KR950001027B1 - Process for preparing cephalosporin derivatives - Google Patents

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Description

Process for preparing cephalosporin derivative

The present invention relates to a process for the preparation of novel cephalosporin derivatives.

Conventionally, compounds having 2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetamide groups in the side chain at the 7-position of the cephalosporin nucleus have been synthesized very much, and the compounds have been described. As a publicly available technique, for example, Japanese Patent Laid-Open Nos. 52-102293, 52-116592, 53-137988, 54-9296, 54-154786, 54-157596, 55-154980 Nos. 56-86187, 57-59895, 57-99592, 57-192394, and 58-174387, and the like. Gram-positive bacteria and Pseudomonas aeruginosa It also shows activity against Gram-negative bacteria resistant to cephalosporin-containing, suggesting that it has excellent antimicrobial activity and broad antimicrobial spectrum.

However, the antimicrobial activity of the compound is non-fermented Gram-negative bacillus such as Pseudomonas aeruginosa, Pseudomonas cepacia, Psedomonas maltophilia, and Acinetobacter calccoaceticus (Acinetobacter calccoaceticus). It is not sufficient for glucose non fermentative gram-negative rods.

Further, compounds having an isoquinoliniomethyl group at the 3-position of the cefe nucleus are disclosed in Japanese Patent Laid-Open Nos. 58-57386 and 59-130294. Japanese Patent Application Laid-Open No. 58-57386 discloses an unsubstituted or mono-substituted isoquinolinium derivative, and as a substituent of this isoquinoline nucleus, a number of substituents are exemplified, but when referring to hydroxyl groups, 5-hydroxy Carcass and 8-hydrobody are just synthesized. Further, Japanese Patent Laid-Open No. 59-130294 discloses that the isoquinoline nucleus may have one or more substituents. However, when referring to the hydroxyl group, only one 5-hydroxy is synthesized. The disclosure of the hydroxyl-substituted derivatives of the above-mentioned publication is only a general description, and particularly, the antimicrobial activity data of the compound substituted with the hydroxyl group is not exemplified at all. In addition, there is no disclosure or suggestion of the specification as well as the synthesis of the point having two receivers in the isoquinoline nucleus, in particular, the 6,7-dihydroxy body having adjacent hydroxyl groups.

In addition, 6,7-dibenzyloxyisoquinoline, 6,7-dimethoxyisoquinoline, etc. are mentioned as a compound of general formula (VIII) which is a raw material compound, The manufacturing method is the Journal of the American Chemical Society (Journal of the American Chemical Society, Vol. 79, p. 3773 (1957), J. Chem., Perkin.Trans, I. 2185 (1974), East 2190 (1974) and the like. However, isoquinoline derivatives which are intermediates of the compounds of the invention are novel compounds which are not described in the literature.

β-lactam antibiotics are selectively toxic only to bacteria and do not affect animal cells. Therefore, β-lactam antibiotics are antibiotics with few side effects and are widely used for the treatment of infections caused by bacteria, and thus have high usefulness.

Recently, however, glucose non-fermented Gram-negative bacillus, especially Pseudomonas aeruginosa, is often isolated as a bacillus bacterium of refractory infectious disease in patients with low immunity. Therefore, the development of antimicrobial agents with improved antimicrobial activity against these bacteria is desired.

The present invention provides a 6,7-dihydroxyisoquinoliniomethyl group or 6,7-diacetoxyisoquinoliniomethyl group at the 3-position of the cefe nucleus for the purpose of providing a novel cephalosporin derivative having excellent antibacterial activity. And a novel cephalosporin derivative having a 2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetamide group at the 7 position. As a result, the compounds of the present invention, when compared to unsubstituted or mono hydroxy substituted isoquinolinium derivatives, are Gram-negative bacteria, in particular Pseudomonas aeruginosa, Pseudomonas sefacia, Pseudomonas maltophilia and acinetobacter chalcaceceticus It has strong antimicrobial activity against non-glucose non-fermented Gram-negative bacillus, and the compound of the present invention shows excellent stability against β-lactamase and β-lactamase inducibility. The present invention was completed by discovering almost nothing.

That is, in the 3-position isoquinoliniomethyl group of the cefe nucleus, the compound of the present invention having a hydroxyl group or an acetoxy group at the 6-position and 7-position of the isoquinoline nucleus is a novel compound not described in the literature, in particular, Isoquinoline nuclei of unsubstituted or monohydroxy substituted compounds (Compounds of Reference Examples 1 and 2 are examples 57 and 36 of Japanese Patent Application Laid-Open No. 59-130294, and the compounds of Reference Examples 2 and 3 -57386, Examples 7 and 6, respectively.), Unexpectedly strong antimicrobial activity against resistant gram-negative bacteria, especially glucose non-fermented gram-negative bacilli containing Pseudomonas aeruginosa, and against β-lactamase. Excellent stability

Moreover, the isoquinoline derivative which is a starting material is a novel compound which is not described in the literature, and is useful as an intermediate raw material of the cephalosporin derivative which has the outstanding antibacterial effect.

The present invention provides a compound represented by the following general formula (I), a method for producing the same, and an antimicrobial agent containing an active ingredient of the compound of general formula (I), and a method of using the same:

(Wherein R represents a straight or branched lower alkyl group, lower alkenyl group, lower alkynyl group or cyclic lower alkyl group, which may be substituted with a carboxyl group, and R ¹ represents a hydrogen atom or an acetyl group) and an intermediate of the compound A novel compound represented by formula (VII), a salt thereof, and a process for preparing the compound are disclosed.

(Wherein R ⁶ represents a hydrogen atom or an alkanoyl group.)

Hereinafter, the symbols and terms described in the present specification will be described.

Substituent R of the compound of general formula (I) represents the linear or branched lower alkyl group, lower alkenyl group, lower alkynyl group, or cyclic lower alkyl group which may be substituted by the carboxyl group.

Substituent R ⁶ in the compound of formula (VII) represents a hydrogen atom or an alkanoyl group. Substituent R ⁷ of the compound of formula (VIII) is lower alkyl group, aralkyl group, aroyl group, lower alkoxycarbonyl group, or R ⁷ is bonded to each other to represent cyclic acetal, cyclic ketal or carbonate group, and is hydrolyzed or contacted. The hydroxyl protecting group which can be removed by reduction is shown.

A straight or branched alkyl group represents an alkyl group having 1 to 6 carbon atoms, and is methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group , n-hexyl group, and the like, and particularly preferred examples thereof include methyl group, ethyl group, n-propyl group and isopropyl group.

The lower alkenyl group represents an alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include vinyl group, allyl group, isopropenyl group, 1, 1-dimethylallyl group, 2-butenyl group, and 3-butenyl group.

Lower alkynyl group represents a C2-C3 alkynyl group, and an ethynyl group, 2-propynyl group, etc. are mentioned specifically ,.

The cyclic lower alkyl group represents a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclonuxyl group, and the like, and in particular, a cyclopropyl group, cyclobutyl group, and cyclo Pentyl groups are preferred.

Preferred examples of the substituent R which may be substituted with a carboxyl group include a carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxy-1-cyclopropyl group, 1-carboxy-1-cyclobutyl group and 1-carboxy-1- Cyclopentyl group, 1-carboxyvinyl group, 2-carboxyvinyl group, 1-carboxyallyl group, 2-carboxyallyl group, 1-carboxymethylvinyl group, 2-carboxyethynyl group, 1-carboxy-2-propynyl group And 3-carboxy-2-propynyl group.

An aralkyl group represents a benzyl group, p-methoxybenzyl group, phenethyl group, etc.

An alkanoyl group is an acetyl group, propionyl group, butyryl group, etc., and especially an acetyl group is preferable.

An aroyl group represents a benzoyl group, toluoyl group, etc.

Lower alkoxycarbonyl group refers to a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group and the like having 2 to 5 carbon atoms, and particularly preferred examples thereof include methoxycarbonyl group and ethoxycarbonyl group. have.

Cyclic acetal refers to methylene acetal, ethylene acetal and the like. Converted ketal represents isopropylidene ketal and the like.

Intermediate raw materials of the cephalosporin derivatives represented by 6,7-dihydroxyisoindolin and 6,7-diacetoxyisoindolin are novel compounds not described in the literature, and are 6,7- at the 3 position of the cephem nucleus. The cephalosporin derivative having a dihydroxyisoquinoliniomethyl group or a 6,7-diacetoxyisoquinolinio methyl group is not synthesized.

The structure of the compounds of the general formulas (I), (II) and (IV) having a 6,7-dihydroxyisoquinoliniomethyl group at the 3-position of the cefe nucleus requires attention to the following points.

In the compounds of the formulas (I), (II) and (VI), the structure of the 6,7-dihydroxyisoquinolini group is described in the present specification for the convenience of the following structural formula (A):

Structural formula (A) has tautomers attributable to the 6,7-dihydroxyisoquinoline nucleus and can be represented by structural formula (A '):

That is, the compounds represented by Structural Formula (A) and Structural Formula (A ') are in a tautomeric equilibrium state that can vary with each other depending on the state of the compound (for example, solid or solution), the kind of solvent, liquidity, temperature, and the like. . Therefore, it is natural that both tautomers fall within the scope of the present invention.

에는 신(syn)-이성체(Z배치 :

) 및 안티(anti)-이성체(E배치 :

)가 존재하며, 일반적으로 신-이성체가 뛰어난 향균 활성을 나타내며, 본 명세서에 있어서도 OR기는 모두 신-이성체이다. E/Z명명법은 저널 오브 디 아메리칸 케미칼 소사이어티(Journal of The American Society), 제 90권, 제 509면(1968년)에 기재되어 있다.Moreover, in the oxyimino group of general formula (I), it is partial structure

There is a syn-isomer (Z):

) And anti-isomers (E arrangement:

), The neo-isomer generally shows excellent antibacterial activity, and even in this specification, all OR groups are neo-isomers. E / Z nomenclature is described in the Journal of The American Society, Vol. 90, p. 509 (1968).

The compound of general formula (I) can be made into the nontoxic salt or the physiologically hydrolysable nontoxic ester by the general method.

Non-toxic salts of the compound of general formula (I) mean pharmaceutically acceptable conventional, carboxyl group at position 4 of the cefe nucleus, carboxyl group substituted at the position R of position 7 at cefe nucleus, or 2-position at position 7 of cefe nucleus. The salt in an aminothiazole group is mentioned.

Organic amine salts such as N, N-dibenzylethylenediamine, procaine, metal salts such as sodium, potassium, calcium, magnesium, aluminum, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, acetic acid, lactic acid, propionic acid, Organic acid salts such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and the like, sulfonic acid salts such as methane sulfonic acid, acethionic acid, p-toluene sulfonic acid, and the like, and amino acid salts such as glutamic acid, aspartic acid, lysine and arginine.

The nontoxic ester of the general formula (I) means a pharmaceutically acceptable conventional one in the 4-position carboxyl group of the cefe nucleus, and includes an alkanoyloxymethyl group such as acetoxymethyl group and pivaloyloxymethyl group; Alkoxycarbonyloxyalkyl groups such as 1- (ethoxycarbonyloxy) ethyl group; Phthalidyl group; And 5-substituted 2-oxo-1, 3-dioxol-4-ylmethyl groups such as 5-methyl-2-oxo-1, 3-dioxol-4-ylmethyl group and the like.

The compound of general formula (VII) can be made into the salt by the general method. Salts of the compounds of general formula (VII) include inorganic acid salts such as acetates, hydrochlorides, hydrobromide salts, sulfates, nitrates and perchlorates, organic sulfonate salts such as methanesulfonate, p-toluenesulfonate, and hydrates thereof. have. In addition, the vitreous body can be prepared by suspending or dissolving in these salts in water and neutralizing it with an alkali metal carbonate such as sodium hydrogen carbonate, alkali metal carbonate such as potassium carbonate, alkali metal hydroxide such as sodium hydroxide, or an aqueous ammonia solution. .

The manufacturing method of the compound of this invention is demonstrated below.

The compound of general formula (I) can be manufactured also by any method of the manufacturing method A or the manufacturing method B shown below.

[Manufacturing Method A]

By reacting the compound represented by the following general formula (IV) or its salt with the compound represented by the following general formula (III), the compound represented by the following general formula (II) is produced, This compound is reduced and / or a protecting group as needed. Compound (I) of the present invention can be prepared by removing.

는 음이온을 나타내며, Y는 S 또는 SO를 나타낸다.Wherein R ² represents a straight or branched lower alkyl group, lower alkenyl group, lower alkynyl group or cyclic lower alkyl group which may be substituted with a protected carboxyl group, R ³ represents a hydrogen atom or a carboxyl-protecting group, and R ⁴ Is a hydrogen atom or an amino-protecting group, R ⁵ is a protecting group of a hydrogen atom or hydroxyl group, X represents a leaving group, X

Represents an anion and Y represents S or SO.

X in general formula (IV) represents a leaving group, and specifically, halogen atoms, such as chlorine, bromine, and iodine, or an acetoxy group, a carbamoyloxy group, a trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc. A bromine atom, an iodine atom, and an acetoxy group are especially preferable.

6,7-dihydroxyisoquinoline and 6,7-diacetoxyisoquinoline represented by general formula (III) are novel compounds, and the hydroxyl group may be protected.

[Manufacturing Method B]

The compound represented by the following general formula (VI) or its salt is acylated by the compound represented by the following general formula (V), or its reactive derivative, and the compound represented by the following general formula (II) is produced, This compound is needed as needed. Compound (I) of the present invention can be prepared by removing reducing and / or protecting groups.

(Wherein among, R ² denotes a mubang optionally substituted by a protected carboxyl group with linear or branched lower alkyl group, lower alkenyl group, lower alkynyl-lower alkyl group or cyclic, R ³ is a hydrogen atom or a carboxyl-represents a protecting group, R ⁴ represents a hydrogen atom or an amino-protecting group, R ⁵ represents a protecting group of a hydrogen atom or a hydroxyl group, X (scan) is an anion, and Y represents S or SO.)

The compound of the present invention wherein R ¹ is an acetyl group has a substitution reaction of 6,7-diacetoxyisoquinoline (III) or a salt thereof and a compound represented by formula (IV) or a salt thereof, wherein R ⁵ is an acetyl group, or R ⁵ is an acetyl group to give 7-amino-3- (6,7-diacetoxy-isoquinolinium no) compound represented by the methyl-3-cephem-4-carboxylic acid derivative (VI) or a salt thereof with the general formula (V) Or a compound represented by the general formula (II) by acylation with a reactive derivative thereof, and prepared by removing a reducing and / or protecting group, if necessary, or a compound of the present invention wherein R ¹ is a hydrogen atom. It can be prepared by selectively acetylating (I) under appropriate conditions.

The manufacturing method A and the manufacturing method B of the compound (I) of this invention are explained in full detail below.

[Manufacturing Method A]

The reaction of the compound of formula (IV) with the 6,7-disubstituted isoquinoline derivative of formula (III) is, for example, methylene chloride, chloroform, ether. It can be performed in organic solvents such as ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. As the disubstituted isoquinoline derivative of the general formula (III), acid addition salts such as hydrochloride, hydrobromide sulfate, nitrate, formate, acetate and the like can also be used. The reaction at this time is carried out in the presence of deoxidizing agents such as triethylamine, diisopropylethylamine, N, N-dimethylaniline, and N-methylmorpholine, for example, in neutralized amounts. Moreover, the disubstituted isoquinoline derivative of general formula (III) can also be used by silicifying with silylating agents, such as N, O-bis (trimethylsilyl) acetamide. The reaction is carried out using 1 to 2 moles of the disubstituted isoquinoline derivative of the general formula (III) per 1 mole of the compound of the general formula (IV), and the reaction temperature and the reaction time are 0.5 to 5 hours at 0 to 40 ° C.

Moreover, reaction of the compound whose general formula (IV) X is an acetoxy group, and the disubstituted isoquinoline derivative of general formula (III) is water, a phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetra, for example. It can be performed in a solvent such as hydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. It is preferable to perform reaction in neutral vicinity, reaction temperature is room temperature to 90 degreeC, and reaction time is 1 to 10 hours. Moreover, this reaction is accelerated by performing in presence of iodide, such as sodium iodide and potassium iodide, and thiocyanate, such as sodium thiocyanate and potassium thiocyanate.

Ammonio compound (II) having a group Y of SO can reduce sulfoxide groups according to the methods described in The Journal of Organic Chemistry, Volume 35, page 2430 (1974), and the like. . That is, the ammonium compound (II) having Y of 50 is reacted for 1 to 5 hours by dropwise addition of acetyl chloride at -40 to 0 ° C in the presence of sodium iodide or potassium iodide in acetone solvent, or of general formula (II) ) Compound can be reduced by dropping phosphorus trichloride at -40 to 0 ° C in a solvent such as N, N-dimethylformamide and reacting for 1 to 5 hours. The reaction uses 3.5-10 mol of iodide and 1.5-5 mol of acetyl chloride or 2-6 mol of phosphorus trichloride based on 1 mol of compound (II) in which group Y is SO.

Compound (I) of the present invention can be prepared by removing a protecting group from the compound of formula (II) wherein the group Y is S, if necessary.

In the above general formula, as the protecting group of the carboxyl group, the amino group and the hydroxyl group, a protecting group usually used in the field of β-lactam synthesis can be arbitrarily selected and used.

The method of introducing and removing a protecting group depends on the type of protecting group, for example, Protective Groups in Organic Synthesis by TWGreen, published by Wiley (1981). Or by a method described in the Protective Groups in Organic Chemistry of JFWMcomie, published by Plenum Press (1973). I can do it.

Examples of the carboxyl protecting group include t-butyl group, 2, 2, 2-trimoloethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group and 1-propionyl Oxyethyl group, 1- (ethoxycarbonyloxy) ethyl group, phthalidyl group, benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis ( 4-methoxyphenyl) methyl group, 5-methyl-2-oxo-1, 3-dioxol-4-yl methyl group, trimethylsilyl group, t-butyldimethylsilyl group, and the like, in particular benzhydryl group, t-butyl group, a silyl group, etc. are preferable.

Examples of the protecting group for the amino group include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, t-butoxycarbonyl group, trimethylsilyl group, t-butylmethylsilyl group and the like.

As a protecting group of a hydroxyl group, 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, t-butyl group, benzyl group, 4-nitrobenzyl group, acetyl, for example Cyclic acetals such as methylene acetal and ethylene acetal formed by group, 2, 2, 2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group, or a protecting group bonded to each other; For example, cyclic ketals, such as isopropylidene ketal, cyclic carbonate, etc. are mentioned.

The removal method of a protecting group is explained concretely. For example, the removal of protecting groups, such as a trityl group, a polyamyl group, t-butoxycarbonyl group, benzhydryl group, t-butyl group, 2-methoxyethoxymethyl group, is mentioned, for example. For example, inorganic acids, organic acids, such as hydrochloric acid, formic acid, trifluoroacetic acid, benzene sulfonic acid, and p-toluene sulfonic acid, etc. can be performed, and especially trifluoroacetic acid is preferable.

When trifluoroacetic acid is used as the acid, the reaction is accelerated by adding anisole, thioanisole or phenol, and side reactions are suppressed.

The reaction can also be carried out in a solvent that is not involved in the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, or a mixed solvent thereof. The reaction temperature and reaction time are arbitrarily selected according to the chemical properties of the compound (II) and the compound (I) of the present invention and the kind of the protecting group, and are particularly preferably carried out under ice-cooling or warming conditions.

Moreover, the compound of this invention whose R <^1> is a hydrogen atom is described, for example in Unexamined-Japanese-Patent No. 57-200393 (Eur. Pat. Appln., 66373 (1982); Chem. Abstr., 98-197884u (1983). It can manufacture according to the method of description.

Moreover, it can also manufacture by treating the compound of this invention whose R <^1> is an acetyl group by alkali hydrolysis or an acylase.

The raw material compound (IV) of the manufacturing method A can be manufactured as follows.

Compounds of general formula (IV) wherein the group Y is S are 7-amino-3-chloromethyl-3-cepem-4-carboxylic acid derivatives [for example, Japanese Patent Laid-Open Nos. 50-76089, 56-86187; Gazette or The Journal of Antibiotics, Vol. 38, synthesized according to the method of p. 1738 (1985), 7-aminocephalosporonic acid or its esters (V) Can be prepared by reacting a compound or a reactive derivative thereof (e.g., acid hologenated moles, mixed acid anhydrides, active esters, and the like).

A compound of formula (IV) wherein group Y is SO is a compound of formula (IV) wherein group Y is S according to the method described in Journal of Organic Chemistry, Vol. 35, p. 2430 (1970). In-chloroperbenzoic acid, hydrogen peroxide or metaperiodic acid of animals in ice-cold or at room temperature in organic solvents not involved in the reaction, for example methylene chloride, ethylene chloride, chloroform, ether, acetic acid, etc. It can be prepared by oxidation.

Compounds of formula (IV) wherein group X is an iodine atom are described, for example, in Japanese Patent Application Laid-Open No. 51-27679 or Synthetic Communications, Vol. 16, pp. 1029-1035 (1986). According to the method, a compound of the general formula (IV) in which the group X is a chlorine atom, for example, is formed of an organic solvent such as acetone, N, N-dimethylformamide, or water in the presence of a correlation transfer catalyst. In the layer system, the group X is prepared by reacting with an iodide such as sodium iodide under ice-cooling to room temperature, or in accordance with the method described in Tetrarahedon Letters, Vol. 22, p. 3915 (1981). Compound (IV) which is an acetoxy group is, for example, methylene chloride, chloroform, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. During It may also be prepared by the action of iodotrimethylsilane, and may be used for the following reaction without isolation or isolation.

6,7-disubstituted isoquinoline of formula (III) is 6,7-dimethoxyisoquinoline [Journal of The American Chemical Society, Vol. 79, p. 3773 (1957); J. Chem. Soc. Perkin Trans. I, p. 2185 (1974); Synthesis according to the method of page 2190 (1974)], or by catalytic reduction of 6,7-bis (benzyloxy) isoquinoline.

2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetic acid derivatives of general formula (V) are described in Chemical and Pharmaceutical Bulletin, Vol. 25, 3115-3119. 2- (2-aminothiazol-4-yl) glyoxylic acid derivative or 2- (2-aminothiazole-4) according to the method described in Cotton (1977), Japanese Chemical Society Nos. 785 to 801 (1981), and the like. -Yl) -2-hydroxyiminoacetic acid ester derivative can be used.

[Manufacturing Method B]

Compounds of formula (II) include compounds of formula (VI) such as water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethylene chloride, benzene, ethyl acetate, N, N- In a solvent that does not affect the reaction, such as dimethylformamide, dimethyl sulfoxide, or the like, or a mixed solvent thereof, a compound of formula (V) or a reactive derivative thereof (e.g., acid halides, mixture anhydrides, active esters, etc.) It can be prepared by reacting.

Reaction uses 1-1.5 mol of compounds of general formula (V) or its reactive derivative with respect to 1 mol of compounds of general formula (VI), and reaction temperature is -40-40 degreeC.

When using an acid halide as a reactive derivative of general formula (V), it is preferable to carry out in presence of deoxidizer, such as triethylamine, N-methylmorpholine, N, N- dimethylaniline, pyridine, for example.

The acid halide formation reaction comprises 1 to 10 moles of halogenating agents such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, and phosgene with respect to 1 mole of the compound (V). 1 to 1.5 mol is used, the reaction temperature is -40 to 100 ℃, preferably -20 to 20 ℃, the reaction time is terminated for 10 to 120 minutes.

The mixed acid anhydride formation reaction is carried out with respect to 1 mole of compound (V), for example, 1 to 1.2 moles of deoxidizing agents such as triethylamine, N-methylformoline, N, N-dimethylaniline, pyridine and methyl, for example. 1 to 1.2 moles of chloroformates such as chloroformate, ethylchloroformate and isobutylchloroformate are used, the reaction temperature is -40 to 20 ° C, preferably -20 to 5 ° C, and the reaction time is 10 It is -60 minutes.

The active ester formation reaction can be carried out with an N-hydroxy compound (e.g., N-hydroxysuccinic acid imide, 1-hydroxybenzotriazole, etc.) or a phenol compound (e.g., 4) per mole of compound (V). -Nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, etc.) to 1 to 1.2 and N, N'-dicyclohexylcarbodiimide to 1 to 1.4 mol, and the reaction temperature is At -10 to 50C, the reaction time is 0.5 to 2 hours.

In the acylation reaction, when the compound of the general formula (V) is used in the form of a free acid, carbodiimides such as N, N'-dicyclohexyl carbodiimide and N, N- which are oxychlorides Compounds of formula (II) can be prepared in the presence of a condensing agent such as dimethylformamide, phosphorus oxychloride adduct. Preparation of the compound (1) of this invention from the compound of general formula (II) is the same as that of the said preparation method A.

The raw material compound (VI) of the manufacturing method B can be manufactured by the method as described in Cephalosporins and Penicillins of the Flenton Academic Press, pages 151-171 (1972), etc. . For example, 7-acylamino-3-halomethyl-3-cepem-4-carboxylic acid derivative (synthesized according to the method of Japanese Patent Laid-Open No. 58-72590, 58-154588) or 7-acyl 6,7-disubstituted isoquinoline of general formula (III) is made to react with an amino cephalosporranic acid derivative, and the compound represented by the following general formula can be manufactured, and then deacylated can be manufactured.

는 음이온을 나타내며, R⁶는 아실기를 나타낸다).(Wherein R ³ is a hydrogen atom or a carboxyl protecting group, R ⁵ is a protecting group of a hydrogen atom or a hydroxyl group, Y is S or SO, and X is

Represents an anion and R ⁶ represents an acyl group).

The deacylation reaction is already known in the art, and in the compound represented by the above general formula, when R ⁶ is, for example, a phenyl acetyl group, a phenoxy acetyl group or an amino adipyl group, Japanese Patent Application No. 49-20319 It can remove according to the method as described in a publication. For example, this compound may be used in benzene, toluene, ethyl acetate, methylene chloride, ethylene chloride or a mixed solvent thereof, such as N, N-dimethylaniline, pyridine, triethylamine, sodium bicarbonate or potassium bicarbonate In the presence of a deoxidizing agent, reacted with phosphorus pentachloride or phosphorus oxychloride at -80 to 50 ° C, preferably at -65 to 0 ° C for 0.5 to 2 hours, for example, lower levels such as methanol, ethanol and propanol. The R ⁶ group can be prepared by treating with alcohol and then hydrolyzing.

In addition, removal of the said phenyl acetyl group, phenoxy acetyl group, or amino adipyl is carried out by the method of Japanese Patent Application No. 61-291431 by the present inventors, ie, water or water and an organic solvent, for example, acetone, acetonitrile. , Penicillin G acylase or immobilized penicillin G acylase at pH 7-8, preferably pH 7.5-7.8 at room temperature in a mixed solvent with methanol, ethanol, tetrahydrofuran and the like. The reaction is preferably carried out by adding a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, tripropylamine or pyridine, and keeping the pH constant.

The manufacturing method of the compound (i) of this invention is demonstrated below.

The compound of this invention can be manufactured by removing the protecting group R <^7> of the hydroxyl group of the compound represented by the following general formula (i), or its salt, and acylating as needed.

[Wherein, R ⁷ represents a protecting group of a hydroxyl group (except where R is an alkanoyl group).

The removal method of the protecting group of a hydroxyl group can be performed according to the method described in the cited literature etc. in description of the manufacturing method of the compound (1) of this invention. As a protecting group of especially preferable hydroxyl group, the methyl group, benzyl group, methylene acetyl group, ethoxycarbonyl group, and carbonate group which can be easily removed by acid hydrolysis or a catalytic reduction are preferable, for example.

(1) Production method by acid hydrolysis

A solution of the compound of general formula (II) 1-10 times, preferably 5-10 times acetic acid and 3-10 times, preferably 5-10 times hydrobromic acid, at 80-120 ° C. in a nitrogen stream, Compounds of the invention can be prepared by bubbling 2-3 hours, cooling and / or concentrating, and then acylating if necessary.

(2) Manufacturing method by contact reduction

The compound of formula (II) is dissolved in water, methanol, ethanol, propanol, isopropanol, acetic acid, aqueous hydrochloric acid solution, aqueous hydrobromic acid solution, sulfuric acid solution or a mixture thereof, and 5-10% palladium carbon is dissolved in general formula (II). 5 to 20% by weight of the compound of, preferably 5 to 10% by weight, the reaction temperature is 20 to 80 ℃, the reaction time is reduced by 2 to 10 hours, and the compound of the present invention by acylating if necessary You can do it.

The acylation reaction can be carried out without isolation or isolation of the product (6,7-dihydroxyisoquinoline or salt thereof) by acid hydrolysis or catalytic reduction.

The acylation reaction is carried out by the catalytic amount or excess Lewis acid in a solvent such as 6,7-dihydroxyisoquinoline or a salt thereof that does not adversely affect the reaction, for example, acetic acid, prefluoroacetic acid and the like. 2 to 3 equivalents of an excess of mixed acid anhydride in the presence of 0.5 to 48 hours at a reaction temperature of 0 to 80 DEG C or acetone, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. It is carried out by reacting with 2 to 2.5 equivalents of acid halide or mixed acid anhydride in the presence of a deoxidizer at a reaction temperature of 0 to 50 ° C. for 0.5 to 10 hours.

After completion of the reaction, known separation means such as solvent extraction, recrystallization, chromatography and the like can be performed to isolate and purify the compound (I) or salt thereof of the present invention from the reaction solution.

Examples of the Lewis acid include trifluoroacetic acid, methanesulfonic acid, p-toluene sulfonic acid, hydrochloric acid, sulfuric acid, boron trifluoride and the like.

As the deoxidizer, for example, alkali metal salts such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium oxide, triethylamine, ethyldiisopropylamine, N-methyl morpholine, pyridine, N, N-dimethylaniline Organic amines, such as these, are mentioned.

Examples of the mixed acid anhydride include acetic anhydride, propionic anhydride and butyric anhydride.

Acid halides include acetyl chloride, propionyl chloride, butyryl chloride.

The compound of the general formula can be produced according to the method described in Journal of the American Chemical Society, Vol. 79, p. 3773 (1957), p. 2190 (1974), and the like.

Subsequently, the in vitro antimicrobial activity against various bacteria of the compound of the present invention was measured by the following agar plate dilution method. In Mueller Hinton broth, platinum (inoculated bacteria amount: 10 ⁶ CFU / ml) of each test strain cultured overnight was inoculated in Muller Hinton agar. The medium contained antibacterial agents at each concentration, and after incubating at 37 ° C. for 16 hours, the minimum growth inhibitory concentration (MIC: μg / ml) was measured. Cefotaxime, ceftazidime and the compounds of Reference Examples 1 to 4 were used as comparative compounds. The results are shown in the following table.

The compounds of the present invention showed excellent antimicrobial activity against gram negative bacteria of susceptibility and resistance, in particular against glucose non-fermenting Gram negative bacillus, such as Pseudomonas aeruginosa Pseudomonas sefacia, Pseudomonas maltophilia, and Acinetobacter caloaceticus.

In addition, the β-lactamase inducing ability of Enterobacter cloacae GN5797 was measured in the compound of Example 4, and the β-lactamase inducing ability was hardly observed.

β-lactamase induction assay

10 ml of Muller Hinton Broth is inoculated with GN5797 to the test bacterium Enterobacter Chloka and shaken overnight at 37 ° C. The solution is diluted 10 times with Muller Hinton Broth, mixed, and then divided into L-shaped tubes by 20 ml. After shaking for 2 hours at 37 ° C, 1 ml of each concentration of drug (final concentration: 501 µg / ml, 101 µg / ml, 11 µg / ml) is added aseptically. After adding the drug, 5 ml samples are taken from each L-shaped tube every hour, and 0.1 ml of 50 mM sodium azide aqueous solution is added thereto, followed by centrifugation (5500 G) at 4 ° C. for 10 minutes to collect. The supernatant was discarded and dispersed by adding 5 ml of 50 mM phosphate buffer (pH 7.0) and sonicated under ice-cooling. The solution is centrifuged (16500 G) for 40 minutes at 4 ° C, and the μ-lactamase activity of the upper layer is measured. β-lactamase activity was determined by spectroscopic method using 100 μM of cephaloridine as a substrate [Antimicrob. Agents Chemother. 17: 355-358 (1980)]. Protein measurement is performed by the Pauline method (J. Biol. Chem. 193, 265-275 (1951)) using a phenol reagent.

Β-lactamase inducing ability measurement results for Enterobacter cloaca GN5797

(Cefalolidin 100βM is used as a substrate.)

Thus, the compounds of formula (I), their nontoxic salts and the physiologically hydrolyzable nontoxic esters are useful as antibacterial agents.

The compounds of the present invention can be mixed with carriers of solid or liquid excipients known in the art to be used in the form of pharmaceutical preparations suitable for parenteral, oral or external application. Examples of the medicinal preparations include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, external preparations such as ointments and suppositories. Moreover, these formulations may contain additives normally used, such as adjuvant, stabilizer, wetting agent, emulsifier, absorption accelerator, surfactant, etc. as needed. Examples of the additive include distilled water for injection, ring gel solution, glucose, sucrose syrup, gelatin, cooking oil, cacao fat, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like.

In addition, the compound of the present invention is an antimicrobial agent, especially those whose gram-negative bacteria contain non-fermented gram-negative bacteria such as Pseudomonas aeruginosa, Pseudomonas sefacia, Pseudomonas maltophilia, and Acinetobacter chalcoaceticus as base bacteria. It can be used for treatment during bacterial infection. The dosage varies depending on the age and sex of the patient, but is usually used in the range of 1 to 100 mg / kg per day, and preferably divided into 2 to 5 times at 1 to 50 mg / kg per day.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1

7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetoamide] -3- (6,7-dihydroxyiminolinio) methyl-3-cepem-4-car Preparation of Cylates (New-Isomers)

(A) 6.35 ml (68 mmol) of phosphorus oxychloride is added to 20 ml of anhydrous ethyl acetate, and 5.28 ml (68 mmol) of N, N-dimethylformamide is added dropwise at 0 ° C, followed by stirring at the same temperature for 15 minutes. To this solution was added 180 ml of anhydrous methylene chloride, 25.2 g (57 mmol) of 2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (new isomer) at 0 ° C was added for 30 minutes. Stir. Subsequently, 23.6 g (57 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cepem-4-carboxylate is added to this solution, and the mixture is stirred at 0 ° C for 2 hours. The reaction solution is adjusted to pH 7.0 and filtered to collect insoluble matter. The filtrate was washed sequentially with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 3-chloromethyl-7- [2-methoxyimino-2- (2- 44.5 g (99% yield) of tritylaminothiazol-4-yl) acetamide] -3-cefe-4-carboxylate (new-isomer) were obtained.

IR (KBr) cm ^-1 : 1780, 1720, 1670, 1520

NMR (DMSO-d ₆ ) δ: 3.67 (2H, br s), 3.85 (3H, s), 4.45 (2H, br s), 5.25 (1H, d, J = 4.5Hz), 5.80 (1H, m) 6.77 (1H, s), 7.00 (1H, s), 7.10-7.70 (25H, m), 8.80 (1H, m), 9.60 (1H, m).

(B) 2.5 g (2.97 mmol) of the compound obtained in (A) was dissolved in 25 ml of benzene, 640 mg (3.27 mmol) of m-chloroperbenzoic acid was added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with 5% aqueous sodium sulfite solution and saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a powdered benzhydryl 3-chloronetyl-7- [2- Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate 1-oxide (new-isomer) was obtained.

NMR (CDCl ₃ ) δ: 3.25 and 3.70 (2H, ABq, J-18 Hz), 4.03 (3H, s), 4.13 and 4.70 (2H, ABq, J = 12 Hz), 4.47 (1H, d, J = 5 Hz) , 6.07 (1H, dd, J = 5 and 9 Hz), 6.67 (1H, s), 6.92 (1H.s), 7.30 (27H, m).

(C) The compound obtained in (B) was dissolved in 50 ml of acetone, and 670 mg (4.47 mmol) of sodium iodide was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution, water and saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a powdered benzhydryl 3-iodine-7. -[2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate 1-oxide (new-isomer) was obtained.

IR (KBr) cm ^-1 : 1790, 1720, 1680, 1510, 1370, 1290, 1230, 1160, 1040

NMR (CDCl ₃ ) δ: 3.40 and 3.68 (2H, ABq, J = 18 Hz), 4.03 (3H, s), 4.48 (1H, d, J = 5 Hz), 6.00 (1H, dd, J = 5 and 9 Hz) , 6.67 (1 H, s), 6.95 (1 H, s), 7.30 (27 H, m).

(D) 1.0 g (1.1 mmol) of the compound obtained in the above (C) and 6,7-dihydroxyisoquinoline, hydrobromide, 300 mg (1.15 mmol) of monohydrate were added to 5 ml of anhydrous N, N-dimethylformamide. It is dissolved, 0.17 ml (1.2 mmol) of triethylamine is added dropwise at room temperature, followed by stirring at the same temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue is extracted with chloroform. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 3- (6,7-dihydroxyisoquinolinio) methyl-7- [2-methoxyimino-2- 1.0 g (yield 85%) of (2-tritylamino thiazol-4-yl) acetamide] -3-cepem-4-carboxylate 1-oxide, iodide (new-isomer) was obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1670, 1630, 1520

NMR (DMSO-d ₆ ) δ: 3.50 to 4.10 (2H, m), 3.82 (3H, s), 5.10 (1H, m) 5.40 (2H, m), 5.95 (1H, m), 6.80 (1H, s ), 7.00 (1H, s), 7.05-8.30 (29H, m), 9.03 (1H, s).

(E) 1.0 g (0.9 mmol) of the compound obtained in (D) and 1.5 g (9.0 mmol) of potassium iodide were suspended in 20 ml of anhydrous acetone, and 0.32 ml (4.5 mmol) of acetyl chloride was added dropwise at -20 ° C. Stir at -10 ° C for 3 hours. The reaction solution is poured into 100 ml of an aqueous 2% sodium metabisulfite solution, filtered and the precipitate is collected and washed with water. The precipitate was dissolved in chloroform, washed with saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 3- (6,7-dihydroxy dlthznlshfflsldh) apxlf-7- [2-apxhrtldlalsh-2- 1.0 g (yield 85%) of (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate, iodide (new-isomer) was obtained.

IR (KBr) cm ^-1 : 1790, 1730, 1680, 1530

NMR (DMSO-d ₆ ) δ: 3.55 (2H, m), 3.80 (3H, s), 5.25 (1H, d, J = 4.5Hz) 5.50 (2H, m), 5.85 (1H, m), 6.70 ( 1H, s), 6.95 (1H, s), 7.00-7.80 (26H, m), 8.75 (1H, m), 9.50 (2H, m).

(F) 0.9 g (0.82 mmol) of the compound obtained in the above (E) was dissolved in 7 ml of anhydrous methylene chloride, 1 ml of anisole was added, and 7 ml of trifluoroacetic acid was added dropwise at 0 ° C. The reaction solution was stirred at the same temperature for 2 hours, concentrated under reduced pressure, ether was added to the residue, and the precipitate was collected by filtration. The precipitate was dissolved in 200 ml of water, the insoluble substance was filtered off, and then reverse phase column chromatography (LC-Sorb RP = 18: Chemco) was used to concentrate the elution fraction (4% aqueous tetrahydrofuran solution) containing the target substance. Lyophilization gave 105 mg (23%) of the title compound.

MP: 180 ° C (decomposition)

IR (KBr) cm ^-1 : 1770, 1620, 1540, 1440

NMR (DMSO-d ₆ ) δ: 3.00 to 3.70 (2H, m), 3.78 (3H, s), 5.13 (1H, d, J = 4.5 Hz) 5.72 (3H, m), 6.70 (1H, s), 7.20 (1 H, s), 7.50 (1 H, s), 7.80 (1 H, m), 8.40 (1 H, m), 9.35 (1 H, br s), 9.50 (1 H, m).

Example 2

7- [2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4 Preparation of Carboxylate (New-Isomer)

(A) 0.41 ml (4.4 mmol) of phosphorus oxychloride is added to 5 ml of ethyl acetate, and 0.35 ml (4.5 mmol) of N, N-dimethylformamide is added dropwise under ice cooling, followed by stirring at room temperature for 15 minutes. To the solution was added 20 ml of a methylene chloride solution containing 1.59 g (3.38 mmol) of 2-isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (new isomer) under ice-cooling and 30 minutes Stir. Benzhydryl 7-amino-3-chloromethyl-3-cepem-4-carboxylate 1.4g (3.37mmol) was added to the reaction solution under ice cooling, and it stirred for 2 hours. 50 ml of ethyl acetate and 20 ml of water are added to the reaction solution, the pH is adjusted to 7.0 using 5 N aqueous sodium hydroxide solution, and then the organic layer is separated and washed sequentially with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the oily residue was purified by silica gel column chromatography (Wakogel C-300: 5% ethyl acetate, benzine) to yield benzhydryl 3-chloromethyl-7-. 1.94 g (yield 66%) of [2-isopropoxyamino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate (new-isomer) were obtained It became.

NMR (CDCl ₃ ) δ: 1.32 (6H, d, J = 6Hz), 3.55 (2H, ABq, J = 19Hz), 4.40 (2H, s), 4.62 (1H, m), 5.07 (1H, d, J = 4.5 Hz), 6.00 (1H, dd, J = 4.5 and 9 Hz), 6.73 (1H, s), 6.97 (1H, s), 7.20-7.60 (25H, br s).

(B) 1.94 g (2.2 mmol) of the compound obtained in (A) was dissolved in 20 ml of benzene, and 480 mg (2.8 mmol) of m-chloroperbenzoic acid was added thereto under ice cooling, followed by stirring for 1 hour. 50 ml of ethyl acetate was added to the reaction solution, washed sequentially with a 2% aqueous meta sodium bisulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Benzhydryl 3-chloromethyl-7- [2- 2.0 g (yield 100%) of isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide-3-cepem-4-carboxylate 1-oxide (new-isomer) were obtained It became.

NMR (DMSO-d ₆ ) δ: 1.25 (6H, m), 5.09 (1H, d, J = 4.5Hz), 5.93 (1H, m), 6.79 (1H, s), 7.00 (1H, s), 7.10 -7.70 (25H, br s), 8.60 (1H, d, J = 9 Hz), 8.73 (1H, br s).

(C) 7.0 g (7.9 mmol) of the compound obtained in the above (B) was dissolved in 130 ml of anhydrous acetone, 2.4 g (16 mmol) of sodium iodide was added, and the mixture was stirred at 0 ° C for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-300; 20% ethyl acetate, hexane) to give benzhydryl 3- Iodinemethyl-7- [2-isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] 3-cephem-4-carboxylate 1-oxide (new-isomer) 5.4 g (yield 70%) was obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1680, 1520

NMR (DMSO-d ₆ ) δ: 1.23 (6H, d, J = 6Hz), 3.90 (2H, br s), 4.10∼4.60 (3H, m), 5.05 (1H, d, J = 4.5Hz), 5.85 (1H, dd, J = 4.5 and 9Hz), 6.75 (1H, s), 6.97 (1H, s), 7.00-7.60 (25H, m), 8.50 (1H, d, J = 9Hz), 8.70 (1H, br s).

(D) From 2.1 g (2.0 mmol) of the compound obtained in (C) and 6,7-dihydroxyisoquinoline, hydrobromide, monohydrate 600 mg (2.3 mmol) as in Example 1 (D) Benzhydryl 3- (6,7-dihydroxyisoquinolinio) methyl-7- [2-isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid by performing the method Amide] -3-cepem-4-carboxylate 1-oxide, iodide (new-isomer) 2.1 g (84% yield) of the foamy product was obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1660, 1520

NMR (DMSO-d ₆ ) δ: 1.20 (6H, d, J = 6Hz), 3.60-4.10 (2H, m), 4.31 (1H, m), 5.13 (1H, m), 5.20 -5.70 (2H, m ), 5.97 (1H, m), 6.77 (1H, m), 7.00 (1H, m), 7.00-8.20 (29H, m), 8.70 (2H, m), 9.03 (1H, br s).

(E) Benzhydryl 3- (6,7-dihydroxyisoquinolinio) by the same method as in Example 1 (E) from 2.1 g (1.7 mmol) of the compound obtained in (D) above. Methyl-7- [2-isopropoxyimino-2- (2-tritylaminoazol-4-yl) acetamide] 3-cepem-4-carboxylate iodide (new-isomer) 2.0 g (yield 96 %) Was obtained.

NMR (DMSO-d ₆ ) δ: 1.20 (6H, d, J = 6Hz), 3.60 (2H, m), 4.20 (1H, m), 5.27 (1H, d, J = 4.5Hz) 5.40 to 5.80 (2H , m), 5.90 (1H, m), 6.73 (1H, m), 6.92 (1H, m), 7.00-7.80 (26H, m), 8.00-8.60 (4H, m), 9.50-9.70 (2H, m) ).

(F) From 2.0 g (1.7 mmol) of the compound obtained in (E), 220 mg (yield 23%) of the title compound were obtained in the same manner as in Example 1 (F).

MP: 180 ° C (decomposition)

IR (KBr) cm ^-1 : 1780, 1670, 1620, 1530

NMR (DMSO-d ₆ ) δ: 1.15 (6H, d, J = 6 Hz), 3.00 to 3.70 (2H, m), 4.25 (1H, m), 5.10 (1H, d, J = 4.5 Hz), 5.00 to 5.60 (2H, m), 5.75 (1H, m), 6.65 (1H, s), 7.10 (2H, br s), 7.47 (1H, s), 7.75 (1H, d, J = 7Hz, 8.35 (1H, d, J = 7 Hz), 9.30 (1H, s), 9.40 (1H, m).

Example 3

7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-car Preparation of Cylates (New-Isomers)

(A) Benzhydryl 7- (2-allyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- iodomethyl-3- cefe-4-carboxylate 1 Benz by performing the same method as in Example 1 (D) from 2.0 g (2.0 mmol) of oxide (new-isomer) and 600 mg (2.3 mmol) of 6,70 dihydroxyisoquinoline, hydrobromide, monohydrate Hydryl 7- [2-allyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem 2.0 g (yield 86%) of 4-carboxylate 1-oxide, iodide (new-isomer) were obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1670, 1640, 1530

NMR (DMSO-d ₆ ) δ: 3.40 to 4.10 (2H, m), 4.55 (2H, m), 5.00 to 5.50 (6H, m), 5.95 (1H, m), 6.95 (1H, s), 7.00 ( 1H, s), 7.05 to 8.00 (29H, m), 8.90 (1H, br s)

(B) From benzhydryl, 7- [2-allyloxyimino-2- (2-), the same procedure as in Example 1 (E) was carried out from 2.0 g (1.8 mmol) of the compound obtained in (A). Tritylaminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate, iodide (new-isomer) 2.0 g (Yield 100%) was obtained.

IR (KBr) cm ^-1 : 1790, 1720, 1680, 1640, 1620, 1520

NMR (DMSO-d ₆ ) δ: 3.60 (2H, m), 4.55 (2H, m), 5.00-6.00 (7H, m), 6.73 (1H, m), 6.92 (1H, m), 7.00-7.30 ( 26H, m), 8.00-8.70 (3H, m), 9.60 (1H, m)

(C) 140 mg (yield 13.5%) of the title compound were obtained in the same manner as in Example 1 (F) from 2.0 g (1.8 mmol) of the compound obtained in (B).

MP: 180 ° C (decomposition)

IR (KBr) cm ^-1 : 1780, 1670, 1620, 1540

NMR (DMSO-d ₆ ) δ: 3.00 to 3.80 (2H, m), 3.52 (2H, m), 5.00 to 5.60 (6H, m), 5.75 (1H, m), 6.67 (1H, s), 6.90 to 7.80 (4H, m), 8.30 (1H, m), 9.20 (1H.m), 9.55 (1H, m)

Example 4

7- [2- (2-iminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) Preparation of Methyl-3-cepem-4-carboxylate (New-Isomer)

(A) 28 g (41 mmol) 2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (new-isomer) and benz 17 g (41 mmol) of hydryl 7-amino-3-chloromethyl-3-cepem-4-carboxylate was dissolved in 300 ml of anhydrous methylene chloride, and 15.6 ml (123 mmol) of N, N-dimethylaniline was added thereto at -10 ° C. After cooling, 4 ml (43 mmol) of phosphorus oxychloride was added dropwise. The reaction solution is stirred at room temperature for 2.5 hours, concentrated under reduced pressure, and the residue is extracted with ethyl acetate. The organic layer was washed sequentially with N-hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to thereby benzhydryl 3-chloromethyl-7- [2- (1-benzhydryloxy Carbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate (new-isomer) 36 g (81% yield) Was obtained.

IR (KBr) cm ^-1 : 1790, 1740, 1690, 1530, 1500, 700

NMR (DMSO-d ₆ ) δ: 1.45 (6H, br, s), 3.62 (2H, m), 4.42 (2H, br s), 5.25 (1H, d, J = 4.5Hz), 5.82 (1H, dd , J = 4.5 and 9 Hz), 6.67 (1H, s), 6.77 (1H, s), 6.97 (1H, s), 7.00 to 7.70 (35H, m), 8.77 (1H, br s), 9.40 (1H, d, J = 9 Hz).

(B) After dissolving 36 g (33 mmol) of the compound obtained in (A) in 360 ml of methylene chloride, 6.0 g (35 mmol) of m-chloroperbenzoic acid is added under ice cooling, followed by stirring at the same temperature for 1 hour. The reaction solution was washed with 2% aqueous sodium metabisulfite solution, concentrated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 3-chloromethyl-7- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- 36 g (yield 98%) of (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate 1-oxide (new-isomer) were obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1680, 1510, 1490

NMR (DMSO-d ₆ ) δ: 1.53 (6H, br s), 3.85 (2H, m), 4.53 (2H, m), 5.10 (1H, d, J = 4.5Hz), 5.97 (1H, m), 6.80 (1H, s), 6.78 (1H, s), 7.00 (1H, s), 7.10-7.70 (35H, m), 8.45 (1H, d, J = 9 Hz), 8.77 (1H, br s).

(C) 36 g (33 mmol) of the compound obtained in (B) above was dissolved in 500 ml of anhydrous acetone, and 12 g (80 mmol) of sodium iodide was added under ice cooling, followed by stirring at the same temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is extracted with ethyl acetate. The organic layer was washed sequentially with 2% aqueous meta sodium bisulfite solution and saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-300: 20% ethyl acetate, hexane) to obtain benzhydryl 7- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino)-. 2- (2-tritylaminothiazol-4-yl) acetamide] -3-iodinemethyl-3-cepem-4-carboxylate 1-oxide (new-isomer) 22.8 g (58.8% yield) Obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1690, 1520, 1500, 700

NMR (DMSO-d ₆ ) δ: 1.53 (6H, br s), 3.90 (2H, br s), 4.43 (2H, m), 5.07 (1H, d, J = 4.5Hz), 5.92 (1H, dd, J = 4.5 and 9 Hz), 6.70 (1H, s), 6.78 (1H, s), 7.00 (1H, s), 7.05 to 7.70 (35H, m), 8.40 (1H, d, J = 9 Hz), 8.73 ( 1H, br s).

(D) 2 g (1.7 mmol) of the compound obtained in (C) and 6,7-dihydroxyisoquinoline, hydrobromide, 580 mg (2.23 mmol) of monohydrate were dissolved in 10 ml of N, N-dimethylformamide, and After 0.3 ml (0.21 mmol) of triethylamine was added dropwise at room temperature, the mixture was stirred for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue is extracted with chloroform. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-300: 5% methanol, chloroform) to obtain benzhydryl 7 [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2. -(2-tritylaminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate 1-oxide, iodine 1.65 g (85.5% yield) of cargo (new-isomer) were obtained.

IR (KBr) cm ^-1 : 1800, 1730, 1680, 1630

NMR (DMSO-d ₆ ) δ: 1.50 (6H, br s), 3.50-4.10 (2H, m), 5.10 (1H, m) 5.60 (2H, m), 6.00 (1H, m), 6.70 (1H, s), 6.80 (2H, br s), 6.90-8.00 (39H, m), 8.05-8.60 (2H, m), 8.70 (1H, s).

(E) 1.65 g (1.2 mmol) of the compound obtained in (D) and 2 g (12 mmol) of potassium iodide are suspended in 30 ml of anhydrous acetone, and 0.53 ml (6.8 mmol) of acetyl chloride is added dropwise at -20 ° C. The reaction solution was stirred at -10 DEG C for 5 hours, then poured into 2% aqueous meta sodium bisulfite solution, filtered and the precipitate was collected and washed with water. The precipitate was dissolved in chloroform, washed with saturated brine and dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. As a result, benzhydryl and 7 [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino ) -2-(2-tritylaminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) -methyl-3-cepem-4-carboxylate, 1.3 g (yield 80%) of iodide (new-isomer) were obtained.

IR (KBr) cm ^-1 : 1790, 1740, 1680, 1640

NMR (DMSO-d ₆ ) δ: 1.50 (6H, br s), 3.53 (2H, m), 5.30 (1H, m) 5.50 (2H, m), 5.90 (1H, m), 6.67 (1H, s) , 6.75 (2H, br s), 6.90 to 7.70 (36H, m), 7.90 to 8.50 (3H, m), 8.80 (1H, m), 9.40 (2H, m).

(F) After dissolving 1.3 g (0.98 mmol) of the compound obtained in (E) above in 20 ml of anhydrous methylene chloride, 1.3 ml of anisole is added, and 20 ml of trifluoroacetic acid is added dropwise at 0 ° C. The reaction solution was stirred at the same temperature for 2.5 hours, concentrated under reduced pressure, ether was added to the residue, and the precipitate was collected by filtration. The precipitate was dissolved in 200 ml of water, the insoluble substance was filtered off, and then reverse phase column chromatography (LC-Sorb RP-18: Chemco) was used to concentrate the elution fraction (5% aqueous tetrahydrofuran solution) containing the target substance. 120 mg (yield 20%) of the title compound were obtained by freeze-drying.

MP: 170 ° C (decomposition)

IR (KBr) cm ^-1 : 1770, 1620, 1540, 1440, 1290, 1200

NMR (DMSO-d ₆ ) δ: 1.40 (6H, br s), 3.00-3.80 (2H, m), 5.15 (1H, d, J = 5Hz) 5.25-5.70 (2H, m), 5.80 (1H, m ), 6.70 (1H, s), 7.00 to 7.50 (3H, m), 7.80 (1H, m), 8.35 (1H, m), 9.35 (1H, m).

Example 5

7- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-cyclopentyloxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) Preparation of Methyl-3-cepem-4-carboxylate (New-Isomer)

(A) 2.12 g (3 mmol) of 2- (1-benzhydryloxycarbonyl-1-cyclopentyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (new-isomer) and 1.24 g (3 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cepem-4-carboxylate was dissolved in 50 ml of methylene chloride, and 1.2 ml (9.6 mmol) of N, N-dimethylaniline was added under ice cooling. Thereafter, 0.29 ml (3.15 mmol) of phosphorus oxychloride was added dropwise and stirred at the same temperature for 4 hours. 30 ml of chloroform and 30 ml of water were added to the reaction solution, the organic layer was washed with water and saturated brine, and then dehydrated and concentrated with anhydrous sodium sulfate to form benzhydryl 7- [2- (1-benzhydryloxycarbonyl-1-cyclo After obtaining and purifying various yloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3-chloromethyl-3-cepem-4-carboxylate (new isomer) It is used for the following reaction.

(B) After dissolving in 50 ml of the compound methylene chloride obtained in the above (A), 710 mg (3.3 mmol) of m-chloroperbenzoic acid purity 80% is added under ice-cooling, and it stirred for 20 minutes. Benzhydryl 7- [2- (1-benzhydryloxycarbonyl-1-cyclopentyloxyimino) -2-2 (2-tritylaminothiazol-4-yl) acetamide] -3 in the reaction solution. -Chloromethyl-3-cepem-4-carboxylate 1-oxide (new-isomer) was obtained and purified for use in the next reaction.

(C) The compound obtained in (B) was dissolved in 40 ml of acetone, and 990 mg (68 mmol) of sodium iodide was added to the solution, followed by stirring at room temperature for 30 minutes. 120 ml of ethyl acetate and 20 ml of 5% aqueous sodium thiosulfate solution were added to the reaction solution and separated. The organic layer is washed with water and saturated brine, then dehydrated with anhydrous sodium sulfate and then concentrated. The concentrated residue was flushed with silica gel column chromatography (Wakogel C-300: ethyl acetate: n-hexane = 1: 2), and the fractions containing the desired product were combined and concentrated under reduced pressure, and the residue was added to isopropyl ether to obtain a powdery benz. Hydrill 7- [2- (1-benzhydryloxycarbonyl010cyclopentyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3-iodomethyl-3- 2.92 g [80.3% yield from (A)] of cefem-4-carboxylate 1-oxide (new-isomer) were obtained.

NMR (DMSO-d ₆ ) δ: 1.80 (4H, m), 2.10 (4H, m), 3.90 (2H, m), 4.40 (2H, m), 5.10 (1H, d, J = 5Hz), 5.95 ( 1H, dd, J = 5 and 9Hz), 6.77 (1H, s), 6.80 (1H, s), 7.35 (35H, m), 8.50 (1H, d, J = 9Hz), 8.80 (1H, br s) .

(D) From 2.5 g (2.1 mmol) of the compound obtained in (C) and 6,7-dihydroxyisoquinoline, hydrobromide, monohydrate 600 mg (2.3 mmol), the same as in Example 4 (D) The process was carried out to carry out benzhydrol 7- [2- (1-benzhydryloxycarbonyl-1-cyclopentyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3 2.6 g (yield 92%) of-(6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate 1-oxide, iodide (new-isomer) were obtained.

NMR (DMSO-d ₆ ) δ: 1.50 to 2.30 (8H, m), 3.50 to 4.10 (2H, m), 5.15 (1H, m), 5.30 to 5.70 (2H, m), 6.03 (1H, m), 6.73 (1H, s), 6.78 (1H, s), 7.00 (H, s), 7.05-8.20 (39H, m), 8.40-8.90 (2H, m), 9.10 (1H, s).

(E) Benzhydryl 7- [2- (1-benzhydryloxycarbonyl-) from 2.6 g (1.9 mmol) of the compound obtained in (D), by the same method as in Example 4 (E). 1-cyclopentyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4- 2.5 g (yield 97%) of carboxylate, iodide (new-isomer) were obtained.

IR (KBr) cm ^-1 : 1790, 1730, 1680, 1640, 1620

NMR (DMSO-d ₆ ) δ: 1.40 to 2.40 (8H, m), 3.60 (2H, m), 5.30 (1H, d, J = 4.5 Hz), 5.40 to 5.80 (2H, m), 5.93 (1H, dd, J = 4.5 Hz and 9 Hz), 6.75 (1H, s), 6.78 (1H, s), 6.93 (1H, s), 7.00 to 7.80 (37H, m), 8.00 to 8.60 (3H, m), 9.20 -9.70 (2H, m).

(F) From 2.5 g (1.8 mmol) of the compound obtained in (E), 50 mg (yield 4%) of the title compound were obtained in the same manner as in Example 4 (F).

MP: 175 ° C (decomposition)

IR (KBr) cm ^-1 : 1770, 1670, 1630, 1540

NMR (DMSO-d ₆ ) δ: 1.40 to 2.20 (8H, m), 3.20 to 3.70 (2H, m), 5.10 (1H, d, J = 4.5 Hz), 5.15 to 5.60 (2H, m), 5.78 ( 1H, m), 6.62 (1H, s), 6.90-7.50 (3H, m), 7.70 (1H, m), 8.25 (1H, m), 9.00-9.90 (2H, m).

Example 6

7- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-vinyloxyimino acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl- Preparation of 3-cepem-4-carboxylate (new-isomer)

(A) 6.03 g (20.8 mmol) of N- (1-t-butoxycarbonyl-1-vinyloxy) phthalamide was dissolved in a mixture of 200 ml of methylene chloride and 10 ml of methanol, followed by 1.88 ml of 80% hydrazine hydrate and methanol. 40 ml of the mixture is added dropwise. After 1.5 hours of stirring at room temperature, the insolubles are filtered off. The filtrate was washed three times with 8% aqueous ammonia and then with saturated brine, then dehydrated with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to leave 0- (1-t-butoxycarbonyl-1-vinyl) hydroxylamine. Collect the mule. After dissolving the residue in 120 ml of methanol, 7.46 g (18 mmol) of 2- (2-tritylaminothiazol-4-yl) glyoxylic acid was added and stirred at room temperature for 3 hours. The precipitated crystals collected by filtration were collected as a result of 2- (1-t-butoxycarbonyl-1-vinyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (new-isomer 7.08 g). (Yield 70.9%) was obtained.

IR (KBr) cm ²¹ : 3400, 2970, 1725, 1630, 1100, 700

NMR (DMSO-d ₆ ) δ: 1.45 (9H, s), 5.20 (1H, br s), 5.33 (1H, br s), 7.05 (1H, s), 7.10 ~ 7.40 (15H, m), 8.82 ( 1H, br s)

(B) 5.06 g (9.76 mmol) of the compound obtained in the above (A) and 4.05 g (9.76 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cepem-4-carboxylate were added to 100 ml of methylene chloride. Dissolve and add 5.56 ml (43.9 mmol) of N, N-dimethylaniline followed by 1.07 ml (11.5 mmol) of phosphorus oxychloride under nip cooling. After 1 hour of stirring at room temperature, the mixture was washed sequentially with 0.5N hydrochloric acid and saturated brine, and dehydrated with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and ether was added to the residue to give benzhydryl 3-chloromethyl-7- [2- (1-t-butoxycarbonyl-1-vinyloxyimino) -2- (2-trityl 8.7 g (yield 96.7%) of aminothiazol-4-yl) acetamide] -3-cefe-4-carboxylate (new-isomer) were obtained.

IR (KBr) cm ²¹ : 3400, 2960, 1790, 1720, 1520, 1150, 700

NMR (DMSO-d ₆ ) δ: 1.48 (9H, s), 3.47 and 3.75 (2H, ABq, J = 18 Hz), 4.45 (2H, s), 5.19 (1H, br s), 5.27 (1H, d, J = 4.5 Hz), 5.35 (1 H, br s), 5.77 (1 H, dd, J = 4.5 and 7.5 Hz), 6.92 (1 H, s), 6.95 (1 H, s), 7.30 (25 H, m), 8.86 (1H, br s), 9.79 (1H, doublet, J = 7.5 Hz).

(C) 2.0 g (2.06 mmol) of the compound obtained in the reaction (B) was dissolved in 30 ml of methylene chloride, and 440 mg (2.55 mmol) of m-chloroperbenzoic acid was added at -10 ° C, followed by stirring at the same temperature for 1 hour. do. The reaction solution was washed sequentially with 2% aqueous sodium metabisulfite solution, 5% aqueous sodium bicarbonate solution and saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 7- [2- (1-t-part Methoxycarbonyl-1-vinyloxy) amino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-chloromethyl-3-cepem-4-carboxylate 1-oxide -Isomer) 2.0 g (yield 98.4%) were obtained.

IR (KBr) cm ²¹ : 1800, 1730, 1690, 1640, 1530, 1370

NMR (DMSO-d ₆ ) δ: 1.47 (9H, s), 3.82 (2H, br s), 4.52 (2H, m), 5.07 (1H, d, J = 4.5Hz), 5.20 (1H, br s) , 5.35 (1H, br s), 5.80 (1H, m), 6.97 (1H, s), 7.00 (1H, s), 7.10 ~ 7.60 (25H, m), 8.80 (1H, br s), 9.37 (1H , d, J = 10 Hz).

(D) 2.0 g (2.03 mmol) of the compound obtained in the reaction (C) was dissolved in 40 ml of anhydrous acetone, and 760 mg (5.07 mmol) of sodium iodide was added under ice cooling, followed by stirring at the same temperature for 1 hour. The reaction solution is concentrated under reduced pressure and the residue is extracted with ethyl acetate. The organic layer was washed successively with 2% aqueous sodium metabisulfite solution and saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (wakogel C-300: 20% ethyl acetate, nucleic acid) to obtain benzhydryl 7- [2-1-t-butoxycarbonyl-1-vinyloxy) amino-2- (2 -Tritylaminothiazol-4-yl) acetamide] -3-iodinemethyl-3-cepem-4-carboxylate 1-oxide (new-isomer) 1.4 g (yield 64.0%) was obtained.

IR (KBr) cm ²¹ : 1800, 1720, 1690, 1630, 1530, 1370

NMR (DMSO-d ₆ ) δ: 1.47 (9H, s), 3.87 (2H, m), 4.45 (2H, m), 5.07 (1H, d, J = 4.5Hz), 5.20 (1H, br s), 5.35 (1H, s), 5.80 (1H, m), 6.98 (1H, s), 7.01 (1H, s), 7.01 ~ 7.60 (25H, m), 8.83 (1H, br s), 9.35 (1H, d , J = 9 Hz).

(E) 1.4 g (1.3 mmol) of the compound obtained in (D) and 6,7-dihydroxyisoquinoline, hydrobromide, and 380 mg (1.46 mmol) of monohydrate were dissolved in 7 ml of N, N-dimethylformamide. And 0.19 ml (1.37 mmol) of triethylamine were added dropwise. The reaction solution is stirred at room temperature for 2 hours, then concentrated under reduced pressure and the residue is extracted in chloroform. The organic layer was washed successively with water and brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 7- [2- (1-t-butoxycarbonyl-1-vinyloxy) amino-2- ( 2-tritylaminothiazol-4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate 1-oxide, iodide ( Neo-isomer) 1.2 g (yield 74.6%) was obtained.

IR (KBr) cm ²¹ : 1800, 1720, 1670, 1640, 1530, 1450

NMR (DMSO-d ₆ ) δ: 1.50 (9H, s), 3.50 to 3.75 (2H, m), 5.10 (1H, d, J = 4.5 Hz), 5.10 to 5.95 (4H, m), 5.87 (1H, m), 7.00 (2H, s), 7.05-8.20 (28H, m), 8.60-9.00 (2H, m), 9.40 (1H, m).

(F) 1.2 g (0.97 mmol) of the compound obtained in the reaction (E) and 1.6 g (9.6 mmol) of potassium iodide were suspended in 30 ml of anhydrous acetone, and 0.35 ml (4.9 ml) of acetyl chloride was added dropwise at -20 ^° C. do. The reaction solution is stirred at -10 ^o C for 4 hours. It is added to 150 ml of 2% aqueous sodium metabisulfite solution, and the precipitate is collected by filtration and washed with water. This precipitate is dissolved in chloroform and washed with saturated brine. The organic layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to benzhydryl 7- [2- (1-t-butoxycarbonyl-1-vinyloxy) imino-2- (2-tritylaminothiazole -4-yl) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate, iodide (new-isomer) 1.1 g (yield 92.9%) Was obtained.

IR (KBr) cm ²¹ : 1790, 1720, 1690, 1640, 1530, 1370

NMR (DMSO-d ₆ ) δ: 1.52 (9H, s), 3.40 ~ 3.70 (2H, m), 5.10 ~ 5.95 (6H, m), 6.90 (1H, s), 6.92 (1H, s), 7.00 ~ 7.70 (27H, m), 7.90-8.60 (2H, m), 8.75 (1H, m), 9.35 (1H, m), 9.73 (1H, m).

(G) 1.1 g (0.9 mmol) of the compound obtained in (F) were dissolved in 7 ml of anhydrous methylene chloride, 1.1 ml of anisole was added, and 15 ml of trifluoroacetic acid was added dropwise at 0 ^° C. The reaction solution is stirred at the same temperature for 2.5 hours and then concentrated under reduced pressure. Ether is added to the residue and the precipitate is collected by filtration. The precipitate was dissolved in 50 ml of 10% methane solution, the insolubles were filtered off, and the filtrate was subjected to reverse phase column chromatography (LC-SOrb RP-18: Chemco) to obtain an elution fraction (20% aqueous methanol solution) containing the target substance. Concentration lyophilization gave 40 mg (yield 7.3%) of the title compound.

MP: 155 ° C (decomposition)

IR (KBr) cm ²¹ : 1770, 1630, 1530, 1440

NMR (DMSO-d ₆ ) δ: 3.10-3.80 (2H, m), 5.00-5.85 (5H, m), 5.80 (1H, m), 6.95 (1H, s), 7.30 (1H, m), 7.95 ( 2H, m), 8.45 (1H, m), 9.25 (1H, m), 9.75 (1H, m).

Example 7

7- [2- (2-aminothiazol-4-yl) -2- (2-propynyloxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3- Preparation of Cefem-4-carboxylate (New-Isomer)

(A) 3.0 g (6.9 mmol) of 2- (2-propynyloxyimino) -2- (2-tritylaminothiazol-4-yl acetic acid (new-isomer) and benzhydryl 7-amino-3- Benzhydryl 3-iodine-methyl-methionate was subjected to the same method as in Example 1 (A), (B), and (C) using 2.86 g (6.9 mmol) of chloromethyl-3-cepem-4-carboxylate. 27- [2- (2-propynyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3-cepem-4-carboxylate 1-oxide (new-isomer) 3.8 g (yield 58.7%) were obtained.

IR (KBr) cm ²¹ : 2120, 1800, 1730, 1690, 1520

NMR (DMSO-d ₆ ) δ: 3.45 (2H, s) 3.90 (2H, br s), 4.40 (2H, m), 4.70 (2H, s), 5.05 (1H, d, J = 4.5Hz), 5.85 (1H, dd, J = 4.5 and 8.0Hz), 6.85 (1H, s), 6.98 (1H, s), 7.10 ~ 7.70 (25H, m), 8.80 (1H, s), 9.00 (1H, d, J = 3.0 Hz)

(B) Example 1 (D), (E) using 2.0 g (2.1 mmol) of the compound obtained in (A) and 6,7-dihydroxyisoquinoline, hydrobromic acid, 600 mg (2.3 mmol) of monohydrate ) And (F) were carried out to give 180 mg (yield 12.6%) of the title compound.

MP: 160 ° C (decomposition)

IR (Kbr) cm ²¹ : 2120, 1770, 1670, 1610, 1540

NMR (DMSO-d ₆ ) δ: 3.00 ~ 3.70 (3H, m), 4.65 (2H, br s), 5.13 (1H, d, J = 4.5Hz), 5.25 ~ 60.00 (3H, m), 6.73 (1H , s), 7.18 (2H, br s), 7.50 (1H, s), 7.80 (1H, d, J = 6.0 Hz), 8.40 (1H, d, J = 6.0 Hz), 9.33 (1H, br s) , 9.60 (1 H, m).

Example 8

3- (6,7-diacetoxyisoquinolinio) methyl-7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-cepem-4- Preparation of carboxylates (new isomers)

(A) Benzhydryl 3-iodinemethyl-7- [2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] obtained in Example 1 (C) -3- Example 1 (D), (Cefme-4-carboxylate 1-oxide (new-isomer) 2.5g (2.7mmol) and 6,7-diacetoxyisoquinoline 1.0g (4.0mmol) were used, 25 mg (yield 1.4%) of the title compound were obtained by the same method as E) and (F).

MP: 185 ° C (decomposition)

IR (Kbr) cm ²¹ : 1780, 1620, 1540, 1380, 1200

NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 2.50 (3H, s), 3.20 ~ 3.70 (2H, m), 3.80 (3H, s), 4.80 ~ 5.60 (3H, m), 5.73 ( 1H, m), 6.70 (1H, s), 7.00 (1H, br s), 7.15 (1H, m), 7.75 (2H, m), 8.27 (1H, m), 9.17 (1H, m), 9.53 ( 1H, m).

Example 9

3- (6,7-diacetoxyisoquinolinio) methyl-7- [2- (1-carboxylate-1-methylethoxyimino) -2- (2-aminothiazol-4-yl) Acetamide] -3-4-carboxylate, preparation of the sodium salt (new-isomer)

Benzhydryl 7- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) obtained in Example 4 (C) Acetamide] -3-iodinemethyl-3-cepem-4-carboxylate 1-oxide (new-isomer) 2.5 g (2.1 mmol) and 6,7-diacetoxyisoquinoline 728 mg (3.16 mmol) And the same method as in Example 1 (D), (E) and (F). However, after removing the amino protecting group and the carboxyl protecting group, the obtained trifluoro acetate salt is suspended in 10 ml of water, adjusted to pH 7.0 with saturated sodium bicarbonate, and then the insolubles are removed. The filtrate was subjected to reverse layer column chromatography (LC-Sorb RP-18: Chemco, eluted with 5% aqueous methanol solution) to concentrate the eluted fraction containing the target product and freeze-dried to obtain 123 mg (yield 7%) of the title compound. It became.

MP: 175 ° C (decomposition)

IR (KBr) cm ²¹ : 3400, 1765, 1595

NMR (DMSO-d ₆ ) δ: 1.40 (3H, br s), 1.46 (3H, br s), 2.30 (6H, s), 4.30 ~ 5.30 (3H, m), 6.00 (1H, m), 6.85 ( 1H, s), 7.00 ~ .910 (5H, m)

Example 10

Preparation of 6,7-dihydroxyisoquinoline, hydrobromide, monohydrate

(A) 73 g (0.172 mol) of 3,4-dibenzyloxybenzaldehyde is dissolved in 500 ml of benzene, 25 ml (0.23 mol) of aminoacetaldehyde diethyl acetal is added, and the resulting water is separated by stirring under reflux for 5 hours. The reaction solution is concentrated under reduced pressure to give a residue of 2- [N- (3,4-dibenzyloxybenzylidene) amino] acetaldehyde diethylacetal. This residue is dissolved in 700 ml of methanol, 6.0 g (0.16 mol) of sodium borohydride is added at room temperature, followed by stirring for 15 minutes. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 2- [N- (3,4-dibenzyloxybenzyl) amino] The residue of acetaldehyde diethylacetal is obtained. After dissolving this residue in 600 ml of anhydrous tetrahydrofuran, 39.8 g (0.21 mol) of p toluenesulfonyl chloride and 59 ml (0.42 mol) of triethylamine were added, and it stirred at room temperature for 17.5 hours. The reaction solution is concentrated under reduced pressure and the residue is extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (10% ethyl acetate, hexane) to give 2- [Np-trisulfonyl-N- (3,4- Dibenzyloxybenzyl) amino] -acetaldehyde diethyl acetal 70g (yield 70.7%) was obtained.

MP: 75 ℃

IR (Kbr) cm ²¹ : 1600, 1520, 1460, 1340, 1250, 1160, 1130

NMR (DMSO-d ₆ ) δ: 1.00 (6H, t, J = 7.5Hz), 2.35 (3H, s), 3.07 (2H, d, J = 6Hz), 3.20 ~ 3.60 (4H, m), 4.32 ( 2H, s), 4.35 (1H, d, J = 6 Hz) 4.90 (2H, s), 5.08 (2H, s), 6.60-7.80 (17H, m).

(B) 22.1 g (39 mmol) of the compound obtained in (A) was dissolved in 300 ml of dioxane and 28 ml of 6N hydrochloric acid was added, followed by stirring under reflux for 5.5 hours in the dark under a nitrogen atmosphere. The reaction solution is adjusted to pH 100 using 20% aqueous sodium hydroxide solution, concentrated under reduced pressure, and the residue is extracted with ethyl acetate.

The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-300: 2% methanol, chloroform) to give 8.6 g (64% yield) of 6,7-dibenzyloxyisoquinoline.

MP: 97 ℃

IR (Kbr) cm ²¹ : 1620, 1580, 1500, 1240, 1240, 1000

NMR (DMSO-d ₆ ) δ: 5.30 (4H, s), 7.25-7.80 (13H, m), 8.30 (1H, d, J = 6 Hz), 9.02 (1H, s).

(C) after dissolving the compound 7.8g (23mmol) obtained in the above (B) in a mixture of methanol and 150ml of 40% hydrobromic acid was added 1.7ml of 10% palladium / carbon catalyst 1.5g, 50 ~ 60 ^o under a hydrogen atmosphere Stir at C temperature for 7.5 hours. The reaction solution is filtered and the filtrate is concentrated under reduced pressure. The residue was recrystallized with an aqueous N-bromic acid solution, and then the precipitated crystals were washed with acetone and dried in vacuo for 5 hours to give 4.75 g (yield 79.4%) of the title compound.

MP: 205 ^o C

IR (KBr) cm ²¹ : 1630, 1610, 1520, 1480, 1430, 1300

NMR (DMSO-d ₆ ) δ: 7.50 (1H, s), 7.70 (1H, s), 8.10 (1H, ABq, J = 6Hz), 8.30 (1H, ABq, J = 6Hz), 9.42 (1H, s )

Elemental Analysis as C ₉ H ₇ NO ₂ , HBr, H ₂ O

Calculated Value: C; 41.56, H; 3.88, N; 5.39, Br; 30.72

Found: C; 41.51, H; 3.85, N; 5.24, Br; 30.10

Example 11

Preparation of 6,7-dihydroxyisoquinoline, hydrobromide, monohydrate

1.9 g (10 mmol) of 6,7-dimethoxyisoquinoline is dissolved in a mixed solution of 15 ml of acetic acid and 15 ml of 40% hydrobromic acid and stirred under reflux for 24 hours under a nitrogen atmosphere. The reaction solution is concentrated under reduced pressure, and the residue is recrystallized from an aqueous N-hydrobromic acid solution to give 2.3 g (yield 88.4%) of the title compound. The melting point, infrared absorption spectrum and nuclear magnetic resonance spectrum of the product are consistent with that of the compound of Example 10.

Example 12

Preparation of 6,7-dihydroxyisoquinoline, hydrobromide

63.4 g (0.28 mol) of 6,7-dimethoxisoisoquinoline and hydrochloride are dissolved in 630 ml of 47% hydrobromic acid and stirred under reflux for 24 hours under a nitrogen atmosphere. Crystals produced by standing under ice cooling are collected by filtration, and then washed with cold water and acetone.

It was air-dried overnight, and then heat dried at 90-95 ° C. for 6 hours to give 66.4 g (yield 97.6%) of the title compound.

MP> 260 ℃

IR (KBr) cm ^-1 : 1630, 1610, 1520, 1480, 1430, 1300

NMR (DMSO-d ₆ ) δ: 7.52 (1H, s), 7.73 (1H, s), 8.14 (1H, d, J = 7Hz), 8.33 (1H, d, J = 7Hz), 9.47 (1H, s ).

Example 13

Preparation of 6,7-dihydroxyisoquinoline

6,7-dihydroxyisoquinoline, 9.78 g (40.4 mmol) of hydrobromide are dissolved in 400 ml of water under heating and then treated with 1 g of activated carbon. The obtained filtrate was adjusted to pH 8.0 using 8% ammonia water, and then the resulting crystals were collected by filtration under ice cooling. The resulting filtrate was washed with ice water and acetone and dried to yield 6.08 g (yield 93.4%) of the title compound. It was.

MP: 258 ~ 260 ℃ (decomposition)

IR (KBr) cm ^-1 : 1640, 1605, 1590, 1565, 1520, 1450, 1340

NMR (DMSO-d ₆ ) δ: 7.13 (1H, s) 7.29 (1H, s), 7.48 (1H, d, J = 6Hz), 8.15 (1H, d, J = 6Hz), 8.91 (1H, s) .

Example 14

Preparation of 6,7-diacetoxyisoquinoline

500 mg (1.9 mmol) of 6,7-dihydroxyisoquinoline, hydrobromide, and monohydrate were suspended in 10 ml of trifluoroacetic acid, 2.0 ml (21 mmol) of acetic anhydride was added at room temperature, followed by stirring at the same temperature for 24 hours. do. The reaction solution is concentrated under reduced pressure, water and ethyl acetate are added to the residue, and then the aqueous layer is adjusted to pH 8.0 using 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure to give 440 mg (yield 93.4%) of the title compound.

IR (KBr) cm ^-1 : 1770, 1620, 1500, 1460, 1380, 1200

NMR (DMSO-d ₆ ) δ: 2.39 (6H, s), 7.85 (1H, d, J = 6.0Hz), 7.90 (1H, s), 8.05 (1H, s), 8.53 (1H, d, J = 6.0 Hz), 9.30 (1 H, s).

Reference Example 1

7- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide] -3-isoquinoliniomethyl-3-cepem-4 Preparation of -carboxylates, monosodium salts (new isomers)

7- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -cephalospotanic acid 450 mg (0.48 mmol) ) And Ascorb 15 mg (0.085 mmol) are dissolved in 3 ml of acetone, 1 ml of water, 2.88 g (19.2 mmol) of sodium iodide and 0.6 ml (50 mmol) of isoquinoline are added, and the mixture is stirred at 50 to 60 ° C for 5 hours. The reaction solution is extracted with chloroform, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is then dissolved in 5 ml of anhydrous methylene chloride, 0.5 ml of anisole is added, then 5 ml of trifluoroacetic acid is added dropwise at 0 ° C. and stirred at the same temperature for 2 hours. The reaction solution is concentrated under reduced pressure, ether is added to the residue, and the precipitate is collected by filtration. This precipitate is dissolved in 100 ml of water, adjusted to pH 6.5 using an aqueous sodium bicarbonate solution, and the insolubles are filtered off. The filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-18: Chemco) to give 15 mg (yield 5%) of the title compound by concentrating and freeze drying the eluted fraction (5% aqueous methanol solution) containing the desired product.

NMR (DMSO-d ₆ ) δ: 1.38 (6H, br S), 3.10 ~ 3.70 (2H, m), 5.05 (1H, d, J = 5Hz), 5.70 (1H, m), 6.65 (1H, s) , 7.10 (2H, m), 7.90-8.60 (6H, m), 9.25 (1H, m).

Reference Example 2

7- [2- (2-aminothiazol-4-yl) -2-methoxyaminoacetamide] -3- (5-hydroxyisoquinolinio) -methyl-3-cepem-4-carboxylate Preparation of (New-Isomers)

500 mg (0.99 mmol) of sepoxtamsim and formate were dissolved in 15 ml of 505 acetone aqueous solution, and 5.95 g (39.7 mmol) of sodium iodide, 1.43 g (9.9 mmol) of 5-hydroxyisoquinoline and 30 mg of ascorbic acid were added thereto. The mixture is stirred at 60-65 ° C. for 4 hours. After the reaction solution was cooled, 40 ml of acetone was added, and silica gel column chromatography (Wakogel C-300: eluted with 20% acetone aqueous solution) was used. The combined fractions containing the desired substance were concentrated to about 40 ml under reduced pressure, reversed phase column chromatography (LC-Sorb RP-18: Chemco, eluted with 20% aqueous methanol solution), and then the elution fractions containing the desired substance were combined and concentrated. 72 mg (13.4%) of the title compound were obtained by lyophilization.

MP: 195 ℃

IR (KBr) cm ^-1 : 1770, 1610, 1530, 1400, 1290

NMR (DMSO-d ₆ ) δ: 3.00 to 3.60 (2H, m), 3.80 (3H, s), 5.10 (1H, d, J = 4.5 Hz), 5.20 to 5.90 (3H, m), 6.72 (1H, s), 7.55 (1H, m), 7.87 (2H, m), 8.50 (1H, d, J = 6.0 Hz), 8.95 (1H, d, J = 6.0 Hz, 10.18 (1H, s).

Reference Example 3

7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (8-hydroxyisoquinolinio) methyl-3-cepem-4-carboxylate Preparation of (New-Isomers)

Sepotaxim, 500 mg (0.99 mmol) of formic acid and 1.43 g (9.9 mmol) of 8-hydroxyisoquinoline were used and 52 mg (yield 9.7%) of the title compound were obtained in the same manner as in Reference Example 2.

MP: 185 ° C (decomposition)

IR (KBr) cm ^-1 : 1770, 1600, 1530, 1380, 1300

NMR (DMSO-d ₆ ) δ: 3.20 to 3.60 (2H, m), 3.80 (3H, s), 5.10 (1H, d, J = 4.5 Hz), 5.20 to 5.90 (3H, m), 6.63 (1H, s), 7.30 (1H, d, J = 7.0 Hz), 7.60 (1H, d, J = 7.0 Hz), 8.03 (1H, t, J = 7.0 Hz), 8.30 (1H, d, J = 6.0 Hz) , 8.80 (1H, s, J = 6.0 Hz), 10.23 (1H, s).

Reference Example 4

7- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide] -3- (5-hydroxyisoquinolinio) methyl Preparation of 3-Cefe-4-carboxylate, sodium salt (pre-isomer)

7- [2- (1-Fershydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] cephalosporanic acid (new-isomer) ) 1.0 g (1.07 mmol) and 1.55 g (10.7 mmol) of 5-hydroxyisoquinoline were used, and 46 mg (yield 6.8%) of the title compound was obtained in the same manner as in Reference Example 1.

MP: 205 ° C (decomposition)

IR (KBr) cm ^-1 : 1770, 1600, 1530, 1400, 1290

NMR (DMSO-d ₆ ) δ: 1.40 (6H, br S), 3.20 ~ 3.60 (2H, m), 5.07 (1H, d, J = 4.5Hz), 5.20 ~ 5.90 (3H, m), 6.70 (1H s), 7.55 (1 H, m), 7.65 (2 H, m), 8.45 (1 H, m), 8.70 (1 H. m), 10.00 (1 H, s).

Compound (I) of the present invention is a novel compound that has not been described in the literature, and has a strong antimicrobial activity against non-glucose non-fermenting Gram-negative bacillus, including susceptible, resistant Gram-positive bacteria and Gram-negative bacteria, especially Pseudomonas aeruginosa, It is useful as an antimicrobial agent because of its excellent stability and low β-lactamase inducing activity.

In particular, in the isoquinolinio methyl group existing at the 3-position of the cefe nucleus, a 6,7-dihydroxyisoquinolinio methyl group or 6 having a hydroxyl or acetoxy group introduced at the 6- and 7-positions of the isoquinoline nucleus Compounds of the present invention having a, 7-diacetoxyisoquinoliniomethyl group, in particular the compounds of Examples 1 to 9, are compounds having unsubstituted isoquinoline nuclei (compounds of Reference Example 1) and monohydroxy substituted compounds ( Compared to the compounds of Reference Examples 2 to 4), unexpectedly strong antibacterial activity is exhibited against Gram-negative bacteria of sensitivity and resistance.

Moreover, the compound (i) of this invention is also a compound useful as an intermediate raw material of the compound of this invention as a novel compound which is not described in literature.

Claims (12)

The compound represented by the following general formula (VI) or a salt thereof is reacted with the compound represented by the following general formula (III) to obtain a compound of the general formula (II), and the compound of the general formula (III) obtained is reduced. Or a method of preparing a compound represented by the general formula (I), a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester, characterized in that the protecting group can be removed.

(Wherein R represents a straight or branched lower alkyl group, lower alkenyl group, lower alkynyl group or cyclic lower alkyl group which may be substituted with a carboxyl group, R ¹ represents a hydrogen atom or an acetyl group, and R ² represents a protected carboxyl group) Is a linear or branched lower alkyl group, lower alkenyl group, lower alkynyl group, or cyclic lower alkyl group which may be substituted with R ³ represents a hydrogen atom or a carboxyl-protecting group, R ⁴ represents a hydrogen atom or an amino-protecting group , R ⁵ is a protecting group of a hydrogen atom or a hydroxyl group, X is a leaving group, represents X ^- anion, and Y represents S or S0.) The compound represented by the following general formula (VI) or a salt thereof is acylated with the compound represented by the following general formula (V) or a reactive derivative thereof to give a compound of the general formula (II), and the obtained general formula (II A process for producing a compound represented by the following general formula (I), a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester, wherein the compound of I) can be reduced or removed.

(Wherein R represents a straight or branched lower alkyl group, lower alkenyl group, lower alkynyl group or cyclic lower alkyl group, which may be substituted with a carboxyl group, R ¹ represents a hydrogen atom or an acetyl group, and R ² represents a protected carboxyl group May be substituted with a linear or branched lower alkyl group, lower alkenyl group, lower alkynyl group, or cyclic lower alkyl group, R ³ represents a hydrogen atom or a carboxyl-protecting group, R ⁴ represents a hydrogen atom or an amino-protecting group R ⁵ represents a protecting group of a hydrogen atom or a hydroxyl group, is X ⁻ anion, and Y represents S or SO. The compound according to claim 1, wherein in formula (I), R is a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, cyclopropyl group, cyclo Butyl group, cyclopentyl group, cyclohexyl group, 1-carboxy-1-cyclopropyl group, 1-cyclocarboxy-1-cyclobutyl group, 1-carboxy-1-cyclopentyl group, 1-carboxy-1-cyclohex Real group, vinyl group, allyl group, isopropenyl group, 1,1-dimethylallyl group, 2-butenyl group, 1-carboxyvinyl group, 1-carboxyallyl group, 2-carboxyallyl group, 1-carboxymethyl vinyl group, A process for producing a compound which is an ethynyl group, 2-propynyl group, 2-carboxyethynyl group, 1-carboxy-2-propynyl group, or 3-carboxy-2-propynyl group, a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester. The process for producing a compound according to claim 1, wherein R ¹ is a hydrogen atom, a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester in formula (I). The method for producing a compound according to claim 1, wherein R ¹ is an acetyl group, a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester in formula (I). The method for producing a compound, a nontoxic salt thereof, or a physiologically hydrolyzable nontoxic ester, according to claim 1, wherein R is a lower alkyl group which may be substituted with a carboxyl group in the general formula (I). The compound of claim 1, wherein 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl- 3-cefe-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3- (6,7-di Hydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamide ] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2 -Aminothiazol-4-yl) -2-propynyloxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (shin- Isomers), 7- [2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-vinyloxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3 -Cefe-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-cyclopropoxyimino) acetamide] -3 -(6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-cyclopentoxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 3- (6,7-Diacetoxyisoquinolinio) methyl-7- [2- (2-aminothiazol-4-yl) -2-methoxy Minoacetamide] -3-cepem-4-carboxylate (new-isomer), or 3- (6,7-diacetoxyisoquinolinio) methyl-7- [2- (2-aminothiazole- 4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3-cepem-4-carboxylate (new-isomer), a nontoxic salt thereof or a physiologically hydrolysable nontoxic Process for the preparation of esters. The compound according to claim 2, wherein in formula (I), R is a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, cyclopropyl group, cyclo Butyl group, cyclopentyl group, cyclohexyl group, 1-carboxy-1-cyclopropyl group, 1-cyclocarboxy-1-cyclobutyl group, 1-carboxy-1-cyclopentyl group, 1-carboxy-1-cyclohex Real group, vinyl group, allyl group, isopropenyl group, 1,1-dimethylallyl group, 2-butenyl group, 1-carboxyvinyl group, 1-carboxyallyl group, 2-carboxyallyl group, 1-carboxymethyl vinyl group, A process for producing a compound which is an ethynyl group, 2-propynyl group, 2-carboxyethynyl group, 1-carboxy-2-propynyl group, or 3-carboxy-2-propynyl group, a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester. The process for producing a compound according to claim 2, wherein R ¹ is a hydrogen atom, a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester in formula (I). The process for producing a compound according to claim 2, wherein R ¹ is an acetyl group, a nontoxic salt thereof, or a physiologically hydrolysable nontoxic ester in formula (I). The method for producing a compound, a nontoxic salt thereof, or a physiologically hydrolyzable nontoxic ester, according to claim 2, wherein R is a lower alkyl group which may be substituted with a carboxyl group in the general formula (I). The compound of claim 2, wherein 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl- 3-cefe-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3- (6,7-di Hydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamide ] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2 -Aminothiazol-4-yl) -2-propynyloxyiminoacetamide] -3- (6,7-dihydroxyisoquinolino) methyl-3-cepem-4-carboxylate (new-isomer) ), 7- [2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2- ( 1-carboxy-1-methylethoxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [ 2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-vinyloxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3- Cefem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-cyclopropoxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), 7- [2- (2-aminothiazol-4-yl) -2- ( 1-carboxy-1-cyclopentoxyimino) acetamide] -3- (6,7-dihydroxyisoquinolinio) methyl-3-cepem-4-carboxylate (new-isomer), or 3- (6,7-Diacetoxyisoquinolinio) methyl-7- [2- (2-aminothiazol-4-yl) -2-methok Cyiminoacetamide] -3-cepem-4-carboxylate (new-isomer), 3- (6,7-diacetoxyisoquinolinio) methyl-7- [2- (2-aminothiazole- 4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3-cepem-4-carboxylate (new-isomer), or a nontoxic salt or physiologically hydrolysable thereof Process for the preparation of nontoxic esters.