JPH0867684A - New cephem compound, its production and antimicrobial agent - Google Patents

Abstract

PURPOSE: To obtain new cephem compound useful as an antimicrobial agent, showing antibacterial action on gram-positive and gram-negative bacteria, by making a specific cephalosporin derivative containing a halomethyl group into a phosphonium compound and reacting the compound with an aldehyde to introduce a double bond. CONSTITUTION: A compound of formula I [R1 is a (protected) amino group; R<2> a group of formula II (R<5> is H, an OH-protecting group or an aralkyl; R<6> is H, an amino-protecting group or an aralkyl); R<3> is H, a metal atom, a carboxyl group-protecting group, an ester residue capable of forming an ester hydrolyzable in vivo or a negative charge; X is a halogen) is reacted with a phosphine of the formula P(R<10> )3 (R<10> is butyl or phenyl) to give a phosphonium salt compound corresponding to the compound of formula I. The compound is reacted with an aldehyde compound of the formula X-CH2 -CHO and the reaction product is further reacted with a thiazole compound to give a new cephem compound (salt) of formula III (R<4> is thiazolium or pyrimidinium).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephem compound useful as an antibacterial agent, a pharmaceutically acceptable salt thereof, a method for producing the same, and an antibacterial agent containing them as an active ingredient.

[0002]

2. Description of the Related Art Various cephalosporin antibacterial agents have been synthesized so as to cope with the transition of infectious disease-causing bacteria in the medical field. The side chains that have been used for these cephalosporin antibacterial agents can be roughly classified into 3-position side chains and 7-position side chains, and as the 3-position side chains, aromatic quaternary ammonium and aromatic heterocycles via sulfur atoms. Alternatively, aromatic quaternary ammonium via a sulfur atom is often introduced. The 7-position side chain has a 2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetamide group or 2- (5-amino-
A 1,2,4-thiadiazol-3-yl) -2-substituted oximinoacetamido group is used, and a substituted lower alkyl group is often introduced into the substituted oximino moiety. As a substituent on the substituted lower alkyl group, a halogen atom, a carboxyl group, or an amide group is often used. Looking at the sulfur atom, a substituent containing a sulfur atom is excluded, except for the simple introduction of a lower alkylthio group. Are rarely used. In addition, there is no knowledge about the improvement of antibacterial activity and the effect of treating infection by introducing a lower alkylthio group. Further, there are only examples in which one aromatic heterocyclic ring is introduced into the 7-position side chain (Japanese Unexamined Patent Publication No. 58-174386 and Japanese Unexamined Patent Publication No. 3-157387). The introduction example of the group heteromonocycle has not been synthesized at all in the past documents, and neither disclosed nor suggested at all.

Recently, cephalosporins having a dihydroxyphenyl derivative and an N-hydroxypyridone group in the side chain of cephalosporins have been disclosed (JP-A-59-93084, JP-A-61-267587, and JP-A-63-58758). No. 152386, JP-A-2-15089, and JP-A-2-152982). These cephalosporins have side chains with dihydroxyphenyl derivatives and N-
Cephalosporin compounds with hydroxypyridone group are effective against Gram-negative bacteria including Pseudomonas aeruginosa, but have weak antibacterial activity against Gram-positive bacteria including Staphylococcus, and some compounds are not effective There are also things. Although the in vitro antibacterial activity of Pseudomonas aeruginosa is excellent, the superior effects seen in the in vitro antibacterial activity were not observed in the systemic therapeutic effect on mice. The significant difference between the two is a major obstacle to clinical application.

Further, since the cephalosporin compound having a dihydroxyphenyl derivative in the side chain of the cephalosporin is similar to catecholamines in its chemical structure, it has a catecholamine-like action in the body, that is, an action on the central system. It has a problem that it appears as a side effect. In addition, because of its chemical structural similarity, catechol-O-
It is also known that it acts as a substrate for enzymes such as methyltransferase and is easily metabolized and inactivated in vivo. Similarity to the chemical structure of these catecholamines reveals its effectiveness in treating infectious diseases in humans or animals. It is thought that this is a difficult cause.

Although a number of cephalosporin type antibacterial agents have been disclosed and reported above, among these compounds, a wide range of powerful antibacterial activity from Gram positive bacteria including Staphylococcus to Gram negative bacteria including Pseudomonas aeruginosa. And, when it has an infectious disease treatment effect, it is none.

[0006]

The cephalosporin antibacterial agent is widely used for the treatment of bacterial infectious diseases as an antibiotic with few side effects because it has selective toxicity only to bacteria and does not affect animal cells. It is a highly useful drug.

However, in recent years, it has been found that the two major bacterial species detected in clinical examination materials in the medical field are gram-positive staphylococci and gram-negative bacterium Pseudomonas aeruginosa. Pseudomonas aeruginosa is frequently isolated from patients with weakened immunity as a causative bacterium of refractory infectious disease, and Staphylococcus aureus (M
RSA) has become a clinically serious social problem. Furthermore, mixed complex infections caused by both of these bacterial species are also common.

[0008] Under such circumstances, MRSA, Gram-positive bacteria including Staphylococcus and Gram-negative bacteria including Pseudomonas aeruginosa are well balanced, exhibit strong antibacterial activity, and have excellent selective toxicity, in other words, safety. Highly effective antibacterial agents are required.

[0009]

Means for Solving the Problems The present inventor provides a novel cephalosporin derivative showing excellent antibacterial activity and a therapeutic effect on infectious diseases in a wide range from Gram-positive bacteria including Staphylococcus to Gram-negative bacteria including Pseudomonas aeruginosa. 2- (2-aminothiazol-4-yl) at the 7-position of the cephem skeleton for the purpose of
-2-substituted oxyiminoacetamide group or 2- (5-
Amino-1,2,4-thiadiazol-3-yl) -2
The cephalosporin derivative having a substituted oxyiminoacetamide group was intensively studied. as a result,
A novel cephalosporin compound having a heterocyclic-substituted hydroxypyridone as a substituent of a substituted oxyimino moiety is a novel compound with no synthetic examples, and further has a cephem skeleton 3
By introducing an ammonium propenyl group at the position,
The novel compound has a wide range of excellent antibacterial activity and infection therapeutic effect from Gram-positive bacteria including Staphylococcus to Gram-negative bacteria including Pseudomonas aeruginosa, and has found the surprising fact that the safety is improved, and the present invention is obtained. completed.

The present inventors previously described in Japanese Patent Application No. 5-77458, 2- (2-aminothiazole-4) at the 7-position of the cephem skeleton.
-Yl) -2-substituted oxyiminoacetamide group or 2
-(5-Amino-1,2,4-thiadiazol-3-yl) -2-substituted novel substituents of the oxyiminoacetamide group, not to mention disclosure of examples introduced in past literatures It has been found that the novel cephalosporin derivative having a plurality of continuous aromatic heteromonocycles through the sulfur atom is an excellent antibacterial agent. This time, the research was further developed by focusing on the 3rd side chain of the new cephalosporin derivative, and the 3rd position of the cephalosporin derivative having a plurality of continuous aromatic heteromonocycles through sulfur atoms in the 7th side chain. We have found a novel cephalosporin derivative with excellent antibacterial activity, therapeutic effect on infection, and low toxicity by introducing ammonium propenyl group into the.

Compared with conventional cephalosporin antibacterial agents, the compounds of the present invention having a novel 7-position substituent and 3-position ammonium propenyl group have a wide range of antibacterial activity from Gram-positive bacteria including Staphylococcus to Gram-negative bacteria including Pseudomonas aeruginosa. On top of
It also shows a remarkable therapeutic effect on the therapeutic effect on systemic infection in mice, indicating its usefulness as a drug. For example, the therapeutic effect on systemic infection of mice using Staphylococcus aureus is anti-MRSA.
It is almost equivalent to Flomoxef used as a drug and is superior to Cefpirome which is a recently developed fourth-generation cephalosporin. On the other hand, it was revealed that the therapeutic effect on systemic infection of mice using Pseudomonas aeruginosa was effective at a significantly low drug concentration, whereas it was ineffective on ceftatidime. In addition, the therapeutic effect on infection of these novel cephalosporin derivatives is the same as in the 7-position side chain.
Compared with the compound described in No. 458, it was superior and the toxicity was reduced. This is a fact that was found as a result of introducing an ammonium propenyl group at the 3-position of the cephem skeleton.

Further, the recently disclosed cephalosporin compound having a dihydroxyphenyl derivative and an N-hydroxypyridone group in its side chain is effective against Gram-negative bacteria including Pseudomonas aeruginosa, but not including staphylococci. Antibacterial activity against positive bacteria is weak and some compounds do not show therapeutic effect, but the compounds of the present invention are excellent in antibacterial activity against both Gram positive bacteria and Gram negative bacteria. Not only that, it also shows a significant therapeutic effect on systemic infections with maso.

Further, since the chemical structure of the compound of the present invention is different from that of catecholamines, it is less susceptible to metabolic inactivation by an enzyme (catechol-O-methyl transferase) and does not show a catecholamine-like central action. The chemical structure is similar to the above-mentioned dihydroxyphenyl group-containing cephalosporin compound, which is a problem in which central nervous system side effects that are easily metabolically inactivated and further allergic side effects have been improved, and in humans or animals. The infectious disease treatment effect could be enhanced.

In view of the above points, the compound of the present invention is a completely novel compound which cannot be classified into any of the known compounds, and the antibacterial activity and infection treatment effect of the compound of the present invention can be seen from the conventional techniques. It was not, and became apparent as disclosed herein by the present invention.

The present invention has the general formula [1] [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge, R ⁴ is thiazolinium,
2,3-cyclopentenopyridinium, pyridazinium, N-methylpyrrolidinium, pyrimidinium, 3-
Amino-4-ethoxypyridinium, N-ethyl-N-
Methyl-N-carbamoyl ammonium, (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group), Represents ] The compound represented by these, its manufacturing method, and the antibacterial agent containing this compound as an active ingredient.

Next, the symbols and terms used in this specification will be described. R ¹ of the compounds of the above general formula [1] and the following general formulas [2], [3] and [5] means an optionally protected amino group.

R ² of the compounds of the above general formula [1] and the following general formulas [2], [3] and [5] is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino-protecting group or an aralkyl group). Here, preferred examples of the aralkyl group include a p-methoxybenzyl group, a benzyl group, a p-nitrobenzyl group, a diphenylmethyl group, a diansylmethyl group and a trityl group.

The above general formula [1] and the following general formula [2],
R ³ of the compounds [3] and [5] is a hydrogen atom, a metal atom,
It means a protective group of a carboxyl group, an ester residue capable of forming a hydrolyzable ester in vivo, or a negative charge.
Here, examples of the metal atom include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and preferable examples include sodium and potassium. The ester residue capable of forming a hydrolyzable ester in vivo may have a lower alkoxycarbonyloxyalkyl group, an alkanoyloxymethyl group and a substituent (2-oxo-1,3-dioxolen-4-). And a particularly preferred example is a 1- (ethoxycarbonyloxy) ethyl group,
A 1,3-dioxolen-4-ylmethyl group may be mentioned.

R ⁴ of the compound of the above general formula [1] is thiazolinium, 2,3-cyclopentenopyridinium, pyridazinium, N-methylpyrrolidinium, pyrimidinium, 3-amino-4-ethoxypyridinium, N-ethyl. -N-methyl-N-carbamoyl ammonium, (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group), Means

X in the compounds of the following general formulas [2] and [3] means a halogen atom. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

When R ⁶ is a hydrogen atom in the partial structure of the pyridone moiety in R ² of the compounds represented by the above general formula [1] and the following general formulas [2], [3] and [5], the following mutual substitution is carried out. Although it has a variable structure, any tautomeric structure is included in the present invention.

The above general formula [1] and the following general formula [2],
In the partial structure of the pyridine moiety in R ² of the compounds [3] and [5], when R ⁵ is a hydrogen atom, it has the following tautomeric structure. In the present invention, any tautomeric structure is used. It also includes.

The above general formula [1] and the following general formula [2],
Partial structure of oxyimino group of compounds [3] and [5] Is a syn isomer And anti isomer , The syn isomer generally exhibits excellent antibacterial activity,
Also in the present invention, all syn isomers. The E / Z nomenclature is described in Journal of the American Chemical Society (J. Am. Chem. Soc.) Vol. 90, Item 509 (1968).

Partial structures in the olefin moiety of the above general formula [1] and the following general formula [2]. In the present invention, the following structural isomers exist, but the present invention includes any structural isomer or a mixture of both structural isomers.

The compound of the above-mentioned general formula [1] can be converted into its pharmacologically acceptable salt or physiologically hydrolyzable carboxylic acid ester by a conventional method.

The compound of the general formula [1] can be produced by the following method. Compound represented by general formula [2] [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge and X represent a halogen atom. ] To the compound represented by: thiazole, 2,3-cyclopentenopyridine, pyridazine, N-methylpyrrolidine, pyrimidine, 3-amino-4-ethoxypyridine, N-ethyl-N-methyl-N-carbamoylamine, or (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group) or The compound [1] of the present invention can be prepared by reacting with and removing the protecting group from the reaction product if necessary.

The compound of the general formula [2] and thiazole or 2,3-cyclopentenopyridine or pyridazine or N
-Methylpyrrolidine or pyrimidine or 3-amino-4
-Ethoxypyridine or N-ethyl-N-methyl-N-
Carbamoylamine or (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group)) or The reaction with can be carried out in an organic solvent such as methylene chloride, chloroform, ether, ethyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, acetone, or a mixed solvent thereof. The reaction is carried out with thiazole, 2,3-cyclopentenopyridine, pyridazine, N-methylpyrrolidine, pyrimidine, 3-amino-4-ethoxypyridine or N-ethyl-N-, based on 1 mol of the compound of the general formula [2]. Methyl-N-carbamoylamine or (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group) or 1 to 5 mol of the compound is used, the reaction temperature is 0 to 40 ° C., and the reaction time is 0.5 to 48 hours.

The protecting group can be removed from the compound [1] of the present invention, if necessary. A carboxyl group in the general formula,
As the protecting group for the amino group and the hydroxyl group, a protecting group usually used in the decomposition of β-lactam synthesis can be appropriately selected and used.

The method of introducing and removing the protective group depends on the type of the protective group, for example, Protective Group
In Organic Synthesis (Protective Groups
in Organic Synthesis: TW Green, Wiley, published in 1981) and the like.

Examples of the carboxyl protecting group include, for example,
t-butyl group, 2,2,2-trichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, benzyl group, 4-methoxybenzyl group, 3,4- Dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group,
Examples thereof include a bis (4-methoxyphenyl) methyl group and a trialkylsilyl group, particularly a 4-methoxybenzyl group,
A benzhydryl group, a 4-nitrobenzyl group, a trimethylsilyl group, a t-butyldimethylsilyl group and the like are preferable.

Examples of the amino group-protecting group include a trityl group, a formyl group, a chloroacetyl group, a trifluoroacetyl group, a t-butoxycarbonyl group, a trimethylsilyl group and a t-butyldimethylsilyl group.

Examples of the hydroxyl-protecting group include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, t-butyl group, benzyl group, 4-methoxybenzyl group. , 4-nitrobenzyl group, formyl group, acetyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group. Group, trityl group and the like.

The method of removing the protecting group will be specifically described.
Trityl group, formyl group, t-butoxycarbonyl group,
Benzhydryl group, 2-methoxyethoxymethyl group, 4
-For removal of a protecting group such as methoxybenzyl group, for example, hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, P
-It can be carried out with an inorganic acid such as toluenesulfonic acid or an organic acid, and trifluoroacetic acid is particularly preferable.

When trifluoroacetic acid is used as the acid, addition of anisole, thioanisole or phenol accelerates the reaction and suppresses side reactions. The reaction can be carried out in a solvent such as water, methylene chloride, chloroform, benzene or the like which does not participate in the reaction or a mixed solvent thereof. The reaction temperature and the reaction time are appropriately selected according to the chemical properties of the compound [1] of the present invention and the kind of the protecting group, and it is particularly preferable to carry out the conditions of ice cooling or heating.

The starting compound [2] of the above-mentioned production method can be produced as follows. General formula [3] [Wherein R ¹ is an optionally protected ami group and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge and X represent a halogen atom. ) The compound represented by the following formula [4] P (R ¹⁰ ) ₃ (4) [wherein R ¹⁰ represents a butyl group or a phenyl group. ] The compound shown by the following general formula [5] is reacted. [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge, R ¹⁰ represents a butyl group or a phenyl group, and X represents a halogen atom. ] To the compound of the following general formula [6] X-CH ₂ CHO [6] [wherein, X represents a halogen atom. ] The compound shown by these is made to react, and if necessary, it can manufacture by removing a protecting group from this reaction product.

The reaction between general formula [3] and general formula [4] is
For example, methylene chloride, chloroform, ether, ethyl acetate, tetrahydrofuran, acetonitrile, N, N-
It can be carried out in an organic solvent such as dimethylformamide, dimethylsulfoxide, acetone, or a mixed solvent thereof. In the reaction, 1 to 5 mol of the compound of general formula [4] is used per 1 mol of the compound of general formula [3], the reaction temperature is 0 to 40 ° C., and the reaction time is preferably 0.5 to 48 hours.

The compound represented by the general formula [5] derived from the general formula [3] and the general formula [4] is reacted with an inorganic or organic base to give the general formula [8]. [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. The electric charge, R ¹⁰ represents a butyl group or a phenyl group. ] It can convert to the phosphorane shown by.

Examples of inorganic or organic bases include alkali metal hydroxides (sodium hydroxide, potassium hydroxide), calcium hydroxide, alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate), alkali metal carbonates (carbonic acid). Sodium, potassium carbonate), calcium carbonate, triethylamine, pyridine, butyllithium.

This reaction is carried out with water, acetone, ethanol,
It can be carried out in a solvent of propanol, methanol, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or a mixed solvent thereof. Further, it may be mixed with water or a two-layer system.
The reaction temperature is not particularly limited and is usually under cooling or heating. The phosphorane of the general formula [8] obtained here is separated or is not separated and is represented by the general formula [6] X—CH ₂ —CHO [6] [wherein, X represents a halogen atom. ] The compound of the general formula [2] as a raw material can be obtained by the reaction with the aldehyde represented by the formula [1].

The reaction between the phosphorane of the general formula [8] and the aldehyde of the general formula [6] is carried out by water, acetone, ethanol, propanol, methanol, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N, N. It may be used in a solvent of dimethylformamide or pyridine, or a mixed solvent thereof, or water, or a two-layer system. The reaction temperature is not particularly limited, and the reaction is carried out under cooling or heating.

The compound of the general formula [3] in the above production method can be produced by the method of Japanese Patent Application No. 5-77458.

[0042] [In the formula, R ¹ represents an optionally protected amino group. ] The compound represented by the general formula [7] is a novel compound which has not been described in the literature, and is obtained by reacting a reactive derivative at a carboxyl group of isonicotinic acid or a salt thereof with an optionally protected ethylenediamine or a salt thereof. Can be manufactured by. Suitable examples of the reactive derivative at the carboxyl group of isonicotinic acid include acid halides, acid azides, acid anhydrides, active amides, active esters, etc. These are appropriately selected depending on the type of ethylenediamine derivative to be used. To be selected. The reaction of the isonicotinic acid-reactive derivative with the optionally protected ethylenediamine derivative is usually carried out such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. It is carried out in a solvent or mixtures thereof, as well as other organic solvents which do not adversely influence the reaction.

When isonicotinic acid is used in this reaction in the form of free acid or salt, examples of the compounding agent include N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholinoethylcarbodiimide,
N, N'-diethylcarbodiimide, N, N-carbonylbis (2-methylimidazole), trialkyl phosphite, ethyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine and dimethyl Formamide and thionyl chloride,
Vilsmeier reagents obtained by reaction with phosgene, phosphorus oxychloride, etc. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

[Biological activity] The compound [1] of the present invention or a salt thereof is a novel compound and exhibits a high antibacterial activity for inhibiting the growth of a wide range of pathogenic microorganisms including Gram-positive and Gram-negative bacteria.

In order to show the usefulness of the compound [1] of the present invention, the following test was carried out using the following compounds as comparative compounds. The results are shown in Table 1.

Comparative Compound A: Ceftatidime Comparative Compound B: 7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-ylmethoxy) Imino) acetamido] -3- (1,2,3-thiadiazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid (KP-73
6).

1. In vitro antibacterial activity (MIC) Measured according to the standard method of the Japanese Society of Chemotherapy.

2. Staphylococcus aureus and Pseudomonas aeruginosa mouse systemic infection protective effect Infection was induced by inoculating the mouse (ICR strain, male, 4 weeks old, N = 5) into the reintroduction space. Each drug was subcutaneously administered 1 hour after infection, and E was determined from the survival rate of mice 1 week after infection.
The D ₅₀ value was calculated.

[0049]

[Table 1]

As shown in Table 1, the compound of the general formula [1] and its pharmacologically acceptable salt or physiologically hydrolyzable non-toxic ester are useful as antibacterial agents. That is, a heterocycle-substituted hydroxypyridone at position 7 of cephalosporin
The novel compound of the present invention having an ammonium propenyl group at the 3-position is compared with Comparative Compound A, which is widely used as a therapeutic agent for Pseudomonas aeruginosa infections, and is compared with gram-positive staphylococcus and Gram-negative bacterium Pseudomonas aeruginosa. It has excellent antibacterial activity against all bacteria and has a remarkably excellent therapeutic effect on infectious diseases. Further, when compared with Comparative Compound B, which is an antibacterial agent currently under development, the compound of the present invention is ineffective against Staphylococcus which is a Gram-positive bacterium, whereas the compound of the present invention is extremely excellent. It is shown that the compound of the present invention has a broad and well-balanced antibacterial spectrum, as well as showing the therapeutic effect on the infectious disease and also showing the excellent therapeutic effect on the infectious disease against Gram-negative bacterium Pseudomonas aeruginosa. ,
It was clarified that it has a strong antibacterial action and a remarkably excellent therapeutic effect on infectious diseases.

The compounds of the present invention can be used in the form of pharmaceutical preparations suitable for parenteral administration, oral administration or external administration, by mixing with carriers of solid or liquid excipients known in the art. Examples of the medicinal materials include injections, syrups, liquids such as emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, these formulations may optionally contain additives such as auxiliary agents, stabilizers, lubricants, emulsifiers, absorption promoters and surfactants which are usually used. Distilled water for injection, Ringer's solution,
Examples thereof include glucose, sucrose syrup, gelatin, edible oil, cocoa oil, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like.

Furthermore, the compound of the present invention can be used as an antibacterial agent for the treatment and prevention of bacterial infections in humans or animals. Although the dose varies depending on the patient's age and sex and other conditions, it is usually preferable to administer 1 to 2000 mg / kg per day in 1 to 5 divided doses.

[0053]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 4-Methoxybenzyl 3-
((Z) -3-Chloro-1-propen-1-yl) -7
β-((Z) -2- (2- (5- (3,4-bis (4-
Methoxybenzyl

4-Methoxybenzyl 3-chloromethyl-7β-((Z) -2- (2- (5- (3,4-bis (4-methoxybenzyloxy) pyridin-6-yl))
1,3,4-oxadiazol-2-yl) thio) ethoxyimino) -2- (2-tritylaminothiazole-
To a solution of 2-yl) acetamido-3-cephem-4-carboxylate (18.0 g, 14.3 mmol) in acetone (60 ml) was added sodium iodide (2.14 g, 14.3 mmol) and triphenylphosphine (4.12 g, 15.7 mmol). Sequentially added and stirred at room temperature for 1 hour. After filtering this with Celite,
The solvent was distilled off. The obtained residue is chloroform (80 ml)
After the solution was dissolved in water, saturated saline (21.5 ml) and 1N aqueous sodium hydroxide solution (21.5 ml) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated and dried over anhydrous magnesium sulfate,
The insoluble material was filtered off. Molecular sieves 4 Å (4.29 g) and N, 0-bis (trimethylsilyl) acetamide (7.07 ml, 28.6 mmol) were sequentially added to this, and after stirring at room temperature for 15 minutes, chloroacetaldehyde chloroform solution (16.8 ml) was further added. Stir for 3 hours.
The reaction solution was concentrated, ethyl acetate (600 ml) was added, the insoluble material was filtered off, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [methylene chloride] to obtain the title compound as a yellow amorphous substance. 6.63 g (yield
36%)

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.27 (1H, d, J = 18.1Hz), 3.42 (1H,
d, J = 18.1Hz), 3.45-3.90 (4H, m), 3.78 (3
H, s), 3.79 (3H, s), 3.81 (3H, s), 4.50
-4.75 (2H, m), 5.04 (1H, d, J = 4.9Hz), 5.
10-5.19 (6H, m), 5.66 (1H, dt, J = 10.7,
8.3Hz), 5.98 (1H, dd, J = 9.3, 4.9Hz), 6.16
(1H, d, J = 11.2Hz), 6.69 (1H, s), 6.84-
6.95 (8H, m), 7.24-7.40 (23H, m), 7.76 (1
H, s), 8.14 (1H, s).

(Example 2) 4-methoxybenzyl 3-
((E) -3-iodo-1-propen-1-yl) -7
β-((Z) -2- (2- (5- (3,4-bis (4-
Methoxybenzyloxy) pyridin-6-yl) 1,
3,4-oxadiazol-2-yl) thio) ethoxyimino) -2- (2-tritylaminothiazol-4-
Il) acetamide-3-cephem-4-carboxylate

A solution of the compound of Example 1 (34.9 mg, 27.2 μmol) in acetone (0.7 ml) was added to sodium iodide (12.2 mg, 8 ml).
1.6 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent, ether was added, and the precipitated crystals were collected by filtration,
The title compound was obtained as a reddish brown powder. 45.1 mg (yield 100
%)

¹ H-NMR (400 MHz, CDCl ₃ ,
δ): 3.79 (6H, s), 3.81 (3H, s), 3.90 (2)
H, d, J = 8.3Hz), 4.97 (1H, d, J = 4.9Hz), 5.
12-5.20 (6H, m), 5.96 (1H, dd, J = 9,5,
4.9Hz), 6.07 (1H, dt, J = 15.6, 7.8Hz), 6.68
(1H, s), 6.85-6.93 (7H, m), 6.91 (1H,
d, J = 15.6Hz), 6.97 (1H, s), 7.28-7.41 (21
H, m), 7.75 (1H, s), 8.14 (1H, s).

Example 3 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3-pyridinio-1-propen-1-yl) -3-cephem-4-carboxylate sulfate

The compound of Example 1 (300 mg, 234 μmol) and sodium iodide (105 mg, 702 μml) in acetone (3 m
l) The solution was stirred at room temperature for 30 minutes and then the solvent was distilled off. This was dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. This was dissolved in N, N-dimethylformamide (1.5 ml) and pyridine (22.7 μl) was added.
, 281 μmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was triturated with diisopropyl ether and then air-dried to obtain a brown powder. Anisole (1.
5 ml) and trifluoroacetic acid (1.5 ml) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Diisopropyl ether (100
(ml) and the precipitated crystals were collected by filtration. This was suspended in water (4 ml), adjusted to pH 7.2 with a saturated sodium hydrogen carbonate aqueous solution, and further adjusted to pH 2 with 6N sulfuric acid, and then Lichroprep RP-8 Loba.
Purify by r column (water: acetonitrile = 4: 1),
Lyophilization gave the title compound as a pale yellow powder. 2
3.1 mg (16% yield)

SIMS (Positive, m / z): 724 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 4.40
(2H, brs), 5.10 (1H, d, J = 4.9Hz), 5.34
(2H, d, J = 5.9Hz), 5.71 (1H, d, J = 4.9H)
z), 5.95-6.10 (1H, m), 6.77 (1H, s), 7.13
(1H, d, J = 15.6Hz), 7.52 (1H, s), 8.06
(1H, s), 8.15 (2H, t, J = 6.8 Hz), 8.60
(1H, t, J = 8.3Hz), 9.02 (2H, d, J = 5.9H)
z).

IR (KBr, cm ^-1 ): 3375, 1765, 162
0.

Example 4 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (carbamoylethylmethyl) ammonio-1-propen-1-yl) -3
-Cephem-4-carboxylate sulfate

The compound of Example 1 (300 mg, 234 μmol) and (ethylmethyl) aminoacetamide (32.6 mg, 281 μm)
(mol) in the same manner as in Example 3 to obtain the title compound as a pale yellow powder. 40.0 mg (20% yield)

SIMS (Positive, m / z): 761 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 1.26
(3H, t, J = 7.3Hz), 3.10 (3H, s), 3.93 (2
H, s), 4.23 (2H, bs), 4.42 (2H, d, J =
6.3Hz), 5.22 (1H, d, J = 5.4Hz), 5.84 (1H,
d, J = 4.4Hz), 6.00-6.15 (1H, m), 6.82 (1
H, s), 7.05 (1H, d, J = 15.6Hz), 7.52 (1
H, s), 8.09 (1H, s).

IR (KBr, cm ^-1 ): 3400, 1755, 167
0.

Example 5 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3-thiazolio-1-propan-1-yl) -3-cephem-4-carboxylate sulfate

Using the compound of Example 1 (400 mg, 312 μmol) and thiazole (26.5 μl, 374 μmol) and in the same manner as in Example 3, the title compound was obtained as a yellow powder.
20.6 mg (8% yield)

SIMS (Positive, m / z): 730 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 4.42
(2H, t, J = 6.8Hz), 5.22 (1H, d, J = 4.9H)
z), 5.32 (2H, d, J = 5.4Hz), 5.84 (1H, d, J
= 4.9Hz), 6,20-6.35 (1H, m), 6.82 (1H,
s), 6.96 (1H, d, J = 16.1Hz), 7.50 (1H,
s), 8.07 (1H, s), 8.35 (1H, t, J = 3.4H
z), 8.50 (1H, d, J = 3.9Hz), 10.19 (1H,
s).

IR (KBr, cm ^-1 ): 3400, 1770, 166
0.

Example 6 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (3-carbamoylpyridinio) -1-propen-1-yl) -3-cephem-4-carboxylate Dihydrochloride

Sodium iodide (210 mg, 1.40 mm) was added to a solution of the compound of Example 1 (600 mg, 467 μmol) in acetone (12 ml).
ol) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off, methylene chloride was added, the insoluble matter was filtered off, and then the solvent was distilled off.
This was dissolved in N, N-dimethylformamide (6 ml), nicotinic acid amide (68.4 mg, 560 μmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was triturated with diisopropyl ether and then air-dried to obtain a brown powder. Anisole (2 ml) and trifluoroacetic acid (2 ml) were sequentially added to this, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (200 ml), and the precipitated crystals were collected by filtration and air-dried to obtain a light brown powder. After suspending this in water (4 ml), the pH was adjusted to 7.2 with a saturated aqueous sodium hydrogen carbonate solution, and the pH was adjusted to 10
Lichroprep RP-8 Lobar after adjusting to pH 2 with 10% HCl
It was purified by column (water: acetonitrile = 4: 1) and freeze-dried to obtain the title compound as a yellowish white powder. 56.8
mg (14% yield)

SIMS (Positive, m / z): 767 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.79
(1H, d, J = 19.5Hz), 4.41 (2H, t, J = 6.4H)
z), 5.22 (1H, d, J = 4.9Hz), 5.44 (2H, d, J
= 5.9Hz), 5.83 (1H, d, J = 4.9Hz), 6.32 (1H,
dt, J = 15.6,7.8Hz), 6.81 (1H, s), 7.07 (1
H, d, J = 15.6Hz), 7.49 (1H, s), 8.07 (1
H, s), 8.27 (1H, t, J = 7.3Hz), 8.94 (1H,
d, J = 7.3Hz), 9.14 (1H, d, J = 5.8Hz), 9.44
(1H, s).

IR (KBr, cm ^-1 ): 3400, 1770, 166
Five.

Example 7 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (2,3-cyclopentenopyridinio) -1-propen-1-yl) -3-
Cephem-4-carboxylate dihydrochloride

The compound of Example 1 (600 mg, 467 μmol) and 2,3-cyclopentenopyridine (65.5 μl, 560 μmo)
By the same method as in Example 6 using l), the title compound was obtained as a colorless powder. 33.8 mg (yield 9%)

SIMS (Positive, m / z): 764 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 2.22
(2H, t, J = 7.3Hz), 3.13 (2H, t, J = 7.3H)
z), 4.38 (2H, t, J = 5.9Hz), 5.06 (1H, d, J
= 4.9Hz), 5.23 (2H, d, J = 5.9Hz), 5.65 (1H,
d, J = 4.9Hz), 5.80-5.90 (1H, m), 6.75 (1
H, s), 7.10 (1H, d, J = 15.6Hz), 7.55 (1
H, s), 7.87 (1H, t, J = 7.3Hz), 8.04 (1H,
s), 8.37 (1H, d, J = 7.3Hz), 8.73 (1H, d,
J = 6.4Hz).

IR (KBr, cm ^-1 ): 3350, 1760, 160
0, 1540.

Example 8 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (4-hydroxyethylthiopyridinio) -1-propen-1-yl) -3
-Cephem-4-carboxylate dihydrochloride

The compound of Example 1 (600 mg, 467 μmol) and 4- (2-hydroxyethylthio) pyridine (86.9 mg,
(560 μmol) and in the same manner as in Example 6 to obtain the title compound as a yellowish white powder. 63.6 mg (yield 16%)

SIMS (Positive, m / z): 800 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.79
(1H, d, J = 17.6Hz), 4.42 (2H, t, J = 6.8H
z), 5.15-5.20 (3H, m), 5.83 (1H, d, J = 4.
9Hz), 6.20-6.30 (1H, m), 6.81 (1H, s), 6.
97 (1H, d, J = 15.1Hz), 7.49 (1H, s), 7.96
(2H, d, J = 7.3Hz), 8.07 (1H, s), 8.63 (2
H, d, J = 7.3 Hz).

IR (KBr, cm ^-1 ): 3350, 1765, 162
0, 1540.

Example 9 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3-pyridazinio-1-
Propen-1-yl) -3-cephem-4-carboxylate dihydrochloride

Using the compound of Example 1 (600 mg, 467 μmol) and pyridazine (40.7 μl, 560 μmol) and in the same manner as in Example 6, the title compound was obtained as a pale yellow powder. 51.0 mg (14% yield)

SIMS (Positive, m / z): 725 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.79
(1H, d, J = 18.1Hz), 4.42 (2H, t, J = 6.8H)
z), 5.22 (1H, d, J = 4.9Hz), 5.59 (2H, d, J
= 6.4Hz), 5.84 (1H, d, J = 4.4Hz), 6.29 (1H,
dt, J = 15.6,7.8Hz), 6.82 (1H, s), 7.09 (1
H, d, J = 15.6Hz), 7.49 (1H, s), 8.07 (1
H, s), 8.58-8.61 (1H, m), 8.69-8.73 (1
H, m), 9.61 (1H, d, J = 3.9Hz), 9.88 (1H,
d, J = 5.9Hz).

IR (KBr, cm ^-1 ): 3400, 1775, 166
0,1545.

Example 10 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (1-methylpyrrolidinio) -1-propen-1-yl) -3-cephem-
4-carboxylate dihydrochloride

Using the compound of Example 1 (600 mg, 467 μmol) and 1-methylpyrrolidine (58.2 μl, 560 μmol),
By a method similar to that in Example 6, the title compound was obtained as a yellowish white powder. 89.5 mg (24% yield)

SIMS (Positive, m / z): 730 ([M +
H] ⁺ )

IR (KBr, cm ^-1 ): 3400, 1760, 167
0, 1565.

Example 11 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (3-amino-4-)
Ethoxypyridinio) -1-propen-1-yl) -3
-Cephem-4-carboxylate trihydrochloride

The compound of Example 1 (600 mg, 467 μmol) and 4-ethoxy-3-tritylaminopyridine (213 mg, 56
(0 μmol) and in the same manner as in Example 6 to give the title compound as a colorless powder. 17.9 mg (5% yield)

SIMS (Positive, m / z): 783 ([M +
H] ⁺ )

IR (KBr, cm ^-1 ): 3300, 1760, 161
0,1535.

(Example 12) 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (4- (1,3-dihydroxypropan-2-yl) thiopyridinio) -1
-Propen-1-yl) -3-cephem-4-carboxylate dihydrochloride

The compound of Example 1 (600 mg, 467 μmol) and 4- (1,3-ditrityloxypropan-2-yl)
The title compound was obtained as a colorless powder by the same method as in Example 6 using thiopyridine (375 mg, 560 μmol). 6
8.0 mg (16% yield)

SIMS (Positive, m / z): 830 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 4.42
(2H, t, J = 6.3Hz), 5.15-5.25 (3H, m), 5.
83 (1H, d, J = 4.4Hz), 6.20-6.30 (1H, m),
6.82 (1H, s), 6.99 (1H, d, J = 15.1Hz), 7.
49 (1H, s), 7.96 (2H, d, J = 7.3Hz), 8.07
(1H, s), 8.62 (2H, d, J = 3.9Hz).

IR (KBr, cm ^-1 ): 3350, 1770, 166
0, 1630, 1540.

Example 13 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (4-carbamoylpyridinio) -1-propen-1-yl) -3-cephem-4-carboxylate Dihydrochloride

Using the compound of Example 1 (600 mg, 467 μmol) and isonicotinic acid amide (68.4 mg, 560 μmol) and in the same manner as in Example 6, the title compound was obtained as a colorless powder. 54.9 mg (14% yield)

SIMS (Positive, m / z): 767 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.79
(1H, d, J = 19.5Hz), 4.42 (2H, t, J = 6.4H
z), 5.22 (1H, d, J = 4.9Hz), 5.44 (2H, br
s), 5.84 (1H, d, J = 4.4Hz), 6.25-6.35 (1
H, m), 6.82 (1H, s), 7.04 (1H, d, J = 1
5.6Hz), 7.49 (1H, s), 8.07 (1H, s), 8.43
(2H, d, J = 6.4Hz), 9.17 (2H, d, J = 6.8H)
z).

IR (KBr, cm ^-1 ): 3470, 1820, 170
0, 1685.

Example 14 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (3-methoxypyridinio) -1-propen-1-yl) -3-cephem-
4-carboxylate dihydrochloride

Using the compound of Example 1 (600 mg, 467 μmol) and 3-methoxypyridine (61.1 mg, 560 μmol) and in the same manner as in Example 6, the title compound was obtained as a yellowish white powder. 25.4 mg (7% yield)

SIMS (Positive, m / z): 754 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.78
(1H, d, J = 17.6Hz), 3.99 (3H, s), 4.41
(2H, t, J = 6.4Hz), 5.22 (1H, d, J = 4.9H)
z), 5.40-5.55 (2H, m), 5.84 (1H, dd, J =
4.4Hz), 6.25-6.35 (1H, m), 6.81 (1H, s),
7.07 (1H, d, J = 15.6Hz), 7.48 (1H, s), 8.
06 (1H, s), 8.28 (1H, t, J = 6.3Hz), 9.01
(1H, d, J = 7.8Hz), 9.22 (1H, d, J = 6.3H
z), 9.59 (1H, s).

IR (KBr, cm ^-1 ): 3410, 1755, 167
5, 1465.

(Example 15) 3-((E) -3- (4-
(N-aminoethyl) carbamoylpyridinio) -1-
Propen-1-yl) -7β-((Z) -2- (2-aminothiazol-4-yl) -2- (2- (5- (3-
Hydroxy-4-pyridone-6-yl) 1,3,4-oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-cephem-4-carboxylate trihydrochloride

A solution of the compound of Example 1 (100 mg, 77.9 μmol) in acetone (1 ml) was added with sodium iodide (35.1 mg, 234 mg).
μmol) was added and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off, methylene chloride was added, the insoluble matter was filtered off, and then the solvent was distilled off. This was dissolved in N, N-dimethylformamide (0.5 ml), then the compound of Example 17 (21.7 mg, 81.8 μmol) was added,
The mixture was stirred at room temperature for 3 hours. The reaction solution was triturated with diisopropyl ether and then air-dried to obtain a brown powder. To this, formic acid (0.4 ml) and anisole (0.2 ml) were added and dissolved, then concentrated hydrochloric acid (100 μl) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, washed with ethyl acetate, and the aqueous layer was washed with an HP-20P column [water → water-acetonitrile (95: 5).
→ 80: 20)] and add a small amount of the resulting yellow powder to 10
% Hydrochloric acid, then use Lichroprep RP-8 Lobar column (water-
It was purified by acetonitrile 80:20) and lyophilized to give the title compound as a yellow powder. 4.00 mg (6% yield)

SIMS (Positive, m / z): 810 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.00
-3.10 (2H, m) 4.35-4.50 (2H, brs), 5.22 (1H, d, J = 5.
4Hz), 5.46 (2H, brs), 5.84 (1H, d, J = 4.
4Hz), 6.25-6.35 (1H, m), 6.82 (1H, s), 7.
07 (1H, d, J = 15.1Hz), 7.51 (1H, s), 8.09
(1H, s), 8.50 (2H, d, J = 5.9Hz), 9.22 (2
H, d, J = 6.3 Hz).

IR (KBr, cm ^-1 ): 3422, 1769, 163
4, 1568, 1555, 1464, 1385.

Example 16 7β-((Z) -2- (2-
Aminothiazol-4-yl) -2- (2- (5- (3
-Hydroxy-4-pyridone-6-yl) 1,3,4-
Oxadiazol-2-yl) thio) ethoxyiminoacetamido) -3-((E) -3- (1- (1,3-dihydroxypropan-2-yl) pyridinium-4-yl) thio-1-propane -1-yl) -3-cephem-
4-carboxylate sulfate

The compound of Example 1 (400 mg, 312 μmol) and 1- (1,3-dihydroxypropan-2-yl) -4
Example 3 using thiopyridone (69.3 mg, 374 μmol)
The title compound was obtained as a pale yellowish white powder by a method similar to. 24.2 mg (8% yield)

SIMS (Positive, m / z): 830 ([M +
H] ⁺ ) ¹ H-NMR (400 MHz, DMSO + D ₂ O, δ): 3.85
(4H, d, J = 4.9Hz), 4.41 (2H, brs), 4.64
(1H, t, J = 5.4Hz), 5.18 (1H, d, J = 4.9H)
z), 5.80 (1H, d, J = 4.9Hz), 6.05-6.20 (1H,
m), 6.80 (1H, s), 7.02 (1H, d, J = 15.6H
z), 7.53 (1H, s), 7.96 (2H, d, J = 5.9H
z), 8.10 (1H, s), 8.72 (2H, d, J = 6.8Hz).

IR (KBr, cm ^-1 ): 3400, 1760, 162
Five.

Example 17 4- (2-t-butoxycarbonylamino) ethylcarbamoylpyridine

Nt-butoxycarbonylethylenediamine hydrochloride (336 mg, 1.71 mmol) and isonicotinic acid (211
dicyclohexylcarbodiimide (388 mg, 1.88 mmol) and triethylamine (238 μl, 1.71 mmol) were sequentially added to a tetrahydrofuran (17 ml) suspension of (mg, 1.71 mmol),
The mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1) to give the title compound as a colorless solid. 179 mg (yield
39%)

¹ H-NMR (90 MHz, CDCl ₃ ): 1.44
(9H, s), 3.20-3.60 (4H, m), 7.67 (2H,
d, J = 6.2Hz), 8.72 (2H, d, J = 6.2Hz).

Claims (6)

[Claims] 1. A novel cephem compound represented by the formula [1] and a pharmacologically acceptable salt thereof. [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge, R ⁴ is thiazolinium,
2,3-cyclopentenopyridinium, pyridazinium, N-methylpyrrolidinium, pyrimidinium, 3-
Amino-4-ethoxypyridinium, N-ethyl-N-
Methyl-N-carbamoyl ammonium, (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group), Represents ] 2. A novel cephem compound represented by the formula [2]. [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Represents an electric charge. ] 3. The following general formula [3] [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge and X represent a halogen atom. ] The compound shown by the following general formula [4] P (R ¹⁰ ) ₃ [4] [In the formula, R ¹⁰ represents a butyl group or a phenyl group. ] The compound shown by the following general formula [5] is reacted. [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge, R ¹⁰ represents a butyl group or a phenyl group, and X represents a halogen atom. ] To the compound of the following general formula [6] X-CH ₂ -CHO [6] [In the formula, X represents a halogen atom. ] The compound shown by these is made to react, and a protecting group is removed from this reaction product if needed, The manufacturing method of the novel cephem compound of Claim 2 characterized by the above-mentioned. 4. The following general formula [2]: [Wherein R ¹ is an optionally protected amino group, and R ² is (R ⁵ is a hydrogen atom, a hydroxyl protecting group or an aralkyl group,
R ⁶ represents a hydrogen atom, an amino group protecting group or an aralkyl group), R ³ represents a hydrogen atom, a metal atom, a carboxyl group protecting group, an ester residue or an anion capable of forming a hydrolyzable ester in vivo. Electric charge and X represent a halogen atom. ] To the compound represented by: thiazole, 2,3-cyclopentenopyridine, pyridazine, N-methylpyrrolidine, pyrimidine, 3-amino-4-ethoxypyridine, N-ethyl-N-methyl-N-carbamoylamine, or (R ⁸ is a hydrogen atom or an optionally protected hydroxymethyl group, n is 0 or 1) or -CONH-
R ⁹ (R ⁹ represents a hydrogen atom or an optionally protected aminoethyl group) or The method for producing a novel cephem compound according to claim 1, wherein the protecting group is removed from the reaction product, if necessary. 5. A novel compound represented by the formula [7]. [In the formula, R ¹ represents an optionally protected amino group. ] 6. A cephem compound according to claim 1, a pharmaceutically acceptable salt thereof, a method for producing the same, and an antibacterial agent containing these as an active ingredient.