JPH07304779A - Cephem compound, production thereof and antibacterial agent containing the compound - Google Patents

Abstract

PURPOSE:To obtain a new compound highly soluble in water, having potent antibacterial activity on Gram-positive bacteria including esp. methicillin- resistant Staphyloococcus aureus, thus useful as an antibacterial agent. CONSTITUTION:The compound of formula I {Q is CH or N; R<1> is carboxylate or carboxyl; R<2> is H, a lower alkyl, a lower alkenyl, etc.; R is of formula II or III [R<3> is (CH2)m-Y ((m) is 1-5; Y is quaternary ammonium), etc.; (n) is 0-4; B<-> is an anion; f is such that when R<1> is carboxylate, it is 0 or 1, when R<1> is carboxyl, it is 2; C-ring is a five-membered heterocycle with <=N4]}, e.g. 7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(1-(3,4me thylmorpholino) propyl)-4-pyridino) thiovinyl]-3-cephem-4-carboxylate chloride. The compound of formula I is obtained by reaction of a compound of formula IV (R<4> is a protective group) with a compound of formula V [R<5> is (protected) amino; R<6> is a protective group, etc.].

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel cephem compound,
The present invention relates to a method for producing the same and an antibacterial agent containing the compound.

[0002]

2. Description of the Related Art Recently, with the widespread use of third-generation cephalosporins, methicillin-resistant Staphylococcus aureus (MR)
Infectious diseases caused by SA) have become an important issue. Third
Although the third-generation cephalosporins have strong antibacterial activity against Gram-negative bacilli, but their antibacterial activity against Gram-positive cocci has decreased, so the use of the third-generation cephalosporins causes β
-The number of Staphylococcus aureus resistant to lactam antibiotics is increasing, which is a serious problem as a refractory infection. Currently, only vancomycin, which is a polypeptide antibiotic, is the only effective drug for treating infections caused by MRSA. However, vancomycin has side effects such as eczema and nephrotoxicity, which requires careful administration.

Conventionally, many cephalosporin antibiotics having a quaternary ammonium salt are known. Although these compounds show strong antibacterial activity, their development as pharmaceuticals has been abandoned because of their low solubility in water. For example, Japanese Patent Application Laid-Open No. 59-130292 (European Patent Publication No. 111281) describes a compound having a thiovinyl-quaternary ammonium salt at the 3-position of a cephalosporin skeleton. There is no mention of introducing a quaternary ammonium substituent. Further, there is no disclosure that the compounds described in the above publications are effective for MRSA.

Generally, in the conventional cephalosporin compounds, the antibacterial activity against Gram-positive bacteria including MRSA decreases as the water solubility increases, and the water solubility and antibacterial activity are in a conflicting relationship. However, it was very difficult to develop a cephalosporin compound having both high water solubility and strong antibacterial activity. Therefore, there is a demand for the development of a cephem compound which exhibits excellent antibacterial activity against MRSA and has high solubility in water.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a novel cephem compound which is highly soluble in water and has an excellent antibacterial activity, particularly effective and safe against Gram-positive bacteria containing MRSA. To provide a compound.

[0006]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have synthesized and studied various cephem compounds. As a result, thiovinyl-
A new 4th addition to compounds with quaternary ammonium salts
It was found that the cephem compound introduced with a quaternary ammonium substituent exhibits high water solubility and has an excellent antibacterial activity, especially a strong antibacterial activity against Gram-positive bacteria including MRSA, and the present invention has been completed here. It was

The cephem compound of the present invention is a novel compound and is represented by the following general formula (1).

[0008]

[Chemical 19]

[In the formula, Q represents CH or N. R ¹ represents a carboxylate or a carboxyl group. R ² is a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent , A carboxy lower alkyl group which may have a substituent, a hydroxy lower alkyl group which may have a substituent, or a lower alkoxy lower alkyl group which may have a substituent. R is

[0010]

[Chemical 20]

Is shown. Here, R ³ is a group — (CH ₂ ) m-
Y or a group - (CH ₂₎ in m-CO-Y (group, m is 1 to 5
, And Y represents a quaternary ammonium group. ) Is shown.
n represents 0 or an integer of 1 to 4. B ⁻ represents an anion. f is 0 or 1 when R ¹ represents a carboxylate, shows a 2 if R ¹ represents a carboxyl group.
The ring represented by C represents a 5-membered heterocyclic group having 4 or less nitrogen atoms which may be substituted with a lower alkyl group. More specifically, the groups shown in the present specification are as follows.

Examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl groups.

Examples of the lower alkenyl group include alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, crotyl, 2-pentenyl and 2-hexenyl groups.

Lower alkynyl groups include ethynyl, 1
Examples include alkynyl groups having 2 to 6 carbon atoms such as -propynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl and 2-hexynyl groups.

Examples of the lower cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

The carboxy lower alkyl group has 1 to 6 carbon atoms in the alkyl moiety such as carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl and 6-carboxyhexyl groups. An example is a carboxyalkyl group.

The hydroxy lower alkyl group has 1 to 6 carbon atoms in the alkyl moiety such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and 6-hydroxyhexyl groups. A hydroxyalkyl group can be illustrated.

As the lower alkoxy lower alkyl group,
Methoxymethyl, methoxyethyl, methoxypropyl,
Examples thereof include alkoxyalkyl groups having 1 to 4 carbon atoms in the alkyl moiety such as methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, and ethoxybutyl groups.

The ring represented by C is a 5-membered heterocyclic group having 4 or less nitrogen atoms which may be substituted with a lower alkyl group.
Specific examples thereof include oxazole, thiazole, isoxazole, isothiazole, pyrazole, imidazole, thiadiazole, triazole, oxatriazole, thiatriazole, and tetrazole, and a lower alkyl group on the nitrogen atom or carbon atom of these heterocycles is 1 It may be replaced individually. More specifically, such a heterocycle is represented by the following structural formula.

[0020]

[Chemical 21]

The quaternary ammonium group also includes a quaternary ammonium group composed of a 5- to 6-membered heterocyclic ring having 1 or 2 nitrogen atoms and at most 1 oxygen atom and 1 sulfur atom. , For example the general formula

[0022]

[Chemical formula 22]

[In the above formulas, R ¹¹ , R ¹² and R ¹³ are the same or different and each represents a lower alkyl group, a lower alkenyl group,
Hydroxy lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkanoyl lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, amino lower alkyl group, lower alkylamino lower alkyl group, di lower alkylamino A lower alkyl group or a sulfo lower alkyl group is shown. R ¹⁴ is a hydrogen atom, a halogen atom, an amino group, a lower alkyl group, a carboxy group, a hydroxy group, a lower alkoxy group, a lower alkoxy lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, a lower alkylamino lower alkyl group, A di-lower alkylamino lower alkyl group, a di-lower alkylamino group, a carboxy lower alkyl group, a carboxy lower alkylamino group, a carbamoyl group, an N-lower alkylcarbamoyl group, a formylamino group, an acylamino group and the like are shown. ] And the like can be exemplified.

The carbamoyl lower alkyl group has 1 to 6 carbon atoms in the alkyl moiety such as carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl, 4-carbamoylbutyl, 5-carbamoylpentyl and 6-carbamoylhexyl groups. An example is a carbamoylalkyl group.

As the lower alkanoyl lower alkyl group, formylmethyl, acetonyl, 3-acetylpropyl, 4-acetylbutyl, 6-propionylhexyl,
5-isobutyryl pentyl, hexanoylmethyl, 6-
An alkanoylalkyl group, such as a hexanoylhexyl group, having an alkanoyl moiety having 1 to 6 carbon atoms and an alkyl moiety having 1 to 6 carbon atoms can be exemplified.

As the lower alkoxycarbonyl lower alkyl group, carbon of the alkyl moiety of methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl group, etc. The number is 1
The alkoxycarbonylalkyl group of ~ 6 can be illustrated.

The amino lower alkyl group has 1 to 6 carbon atoms in the alkyl moiety of aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and the like. An aminoalkyl group can be illustrated.

As the lower alkylamino lower alkyl group, methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, pentylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, An alkylamino moiety such as a 5-methylaminopentyl group and an alkylamino alkyl group having 1 to 5 carbon atoms can be exemplified.

Examples of the di-lower alkylamino-lower alkyl group include dimethylaminomethyl, diethylaminomethyl,
Dipropylaminomethyl, dibutylaminomethyl, 2-
Dimethylaminoethyl, 3-dimethylaminopropyl,
A dialkylaminoalkyl group in which the carbon number of the dialkylamino moiety such as 4-dimethylaminobutyl, 5-dimethylaminopentyl, and 6-dimethylaminohexyl group is 2 to 8 and the alkyl moiety has 1 to 6 can be exemplified. .

Examples of the sulfo lower alkyl group include a sulfoalkyl group having an alkyl moiety having 1 to 5 carbon atoms such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid and pentanesulfonic acid.

Examples of the halogen atom include chlorine atom, bromine atom, fluorine atom and iodine atom.

Examples of the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups.

Examples of the di-lower alkylamino group include dialkylamino groups having 2 to 8 carbon atoms such as dimethylamino, diethylamino, dipropylamino and dibutylamino groups.

The carboxy lower alkylamino group is an alkyl moiety such as carboxymethylamino, 2-carboxyethylamino, 3-carboxypropylamino, 4-carboxybutylamino, 5-carboxypentylamino, 6-carboxyhexylamino group. An alkylamino group having 1 to 6 carbon atoms can be exemplified.

Examples of the acylamino group include acylamino groups having 1 to 6 carbon atoms in the alkyl moiety such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and pivaloylamino groups.

Examples of the N-lower alkylcarbamoyl group include N-alkylcarbamoyl groups having 1 to 4 carbon atoms in the alkyl moiety such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and butylcarbamoyl groups.

[0037] B ^- The anion represented by, hydrochloric, hydrobromic, nitric, sulfuric, inorganic acids such as perchloric acid, methanesulfonic acid, ethanesulfonic acid, 2-chloroethane sulfonic acid, benzenesulfonic acid, Examples thereof include acid residues of organic acids such as tosylic acid, p-ethylsulfonic acid, p-chlorosulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and formic acid.

[0038] The cephem carboxyl protecting group includes a protective ester generally used in the synthesis of cephem and a pharmaceutically acceptable protective ester. The protected ester generally used in the synthesis of cephem is stable when various chemical modifications are applied to a β-lactam compound, and is easily eliminated when the β-lactam compound is converted into a pharmaceutically acceptable protected ester described below. Is an ester that can. The pharmaceutically acceptable protected ester is a non-toxic ester that can be easily hydrolyzed in vivo and can be rapidly decomposed in human blood or tissues. These esters may be publicly known ones usually used in the field of antibiotics, and specific examples thereof include JP-A-49-8138.
No. 0 publication and Etch. E. Any of those described in Flein's Cephalosporins and Penicillins and Chemistry and Biology (published by Academic Press in 1972) can be used. Preferred are, for example, methyl, ethyl, propyl, butyl, ter.
t-butyl, 1,1-dimethylpropyl, 1-cyclopropylmethyl, pentyl, hexyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and other alkyl groups having 1 to 18 carbon atoms, iododecyl,
Chlormethyl, 2,2-dibromoethyl, 2,2,2-
A halogeno lower alkyl group substituted with 1 to 3 chlorine, bromine or iodine atoms such as trichloroethyl, 2,2,2-tribromoethyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, o-methoxybenzyl, p −
Methyl group substituted with 1 to 3 phenyl groups which may be substituted with nitro group or alkoxy group such as methoxybenzyl, di (p-methoxyphenyl) methyl, methoxymethyl, ethoxymethyl, n-propyloxymethyl, isopropyl Lower alkoxymethyl groups such as oxymethyl, n-butoxymethyl, isobutoxymethyl, acetoxymethyl, acetoxyethyl, propionyloxyethyl,
n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, 1-acetoxyethyl,
Pivaloyloxyethyl, pivaloyloxypropyl,
Lower alkylcarbonyloxy lower alkyl group such as 1-propionyloxybutyl, cyclopentylcarbonyloxymethyl, cycloalkylcarbonyloxy-lower alkyl group having 5 to 7 carbon atoms such as cyclohexylcarbonyloxymethyl, benzylcarbonyl such as benzylcarbonyloxymethyl Oxy lower alkyl groups, benzoyloxymethyl, benzoyloxyethyl and other benzoyloxy lower alkyl groups, methoxy-carbonyloxymethyl, 1-ethoxy-carbonyloxyethyl, 3-methoxy-carbonyloxypropyl and other lower alkoxycarbonyloxy lower alkyl groups , Benzyloxymethyl, benzyloxyethyl, and other benzyloxy lower alkyl groups, 2-cyano-1,1-dimethylethyl,
Bromobenzoylmethyl, p-nitrobenzoylmethyl, dimethylaminomethyl, methylthiomethyl, phenylthiomethyl, succinimidomethyl, 1,1-dimethyl-2-propenyl, 1,3-dimethyl-3-butenyl, 3-phthalidyl, crotono Lactone-4-yl, γ
-Butyrolactone-4-yl, tetrahydropyranyl,
Dimethylaminoethyl, dimethylchlorosilyl, trichlorosilyl, (2-oxo-1,3-dioxoden-4
-Yl) methyl, (5-methyl-2-oxo-1,3-
Dioxoden-4-yl) methyl, (5-phenyl-2
-Oxo-1,3-dioxoden-4-yl) methyl,
Pyridine-1-oxide-2-methyl, quinoline-1
Examples thereof include -oxide-2-methyl group.

The non-toxic salts of the compound of the general formula (1) include pharmaceutically acceptable salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, citrate and maleate. , Organic carboxylic acid such as lactate, tartrate, methanesulfonic acid, hydroxymethanesulfonic acid, taurine salt, benzenesulfonic acid, toluenesulfonic acid and other organic sulfonic acid salt, arginine salt, lysine salt, serine salt, asparagine Examples thereof include amino acid salts such as acid salts, glutamate and glycinate, alkali metal salts such as sodium salts, potassium salts and lithium salts, and alkaline earth metal salts such as calcium salts and magnesium salts.

CH is preferably CH.
R ¹ is preferably a carboxylate. R ² is preferably a hydrogen atom or a lower cycloalkyl group, and more preferably a hydrogen atom. R is preferably

[0041]

[Chemical formula 23]

And m is preferably 2 or 3, and Y is a lower alkyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, a lower alkanoyl lower alkyl group, a lower alkoxycarbonyl lower. Examples thereof include a quaternary ammonium group substituted with an alkyl group or a sulfo lower alkyl group, a morpholinio group substituted with a lower alkyl group, and a piperidinio group substituted with a lower alkyl group. B is preferably a halogen atom, more preferably a chlorine atom.

Among the compounds of the above general formula (1) and their non-toxic salts, preferable ones are listed below.

7- [2-hydroxyimino-2- (2-
Aminothiazol-4-yl) acetamide] -3-
[2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-
4-carboxylate chloride or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1-
(2-Trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or its salt 7- [2-hydroxyimino-2-]
(2-Aminothiazol-4-yl) acetamide]-
3- [2- (1- (2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]-
3-Cephem-4-carboxylate chloride or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1-
(2- (4-Methylmorpholinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazole- 4-yl) acetamide] -3- [2- (1-
(2-acetonyl-dimethylammonioethyl) -4-
Pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-
(2- (1-Methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazole- 4-yl) acetamide] -3- [2- (1-
(2-carboxylate methyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) ) Acetamide] -3- [2- (1-
(2-hydroxyethyl-dimethylammonioethyl)
-4-Pyridinio) thiovinyl] -3-cephem-4-
Carboxylate chloride or its salt 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1-
(2-Ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof 7- [2-cyclopentyloxyimino-2- (2-aminothiazole) -4-yl) acetamido] -3- [2
-(1- (2-Trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof 7- [2-hydroxyimino-2- (2-aminothiazole-4) -Yl) acetamide] -3- [2- (1-
(Sulfonate ethyl-dimethylammonioethyl)-
4-pyridinio) thiovinyl] -3-cephem-4-carboxylate or a salt thereof.

The compound (1) and the starting material compound of the present invention include cis isomers, trans isomers, and cis, trans mixtures.

Regarding the compound (1), for example, a cis isomer means one of geometric isomers having a partial structure represented by the following general formula (4), and a trans isomer is represented by the following formula (5). It means other geometric isomers having a partial structure.

[0047]

[Chemical formula 24]

[0048]

[Chemical 25]

The compound (1) of the present invention and a salt thereof can be produced by various methods, and if a preferable method is shown, it can be produced according to the following production method I.

[0050]

[Chemical formula 26]

[Wherein R ⁴ is a cephem carboxyl-protecting group and R'is

[0052]

[Chemical 27]

Is shown. Here, R ³ , n, B ⁻ and C are the same as above. R ⁵ represents an amino group or a protected amino group. R ⁶ represents an oxime protecting group or an R ^{2 ′} group (the R ^{2 ′} group is an R ² group other than a hydrogen atom). Q, R, R ¹ and R ² are the same as above. In the above Production Method-I, the compound represented by the general formula (1) is obtained by activating the amine compound represented by the general formula (6) and the carboxylic acid compound represented by the general formula (7) or the carboxy group thereof. It can be produced by subjecting a reactive derivative to an ordinary amide bond formation reaction, and then removing a protecting group from the resulting product, if necessary.

The protective group for the carboxy group represented by R ⁴ is a tri (lower) alkylsilyl group such as trimethylsilyl group, benzhydryl group, p-methoxybenzyl group, tert-butyl group, p-nitrobenzyl group, Examples thereof include a phenacyl group and the like, which are commonly used in this field and which can be easily removed are carboxy-protecting groups.

As the protecting group for the protected amino group of R ^5, a protecting group which can be easily removed under mild conditions can be widely used, and specifically, a tri (lower) alkylsilyl group such as trimethylsilyl group and a formyl group can be used. , Trifluoroacetyl group, acetyl group, tert-butylcarbonyl group, methoxyacetyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and other acyl-based protecting groups, benzyl group, benzhydryl group, trityl group and other aralkyl groups Examples of the protecting group of the system can be given.

The oxime-protecting group represented by R ⁶ includes
Examples thereof include acetyl group, trityl group, tetrahydropyranyl group and the like, which are commonly used in this field and which can be easily removed under mild conditions.

For the reaction of the compound (6) with the compound (7) or its reactive derivative, the commonly used conditions for a known amide bond-forming reaction can be applied.

Examples of the reactive derivative of the compound (7) include acid halides such as acid chlorides and acid bromides, substituted phosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkyl carbonate, organic carboxylic acid and the like. Acid anhydrides with acids and symmetrical acid anhydrides, active acid amides with imidazole, dimethylpyrazole, etc., p-nitrophenyl ester, phenylthioester, carboxymethylthioester or N-hydroxypiperidine, N-hydroxysuccinimide, N
Examples include active esters such as esters with N-hydroxy compounds such as -hydroxyphthalimide.

In the present invention, when the compound (7) is used in the form of a free carboxylic acid, it is preferable to use a condensing agent such as N, N-diethylcarbodiimide or N, N-dicyclohexylcarbodiimide.

The solvent used in the above reaction is not particularly limited as long as it does not participate in the reaction, and the reaction temperature is usually under cooling or around room temperature. As the solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, aromatic hydrocarbons such as benzene and toluene, amines such as pyridine, piperidine and triethylamine, esters such as ethyl acetate and ethyl formate, dimethylformamide, hexamethylphosphoric triamide Examples thereof include aprotic polar solvents such as dimethylsulfoxide, acetone, and mixed solvents thereof.

Depending on the reactive derivative of the carboxylic acid used, it may be preferable to carry out in the presence of a basic compound. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, and 1,8-diazabicyclo [5.4.
0] -7-undecene and the like organic bases, and sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like inorganic bases.

In the above reaction, the amount of the carboxylic acid compound represented by the general formula (7) or its reactive derivative is usually 1 with respect to the amine compound represented by the general formula (6).
The molar amount is about 10 to 10 times, preferably about 1 to 3 times. Further, the amount of the basic compound used with respect to the amine compound represented by the general formula (6) is usually about 1 to 30 times by mole, preferably about 2 to 10 times by mole.
The reaction time is usually about 1 to 24 hours, preferably about 1 to 6 hours.

The protecting group can be removed from the amide bond product obtained above by treating with water when the protecting group is a tri (lower) alkylsilyl group or the like. When it is a protective group such as benzhydryl group, trityl group, p-methoxybenzyl group, tert-butyl group, and formyl group, formic acid, hydrochloric acid, trifluoroacetic acid, anisole-trifluoroacetic acid, acetic acid, phenol, cresol It can be removed by treating with a kind or the like. After the reaction is completed, Diaion HP-20, HP-21, SP
-207, CHP-20P (Mitsubishi Kasei) and other high-porous polymers, Amberlite XAD-2 (ROHM &
The compound of the present invention represented by the general formula (1) can be obtained by purification by column chromatography using a lotus, etc.

[0064]

[Chemical 28]

[Wherein Q, R, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ and R ′ are the same as above. R ⁷ represents a halogen atom, a lower acyloxy group or a sulfonyloxy group. R ⁸ is

[0066]

[Chemical 29]

Is shown. Here, C and n are the same as above. X
Represents a halogen atom. M represents a hydrogen atom or a metal atom. In the above Production Method-II, the compound of the present invention represented by the general formula (1) is obtained by reacting a cephalosporin compound represented by the general formula (8) or a salt thereof with a mercapto compound represented by the general formula (9). , Then the general formula (1
The compound of formula (1) is reacted with the halogenated organic compound of formula (11), and the protecting group is removed from the resulting compound of formula (12).
The compound of the present invention can be obtained.

The reaction between the compound (8) and the compound (9) is
Usually, ketones such as acetone, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as acetonitrile, methanol and ethanol, dimethyl sulfoxide, dimethylformamide, water and phosphorus. It is carried out in a mixed solution of water with an organic solvent such as an acid buffer solution or a hydrophilic organic solvent. The reaction can be promoted by adding a base or a salt to the reaction system. Examples of these bases and salts include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and organic amines such as trialkylamines such as triethylamine and diisopropylamine. Examples of salts include quaternary ammonium salts such as tetrabutylammonium salt.
The ratio of the compound (8) to the compound (9) used is not particularly limited, but the compound (9) is usually used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to the compound (8). Is good. The reaction is usually performed under cooling or around room temperature.

Examples of the solvent used in the reaction between the compound (10) and the compound (11) include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic compounds such as benzene, toluene and xylene. Examples include hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile and the like. The ratio of the compound (10) to the compound (11) used varies depending on the type of the compound (11) and the like and cannot be generally stated, but usually 1 to 100 equivalents of the compound (11) with respect to the compound (10), It is preferable to use 5 to 50 equivalents. The reaction is carried out at room temperature to about 80 ° C, preferably about 20 to 50 ° C, and is generally completed in about 1 to 20 hours.

Examples of the halogenated organic compound represented by the general formula (11) include 2-bromo-ethyltrimethylammonium iodide, 3-bromo-propyltrimethylammonium iodide, 2-bromoethyl-hydroxyethyl-dimethylammonium iodide. , 2-bromoethyl-carbamoylmethyl-dimethylammonium iodide, N- (2-bromoethyl)
-N-methyl-morphonium iodide, N- (2-
Bromoethyl) -N-carbamoylmethyl-morphonium iodide, N- (2-bromoethyl) -N-methyl-piperidinium iodide, 1- (2-bromoethyl) -1-methyl-piperazinium iodide, 1
-(2-Bromoethyl) -1-carbamoylmethyl-piperazinium iodide, 1- (2-bromoethyl)
-1,4-Dimethyl-piperazinium iodide, 1
-(2-Bromoethyl) -1-carbamoylmethyl-4
-Methyl-piperazinium iodide, 1- (2-bromoethyl) -4,4-dimethyl-piperazinium iodide, 1- (2-bromoethyl) -1-methyl-pyrrolidinium iodide, 1- (2-bromoethyl)
Examples include -1-carbamoylmethyl-pyrrolidinium.iodide.

The compound of the general formula (12) thus obtained can be removed of the protecting group by the method shown in Production method-I, and the compound of the present invention of the general formula (1) can be easily produced. It

[0072]

[Chemical 30]

[In the formula, Q, R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ′, B ⁻ and C are the same as above. The compound of general formula (12) can also be produced by the above production method-III. That is, according to the production method-III, the compound of the general formula (12) is obtained by reacting the compound of the general formula (8) with the quaternized mercapto compound represented by the general formula (13) or (14). Is manufactured.

The reaction of the compound of the general formula (8) with the compound of the general formula (13) or (14) is similar to the reaction between the compound of the general formula (8) and the compound of the general formula (9). It can be done under conditions.

[0075]

[Chemical 31]

[Wherein Q, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ′ are the same as defined above. R ⁹ is

[0077]

[Chemical 32]

Is shown. Here, R ¹⁰ is a group-(CH ₂ ) m-
Z or a group - (CH ₂₎ in m-CO-Z (group, m is 1 to 5
Is an integer and Z is a tertiary amino group. ) Is shown. R ¹¹ is a lower alkyl group, a lower alkenyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, a lower alkanoyl lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an amino lower alkyl group, A lower alkylamino lower alkyl group, a di lower alkylamino lower alkyl group or a sulfo lower alkyl group is shown. n is 0 or 1
Indicates an integer of ˜4. The compound of general formula (12) can also be produced by the above production method-IV.

The reaction of the compound of the general formula (8) with the compound of the general formula (15) or (16) is similar to the reaction between the compound of the general formula (8) and the compound of the general formula (9). It can be done under conditions. The reaction between the compound of general formula (17) and the compound of general formula (18) can be carried out under the same reaction conditions as the reaction between the compound of general formula (10) and the compound of general formula (11). . Examples of the halogenated organic compound represented by the general formula (18) include lower alkyl halides, lower alkenyl halides, hydroxy lower alkyl halides, carboxy lower alkyl halides, carbamoyl lower alkyl halides, lower alkanoyl lower alkyl halides, lower alkoxy lower alkyl halides. , Lower alkoxycarbonyl lower alkyl halide,
Amino lower alkyl halides, lower alkylamino lower alkyl halides, di lower alkylamino lower alkyl halides, sulfo lower alkyl halides and the like,
As the above various halides, chloride, bromide,
Examples include iodide and the like.

The pyridine derivatives of the general formulas (9), (13) and (15) are in a tautomeric equilibrium state depending on the bonding position of the thiol group.
The pyridine derivative of is in the following relationship, and such isomers are included in the same category as the compound itself.
General formulas (9) and (13) containing such tautomeric forms
It is needless to say that the pyridine derivatives of (15) and (15) use one expression for convenience, but include the other isomer.

[0081]

[Chemical 33]

[In the formula, R ¹⁰ and n are the same as defined above. The compound of the present invention is made into a pharmaceutical composition according to a conventional method using an appropriate pharmaceutical carrier. Examples of the carrier used here include various substances commonly used for ordinary drugs, for example, excipients, binders, disintegrants, lubricants, colorants, flavoring agents, flavoring agents, surfactants and the like. .

Infections of mammals, including humans, with the formulations of the invention,
In particular, the dosage unit form when used as a therapeutic agent for an infectious disease caused by methicillin-resistant Staphylococcus aureus is not particularly limited, and can be appropriately selected according to the purpose of treatment, and specifically, injections, suppositories, eye drops , Parenteral agents such as ointments and aerosols, tablets, coated tablets, powders, granules, capsules,
Examples of oral agents include liquids, pills, suspensions and emulsions.

The above-mentioned various drugs are formulated by a formulation method generally known in this field. When formed into a solid oral dosage form such as tablets, powders, granules, etc., as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin. , Excipients such as sodium alginate and gum arabic, simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, etc. Binder, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, steari Acid monoglyceride, starch, disintegrating agents such as lactose, sucrose,
Disintegration inhibitors such as stearic acid, cocoa butter, hydrogenated oil, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid. Adsorbents such as and the like, purified talc, stearates, boric acid powders, lubricants such as polyethylene glycol and the like can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multi-layer tablets.

In the case of molding in the form of pills, as a carrier, for example, an excipient such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc., a binder such as gum arabic powder, tragacanth powder, gelatin, etc., Laminaran,
A disintegrant such as agar can be used.

Capsules are prepared by mixing the above-exemplified various carriers and filling hard gelatin capsules, soft capsules and the like.

In the case of molding into a suppository, as a carrier, for example, polyethylene glycol, cacao butter, lanolin, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, Witepsol (registered trademark, Dynamite Nobel), etc. Can be used by adding an appropriate absorption promoter.

In the case of molding in the form of an injection, diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. are used as carriers. ,
PH adjusters and buffers such as sodium citrate, sodium acetate, sodium phosphate, sodium pyrosulfite,
Stabilizers such as ethylenediaminetetraacetic acid, thioglycolic acid, and thiolactic acid can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, soothing agent, local anesthetic, etc. are added. You may.
By adding these carriers, subcutaneous, intramuscular, and intravenous injections can be produced by a conventional method.

Liquid formulations include aqueous or oily suspensions, solutions,
It may be a syrup or an elixir, and these are prepared according to a conventional method using usual additives.

For preparing ointments such as pastes, creams and gels, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The amount of the compound of the present invention to be contained in the above-mentioned preparation varies depending on the dosage form, administration route, administration schedule and the like, and cannot be said unequivocally and is appropriately selected from a wide range. It is preferable to be about 70% by weight.

The above-mentioned preparation can be administered by, for example, enteral administration,
Oral administration, rectal administration, buccal administration, transdermal administration, etc. are not particularly limited and are appropriately determined depending on various formulation forms, patient's age, sex and other conditions, patient's symptom level, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. Further, in the case of an injection, it is intravenously administered alone or mixed with a normal replacement fluid such as glucose and amino acid, and further intramuscularly alone if necessary,
It is administered intradermally, subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally. The ointment is applied to the skin, the mucous membrane in the oral cavity, and the like.

The dose of the compound of the present invention is appropriately selected according to the usage, the age and condition of the patient, the kind of disease, the kind of the compound of the present invention to be administered and the like. Generally, 100 mg to about 10 g per day, or even more, can be administered to a patient. For the treatment of pathogenic infections, the average dose of the compound of the present invention is about 50 mg, 100 mg, 250 mg, 1
Quantities of 000 mg and 2000 mg can be used.

In order to show the usefulness of the target compound, an antibacterial activity test against various bacteria was carried out by the agar plate dilution method of the representative compounds of the present invention, and the minimum growth inhibitory concentration (MIC value) against various bacteria was determined to be FMOX (flomoxef). ) And the MIC-80 values against clinically isolated methicillin resistant, ciprofloxacin highly resistant Staphylococcus aureus VCM (vancomycin), FMO.
Table 2 shows the results of comparison with X and CPFX (ciprofloxacin). The test compounds are as follows.

Test compound (a): 7- [2-cyclopentyloxyimino-2-
(2-Aminothiazol-4-yl) acetamide]-
3- [2- (1- (2-trimethylammonioethyl)
-4-Pyridinio) thiovinyl] -3-cephem-4-
Carboxylate chloride (b): 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2-
(1- (2-Trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride (c): 7- [2-hydroxyimino-2- (2-aminothiazole-4) -Yl) acetamide] -3- [2-
(1- (2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride (d): 7- [2-hydroxyimino-2- (2-amino Thiazol-4-yl) acetamido] -3- [2-
(1- (2-acetonyl-dimethylammonioethyl)
-4-Pyridinio) thiovinyl] -3-cephem-4-
Carboxylate chloride (e): 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2-
(1- (2-Hydroxyethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride (f): 7- [2-hydroxyimino-2- (2-amino Thiazol-4-yl) acetamido] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
-Pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride

[0096]

[Table 1]

[0097]

[Table 2]

[0098]

[Examples] Examples will be given below.

Example 1

[0100]

[Chemical 34]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamido] -3- (2-trifluoromethanesulfonyloxyvinyl) -3-cephem-4-carboxylic acid benzhydryl ester 19.7 g (0.0165 mol) and 1-
(2-Dimethylaminoethyl) -4-pyridothione 3.
16 g (0.017 mol) of 150 ml of anhydrous dimethylformamide was added and dissolved, and the mixture was stirred at room temperature for 2.5 hours.
After the reaction was completed, it was extracted with acetic acid ethyl ester (1200 ml), washed with water three times and once with 10% brine, the organic layer was dried over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure. Thing 7- [2-trityloxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester 20.3 g of trifluoromethanesulfonate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.15 (6H, s), 2.69 (2H, m),
3.77 (1H, ABq, J = 17.1 Hz), 4.1
8 (1H, ABq, J = 17.1 Hz), 4.55 (2
H, m), 5.35 (1H, d, J = 4.8 Hz),
5.98 (1H, dd, J = 4.8Hz, 7.8H
z), 6.63 (1H, s), 6.97 (1H, s),
7.1-7.6 (42H, m), 8.09 (2H, d,
J = 6.9 Hz), 8.75 (2H, d, J = 6.9H)
z), 8.79 (1H, s), 9.93 (1H, d, J
= 7.8 Hz).

Example 2

[0104]

[Chemical 35]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-
4-Carboxylic acid benzhydryl ester trifluoromethanesulfonate 20.3 g (0.016 mol) was dissolved in acetonitrile 100 ml to prepare methyl iodide 10.3.
ml (0.16 mol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give 7- [2-trityloxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide (22.6 g) was obtained. It was. ¹ H-NMR (DMSO-d ₆ ) δ ppm; 3.15
(9H, s), 3.77 (1H, ABq, J = 17.1)
Hz), 3.91 (2H, m), 4.18 (1H, AB
q, J = 17.1 Hz), 4.96 (2H, m), 5.
35 (1H, d, J = 4.8Hz), 5.98 (1H,
dd, J = 4.8 Hz, 7.8 Hz), 6.62 (1
H, s), 6.97 (1H, s), 7.1-7.6 (4
2H, m), 8.20 (2H, d, J = 6.9Hz),
8.79 (1H, brs), 8.82 (2H, d, J =
6.9 Hz), 9.93 (1H, d, J = 7.8H
z).

Example 3

[0107]

[Chemical 36]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester Iodide 2
2.6 g (0.016 mol) was dissolved in 70 ml of chloroform, 40 ml of 88% formic acid and 5.5 ml of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the formic acid layer was washed with chloroform (70 ml × 3), and this was added dropwise to isopropyl ether / acetone (200 ml / 600 ml). The precipitate was collected by filtration and 7- [2-hydroxyimino-
2- (2-Aminothiazol-4-yl) acetamide] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate crude product 7.0 g of the product was obtained. This crude product was dissolved in 130 ml of 0.1 N hydrochloric acid and adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column, and developed with water and then water / acetonitrile.
Fractions containing the desired product were collected, concentrated under reduced pressure and lyophilized to give 3.0 g of 7- [2-hydroxyimino-2- (2
-Aminothiazol-4-yl) acetamide] -3-
[2- (1- (2-trimethylammonioethyl) -4
A chloride of -pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.18 (9H, s), 3.59 (1H, ABq,
J = 17.1 Hz), 3.87 (1H, ABq, J = 1
7.1 Hz), 4.00 (2H, m), 5.04 (2
H, m), 5.13 (1H, d, J = 4.8 Hz),
5.70 (1H, dd, J = 4.8Hz, 7.8H
z), 6.64 (1H, s), 6.6-6.8 (1H,
m), 7.13 (2H, m), 7.42 (1H, d, J
= 15.3 Hz), 8.12 (2H, d, J = 6.6H)
z), 8.96 (2H, d, J = 6.6Hz), 9.4.
5 (1H, d, J = 7.8Hz), 11.38 (1H,
s).

Example 4

[0111]

[Chemical 37]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-
3.0 g (0.0024 mol) of 4-carboxylic acid benzhydryl ester / trifluoromethanesulfonate was dissolved in 15 ml of acetonitrile, 1.8 g (0.098 mol) of 2-iodoacetamide was added, and the mixture was stirred at room temperature for 4 hours. . After completion of the reaction, the solvent was distilled off under reduced pressure to give 7- [2-
Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1-
(2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-
4-Carboxylic acid benzhydryl ester / iodide and 2-
4.8 g of a mixture of iodoacetamide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.15 (6H, s), 3.75 (1H, ABq,
J = 17.1 Hz), 4.1-4.2 (5H, m),
4.97 (2H, m), 5.35 (1H, d, J = 5.
1 Hz), 5.98 (1 H, dd, J = 5.1 Hz,
8.1 Hz), 6.62 (1 H, s), 6.95 (1
H, s), 7.0-8.0 (44H, m), 8.18.
(2H, d, J = 6.6 Hz), 8.78 (1H,
s), 8.86 (2H, d, J = 6.6Hz), 9.9
2 (1H, d, J = 8.1 Hz).

Example 5

[0115]

[Chemical 38]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-carbamoylmethyl-
Dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide 4.8 g was dissolved in chloroform 8 ml, and 88% formic acid 6 ml and concentrated hydrochloric acid 0.8 ml were added. Stir at room temperature for 3.5 hours. After completion of the reaction, the formic acid layer was washed with chloroform (8 ml × 3), and this was added dropwise to isopropyl ether / acetone (50 ml / 100 ml).
The precipitate was collected by filtration and 7- [2-hydroxyimino-2-
(2-Aminothiazol-4-yl) acetamide]-
3- [2- (1- (2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]-
Crude product of 3-cephem-4-carboxylate 1.4
g was obtained. This crude product was dissolved in 14 ml of water, adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column, and developed with water and then water / acetonitrile. Fractions containing the desired product are collected, concentrated under reduced pressure and lyophilized,
327 mg of 7- [2-hydroxyimino-2- (2-
Aminothiazol-4-yl) acetamide] -3-
[2- (1- (2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-
The chloride of cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.34 (6H, s), 3.60 (1H, ABq,
J = 17.1 Hz), 3.92 (1H, ABq, J = 1
7.1 Hz), 4.21 (2H, m), 4.29 (2
H, s), 5.11 (2H, m), 5.13 (1H,
d, J = 5.1 Hz), 5.72 (1H, dd, J =
5.1 Hz, 8.1 Hz), 6.65 (1 H, s),
6.6-6.8 (1H, m), 7.12 (2H, br
s), 7.40 (1H, d, J = 15.0 Hz), 7.
72 (1H, brs), 8.19 (2H, d, J = 6.
6 Hz), 8.32 (1 H, brs), 8.97 (2
H, d, J = 6.6 Hz), 9.44 (1H, d, J =
8.1 Hz), 11.38 (1 H, s).

Example 6

[0119]

[Chemical Formula 39]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamido] -3- (2-trifluoromethanesulfonyloxyvinyl) -3-cephem-4-carboxylic acid benzhydryl ester 15.7 g (0.0132 mol) and 1-
(2-morpholinoethyl) -4-pyridothione 3.1 g
(0.014 mol) of anhydrous dimethylformamide 80m
1 was added and dissolved, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (800 ml), washed twice with water and twice with 10% brine, the organic layer was dried over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure.
7- [2-trityloxyimino-2- (2-
Tritylaminothiazol-4-yl) acetamide]
13.1 g of -3- [2- (1- (2-morpholinoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.41 (4H, m), 2.75 (2H, m),
3.48 (4H, m), 3.76 (1H, ABq, J =
18.0 Hz), 4.16 (1H, ABq, J = 18.
0Hz), 4.55 (2H, m), 5.35 (1H,
d, J = 4.8 Hz, 5.97 (1H, dd, J =
4.8 Hz, 7.8 Hz), 6.63 (1 H, s),
6.99 (1H, s), 7.1-7.6 (42H,
m), 8.07 (2H, d, J = 7.2 Hz), 8.7
2 (2H, d, J = 7.2 Hz), 8.77 (1H,
s), 9.93 (1H, d, J = 7.8Hz).

Example 7

[0123]

[Chemical 40]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-morpholinoethyl)-
4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate (2 g, 0.0016 mol) and methyl iodide 1
0 ml (0.16 mol) was added and the mixture was stirred at room temperature for 64 hours. After completion of the reaction, methyl iodide was distilled off under reduced pressure to obtain 7-
[2-Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
2.15 g of -pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.28 (3H, s), 3.52 (4H, m),
3.77 (1H, ABq, J = 18.0 Hz), 3.9
6 (4H, m), 4.07 (2H, m), 4.18 (1
H, ABq, J = 18.0 Hz), 4.99 (2H,
m), 5.35 (1H, d, J = 5.1Hz), 5.9.
8 (1H, dd, J = 5.1Hz, 8.4Hz), 6.
63 (1H, s), 6.98 (1H, s), 7.1-
7.6 (42H, m), 8.21 (2H, d, J = 6.
9Hz), 8.78 (1H, s), 8.87 (2H,
d, J = 6.9 Hz), 9.94 (1H, d, J = 8.
4 Hz).

Example 8

[0127]

[Chemical 41]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2- (4-methylmorpholinio) ethyl) -4-pyridinio) thiovinyl] -3-
Dissolve 2.1 g of cephem-4-carboxylic acid benzhydryl ester / iodide in 5 ml of chloroform to give 88%.
Formic acid (3.2 ml) and concentrated hydrochloric acid (0.496 ml) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the formic acid layer was mixed with chloroform (5
It was washed with ml × 3), and this was added dropwise to isopropyl ether / acetone (20 ml / 50 ml). The precipitate was collected by filtration and used as 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
0.55 g of crude product of -pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained. This crude product was dissolved in 5 ml of 0.1N hydrochloric acid and adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column,
Developing with water followed by water / acetonitrile. Fractions containing the desired product were collected, concentrated under reduced pressure, and lyophilized to give 0.15
6 g of 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
A chloride of -pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.30 (3H, s), 3.53 (4H, m),
3.61 (1H, ABq, J = 16.8Hz), 3.9
5 (6H, m), 4.01 (2H, m), 5.02 (2
H, m), 5.15 (1H, d, J = 5.1Hz),
5.73 (1H, dd, J = 5.1Hz, 8.4H
z), 6.66 (1H, s), 6.80 (1H, m),
7.11 (2H, m), 7.41 (1H, d, J = 1
5.0 Hz), 8.15 (2H, d, J = 6.9H)
z), 8.91 (2H, d, J = 6.9Hz), 9.4.
6 (1H, d, J = 8.4 Hz), 11.32 (1H,
s).

Example 9

[0131]

[Chemical 42]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- (2-trifluoromethanesulfonyloxyvinyl) -3-cephem-4-carboxylic acid benzhydryl ester 2.0 g and 1- (2-piperidinoethyl) -4 -0.4 g of pyridothione was dissolved by adding 10 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 4 hours.
After completion of the reaction, it was extracted with ethyl acetate (100 ml), washed twice with water and twice with 10% brine, the organic layer was dried over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure. Dissolve in 10 ml of chloroform and add 100
7- [2-Trityloxyimino-2- (2-tritylaminothiazol-4-yl), the target compound, was added dropwise to ml of isopropyl ether, and the resulting precipitate was collected by filtration and dried.
Acetamide] -3- [2- (1- (2-piperidinoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate (1.99 g) was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.3-1.5 (6H, m), 2.3-2.4 (4
H, m), 2.7 (2H, m), 3.75 (1H, AB
q, J = 17.1 Hz), 4.15 (1H, ABq, J
= 17.1 Hz), 4.5 (2H, m), 5.32 (1
H, d, J = 4.8 Hz, 5.97 (1H, dd, J
= 4.8 Hz, 8.2 Hz), 6.61 (1H, s),
6.98 (1H, s), 7.0-7.6 (42H,
m), 8.05 (2H, d, J = 6.9Hz), 8.6
8 (2H, d, J = 6.9 Hz), 9.93 (1H,
d, J = 8.2 Hz).

Example 10

[0135]

[Chemical 43]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-piperidinoethyl)-]
2-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate (2 g) was dissolved in 6 ml of acetonitrile, 2.6 ml of methyl iodide was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, a precipitate formed by dropping in 86 ml of isopropyl ether was collected by filtration and dried to give 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-. [2- (1- (2-
There were obtained 1.93 g of (1-methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.5-1.6 (2H, m), 1.7-1.9 (4
H, m), 3.15 (3H, s), 3.3-3.5 (4)
H, m), 3.77 (1H, ABq, J = 17.1H
z), 3.9-4.0 (2H, m), 4.18 (1H,
ABq, J = 17.1 Hz), 4.9-5.0 (2H,
m), 5.35 (1H, d, J = 4.8Hz), 5.9.
8 (1H, dd, J = 4.8Hz, 8.2Hz), 6.
62 (1H, s), 6.99 (1H, s), 7.0-
7.6 (42H, m), 8.2 (2H, d, J = 6.9)
Hz), 8.87 (2H, d, J = 6.9 Hz), 9.
92 (1H, d, J = 8.2 Hz).

Example 11

[0139]

[Chemical 44]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2- (1-methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-
Cefem-4-carboxylic acid benzhydryl ester / iodide (1.8 g) was dissolved in chloroform (5.1 ml) to give 8
3.4 ml of 8% formic acid and 0.296 ml of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the formic acid layer was washed with chloroform (5 ml × 3), and this was added dropwise to isopropyl ether / acetone (8.5 ml / 31 ml).
The precipitate was collected by filtration and 7- [2-hydroxyimino-2-
(2-Aminothiazol-4-yl) acetamide]-
0.65 g of a crude product of 3- [2- (1- (2- (1-methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.
This crude product was dissolved in water, adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column, and developed with water and then water / acetonitrile. Fractions containing the desired product were collected, concentrated under reduced pressure and lyophilized to give 0.273 g of 7-
[2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2-
A chloride of (1-methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.4-1.6 (2H, m), 1.7-1.9 (4
H, m), 3.19 (3H, s), 3.3-3.5 (4)
H, m), 3.58 (1H, d, J = 17.1 Hz),
3.85 (1H, d, J = 17.1 Hz), 4.0-
4.1 (2H, m), 5.0-5.1 (2H, m),
5.12 (1H, d, J = 4.8Hz), 5.70 (1
H, dd, J = 4.8 Hz, 8.2 Hz), 6.63
(1H, d, J = 15.3 Hz), 6.65 (1H,
s), 7.15 (2H, brs), 7.41 (1H,
d, J = 15.3 Hz), 8.08 (2H, d, J =
6.9 Hz), 9.00 (2H, d, J = 6.9H)
z), 9.45 (1H, d, J = 8.2 Hz), 11.
48 (1H, s).

Example 12

[0143]

[Chemical formula 45]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- (2-trifluoromethanesulfonyloxyvinyl) -3-cephem-4-carboxylic acid benzhydryl ester 3.28 g and 1- (3-morpholinopropyl)- 0.73 g of 4-pyridothione was dissolved in 10 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 62.5 hours. After completion of the reaction, ethyl acetate (100 m
l), washed twice with water and twice with 10% brine, dried the organic layer over anhydrous magnesium sulfate and distilled off the organic solvent under reduced pressure, then dissolved in 15 ml of chloroform to obtain 700 ml of The mixture was added dropwise to isopropyl ether, and the resulting precipitate was collected by filtration and dried to give the desired product, 7- [2-trityloxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3- [2- (1- (3-morpholinopropyl) -4-pyridinio) thiovinyl]-
2.8 g of 3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.05 (2H, m), 2.23 (6H, m),
3.43 (4H, brs), 3.74 (1H, d, J =
17.4 Hz), 4.17 (1H, d, J = 17.4H)
z), 4.48 (2H, brs), 5.36 (1H,
d, J = 4.8 Hz, 5.96 (1H, dd, J =
4.8 Hz, 8.4 Hz), 6.60 (1 H, s),
6.96 (1H, s), 7.1-7.6 (42H,
m), 8.06 (2H, d, J = 6.0 Hz), 8.7
8 (3H, m), 9.95 (1H, d, J = 8.4H
z).

Example 13

[0147]

[Chemical formula 46]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (3-morpholinopropyl)]
-4-Pyridinio) thiovinyl] -3-cephem-4-
To 1.36 g of carboxylic acid benzhydryl ester / trifluoromethanesulfonate, 15 ml of methyl iodide was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide]-.
1.4 g of 3- [2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.38 (2H, m), 3.10 (3H, s),
3.40 (4H, m), 3.48 (2H, m), 3.7
8 (1H, d, J = 17.4Hz), 3.92 (4H,
brs), 4.19 (1H, d, J = 17.4 Hz),
4.53 (2H, brs), 5.37 (1H, d, J =
4.8 Hz), 5.98 (1H, dd, J = 4.8H)
z, 8.4 Hz), 6.61 (1H, s), 6.96
(1H, s), 7.1-7.6 (42H, m), 8.1
8 (2H, d, J = 6.0 Hz), 8.78 (3H,
m), 9.95 (1H, d, J = 8.4 Hz).

Example 14

[0151]

[Chemical 47]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3
-Cephem-4-carboxylic acid benzhydryl ester-
Dissolve 1.7 g of iodide in 3.8 ml of chloroform,
2.5 ml of 88% formic acid and 0.278 ml of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the formic acid layer was washed with chloroform (4 ml × 5), and this was added dropwise to isopropyl ether / acetone (20 ml / 40 ml).
The precipitate was collected by filtration and 7- [2-hydroxyimino-2-
(2-Aminothiazol-4-yl) acetamide]-
0.53 g of a crude product of 3- [2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained. This crude product was dissolved in water, adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column, and developed with water and then water / acetonitrile. Fractions containing the desired product were collected, concentrated under reduced pressure and lyophilized to give 0.112 g of 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- ( 1-
A chloride of (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.36 (2H, m), 3.09 (3H, s),
3.43 (4H, m), 3.58 (2H, m), 3.7
5 (1H, d, J = 17.4Hz), 3.92 (4H,
brs), 4.20 (1H, d, J = 17.4 Hz),
4.58 (2H, brs), 5.23 (1H, d, J =
4.8 Hz), 5.83 (1H, dd, J = 4.8H)
z, 8.4 Hz), 6.48 (1H, m), 6.63
(1H, s), 7.08 (2H, brs), 7.45
(1H, d, J = 15.4Hz), 8.06 (2H,
d, J = 6.0 Hz, 8.74 (2H, d, J = 6.
0 Hz), 9.42 (1H, d, J = 8.4 Hz), 1
1.30 (1H, s).

Example 15

[0155]

[Chemical 48]

7- [2-cyclopentyloxyimino-]
2- (2-Tritylaminothiazol-4-yl) acetamido] -3- (2-trifluoromethanesulfonyloxyvinyl) -3-cephem-4-carboxylic acid benzhydryl ester 1.59 g and 1- (2-dimethylamino) Ethyl) -4-pyridothione (0.3 g) was dissolved by adding 8.0 ml of anhydrous dimethylformamide, and the mixture was dissolved at room temperature to 4.5.
Stir for hours. After the reaction was completed, ethyl acetate (12
It was extracted with water (0 ml), washed with water three times and once with 10% saline, and the organic layer was dried over anhydrous magnesium sulfate, and then the organic solvent was distilled off under reduced pressure. Then add this to chloroform 8
The precipitate was dissolved in 80 ml of diisopropyl ether and added dropwise to 80 ml of diisopropyl ether.
-Cyclopentyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2
1.43 g of-(1- (2-dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.4-1.9 (8H, m), 2.15 (6H,
s), 2.69 (2H, m), 3.70 (1H, d, J
= 17.0 Hz), 4.15 (1H, d, J = 17.0)
Hz), 4.55 (2H, m), 4.63 (1H,
m), 5.25 (1H, d, J = 5.1Hz), 5.7
8 (1H, dd, J = 5.1Hz, 8.4Hz), 6.
65 (1H, s), 6.98 (1H, s), 7.0-
7.6 (42H, m), 8.06 (2H, d, J = 6.
9 Hz), 8.72 (2H, d, J = 6.9 Hz),
9.52 (1H, d, J = 8.4 Hz).

Example 16

[0159]

[Chemical 49]

7- [2-cyclopentyloxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester -Trifluoromethanesulfonic acid salt 1.42 g was added to acetonitrile 7.
It was dissolved in 1 ml, 0.75 ml of methyl iodide was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, a precipitate formed by dropping in diisopropyl ether was collected by filtration, dried and dried in 7-
[2-Cyclopentyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-
[2- (1- (2-trimethylammonioethyl) -4
1.52 g of -pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.4-1.9 (8H, m), 3.16 (9H,
s), 3.71 (1H, d, J = 17.0 Hz), 3.
85-3.95 (2H, m), 4.18 (1H, d, J
= 17.0 Hz), 4.62 (1 H, m), 4.9-
5.0 (2H, m), 5.27 (1H, d, J = 5.1
Hz), 5.78 (1H, dd, J = 5.1 Hz, 8.
4 Hz), 6.65 (1 H, s), 6.97 (1 H,
s), 7.0-7.6 (42H, m), 8.20 (1
H, d, J = 6.9 Hz), 8.84 (2H, d, J =
6.9 Hz), 9.52 (1H, d, J = 8.4H
z).

Example 17

[0163]

[Chemical 50]

7- [2-cyclopentyloxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydrido Ruester / iodide 1.41 g was dissolved in chloroform 4.7 ml to give 8
8% Formic acid (3.1 ml) and concentrated hydrochloric acid (0.268 ml) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the formic acid layer was washed with chloroform (5 ml × 3), and this was added dropwise to diisopropyl ether / acetone (7.6 ml / 28 ml). The precipitate was collected by filtration and used as 7- [2-cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2-trimethylammonioethyl) -4-. 0.57 g of crude product of pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.
This crude product was dissolved in water, adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column, and developed with water and then water / acetonitrile. Fractions containing the desired product were collected, concentrated under reduced pressure and lyophilized to give 0.42 g of 7-
[2-Cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2-
A chloride of (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.4-1.9 (8H, m), 3.19 (9H,
s), 3.57 (1H, d, J = 17.0 Hz), 3.
83 (1H, d, J = 17.0 Hz), 4.0-4.1
(2H, m), 4.62 (1H, m), 5.0-5.1
(2H, m), 5.11 (1H, d, J = 5.1H
z), 5.66 (1H, dd, J = 5.1Hz, 8.4)
Hz), 6.61 (1H, d, J = 15.3Hz),
6.68 (1H, s), 7.22 (2H, brs),
7.41 (1H, d, J = 15.3Hz), 8.09
(2H, d, J = 6.9 Hz), 8.95 (2H, d,
J = 6.9 Hz), 9.48 (1H, d, J = 8.4H
z).

Example 18

[0167]

[Chemical 51]

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
Dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonic acid salt 3.0 g and 885 μl of iodoacetone were added to give 7- [2-trityloxyimino-2- ( 2-tritylaminothiazole-4
-Yl) acetamido] -3- [2- (1- (2-acetonyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide (3.51 g) Obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.15 (3H, s), 3.25 (6H, s),
3.77 (1H, ABq, J = 17.0 Hz), 4.0
-4.1 (2H, m), 4.18 (1H, ABq, J =
17.0 Hz), 4.64 (2H, brs), 4.9-
5.0 (2H, m), 5.34 (1H, d, J = 5.3
Hz), 5.98 (1H, dd, J = 5.3Hz, 8.
3 Hz), 6.62 (1H, s), 6.99 (1H,
s), 7.0-7.6 (42H, m), 8.20 (2
H, d, J = 6.9 Hz), 8.83 (2H, d, J =
6.9 Hz), 9.95 (1H, d, J = 8.3H)
z).

Example 19

[0171]

[Chemical 52]

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
7- [2- Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-
[2- (1- (2-benzhydryloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio)
2.61 g of thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / bromide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.31 (6H, s), 3.77 (1H, ABq,
J = 17.0 Hz), 4.05-4.15 (2H,
m), 4.18 (1H, ABq, J = 17.0 Hz),
4.84 (2H, brs), 5.0-5.1 (2H,
m), 5.34 (1H, d, J = 5.1Hz), 5.9
8 (1H, dd, J = 5.1Hz, 8.3Hz), 6.
62 (1H, s), 6.90 (1H, s), 6.99
(1H, s), 7.0-7.6 (52H, m), 8.2
0 (2H, d, J = 6.6Hz), 8.90 (2H,
d, J = 6.6 Hz), 9.95 (1H, d, J = 8.
3 Hz).

Example 20

[0175]

[Chemical 53]

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-
Dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonic acid salt 3.0 g and 2-iodoethanol 19 g were used to prepare 7- [2-trityloxyimino-2]. -(2-Tritylaminothiazole-
4-yl) acetamido] -3- [2- (1- (2-hydroxyethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide .21 g was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.18 (6H, s), 3.5-3.6 (2H,
m), 3.74 (1H, ABq, J = 17.0 Hz),
3.8-3.9 (2H, m), 3.9-4.0 (2H,
m), 4.18 (1H, ABq, J = 17.0 Hz),
4.9-5.0 (2H, m), 5.37 (1H, d, J
= 5.1 Hz), 5.98 (1H, dd, J = 5.1H)
z, 8.3 Hz), 6.62 (1H, s), 6.99
(1H, s), 7.0-7.6 (42H, m), 8.1
9 (2H, d, J = 6.9 Hz), 8.82 (2H,
d, J = 6.9 Hz), 9.95 (1H, d, J = 8.
3 Hz).

Example 21

[0179]

[Chemical 54]

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-
Dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonic acid salt 2.5 g and 2-bromoacetic acid ethyl ester 3.0 ml 7-
[2-Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [2-
(1- (2-Ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]-
2.5 g of 3-cephem-4-carboxylic acid benzhydryl ester / bromide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.22 (3H, t, J = 7.2Hz), 3.30
(6H, s), 3.77 (1H, ABq, J = 17.0)
Hz), 4.05-4.15 (2H, m), 4.18.
(1H, ABq, J = 17.0 Hz), 4.19 (2
H, q, J = 7.2 Hz), 4.56 (2H, br
s), 5.0-5.1 (2H, m), 5.37 (1H,
d, J = 4.8 Hz, 5.98 (1H, dd, J =
4.8 Hz, 8.1 Hz), 6.62 (1 H, s),
6.98 (1H, s), 7.0-7.6 (42H,
m), 8.20 (2H, d, J = 7.0 Hz), 8.9
0 (2H, d, J = 7.0Hz), 9.95 (1H,
d, J = 8.1 Hz).

Example 22

[0183]

[Chemical 55]

According to the method of Example 3, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-
Acetonyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide 3.5 g 7- [2-
Hydroxyimino-2- (2-aminothiazole-4-
Iyl) acetamido] -3- [2- (1- (2-acetonyl-dimethylammonioethyl) -4-pyridinio)
Thiovinyl] -3-cephem-4-carboxylate
Obtained 535 mg of chloride.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.15 (3H, s), 3.28 (6H, s),
3.56 (1H, ABq, J = 17.0 Hz), 3.7
9 (1H, ABq, J = 17.0 Hz), 4.1-4.
2 (2H, m), 4.84 (2H, brs), 5.0-
5.1 (2H, m), 5.13 (1H, d, J = 5.3
Hz), 5.69 (1H, dd, J = 5.3 Hz, 8.
3Hz), 6.53 (1H, d, J = 15.3Hz),
6.62 (1H, s), 7.13 (2H, brs),
7.41 (1H, d, J = 15.3Hz), 8.05
(2H, d, J = 6.9 Hz), 8.91 (2H, d, J
J = 6.9 Hz), 9.43 (1H, d, J = 8.3H)
z), 11.5 (1H, s).

Example 23

[0187]

[Chemical 56]

According to the method of Example 3, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
Benzhydryloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-
Cephem-4-carboxylic acid benzhydryl ester / bromide 2.41 g of 7- [2-hydroxyimino-2-
(2-Aminothiazol-4-yl) acetamide]-
289 m of 3- [2- (1- (2-carboxylate methyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate.
g was obtained.

¹ H-NMR (D ₂ O) δ ppm; 3.1
8 (6H, s), 3.54 (1H, ABq, J = 17.
0 Hz), 3.71 (2H, brs), 3.75 (1
H, ABq, J = 17.0 Hz), 4.08-4.18.
(2H, m), 4.8-4.9 (2H, m), 5.06
(1H, d, J = 5.1Hz), 5.65 (1H, d,
J = 5.1 Hz), 6.54 (1H, d, J = 15.3)
Hz), 6.64 (1H, s), 7.39 (1H, d,
J = 15.3 Hz), 7.94 (2H, d, J = 6.9)
Hz), 8.68 (2H, d, J = 6.9 Hz).

Example 24

[0191]

[Chemical 57]

According to the method of Example 3, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
Hydroxyethyl-dimethylammonioethyl) -4-
Pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide 7 g from 3.2 g
[2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2-
Hydroxyethyl-dimethylammonioethyl) -4-
160 mg of pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.21 (6H, s), 3.55 (2H, br
s), 3.64 (1H, ABq, J = 17.0 Hz),
3.85 (2H, brs), 4.08 (1H, ABq,
J = 17.0 Hz), 4.0-4.1 (2H, m),
5.0-5.1 (2H, m), 5.19 (1H, d, J
= 5.1 Hz), 5.80 (1H, dd, J = 5.1H)
z, 8.3 Hz), 6.65 (1H, s), 7.02
(1H, d, J = 15.3 Hz), 7.13 (2H, b
rs), 7.34 (1H, d, J = 15.3 Hz),
8.18 (2H, d, J = 6.9Hz), 9.00 (2
H, d, J = 6.9 Hz), 9.48 (1H, d, J =
8.3 Hz), 11.35 (1 H, s).

Example 25

[0195]

[Chemical 58]

According to the method of Example 3, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
1. Ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester bromide
From 49 g, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2
-(1- (2-ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]
-3-Cephem-4-carboxylate chloride 32
0 mg was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.23 (3H, t, J = 7.2Hz), 3.29
(6H, s), 3.67 (1H, ABq, J = 17.0)
Hz), 4.08 (1H, ABq, J = 17.0H
z), 4.18 (2H, q, J = 7.2 Hz), 4.1
-4.2 (2H, m), 4.60 (2H, brs),
5.0-5.1 (2H, m), 5.20 (1H, d, J
= 4.8 Hz), 5.80 (1H, dd, J = 4.8H)
z, 8.1 Hz), 6.65 (1H, s), 7.02
(1H, d, J = 15.0 Hz), 7.12 (2H, b
rs), 7.35 (1H, d, J = 15.0Hz),
8.19 (2H, d, J = 7.0Hz), 8.95 (2
H, d, J = 7.0 Hz), 9.48 (1H, d, J =
8.1 Hz), 11.32 (1 H, s).

Example 26

[0199]

[Chemical 59]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamido] -3- (2-trifluoromethanesulfonyloxyvinyl) -3-cephem-4-carboxylic acid benzhydryl ester 2.5 g and 1- (2-sulfoethyl-methylamino) 0.75 g of ethyl) -4-pyridothione was dissolved in 11 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, the organic solvent was evaporated under reduced pressure, and then dissolved in 15 ml of methylene chloride, 150 ml
Was added dropwise to isopropyl ether. The resulting precipitate was collected by filtration and dried under reduced pressure to give the desired 7- [2-trityloxyimino-2- (2-tritylaminothiazole-4-
Yl) acetamido] -3- [2- (1- (2-sulfoethyl-methylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate. Four
g was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 2.17 (3H, brs), 2.4-2.5 (2
H, m), 2.7-2.8 (2H, m), 2.7-2.
8 (2H, m), 3.76 (1H, ABq, J = 17.
7Hz), 4.17 (1H, ABq, J = 17.7H
z), 4.5-4.6 (2H, m), 5.34 (1H,
d, J = 5.1 Hz), 5.97 (1H, dd, J =
5.1 Hz, 8.4 Hz), 6.62 (1 H, s),
6.98 (1H, s), 7.1-7.5 (42H,
m), 8.05 (2H, d, J = 6.9 Hz), 8.7
6 (1H, s), 8.78 (2H, d, J = 6.9H
z), 9.94 (1H, d, J = 8.4 Hz).

Example 27

[0203]

[Chemical 60]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-sulfoethyl-methylaminoethyl) -4-pyridinio) thiovinyl] -3-
Cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonate (0.67 g) was used, and 7- [2-trityloxyimino-2- (2-tritylaminothiazole-4) of the target compound was prepared in the same manner as in Example 10. -Yl) acetamido] -3- [2- (1- (2-sulfoethyl-dimethylammonioethyl) -4-pyridinio)
0.63 g of thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 3.0-3.1 (2H, m), 3.13 (6H,
s), 3.7-3.8 (2H, m), 3.83 (1H,
ABq, J = 17.4 Hz) 3.8-3.9 (2H,
m), 4.18 (1H, ABq, J = 17.4 Hz),
4.9-5.0 (2H, m), 5.35 (1H, d, J
= 5.1 Hz), 5.98 (1H, dd, J = 5.1H)
z, 8.4 Hz), 6.62 (1H, s), 6.98
(1H, s), 7.1-7.5 (42H, m), 8.1
8 (2H, d, J = 7.2 Hz), 8.79 (1H,
s), 8.85 (2H, d, J = 7.2 Hz), 9.9
4 (1H, d, J = 8.4 Hz).

Example 28

[0207]

[Chemical formula 61]

7- [2-Trityloxyimino-2-]
(2-Tritylaminothiazol-4-yl) acetamide] -3- [2- (1- (2-sulfoethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]
In the same manner as in Example 3 except that 0.61 g of -3-cephem-4-carboxylic acid benzhydryl ester / iodide was used,
-[2-Hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2
-Sulfonate ethyl-dimethylammonioethyl)-
0.15 g of 4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ + D ₂ O)
δppm; 3.0-3.1 (2H, m), 3.13 (6)
H, s), 3.54 (1H, ABq, J = 17.1H
z), 3.6-3.7 (2H, m), 3.76 (1H,
ABq, J = 17.1 Hz), 3.8-3.9 (2H,
m), 4.85-4.95 (2H, m), 5.07 (1
H, d, J = 4.8 Hz, 5.66 (1H, d, J =
4.8Hz), 6.55 (1H, d, J = 15.3H
z), 7.42 (1H, d, J = 15.3 Hz), 8.
01 (2H, d, J = 7.1 Hz), 8.73 (2H,
d, J = 7.1 Hz).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kenie Yamada, 463 Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture, Tokushima Research Institute, Otsuka Chemical Co., Ltd. (72) Masahiro Ito, 463, Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture (72) Inventor Hideaki Hanaki 224-2 Hiraishi Isano, Kawauchi-cho, Tokushima City, Tokushima Prefecture (72) In Taiho Pharmaceutical Co., Ltd. (72) Inventor Akio Hyodo Isashino Hiraishi, Kawauchi-cho, Tokushima City, Tokushima Prefecture 224-2 Taiho Pharmaceutical Co., Ltd.

Claims (12)

[Claims] 1. A general formula: [In formula, Q shows CH or N. R ¹ represents a carboxylate or a carboxyl group. R ² is a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent , A carboxy lower alkyl group which may have a substituent, a hydroxy lower alkyl group which may have a substituent, or a lower alkoxy lower alkyl group which may have a substituent. R is Indicates. Here, R ³ is a group — (CH ₂ ) m—Y or a group —
(CH ₂ ) m-CO-Y (wherein m is an integer of 1 to 5, Y
Represents a quaternary ammonium group). n represents 0 or an integer of 1 to 4. B ⁻ represents an anion. f is 0 or 1 when R ¹ represents a carboxylate, shows a 2 if R ¹ represents a carboxyl group. The ring represented by C may be substituted with a lower alkyl group and has 5 or less nitrogen atoms.
A membered heterocyclic group is shown. ] The cephem compound represented by these, its cephem carboxy protected ester, and its nontoxic salt. 2. The compound according to claim 1, wherein Q is CH. 3. R is (R ³ represents a group — (CH ₂ ) m—Y. N, B ⁻ , f,
and m and Y are the same as above). 4. The compound according to claim ² , wherein R ² is a hydrogen atom or a lower cycloalkyl group. 5. R is The compound according to claim 4, wherein (B ⁻ , f, m and Y are the same as the above). 6. A 7- [2-hydroxyimino-2- (2
-Aminothiazol-4-yl) acetamide] -3-
[2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-
4-carboxylate chloride or salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2-trimethylammonioethyl)- 4-pyridinio) thiovinyl]
-3-Cephem-4-carboxylate chloride or its salt, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1
-(2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-
4-carboxylate chloride or a salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2- (4-methylmorpholine) Nio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3 -[2
-(1- (2-acetonyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-
4-carboxylate chloride or its salt, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2- (1-methylpiperidi Nio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3 -[2
-(1- (2-carboxylate methyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-
Cephem-4-carboxylate or a salt thereof, 7- [2
-Hydroxyimino-2- (2-aminothiazole-4)
-Yl) acetamido] -3- [2- (1- (2-hydroxyethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a salt thereof, 7- [ 2-Hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2-ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3 -Cephem-4-carboxylate chloride or a salt thereof, 7- [2-cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (2-trimethylammonium Oethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof and 7
-[2-Hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [2- (1- (sulfonate ethyl-dimethylammonioethyl) -4-
Pyridinio) thiovinyl] -3-cephem-4-carboxylate or at least one cephem compound selected from salts thereof. 7. A general formula: [In the formula, R ⁴ represents a cephem carboxyl-protecting group. R '
Is Indicates. Here, R ³ , n, B ⁻ and C are the same as above. ]
The compound represented by the general formula: [In the formula, R ⁵ represents an amino group or a protected amino group.
R ⁶ represents an oxime protecting group or an R ^{2 ′} group (the R ^{2 ′} group is an R ² group other than a hydrogen atom). Q is the same as above. ] The compound represented by the formula or a reactive derivative thereof is reacted, and the protecting group is further removed if necessary. [In the formula, Q, R ¹ , R ² and R are the same as defined above. ] The manufacturing method of the cephem compound represented by these, its cephem carboxy protected ester, and its nontoxic salt. 8. A general formula: [In the formula, R ⁴ , R ⁵ and R ⁶ are the same as defined above. R ⁷ represents a halogen atom, a lower acyloxy group or a sulfonyloxy group. ] To the compound represented by the general formula: [In the formula, R ³ , n and B are the same as defined above. ] The compound represented by the formula: is reacted and, if necessary, a protecting group is removed. [In the formula, Q, R ¹ , R ² and R are the same as defined above. ] The manufacturing method of the cephem compound represented by these, its cephem carboxy protected ester, and its nontoxic salt. 9. A general formula: [Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. ] To the compound represented by the general formula R ⁸ -SM, wherein R ⁸ is Indicates. Here, n and C are the same as above. M represents a hydrogen atom or a metal atom. ] By reacting a compound represented by
Then the general formula R ³ -X [wherein X represents a halogen atom. R ³ is the same as above. ]
A compound represented by the general formula: embedded image wherein the protecting group is removed if necessary. [In the formula, Q, R ¹ , R ² and R are the same as defined above. ] The manufacturing method of the cephem compound represented by these, its cephem carboxy protected ester, and its nontoxic salt. 10. A general formula: [Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. ] To the compound represented by the general formula: [Wherein R ¹⁰ is a group — (CH ₂ ) m-Z or a group — (CH ₂ ))
m-CO-Z (in the group, m is an integer of 1 to 5 and Z is a tertiary amino group). n represents 0 or an integer of 1 to 4. And then reacting with a compound represented by the general formula R ¹¹ -X, wherein R ¹¹ is a lower alkyl group, lower alkenyl group, hydroxy lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, lower alkanoyl lower alkyl group. , Lower alkoxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, amino lower alkyl group,
A lower alkylamino lower alkyl group, a di lower alkylamino lower alkyl group or a sulfo lower alkyl group is shown.
X represents a halogen atom. ] The compound represented by the following formula is reacted and, if necessary, a protecting group is removed. [In the formula, Q, R ¹ , R ² and R are the same as defined above. ] The manufacturing method of the cephem compound represented by these, its cephem carboxy protected ester, and its nontoxic salt. 11. A general formula: [In the formula, Q, R ¹ , R ² and R are the same as defined above. ] The antibacterial agent which consists of the cephem compound represented by these, its cephem carboxy protected ester, its nontoxic salt, and a pharmaceutically acceptable carrier. 12. The antibacterial agent according to claim 11, which has a strong antibacterial activity against methicillin-resistant Staphylococcus aureus.