JPS62289585A - Novel cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (crboxyl-substituted) lower alkyl, lower alkenyl or lower alkynyl; R<2> and R<3> are H or acetoxy; n is 1-3]. EXAMPLE:Benzhydryl 7beta-[( Z )-2-methoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3- yl)acetamido]-3-(5,6-dihydroxyisoindolin-2-yl)methyl-3-cephem-4-carbox ylate 1- oxide. USE:An antibacterial agent exhibiting strong antibacterial activity even against Pseudomonas aeruginosa, etc. PREPARATION:For example, the compound of formula I (R<4> is lower alkyl, lower alkynyl, etc.; R<5> is H or protecting group; R<6> is H or protecting group; X is halogen or eliminable group; Y is S or SO) is made to react with the compound of formula III (R<7> is H or methyl; R<8> and R<9> are OH, etc.; n is 1-3). The resultant compound of formula IV (X<-> is anion) is optionally methylated and/or reduced and optionally further deprotected.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel cephalosporin derivative, a method for producing the same, and an antibacterial agent containing the same as an active ingredient.

Prior Art In the past, a large number of compounds having a 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamide group in the 7-position side chain of the cephalosporin core have been synthesized, and their descriptions have been limited. For example, Japanese Patent Application Laid-open No. 52
-102294, 52-116492, 53-
No. 137988, No. 54-9296, No. 54-154
No. 786, No. 54-157596, No. 55-1549
No. 80, No. 56-86187, No. 57-59895, No. 57-99592, No. 57-192394, and No. 58-17.1387.
It is also shown to be active against cephalosporin-resistant Durham-negative bacteria, including Ilonas aeruginosa, and is suggested to have excellent antibacterial activity and a broad spectrum of antimicrobial activity.

The interpressure point β-lactam antibiotic to be solved by the invention exhibits selective toxicity only to bacteria;
Since it has no effect on excitonic cells, it is a highly useful drug that is widely used in the treatment of bacterial infections as an antibiotic with few side effects.

However, in recent years, the frequency of isolation of resistant Durum-positive bacteria and resistant glucose non-fermenting Durum-negative rods has been increasing as pathogenic bacteria of infectious diseases, and there is a desire to increase antibacterial activity against these bacteria.

Means to solve the pressure, wood brother! 9'J et al. aimed to provide cephalosporin derivatives with excellent antibacterial activity, and
pbew+) at position 3 of the nucleus (5,6-disubstituted funinyl)-
2-methyl-isoindolinium methyl group, (6,7-
(disubstituted phenyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinium methyl group, or (7,
8-diZ FA phenyl)-2-methyl-2,3,4,
A 5-tetrahydro-111-2-benz1zepinium methyl group was added to the 7-position of the cephem nucleus by a 2-substituted oxyimino-
2-(5-amino-1,2,4-thiadiazole-3-
As a result of research on compounds having an acetamide group, it was found that they exhibit strong antibacterial activity against Durham-negative bacteria, including Rokushi:4 bacteria.

Working tree! ? ! IIJJ is represented by the general formula (1) [wherein t<' is a lower alkyl group, a lower alkenyl group, or a lower alkynyl group which may be substituted with a carboxyl group, R2 and R3 are the same or different, water r
! 11 group or an acetoxy group, n is a Li number of 1 to 3, a non-toxic salt thereof, or a physiologically hydrolyzable, saline-toxic ester thereof, a method for producing the same, and an effective method for using the compound. Regarding antibacterial agents as ingredients.

Next, the symbols and usages used in this specification will be explained.

The substituent R' in the compound of general formula (1) contains a lower alkyl group, a lower alkenyl group, or a lower alkynyl group, which may be substituted with a carboxyl group.

Examples of the lower alkyl group include 1α chain, branched and cyclic lower alkyl groups. Linear and branched lower alkyl groups refer to carbon chains having 1 to 6 carbon atoms, and cyclic lower alkyl groups refer to cyclic alkyl groups having 3 to 6 carbon atoms.

Examples of linear, branched and cyclic lower alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, isobutyl group, 5ee-butyl group, t
Examples include ert-butyl group, n-pentyl group, 11-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and particularly preferred examples include methyl group, ethyl group, 1-propyl group, etc. , isopropyl group, cyclopropyl group, cyclobutyl group, and cyclopentyl group.

Examples of the lower alkenyl group include straight branched and cyclic lower alkenyl groups. Specifically, vinyl group,
Allyl group, impropenyl group, l.

Examples include l-dimethylallyl group, 2-butenyl group, 3-butenyl group, cyclopentenyl group, cyclohexenyl group, and the like.

Specifically, lower alkynyl groups include ethynyl group, 2
-propynyl group, 1,1-dimethylpropynyl group, etc.

In addition, the partial groove structure in the oximino group of general formula (1) has a syn isomer (Z coordination) and an anti isomer (E coordination), and the syn isomer (Z coordination) generally has excellent antibacterial activity. In this specification, all OR' groups are syn isomers (Z-coordination).

In addition, n is 1 in the ammonio side chain at position 3 of the cephem nucleus.
Indicates an integer from 3 to 3, for example, 5.6-(disubstituted phenyl)-2-methyl-2-isoindolinium methyl group,
6.7-(disubstituted phenyl)-2-methyl-1,2,3
, 4-tetrahydro-2-isoquinolinium methyl group,
7,8-(disubstituted phenyl)-2-methyl-2,3,4
, 5-tetrahydro-111-2-penzazebinium methyl group can be expressed as the ammonio side chain at the 3-position of the cephem nucleus. Specifically, 5,6-cyhydroxy-2-methyl-2-isoindolinium methyl group, 5,6
-Diacedoxy-2-methyl-2-isoindolinium methyl group, 6°7-cyhydroxy-2-methyl-1,2
, 3,4-tetravitro-2-isoquinolinium methyl group, 6,7-diacedoxy-2-methyl-1,2,3,
4-tetrahydro-2-isoquinolinium methyl group, 7
, 8-dihydroxy-2-methyl-2,3,4,5-tetrahydro-IH-2-penzazebinium methyl group,
and 7,8-diacetoxy-2-methyl-2,3°4.
Examples include 5-tetrahydro-111-2-penzazebinium methyl group 9 and the like.

The compound of general formula ([) can be converted into its non-toxic salt or physiologically hydrolyzable non-toxic ester by a conventional method.

Non-toxic salts of the compound of general formula <1) include i1 therapeutically acceptable and customary salts, such as metal salts of sodium, potassium, calcium, magnesium, aluminum, etc., N,N'-dibenzylethylenediamine; , organic amine salts such as brocaine, inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, etc.

Acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid,
I-organic acid salts such as malic acid, tartaric acid, and citric acid; sulfonic acid salts such as methanesulfonic acid, isethionic acid, and pH-luenesulfonic acid; and amino acid salts such as glutamic acid, aspartic acid, lysine, and arginine. It will be done.

=lil'J The non-toxic ester of formula (1) means a conventional medically acceptable carboxyl group, such as alkanoyloxymethyl groups such as acetoxymethyl group and pivaloyloxymethyl group, Alkoxycarbonyloxyalkyl groups such as 1-toxycarbonyloxy)ethyl groups, phthalidyl groups, 5-methyl-2
5-substituted -2-oxo-1,3-dioxo-4- such as -oxo-1,3-dioxo-4-ylmethyl group
ylmethyl group etc. are punched.

The compound of general formula (+) can be produced by either Production Method A or Production Method B shown below.

Production method A General formula (■) [In the formula, R' is a lower alkyl group, a lower alkenyl group, or a lower alkynyl group that may be substituted with a protected carboxyl group, and 7<% is a hydrogen atom or a carboxyl protecting group , Ro is a hydrogen atom or an amino-protecting group, X is a halogen atom or a leaving group, and Y is S or SO. Hydrogen atom or methyl group, R1 and R' are the same or different, optionally protected hydroxyl group, 11
represents an integer from 1 to 3] to form a compound represented by the general formula (II) [wherein R4, R'', R', R7, R'', R'Y and n
has the above-mentioned meaning, and X- represents an anion], and if necessary, after methylating and/or reducing it and removing the protective group if necessary, 1
The compound (+) of the present invention can be produced.

As the carboxyl group protecting group in the above general formula, t
ert-butyl group, 2,2.2-trichloroethyl group,
Acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxy group-deprived group, 1
-Propionyloxyethyl group, 1-(ethoxycarbonyloxy)ethyl group, phthalidyl group, benzyl group, 4
-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis(4
-methoxyphenyl)methyl group, 5-methyl-2-oxo-1,3-dioxo-4-yl-methyl group, trimethylsilyl group, tert-butyldimethylsilyl group, etc., especially benzhydryl group, tert-butyl and the like are preferred.

In the general formula (II), In particular, halogen atoms such as bromine and iodine are preferred.

Examples of the compound of general formula (111) include 5,6-hydroxy-2-methylisoindoline, 5,6-diacetoxy-2-methylisoindoline, 6,7-hydroxy-2-methyl-1,2,3,4 -tetrahydro-2-isoquinoline, 6゜7-diacedoxy-2-methyl-1,2
, 3,4-tetrahydro-2-isoquinoline, 7,8-
Dihydroxy-2-methyl-2゜3.4.5-tetrahydro-111-2-benzazepine, 7,8-diacetoxy-2-methyl-2,3,4,5-tetrahydro-1
11-2-Benzazepine, 5,6-dihydroxyisoindoline, 5,6-diacedoxyisoindoline, 6
, 7-cyhydroxy-1.2,3.4-tetrahydroisoquinoline, 6,7-diacetoxy-1.2,3.4-
Tetrahydro-2-isoquinoline, 7,8-dihydroxy-2,3,4,5-tetrahydro-111-2-benzazepine, 7,8-diacetoxy-2,3,4,5-
Tetrahydro-111-2-benzazepine is mentioned.

Preparation method B General formula (VI) [wherein, R is a hydrogen atom or a carboxyl protecting group, R7
is a hydrogen atom or a methyl group, R1 and R3 are the same or different and optionally protected hydroxyl group, Y is s, 4 is SO
, n is a J3 number of 1 to 3, and acylated with a carboxylic acid or a reactive derivative thereof represented by a lower alkyl group, a lower alkenyl group, or a lower alkynyl group which may be substituted with a protected carboxyl group to form the compound of the general formula (11) [in the formula , R4, R', R', R', R", R',
Y and 口 have the above meanings, and X- is a compound represented by ko indicating a protective ion, which is methylated and/or reduced as necessary, and then the protective group is removed if necessary. Compound (1) of the present invention can be produced by the following steps.

When the compound of the present invention has an acetoxy group as a substituent on the phenyl nucleus of the isoindolinium methyl group, inquinolinium methyl group, and penzazebinium methyl group at the 3-position of the cephem nucleus, the phenyl nucleus as a raw material compound has an acetoxy group. It can be produced by production method A or 'XJ production method B, respectively, using general formula (III) or general formula (VI) having an acetoxy group, but it is also possible to produce iso in -(general formula +) or (II) Monoacetoxy forms and diacetoxy forms are obtained by selectively acetylating compounds having a hydroxyl group on the phenyl nucleus of indolinium methyl groups, isoquinolinium methyl groups, and penzazepinium methyl groups under appropriate conditions. I can do it.

In addition, as the protecting group for carboxyl group, amino group and hydroxyl group in the above general formula, as the protecting group for β-lactacarboxyl group, tett-butyl group, 2,2.2-
) Lichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyloxyethyl group,
1-(ethoxycarbonyloxy)ethyl group, phthalidyl group, benzyl group, 4-methoxybenzyl group, 3,4-
dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis(4-methoxyphenyl)methyl group,
5-Methyl-2-oxo-1,3-dioxo-4-
Examples include yl-methyl group, trimethylsilyl group, tert-butyldimethylsilyl group, and particularly preferred are benzhydryl group, tert-butyl group, silyl group, and the like.

As protecting groups for amino groups, trityl group, formyl group,
Chloroacetyl group, trifluoroacetyl group, tert
-butoxycarbonyl group, trimethylsilyl group, ter
A t-butyldimethylsilyl group and the like are included.

group, tetrahydropyranyl group, phenacyl group, isopropyl group, tert-butyl group, benzyl group, 4-nitrobenzyl group, acetyl group, 2.2.2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, acetonide, trimethylsilyl group , tert-butyldimethylsilyl group, and the like.

Next, the manufacturing method A and the manufacturing method B of the compound (1) of the present invention will be explained in detail.

Production method A ゛The reaction between the compound of general formula (IV) and the amine of general formula (,111) is carried out using methylene chloride, chloroform, ether,
The addition of ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc. can be carried out in a solvent or a mixed solvent thereof. As the amine of general formula (m), amine salts such as hydrochloride, hydrobromide, sulfate, nitrate, and acetate may be used. In this case, the reaction was carried out using neutralizing amounts of triethylamine, filtrate, lobylethylamine, N,N-dimethylaniline, and N-amine of general formula (III).
The reaction can also be used by silylation with a silylating agent such as N,0-bistrimethylsilylacetamide.
amine is used in an amount of 1 to 2 moles, the reaction temperature is 0 to 40°C, and the time is 0.5 to S.

When using the amine of the general formula (111) in which R' is a hydrogen atom, an N-methylation reaction is further performed to obtain the N-methylammonio compound (II), and the methylation reaction is performed using the general formula (1). 1 to 30 moles of methyl iodide in the organic solvent or an excess of methyl iodide may be used as a solvent per mole of the tertiary amine compound ().

The reaction temperature is -30°C to 35°C, and the reaction is completed in several hours to several days.

Compounds of the general formula (■) in which the group Y is SO are published in the Journal of Organic Chemistry (Journal of O
rganic chemistry) volume 35, 2430
A sulfoxide group can be added by the method described in P. (1974) and others. For example, ammonio compound (II) where gY is SO can be reduced by dropping acetyl chloride in an acetone solvent in the presence of sodium iodide or potassium iodide at -40 to 0°C and reacting for 1 to 2 hours. The 0 reaction in which IJY is SO is 3.5 to 10 iodides per 1 mole of the compound (■).
1.5 to 5 mol and acetyl chloride are used.

Compound (I) of the present invention can be produced by removing a protecting group from a compound of general formula (11) in which group Y is S, if necessary. The method for removing the protecting group depends on the type of the protecting group, for example, the method described in Protective Groups in Organic Synthesis (Pr.
otective Groups in Organi
cSyn these is ) 1981 etc. can be carried out by appropriately selecting the commonly used method. For example,
Removal of protective groups such as trityl group, formyl group, tert-butoxycarbonyl group, benzhydryl group, tert-butyl group, and 2-methoxyethoxymethyl group can be performed using hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid. Trifluoroacetic acid is particularly suitable. When trifluoroacetic acid is used as the acid, side reactions are suppressed and the deprotection reaction is promoted by adding anisole. In addition, the reaction can be carried out in a solvent that does not participate in the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, etc., or in a mixed solvent thereof. It is suitably selected depending on the chemical properties of 1) and the type of protecting group, and it is particularly preferable to conduct the reaction under mild conditions such as water cooling or heating.

Raw material compound (IV) of production method A can be produced as follows. The compound of the general formula (■) in which the group Y is S is a compound of the general formula (n)
It can be produced by reacting carboxylic acids or reactive derivatives thereof (for example, acid halides, mixed acid anhydrides, active esters, etc.). A compound of general formula (IV) in which JuYfJ<SO can be obtained by cooling a compound of general formula (IV) in which group Y is S in a solvent that does not participate in the reaction, such as methylene chloride, ethylene chloride, or chloroform, under cooling with water. mole m-
It can be produced by oxidation with chloroperbenzoic acid. A compound of the general formula Hv) in which the group X is an iodine atom is a compound of the general formula (IV) in which the group
, N-dimethylformamide, etc., at water cooling or at room temperature, by reacting with an iodide such as sodium iodide, and may be isolated or used in the next reaction without isolation.

Production method B The compound of the general formula <11) is a compound of the general formula (VI),
In a solvent that does not adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethylene chloride, benzene, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof. Among them, general formula (V)
It can be produced by reacting carboxylic acids or reactive derivatives thereof (for example, acid halides, mixed acid anhydrides, active esters, etc.). The reaction is expressed by the general formula (VI
) compound 1, the reactivity of the general formula (l) for ale, 1 to 1.5 mol of the derivative was used, and the reaction temperature was -40 to 40°C.
It is. When using an acid halide as the reactive derivative of general formula (V), it is preferable to react it with triethylamine, N-methylmorpholine, N,N-dimethylaniline in the presence of a deoxidizing agent such as lysine. . In the acid halide formation reaction, 1 to 1 mol of a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, or phosgene is added to 1 mol of carboxylic acid (V). 10 mol, preferably 1 to 1.5 mol, is used, and the reaction temperature is -40 to 100°C, preferably -2
At 0-20°C, the reaction time is completed in a few hours.

In the mixed acid anhydride formation reaction, triethylamine, N-methylmorpholine, N, N
- Using 1 to 1.2 moles of a chlorocarbonate such as methyl chloroformate, ethyl chloroformate, or isobutyl chloroformate in the presence of 1 to 1.2 moles of IJ52 v agent such as dimethylaniline or pyrrolidine; The reaction temperature is -40 to 20°C, preferably -2α5.5, and the reaction time is 10 to 60 minutes. In the active ester formation reaction, N- and a doxy compound (for example, N-hydroxysuccinimide, 1-hydroxybenztriazole, etc.) or a phenol compound (for example, 4-nitrophenol, 2 , 4-dinitrophenol, trichlorophenol, etc.) and 1 to 1.2 mol of N,N-dicyclohexylcarbodiimide.
4 mol is used, the reaction temperature is -10 to 50°C, and the reaction time is 30 to 120 minutes.

In addition, in the acylation reaction, when the carboxylic acid of general formula (V) is used in the form of a free acid, carbodiimides such as N,N-dicyclohexylcarbodiimide, phosphorus oxychloride, N,N-dimethylformamide, etc. The compound of general formula (n) can also be produced in the presence of a condensing agent such as a phosphorus oxychloride adduct.

Production of the compound (1) of the present invention from general formula (11) is as follows: 1)
Proceed by pruning according to manufacturing method A described in u.

The raw material compound (VI) for production method B is from Cephalosporins and Penicillins by Flynn, Academic Press (C
epbalosporins and Pencil
lins-Academic PrH Thick) 151-17
It can be produced by the general method described in, eg, p. 1, 1972.

For example, the compound of general formula (VI) is disclosed in JP-A-53-725
90, No. 58-154588, etc. 1t32 7-acylamino-3-halomethyl-3-cephem-4
-A carboxylate derivative is reacted with an amine of the general formula (1), and a compound of the general formula [wherein R'' is a hydrogen atom or a carboxy group 3UU, R'
is a hydrogen atom or a methyl group, R1 and R' are the same or different and optionally protected hydroxyl group, Y is S or SO,
n is an integer from 1 to 3, X- represents an anion], and then +jt? , can be produced by acylation.

Deacylation reactions are already known in the art, and include, for example, a method consisting of iminochlorination with phosphorus pentoxide, iminoetherification and hydrolysis with blown methanol, etc., or a method using acylase. Examples include phenyl acetyl group and phenoxyacetyl group.

In order to demonstrate the effectiveness of the compounds of the present invention, the in vitro antibacterial activity against various bacteria was measured using the following agar plate dilution method. Mueller Hinton Broth
Each test strain was cultured overnight in 1lintou broLh).
Mueller Hinton Agar (M, Il, aga)
r, Dirco). This medium contains antibacterial agents at various concentrations, and after culturing at 37°C for 16 hours,
The minimum inhibitory concentration (Mt: μg/ml) was determined.

The results will be shown on the screen.

MIC (g/wit: 1 o・cFv, y,
) MIC<, 4i=z=1°・. FUN) The compounds of the invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical formulations suitable for parenteral, oral or external administration. Pharmaceutical preparations include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.

These preparations may also contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, and surfactants, as required. Examples of additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn flour, magnesium stearate, and talc.

The compounds of the invention can be used as antibacterial agents in the treatment of bacterial infections in humans. The dosage varies depending on the person's age, gender, etc., but is usually 1 to 10 doses per day.
Used in the range 0mg/kg, 5-3 per day
The present invention will be explained in more detail with reference to Examples. II is not limited to this.

Examples Example 1 (A) Benzhydryl 7β-[:(Z)-2-methoxyimino-2-(5-tritylamino-1,z,4-thiadiazol-3-yl)acetamide]-3-(5+o
-dihydroxyisoindolin-2-yl)methyl-3
~cephem-4-carboxylate 1-oxide benzhydryl 7β-[(Z)-2-methoxyimino-
2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido-3-iodomethyl-3
-cephem-4-lupoxylate l-oxide 3.
Dissolve 66 g (3,86 mmol) in 35 kg of N,N-dimethylformamide, and dissolve 116 g (5 m + no 1) of 5,6-dihydroxyisoindoline hydrobromide and 1.29 ml (9,25 +++++) of triethylamine.
After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure. Add 7 liters of ethyl acetate and 50 liters of water to the residue.
i 1 was added, and ifl:AFJ was collected, dried over 144% sodium hydroxide sulfate, and dried under reduced pressure. Remaining≦1
Silica gel flash-column chromatography (2
0-40% acetone-methylene chloride) to obtain 3.13 g (yield: 83.5%) of the amorphous title compound.

IR(KBr)cffl :1800.1730.1
690.1520.1340゜1300.1220,1
180.1160.1040CB) Benzhydryl 7β
-C(Z)-2-methoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamide]-3-(5,6-cyhydroxy-2-methyl-2-isoindoly ) Methyl-3-cephem-4
-Dissolve 3.13 g (3.22 smol) of the compound obtained from carboxylate 1-oxide iodo salt (A) in 6 ml of methylene chloride, add 6 ml of methyl iodide and N,N
- After adding 0.03 ml of dimethylformamide and allowing it to stand for 16 hours, it was concentrated under reduced pressure to obtain a residue of the title compound, h?
5:! It was used in the next reaction without further treatment.

I R(KBr)aB :1800.1730.166
0.2620.1520゜1350.10110 (C) Benzhydryl 7β-[(Z)-2-methoxyimino-2-(5-tritylamino-'A I214-thiadiazol-3-yl)Ahe7midocor3-< 5.6
-Cihydroxydi2-methyl-2-isoindolinium) methyl-3-cephem-4-carboxylate The residue obtained from iodo salt (B) was dissolved in 74 ml of acetone, and 2.74 g (16.5 ml of potassium iodide) was added. In addition,
Acetyl chloride 0.586 ml (8,24
+omol) was added dropwise, and the mixture was stirred at 0°C or lower for 1 hour. −
Cool to 20°C and add 2.74g (1,
65 mmol) and acetyl chloride 0.586 ml
(8.24 mmol) was added and stirred for 1 hour at 0° C. or below. To the reaction solution, 100a+1 of a cooled 5% sodium metabisulfite aqueous solution was added and stirred for 10 minutes, followed by extraction with 300 ml of chloroform. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a residue of the title compound, which was used in the next reaction without purification.

IR(KBr)aff:1790.1730.16
80.1620.1530゜1450.1370,12
30.1040(D) 7β-[(Z)-2-methoxyimino-2-(5-amino-1,2°4-thiadiazol-3-yl)acetamide]-3-(5,6-cyhydroxy-2- Methyl-2-isoindolinium)methyl-
The residue obtained from 3-cephem-4-carboxylate (C) was dissolved in 15 ml of methylene chloride and 2 ml of anisole, and 40 ml of a solution of methylene chloride containing 20 ml of trifluoroacetic acid was added dropwise under water cooling. After stirring at room temperature for 3 hours, the reaction solution was poured into 120 ml of ether, and insoluble matter was filtered off. After adding the insoluble matter to 300 ml of water and stirring for 30 minutes, the insoluble matter was removed, and the Δ solution was subjected to reverse phase column chromatography (ODS, 500 ml of water, 1% TIIF-water).
Fractions containing the target compound were collected, concentrated under reduced pressure, and then lyophilized to obtain 600 mg of the title compound (C(A) in a yield of 33%).

ll1p: 155℃ (decomposition) I R (KBr) ail: 1780, 1670, 162
0,1520,1470°1400.1350.104
ONMR(DMSO-d, )δ: 3.65(3H,
br s), 3.50-5.00 (8H, m), 3.9
5 (3!l, s), 5.10 (111, d, 511z
).

5.70 (111, dd, J=5 and 9Hz), 6.8
2(2H,s), 9.55(111,d, J=9)IZ
) Example 2 Monodihydroxy-2-methyl-2-isoindolinium)methyl-3-cephem-4-carboxylate benzhydryl 7β-[(Z)-2-ethoxyimino-2-(
5-tritylamino-1,2,4-thiadiazole-3
-yl)acetamide]-3-iodomethyl-3-cephem-4-carboxylate 1-oxide2. OOg
<2.08IIllIlol) and 724 mg (3,12 m
Example 1-(A), CB), (C)
, and treated in the same manner as in method (D) to obtain the title compound 14.
0+++g (yield 12%) was obtained.

mp: 160°C (decomposition) I R (KBr) ail: 1780, 1670, 162
0,1520,1470°1400.1350.104
O N MR (DMSO-d C113COOII) δ
: 1.30<311. t, J=711z), 3.10
(311, br s), 3.53 (ill, d, J=1
811zL4, 1-5.0 (811, m), 5.28 (
ill, d, J=511z), 5.93(ill
.

dd, J=5 and 811z), 6.80 (211,s)
, 9.60 (ill, d, J=811z) Example 3 No 1.2.4-thiadiazol-3-yl)acetamide]-3-(5,6-cyhydroxy-2-methyl-2
-isoindolinium) methyl-3-cephem-4-carboxylate benzhydryl 7β-m(Z)-2-isopropoxyimino-2-<5- tritylamino-1
,2,4-thiadiazol-3-yl)acetamitoco-3-iodomethyl-3-cephem-4-carboxylate 1-oxide2. OOg (2,05n+mol)
Example 1-
380 mg (yield: 32%) of the title compound was obtained by treating in the same manner as in methods (A), (B), (C), and (D).

mp: 155°C (decomposition) I R (KBr) Gif: 1780, 1670, 162
0.1520,1470°1400.1350.101
ONMR(DMSO-d, )δ: 1.30(611
,d,,J:5i1z),3.05(311,br s
), 3.40 (11+, d, J=1811z), 3.1
37 (Ill, d.

J=18+lz), 4.10-5.10(7+1.m)
, 5.13 (+1!, d, to 511z), 5.75 (H
l, dd, J=5 and 8tlz), 6.80 (211,
s).

9.52 (Ill, d, J=811z) Example 4 (A) Benzhydryl 7β-[(Z)-2-allyloxyimino-2-(5-tritylamino-1,2,4-thiadiazole-3- yl)acetamitoco-3-(5,
6-hydroxyisoindolin-2-yl)methyl-
3-cephem-4-carboxylate l-oxidebenzhydryl 7β-[(Z)-2-allyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido-3 -Chloromethyl-3-cephem-4-carboxylate l-oxide 2.03 g (2,3 gaol) is dissolved in 20+ml of N,N-dimethylformamide and 1.0ml of sodium iodide.
72g (11.5mg+ol) was added and stirred at room temperature for 50 minutes. 5,6-dihydroxyisoindoline A hydrohydride 800 mg (3,45a+wol) and triethylamine 0.48+al (3,45w+nol)
) was added thereto and incubated at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. 70 ml of chloroform and 40 ml of water were added to the residue, and the organic layer was separated, washed with 40,011 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography (10% methanol-chloroform) to obtain 1.75 g (yield: 76 mm) of the amorphous title compound.

I R(KBr)aH: 1800, 1730, 1660
,1620,1520.70ON MR(DMSO-
d, ) δ: 3.0O-4.00 (8H, +n), 4.
68 (211, d, J=411z), 5.04 (11!
, d, J=4.51! z), 5.10-5.40 (2H
, m), 5.80-6.20 (IH, m), 5.97 (
1! l, dd.

J=4.5 and 911z), 6.56(211,s),
6.97 (1!l,s).

7.33 (251+, s), 8.60 (211, br
s), 8.95 (III, d, 911z), 9.93
(ill, 5) (B) Benzhydryl 7β-[(Z)-2-allyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamitoco-3-(5,
6-hydroxy-2-methyl-2-isoindolinium)methyl-3-t! Femu 4-carboxylate 1
5.2 ml of methyl iodide was added to and dissolved in 1.75 g (1.75 mmol) of the compound obtained from -oxide iodo salt (A), and the mixture was allowed to stand at room temperature for 16 hours.

T! the reaction solution! After A contraction, add ether 8+++1,
The precipitated insoluble matter was collected by filtration and dried under reduced pressure to obtain 1.80 g (yield: 90%) of the title compound in powder form.

1020.70O NMR(D?l5O-d, )δ: 3.80-4.
70 (811, III), 4.67 (211, d, js
411z), 5.10 (III, d, J=4.5112
), 5.10-5.40 (211, +o), 5.80-
6.20 (111, m), 6.07 (111, dd.

J=4.5 and 9! lz), 6.70 (211,s),
6.97<111. s).

7.32 (2511, s), 9.24 (111, d, J
=911z), 9.26 (211°br s), 9.9
2(III,5) (C)7β-[(Z)-2-allyloxyimino-2-
(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5,6-cyhydroxy-2-
Compound obtained with methyl-2-isoindolinium) methyl-3-cephem-4-carboxylate (B) 1.90
Example 1-(C) and (
It was treated in the same manner as in method D) to obtain 115 mg (yield 12%) of the title compound.

mp: 150°C (decomposition) I R (KBr) aff: 1780, 1670, 162
0,1520,1470°1400,1350.102
O NMR (DMSO-d, , CF, C0011)
δ: 3.10 (311, br s).

6.10 (211, m), 6.80 (211, s),
9.67(III, d, J=8+1z) Example 5 (A) Benzhydryl 7β-1: (Z)-2-allyloxyimino-2-(5-)ditylamino-1,2,4-
thiadiazol-3-yl)acetamide 1=3-(6
,7-cyhydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinium)methyl-3-cephem-4-carboxylate 1-oxide iodo salt benzhydryl 7β-[(Z)-2-allyloxy imino-2-<5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido-3-chloromethyl-3-cephem-4-carboxylate 1-oxide 1.65 g (1,87 mmol), iodine Sodium chloride 1
．． Same method as in Examples (A) and (B) using 40 g (9.35 mmol) and 690 mg (2.8 mol) of 6°7-hydroxy-1.2,3.4-tetrahydroisoquinoline hydrobromide. 51 g (yield 70%) of the title compound i was obtained.

E R (KBr) GIf: 1800, 1730, 166
0,1620.1530d, J:4.511z), 5.
10-5.50 (211, i), 5.70-6.20 (
111,m), 6.08 (111,dd, J=4.5 and 911z), 6.42 (III.

s), 6.57 (Ill, s), 7.08 (11i, s)
), 7.10-7.70 (2511°m), 9.03 (
111, s), 9.10 (211, br s), 9.2
4(lit, d.

J=911Z) (B) 7β-[(Z)-2-7lyloxiimi/
-2-(5-7mino-1,2,/l-thiadiazole-
3-yl)acetamitoco-3-(6,7-cyhydroxy-2-methyl-1,2,3,4-tetrahydro-2-
Using 1.40 g (1,21 mmol) of the compound obtained from isoquinolinium) methyl-3-cephem-4-carboxylate (A), the following treatment was carried out in the same manner as in Example 1-(C) and (D). Compound 68B (yield 9.3%) was obtained.

1+Ip: 175℃ (decomposition) I R (KBr): 1780, 1670, 1620,
1530. +400°1350.1280.102O NMR (DMSO-d, , CF, C0011)
δ: 3.02 (311, br s).

3.40-4.80 (1011, n), 5.15-5.
45 (511, a+), 5.80-6.05 (211,
m), 6.55 (111, s), 6.67 (III, s
), 9.67 Example 6 (A) Benzhydryl 7β-[(Z)-2-propargyloxyimino-2-(5-tritylamino-1,2,
4-thiadiazol-3-yl)acetamide E-3-
(7,8-dihydroxy-2-methyl-2,3,4,5
-tetrahydro-111-2-penzazebinium) methyl-3-cephem-4-carboxylate 1-oxide iodo salt benzhydryl 7β-[(Z)-2-propargyloxyimino-2-(5-tritylamino- 1,2,4-thiadiazol-3-yl)acetamitoco-3-chloromethyl-3-cephem-4-carboxylate 900 mg (1 m+iol) 1-oxide, 750 mg (5 mmol) sodium iodide and 7,8-dihydroxy-2 , 3,4,5-tetrahydro-111-2-benzazepine hydrobromide 3.90+++g (1,5m
mol) was treated in the same manner as in Example 4-(A) and (B) to obtain 550 mg (yield: 47%) of the title compound.

IR(KBr)cffl :1800.1730.1
660.152ON MR(DMSO-d, )δ:
2.73 (311, s), 3.00-4.60 (131
1,m), 4.78(2+1.br s), 5.12(
III, d, J=lIlz).

(211, br s), 7.33 (2511, s), 8
．． 90 (III, br s).

9.27 (III, br s), 9.33 (lit, d
, J=7+1z), 9.98 (III.

br 5) (B) 7β-[(Z)-2-propargyloxyimino-2-(5-amino-1,2,4-thiadiazole-3
-yl)acetamitoco-3-(7,8-dihydroxy-2-methyl-2,3,4,5-tetrahydro-111
-2-penzazepinium)methyl-3-cephem-4
-Using 460 mg (0-39 mmol) of the compound obtained from carboxylate (A), the same procedure as in Example 1-(C) and (D) was used to obtain 3 g (yield 12%) of the title compound. Obtained.

1Ilp: 155°C (decomposition) I R (KBr) reciprocity: 2130.1780.1670.
1620.1530゜1400.1350.101O NMR (DMSO-d, , CF, C0011)
δ: 2.00 (211, m).

2.80-2.90 (411, m), 3.40-5.0
0 (1211, m), 5.33 (111, d, J=51
1z), 5.90 (III, dd, J=5 and 811z
).

6.70 (III, s), 6.82 (111, s), 9
．． 70(III, d, J=811z) Example 7 Oximino 2-(5-tritylamino-1,2,4
-thiadiazol-3-yl)acetamitoco-3-(
5,6-cyhydroxy-2-methyl-2-isoindolinium) methyl-3-cephem-4-carboxylate 1-oxide iodo salt benzhydryl 7β-[(Z)-2-cyclopentyloxyimino-2-(5- Tritylamino-1,2,4-
thiadiazol-3-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxylate 1-
1.55 g (1,70 amol) of oxide, 1.27 g (8,50 mmol) of sodium iodide and 5,6-
Hydroxyisoindoly〉・Hydrobromide 592m
g (2,55imo 1 ) and treated in the same manner as in Example 4-(g and (B)) to obtain 1.51 g of the title compound.
(Yield 76x) was obtained.

IR(KBr)ail:1800,1660,152
0,1350.100ON MR(D?!5o-d,
) δ: 1.30-2.00 (811, m), 3.2
0-4, 10 (811, i), 4, 72 (IH, m
), 5.02 (III, d, J=4!Iz
).

5.92 (fil, dd, J:ll and 911z), 6
．． 93 (ill, s), 7.30 (271! 1m)
+ 3.57 (2!I, s) + 8-75 (
11i + d, J =91i z ) +9.8N
HI, s) J (B) 7β-[(Z)-2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(s,6-cyhydroxy-2-isoindolinium)methyl-3-cephem-
1.40 g of the compound obtained with 4-carboxylate (A) (
1,22aIInol) and treated in the same manner as in Example 1-(C) and CD) to obtain the title compound 130Il.
1 g (yield 17%) was obtained.

tap: 150℃ (decomposition) I R (KI3r) aH: 1780.1670+ 16
20.1520.1400°35O NMR (DMSO-d, , CI?, C0011
) δ: 1.40 to 2.00 (8+1°111), 3.1
0 (311, br s), 3.63 (III, d, J=
1811z).

4.02 (III, d, J=1811z), 4.30
-5.00 (711, m), 5.27 (ill, d, J
'511z), 5.93 (Ill, dd, J=5 and 811z).

6JO(211,s), 9.57(111,d,J:8
+1z) Example 8 (A) Benzhydryl 7β-[(Z)-2-(1-methyl-1-benzhydryloxycarbonylethoxyimino)-thyl-2-isoindolinium)methyl-3-cephem-41- Carboxylate 1-oxide iodo salt Benzhydryl 7β-[(Z)-2-(1-methyl-1-benzhydryloxycarbonylethoxyimino)-2=(5-tritylamino-1,2,4-thiadiazole- 3-yl)acetamitoco-3-chloromethyl-3-cephem-4-carboxylate 1-oxide 2.30 g (2.10 mmol), sodium iodide 1
．． 57 g (10,5 mmol) and 520 mg (2,24
+n+nol) and treated in the same manner as in Example 4-(A) and (B) to obtain the title compound t, o4g (yield 37
%) was obtained.

(B) 7β-[(Z)-2-(1-carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4
-thiadiazol-3-yl)acetamitoco-3-(
Compound 1 obtained with 5,6-cyhydroxy-2-methyl-2-isoindolinium)methyl-3-cephem-4-carboxylate (A). OOg (7,,39 mmol)
The product was treated in the same manner as in Example 1-(C) and (D) to obtain 230 mg (yield: 49%) of the title compound.

IIIp: 7°C (decomposition) I R (KBr) aii: 1780, 1680, 162
0.1520,1470°1400.1340,118
0.116ON MR (DMSO-d, , CF3
CO0H) 5: 1.52 (6H, s).

3.10<311. br s), 3.68 (IH, d,
J=1511z), 4.02<lft, d, J=15!
lz), 4.30-5.10 (611, +l+), 5.
32 (1!I.

d, J=511z), 6.00(ill, dd, J=5
and 811z), 6.80 (211, br s), 9.
58(III, d, J=811y,) Example 9 (A) Benzhydryl 7β-C(Z)-2-(1-methyl-1-benzhydryloxycarbonylethoxyimino)-2-(5-tritylamino -1,2,,1-thiadiazol-3-yl)acetamide]-3-(sz7
-cyhydroxy-2-methyl-L2+3+4-tetrahydro-2-isoquinolinium)methyl-3-cephem-
・1-Lupoxylate l-oxide ・Iodo salt Benzhydryl 7β-CZ)-2-(1-Methyl-1
-benzhydryloxycarbonylethoxyimino)-
2-(5-trityl 7minor 1,2..1-thiadiazol-3-yl)acetamitoco-3-chloro)thyl-
3-cephem-1 sodium iodide 1.03g (6,
78ia+ol) and 510 mg of 6,7-hydroxytetrahydroisoquinoline hydrobromide (2,07
Omol) was treated in the same manner as in Example 4-(A) and CB) to obtain 1.23 g (yield: 66%) of the title compound.
) was obtained.

I R(KBr)aH: 1805, 1735, 1685
,1625,1530°+495.1450,1285
．． 122ON MR (DMSO-d, )δ: 1.5
9 (611, s), 2.50-4.80 (1311, m
), 5.19 (111, d, J'511z), 6.15
(III, dd, J=5 and 911z), 6.42 (1
11, s), 6.58 (III, s), 6.80 (li
t.

s ) + 7, 03 (I II + s ) +
7, JO (35II + m) + 8.95
(1if + d + J@= 911z), 9.10 (211, br sL9.95 (
111+5)(B) 7 B-[(Z)-2-(1" force/L, boxy-1-mef)Lt ethoxyimino)-
2-(5-amino-1,2,4-thiadiazole-3-
Compound obtained with methyl-3-cephem-tocarboxylate (A) 1, OOg(0,-,32
mzoi) and treated in the same manner as in Example 1-(C) and (D) to obtain 3501 g of the title compound (yield 7E
%) was obtained.

〜, mp: 165°C (decomposition) IR(KBr)aif: 1780, 1620. ! 53
0.1400,136ON MR (DMSO-d,
, CF, C0011) δ: 1.56 (611, s).

3.05 (311, br s), 3.30-3.50 (
loft, m), 5.35 (III.

d, J=511z), 5.95<111. dd, J=5
and 811z), 6.57(111,s), 6.67(
111,s), 9.60 (111,d, J=811z)
Example 10 (Δ) Benzhydryl 7β-[(Z-2-(l-methyl-1-benzhydryloxycarbonylethoxyimino)-2-(5-tritylamino-1,z,4-thiadiazole-3- yl)acetamide]-3-(7,8-
Dihydroxy-2-methyl-2,3,4,5-tetrahydro-111-2-penzazebinium)methyl-3-
Cephem-4-carboxylate 1-oxide iodo salt Benzhydryl 7β-[(Z-2-(l-methyl-1
-benzhydryloxycarbonylethoxyimino)-
2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamitoco-3-chloromethyl-3
-cephem-4hydroxy-2,3,4,5-tetrahydro-11-2-benzazepine hydrobromide 540
Example 4-(A
) and (B) to obtain the title compound 1.
20 g (yield 64%) was obtained.

IR(KBr)aii:1805,1?35,168
5,1620,1520°+495.1450,129
5,1220,1175.115ON! vl R(D
MSO-d, ) δ: 1.58 (611, s), 2.4
0-4.90 (+511.m), 5.19 (111,d
, 4.5i1z), 6.15(ill, dd.

J=4.5 and 911z), 6.63(111,s),
6.72 (lil, s).

6.80 (211, s), 7.32 (3511, l11
), 8.90 (Ill, br s>.

8.95 (111, d, J:911z), 9.27 (1
11, br s), 9.97 (III.

br 5) (B) 7β-[(Z)-2-(+-carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4
-thiadiazol-3-yl)acetamide]-3-<
7.8-dihydroxy-2-methyl-2,3,4,5-
Using compound 1 obtained with tetrahydro-111-2-penzazebinium) methyl-3-cephem-4-carboxylate (A), OOg (0,724 wmol),
The treatment was carried out in the same manner as in Example 1-(C) and (D) to obtain 1 g (yield: 6 mm) of the title compound 330II.

■++p: 165℃ (decomposition) I R (KBr) aii: 1780, 1610, 153
0.1400.136ON MR(DMSO-d,
, CF, C0011) δ: 1.55 (611, s).

2.00 (241, m), 2.80 (311, br s
), 3.30-5.00 (1011゜m), 5.35 (
111, d, J=511z), 5.96 (III, dd
, J=5 and 811z), 6.70 (111,s), 6
．． 84 (111, s) 9.60 (III, d, J=!3
i1z) Example 11 (A) Benzhydryl 7β-[(Z)-2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(5-)ritylamino 1.2.4-
thiazol-3-yl)acetamide]-3-(5,t
3-dihydroxy-2-methyl-2-isoindolinium)methyl-3-cephem-4-carboxylate 1-
Oxide/iodo salt benzhydryl 7 B-[(Z)
-2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(5-tritylamino-1,2,!!-thiadiazol-3-yl)acetamido-3-chloromethyl-3-cephem -4-carboxylate l-oxide 3.20 g (2.85 mm
oi), 1.57 g of sodium iodide (10.5 mm
ol) and 324 mg (1,40 mmol) of 5,6-cyhydroxyisoindoline hydrobromide were treated in the same manner as in Example 4-(A) and (B) to yield 750 mg (yield) of the title compound. 30%).

NMR(DMSO-d, )δ: 1.77(41
1, m), 2.10 (4 tl, m).

3.90-5.00 (911, n+), 4.53 (31
1, br s), 5.13 (fil.

d, J = 4.511z), 6.15 (111, dd, J
= 11.5 and 911z).

6.72 (2H, s), 6.82 (1!I, s), 6.
98 (111, s), 7.33 (3511, n+), 9
．． 02 (111, d, J=9tlz), 9.27 (21
1,s).

10.0<111,5) (B) 7β-[(Z)-2-(1-carboxy-1-
Compound 1.10 g (0,798 amol
) was treated in the same manner as in Example 1-(C) and (D) to obtain 100 mg of compound L7' (yield: 19
%) was obtained.

m p : 165'C (decomposition) I R (KB r ) OTj ' 1780 + 1
680 + 1620.1520 + iIOo.

1350.1190 NMR (DMSO-d, CF, C0011)
δ: 1.73 (411, n+).

2.08 (411, l11), 3.10 (311, br
s, 3.73 (111, d, J=1811z),
4.05 (I II, d, J = 1811
7. ), 4.30-5.10 (711, +u )5
．． 28 (111, d, J=51iz), 5.96 (11
1, dd, J=5 and 811z) 6.80 (211,s
), 9.52 (III, d, J=811z) Effects of the Invention The compounds of the present invention exhibit strong antibacterial activity against susceptible and resistant Durum-positive bacteria and Durham-negative bacteria including Pseudomonas aeruginosa,
It is useful as a therapeutic agent for bacterial 1δ beams.

Claims (4)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a lower alkyl group, lower alkenyl group, or lower alkynyl group, which may be substituted with a carboxyl group, R^ 2 and R^3 are the same or different, a hydroxyl group or an acetoxy group, and n represents an integer of 1 to 3], a non-toxic salt thereof, or a physiologically hydrolyzable non-toxic ester thereof. (2) General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^4 is a lower alkyl group, lower alkenyl group, or lower alkynyl group that may be substituted with a protected carboxyl group. , R^5 is a hydrogen atom or a carboxyl protecting group, R^6 is a hydrogen atom or an amino protecting group, X is a halogen atom or a leaving group, Y is S or SO] or a salt thereof, General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^7 is a hydrogen atom or a methyl group, R^8 and R
^9 is the same or different hydroxyl group that may be protected, n is an integer from 1 to 3] is reacted to form the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^4, R^5, R^6, R^7, R^8, R
^9, Y and n have the above-mentioned meanings, and X^- represents an anion], and if necessary,
General formula (I) characterized by removing a protective group if necessary after methylation and/or reduction ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is substituted with a carboxyl group] a lower alkyl group, a lower alkenyl group, or a lower alkynyl group that may be , a non-toxic salt thereof, or a physiologically hydrolyzable non-toxic ester thereof. (3) General formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^5 is a hydrogen atom or a carboxyl protecting group, R
^7 is a hydrogen atom or a methyl group, R^8 and R^9 are the same or different and may be protected hydroxyl groups, Y is S or SO, n is an integer from 1 to 3, X^- is an anion [In the formula, R^6 is a hydrogen atom or an amino protecting group, and R^4 is a protected Acylated with a carboxylic acid or a reactive derivative thereof represented by a lower alkyl group, a lower alkenyl group, or a lower alkynyl group which may be substituted with a carboxyl group to form the general formula (II) ▲ Numerical formula, chemical formula, table etc. ▼ [In the formula, R^4, R^5, R^6, R^7, R^8, R
^9, Y and n have the above-mentioned meanings, and General formula (I) characterized by the removal of alkynyl group, R^2 and R^3 are the same or different, hydroxyl group or acetoxy group, n represents an integer from 1 to 3], non-toxic salts thereof, or physiologically hydrolyzable The manufacturing method of the non-toxic ester. (4) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a lower alkyl group, lower alkenyl group, or lower alkynyl group, which may be substituted with a carboxyl group, R^ 2 and R^3 are the same or different, hydroxyl group or acetoxy group, n represents an integer of 1 to 3], a non-toxic salt thereof, or a physiologically hydrolyzable non-toxic ester thereof. Antibacterial agent contained as an active ingredient.