JPS6322587A - Cephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is thiazolyl having (protected) amino group or thiadiazolyl having (protected) amino group; R<2> is cycloalkyl; R<3> is thiazolyl or thiadiazolyl which may optionally have amino, cyano, hydroxy lower alkyl or carbamoyl group as substituent group]. EXAMPLE:p-Methoxybenzyl 7beta-[2-(2-tritylaminothiazol-4-yl)-2-cyclopentyloxyimi noace-tamido]-3-[(1,2,3-thidiazol-5-yl)thiomethyl]-DELTA<3>-cephem-4-c arboxylate (synisomer). USE:An antimicrobial agent, having low toxicity and effective for resistant germs and clinical separated germs with hardly any side effects. PREPARATION:For example, a compound expressed by formula II (R<4> is H or ester residue; R<6> is protecting group) is subjected to deprotection and the resultant amine compound expressed by formula III is then reacted with a carboxylic acid compound expressed by formula IV in the presence of a condensing agent to form amide bond between both compounds.

Description

[Detailed description of the invention] Ming technical field The present invention relates to cephem derivatives having antibacterial activity.

Various compounds are known as cephem derivatives having antibacterial activity, but the cephem derivative of the present invention is a novel compound that has not been described in any literature, and is represented by general formula (1).

○In the formula, R1 is a thiazolyl group having an optionally protected amino group, or a thiadiazolyl group having an optionally protected amino group; R2 is a cycloalkyl group; R3 is a thiazolyl group or a thiadiazolyl group; , the thiazolyl LS113 and the thiadiazolyl group have as substituents an amino group, a cyano group, a hydroxy lower alkyl group,
Alternatively, it may have a carbamoyl group. ] The compound of the present invention represented by the above general formula (1) exhibits excellent antibacterial activity against a wide range of Durum-positive bacteria and Gram catfish bacteria, and is particularly effective against Staphylococcus aureus as Durum-positive bacteria. (Staph-ylococcu
s aureus FD8-209-P), Streptococcus pneumonia
s pneumoniae) and Corynbacterium diphtheriae (Corync-bacterium d
phthria). Furthermore, the compound of the present invention has the characteristics of good absorption into the body, long duration of medicinal efficacy, and low toxicity, and exhibits excellent effects against resistant bacteria and clinically isolated bacteria. Furthermore, the compound of the present invention has high stability and excellent absorption and excretion properties. In addition, it has high excretion and good bile transfer. It is also highly distributed in various organs including the lungs. There is little difference between the minimum inhibitory concentration and the minimum bactericidal concentration, and there are few side effects such as immunosuppressive effects and allergic effects.

Therefore, the compounds of the present invention are useful as 1fA drugs for treating diseases of humans, animals, and fish caused by various pathogenic bacteria, and are also useful as external disinfectants and disinfectants for medical instruments and the like.

More specifically, each element shown in the above general formula (1) is as follows.

As the thiazolyl group, 1.3-thiazolyl, 1.2-
Examples of the thiadiazolyl group include 1,2.3-thiadiazolyl, 1.2.4-thiadiazolyl, and 1.3.4-thiadiazolyl groups.

As the 5H group in the optionally protected amino group, lower alkanoyl 11 halogen-substituted lower alkanoyl group, lower alkoxycarbonyl group, phenyl group 1 to 3
Examples include a phenyl lower alkyl group or a phenyl lower alkoxycarbonyl group.

Therefore, preferred examples of protected amine groups include alkanoylamino groups having 1 to 6 carbon atoms such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, and hexanoylamino: For example, monochloroacetylamino, monofluoroacetylamino, monobromoacetylamino, monoiodoacetylamino, dichloroacetylamino, trichloroacetylamino, tribromoacetylamino, 3-chloropropionylamino, 2.3-
Dichloropropionylamino, 3,3゜3-trichloropropionylamino, 4-chlorobutyrylamino, 5-
Alkanoylamino group having 2 to 6 carbon atoms substituted with 1 to 3 halogens such as chloropentanoylamino, 6-chloropentanoylamino, 3-fluoropropionylamino, 4-fluorobutyrylamino: for example, methoxycarbonylaminoxy Alkoxycarbonylamino group having 1 to 6 carbon atoms in the alkoxy moiety of carbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, tertiary butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino; for example, benzylamino, α - A phenylalkylamino group having 1 to 3 phenyl groups and having 1 to 6 carbon atoms in the alkyl moiety, such as phenethylamino, β-phenethylamino, 3-phenylpropylamino, benzhydrylamino, and tritylamino: e.g. , benzyloxycarbonylamino, 1
-The number of carbon atoms in the alkoxy moiety is 1 to 6, such as phenylethoxycarbonylamino, 2-phenylethoxycarbonylamino, 3-phenylpropoxycarbonylamino, 4-phenylbutoxycarbonylamino, 5-phenylpentyloxycarbonylaminophenylhexyloxycarbonylamino An example is a phenylalkoxycarbonylamino group.

Preferred examples of the thiazolyl group having an amine group which may be protected include 2-small lumylamino-1,3-thiazolyl, 4-formylamino-1,3-thiazolyl,
5-formylamino-1゜3-thiazolyl, 3-formylamino-1,2-thiazolyl, 4-formylamino-
1,2-thiazolyl, 5-polmylamino-1,2-deazolyl, 2-acetylamino-1,3-thiazolyl,
5-acetylamino-1,3-deazolyl, 3-alethylamino-1,2-thiazolyl, 4-acetylamino-
1,2-thiazolyl, 2-propionylamino-1,3
-thiazolyl, 5-propionylamino-1,2-thiazolyl, 2-butyrylamino-1,3-thiazolyl, 4
-butyrylamino-1,2-thiazolyl, 2-pentanoylamino-1,3-thiazole, 5-pentanoylamino-1,2-thiazole, 2-hexanoylamino-
1,3-thiazolyl, 4-hexanoylamino-1,2
-thiazolyl, 2-benzylamino-1,3-thiazolyl, 4-benzylamino-1゜2-thiazolyl, 2-benzhydrylamino-1゜3-thiazolyl, 4-benzhydrylamino-1゜2-thiazolyl , 2-tritylamino-1,3-thiazolyl, 2-benzyloxycarbonylamino-1,3-thiazolyl, 3-benzyloxycarbonylamino-1,2-thiazolyl, 2-(2-phenethyloxycarbonylamino-thiazolyl, 4-(2-phenethyloxycarbonylamino)-1,2-thiazolyl, 2-chloroacetylamino-1,3-thiazolyl, 5-chloroacetylamino-1,2-thiazolyl, 2-dichloroacederamino-
1.3-thiazolyl, 4-dichloroacetylamino-1
．． 2-thiazolyl, 2-tert-butoxycarbonylamino-1.

Examples include 3-thiazolyl, 3-tertiary butoxycarbonylamino-1,2-thiazolyl, and the like.

In addition, as a preferable example of the thiadiazolyl group to which amino l may be protected, 4-formylamino-
1.2.3-thiadiazolyl, 5-formylamino-1
．． 2.3-thiadiazolyl, 3-formylamino-1.
2.4-thiadiazolyl, 5-formylamino-1.2
．． 4-thiadiazolyl, 2-formylamino-1.3.
4-thiadiazolyl, 4-7cetylamino1.2.3
-thiadiazolyl, 5-acetylamino-1.2.

4-thiadiazolyl, 2-acetylamino-1.

3,4-thiadiazolyl, 5-propionylamino-1
．． 2.4-thiadiazolyl, 5-1 tyrylamino-1.
2.4-thiadiazolyl, 5-pentanoylamino-1
．． 2.4-thiadiazolyl, 5-hexanoylamino-
1.2.4-thiadiazolyl, 4-benzylamino-1
．． 2.3-thiadiazolyl, 5-benzylamino-1.
2.4-thiadiazolyl, 2-benzylamino-1.3
.

4-thiadiazolyl, 5-benzhydrylamino-1.
2.3-thiadiazolyl, 5-benzhydrylamino-
1.2.4-thiadiazolyl, 2-penzhydrylamino-1,3.4-thiadiazolyl, 5-tritylamino-1.2.3-thiadiazolyl, 5-tritylamino-
1.2.4-thiadiazolyl, 2-tritylamino-1
．． 3.4-thiadiazolyl, 5-benzyloxycarbonylamino-endyloxycarbonylamino-diazolyl, 5-(2-phenethyloxycarbonylamino-5-chloroacetylamino-1.2.4-thiadiazolyl, 5-dichloroacetylamino- 1.2.

Examples include 4-thiadiazolyl, 5-tert-butoxycarbonylamino-1.2.4-thiadiazolyl, and 5-tert-butoxycarbonylamino-1.3.4-thiadiazolyl.

Examples of the cycloalkyl group include cyclopropyl,
Examples include cycloalkyl groups having 3 to 8 carbon atoms such as cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, and cyclooctyl.

Examples of the hydroxy lower alkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydro-xyedyl, 1-hydroxy-1-methylethyl, 1,1-dimethyl-2-hydroxyethyl, 3-human oxypropyl, 2- Hydroxybutyl, 4-hydroxybutyl, 3
-Hydroxypentyl, 5-hydroxypentyl, 4-
Hydroxyhexyl, 6-hydroxyhexyl, 5.6
Examples include hydroxyalkyl groups having 1 to 6 carbon atoms such as -cyhydroxyhexyl.

Examples of the thiazolyl group which may have an amino group, cyano group, hydroxy lower alkyl group, or carbamoyl group as a substituent include 2-amino-1,3-thiazolyl,
4-amino-1,3-thiazolyl, 5-amino-1,3
-thiazolyl, 3-amino-1,2-thiazolyl, 4-
Amino-1゜2-thiazolyl, 5-amino-1,2-thiazolyl, 2-cyano-1,3-thiazolyl, 4-cyano-1,3-thiazolyl, 5-cyano-1,3-thiazolyl, 3- Cyano-1,2-thiazolyl, 4-cyano-
1,2-thiazolyl, 5-cyano-1,2-thiazolyl, 2-hydroxymethyl-1゜3-thiazolyl, 2-(
1-hydroxy-1-methylethyl)-1,3-thiazolyl, 2-(2-hydroxybutyl)-1,3-deazolyl, 4-(2-hydroxyethyl)-1,3-thiazolyl, 4-(1 , 1-dimethyl-2-hydroxyethyl)-1,3-thiazolyl, 4-(3-hydroxyhexyl)-1,3-thiazolyl, 5-(1-hydroxyethyl)-1,3-thiazolyl, 5-( 4-hydroxybutyl)-1,3-thiazolyl, 5-(5-hydroxypentyl)-1,3-thiazolyl, 3-(3-hydroxypropyl)-1,2-thiazolyl, 3-(3- and droxy pentyl)-1,2-thiazolyl, 3-(6-hydroxyhexyl)-1,2-thiazolyl, 4-hydroxymethyl-1,2-thiazolyl, 4-(1,1-dimethyl-2-hydroxyethyl)- 1,2-thiazolyl, 4
-(3-hydroxypropyl)-1゜2-deazolyl,
4- (5- and droxypentyl)-1,2-thiazolyl, 5-(1-hydroxyethyl)-1,2-thiazolyl, 5-(1,1-dimethyl-2-hydroxyethyl)
-1,2-thiazolyl, 5-(3-hydroxyhexyl)-1゜2-thiazolyl, 5-(6-hydroxyhexyl)-1,2-thiazolyl, 2-carbamoyl-3-thiazolyl, 4-carbamoyl-1 .3-thiazolyl, 5
Examples include -carbamoyl-1,3-thiazolyl, 3-carbamoyl- -carbamoyl-bamoyl-1,2-thiazolyl, and the like.

Examples of the thiadiazolyl group which may have an amino group, cyano group, hydroxy lower alkyl group, or carbamoyl group as a substituent include 4-amino-1.2.3-thiadiazol-5-yl, 5-amino-1 .2.3-thiadiazol-4-yl, 4-cyano-1.2.3-thiadiazol-5-yl, 5-cyano-1.2.3-thiadiazol-4-yl, 4-hydroxymethyl-1. 2
.

3-Thiadiazol-5-yl, 4-(1-hydroxy-1-methylethyl)-1.2.3-thiadiazole-
5-yl, 4-(3-hydroxypropyl)-1,'2
．． 3-thiadiazol-5-yl, 4-(2-hydroxybutyl)-1.2.3-thiadiazol-5-yl,
5-(1-and droxyethyl)-1.2.3-thiadiazol-4-yl, 5-(4-hydroxybutyl)-1
．． 2.

3-thiadiazol-4-yl, 5-(5-hydroxypentyl)-1.2.3-thiadiazol-4-yl,
4-carbamoyl-1.2.3-thiadiazole-5-
yl, 5-carbamoyl-1.

2,3-thiadiazol-4-yl, 3-amino-1.
2.4-thiadiazol-5-yl, 5-amino-1.
2.4-thiadiazol-3-yl, 3-cyano-1.
2.4-thiadiazol-5-yl, 5-cyano-1.
2.4-thiadiazol-3-yl, 3-(2-hydroxyethyl)-1.

2,4-thiadiazol-5-yl, 3-(1.

1-dimethyl-2- and droxyethyl)-1.2.

4-thiadiazol-5-yl, 3-(3-hydroxyhexyl)-1.2.4-thiadiazol-5-yl,
5-(3-Hydroxypropyl)-1,2.,4-thiadiazol-3-yl, 5-(3-human 0xypentyl)-1.2.4-thiadiazol-3-yl, 5-(
6-hydroxyhexyl)-1.2.4-thiadiazol-3-yl, 3-carbamoyl-1.2.4-thiadiazol-5-yl, 5-carbamoyl-1,2,4-yl
Thiadiazol-3-yl, 2-amino-1゜3.4-
Thiadiazol-5-yl, 2-cyano-1,3,4-
Thiadiazol-5-yl, 2-hydroxymethyl-1
, 3,4-thiadiazol-5-yl, 2-(1-hydroxyethyl)-1゜3.4-thiadiazol-5-yl, 2-(2-hydroxyethyl)-1,3,4-thiadiazol-5 -yl, 2-(1-hydroxy-1-
methylethyl)-1,3,4-thiadiazol-5-yl, 2-(1,1-dimethyl-2-hydroxyethyl)
-1,3,4-thiadiazol-5-yl, 2-(3-
Hydroxypropyl)-1,3゜4-thiadiazole-
5-yl, 2-(2-hydroxybutyl)-1,3,4
-thiadiazol-5-yl, 2-(4-hydroxybutyl)-1゜3.4-thiadiazol-5-yl, 2-
(3-hydroxypentyl)-1,3,4-deadiazol-5-yl, 2-(5-hydroxypentyl)
-1,3,4-thiadiazol-5-yl, 2-(3-
hydroxyhexyl)-1,3,4-thiadiazole-
5-yl, 2-(6-hydroxyhexyl)-1,3,
4-thiadiazol-5-yl, 2-carbamoyl-1
, 3,4-thiadiazol-5-yl and the like.

Examples of the ester residue of the carboxylic acid ester include conventional ester residues, such as alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, inbutyl, tertiary butyl, pentyl, and hexyl; benzyl; , benzhydryl, α-phenethyl, β-7enethyl,
α, β-diphenylethyl, 3-phenylpropyl, 4
- (Mono or di) phenyl lower alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as phenylbutyl, 5-phenylpentyl, 6-phenylhexyl: vinyl, allyl,
Alkenyl having 2 to 6 carbon atoms such as crotyl, 2-pentenyl, 2-hexenyl, dichloropropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
Cycloalkyl group having 3 to 8 carbon atoms such as cyclooctyl, dichlorohexylmethyl, 2-cyclohexylethyl, 3
-Cycloalkyl such as cyclohexylbutyl, 4-cyclohexylbutyl, 5-cyclohexylpentyl, 6-cyclohexylhexyl, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cycloheptylethyl, cyclooctylmethyl, etc. Examples include cycloalkyl (lower) alkyl groups in which the moiety has 3 to 8 carbon atoms and the alkyl portion has 1 to 6 carbon atoms.

The phenyl moiety in the (mono- or di-)phenyl lower alkyl group of the ester residue has the following properties: As a group, for example, a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom, an iodine atom, and a carbon number of 1 to 6 such as methyl, ethyl, propyl, isopropyl, butyl, inbutyl, tertiary butyl, pentyl, hexyl, etc. Lower alkyl group: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy and other lower alkoxy groups having 1 to 6 carbon atoms; nitro group; callevoxy group Nidiano group: methoxycarbonyl, ethoxy Lower alkoxycarbonyl groups having 1 to 6 carbon atoms in the phenyl moiety such as carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl: hydroxyl group; and formyloxy,
1 to 3 substituents selected from the group consisting of lower alkanoyloxy groups having a number of 1 to 6 in the alkanoyl moiety such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, hexanoyloxy, etc. or a lower alkylenedioxy group having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy.

In addition, the lower alkyl group of the ester residue has, for example, 1 to 3 of the above halogen atoms as a substituent,
Water M group, mercapto group, lower alkoxy group mentioned above, lower alkanoyloxy group mentioned above, carboxy group, cyano group, nitro group, amino group, lower alkyl group mentioned above, methylamino, dimedylamino, ethylamino, diethylamino, propylamino , a mono- or di-substituted lower alkylamino group such as butylamino°, a lower alkanoylamino group such as formylamino or acetylamino, or a lower alkylthio group such as methylthio, ethylthio or propylthio.

The quaternary ammonium salt of the present invention can be obtained, for example, by reacting a corresponding compound with a lower alkyl halide, lower alkenyl halide, phenyl-substituted lower alkoxycarbonyl lower alkyl halide, carboxy lower alkyl halide, etc. The phenyl-substituted lower alkoxycarbonyl lower alkyl of the phenyl-substituted lower alkoxycarbonyl lower alkyl halide includes, for example, benzyloxycarbonylmethyl, benzhydryloxycarbonylmethylloxycarbonylmethyl, 2-phenylethoxycarbonylmethylsilurponylmethyl, tritylmethoxy Examples include carbonylmethylethyl group. Examples of the carboxy lower alkyl group of the carboxy lower alkyl halide include carboxymethyl, 2-carboxypropyl, 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 5-carboxypentyl 6-carboxyhexyl Examples include groups. Examples of the lower alkyl group of the lower alkyl halide and the lower alkenyl group of the lower alkenyl halide include the same groups as mentioned above. Further, examples of the halide of the above halide compound include chloride, bromide, iodite, and the like.

Compounds of the invention can be used in a variety of ways! For example, they can be produced by the methods shown in Reaction Schemes 1 to 5 below.

(The following is a blank space) Reaction Scheme-1 In the formula R1, R2 and R3 are the same as above, R4 is a hydrogen atom or an ester residue, and R5 is an amino protecting group. ] In the above reaction scheme-1, the compound represented by the general formula (3) can be produced by subjecting the compound represented by the general formula (a) to the Ili2 reaction of the amino-retaining IH represented by R5. Examples of the amine protecting group represented by R5 include amino group 35, which is exemplified as a protecting group for amino groups such as the thiazolyl group.

This elimination reaction of the amine protecting group can be carried out by conventional methods such as hydrolysis and catalytic reduction, and in the case where the amino protecting group is an acyl group, reaction with an iminohalogenating agent is followed by iminoetherification. It can also be carried out by a method (referred to as an iminoetherification method) in which an agent is applied and, if necessary, hydrolysis is performed, and these methods are appropriately selected depending on the type of protecting group to be eliminated.

When the above-mentioned elimination reaction of the amine protecting group is carried out by hydrolysis, the reaction is carried out without a solvent or in a suitable inert solvent in the presence of a hydrolysis catalyst. The catalyst used is appropriately selected depending on the type of amino protecting group, and includes anhydrous aluminum chloride, stannic chloride, titanium tetrachloride, boron trichloride, boron trifluoride-ethyl ether complex, Lewis acids such as zinc chloride, hydrochloric acid, Acids such as n-free acids such as nitric acid and sulfuric acid, g1 acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, and acetic acid, trialkylamines such as triethylamine and tributylamine, pyridine, picoline, and 1,5-diazabicyclo[ Organic bases such as 4,3,0]nonene-5,1,4-diazapisic O[2,2,21 octane, 1,8-diazapisic O[5,4,0]undecene-7, sodium hydroxide, water Examples include bases such as alkali metal hydroxides such as potassium oxide, alkali metal carbonate salts such as sodium carbonate and potassium carbonate, and inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. .

Examples of inert solvents include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroborum, and carbon tetrachloride; ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, and anisole; nitro compounds such as nitromethane and nitrobenzene;
Alcohols such as methanol and ethanol, acetate ester compounds such as ethyl acetate and methyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, dimethylformamide (DMF), hexamethyl phosphate triamide ()
-IMPA), aprotic polar solvents such as dimethyl sulfoxide<DMS○), carbon disulfide, and the like.

In the above hydrolysis, the ratio of the acid or base used to the compound represented by the general formula (21) is preferably 1 to 100 times the molar amount, preferably 1 to 20 times the molar amount. , -20 to 80°C, preferably -10 to 5
The reaction may be carried out at 0° C. for 30 minutes to 48 hours, preferably 1 to 24 hours.

The elimination reaction can also be carried out by a tangential M reduction method when the amine protecting group for R5 is an amino protecting group that can be easily eliminated by a catalytic reduction method, such as a benzyl group or a benzhydryl group. Examples of the catalyst used in the catalytic reduction method include palladium black, palladium chloride, platinum dioxide, and platinum black. In the catalytic reduction method,
The usage ratio of the catalytic reduction catalyst to the compound represented by general formula (2) is 0.1 to 10 times molar, preferably 0.1
It is preferable to use ~1 times the molar ratio. Moreover, the reaction is 0 to 2
00°C, preferably 0 to 100°C, at a temperature of 30°C.
It may be carried out for about minutes to 48 hours, preferably about 30 minutes to 6 hours.

In addition, when the elimination reaction of amino carrier II is carried out by the iminoetherification method, the iminohalogenation reaction is carried out without a solvent or in an inert solvent in the presence of a basic compound using the general formula (
This is carried out by reacting the compound represented by a with an iminohalogenating agent.

Examples of the iminohalogenating agent include phosphorus pentachloride and phosphorus pentabromide, and examples of the Jul-containing gold compound include the salts exemplified in the above-mentioned hydrolysis method.

Examples of inert solvents include dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as tetracarbohydrates, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, and dioxane, nitro compounds such as nitromethane and nitrobenzene, hexane,
Examples include aliphatic hydrocarbons such as heptane and octane. In this reaction, the ratio of the iminohalogenating agent to the compound represented by the general formula ('2J) is preferably at least equal molar m1, preferably 1 to 2 molar molar. It is carried out at 30°C to room temperature, preferably -10°C to 10°C, and is completed in about 30 minutes to 10 hours, preferably about 1 to 5 hours.

The next iminoetherification reaction is carried out by reacting the iminohalide obtained above with an iminoetherification agent. As an iminoetherification agent,
Examples include lower alcohols such as methanol, ethanol, and propatool, and the iminoetherifying agent is usually used in excess of the iminohalide. The reaction is usually carried out at about -20°C to 50°C, preferably about 0°C to room temperature, and is completed in about 5 minutes to 3 hours, preferably about 10 minutes to 1 hour.

The amine compound represented by the general formula (3) thus obtained and the carboxylic acid compound represented by the general formula (4) or a compound in which the carboxylic acid thereof has been activated are combined to form a normal amide bond. By reaction, general formula (1-a)
The compound of the present invention represented by is obtained.

As the amide bond forming reaction, any known amide bond forming reaction conditions can be applied. For example, a) method using a condensing agent: that is, a method in which carboxylic acid compound (4) and amine compound (3) are reacted in the presence of a condensing agent =
b) Mixed acid anhydride method: i.e. carboxylic acid compound (4
) with an alkylhalocarboxylic acid to form a mixed acid anhydride, which is then reacted with an amine compound (3) Method 2C
) Active esterification method: That is, carboxylic acid compound vA (
A method of converting 41 into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting this with an amine compound (3): d) Carboxylic acid compound (4)
) is converted to carboxylic anhydride with a dehydrating agent such as acetic anhydride,
A method of reacting this with an amine compound (3): e) A method of reacting a lower alcohol ester of a carboxylic acid compound (4) with an amine compound (3) at high temperature and high pressure; f>
Examples include a method in which the carboxylic acid compound (4) is an acid halide, that is, a carboxylic acid halide, and the amine compound (3) is reacted with this.

Next, an example of the amide bond forming reaction will be explained in more detail.

The compound of the present invention represented by general formula (1-a) is obtained by adding a carboxylic acid compound represented by general formula (4) to an amine compound represented by general formula (3) in the presence of a condensing agent without a solvent. Alternatively, it can be obtained by reacting in the presence of an inert solvent.

Condensing agents used in the reaction include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, Vilsmeyer reagent, dicyclohexylcarbodiimide (DCC), and 2,2'-pyridinyldisphite-1- Examples include condensing agents such as liphenylbosphine.

As the solvent, any solvent can be used as long as it does not adversely affect this reaction; for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.
Dichloromethane, Tsuku1] Halogenated hydrocarbons such as loethane, chloroform, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene, amines such as pyridine, piperidine, and triethylamine, and aliphatics such as hexane and heptane. Hydrocarbons, methanol, ethanol,
Alcohols such as propatool, dimethylformamide (DMF), hexamethylphosphoric triamide (1-IM
Examples include aprotic polar solvents such as PA), dimethyl sulfoxide (DMSO), and carbon disulfide.

The above reaction is more preferably carried out in the presence of a basic compound. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine;
Pyridine, picoline, 1゜5-diazabicyclo[4,3
,0]nonene-5,1,4-diazabicyclo[2,2,
2] Octane, 1,8-diazabicyclo[5,4,0]
Organic f4g such as undecene-7, mono-1-limethylsilylacetamide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali gold J2 such as sodium carbonate and potassium carbonate! Examples include inorganic bases such as carbonates, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, and potassium hydrogen carbonate.

In addition, in the above reaction, the ratio of the carboxylic acid compound represented by the general formula (4) to the amine compound represented by the general formula (3) is 1 to 10 times molar, preferably 1 to 10 times the molar ratio.
It is best to use ~3 times the molar ratio. The ratio of the basic compound used to the amine compound represented by the general formula (3) is preferably equal to 40 times the molar amount, preferably 5 to 20 times the molar amount.

The above reaction is carried out at -20 to 100°C, preferably -20 to 100°C.
Under a temperature condition of 50°C for 30 minutes to 24 hours, preferably 3
It takes about 0 minutes to 10 hours.

In this way, the compound of the present invention represented by general formula (1-8) is obtained.

In addition, in the reaction between the amine compound represented by the above general formula (3) and the carboxylic acid compound represented by the general formula (4), when the group R4 is a hydrogen atom, in the general formula (1-8), A compound may be obtained in which the carboxy group of the target compound represented by the formula (3) is condensed with the carboxy group of the amine compound represented by the general formula (3). In this case, an acid catalyst, e.g.
The compound of the present invention represented by the general formula (1-a) can be obtained by hydrolyzing the condensed compound in the presence of an inorganic or organic acid such as hydrochloric acid or hydrogen bromide M1]-refluoroFA acid.

Reaction Scheme-2 [In the formula, R2, R3 and R4 are the same as above, Rla is a thiazolyl group having a protected amino group, or thiadiazolyl u having a protected amino group, R1
b represents a thiazolyl group having an amine group or a thiadiazolyl group having an amino group. ] The compound of the present invention represented by the general formula (1-C) can be produced by subjecting the compound represented by the general formula (1-b) to the 1112M reaction of the amino protecting group represented by Rla. Can be done. The 111-elimination reaction of the amino-protecting group can be carried out in substantially the same manner as the elimination reaction of the amino-protecting group 11t in the reaction scheme-1, and the reaction method (hydrolysis,
catalytic reduction, etc.), reaction conditions (acid, base, reduction catalyst, solvent,
Regarding the reaction temperature, reaction time, etc., the explanation of the reaction process scheme-1 can be referred to.

In addition, in the above-mentioned elimination reaction of the amino protecting group 11, when R4 of the compound represented by the general formula (1-b) is an ester residue U, depending on the type of the ester residue, the elimination reaction of the amino protecting group With the separation, the ester residue is separated by 1152,
In the compound represented by the general formula (1-c), a compound in which R4 is a hydrogen atom may be produced, but this case is also included within the scope of the method for producing the compound of the present invention.

Reaction Scheme-3 R2 [Wherein, R1, R2, and R3 are the same as above, and R6 represents an ester residue. ] The compound of the present invention represented by the general formula (1) is produced by subjecting the ester compound represented by the above-mentioned general formula (1-d) to a deesterification reaction.

The deesterification reaction can be carried out under conditions substantially similar to the conditions for the elimination reaction of the amino protecting group in Reaction Formula-1, for example, without a solvent or in the presence of an appropriate solvent, using an acid or It can be obtained by reacting with a basic compound or by subjecting it to a catalytic reduction reaction.

There are no particular limitations on the solvent used in the reaction, and for example, in Reaction Scheme-1, the solvent used to obtain the compound represented by general formula (3) from the compound represented by general formula ('2J) Examples include solvents such as water, water, etc.

The above acidic compounds include hydrochloric acid, hydrobromic acid, sulfuric acid,
Examples include inorganic acids such as nitric acid, organic acids such as trifluoroacetic acid, acetic acid, and formic acid, and acid type ion exchange resins. Among these acidic compounds, liquid ones can be used also as a solvent.

In addition, basic compounds include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, and 1,5-diazabicyclo[4,3,0]nonene-
5,1,4-diazabicyclo[2,2,2]octane,
1.8-diazabicyclo[5,4,01 undecene-7
Organic [i] such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbon Pli salts such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate,
Examples include alkali metal salts such as potassium hydrogen carbonate, inorganic 18 groups such as carbonated water salts, and urea compounds such as thiourea and urea.

When adding water to the reaction system, the water is preferably about 10 to 80 V/V% relative to the acidic compound or basic compound,
Once the reaction has finished, it is best to add 10 to 20 times more.

In addition, when deesterification reaction is carried out by catalytic reduction reaction,
For the conditions of the catalytic reduction reaction, the catalytic reduction reaction conditions of the above reaction scheme-1 can be used.

The ratio of the acid or basic compound used to the compound of the present invention represented by the general formula (1-d) is from 1 to 100 times by mole, preferably from 2 to 10 times by mole. In addition, the reaction temperature is preferably -20 to 80°C, preferably -10 to 50°C when a 3214 compound is used. The reaction takes about 1 to 24 hours.

In this way, a compound represented by general formula (1), which is a compound of the present invention, is obtained.

In addition, by subjecting the carboxylic acid compound represented by general formula (1) to a normal esterification reaction, general formula (1-d) can be obtained.
An ester compound represented by can be obtained.

For example, the above esterification reaction is carried out in the presence of a catalyst, and the catalyst used is a catalyst commonly used for esterification reactions. Specifically, hydrochloric acid gas, concentrated sulfuric acid,
Phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfone N, p-1-luenesulfonic acid,
Organic acids such as benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride, and dimethyl acetal thione exchange resin (M type) can also be used.

The above esterification reaction is carried out in an undissolved solution or in the presence of a suitable solvent. As the solvent used, any solvent commonly used in esterification reactions can be used, such as aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. Examples include ethers such as diethyl ether, tetrahydrofuran, and dioxane.

The ratio of the acid to the compound represented by the general formula (11) is preferably 1 to 100 molar times, preferably 10 to 30 molar times.The reaction temperature is 120 to 200 molar times.
C., preferably 0 to 150.degree.

Furthermore, the ester compound represented by general formula (1-d) is
It can also be obtained by the following method.

For example, 1) Ii52 salt condensed salt water method is a method in which an alkali metal salt such as sodium or potassium of general formula (1) is reacted with a halide corresponding to R6, and the solvent is one that does not affect the reaction. Any can be used, such as dimethyl ether,
Examples include ethers such as diethyl ether, tetrahydrofuran, and dioxane, alcohols such as methanol and ethanol, and aprotic polarities such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and hexamethylphosphate triamide (HMPA). can. The ratio of the halide to the alkali metal salt of the general formula (1) is preferably at least equimolar, preferably about 1 to 3 times molar. Moreover, the reaction is -10 to 10
It may be carried out for about 1 to 12 hours at a temperature of 0°C, preferably 0°C to room temperature.

2) Diazotization method In this reaction, the compound of general formula (1) is reacted with a diazi compound corresponding to R6, such as diazomethane, phenyldiazomethane, diphenyldiazomethane, etc., in the presence of an inert solvent. Examples of solvents include:
Dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, dimethyl ether,
Ethers such as diethyl ether, tetrahydrofuran and dioxane, nitro compounds such as nido-O-methane and nitrobenzene, alcohols such as methanol and ethanol,
&li esters such as methyl acetate and ethyl acetate, aliphatic hydrocarbons such as hexane, heptane, and octane, dimethylformamide (DMF), dimethyl sulfoxide ([
) MSO), hegisamethyl phosphate triamide (HMP
Examples include aprotic polar solvents such as A), carbon disulfide, and the like. The ratio of the diazo compound used to the compound of general formula (1) is at least equimolar, preferably about 1 to 3 times the molar amount. Further, the reaction proceeds well at 0° C. to room temperature, and usually completes in about 10 minutes to 6 hours.

(Left space below) Reaction scheme-4 [In the formula, R3 and R4 are the same as above, R7 is an amino protecting group or group: R2 R1-C-C0- (In the formula, R1 and R2 are the same as above), R8 represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group. ] There are various methods for introducing a thiomethyl group having a thiazolyl or thiadiazolyl ring into the 3-position of the cephem skeleton of the compound of the present invention, and one example of the method is shown in Reaction Scheme-4.

That is, in a suitable inert solvent, a compound represented by the general formula (S) and a thiol compound represented by the general formula (6),
By reacting in the presence of a salt compound, a thiomethyl compound having a thiazolyl or thiadiazolyl ring represented by the general formula (7), which partially includes the compound of the present invention, is obtained.

In the compound represented by the general formula (51), the halogen atom represented by R8 includes chlorine, bromine, iodine, fluorine, etc., and the lower alkanesulfonyloxy group includes methanesulfonyloxy, ethanesulfonyloxy, propane Examples of the arylsulfonyloxy group include benzenesulfonyloxy and toluenesulfonyloxy.

Examples of salt-based compounds used in the above reaction include major salt-based compounds such as tertiary amines such as triethylamine and pyridine, and salt-based compounds such as sodium carbonate and potassium carbonate.
! Basic compounds can be exemplified. As the inert solvent, a wide variety of solvents used in the above-mentioned Reaction Scheme-1 can be used.

The ratio of the compound represented by the general formula (6) to the compound represented by the general formula (S) should be at least equimolar, preferably 1 to 2 times the molar amount, and 6)
The usage ratio of the basic compound to the compound represented by is,
It is preferable to use at least an equimolar amount of stone, preferably an equimolar to twice a mole amount. The reaction temperature is preferably -10 to 100°C, preferably 0 to 50'C.

In this way, a thiomethyl compound having a thiazolyl or thiadiazolyl ring represented by the general formula is obtained.

Furthermore, among the compounds of the present invention, compounds having a quaternary ammonium base include lower alkyl halides, lower alkenyl halides, phenyl iUI, etc., in addition to the corresponding compounds of the present invention.
It can be produced by reacting M lower alkoxycarbonyl lower alkyl halide, carboxy lower alkyl halide, etc.

The reaction is carried out in a suitable inert solvent at a temperature between seedling temperature and 100°C.
It can be carried out for 30 minutes to 12 hours.

The use of the lower alkyl halide and the like for the corresponding compound of the present invention is carried out in at least an equimolar amount, preferably about 1 to 2 times the molar amount.

Examples of the inert solvent include the solvents exemplified in Reaction Scheme-1 above.

Among the compounds represented by the general formula (1) of the present invention, the compound having a basic group can be treated with a pharmaceutically acceptable acid, and the compound having an acidic group can be treated with a pharmaceutically acceptable ml property. Salts can be easily formed by reacting with compounds. Examples of sulfuric acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, and p-t-luenesulfone. Examples of the ml-type compounds include total hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, and hydrogen carbonate. Examples include alkali metal carbon salts such as potassium or bicarbonates.

Furthermore, the salts of the compounds of the present invention naturally include inner salts.

The compound of the present invention thus obtained can be easily isolated and purified by conventional separation means. As the separation means, for example, a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, a pre-variant 1) W chromatography, etc. can be employed.

The compound represented by the general formula (1) of the present invention naturally includes optical isomers, syn isomers, and anti isomers. These isomers can be determined using conventional resolution methods, e.g.
Separation can be performed by methods using optical resolution agents, enzymes, etc.

The compounds of the invention are usually in the form of common pharmaceutical formulations r1! i
used in The formulation contains commonly used fillers, thickeners,
It is prepared using diluents or excipients such as binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this drug can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, solutions, suspensions,
Emulsions, granules, capsules, suppositories, injections (liquids,!!
clouding agents, etc.). When forming into a tablet, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, cellulose crystals, silicic acid, etc. Excipients such as water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar , laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and other disintegrants; sucrose, stearin, cocoa butter, hydrogenated oil, and other disintegration inhibitors ,
Quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, talc, stearate,
Examples include lubricants such as boric acid powder and polyethylene glycol. Zarani tablets are tablets with conventional coatings as required, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets,
They can be film-coated tablets, double tablets, or multilayer tablets. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide range of conventionally known carriers can be used, including polyethylene glycol, kakadaijima, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. Can be done. When prepared as injections, solutions, emulsions, and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions, and suspensions, dilution is required. All agents commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. . In this case, the pharmaceutical preparation may contain enough salt, glucose or glycerin to prepare an isotonic solution, and the usual solubilizing agents, buffers, soothing agents, etc. Furthermore, if necessary, the therapeutic agent may contain coloring agents, preservatives, preservatives, flavoring agents, sweeteners, and other pharmaceutical agents. paste,
When molding into a cream or gel form, for example, white vaseline, paraffin, glycerin, Mm cellulose, polyethylene glycol, silicone, betonite, etc. can be used as a diluent.

The amount of the compound represented by general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be selected from a wide range, but usually 1 to 70% by weight in the total composition. It is better to

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and the method of administering the pharmaceutical preparation of the present invention is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly, intramuscularly, or intravenously.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally.

Administration of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
Usually, the compound of the present invention contains 1 to 1 per kilogram of body weight per day.
00111(+, preferably 5 to 20 ml), and the preparation can be administered in 2 to 4 divided doses per day.

(Hereinafter, blank spaces) <Example> The present invention will be described in detail below based on Reference Examples, Examples, Formulation Examples, and antibacterial activity tests.

Reference Example 1 Boxylate p-methoxybenzyl 3-chloromethyl-7β-phenylacetamide-Δ3-zephemu 4-carboxylate 5. og (10,3 mmol), sodium 1
．． A mixed solution of 2.85 g (16° 1 mmol) of 2.3-thiadiazole-5-thiolate dihydrate, 10a2 of N,N-dimethylformamide, and 150d of dioxane is stirred at room temperature overnight. After concentrating the reaction solution, the residue is dissolved in ethyl acetate, washed successively with water, aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the title compound was dissolved in 3.3
g get.

NMR (CDCJ3 > δ: 8.42 (s,
1)-1> , 7.15~7.31 (m, 7
H), 6.86 (d.

2H, J=9Hz), 6. 04 (
d, 1 t1, J = 9 t1z)
, 5. 76 (dd, IH, J
=9Hz.

5Hz), 5.12 (s, 2H), 4.90 (
d.

21-1. J=5Hz), 4.08 (s, 2H)
, 3.80 (s, 3H), 3.64 (s, 2
H) , 3, 60 (d, IH, J=
18 g12), 3.30(d, 1H
, J=18Hz) Reference Example 2 Boxylene-1-5-mercapto-1,2,4-thiadiazole 1.2 g
(10.2 mmol) was dissolved in 10.7 d of aqueous 114 sodium hydroxide solution, and then lyophilized to obtain sodium
1.2.4-thiadiazole-5-thiolate.

p-Methoxybenzyl 3-chloromethyl-7β-phenylacetamidome 3-cephem-4-carboxylate 4°09 (8.2 mmol) was added to 100 m of dioxane.
To this, add all of the thiolate, add 101d of water to make a homogeneous solution, and stir overnight at room temperature.

After concentrating the reaction solution, it is dissolved in chloroform, washed successively with an aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the mixture is concentrated and ethyl acetate is added to the residue to precipitate Δ2-cephem. Unnecessary Δ2-cephem is separated, and the concentrated oil is dissolved by adding 3 portions of chloroform. When hexane is added to this, the target product is solidified. Isolation and drying under reduced pressure yield 3.7 g of the title compound.

NMR (CDCjs) δ: 8.34 (s, IH),
7.16-7.43 (m, 7l-1), 6.86 (
d.

2H, J=9Hz), 6.07 (d, IH, J=9
Hz, ), 5. 77 (d-d,
1)1. J-91-1z.

5Hz), 5.22 (s, 2H>, 4.' 89
(d.

IH, J=5Hz), 4.64 (d, 1H, J=13
H2), 4. 16 (d, 1
)-1, J=13 112), 3.79 (S, 3H
), 3.62 (s, 2H), 3.59 (S
, 1H), 3.53 (s, 1H) Example 1 Phosphorus pentachloride 1.59 (7.2 mmol), pyridine 0.
A mixed solution of 69 (7.6 mmol) and 50 d of methylene chloride was stirred in a water bath, and p-methoxybenzyl
3-(1,2,3-thiadiazol-5-yl)thiomethyl-7β-phenylace I to amido Δa-cephem-4-carboxylate 3.3 g (5,8 mmol)
and react in a water bath for 3 hours. Methanol 20-
After reacting for an additional 30 minutes, the mixture is washed with water, an aqueous sodium bicarbonate solution, and saturated brine in this order, and dried over anhydrous magnesium sulfate. After filtration and concentration, crude p-methoxybenzyl 7β-amino-3-(1,
2,3-thiadiazol-5-yl)thiomediruΔ3
-cephemu 4-carboxylate is obtained. This entire solution is dissolved in 20 d of methylene chloride (this is called Solution A).

On the other hand, 4.3 g (8.6 mmol) of 2-(2-tritylaminothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer), 1.29 g (8.6 mmol) of 1-hydroxybenzotriazole (8.9 mmol) ), 1.8 g (8.9 mmol) of dicyclohexylcarbodiimide is added to a mixed solution of 100 IIti of methylene chloride under cooling with water, and reacted in suspension for 1 hour. Next, the above solution A was added under water cooling, and the mixture was allowed to react for 1 hour, and then allowed to react overnight at room temperature.

After filtering off the insoluble matter, ethyl acetate is added to the residue, and the insoluble matter is further filtered off. Add the filtrate to aqueous sodium hydrogen carbonate solution,
Wash with saturated saline and dry with anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated and subjected to silica gel column chromatography using chloroform as a solvent.

When the column eluate was concentrated and hexane was added, the desired product precipitated, so it was isolated and dried under reduced pressure to obtain 1.3 g of the title compound.

NMR (CDCjs) δ: 8.44 (s, 1H),
6.73-7.42 (m, 22H), 7.29 (s,
22H), 5.86 (dd, IH, J=9Hz, 6
Hz), 5.14 (s, 2H), 4.99 (d, I
H, J=6Hz), 4.87-4.98 (m, I H
), 4.12 (s, 2l-1), 3.80 (s,
3l-1), 3.55 (s, 1H), 3.49
(s, 1H), 1.54-1.96 (m.

8 t1) Example 2 p-methoxybenzyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-cyclobentyloxyiminoacetamide 1-3-[(1,2,3-thiadiazol- 5-yl)thiomethyl]-Δ3-cephem-
4-carboxylate (synthetic compound) 0.709 (0
, 75 mmol) and anisole 1.0-,
Add trifluoro vinegar M8111 under water cooling and stir for 40 minutes.

After concentrating the reaction solution under reduced pressure, diethyl ether is added to precipitate a solid. Next, add 1 portion of this solid to vinegar! i! 21
Dissolve in 5M1, add 10ml of water, and react at 40°C for 1°5 hours. The solvent was distilled off under reduced pressure, and methanol 15
m is added and distilled off again. The residue was dissolved in an aqueous sodium bicarbonate solution and extracted with ethyl acetate. 10% hydrochloric acid was added dropwise to the aqueous layer to adjust the p lt to 3°5, and the precipitate was collected by filtration.
After washing with water, it is dried under reduced pressure to obtain 0.05 g of the title compound.

Shape: pale yellow powder mp: Gradual discoloration from around 135℃ NMR (DMSO-dQ) δ: 9.50 (d.

IH, J=8Hz), 8. 88 (
s, IH), 7.17 (bs, 2H),
6.69 (s, IH), 5.72 (dd, 1)
-1, J=81-1z, 5) (z) , 5, 15
(d, 1H, J=5 t12),
4. 64 (bs, IH), 4.25 (s, 2
H), 3.65 (s, IH),
3. 60 (s, 1 to 1),
1. 56-1.73 (m, 8H) Example 3 p-methoxybenzyl 3-(1,2,4-thiadiazol-5-yl)thiomethyl-7β-phenylacetamide-Δ3-cephemu 4-carboxylate 6.69
(11.6 mmol) was added to 7β in the same manner as in Example 1.
-amino-3-(1゜2.4-thiadiazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylate, which was further reacted in the same manner as in Example 1 and separated by column chromatography. , 2.7 g of the title compound is obtained.

NMR (CDCJz) δ: 8.35 (s, 1H)
6.72-7.42 (m, 22H), 7.29 (s,
221-1), 5.87 (dd, IH, J-91
-1z, 5Hz), 5.26 (s, IH), 5,
24 (s, 1H), 4, 9
8 (d, 1 t1. J=5t-(
z), 4.85-4.93 <m, IH), 4, 6
6 (d, 1H, J=13 t12)
, 4.19 (d, IH, J=13 total!
Z), 3. 80 (s.

3H), 3.64 (s, IH), 3.58 (s.

IH), 1. 50 ~1. 90
(m, 8 to1) Example 4 p-methoxybenzyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-cyclopentyloxyiminoacetamide]-3-[(1,2,4-thiadiazole) -5-yl)thiomethyl]-Δ3-cephem-
4-carboxylate (syn isomer) 1.80 g (1,
94 mmol) in the same manner as in Example 2 to obtain 0.249 of the title compound.

Shape: pale yellow powder mp: Gradual discoloration from around 144℃ NMR (DMSO-d,) δ: 9.46 (d.

1H, J=8f-12), 8.71 (s, ll-1>
, 7.00-7.25 (m, 2l-1), 5.74(
dd, IH, J-8Hz, 5Hz)
, 5. 15 (d, 1H, J=5Hz), 4
．． 54-4.69 (m, 2H),
4. 29 (d, 1 F+, J=13
1-1z), 3.67 (s, 1H), 3.63 <
s.

IH), 1.45-1.85 (m, 8H) Example 5 monoyl)-2-cyclobentyloxyiminoacedeamide]-3-(1,2,3-thiadiazole phosphorus pentachloride 3
g (14.4 mmol), pyridine 1.29 (15,
2 mmol) and 100 d of methylene chloride are stirred under water cooling. To this, p-methoxybenzyl 3- (
1,2,3-thiadiazol-5-yl)thiomethyl-
Add 6.6 g (11.6 mmol) of 7β-phenylacetamide-Δ3-zephemu 4-carboxylate;
React for 3 hours in a water bath. Methanol 40ai! After reacting for an additional 30 minutes, the mixture is washed with water, an aqueous sodium bicarbonate solution, and saturated brine in this order, and the organic layer is dried over anhydrous magnesium sulfate. After filtration, the crude p-methoxybenzyl 7β-amino-3-(1,2
,3-deadiazol-5-yl)thiomethyl-Δ3-
Cephemu 4-carboxylate is obtained. This solution was dissolved in 40 ml of methylene chloride (referred to as Solution A).

On the other hand, 8.5 g (17.2 mmol) of 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer)
, 1-hydroxybenzotriazole 2.49 (17
, 8 mmol), dicyclohexylcarbodiimide (3.69 (17,4
millimole) was added under water cooling and allowed to react for 2 hours. Next, the above solution A was added under water cooling, and the mixture was reacted for 2 hours, and then further stirred at room temperature overnight. After filtering off the insoluble matter, ethyl acetate is added to the residue, and the insoluble matter is further filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous TaM magnesium. After drying, filter and concentrate the filtrate.
The title compound 4. was isolated and purified by silica gel column chromatography (elution solvent: chloroform).
Obtain 3g.

NMR (CDCJ*) δ: 8.45 (S, 1H),
6.73-7.3 (m,, 211-1), 5.85 (
dd, IH, J=9H2,6H2), 5.20 (s
, 2H), 4.97 (d, IH, J-6Hz), 4.
8-4.95 (m, 1l-1), 4.15 (S, 2H
), 3.83 (8,3H), 3.53 (s, IH)
, 3.46 (s, 1l-1), 1.5-2.0
(m, 8H) Example 6 p-methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2-
cyclopentyloxyiminoacetamide] -3-(
1,2,3-thiadiazol-5-yl)thiomethyl-
Δ3-cephemu 4-carboxylate (syn isomer)
1.5g (1°5 mmol), Anisole 2I+Li!
Add 16 d of trifluoroacetic acid to the mixed solution under water cooling and leave for 1 hour. After concentrating the reaction solution under reduced pressure, diethyl ether is added to precipitate a solid. Next, this solid was dissolved in 30 Id of vinegar, 20 d of water was added, and the mixture was reacted at 40° C. for 2 hours. The solvent was distilled off under reduced pressure, and methanol 3
0m was added and distilled off again under reduced pressure. A 3% sodium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. 1 in the water layer
0% hydrochloric acid was added dropwise to adjust the pH to 3.5, and the precipitate was filtered with oil, washed with water, and dried under reduced pressure to obtain 0.36 g of the title compound.

m+): 127℃ discoloration NMR (DMSO-66) δ: 9.50 (d.

IH, J=8Hz), 8.75 (s, 1H), 7,
2 (bs, 2H), 5. 75 (
d-6,1H.

J=8Hz, 5Hz), 5.20 (cj, 1)-1,
J-5H2), 4.68 (M, 1l-1), 4.27
(5, 2 to I), 3. 65 (s,
IH), 3. 61 (S, IH), 1.
58-1.75 (m, 8H) Example 7 The title compound is obtained in the same manner as in Example 6 using appropriate starting materials.

mp: 139℃ discoloration NMR (DMSO-d6) δ: 9.52 (d.

1)1. J=8Hz), 9. 50
(s, 1 t1) , 7.15 (
bs, 2H), 5.73 (dd.

1H, J=8Hz, 5Hz), 5.20 (d.

1H, J=5Hz), 4. 69 (
bs, IH), 4.27 (,8,2H)
, 3.63 (s, 1H), 3.59 (s, IH),
1.57-1.76 (m.

8H) Example 8 The title compound is obtained in the same manner as in Example 6 using appropriate starting materials.

mp: 121℃ discoloration NMR (DMSO-d,) δ: 9.51 (d.

1H, J=8Hz>, 8.70 (s, IH),
7.13 (bs, 2H), 5.71 (dd.

1H, J=8Hz, 5Hz), 5. 18 (d.

1H, J=5 t1z), 4. 71
(bs, 1H), 4.30 (s, 2H
), 3.65 (s, 1H), 3.61 (S
, 1H), 1.59-1.75 (m.

8H) Formulation Example 1 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide] -3-(1,2,3-thiadiazol-5-yl ) Thiomethyl-Δ3-cefemu-4-carboxylic acid (syn isomer) 20hi glucose 250■ Distilled water for injection Tekhi Zenro
7β-[2
-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]
After dissolving -3-<1.2.3-thiadiazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid (syn isomer) and glucose, it was poured into a 5Id ampoule, and after being replaced with nitrogen, it was heated to 121°C. The mixture is autoclaved for 15 minutes to obtain an injection having the above composition.

Formulation Example, 2 7β-[2-(5-amine-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]-3-(1,2,3-thiadiazol-5-yl) Thiomethyl-Δ3 monocephemu-4-carboxylic acid (syn isomer) 100g Avicel (trade name, manufactured by Asahi Kasei) 40g corn starch
30g Magnesium stearate 29TC-5 (trade name, Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) 1
0g polyethylene glycol-600039 castor oil
409 ethanol
4097β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]-3-(1,
2,3-thiadiazol-5-yl)thiomethyl-Δ3
-cephemu 4-carboxylic acid isomer), Avicel, corn starch and magnesium stearate,
After mixing and polishing, the mixture is compressed into tablets using a sugar-coated R10i* kine. The obtained tablets were mixed with TC-5 and polyethylene glycol-6000.
, a film-coating agent coating consisting of castor oil and ethanol is applied to produce a film-coated tablet having the above composition.

Formulation Example 3 7β-[2-(5-amine-1,2,4-thiadiazol-3-yl>-2-cyclobentyloxyiminoacetamide]-3-(1,2,3-thiadiazol-5-yl) ) Thiomethyl-Δ3-cephemu-4-carboxylic acid (syn isomer) 1 Purified lanolin 5g white beeswax 5g white petrolatum
889 all r11ioog Warm beeswax to make it liquid, then 7β-[
2-(5-amino-1,2,4-thiadiazole-3-
yl)-2-cyclopentyloxyiminoacetamide]-3-(1,2,3-thiadiazol-5-yl)thiomedylu Δ3-cephemu 4-carboxylic acid (syn isomer), l/i\J lanolin and white petrolatum In addition,
After heating until it becomes liquid, stir until it begins to solidify.
An ointment having the above composition is obtained.

[Antibacterial Activity Test] In order to examine the antibacterial activity of the test compounds shown below against various bacteria, the minimum growth inhibition temperature (MIC) was determined by the agar dilution plate method. [CHEMOTHERAPY
, 22.1126-1128 (1974)] The results obtained are shown in Table 1. In addition, each type of bacteria is 1X10
6i411! /Id(0,o,600mμ,0°07～
0.16).

(Hereafter, margin)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a thiazolyl group having an optionally protected amino group, or an optionally protected amino group thiadiazolyl group; R^2 is a cycloalkyl group; R^3 represents a thiazolyl group or a thiadiazolyl group,
The thiazolyl group and thiadiazolyl group may have an amino group, cyano group, hydroxy lower alkyl group, or carbamoyl group as a substituent. ] Cefem derivatives represented by these, pharmaceutically acceptable salts of these compounds, carboxylic acid ester compounds at the 4-position thereof, and quaternary ammonium salts of the compounds.