JP3218363B2 - Cephem compound, method for producing the same, and antibacterial agent containing the compound - Google Patents

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]

In recent years, with the widespread use of third generation cephalosporins, methicillin-resistant Staphylococcus aureus (MR)
The infection caused by SA) is an important problem. Third
Generation cephalosporins have a strong antibacterial activity against Gram-negative bacilli, but have a reduced antibacterial activity against Gram-positive cocci.
-An increase in Staphylococcus aureus resistant to lactam antibiotics has become a serious problem as intractable infections. At present, vancomycin, which is a polypeptide antibiotic, is the only effective drug for treating infectious diseases caused by MRSA, but vancomycin requires eczema, nephrotoxic side effects and the like, and requires careful administration.

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

In general, in conventional cephalosporin compounds, the antibacterial activity against Gram-positive bacteria including MRSA decreases as the water solubility increases, and the water solubility and the antibacterial activity are in a contradictory relationship. It has been 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 cephem compounds that exhibit excellent antibacterial activity against MRSA and have high solubility in water.

[0005]

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

[0006]

Means for Solving the Problems To solve the above problems, the present inventors have synthesized and studied various cephem compounds.
Further new quaternary ammonium compounds
It has been found that a cephem compound into which a quaternary ammonium substituent has been introduced has high water solubility and has excellent antibacterial activity, in particular, strong antibacterial activity against Gram-positive bacteria including MRSA. Was.

[0007] The cephem compound of the present invention is a novel compound and is represented by the following general formula (1).

[0008]

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[Wherein 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]

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FIG. Here, R ³ is a group — (CH ₂ ) m—
Y or a group — (CH ₂ ) m —CO—Y (wherein m is 1 to 5)
And Y represents a quaternary ammonium group. ).
n shows 0 or the integer of 1-4. 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. The groups shown in the present specification are more specifically 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.

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.

As the lower alkynyl group, ethynyl, 1
Examples thereof 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.

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

Examples of the carboxy lower alkyl group include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl and the like. A carboxyalkyl group can be exemplified.

Examples of the hydroxy lower alkyl group include those having 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 exemplified.

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

The ring represented by C is a 5-membered heterocyclic group having a nitrogen number of 4 or less which may be substituted by a lower alkyl group,
Specifically, oxazole, thiazole, isoxazole, isothiazole, pyrazole, imidazole, thiadiazole, triazole, oxatriazole, thiatriazole, tetrazole and the like can be exemplified, and a lower alkyl group on the nitrogen atom or carbon atom of these heterocycles has 1 May be substituted. Such a heterocyclic ring is more specifically represented by the following structural formula.

[0020]

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

[0022]

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[In the above formulas, R ¹¹ , R ¹² and R ¹³ are the same or different and each is 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 It represents a lower alkyl group or a sulfo lower alkyl group. 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, And di-lower alkylamino lower alkyl, di-lower alkylamino, carboxy lower alkyl, carboxy lower alkylamino, carbamoyl, N-lower alkylcarbamoyl, formylamino, acylamino and the like. And the like.

Examples of the carbamoyl lower alkyl group include carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl, 4-carbamoylbutyl, 5-carbamoylpentyl, 6-carbamoylhexyl and the like. A carbamoylalkyl group can be exemplified.

Examples of the lower alkanoyl lower alkyl group include formylmethyl, acetonyl, 3-acetylpropyl, 4-acetylbutyl, 6-propionylhexyl,
5-isobutyrylpentyl, hexanoylmethyl, 6-
An alkanoylalkyl group in which the alkanoyl moiety such as a hexanoylhexyl group has 1 to 6 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms can be exemplified.

Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, and ethoxycarbonylbutyl. Number one
To 6 alkoxycarbonylalkyl groups.

Examples of the amino lower alkyl group include those having 1 to 6 carbon atoms in the alkyl moiety such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, and 6-aminohexyl. An aminoalkyl group can be exemplified.

Lower alkylamino Lower alkyl groups include methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, pentylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, Examples thereof include an alkylamino moiety such as a 5-methylaminopentyl group and an alkylaminoalkyl group having 1 to 5 carbon atoms in the alkyl moiety.

Di-lower alkylamino Lower alkyl groups include dimethylaminomethyl, diethylaminomethyl,
Dipropylaminomethyl, dibutylaminomethyl, 2-
Dimethylaminoethyl, 3-dimethylaminopropyl,
Dialkylamino moieties such as 4-dimethylaminobutyl, 5-dimethylaminopentyl, and 6-dimethylaminohexyl groups have 2 to 8 carbon atoms, and the alkyl moieties have 1 to 6 carbon atoms. .

Examples of the sulfo lower alkyl group include sulfoalkyl groups having 1 to 5 carbon atoms in the alkyl portion thereof, such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, and pentanesulfonic acid.

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

Examples of the lower alkoxy group include C1-C6 alkoxy groups 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.

Examples of the carboxy lower alkylamino group include carboxymethylamino, 2-carboxyethylamino, 3-carboxypropylamino, 4-carboxybutylamino, 5-carboxypentylamino and 6-carboxyhexylamino groups. 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 portion thereof, 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 portion thereof, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and butylcarbamoyl.

[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.

Cephem carboxyl protecting groups include protected esters commonly used in cephem synthesis and pharmaceutically acceptable protected esters. A protected ester widely used in cephem synthesis is stable when various chemical modifications are applied to a β-lactam compound, and is easily eliminated when a pharmaceutically acceptable protected ester described below is introduced. Is an ester that can be Pharmaceutically acceptable protected esters are non-toxic esters that can be readily hydrolyzed in vivo and that can be rapidly degraded in human blood and tissues. As these esters, known esters generally used in the field of antibiotics may be used, and specifically, for example, JP-A-49-8138.
No. 0 and Etch. E. Any of those described in Fline edition, Cephalosporin and Penicillins, Chemistry and Biology (issued 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, alkyl groups having 1 to 18 carbon atoms such as octadecyl, iododecyl,
Chloromethyl, 2,2-dibromoethyl, 2,2,2-
A halogeno lower alkyl group in which 1 to 3 chlorine, bromine or iodine atoms are substituted, such as trichloroethyl, 2,2,2-tribromoethyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, o-methoxybenzyl, p −
A nitro group such as methoxybenzyl or di (p-methoxyphenyl) methyl or a methyl group substituted with 1 to 3 phenyl groups which may be substituted with an alkoxy group, methoxymethyl, ethoxymethyl, n-propyloxymethyl, isopropyl Oxymethyl, n-butoxymethyl, lower alkoxymethyl groups such as isobutoxymethyl, acetoxymethyl, acetoxyethyl, propionyloxyethyl,
n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, 1-acetoxyethyl,
Pivaloyloxyethyl, pivaloyloxypropyl,
Lower alkylcarbonyloxy lower alkyl groups such as 1-propionyloxybutyl and the like; cycloalkylcarbonyloxy-lower alkyl groups having 5 to 7 carbon atoms such as cyclopentylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl; benzylcarbonyl such as benzylcarbonyloxymethyl Oxy lower alkyl groups, benzoyloxy lower alkyl groups such as benzoyloxymethyl and benzoyloxyethyl, and lower alkoxycarbonyloxy lower alkyl groups such as methoxy-carbonyloxymethyl, 1-ethoxy-carbonyloxyethyl and 3-methoxy-carbonyloxypropyl Benzyloxy lower alkyl groups such as benzyloxymethyl, benzyloxyethyl and the like; 2-cyano-1,1-dimethylethyl;
Bromobenzoylmethyl, p-nitrobenzoylmethyl, dimethylaminomethyl, methylthiomethyl, phenylthiomethyl, succinimidemethyl, 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
-Oxide-2-methyl group and the like.

The non-toxic salt of the compound of the formula (1) includes pharmaceutically acceptable salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, citrate and maleate. Organic lactates, lactates, tartrate and other organic carboxylic acids, methanesulfonic acid, hydroxymethanesulfonic acid, taurine salts, benzenesulfonate, toluenesulfonate and other organic sulfonates, arginine salts, lysine salts, serine salts, asparagine Acid salts, glutamates, glycinates and the like, alkali metal salts such as sodium salts, potassium salts and lithium salts, and alkaline earth metal salts such as calcium salts and magnesium salts.

Q 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. Preferably, R is

[0041]

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Wherein 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 alkyl group. Examples 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.

Preferred compounds among the compounds of the above formula (1) and their non-toxic salts are listed below.

7- [2-hydroxyimino-2- (2-
Aminothiazol-4-yl) acetamido] -3-
[2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-
4-carboxylate chloride or a salt thereof 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-
(2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or salt thereof 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) acetamido] -3- [2- (1-
(2- (4-methylmorpholinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a 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 a 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 a salt thereof 7- [2-hydroxyimino-2- (2-aminothiazole- 4-yl) acetamide] -3- [2- (1-
(2-carboxylatemethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate or a 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 a salt thereof 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-
(2-ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a salt thereof 7- [2-cyclopentyloxyimino-2- (2-aminothiazole) -4-yl) acetamide] -3- [2
-(1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a salt thereof 7- [2-hydroxyimino-2- (2-aminothiazole-4) -Yl) acetamide] -3- [2- (1-
(Sulfonateethyl-dimethylammonioethyl)-
4-pyridinio) thiovinyl] -3-cephem-4-carboxylate or a salt thereof.

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

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

[0047]

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[0048]

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

[0050]

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Wherein R ⁴ is a cephem carboxyl protecting group and R ′ is

[0052]

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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 (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 is activated. The compound 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 includes tri (lower) alkylsilyl groups such as trimethylsilyl group, benzhydryl group, p-methoxybenzyl group, tert-butyl group, p-nitrobenzyl group, Examples of a carboxy group-protecting group that can be easily removed, such as a phenacyl group, which are usually used in this field can be given.

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

The oxime protecting group represented by R ⁶ includes
Examples of protecting groups generally used in this field, such as acetyl, trityl, and tetrahydropyranyl groups, which can be easily removed under mild conditions, can be exemplified.

The reaction of the compound (6) with the compound (7) or a reactive derivative thereof can be carried out under the conditions of a commonly used known amide bond forming reaction.

Examples of the reactive derivative of the compound (7) include acid halides such as acid chlorides and acid bromides, substituted phosphoric acids, dialkyl phosphorous acids, sulfurous acids, thiosulfuric acids, alkyl carbonates, organic carboxylic acids and the like. Acid anhydrides with acids and symmetric acid anhydrides, active acid amides with imidazole, dimethylpyrazole and the like, p-nitrophenyl ester, phenylthioester, carboxymethylthioester or N-hydroxypiperidine, N-hydroxysuccinoimide, N-hydroxysuccinimide
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, 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 is usually carried out under cooling or near 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 And aprotic polar solvents such as dimethyl sulfoxide, acetone and the like, and mixed solvents thereof.

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

In the above reaction, the amount of the carboxylic acid compound represented by the general formula (7) or the reactive derivative thereof to the amine compound represented by the general formula (6) is usually 1
The molar amount is about 10 to 10 times, preferably about 1 to 3 times. The amount of the basic compound to be used is usually about 1 to 30 times, preferably about 2 to 10 times the molar amount of the amine compound represented by the general formula (6).
The reaction time is generally 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, for example, treating with water when the protecting group is a tri (lower) alkylsilyl group or the like. When the protective group is a benzhydryl group, a trityl group, a p-methoxybenzyl group, a tert-butyl group, a formyl group or the like, formic acid, hydrochloric acid, trifluoroacetic acid, anisole-trifluoroacetic acid, acetic acid, phenol, cresol It can be removed by treating with a kind. After completion of the reaction, Diaion HP-20, HP-21, SP
-207, CHP-20P (Mitsubishi Chemical Industries) 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, for example, Hass Corporation.

[0064]

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[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]

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FIG. 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 reacted with a cephalosporin compound represented by the general formula (8) or a salt thereof and a mercapto compound represented by the general formula (9). And then the resulting general formula (1
The compound of the formula (1) is reacted with the halogenated organic compound represented by the formula (11), and the protecting group is removed from the compound of the formula (12).
Of the present invention can be obtained.

The reaction between compound (8) and compound (9)
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 The reaction is carried out in an organic solvent such as an acid buffer or a mixture of a hydrophilic organic solvent and water. 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 trialkylamine such as triethylamine and diisopropylamine. Examples of the salts include quaternary ammonium salts such as tetrabutylammonium salts.
The use ratio of the compound (8) and the compound (9) is not particularly limited, but is usually 1 to 5 equivalents, preferably 1 to 2 equivalents of the compound (9) relative to the compound (8). Is good. The reaction is usually performed under cooling or at 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, and aromatic hydrocarbons such as benzene, toluene and xylene. Examples thereof include hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and acetonitrile. The ratio of the compound (10) to the compound (11) used depends on the type of the compound (11) and the like and cannot be unconditionally determined, but usually 1 to 100 equivalents of the compound (11) relative to the compound (10), Preferably, 5 to 50 equivalents are used. 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, and 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,
-(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)
-1-carbamoylmethyl-pyrrolidinium iodide and the like.

The thus-obtained compound of the general formula (12) can be subjected to the removal of the protecting group by the method shown in Production Method-I, whereby the compound of the present invention of the general formula (1) can be easily produced. You.

[0072]

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

The reaction between the compound of the general formula (8) and the compound of the general formula (13) or (14) is the same as the reaction between the compound of the general formula (8) and the compound of the general formula (9). Can be performed under conditions.

[0075]

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

[0077]

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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
And Z represents a tertiary amino group. ). 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, It represents a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group or a sulfo lower alkyl group. n is 0 or 1
Shows an integer of ~ 4. The compound of the general formula (12) can also be produced by the above-mentioned production method-IV.

The reaction between the compound of the general formula (8) and the compound of the general formula (15) or (16) is the same as the reaction between the compound of the general formula (8) and the compound of the general formula (9). Can be performed under conditions. The reaction between the compound of the general formula (17) and the compound of the general formula (18) can be performed under the same reaction conditions as the reaction between the compound of the general formula (10) and the compound of the general formula (11). . Examples of the halogenated organic compound represented by the general formula (18) include, for example, lower alkyl halide, lower alkenyl halide, hydroxy lower alkyl halide, carboxy lower alkyl halide, carbamoyl lower alkyl halide, lower alkanoyl lower alkyl halide, lower alkoxy lower alkyl halide , Lower alkoxycarbonyl lower alkyl halide,
Amino lower alkyl halide, lower alkylamino lower alkyl halide, di-lower alkylamino lower alkyl halide, sulfo lower alkyl halide, and the like,
The various halides include chloride, bromide,
Iodide and the like can be exemplified.

The pyridine derivatives of the general formulas (9), (13) and (15) are in a tautomeric equilibrium depending on the bonding position of the thiol group.
In the pyridine derivative of the above, the following relationship is established, and such isomers are included in the same category as the compound itself.
General formulas (9) and (13) containing such tautomeric forms
For the pyridine derivative of (15), one expression is used for convenience, but it goes without saying that the pyridine derivative also includes the other isomer.

[0081]

Embedded image

[Wherein R ¹⁰ and n are the same as above. The compound of the present invention is made into a pharmaceutical composition according to a usual method using a suitable pharmaceutical carrier. Examples of the carrier used here include various types commonly used for ordinary drugs, for example, excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, surfactants and the like. .

The preparation of the present invention can be used for infectious diseases of mammals including humans,
In particular, the dosage unit form when used as a therapeutic agent for infectious diseases caused by methicillin-resistant Staphylococcus aureus is not particularly limited and can be appropriately selected depending on the purpose of the treatment. Specifically, injections, suppositories, eye drops Ointments, parenteral preparations such as aerosols, tablets, coated tablets, powders, granules, capsules,
Oral preparations such as liquid preparations, pills, suspensions and emulsions can be exemplified.

The above-mentioned various drugs are prepared by a preparation method generally known in this field. Tablets, powders, granules and the like for solid oral preparations such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin , Excipients such as sodium alginate, 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, dried starch, sodium alginate, agar powder, laminarane 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, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid And a lubricant such as purified talc, stearate, boric acid powder, polyethylene glycol and the like. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.

In the case of molding into a pill form, carriers include, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic powder, tragacanth powder, gelatin and the like; Laminaran,
Disintegrators such as agar can be used.

Capsules are prepared by mixing with the various carriers described above and filling them in hard gelatin capsules, soft capsules or the like.

In forming into suppositories, carriers such as polyethylene glycol, cocoa butter, lanolin, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, and Witepsol (registered trademark Dynamite Nobel) are used as carriers. And an appropriate absorption enhancer.

In molding into an injection, diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters 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 included in the pharmaceutical preparation, and a usual solubilizing agent, soothing agent, local anesthetic, etc. may be added. May be.
By adding these carriers, injections for subcutaneous, intramuscular, and intravenous injections can be produced by a conventional method.

Liquid preparations can be aqueous or oily suspensions, solutions,
Syrups and elixirs may be prepared according to a conventional method using ordinary additives.

In preparing an ointment such as paste, cream and gel, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used.

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 specified unconditionally and is appropriately selected from a wide range. The content is preferably about 70% by weight.

The above-mentioned preparations can be administered, for example, by enteral administration,
Oral administration, rectal administration, buccal administration, transdermal administration and the like are not particularly limited, and are appropriately determined according to various preparation forms, age, sex and other conditions of the patient, degree of symptoms of the patient, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered. In the case of an injection, it is administered alone or mixed with a normal replenisher such as glucose and amino acids, and administered intravenously.
It is administered intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally. The ointment is applied to skin, oral mucosa, 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 type of disease, the type of the compound of the present invention to be administered, and the like. Generally, from 100 mg to about 10 g per day, or more, can be administered to a patient. For the treatment of pathogenic bacterial infections, the average dose of the compound of the present invention is about 50 mg, 100 mg, 250 mg, 1 mg.
Amounts of 000 mg, 2000 mg can be used.

In order to show the usefulness of the target compound, an antibacterial activity test of representative compounds of the present invention against various bacteria was carried out by the agar plate dilution method, and the minimum inhibitory concentration (MIC value) against the various bacteria was determined to be FMOX (Flomoxef). MIC-80 values against clinically isolated methicillin-resistant and highly-resistant ciprofloxacin-resistant Staphylococcus aureus are shown in Table 1, and 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) acetamido] -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) acetamido] -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 are given below.

Embodiment 1

[0100]

Embedded image

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-pyridothione3.
16 g (0.017 mol) was dissolved by adding 150 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 2.5 hours.
After completion of the reaction, the reaction mixture was extracted with ethyl acetate (1200 ml), washed three times with water and once with 10% brine, dried over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure. 7- [2-trityloxyimino-
2- (2-tritylaminothiazol-4-yl) acetamido] -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 = 4.8 Hz, 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).

Embodiment 2

[0104]

Embedded image

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 (20.3 g, 0.016 mol) was dissolved in acetonitrile (100 ml) and methyl iodide was added to the solution.
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 remove 7- [2-trityloxyimino-2- (2-tritylaminothiazole-).
22.6 g of 4-yl) acetamido] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester iodide was obtained. 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 = 4.8 Hz), 5.98 (1H, d, J = 4.8 Hz)
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 = 6.9 Hz),
8.79 (1H, brs), 8.82 (2H, d, J =
6.9 Hz), 9.93 (1H, d, J = 7.8H)
z).

Embodiment 3

[0107]

Embedded image

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 the completion of the reaction, the formic acid layer was washed with chloroform (70 ml × 3) and added dropwise to isopropyl ether / acetone (200 ml / 600 ml). The precipitate was collected by filtration and treated with 7- [2-hydroxyimino-
Crude formation of 2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate 7.0 g of the product were obtained. This crude product was dissolved in 130 ml of 0.1 N hydrochloric acid, adsorbed on a column of a high-porous polymer Mitsubishi Diaion HP-21, and developed with water and then with water / acetonitrile.
The fractions containing the target compound were collected, concentrated under reduced pressure, and freeze-dried, and 3.0 g of 7- [2-hydroxyimino-2- (2
-Aminothiazol-4-yl) acetamido] -3-
[2- (1- (2-trimethylammonioethyl) -4
-Pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride 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 = 6.6 Hz), 9.4
5 (1H, d, J = 7.8 Hz), 11.38 (1H,
s).

Embodiment 4

[0111]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -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 (1H, dd, J = 5.1 Hz,
8.1 Hz), 6.62 (1H, 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 = 6.6 Hz), 9.9
2 (1H, d, J = 8.1 Hz).

Embodiment 5

[0115]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-carbamoylmethyl-
Dissolve 4.8 g of dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate benzhydryl ester iodide in 8 ml of chloroform and add 6 ml of 88% formic acid and 0.8 ml of concentrated hydrochloric acid. Stirred 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 treated with 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 column of a high-porous polymer Mitsubishi Diaion HP-21, and developed with water and then with water / acetonitrile. Collect fractions containing the target substance, concentrate under reduced pressure, freeze-dry,
327 mg of 7- [2-hydroxyimino-2- (2-
Aminothiazol-4-yl) acetamido] -3-
[2- (1- (2-carbamoylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-
Cephem-4-carboxylate chloride 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 =
5.1Hz, 8.1Hz), 6.65 (1H, 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.
6Hz), 8.32 (1H, brs), 8.97 (2
H, d, J = 6.6 Hz), 9.44 (1H, d, J =
8.1 Hz), 11.38 (1 H, s).

Embodiment 6

[0119]

Embedded image

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-
3.1 g of (2-morpholinoethyl) -4-pyridothione
(0.014 mol) in anhydrous dimethylformamide 80m
1 was added and dissolved, followed by stirring at room temperature for 2.5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (800 ml), washed twice with water and twice with 10% brine, dried over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure.
The desired 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.
0 Hz), 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 (1H, 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 = 7.8 Hz).

Embodiment 7

[0123]

Embedded image

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 give 7-
[2-Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
-Pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide (2.15 g) 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 = 5.1 Hz), 5.9
5 (1H, dd, J = 5.1 Hz, 8.4 Hz);
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).

Embodiment 8

[0127]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -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 obtain 88%
3.2 ml of formic acid and 0.496 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 removed with chloroform (5
ml × 3), and this was added dropwise to isopropyl ether / acetone (20 ml / 50 ml). The precipitate was collected by filtration and 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
0.55 g of a crude product of -pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained. This crude product was dissolved in 5 ml of 0.1 N hydrochloric acid and adsorbed on a high-porous polymer Mitsubishi Diaion HP-21 column.
Developed with water, then water / acetonitrile. The fractions containing the target compound were collected, concentrated under reduced pressure, and lyophilized to give 0.15
6 g of 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2-
(1- (2- (4-methylmorpholinio) ethyl) -4
-Pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride was obtained.

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

Embodiment 9

[0131]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -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, the reaction mixture was extracted with ethyl acetate (100 ml), washed twice with water and twice with 10% saline, and the organic layer was dried over anhydrous magnesium sulfate. Dissolve in 10 ml of chloroform and add 100
The resulting precipitate was collected by filtration, dried, and dried to obtain the desired product, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl).
1.99 g of acetamido] -3- [2- (1- (2-piperidinoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonate 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 = 6.9 Hz), 8.6
8 (2H, d, J = 6.9 Hz), 9.93 (1H,
d, J = 8.2 Hz).

Embodiment 10

[0135]

Embedded image

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 into 86 ml of isopropyl ether was collected by filtration, dried and dried to give 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-. [2- (1- (2-
1.93 g of (1-methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide was obtained.

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 = 4.8 Hz), 5.9
5 (1H, dd, J = 4.8 Hz, 8.2 Hz);
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).

Embodiment 11

[0139]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2- (1-methylpiperidinio) ethyl) -4-pyridinio) thiovinyl] -3-
1.8 g of cephem-4-carboxylic acid benzhydryl ester iodide was dissolved in 5.1 ml of chloroform.
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 treated with 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 column of a high-porous polymer Mitsubishi Diaion HP-21, and developed with water and then with water / acetonitrile. The fractions containing the target compound were collected, concentrated under reduced pressure, and lyophilized to give 0.273 g of 7-
[2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2-
The 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 = 4.8 Hz), 5.70 (1
H, dd, J = 4.8 Hz, 8.2 Hz), 6.63
(1H, d, J = 15.3 Hz), 6.65 (1H, d, J = 15.3 Hz)
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).

Embodiment 12

[0143]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -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 by adding 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
1), washed twice with water and twice with 10% saline, and the organic layer was dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure, and the residue was dissolved in 15 ml of chloroform. The resulting precipitate was collected by filtration, dried 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).

Embodiment 13

[0147]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (3-morpholinopropyl)
-4-pyridinio) thiovinyl] -3-cephem-4-
15 ml of methyl iodide was added to 1.36 g of carboxylic acid benzhydryl ester / trifluoromethanesulfonate, 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 = 17.4 Hz), 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).

Embodiment 14

[0151]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3
-Cephem-4-carboxylic acid benzhydryl ester
1.7 g of iodide was dissolved 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 treated with 7- [2-hydroxyimino-2-
(2-aminothiazol-4-yl) acetamide]-
0.53 g of 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 column of a high-porous polymer Mitsubishi Diaion HP-21, and developed with water and then with water / acetonitrile. The fractions containing the target compound were collected, concentrated under reduced pressure, and freeze-dried, and 0.112 g of 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- ( 1-
The 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 = 17.4 Hz), 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 = 15.4 Hz), 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).

Embodiment 15

[0155]

Embedded image

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 in anhydrous dimethylformamide (8.0 ml) and dissolved at room temperature.
Stirred for hours. After completion of the reaction, ethyl acetate (12
0 ml), washed three times with water and once with 10% saline, dried the organic layer over anhydrous magnesium sulfate, and distilled off the organic solvent under reduced pressure. Then, this was added to chloroform 8
The resulting precipitate was added dropwise to 80 ml of diisopropyl ether, and the resulting precipitate was collected by filtration and dried to give 7- [2
-Cyclopentyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -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 = 5.1 Hz), 5.7
5 (1H, dd, J = 5.1 Hz, 8.4 Hz);
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).

Embodiment 16

[0159]

Embedded image

7- [2-cyclopentyloxyimino-
2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester Acetonitrile, 1.42 g of trifluoromethanesulfonate.
After dissolving 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, the precipitate formed by dropping in diisopropyl ether was collected by filtration, dried and dried.
[2-Cyclopentyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-
[2- (1- (2-trimethylammonioethyl) -4
-Pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide (1.52 g) 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);
85-3.95 (2H, m), 4.18 (1H, d, J
= 17.0 Hz), 4.62 (1H, 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 (1H, s), 6.97 (1H,
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).

Embodiment 17

[0163]

Embedded image

7- [2-cyclopentyloxyimino-
2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-trimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydrido Dissolve 1.41 g of ester and iodide in 4.7 ml of chloroform.
3.1 ml of 8% formic acid and 0.268 ml of concentrated hydrochloric acid 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 7- [2-cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2-trimethylammonioethyl) -4- 0.57 g of a crude product of pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.
This crude product was dissolved in water, adsorbed on a column of a high-porous polymer Mitsubishi Diaion HP-21, and developed with water and then with water / acetonitrile. The 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);
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 = 5.1 Hz, 8.4)
Hz), 6.61 (1H, d, J = 15.3 Hz),
6.68 (1H, s), 7.22 (2H, brs),
7.41 (1H, d, J = 15.3 Hz), 8.09
(2H, d, J = 6.9 Hz), 8.95 (2H, d,
J = 6.9 Hz), 9.48 (1H, d, J = 8.4H)
z).

Embodiment 18

[0167]

Embedded image

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
From 7 g of dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate and 885 μl of iodoacetone, 7- [2-trityloxyimino-2- ( 2-tritylaminothiazole-4
3.51 g of -yl) acetamide] -3- [2- (1- (2-acetonyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester iodide 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 = 5.3 Hz, 8.
3Hz), 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).

Embodiment 19

[0171]

Embedded image

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
From 7 g of dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonate and 8.32 g of 2-bromoacetic acid benzhydryl ester, 7- [2- Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-
[2- (1- (2-benzhydryloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio)
2.61 g of thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / bromide were 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 = 5.1 Hz), 5.9
8 (1H, dd, J = 5.1 Hz, 8.3 Hz);
62 (1H, s), 6.90 (1H, s), 6.99
(1H, s), 7.0-7.6 (52H, m), 8.2
0 (2H, d, J = 6.6 Hz), 8.90 (2H, d, J = 6.6 Hz)
d, J = 6.6 Hz), 9.95 (1H, d, J = 8.
3 Hz).

Embodiment 20

[0175]

Embedded image

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
From 7 g of dimethylaminoethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester trifluoromethanesulfonate and 19 g of 2-iodoethanol, 7- [2-trityloxyimino-2] was obtained. -(2-tritylaminothiazole-
4-yl) acetamido] -3- [2- (1- (2-hydroxyethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester / iodide .21 g were 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).

Embodiment 21

[0179]

Embedded image

According to the method of Example 4, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-
From 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 = 7.2 Hz), 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 (1H, 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 = 7.0 Hz), 9.95 (1H,
d, J = 8.1 Hz).

Embodiment 22

[0183]

Embedded image

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

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 = 15.3 Hz),
6.62 (1H, s), 7.13 (2H, brs),
7.41 (1H, d, J = 15.3 Hz), 8.05
(2H, d, J = 6.9 Hz), 8.91 (2H, d,
J = 6.9 Hz), 9.43 (1H, d, J = 8.3H)
z), 11.5 (1H, s).

Embodiment 23

[0187]

Embedded image

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-
From 2.41 g of cephem-4-carboxylic acid benzhydryl ester / bromide, 7- [2-hydroxyimino-2-
(2-aminothiazol-4-yl) acetamide]-
289 m of 3- [2- (1- (2-carboxylatemethyl-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 = 5.1 Hz), 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).

Embodiment 24

[0191]

Embedded image

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 3.2 g to 7-
[2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -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 = 6.9 Hz), 9.00 (2
H, d, J = 6.9 Hz), 9.48 (1H, d, J =
8.3 Hz), 11.35 (1 H, s).

Embodiment 25

[0195]

Embedded image

According to the method of Example 3, 7- [2-trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2- (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) acetamido] -3- [2
-(1- (2-Ethyloxycarbonylmethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]
-3-Cephem-4-carboxylate chloride
0 mg was obtained.

¹ H-NMR (DMSO-d ₆ ) δpp
m; 1.23 (3H, t, J = 7.2 Hz), 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 = 15.0 Hz),
8.19 (2H, d, J = 7.0 Hz), 8.95 (2
H, d, J = 7.0 Hz), 9.48 (1H, d, J =
8.1 Hz), 11.32 (1H, s).

Embodiment 26

[0199]

Embedded image

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 by adding 11 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate.
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. 4
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 =
5.1Hz, 8.4Hz), 6.62 (1H, 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).

Embodiment 27

[0203]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-sulfoethyl-methylaminoethyl) -4-pyridinio) thiovinyl] -3-
Using 0.67 g of cephem-4-carboxylic acid benzhydryl ester / trifluoromethanesulfonate, the desired product 7- [2-trityloxyimino-2- (2-tritylaminothiazole-4) was obtained in the same manner as in Example 10. -Yl) acetamide] -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).

Embodiment 28

[0207]

Embedded image

7- [2-Trityloxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [2- (1- (2-sulfoethyl-dimethylammonioethyl) -4-pyridinio) thiovinyl]
Using 0.61 g of -3-cephem-4-carboxylic acid benzhydryl ester iodide, 7
-[2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2
-Sulfonateethyl-dimethylammonioethyl)-
0.15 g of 4-pyridinio) thiovinyl] -3-cephem-4-carboxylate was obtained.

¹ H-NMR (DMSO-d ₆ + D ₂ O)
δ ppm; 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 =
4.8 Hz), 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)
d, J = 7.1 Hz).

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Kenne Yamada 463 Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture Inside the Tokushima Research Laboratory, Otsuka Chemical Co., Ltd. Inside the Tokushima Research Laboratories of Chemical Co., Ltd. Taiho Pharmaceutical Co., Ltd. (56) References JP-A-59-130292 (JP, A) JP-A-55-154980 (JP, A) JP-A-61-246189 (JP, A) JP-A-61-165392 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 501/00-501/62 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. A compound of the general formula [Wherein Q represents CH . R ¹ represents a carboxylate or a carboxyl group. R ² is a hydrogen atom or lower cycloalkyl
Represents a alkyl group . R is a group Is shown. Here , m represents an integer of 1 to 5, Y represents a quaternary ammonium group, and 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. And a cephem carboxy-protected ester thereof and a non-toxic salt thereof. 2. 7- [2-hydroxyimino-2- (2
-Aminothiazol-4-yl) acetamido] -3-
[2- (1- (3- (4-methylmorpholinio) propyl) -4-pyridinio) thiovinyl] -3-cephem-
4-carboxylate chloride or a salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2-trimethylammonioethyl)- 4-pyridinio) thiovinyl]
-3-cephem-4-carboxylate chloride or a salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -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) acetamido] -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 a salt thereof, 7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (2- (1-methylpiperididiene) 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-carboxylatemethyl-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) acetamido] -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) acetamido] -3- [2- (1- (2-trimethylammonium) Oethyl) -4-pyridinio) thiovinyl] -3-cephem-4-carboxylate chloride or a salt thereof, and 7
-[2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- (sulfonateethyl-dimethylammonioethyl) -4-
At least one cephem compound selected from pyridinio) thiovinyl] -3-cephem-4-carboxylate or a salt thereof. 3. A compound of the general formula [Wherein R ⁴ represents a cephem carboxyl protecting group. R '
Is the group Is shown. Here, m 1, Y and B ⁻ are the same as above. And a compound represented by the general formula: [Wherein R ⁵ represents an amino group or a protected amino group.
R ⁶ represents an oxime protecting group or an R ^{2 ′} group (R ^{2 ′} group is an R ² group other than a hydrogen atom). Q is the same as above. Or a reactive derivative thereof, and, if necessary, removing a protecting group. Wherein Q, R ¹ , R ² and R are the same as above. And a method for producing the cephem carboxy-protected ester thereof and a non-toxic salt thereof. 4. A compound of the general formula Wherein R ⁴ , R ⁵ and R ⁶ are 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: Wherein m, Y and B ⁻ are the same as above. Wherein the compound represented by the general formula (1) is further reacted with a compound represented by the general formula: Wherein Q, R ¹ , R ² and R are the same as above. And a method for producing the cephem carboxy-protected ester thereof and a non-toxic salt thereof. 5. A compound of the general formula Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as above. To the compound represented by the general formula R ⁸ -SM wherein R ⁸ is a group Is shown . M represents a hydrogen atom or a metal atom. ] In the compound reacted represented, then the general formula Y- (CH _{2) m} -X [wherein X represents a halogen atom. m and Y are the same as above. Wherein the compound represented by the general formula (1) is further reacted with a compound represented by the general formula: Wherein Q, R ¹ , R ² and R are the same as above. And a method for producing the cephem carboxy-protected ester thereof and a non-toxic salt thereof. 6. A compound of the general formula Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as above. To the compound represented by the general formula: [In the formula , Z represents a tertiary amino group. m is the same as above
Same. And then reacting a compound represented by the general formula R ¹¹ -X wherein 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,
It represents a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group or a sulfo lower alkyl group.
X represents a halogen atom. Wherein the protecting group is removed as required. Wherein Q, R ¹ , R ² and R are the same as above. And a method for producing the cephem carboxy-protected ester thereof and a non-toxic salt thereof. 7. A compound of the general formula Wherein Q, R ¹ , R ² and R are the same as above. An antibacterial agent comprising a cephem compound represented by the formula (I), a protected cephem carboxy ester thereof and a non-toxic salt thereof, and a pharmaceutically acceptable carrier. 8. The antibacterial agent according to claim 7, which has a strong antibacterial activity against methicillin-resistant Staphylococcus aureus.