JPH068300B2 - New cefalosporin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative, more specifically 7- [2- (2-aminothiazol-4-yl) -2- (substituted oxyimino) acetamide]- 3- (N, N-dimethyl-N-substituted phenylalkylammonium methyl) -3-cephem-4-
The present invention relates to a carboxylate derivative, a method for producing the same, and its use.

Prior art β-lactam antibiotics show selective toxicity only to bacteria,
Since it does not affect animal cells, it plays an important role in the prevention and treatment of bacterial infections as an antibiotic with few side effects. In particular, cephalosporin derivatives are generally stable against penicillinase, have a broad antibacterial spectrum, and are often used for prevention and treatment of bacterial infections.

However, on the one hand, resistant staphylococci or resistant Pseudomonas esginosa (Pseud
omonas aeruginosa), for the treatment of intractable infectious diseases caused by glucose non-fermenting Gram-negative bacilli such as Acinetbacter calcoaceticus (Acinetbactercalcoa ceticus),
There is a need for new cephalosporin derivatives that are more potent and have a broad spectrum.

Cephalosporin derivatives having a quaternary ammonium salt structure are disclosed in JP-A-53-53690, JP-A-55-59196, and JP-A-58-174387.
No. 58-198490, No. 60-97983, etc. Particularly, JP-A-58-198490 discloses a compound similar to the compound of the present invention "Example 1: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide]-". 3-
(Tritylammonium) methyl-3-cephem-4-carboxylate] and the like are disclosed compounds in which a quaternary ammonium methyl group is introduced as the 3-side chain of the cephem nucleus.
Further, in the claims of the publication, a benzyl group or a phenethyl group is mentioned as a substituent of the quaternary ammonium group, but regarding the compounds of these substituents, let alone concrete examples, No reference is made to the substituent of the phenyl group as the substituent.

Further, JP-A-60-97983 describes that a cephem compound having a substituted ammonium methyl group at the 3-position and that compound has antibacterial activity. In that claim, the substituted ammonium moiety A at the 3-position of the cephem nucleus is defined as an optionally substituted aliphatic or cyclic ammonio group. Further, in the lower left column on page 3 and the lower right column on page 4 of the publication, the substituted ammonium moiety A
Is described.

In the case of the former, "A is an ammonio group derived from a tertiary aliphatic or a 5- to 7-membered (preferably 5- to 6-membered) cyclic amine, and the ammonio group is 11 kinds of groups including a hydroxyl group. Ordinary substituents may be mono- or poly-substituted ".

Further, in the latter case, since it is an example of a preferable compound, it is explained in a slightly more concrete form than the former, and "A is 3
It is only described as "ammonio group derived from higher grade organic aliphatic or cyclic amine". The description of the publication relating to the compound similar to the present application is described only slightly on page 4, lower right column, line 7, “dimethylbenzylammonium group” and Example 30.
And only Example 32.

However, N, N-, which is the substituent at the 3-position of the cephem nucleus,
N, N-dimethyl-N-substituted phenyl lower alkylammonium methylcephem compounds having adjacent hydroxyl groups as substituents of the phenyl group of the dimethyl-N-substituted phenyl lower alkylammonium methyl group are not shown at all. Currently cefotaxime [Antimicrobial Agents and Chemotherapy] Volume 14, 749
Page (1978)], etc., the third-generation cephalosporin derivatives show excellent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, especially intestinal bacteria, but have a strong antibacterial action against Pseudomonas, Acinetobacter, etc. Is rare.

Therefore, a more potent and effective therapeutic agent is desired for the treatment of serious infectious diseases caused by these bacteria or a mixed infection of these bacteria and other bacteria.

PROBLEMS TO BE SOLVED BY THE INVENTION Existing cephalosporin derivatives are resistant to Staphylococcus with various resistance mechanisms or resistant Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Serratia marcescens (Serratiamarcescens) and other glucose non- Low antibacterial activity against issued Gram-negative bacilli.

Cefotaxime and other third-generation cephalosporin derivatives show excellent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, especially intestinal bacteria, but rarely show strong antibacterial activity against Pseudomonas and Acinetobacter. Is.

Ceftazidime [Antimicrobial Agent and Chemotherapy
al Agents and Chemotherapy), 17: 876, (1980
Year]] is the most excellent compound among existing cephalosporin compounds against Pseudomonas and Acinetobacter, but there are various resistant bacteria and it is not always satisfactory.

Therefore, for the treatment of intractable infections caused by these bacteria or a mixed infection of these bacteria with other bacteria, new cephalosporin derivatives having a stronger and broad spectrum are required.

Means for Solving the Problems The present inventors have studied a novel cephem compound having an N, N-dimethyl-N-substituted phenyl lower alkylammonium methyl group as the 3-side chain of the cephem nucleus, and as a result, N, N An N, N-dimethyl-N-substituted phenyl lower alkylammonium methylcephem derivative having an adjacent hydroxyl group as a phenyl group of a dimethyl-N-substituted phenyl lower alkylammonium methyl group,
The antibacterial activity is remarkably strong against Gram-negative bacteria, particularly Pseudomonas aeruginosa, Pseudomonas cepacia, and other glucose-nonfermenting Gram-negative bacilli, in comparison with known cephalosporin derivatives in which the phenyl group is unsubstituted. Find out that
The present invention has been completed.

The present invention has the general formula (In the formula, R ¹ may be substituted with a carboxyl group, a linear, branched or cyclic lower alkyl group, R ² is a hydrogen atom or a hydroxyl group, R ³ and R ⁴ are the same and are adjacent to each other. The present invention relates to a compound represented by a hydroxyl group bonded to a carbon atom, n is an integer of 1 to 5), a salt thereof or a physiologically hydrolyzable ester thereof, a method for producing the same and use thereof.

The compound [I] of the present invention shows an excellent antibacterial action and also an excellent antibacterial action against Pseudomonas and Acinetobacter which are resistant to ceftazidime.

The compound of the present invention has a 2- (2-aminothiazol-4-yl) -2- (substituted oxyimino) acetamide group as a side chain at the 7-position, and has N, N-dimethyl-N- (3, The compound having a 4-dihydroxyphenyl) ammoniummethyl group is particularly excellent in antibacterial action.

Generally, the substitution on the oximino group can take the geometrical isomeric structure of E or Z, but the substitution on the oximino group contained in the acylamino moiety at the 7-position of the compound of the general formula [I] is Z.
It has the structure of.

Next, various terms and symbols referred to in this specification will be described.

Linear, optionally substituted by a carboxyl group,
The branched or cyclic lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms or a cyclic alkyl group having 3 to 7 carbon atoms, which may be substituted with a carboxyl group, For example, methyl group, ethyl group,
n-propyl group, isopropyl group, n-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxy-1-cyclopropyl group, 1-carboxy-2-cyclobutyl group, 1-
Carboxy-1-cyclopentyl group, 1-carboxy-
Examples thereof include a 1-cyclohexyl group.

The substituted phenyl group of the N, N-dimethyl-N-substituted phenyl lower alkylammonium methyl group at the 3-position of the cephem nucleus is, for example, 2,3-dihydroxyphenyl, 3,4-dihydroxyphenyl or 2,3,4-triphenyl. Hydroxyphenyl, 2,
Examples include 3,5-trihydroxyphenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, 2,4,6-trihydroxyphenyl and 3,4,5-trihydroxyphenyl. To be

The substituted phenyl lower alkyl group is, for example, a substituted phenylmethylene group, a substituted phenyldimethylene group, a substituted phenyltrimethylene group, a substituted phenyltetramethylene group, a substituted phenylpentamethylene group and the like.

Examples of the amino protecting group include a trityl group, a formyl group, a chloroacetyl group, a trifluoroacetyl group, a t-butoxycarbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, and the like, and trityl which can be easily removed by an acid treatment. Groups are particularly preferred.

Examples of the carboxyl protecting group include the following groups. Lower alkyl group such as t-butyl group; haloalkyl group such as 2,2,2-trichloroethyl group; alkanoyloxyalkyl group such as acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 2-acetoxyethyl group, 1 -Propionyloxyethyl group; 1- (ethoxycarbonyloxy) ethyl group; phthalidyl group; alkanesulfonylalkyl group such as methanesulfonylmethyl group, 1-methanesulfonylethyl group; aralkyl group such as benzyl group, 4-methoxybenzyl group, 4- Nitrobenzyl group, phenethyl group, trityl group, benzhydryl group, bis (4-methoxyphenyl) methyl group, 3,4-dimethoxybenzyl group; (5-substituted-2-oxo-1,3-dioxole
-4-yl) methyl group such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group; alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group, and acid treatment Particularly preferred are benzhydryl groups and t-butyl groups, which can be easily removed by.

The protective group for the hydroxyl group, 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, t-butyl group, benzyl group, 4-nitrobenzyl group, acetyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, acetonide, trimethylsilyl group, t-butyldimethylsilyl group and the like can be mentioned.

Examples of the halogen atom for X include chlorine, bromine, iodine and the like. Examples of the leaving group include an acetoxy group,
Examples thereof include a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a phenylsulfonyloxy group and a p-toluenesulfonyloxy group, and X is particularly preferably a bromine atom or an iodine atom.

X Examples of the anions include chlorine ion and bromine ion.
Halogen ions such as iodine and iodine ions, sulfate ions, sulfur ions
Acid hydrogen ion, methyl sulfate ion, p-toluene sulfone
Acid ion, methanesulfonate ion, trifluoroacetic acid
Anions such as ions may be mentioned.

R ² , R ³ and R ^{4 of the} general formula [I] and R ⁸ , R ⁹ and R of the general formula [III], the general formula [IV], the general formula [V] and the general formula [VII]
The substitution position of ¹⁰ is not particularly limited as long as it is on the benzene ring, but a compound having a hydroxyl group adjacent to the 3rd and 4th positions of the phenyl group is particularly preferable.

The compound of the general formula [I] can be produced by any of the following Method A and Method B.

Method A general formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁶Is a hydrogen atom
Or carboxyl protecting group, R⁷Protected carboxyl
Linear, branched or cyclic, which may be substituted by a group
-Like lower alkyl group, X is a halogen atom or a leaving group, Y
Represents S or SO) or a salt thereof
And the general formula(In the formula, R⁸Is a hydrogen atom or optionally protected hydroxy
Base, R⁹And R^TenAre identical and bond to adjacent carbon atoms
Optionally protected hydroxyl group, R¹¹Is a hydrogen atom or
Methyl group, n is an integer of 1 to 5)
Reaction with the general formula(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^Ten, R¹¹, Y and n are forward
X has the following meaning Is an anion)
Compound and, if necessary, methylated and / or
After reduction, the protecting group is removed.

When the compound of general formula [I] is produced by the method A, the compound of general formula [II] is first reacted with the compound of general formula [III] or a salt thereof in a solvent. When a hydrochloride, hydrobromide, sulfate, acetate or the like is used as the salt of the compound of the general formula [III], the reaction is carried out in the presence of a neutralizing amount of a tertiary amine such as triethylamine. Examples of the solvent include methylene chloride, chloroform, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-
A non-aqueous organic solvent such as dimethylformamide or dimethyl sulfoxide, or a mixture thereof is used. General formula [II
The compound [I] can be used after being silylated with a silylating agent such as N, O-bis (trimethylsilyl) acetamide in the above solvent. The amount of the compound of the general formula [III] used is 1 to 2 mol per 1 mol of the compound of the general formula [II]. The reaction temperature is 0 to 35 ° C, and the reaction is completed in 0.5 to 5 hours.

Further, after reacting the compound of the general formula [III] and the compound of the general formula [II] in which the substituent R ¹¹ is a hydrogen atom, the product is isolated,
Or subjected to methylation reaction with no example methyl iodide to isolate, ammonio compound R ¹¹ is a methyl group [I
V] can also be obtained.

When this methylation reaction is carried out in the above non-aqueous organic solvent,
The amount of methyl iodide used is 1 to 30 mol, preferably 3 to 15 mol, per 1 mol of the product, and the reaction temperature is -30 to +35.
The reaction is completed in 5 to 48 hours at ℃. Further, an ammonio compound [IV] in which R ⁹ is a methyl group can also be obtained by reacting the product with excess methyl iodide at 10 to 35 ° C. for 5 to 20 hours in the absence of a solvent.

When the compound of the general formula [II] in which the group Y is SO is used, the compound of the general formula [IV] is prepared by a known method, for example, Journal of Organic Chemistry.
ganic Chemistry), 35, 2430, (1970), Synthesis, 58, (1979) or journal
Chemical Research, 34
Reduce by the method described on page 1, (1979), etc. For example, the compound of the general formula [IV] in which the group Y is SO is dissolved in an inert organic solvent such as acetone, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and the like, potassium iodide or sodium iodide is added, and It can be reduced by adding acetyl chloride dropwise at 0 ° C and reacting at -20 to -10 ° C for 1 to 2 hours. The amount of iodide used is 3.5 to 10 mol, and the amount of acetyl chloride used is 1.5 to 5 mol, based on 1 mol of the compound of the general formula [IV]. When the compound thus obtained has a carboxyl protecting group, an amino protecting group or a hydroxy protecting group, the compound of the general formula [I] is obtained by removing the protecting group.

The protecting group can be removed by appropriately selecting a conventional method according to the type of the protecting group. Removal of the protecting group
For example, a method using an acid is preferable, and examples of the acid include inorganic or organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid.
Trifluoroacetic acid is particularly preferable. When trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole. Further, this reaction is preferably carried out in an inert solvent such as an organic solvent such as methylene chloride, ethylene chloride, benzene or a mixed solvent thereof, particularly methylene chloride. The reaction temperature is not particularly limited, and may be appropriately selected according to the chemical properties of the raw material compound and the reaction product, the type of protective group, the type of removal method, or the like, or the reaction is performed under mild conditions such as cooling or heating. Is preferred.

The compound of the general formula [II] in which the group Y is S has the general formula (Wherein R ⁶ and X have the above-mentioned meanings and Z represents a hydrogen atom or an acyl group), and the compound is acylated with a carboxylic acid of the general formula [VI] or a reactive derivative thereof. It is obtained by The general formula [II] in which the group Y is SO
Is a compound of the general formula [II] in which the group Y is S is oxidized with an equimolar amount of m-chloroperbenzoic acid in an organic solvent that does not participate in the reaction such as methylene chloride, ethylene chloride and chloroform under ice cooling. It is obtained by doing. The compound of the general formula [II] in which the substituent X is an iodine atom can be produced by reacting the compound of the general formula [II] in which X is a chlorine atom with sodium iodide.

The compound of the general formula [V] is a compound of the general formula [V
It can be obtained by reacting a compound of formula [III] with a compound of general formula [III] in which R ¹¹ is a methyl group, and then deacylating.

The compound of the general formula [VIII] has the general formula Easily prepared by treating the compound represented by the formula (wherein R ⁶ and Z have the above-mentioned meanings) according to the method described in, for example, JP-A Nos. 50-76089 and 56-86187. can do.

Method B general formula(In the formula, R⁶Is a hydrogen atom or a carboxyl protecting group, R⁸Is water
Elementary atom or optionally protected hydroxyl group, R⁹And R^TenIs
Identical and protected attached to adjacent carbon atoms
Optionally a hydroxyl group, n is an integer of 1 to 5, X Is an anion
Shown), a salt thereof or a silyl compound thereof
General formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁷Is protected
A straight chain which may be substituted by a carboxyl group
A branched, branched or cyclic lower alkyl group)
Acylated with carboxylic acid or its reactive derivative
General formula(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^Ten, N and X Is the above
The compound represented by
Remove the guardian.

When the compound of the general formula [I] is produced by the method B, the compound of the general formula [V] is first reacted with the carboxylic acid of the general formula [VI] or its reactive derivative in a solvent. Is preferably used. The reaction is carried out in an inert solvent such as water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide and the like or a mixture thereof. The amount of the reactive derivative of the compound of general formula [VI] used is 1 to 1.5 mol per 1 mol of the compound of general formula [V]. Reaction temperature is -40 to +
The temperature is 40 ° C, preferably -20 to + 30 ° C. When the acid chloride of the compound of the general formula [VI] is used, it is preferable to carry out the reaction in the presence of an alkali metal carbonate or an organic amine such as trimethylamine, triethylamine, N-methylmorpholine and the like.

As the reactive derivative of the compound of the general formula [VI], for example, acid halide, mixed acid anhydride, active ester and the like are used. The acid halide of the compound of general formula [VI] has the general formula
It is obtained by reacting the compound of [VI] with a halogenating agent. The reaction is carried out in an inert solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene and the like or a mixture thereof. As a halogenating agent,
For example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene and the like are used. The amount of halogenating agent used is 1-10 mol, preferably 1-1.5 mol, per 1 mol of the compound of the general formula [VI], and the reaction temperature is -40 to + 100 ° C, preferably -20 to + 20 ° C. , The reaction is 10-60 minutes.

The mixed acid anhydride of the compound of general formula [VI] can be obtained by reacting the compound of general formula [VI] with alkyl chlorocarbonate, aliphatic carboxylic acid chloride and the like. The reaction is carried out in an inert solvent such as acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide and the like or a mixture thereof. The reaction is preferably carried out in the presence of a tertiary amine such as triethylamine and N-methylmorpholine, the reaction temperature is -30 to + 20 ° C, preferably -15 to 0 ° C, and the reaction is 10 to 30 minutes. is there.

The active ester of the compound of general formula [VI] is obtained by reacting the compound of general group [VI] with preferably 1 to 1.2 mol of N-hydroxy compound or phenol compound.
The reaction is carried out in an inert solvent such as acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, N, N-dimethylformamide, etc. or a mixture thereof. Examples of N-hydroxy compounds include N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxybenzotriazole, and examples of phenol compounds include 4-nitrophenol, 2,4-dinitrophenol, and 2,4,5-trichlorophenol. , Pentachlorophenol, etc. are used. The reaction is preferably carried out in the presence of 1-1.2 mol of a condensing agent, for example N, N'-dicyclohexylcarbodiimide. The reaction temperature is -30 to + 40 ° C, preferably -10 to + 25 ° C, and the reaction time is
30 to 120 minutes.

After completion of the reaction, the product [VII] is separated and, if necessary, the protecting group is removed in the same manner as in Method A to obtain the compound of the general formula [I].

The compound of general formula [I] can be converted into a salt or a physiologically hydrolyzable ester by a conventional method.

The salt of the compound of the general formula [I] is a pharmaceutically acceptable conventional salt, for example, a salt with an alkali metal such as sodium and potassium; a salt with an alkaline earth metal such as calcium and magnesium; N, N ′ -Dibenzylethylenediamine,
Salts with organic amines such as procaine; hydrochloric acid, sulfuric acid, nitric acid,
Salts with inorganic acids such as perchloric acid and hydrobromic acid; salts with organic acids such as acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid; methanesulfonic acid, isethionic acid , Salts with organic sulfonic acids such as p-toluenesulfonic acid; salts with amino acids such as aspartic acid and glutamic acid.

Examples of the physiologically hydrolyzable ester represented by the general formula [I] include alkanoyloxyalkyl esters such as acetoxymethyl ester and pivaloyloxymethyl ester,
Alkoxycarbonyloxyalkyl esters such as 1- (ethoxycarbonyloxy) ethyl, phthalidyl esters, and (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl (5-substituted-2- Oxo-1,3-dioxole-4
-Yl) methyl esters and the like are preferable.

The minimum inhibitory concentration (MIC: μ / m) of the compound of the present invention against various bacteria was cefotaxime, ceftazidime, comparative compound 1, comparative compound, comparative compound 3 and comparative compound 4 as comparative compounds. It was measured by the agar plate dilution method using (Nissui) (bacteria number: 10 ⁶ CFU / m). The results are shown in the table below.

As is clear from this result, among the compounds of formula I, compounds having two hydroxyl groups adjacent to the benzene nucleus are gram-negative bacteria, especially glucose non-fermenting gram-negative bacilli such as Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas maltophilia. , Shows excellent antibacterial activity against Acinetobacter calcoaceticus. In particular, these compounds are Pseudomonas aeruginosa AKR-resistant to known cephalosporin derivatives.
Pseudomonas resistant to 17 and ceftazidime
It is also excellent in exhibiting strong antibacterial activity against Martophylla IID1275.

Introducing a hydroxy group at the 3- and 4-positions of the benzene nucleus dramatically increases the antibacterial activity against Gram-negative bacteria in general, and especially Pseudomonas and Acinetobacter. For example, Pseudomonas aeruginosa AK109 has a 2,3-dihydroxy form. The compounds of Examples 1, 2, 4 and 5 exhibited 125 times, 32 times, 500 times, and 500 times antibacterial activity, respectively, as compared to the compound having no substituent on the benzene nucleus (Comparative Compound 4). .

For Pseudomonas aeruginosa AKR17 resistant to all cephalosporins including ceftazidime, the compounds of Examples 1, 2, 4 and 5 were 128 times, 32 times and 2000 times, respectively, of the unsubstituted compound (Comparative Compound 4). , And showed 2000 times the antibacterial activity.

For Pseudomonas cepacia 23, the compounds of Examples 1, 2, 4, and 5 were 16 times, 16 times, and 10 times that of comparative compound 4, respectively.
The antibacterial activity was 00 times and 500 times.

The compounds of Examples 1, 2, 4, and 5 were 128 times, 64 times, and 250 times, respectively, against Acinetobacter calcoaceticus.
The antibacterial activity was doubled and 250 times higher.

The compounds of Examples 4 and 5 each showed 8-fold antibacterial activity against Pseudomonas maltophilia, which is resistant to ceftazidime.

The compounds of the present invention showed strong antibacterial activity against susceptible and resistant Gram-positive and Gram-negative bacteria, especially resistant Pseudomonas aeruginosa, Pseudomonas cepacia, Acinetobacter calcoaceticus and the like.

Accordingly, the present invention is further useful as an antibacterial agent containing a salt of the compound of formula I or a physiologically hydrolyzable ester thereof as an active ingredient.

The compound of the present invention can be used in the form of a pharmaceutical preparation suitable for oral administration, parenteral administration or external administration, by mixing with a carrier of a solid or liquid excipient. Examples of the pharmaceutical preparation include injections, syrups, liquids such as emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.

The above-mentioned preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, the injection may contain additives such as distilled water for injection, physiological saline, a solution such as Ringer's solution, a preservative such as methyl paraoxybenzoate and propyl paraoxybenzoate.

Liquids such as syrups and emulsions include sorbitol syrup, methylcellulose, glucose, sucrose syrup,
Gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, edible oil, tonsil oil, coconut oil, oily ester, sorbitan monooleate, propylene glycol, glycerin, ethyl alcohol, water, etc., gum arabic, gelatin, lecithin, etc. The emulsifier, surfactant such as tween, span, etc. may be contained. As the solid agent, lactose, sucrose, corn starch, calcium phosphate, magnesium stearate, talc, silicic acid, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, polyethylene glycol, sodium lauryl sulfate and the like are used. Examples of bases for ointments and suppositories include cocoa butter, glycerides, polyethylene glycols, white vaseline and the like. You may contain a surfactant and an absorption promoter as needed.

The compound I of the present invention can be used for the treatment and prevention of bacterial infections such as respiratory infections, urinary tract infections, obstetrics and gynecologic infections, purulent diseases, and surgical infections. The dose varies depending on the age and condition of the patient, but usually 1 to 10 per day.
Used in the range of 0mg / Kg, 5-30mg / Kg per day 2
It is preferable to administer in 4 divided doses.

Here, using the compound of Example 5 as a representative compound, "GLP
4 weeks IC according to “Guideline for Standards and Toxicity Test Law” (supervised by the Ministry of Health and Welfare Pharmaceutical Affairs Bureau Examination Division; Pharmaceutical Affairs Daily)
R Female mice (n = 3) were treated as a group, and the concentration of the drug solution was 100 m with distilled water for injection containing a neutralizing amount of sodium hydrogen carbonate.
It was diluted to g / ml, and a single intravenous administration was performed at a dose rate of 1 ml / min. As a result, the acute toxicity value (ED ₅₀ ) for the mouse was 1.5 g / Kg or more. In addition,
No deaths of mice for 3 days including the administration day were observed.

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

Reference Example Reference Example 1 7-[(Z) -2 (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [N, N-dimethyl-N- (4-hydroxy-3-methoxy) benzylammonium] methyl-3-cephem-4-carboxylate (A) Benzhydryl 3-chloromethyl-7- [(Z) -2
-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1-oxide benzhydryl 3-chloromethyl-7-[(Z) -2-
2.5 g (2.79 mmol) of methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate was dissolved in 25 m of benzene, and 640 mg of metachloroperbenzoic acid (3.27) under ice cooling. (Mmol) and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, and then washed with a 5% aqueous solution of acidic sodium sulfite and saturated saline. The extracted solution was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound as a powder.

NMR (CDCl ₃ ) δ: 3.25 and 3.70 (2H, ABq, J = 18Hz), 4.03 (3
H, s), 4.13 and 4.70 (2H, ABq, J = 12Hz), 4.47 (1H, d, J = 5H
z), 6.07 (1H, dd, J = 5 and 9Hz), 6.67 (1H, s), 6.92 (1H, s),
7.3 (27H, m) (B) Benzhydryl 3-iodomethyl-7-[(Z) -2
-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate The compound obtained in 1-oxide (A) was dissolved in 50 m of acetone and 670 mg of sodium iodide ( 4.47 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, and then washed with 5% aqueous sodium thiosulfate solution, water and saturated brine. The extracted solution was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound as a powder.

IR (KBr): 1790,1720,1680,1510,1370,1290,1230,1160,1
040 cm ^-1 NMR (CDCl ₃ ) δ: 3.4 and 3.68 (2H, ABq, J = 18Hz), 4.03 (3H,
s), 4.48 (1H, d, J = 5Hz), 6.0 (1H, d, J = 5 and 9Hz), 6.67 (1
H, s), 6.95 (1H, s), 7.3 (27H, m) (C) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3- [N- (4-hydroxy-3-methoxy) benzyl-N-methylamino] methyl-3-cephem-4-carboxylate 1-oxide 2.0 g (2.1 mmol) of the compound obtained in (B) was added to methylene chloride 4
The solution was dissolved in 0 m, 0.53 g (3.2 mmol) of N- (4-hydroxy-3-methoxy) benzyl-N-methylamine and 0.29 m (3.2 mmol) of triethylamine were added at room temperature, and the mixture was stirred for 1 hour, and then again N- (. 4-hydroxy-3-methoxy) benzyl-N-methylamine 0.53
g (3.2 mmol) and triethylamine 0.29 m (3.2
Mmol) was added. After stirring the reaction solution for 1 hour,
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 1) to obtain 1.92 g (yield 95%) of the title compound.

NMR (DMSO-d ₆ ) δ: 1.94 (3H, bs), 3.18 (2H, bs), 3.39 (2H,
m), 3.76 (3H, S), 3.79 (2H, bs), 3.87 (3H, S), 5.05 (1H, d, J =
5Hz), 5.87 (1H, dd, J = 5 and 7Hz), 6.67 (1H, d, J = 2Hz), 6.7
6 (1H, d, J = 2Hz), 6.80 (1H, bs), 6.85 (1H, S), 7.01 (1H, S),
8.77 (1H, bs), 8.88 (1H, bd, J = 7Hz) (D) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3- [N, N-dimethyl-N- (4-hydroxy-3-methoxy) benzylammonium] methyl-3-cephem-4-carboxylate 1 -Oxide / iodo salt (C) 1.97 g (2.0 mmol) of the compound obtained in methyl iodide
It was dissolved in 20 m (321 mmol) and left at room temperature for 9 hours. After distilling off excess methyl iodide under reduced pressure, the residue was purified by silica gel column chromatography (20% methanol / methylene chloride) to give 847 mg of the title compound (yield 3
7.5%) was obtained.

NMR (DMSO-d ₆ ) δ: 2.95 (6H, bs), 3.44 (2H, bs), 3.88 (3H,
S), 3.89 (3H, S), 4.2 (2H, m), 4.56 (2H, bs), 5.28 (1H, d, J = 5
Hz), 6.00 (1H, dd, J = 5 and 7Hz), 6.87 (1H, S), 7.12 (1H, S),
7.1 to 7.8 (28H, m), 8.76 (1H, bs), 9.21 (1H, bd, J = 7Hz) (E) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3- [N, N-dimethyl-N- (4-hydroxy-3-methoxy) benzylammonium] methyl-3-cephem-4-carboxylate. 800 mg (0.71 mmol) of the compound obtained in iodine salt (D) was added to 8 m of acetone.
470 mg (2.8 mmol) of potassium iodide was added, 0.10 m (1.4 mmol) of acetyl chloride was added at -5 ° C, and the mixture was stirred for 1 hour. Aqueous sodium metabisulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dehydrated with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was redissolved in 8 m of acetone again, and the above operation was repeated to complete the reduction reaction to obtain the title compound, which was used for the next reaction without purification.

(F) 7-[(Z) -2 (2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide] -3- [N, N-
Dimethyl-N- (4-hydroxy-3-methoxy) benzylammonium] methyl-3-cephem-4-carboxylate (E) The residue obtained in methylene chloride 1.6 m and anisole 1.
It was dissolved in 6 m, 4 m of trifluoroacetic acid was added at 0 ° C, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and extracted with water. The aqueous layer was concentrated, applied to an ODS column (Lobar C-18), and eluted with 10% aqueous tetrahydrofuran solution. Fractions containing the target compound were collected, concentrated and freeze-dried to give 163 mg of the title compound (recovery from the previous step). Rate 39.0%).

Melting point: 152 ° C (decomposition) IR (KBr): 3430,1780,1625cm ^-1 NMR (CF ₃ COOH) δ: 2.90 (6H, bs), 3.35 (2H, bs), 3.80 (3H,
S), 3.81 (3H, S), 4.2 (4H, m), 5.00 (1H, d, J = 5Hz), 5.45 (1H,
dd, J = 5 and 7Hz), 6.2 (3H, m), 6.90 (1H, S), 8.08 (1H, bd, J
= 7 Hz) Reference Example 2 7-[(Z) by the same method as that described in Reference Example 1
-2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [N, N-dimethyl-
N-phenethylammonium) methyl-3-cephem-
4-carboxylate was obtained.

Melting point: 158 ° C (decomposition) IR (KBr): 3440,1780,1620cm ^-1 NMR (CF ₃ COOH) δ: 2.76 (2H, m), 2.87 (6H, bs), 3.28 (2H, m),
3.31 (2H, bs), 3.77 (3H, s), 4.15 (1H, d, J = 12Hz), 4.52 (1H,
d, J = 12Hz), 5.00 (1H, d, J = 5Hz), 5.40 (1H, dd, J = 5 and 8H
z), 6.80 (5H, m), 6.90 (1H, s), 8.06 (1H, d, J = 8Hz) Example Next, Example 1 and Example 1 were carried out by the same method as that described in Reference Example 1. Example 2 was obtained.

Example 1 7-[(Z) -2- (2-aminothiazol-4-yl)
2-Methoxyiminoacetamide] -3- [N-3,
4-dihydroxy) phenethyl-N, N-dimethylammonium) methyl-3-cephem-4-carboxylate Melting point: 196 ° C. (decomposition) IR (KBr): 3425,1780,1620 cm ⁻¹ NMR (CF ₃ COOH) δ: 2.7 (2H, m), 2.85 (6H, bs), 3.2 (2H, m), 3.
30 (2H, bs), 3.78 (3H, s), 4.14 (1H, d, J = 12Hz), 4.54 (1H, d,
J = 12Hz), 4.97 (1H, d, J = 5Hz), 5.40 (1H, dd, J = 5 and 7H
z), 6.30 (1H, bd, J = 8Hz), 6.45 (1H, s), 6.50 (1H, bd, J = 8H
z), 6.90 (1H, s), 8.08 (1H, bd, J = 7Hz) Example 2 7-[(Z) -2- (2-aminothiazol-4-yl)
2-Methoxyiminoacetamide] -3- [N- [3
-(3,4-dihydroxyphenyl) propyl] -N,
N-Dimethylammonium] methyl-3-cephem-4
-Carboxylate Melting point: 163 ° C (decomposition) IR (KBr): 3420,1781,1679,1621cm ^-1 NMR (CF ₃ COOH) δ: 1.80 (2H, m), 2.28 (2H, m), 2.78 (6H, bs),
3.0 (2H, m), 3.18 (2H, bs), 3.79 (3H, s), 4.02 (1H, d, J = 12H
z), 4.40 (1H, d, J = 12Hz), 4.97 (1H, d, J = 5Hz), 5.41 (1H, d
d, J = 5 and 7Hz), 6.27 (1H, bd, J = 8Hz), 6.38 (1H, s), 6.40
(1H, d, J = 8H), 6.89 (1H, s), 8.04 (1H, d, J = 7Hz) Example 3 7-[(Z) -2- (2-aminothiazol-4-yl)
-2- (1-carboxy-1-methylethoxyimino)
Acetamide] -3- [N- (3,4-dihydroxy) benzyl-N, N-dimethylammonium] methyl-3-cephem-4-carboxylate (A) Benzhydryl 3-chloromethyl-7-[(Z) -2
-(1-tert-Butoxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3-cephem-4-carboxylate 1-oxide benzhydryl 3-chloromethyl-7-[(Z) -2-
(1-tert-Butoxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazole-4-
10 g (10.3 mmol) of (yl) acetamide] -3-cephem-4-carboxylate was dissolved in 200 m of methylene chloride, and under ice cooling, 1.78 g (10.3 mmol) of metachloroperbenzoic acid was added over 10 minutes, followed by stirring for 20 minutes. did. After 40 m of a 10% aqueous sodium thiosulfate solution was added to the reaction solution to separate the layers, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a powder.

IR (KBr): 1795,1720,1680,1500,1365,1300,1250,1170,1
140,1050 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 1.45 (6H, s), 3.9 (2H, m), 4.
55 (2H, m), 5.1 (1H, d, J = 5Hz), 6.0 (1H, dd, J = 5 and 9), 6.8
(1H, s), 7.0 (1H, s), 7.3 (25H, bs), 8.15 (1H, d, J = 9Hz), 8.7
(1H, s) (B) Benzhydryl 3-iodomethyl-7-[(Z) -2
-(1-tert-Butoxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3-cephem-4-carboxylate The compound obtained with 1-oxide (A) was dissolved in 20 m of acetone, 3.38 g (22.5 mmol) of sodium iodide was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate 600m and 1 cooled to the reaction solution
After 200 m of a 0% aqueous sodium thiosulfate solution was added for liquid separation, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2). . Fractions containing the target compound were collected and concentrated, and then diisopropyl ether was added to the residue to obtain 7.0 g of the title compound in powder form (yield from the previous step: 63.0%).

IR (KBr): 1795,1270,1680,1500,1370,1300,1250,1170,1
140,1050 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 1.45 (6H, s), 3.95 (2H, m),
4.45 (2H, m), 5.1 (1H, d, J = 5Hz), 6.0 (1H, dd, J = 5 and 9H
z), 6.8 (1H, s), 7.0 (1H, s), 7.3 (25H, bs), 8.15 (1H, d, J = 9H
z), 8.7 (1H, s) (C) Benzhydryl 7-[(Z) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamide] -3- [N- (3,4-dihydroxy) benzyl-N-methylamino] methyl-3-cephem-4-carboxylate 1-oxide (B) 3.0 g (2.8 mmol) of the obtained compound was dissolved in 30 m of dimethylformamide to give N- (3,4-dihydroxy).
Benzyl-N-methylamine hydrobromide 0.66 g (2.
77 mmol) and triethylamine 0.78 m (5.54 mmol) were added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane (3: 1) → 1% methanol / methylene chloride) to obtain 1.51 g of the title compound (yield 43%). Obtained.

NMR (DMSO-d ₆ ) δ: 1.38 (9H, s), 1.48 (6H, s), 1.94 (3H, bs),
3.20 (2H, m), 3.76 (4H, s), 5.10 (1H, d, J = 5Hz), 5.98 (1H, d
d, J = 5 and 7 Hz), 6.75 (3H, m), 6.83 (1H, s), 7.02 (1H, s), 7.
1-7.7 (25H, m), 8.71 (1H, bs), 8.75 (1H, bd, J = 7Hz) (D) Benzhydryl 7-[(Z) -2- (1-tert-butoxycarbonyl-1-methyl) Ethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [N- (3,4-dihydroxy) benzyl-N, N-dimethylammonium] methyl-3-cephem-4-carboxylate 1-oxide iodo 1.5 g (1.21 mmol) of the compound obtained in salt (C) was added to methyl iodide.
It was dissolved in 10 m (160 mmol) and left at room temperature for 12 hours. After distilling off excess methyl iodide under reduced pressure, the residue was purified by silica gel column chromatography (5% methanol / methylene chloride) to give 806 mg of the title compound (yield 4
8%).

NMR (DMSO-d ₆ ) δ: 1.17 (9H, s), 1.48 (6H, s), 2.75 (3H, s),
2.90 (3H, s), 3.40 (2H, bs), 3.87 (2H, bs), 4.20 (2H, m), 5.28
(1H, d, J = 5Hz), 6.10 (1H, dd, J = 5 and 7Hz), 6.84 (1H, s),
7.04 (1H, s), 7.0 ~ 7.7 (28H, m), 8.73 (1H, bs), 9.20 (1H, d, J
= 7Hz) (E) Benzhydryl 7-[(Z) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamide] -3- [N- (3,4-dihydroxy) benzyl-N, N-dimethylammonium] methyl-3-cephem-4-carboxylate iodo salt (D ) Compound obtained in 800 mg (0.58 mmol) was added to 16 m of acetone.
6.4 mg (2.32 mmol) of potassium iodide was added to the solution, and then 0.082 m (1.16 mmol) of acetyl chloride was added at 0 ° C.
(Mmol) and stirred for 1 hour. Aqueous sodium metabisulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound residue, which was used in the next reaction step without purification.

(F) 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamide] -3- [N- (3,4-dihydroxy ) Benzyl-N, N-dimethylammonium] methyl-3-cephem-4-carboxylate (E) The residue obtained with methylene chloride 1.8 m and anisole 1.
After dissolving in 8 m, 4.3 m of trifluoroacetic acid was added at 0 ° C. and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and extracted with water. After concentrating the aqueous layer,
The mixture was applied to an ODS column (LC-Sorb), 3% tetrahydrofuran aqueous solution eluate fractions were collected, concentrated and freeze-dried to obtain 56 mg of the title compound (yield 15% from the previous step).

Melting point: 163 ° C (decomposition) IR (KBr): 3420,1780,1620cm ^-1 NMR (CF ₃ COOH) δ: 1.76 (6H, s), 2.70 (3H, bs), 2.78 (3H, b
s), 3.35 (2H, bs), 4.12 (2H, bs), 4.3 (2H, m), 5.00 (1H, d, J =
5Hz), 5.44 (1H, dd, J = 5 and 7Hz), 6.62 (3H, m), 6.90 (1H,
s), 8.09 (1H, bd, J = 7Hz) Next, Example 4 and Example 5 were obtained by the same method as that described in Example 3.

Example 4 7-[(Z) -2- (2-aminothiazol-4-yl)
-2- (1-carboxy-1-methylethoxyimino)
Acetamide] -3- [N- (3,4-dihydroxy)
Phenethyl-N, N-dimethylammonium] methyl-
3-Cephem-4-carboxylate Melting point: 177 ° C. (decomposition) IR (KBr): 3420,1780,1672,1618 cm ⁻¹ NMR (CF ₃ COOH) δ: 1.35 (6H, s), 2.7 (2H, m) , 3.35 (2H, bs),
4.3 (2H, m), 4.99 (1H, d, J = 5Hz), 5.48 (1H, dd, J = 5 and 7H
z), 6.30 (1H, bd, J = 8Hz), 6.46 (1H, s), 6.52 (1H, bd, J = 8H
z), 6.89 (1H, s), 8.08 (1H, bd, J = 7Hz) Example 5 7-[(Z) -2- (2-aminothiazol-4-yl)
-2- (1-Carboxy-1-cyclopropoxyimino) acetamide] -3- [N- (3,4-dihydroxy) phenethyl-N, N-dimethylammonium] methyl-3-cephem-4-carboxylate Melting point: 162 ℃ (decomposition) IR (KBr): 3420,1780,1620cm ^-1 NMR (CF ₃ COOH) δ: 1.37 (4H, m), 2.75 (2H, m), 2.85 (6H, bs),
3.3 (2H, m), 3.32 (1H, bs), 4.38 (2H, m), 5.00 (1H, d, J = 5H
z), 5.44 (1H, dd, J = 5 and 7Hz), 6.30 (1H, bd, J = 8Hz), 6.48
(1H, s), 6.52 (1H, bd, J = 8Hz), 6.89 (1H, s), 8.12 (1H, bd, J
The effect of the present invention is that the compound of the present invention has a strong antibacterial activity against Gram-negative bacteria, particularly glucose-nonfermenting Gram-negative bacilli, such as Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas maltophilia, Acinetobacter calcoaceticus, etc. It shows activity and is expected as a therapeutic drug for bacterial infections.

In particular, 2- (2-aminothiazole-
4-yl) -2-substituted oxyiminoacetyl group,
The compound having an N, N-dimethyl-N-substituted phenylalkylammonium methyl group at the 3-position has strong antibacterial activity.

Claims (4)

[Claims] 1. A general formula (In the formula, R ¹ may be substituted with a carboxyl group, a linear, branched or cyclic lower alkyl group, R ² is a hydrogen atom or a hydroxyl group, R ³ and R ⁴ are the same and are adjacent to each other. A compound represented by a hydroxyl group bonded to a carbon atom, n is an integer of 1 to 5, a salt thereof, or a physiologically hydrolyzable ester thereof. 2. General formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁶Is a hydrogen atom
Or carboxyl protecting group, R⁷Protected carboxyl
Linear, branched or cyclic, which may be substituted by a group
-Like lower alkyl group, X is a halogen atom or a leaving group, Y
Represents S or SO) or a salt thereof
And the general formula(In the formula, R⁸Is a hydrogen atom or optionally protected hydroxy
Base, R⁹And R^TenAre identical and bond to adjacent carbon atoms
Optionally protected hydroxyl group, R¹¹Is a hydrogen atom or
Methyl group, n is an integer of 1 to 5)
Reaction with the general formula(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^Ten, R¹¹, Y and n are forward
X has the following meaning Is an anion)
Compound and, if necessary, methylated and / or
After reduction, the protecting group is removed,
General formula(In the formula, R¹May be substituted by a carboxyl group
Linear, branched or cyclic lower alkyl group, R²Is water
Elementary atom or hydroxyl group, R³And R^FourAre the same and adjacent charcoal
A hydroxyl group bonded to an elementary atom, n has the above meaning)
Represented compound, its salt or physiologically hydrolysable
How to make the ester. 3. General formula(In the formula, R⁶Is a hydrogen atom or a carboxyl protecting group, R⁸Is water
Elementary atom or optionally protected hydroxyl group, R⁹And R^TenIs
Identical and protected attached to adjacent carbon atoms
Optionally a hydroxyl group, n is an integer of 1 to 5, X Is an anion
Shown), a salt thereof or a silyl compound thereof
General formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁷Is protected
A straight chain which may be substituted by a carboxyl group
A branched, branched or cyclic lower alkyl group)
Acylated with carboxylic acid or its reactive derivative
General formula(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^Ten, N and X Is the above
The compound represented by
General formula, characterized by removing protective groups(In the formula, R¹May be substituted by a carboxyl group
Linear, branched or cyclic lower alkyl group, R²Is water
Elementary atom or hydroxyl group, R³And R^FourAre the same and adjacent charcoal
A hydroxyl group bonded to an elementary atom, n has the above meaning)
Represented compound, its salt or physiologically hydrolysable
How to make the ester. 4. A general formula (In the formula, R ¹ may be substituted with a carboxyl group, a linear, branched or cyclic lower alkyl group, R ² is a hydrogen atom or a hydroxyl group, R ³ and R ⁴ are the same and are adjacent to each other. An antibacterial agent containing a compound represented by a hydroxyl group bonded to a carbon atom, n is an integer of 1 to 5, a salt thereof or a physiologically hydrolyzable ester thereof as an active ingredient.