymethyl-cyclopentano (b)-4-thiopyridone. By doing so, the compounds of Examples 2 to 12 were obtained.

Example 2 [B] 1-Rubamoylmethyl-cyclopentano [b
] 4-thiopyridone NMR (D20) δ, 2.18 (m, 2B), 2', 88 (
t, 2H), 3.07 (t, 2■), 3.45
(ABq, 20) , 3.86 (s, 3H) ,
4.19 (^BQ+28), 4.77 (s, 2
1(>, 5.04 (d, IH), 5.65(
d, IH), 6.88 (s, IH), 7.5
2 (d, IH) , 8.08 (d, IH) Example 3 [B] 1-cyanomethyl-cyclopentano (b) 4
-Thiopyridone NMR (D20) δ, 2.20 (m, 2H), 2.85 (t, 2
H), 3.23 (t, 2H), 3.45 (ABq
, 2H) , 3.82 (s, 3H) , 4.18 (
8BQ+2H), 4.62 (s, 28), 5.
03 (d, IH), 5.61 (d, IH), 6.
82 (s, IH), 7.58 (d, IH), 8.
21 (d, IH) Example 4 CB) 1-(2-hydroxyethyl)-cyclopentano (b)-4-thiopyridone NMR(Dp, O+ CD30D) δ,
2.21 (m, 2H), 2.91 (t, 2H
), 3.24 (t, 28), 3.49 (ABq,
2H), 3.90 (d, 3H), 4.29 (A
Bq.

2H), 4.39 (m, 2M), 5.06 (d
, IH) , 5.66 (d, IH) , 6.82 (s
, 1 ■), 7.69 (d, IFI), 8.12 (d
, IH) Example 5 CB) 1-(2-dimethylaminoethyl)cyclopentano (b)-4-thiopyridone NMR (D20) δ, 2.26 (m, 2H) , 2.27 (s, 6
H), 2.75-2.95 (m, 4H), 3.26
(m, 2H), 3.56 (ABq, 2H), 3.
83 (s, 3H), 4.30 (ABq, 2H)
, 4.41 (m, 2H), 5.14 (d, IH)
, 5.68 (d, IH) , 6.87 (s, IH)
, 7.64 (d, IH) , 8.21 (d, IH)
Example 6 (B) 1-(2-sulfoethyl)-cyclopentano
(b) -14-thiopyridone NMR (D20) δ, 2.19 (m, 2H), 2.85 (t,
2H), 3.24 (t, 2H), 3.36 (
t, 28), 3.47 (ABq, 2H), 3.8
6 (s, 38), 4.17 (ABq, 2H), 4
．． 61 (t, 2H), 5.06 (d, IH), 5
．． 65 (d, LH), 6.87 ('s, LH)
, 7.51 (d, 18) , 8.21 (d,
l1l) Example 7 [B] 1-Methylmeomethyl-cyclopentano (b)
-4-Thiopyridone NMR (D20) δ, 1.99 (s, 3H), 2.16 (m,
2H), 2.82 (t, 2H), 3.19 (t, 2
1ri, 3.43 (ABq, 28), 3.81 (
s, 3H), 4.17 (ABq, 2H), 5.00
(d, III), 5.25 (s, 2H), 5.5
7 (d, IFI), 6.79 (s, 10), 7
．． 53 (d, IH), 8.25 (d, 1■) Example 8 Boxyethyl)pyridinium-4-yl]thiometo(B) L-(2-carboxyethyl)-cyclopentano [b] 4-thiopyridone NMR ( D20) δ, 2.18 (m, 2H), 2.86 (t
, 2H), 3.05 (t, 2H), 3.24 (t
, 2H) , 3.48 (ABq, 2H) , 3.85
(s, 3H), 4.16 (^Bq, 2H), 4.
68 (t, 2H), 5.06 (d, IH), 5.
64 (d, 1) 1), 6.89 (s, LH),
7.54 (d, LH), 8.19 (d, IH) Example 9 [B] 1-Carboxymethyl-cyclohexano (b)
-4-thiopyridone NMR (D20) δ, 1. '68 (m, 211), 1.75
(m, 28) , 2.53 (t, 2■) , 2.8
0 (t, 2H), 3.46 (ABq, 2H)
, 3.86 (s, 3H) , 4.14 (^Bq
, 2H) , 4.77 (s, 2H) , 5.05
(d, IH) -5,62 (d, IH), 6.8
4 (s, 01), 7.51 (d, IH), 8
．． 04 (d, LH) Example 10 [B] 1-Carpoxymethyl-cyclopencs CC)
-2-Thiopyridone NMR (D20) δ, 2.08 (m, 211), 2.95-3.1
5 (m, 4H), 3.55 (8Bq, 2H),
3.86 (s, 3H), 4.06 (A
Bq, 2H), 4.80 (s, 2tl), 5.
06 (d, IH), 5.60 (d, IH), 6.
87 (s, LH), 7.65 (d, IH), 8
．． 50 ('d, LH) Example 11 Syn-7-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-[B] 1-methyl-cyclopentano CC)-2-thiopyridone NMR (D20) δ, 2.08 (m, 2H), 3.08 (m, 4
H), 3.60 (ABq, 2■), 3.87 (
s, 3■), 3.96 (8Bq, 2H)
, 4.27 (s, 3FI) , 5.07 (d
, IH), 5.58 (d, 1 ■), 6.89 (
s, IH), 7.63 (d, In), 8.48 (
d, In) Example 12 [B] 1-Hydroxy-cyclopentano (b)-4
-Thiopyridone NMR (D20) δ+, 2.12 (m, 211), 2.86 (
m, 2H) , 3.03 (t, 2) 1) , 3.
51 (ABq, 2) 1) , 3.93 (s, 3H
), 4.32 (ABq.

2H), 5.08 (d, IH), 5.67
(d, LH), 6.91 (s, 18), 7.23
(d, IH), 7.91 (d, IH) syn-7-
(2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide) -3-acetoxymethyl-
3-cephem-4-carboxylic acid sodium salt and reagent C
Compounds of Examples 13 to 15 were obtained by treatment using B) in the same manner as in Example 1.

Example 13 [B] 1-carboxymethyl-cyclopentano [b]
4-thiopyridone NMR (D20) δ, 1.17 (t, 3H), 2.16 (n+
, 21+) , 2.86 (t, 28), 3.04 (
t, 2H), 3.47 (ABq, 2H), 4.1
3 (q, 2H), 4.18 (ABq, 2H),
4.80 (s, 2H), 5.06 (d, 1B),
5.65 (d, 18), 6.83 (s, IH)
, 7.49 (d, IH), 8.05 (d, IH) Example 14 [B] 1-Carbamoylmethyl-cyclopentano [b
] 4-thiopyridone NMR (D20) δ, 1.17 (t, 3H), 2.18 (m, 2
H), 2.89 (t, 2H), 3.08 (t, 2
H) , 3.45 (ABq, 2H) , 4.13 (
q, 2H), 4.19 (ABq, 2H), 4.77
(s, 2B), 5.04 (d, IB), 5.66
(d, IH), 6.88 (s, LH), 7.4
9 (d, IH), 8.08 (d, IH) Example 15 Syn-7-(2-(2-aminothiazol-4-yl)
-2-Ethoxyiminoacetamide]-CB)1- (
2-Sulfoethyl)-cyclopentano (b)-4-thiopyridone NMR (D20) δ, 1.17 (t, 30), 2.19 (m, 2
)1), 2.85 (t, 2H), 3.24 (t,
2B), 3.36 (t12H), 3.47 (AB
Q, 2H), 4.13 (q, 2H), 4.17 (
ABq, 2H), 4.60 (t, 28), 5.05
(d, IH), 5.67 (d, IH), 6.8
7 (s, IH), 7.48 (d, LH), 8.2
1 (d, IH) Example 16 Sodium syn-7-(2-<2-aminothiazol-4-yl)-2-(carbamoylmethoxyimino)acetamide]-3-acetoxymethyl-3-cephem-4-carboxylate Dissolve 500 ml of salt in 2 m 12 of water and 2 ml of acetonitrile, and add 1 ml of sodium iodide.
5g and 182μ of 1-methyl-cyclopentano-(b)-4-thiopyridone were added, and the pH of the reaction solution was adjusted to 6.5-7.
．． The reaction was carried out at 65 to 70°C for 5 hours while maintaining the temperature at 0°C.

After the reaction was completed, the same procedure as in Example 1 was carried out, and the resulting precipitate was dissolved in a small amount of 50% methanol water, followed by Sephadex L.
It was purified by H-20 column chromatography (packed with 50% methanol water), and the fraction containing the target product was concentrated and lyophilized to obtain the title compound 240.

NMR (D20-CDa OD) δ, 2.16 (m, 2B), 2.83 (L, 2H), 3
．． 12 (t, 2H), 3.43 (ABq, 2H),
3.91 (s, 3H), 4.18 (ABq.

2H), 4.54 (s, 2H), 5.01 (d
, IH) , 5.63 (d, IH) , 6.88 (s
, IH), 7.50 (d, IH), 8.09 (d
, IH) Example 17 Syn-7- (2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)ium salt Syn-7-, (2-(2-aminothiazol-4-yl) yl)-2-(2-fluoroethoxyimino)acetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt 255 and 1-carboxymethyl-
110 μl of cyclopentano(b)-4-thiopyridone was reacted and purified in the same manner as in Example 1 to obtain the title compound 15.
I got 0■.

NMR (D20) δ, 2.18 (m, 2M), 2.87 (t, 2
H), 3.04 (t, 2H), 3.48 (8B
q, 2H), 4.18 (^Bq, 2H)
, 4.45~4.60 (m, 28), 4.70~
4.90 (m, 2H), 4.80 (s, 2H),
5.06 (d, II), 5.67 (d, IH),
6.90 (s, IH), 7.49 (d, IN>
, 8.05 (d, IH) Example 18 Syn-7-(2-(2-aminothiazol-4-yl)
-2-(carboxymethoxyimino)acyn~7- (
2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamide]-3-acetoxy-3-cephem-4-carboxylic acid sodium salt 615
■ Add 1.5 ml of water and 3.0 ml of acetonitrile. Omjl! To this, 1.5 g of sodium iodide and l-
Methyl-cyclopentano-(b)-4-thiopyridone 1
82■ was added, and the reaction was carried out at 65° C. for 9 hours while maintaining the pi of the reaction solution at 6.5 to 7.0. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetonitrile, and then another ml of acetone was added. The resulting precipitate was collected by filtration, thoroughly washed with acetone, dissolved in a small amount of water, purified by HP-20 chromatography, and the fraction containing the target product was concentrated and lyophilized to obtain the title compound. Obtained 280 ■.

NMR (D20) δ, 2.16 (m, 28), 2.85 (m, 2
H) , 3.11 (t, 2H) , 3.47 (
ABq, 2H) 5.3.90 (s, 3H), 4
．． 16 (ABq.

2H), 4.42 (s, 2H), 5.05
(d, IH) , 5.61 (d, IH) , 6.8
2 (s, IH), 7.54 (d, l1l)
, 8.03 (d, LH) In Example 18, 1-methyl-cyclopentano [
b] In addition to 4-thiopyridone, using reagent (B),
Compounds of Examples 19 to 20 are obtained by treatment in a similar manner.

Example 19 Lithium salt [B] 1-hydroxymethyl-cyclobentano (b)
-4-Thiopyridone NMR (DaO) δ, 2.16 (m, 2H), 2.85 (t, 2
H), 3.03 (t, 2H), 3.48 (ABq
, 2H) , 4.18 (ABq, 2H) , 4.41
(s, 2H) , 4.81 (s, 2B) , 5.06
(d, IH), 5.62 (d, LH), 6.82
(s, IH), 7.52 (d, IH), 8.0
5 (d, LH) Example 20 CB) 1-(2-sulfoethyl)-cyclopentano (
b: 1-4-thiopyridone NMR (D20) δ, 2.19 (m, 2H), 2.85 (t,
2H), 3.24 (t, 2H), 3.36 (t,
2H) , 3.47 (ABq, 2H) , 4.17
(ABq.

2H) , 4.42 (s, 2H) , 4.61 (t
, 2H), 5.06 (d, IB), 5.64 (d
, 1 ■), 6.86 (s, IH), 7.51 (d
, IH) , 8.21 (d, IH) syn-7-(2-
(sodium 2-aminothiazo--4-yl-12-'(1-methyl-1-carboxyethoxyimino)acetamide-3-acetoxy-3-cephem-4-carboxylate and reagent CB) and Example 18. Compounds of Examples 21 to 24 were obtained by processing in a similar manner.

Example 21 CB) 1-carbamoylmethyl-cyclopentano (b)
-4-thiopyridone δ, 1.35 (s, 3H), 1.36 (s,
3H), 2.16 (m, 28), 2.89 (t,
2H) , 3.09 (t, 2H) , 3.46 (^
Bq, 2H) -4,19(ABq, 2H), 4.7
8 (s, 2H), 5.05 (d, IH), 5.6
7 (d, IH), 6.87 (s, IH), 7.
52 (d, IH), 8.08 (d, 11() Example 22 [B] 1-carboxymethyl-cyclopentano (b)
, -4-thiopyridone NMR (D20) δ, 1.36 (s, 3H) , 1.37 (s,
3H), 2.16 (m, 2B), 2.86 (t,
2H), 3.04 (t, 2H), 3.47 (A
Bq, 2H), 4.18 (ABq, 2B), 4.8
1 (s, 2H), 5.06 (d, IH), 5.6
4 (d, LH), 6.85 (s, IH), 7.
52 (d, IH), 8.05 (d, 18) Example (2,3-cyclopenteno-1-carboxymethylpyridinium-4-yl)thiomethyl-3-se1a) DL-
Dissolve 11.9 g of homoserine in 200 m It of water,
10 g of sodium carbonate and 150 m# of dioxane were added. To this, 27.5 g of di-t-butyl dicarbonate
50 ml of a dioxane solution containing was added dropwise over 1 hour under water cooling. Further, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction, dioxane was removed under reduced pressure, washed with ethyl acetate, adjusted to pH 2 with 5N hydrochloric acid under cooling, and extracted twice with 400 mL of ethyl acetate.The ethyl acetate layer was washed with saturated brine. , dried over magnesium sulfate and concentrated to dryness to give Nt-butoxycarbonyl DL-homoserine 1
8.5g was obtained.

6 g of the obtained N-t-butoxycarbonyl DL-homoserine was dissolved in 100 mjt of methylene chloride, and 59 g of a methylene chloride solution containing 6 g of diphenyldiazomethane was added.
mj! was added dropwise over a period of 1 hour.

After the reaction was completed, the reaction solution was concentrated to a small amount and petroleum ether was added. The formed crystals were collected by filtration, and 8.6 g of Nt-butoxycarbonyl DL-homoserine benzhydryl ester was obtained.
I got it.

(b) 6.7!5 g of N-t-butoxycarbonyl DL-homoserine benzhydryl ester are dissolved in 150 ml of dry tetrahydrofuran, 2.85 g of N-hydroxyphthalimide and triphenate. Nylphosphine4.
Add 6g of diethyl azodicarboxylate to this and add 2.7g of diethyl azodicarboxylate.
5 ml of the mixture was added and the mixture was reacted for 3 hours at room temperature under an argon atmosphere.

After the reaction was completed, the reaction solution was concentrated under reduced pressure, and 30 mj of ether was added.
! dissolved in

The precipitated crystals were collected by filtration and subjected to Nt-butoxycarbonyl ester to obtain 7 g of 10-phthalimide DL-homoserine benzhydryl ester.

NMR (CDC1a) δ, 1.44 (s, 9H), 2.33 (m,
2H), 4.27 (t, 21), 4.68 (m,
IB), 5.79 (d, IH), 6.93 (s
, IH), 7.34 (m, IOH), 7.81
(m, 4H) (C) N-t-butoxycarbonyl-〇-
5.52 g of phthalimide DL-homoserine-benzhydryl ester was dissolved in 100 ml of dry dichloromethane, and 0.51 ml of hydrazine hydrate was added thereto.
The reaction was allowed to proceed for 1 hour under water cooling. Furthermore, hydrazine 0.12m
1 was added, and the mixture was allowed to react at the same temperature for 1 hour. After the reaction was completed, the insoluble portion was removed by filtration, and the filtrate was washed successively with water and aqueous ammonia, dried over magnesium sulfate, and concentrated to dryness under reduced pressure.

The residue was dissolved in 700 m 12 of ether, the precipitated crystals were filtered off, the filtrate was concentrated, and the precipitated crystals were further filtered off.
The filtrate was concentrated to dryness to obtain 3.88 g of N-t-butoxycarbonyl-hydryl ester.

NMR (CDC13) δ, 1.43 (s, 9H), 2.08 (m.2
H) ,3.68 (,t,2H),4,,53 (m
,1)1) ,5.27 (m,2)1) ,6.93
(s, IH), 7-35(m+10H) (dl (2-chloroacetylamino-thiazole-
1.71 g of 4-yl)glyoxyl M was dissolved in 30 ml of a 1:2 mixture of tetrahydrofuran and water, and N-
Add 30 m, (l) of a tetrahydrofuran solution containing 2.88 g of t-butoxycarbonyl-〇-amino-DL-homoserine benzhydryl ester, adjust the pH to 5.1 with IN-caustic soda, and react at room temperature for 6 hours. After the reaction is complete, The pH of the reaction solution was adjusted to 6.5, concentrated under reduced pressure, tetrahydrofuran was removed, 100 mA of water was added, the pH of the solution was adjusted to 8, and after washing with 100 mJ of ether, the pH was adjusted with 2N hydrochloric acid under water cooling. 2 and extracted with 250 ml of ethyl acetate. After washing the ethyl acetate layer with water,
It was dried over magnesium sulfate and concentrated under reduced pressure. The remaining amount is ether 100mj! Dissolve in solution, remove the insoluble part by filtration, and thin
2-(2-chloroacetylamino-thiazol-4-yl)-2-(3DL-3-t-butoxycarbonylamino-3-diphenylmethoxycarbonyl)propyloxyiminoacetic acid3. 15g was obtained.

NMR (acetone d6) δ. 1.48 (s, 98), 2.28 (m,
2H), 4.30 (t.2H), 4,57 (m.
IH), 4.50 (s, 2H), 6.88 (s
．． IH), 7, 36 (m, IOH), 7.56
(s.IH) (e) Syn-2-(2-chloroacetylaminothiazol-4-yl)-2-(3DL-3
1.4 g of -t-butoxycarbonylamino-3-diphenylmethoxycarbonyl)propyloxyiminoacetic acid was dissolved in 15 ml of N,N-Schif'thylformamide, and
-Hydroxybenztriazole 300■ and N,N-
465 μl of dicyclohexylcarbodiimide was added and reacted at room temperature for 1 hour. This was cooled with water, 7-amino-3-
985 μl of acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester was added and reacted at the same temperature for 5 hours.

After the reaction was completed, the insoluble portion was filtered off, and 150 mj of diclumethane was added.
! The mixture was washed with diluted hydrochloric acid and then water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure.

This was purified by silica gel column chromatography (developing solvent benzene-ethyl acetate 5:2), and Syn-7
-(2-42-chloroacetylaminothiazole-4-
1.35 g of yl'I-2-(3DL-3-t-butoxycarbonylamino-3-diphenylmethoxycarbonyl)propyloxyimino)acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester was obtained. Ta.

(f) Dissolve this in 12 ml of anisole, add 12 ml of trifluoroacetic acid under water cooling, and react at the same temperature for 1.5 hours. After the reaction was completed, trifluoroacetic acid was removed under reduced pressure, and the residue was diluted with hexane 15 cooled to -20°C to -30°C.
The solution was poured into 0 mJ, 70 mβ of ether was added thereto, and the supernatant was removed. The residue was washed with ether, the precipitate was collected by filtration, and syn-7-(2= (2-chloroacetylamino-
Thiazol-4-yl)-2-(3DL-3-amino-
3-Carboxypropyloxyimino)acetamide-
750 ml of 3-acetoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate was obtained.

This was suspended in 75ml of water and adjusted to pH 6.5 with a saturated aqueous sodium bicarbonate solution, and then 200ml of sodium N-methyl-dithiocarbamate was added and
Allowed time to react. After the reaction was completed, washed with ethyl acetate, and then washed with H
Purification was performed using P-20 column chromatography, and the fraction containing the target product was concentrated, lyophilized, and synthesized.
7-(2-(2-aminothiazol-4-yl)-2-
(3DL-3-amino-13-carboxypropyloxyimino)acetamido-3-acetoxymethyl-3-
490 ml of cephem-4-carboxylate was obtained.

NMR (D2 0) δ, 2.06 (s, 3H), 2.09 (m, 2
H), 3.51 (ABq, 2H), 4.09 (m
, LH), 4.58 (m, 2H), 4.77 (
ABq, 2H), 5.20 (d, IH), 5.79
(d, In), 7.06 (s, IH) (gl
(Compound 540 of fl was dissolved in 5 ml of water and 5 ml of acetonitrile, and 1.5 ml of sodium iodide was added to it.
g and 1-carboxymethyl-cyclopentano (b)
Add 310 μl of -4-thiopyridone to adjust the pH of the reaction solution to 6.
．． It was made to react at 65 degreeC for 4 hours, adjusting to 5-7.0.

After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetonitrile, then acetone 5QmA was added, the resulting precipitate was collected by filtration, washed well with acetone, and then dissolved in a small amount of water.
The product was purified by HP-20 chromatography, and the fraction containing the target product was concentrated and lyophilized to obtain the title compound 230.

NMR (D20) δ, 2.10 (m, 2H), 2.16 (m, 2
H), 2.85 (t, 2H), 3.03 (t, 2
H), 3.48 (^Bq, 2H), 3.90 (
m, IH), 4.19 (ABq, 2H), 4.45
(m, 2H), 4.81 (s, 2H), 5.03
(d, IH) , 5.61 (d, IH) , 6.8
7 (d, IH), 7.52 (d, IH), 8.0
5 (d, IH) Example U (al 2 g of D-cycloserine was dissolved in 50% concentrated hydrochloric acid 11
m4 and hydrolyzed for several hours at (a)°C. After the reaction is completed, the mixture is concentrated under reduced pressure, subjected to azeotropic distillation several times with ethanol, and then dried under reduced pressure overnight to obtain β-aminoxy-D-alanine dihydrochloride. This is 100m7 of ethanol! 9.5 g of diphenyl diadimethano dissolved in 5-10℃
The ethanol solution containing 80mβ was completely consumed in 2.5 hours. After the reaction is completed, the reaction solution is concentrated to a small amount, and 60 mj! of ether is added to it. and add 80 mβ of hexane. The supernatant was removed. The remaining gold was crystallized from ethanol/ether, and β
-Aminoxy-D-alanine benzhydryl ester 2
5.5 g of hydrochloride was obtained.

fbl (2-chloroacetylaminothiazole-4
1.86 g of glyoxylic acid (a
2.96 g of β-aminoxy-D-alanine benzhydryl ester dihydrochloride obtained in ) was added, and p of the reaction solution was
H was adjusted to 5 with a saturated aqueous sodium hydrogen carbonate solution, and the reaction was allowed to proceed at room temperature for 3 hours. Next, the pH of the reaction solution was adjusted to 8.5, the crystals formed were dissolved, and 20 mj! of a tetrahydrofuran solution containing 2.15 g of di-t-butyl dicarbonate was added thereto. was added and reacted at room temperature for 4.5 hours.

After the reaction, tetrahydrofuran was removed under reduced pressure, the pH was adjusted to 2 with 5N hydrochloric acid under cooling, and 200 mβ of ethyl acetate was added.
The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. This was crystallized from ethyl acetate-petroleum ether, and Syn-2
-(2-chloroacetylaminothiazol-4-yl)
-1(2D-2-t-butoxycarbonylamino-2
3.6 g of -diphenylmethoxycarbonyl)ethoxyiminoacetic acid was obtained.

(C) Syn-2-(2-chloroacetylaminothiazol-4-yl)-2=(2D-2-t-butoxycarbonylamino-2-diphenylmethoxycarbonyl)
Example 23-(81,(
Syn-7-(2-(2-aminothiazol-4-yl)-2-(2D-2-amino-2-
Carboxyethoxyimino)acetamide]-3-acetoxymethyl-3-cephem-4-carboxylate 9
I got 70■.

NMR (D20) δ, 2.06 (s, 3H), 3.51 (A[l
q, 2H), 4.12 (dd.

IH), 4.60 (m, 211), 4', 7
7 (^BQ, 2H), 5.19 (d, IH)
, 5.79 (d, LH) , 7.05 (s, 18
) + d) Of this, 260■ is water 1.5mj! and 1.5 mj of acetonitrile! To this, add 750 μ of sodium iodide and 150 μ of 1-carbemoylmethyl-cyclopentano [b] 4-thiopyridone,
The reaction is carried out at 65° C. for 4 hours while maintaining the pH of the reaction solution at 6.5 to 7.0. After the reaction was completed, Example 23- (gl
The mixture was treated in the same manner as above to obtain the title compound 95■.

NMR (D20) δ, 2.18 (m, 28), 2.88 (t, 2
H), 3.08 (t, 28), 3.46 (AB
q, 2H), 3.87 (m, IH),
4.16 (8 Bq.

2H), 4.42 (m, 2B), 4.74 (s
, 2H), 5.06 (d, IH), 5.63 (d,
IH), 6.86 (s, 1■), 7.51 (d,
IH) 1.8.06 (d, IH) Example 24-(d
), 1-rubamoylmethylcyclopentano
[b] By using reagent CB) in place of 4-thiopyridone and treating in the same manner, the compounds of Example δ to Example 6 were obtained.

Example 25 Boxylate [B] 1-Methyl-cyclopentano (C)-2-thiopyridone NMR (D20) δ, 2.08 (m, 2H), 3.10 (m, 4
t(), 3.58 (ABq, 2H), 3.90 (
m, IH), 4.04 (ABq, 2H), 4.2
6 (s, 3H), 4.40 (m, 28), 5.0
7 (d, IH), 5.60 (d, IH), 6.8
8 (s, IH), 7.60 (d, IH), 8.
47 (d, IH) Example part xyethoxyimino)acetamide)-3-(2゜3-
Cyclopenteno-''1-methylpyridinium-boxylate [B] 1-Methyl-cyclopencts (b)-4-thiopyridone NMR (D20) δ, 2.17 (m, 2H), 2.85 (t, 2
H), 3.10 (t, 2H), 3.48 (^Bq
, 28) , 3.86 (s, 3H) , 3.91 (
n+, IH), 4.18 (8Bq, 2H),
4.40 (m, 2H), 5.05 (d,
III), 5.60 (d, LH), 6.84
(s, 18), 7.52 (d, IH), 8.06
(d, IH) Example 27 Syn-7-(2-(2-aminothiazol-2-yl)-2-methoxyiminoacetomide) 546 μl of 3-acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in anhydrous dichlormedan. 5.6 mε, 0.64 mIt of N,O-bistrimethylsilyltrifluoroacetamide was added under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour.To this, 0.51 mβ of trimethylsilyl iodide was added.
The reaction was further continued for 1 hour at room temperature. Then, concentrate under reduced pressure,
Dissolve the residue in 3.0 ml of anhydrous acetonitrile, and
Add 0.2 ml of anhydrous tetrahydrofuran. 1m7 of anhydrous dichloromethane after 5 minutes! 1-Methyl-cyclopentano [C] 2-thiopyridone dissolved in 240■
was added and reacted at room temperature for 1.5 hours.

After the reaction was completed, 0.24 mj+ of cooled sewage water was added, and further 20 mk of ether was added.

The formed precipitate was collected by filtration, thoroughly washed with acetonitrile-ether mixture, dried, suspended in a small amount of water, dissolved with saturated aqueous sodium bicarbonate solution at pH 7.2, and subjected to HP-20 column chromatography. Refined at E,
The fraction containing the target product was concentrated and lyophilized to obtain the title compound 210. The spectral data of this compound matched that of the compound obtained in Example 11.

Example 4 Syn-2-(2-aminothiazol-4-yl)=2-
400 ml of methoxyiminoacetic acid was dissolved in 4 ml of N,N-dimethylformamide, and 270 ml of N-hydroxybenztriazole and 415 ml of N,N-dicyclohexylcarbodiimide were added thereto and reacted at room temperature for 1 hour.

On the other hand, 7-amino-3-(2,3-cyclopenteno-1
820 μl of -carbamoylmethylpyridinium-4-yl)thiomethyl-3-cephem-4-carboxylate was suspended in 5 mβ of N,N-dimethylformamide, and 0.45 ml of triethylamine was added thereto under water cooling. Next, the above reaction solution was added, and the mixture was allowed to react at 5° C. overnight.

After the reaction was completed, the insoluble portion was filtered off, and ether was added.
The resulting precipitate was collected by filtration and washed with ethyl acetate.

This was dissolved in a small amount of water, the pH was adjusted to 6.5 to 7.0, and purified using HP-20 column chromatography. The fraction containing the target product was concentrated and lyophilized. , the title compound was obtained. The spectral data of this compound matched that of Example 2.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R^1 is a straight or branched alkyl group having 1 to 5 carbon atoms, or a straight chain or branched alkyl group having 3 to 6 carbon atoms. cycloalkanomethyl groups (these groups may be substituted with halogen atoms), or ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [m represents 0 or an integer from 1 to 3, A represents the group -COR ＾6＾＾＾｛＾＾＾＾＾＾＾＾＾＾ﾔ
is the same or different hydrogen atom or an alkyl group having 1 to 5 carbon atoms)}, a group ▲ has a numerical formula, chemical formula, table, etc. ▼ or a 5- to 6-membered heterocyclic group containing nitrogen or sulfur, ^4 and R^5 are a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or R^4 and R^5 combine to form a hydrogen atom having 3 to 5 carbon atoms.
cycloalkylidene group having 1 to 5 carbon atoms], R^3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R^2 represents an alkyl group having 1 to 5 carbon atoms. , an alkenyl group, an oxygen atom or -(CH_2)_pB (p represents 0 or an integer of 1 to 3, B is an amino group, an alkyl-substituted amino group, a hydroxyl group, an alkoxy group, a carboxyl group, a carbamoyl group, a sulfonic acid group, sulfonamide group, cyano group, thiol group, alkylthio group, methanesulfonylaminocarbonyl group, or acetamidosulfonyl group), and n is an integer of 3 to 5. its pharmacologically acceptable salts. 2. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R^2 is an alkyl group having 1 to 5 carbon atoms. , alkenyl group, oxygen atom or group -(CH_2)_pB (p represents 0 or an integer of 1 to 3, B is an amino group, an alkyl-substituted amino group, a hydroxyl group, an alkoxy group, a carboxyl group, a carbamoyl group, a sulfonic acid group) , a sulfonamide group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylaminocarbonyl group, or an acetamidosulfonyl group), n is an integer of 3 to 5, or a salt thereof or carboxyl Protecting groups include the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ In the formula, R^9 represents a hydrogen atom or a protecting group for an amino group, and R^1^0 represents a straight chain or a group having 1 to 5 carbon atoms. A branched alkyl group, a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with a halogen atom), or a mathematical formula, chemical formula, table, etc. represents 0 or an integer from 1 to 3, and A' is the group -COR^6'{R^6
' is OR^1^1 (R^1^1 indicates a carboxyl group protecting group), group ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (R^7, R^8
represents the same or different hydrogen atoms or alkyl groups having 1 to 5 carbon atoms)} Group ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R^1^1 has the same meaning as above, R^1 ^2 represents a protecting group for an amino group) or a 5- to 6-membered heterocyclic group containing nitrogen and sulfur, R^4 and R^5 are a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or R 2-(2-aminothiazol-4-yl)2- having a group represented by ^4 and R^5 combined to represent a cycloalkylidene group having 1 to 5 carbon atoms]
Formulas that are characterized by reacting syn-substituted oximinoacetic acid or its reactive derivative at the carboxyl group and removing the protecting group for the amino group and the protecting group for the carboxyl group▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R^1 is a linear or branched alkyl group having 1 to 5 carbon atoms, or a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with a halogen atom). ), or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [m indicates 0 or an integer from 1 to 3, A is a group -COR^6 {R^6 is a hydroxyl group, Group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(R^7, R^8
is the same or different hydrogen atom or an alkyl group having 1 to 5 carbon atoms)}, a group ▲ has a numerical formula, chemical formula, table, etc. ▼ or a 5- to 6-membered heterocyclic group containing nitrogen or sulfur, ^4 and R^5 are a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or R^4 and R^5 combine to form a hydrogen atom having 3 to 5 carbon atoms.
represents a cycloalkylidene group having 1 to 5 carbon atoms], R^3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R^2 represents a cycloalkylidene group having 1 to 5 carbon atoms. Alkyl group, alkenyl group, oxygen atom or -(CH_2)_pB (p represents 0 or an integer from 1 to 3, B is amino group, alkyl-substituted amino group, hydroxyl group, alkoxy group, carboxyl group, carbamoyl group, sulfonic acid group) represents a group represented by a sulfonamide group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylaminocarbonyl group, or an acetamidosulfonyl group, and n represents an integer of 3 to 5. Process for producing compounds and their pharmacologically acceptable salts. 3. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^9 represents a hydrogen atom or a protecting group for an amino group, and R^1^3 is a straight or branched chain having 1 to 5 carbon atoms. an alkyl group, a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with a halogen atom), or ▲numerical formula, chemical formula, table, etc.▼ [m is 0 or 1 Indicates an integer from 3 to 3, A″ is the group -COR^6″{R^6
'' is OR^1^1'(R^1^1' is a protecting group for hydroxyl or carboxyl group, group ▲ Numerical formula, chemical formula, table, etc. ▼ (R^7, R^8 are the same or different hydrogen atoms or Indicates an alkyl group having 1 to 5 carbon atoms)} Group ▲ Numerical formula, chemical formula, table, etc. ▼ (R^1^1' has the same meaning as above, R^9 is a hydrogen atom or an amino group ) or a 5- to 6-membered heterocyclic group containing nitrogen and sulfur, R^4 and R^5 are hydrogen atoms,
An alkyl group having 1 to 5 carbon atoms or a cycloalkylidene group having 3 to 5 carbon atoms by combining R^4 and R^5], where X is a substitution of a nucleophile. Compounds with the formula ▲ mathematical formulas, chemical formulas, tables, etc., which represent possible residues, include: ▼ In the formula, R^3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R^2 represents a carbon Alkyl group, alkenyl group, oxygen atom or group -(CH_2)_pB (P represents 0 or an integer of 1 to 3, B is an amino group, an alkyl-substituted amino group, a hydroxyl group, an alkoxy group, represents a carboxyl group, carbamoyl group, sulfonic acid group, sulfonic acid amide group, cyano group, thiol group, alkylthio group, methanesulfonylaminocarbonyl group or acetamidosulfonyl group, and n represents an integer of 3 to 5. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 is 1 carbon number. A straight or branched alkyl group having 5 to 5 carbon atoms, a cycloalkanomethyl group having 3 to 6 carbon atoms (these groups may be substituted with halogen atoms), or ▲ mathematical formula, chemical formula, table etc. ▼ [m indicates 0 or an integer from 1 to 3, A is a group -COR^6 {R^6 is a hydroxyl group, group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^7, R^8
are the same or different hydrogen atoms or alkyl groups having 1 to 5 carbon atoms)}, groups ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ or 5- to 6-membered heterocyclic groups containing nitrogen and sulfur, R^4 and R^5 are a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or R^4 and R^5 combine to form a hydrogen atom having 3 to 5 carbon atoms.
represents a cycloalkylidene group having 1 to 5 carbon atoms], R^3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R^2 represents a cycloalkylidene group having 1 to 5 carbon atoms. Alkyl group, alkenyl group, oxygen atom or group -(CH_2)_pB (p represents 0 or an integer from 1 to 3, B is amino group, alkyl-substituted amino group, hydroxyl group, alkoxy group, carboxyl group, carbamoyl group, sulfone represents an acid group, a sulfonic acid amide group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylaminocarbonyl group, or an acetamidosulfonyl group, and n represents an integer of 3 to 5; Process for producing pharmacologically acceptable salts.