JPH02289584A - Cephalosporin gamma-lactone compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is acyl; R<2> is methyl substituted with electron-attracting group; n is 0 or 1). EXAMPLE:(9R,10R)-4-oxa-3,11-dioxo-5-(2-oxopropyl)-10-phenyl-acetamido- 8-thia-1- azatricyclo[7,2,0,0<2>,<6>]undeca-2(6)-ene of formula II. USE:An antibacterial agent useful for the remedy of diseases caused by bacteria resistant to penicillin antibiotic substances and the remedy of a penicillin- sensitive patient. PREPARATION:A compound (salt) of formula III (R<2>' is methylene substituted with one or two electron-attracting groups; R<7> is M or carboxylprotecting group removable under acidic condition) is subjected to lactonization reaction under acidic condition.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel se7acosporin γ-lactone compound. The cephalosporin gamma-lactone compound of the present invention is used as an antibacterial agent.

(Prior Art) Several types of Cephasporin γ-lactone compounds have been produced and reported.

For example, JP-A-51-82291, JP-A-52-83778
, Journal of Pharmacy
calSciences) ヱ6.208 (19
87) etc. have described cephalosporin γ-lactone compounds in which a methyl group or phenyl group is substituted on the lactone ring. There have been no reports on allosporin γ-lactone compounds.

(Problem to be Solved by the Invention) Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, such as the treatment of diseases caused by bacteria that are resistant to penicillin antibiotics. and is particularly useful in the treatment of penicillin-sensitive patients.

However, cephalosporin γ-lactone compounds are poorly soluble in water and their antibacterial activity is generally low and unsatisfactory for practical use.

Therefore, it is desired to develop a cephalosporin γ-lactone compound that exhibits excellent antibacterial activity.

(Means for Solving the Problems) The present invention is based on the general formula (1) [wherein Rl represents an acyl group, R! relates to a cephalosporin lactone compound or a salt thereof, represented by J, in which n represents a methyl group substituted with an electron-withdrawing group, and n represents 0 or l.

The compound of the present invention has a structural feature in that it has a methyl group substituted with an electron-withdrawing group on the lactone ring, and based on this structural feature, it exhibits excellent antibacterial activity.

In the above general formula (I), the acyl group represented by Rl preferably represents an acyl group derived from an organic carboxylic acid.

More preferably, R' is an acyl group substituted at the amino group at the 6-position of a conventionally known penicillin derivative, an acyl group substituted at the amino group at the 7-position of a c7em derivative, or the like. .

Specific examples of such acyl groups include formyl group, alkylcarbonyl group (alkanoyl group), preferably C, -C, alkylcarbonyl group (e.g., acetyl.propionyl, butyryl, isobutyryl, valeryl,
Isovaleryl. bivaloyl or hexanoyl), arylcarbonyl group (aroyl group), preferably C.I. ~
Cl47 lyluponyl group (e.g., benzoyl.1- or 2-naphthoyl, etc.), aralkylcarbonyl group,
Preferably C, ~C, . Aralkylcarbonyl group (e.g., penzylcarbonyl.2-7enethylcarbonyl.1
- or 2-naphthylmethyl group or penzhydryl group), 5- to 6-membered aromatic heterocyclic carbonyl group (e.g., 2- or 3-thenoyl, 2-t:-
Ha3-Froil. Nicotinoyl. Isonicotinoyl. 4
- or 5-thiazolyl or l. 2.4-
thiadiazol-3- or -5-ylcarbonyl, etc.)
, 5- to 6-membered aromatic heterocyclic acetyl group (e.g., 2- or 3
-thhenylacetyl, 2- or 3-7lylacetyl.
4-Thiazolylacetyl. l. 2.4-Thiadiazol-3-ylacetyl. l-tetrazolylacetyl, etc.),
Alkoxycarbonyl groups, preferably C, -C, alkoxycarbonyl groups (e.g. methoxycarbonyl.ethoxycarbonyl, glopoxycarbonyl.impropoxycarbonyl.putoxycanolebonyl, isobutoxycarbonyl or tertiary butoxycarbonyl) ), aryloxy carbonyl group, preferably C. ~Cl. Aryloxycarponyl group (e.g., phenoxycarponyl.l
(1- or 2-naphthoxylponyl, etc.), aralkyloxycarbonyl groups, preferably C7-cps aranolekyloxycarbonyl groups (eg, benzyloxycarbonyl, etc.), and these include amino. Nitro, halogen (e.g. fluorine, chlorine or bromine, etc.), hydroxyl. Oxo. Carbamoyl, 01-C, alkyl group (e.g., methyl, ethyl, proyl, isopropyl, or butyl, etc.), alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl group that may be esterified. C, -C, alkoxyimino groups optionally substituted with carboxyl (e.g., methoxyimino, ethoxyimino, carpoxymethoxyimino, l
It may be substituted with 1 to 3 substituents such as hydroxyimino, 4-ethyl-2,3-dioxopiperazino, luponylamino, etc.

In addition, the above-mentioned 5- to 6-membered aromatic heterocyclic carbonyl group and 5
~The heterocyclic group in the 6-membered aromatic heterocyclic acetyl group is a nitrogen atom (which may be oxidized). An aromatic heterocyclic group containing 1 to 4 heteroatoms such as an oxygen atom or a sulfur atom (which may be mono- or dioxidized) is used. Specific examples of such aromatic heterocyclic groups include thenoyl, chenyl. Froil. Nicotinoyl. Isonicotinoyl. Pyrrolyl, imidazolyl, pyrazolyl. Pyrimidinyl, pyrazinyl, pyridazinyl.
Indolyl. Thiazolyl. inthiazol, thiadiazolyl, tetrazolyl, oxazolyl, inoxazolyl,
Triazolyl and the like are used.

R1 is more preferably a group represented by the general formula (1) (wherein A is a nitrogen atom, CH or CCI, and R' is a hydrogen atom or a lower alkyl group optionally substituted with a carpoxyl group); (2) General formula (wherein, R6 represents a lower alkyl group, R' represents a hydroxyl group spanning a hydrogen atom), or (3) General formula (wherein, X represents a hydrogen atom, a halogen atom, or a hydroxyl group) ).

Among these, the group represented by (1) is particularly preferred.

R! The electron-withdrawing group in the methyl group substituted with an electron-withdrawing group represented by means a group that tends to attract electrons from others when hydrogen is the standard in the molecule. Such electron-withdrawing groups are preferably cyano groups, nitro groups,
Trihalogenomethyl group, or formula COOQ, -coq, -S (0). Q. -O-Q, -OCO-Q or C O N Q IQ! In one formula, Q. Q. Q! is a hydrogen atom. An optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, where m is 0.1 or 2], etc. are used.

R2 preferably represents a methyl group substituted with 1 to 2 electron-withdrawing groups.

R2 means a methyl group which may be substituted with at least 1 or 2 electron-withdrawing groups; examples of such groups include methyl groups substituted with 1 or 2 electron-withdrawing groups; An electron-withdrawing group and one optionally substituted hydrocarbon group or optionally substituted heterocyclic group represented by Q above, or a halogen atom. A methyl group substituted with -NHQ or -NHCOQ is used.

Q. Q. Examples of the hydrocarbon group in the optionally substituted hydrocarbon group represented by and Q include methyl,
Ethyl, provil. Isoprovil, butyl. Isobutyl. Tertiary butyl, pentyl. Straight chain or branched alkyl groups having 1 to 6 carbon atoms such as tertiary pentyl and hexyl,
Cycloalkyl groups having 5 to 6 carbon atoms such as cyclobentyl and cyclohexyl, vinyl. Alkenyl groups having 2 to 6 carbon atoms such as allyl, phenyl, natyl. Aryl groups having 6 to 14 carbon atoms such as bi7enyl, anthryl, benzyl, phenylethyl, phenacyl. Carbon number 7 to 1, such as trityl
A hydrocarbon group such as an aralkyl group of No. 9 is used.

Q. The hydrocarbon groups represented by Q+ and Q2 may have a substituent, and such substituents preferably include a hydroxyl group, a nitro group, an amino group, a cyano group, a carpoxyl group, a carbamoyl group, and a carbon group. Cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), alkylthio group having 1 to 4 carbon atoms (e.g. methylthio or ethylthio)
, an alkoxy group having 1 to 4 carbon atoms (for example, methoxy or ethoxy), an alkoxy group having 1 to 4 carbon atoms (for example, methoxycarbonyl or ethoxycarbonyl), a halogen atom (for example, fluorine, chlorine, bromine, etc.) , 7- or di-alkylamino groups having 1 to 4 carbon atoms (e.g. methylamino, dimethylamino or jetylamino, etc.), alkanoylamino groups having 1 to 4 carbon atoms (e.g. formamide or acetamide, etc.), heterocyclic groups (e.g. 2- Furyl, 3-furyl.2-chenyl, 3-chenyl, 2-thiazolyl, 4-thiazolyl, l
．． 2,4-thiadiazolyl-3yl, etc.) are used. The number of substituents is preferably 1 to 3.

Furthermore, Q. Q, and Q represent an aryl group or an aralkyl group. For example, if the
It may have 1 to 3 substituents such as (butyl, etc.).

The heterocyclic group represented by Q in the heterocyclic group optionally having a substituent is a 5- or 6-membered heterocyclic group containing 1 to 4 petro atoms, such as N, S, O, etc. Those having bonding hands on the carbon atoms constituting the are used.

Specifically, such a heterocyclic group is 2-furinomutsu3
-furyl, 2-chenyl, 3-chenyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, l. 2.3-thiadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, lH-tetrazol-5-yl, 1.3.4-thiadiazol-5-
yl, 1,2,4-thiadiazol-5-yl, pyridin-3-yl, pyridin-4-yl, etc. are used. Such a heterocyclic group may have a substituent, and examples of the substituent include a hydroxyl group, an amino group, a carpoxy group, an alkyl group having 1 to 4 carbon atoms (for example, methyl or ethyl, etc.), and a substituent having 1 to 4 carbon atoms. to 4 alkoxy groups (e.g., methoxy, ethoxy, etc.), hydroxyl alkyl groups having 1 to 4 carbon atoms (e.g., hydroxymethyl or hydroxyethyl, etc.), halogen atoms (e.g., fluorine, chlorine, bromine, etc.), etc. are used. . The number of substituents is preferably l
There are 3 pieces.

As the trihalogenomethyl group, preferably a trifluoromethyl group or a trichloromethyl group is used.

Preferred specific examples of the group represented by the formula -COOQ? For example, carboxyl group. It is a linear or branched alkyloxy group having 1 to 6 carbon atoms.

Preferred specific examples of the group represented by the formula 100Q include a linear or branched alkyl carbonyl group having 1 to 6 carbon atoms and an aryl carbonyl group having 6 to 14 carbon atoms.

Formula 1 S (0). A preferred specific example of the group represented by Q is a straight or branched alkylsulfonyl group having 1 to 6 carbon atoms.

Preferred specific examples of the group represented by formula 10-Q are. It is a straight chain or branched alkyloxy group having 1 to 6 carbon atoms.

A preferred specific example of the group represented by the formula 1000-Q is a linear or branched alkynolecanoleponyloxy group having 1 to 6 carbon atoms.

Formula-CONQ. Preferred specific examples of the group represented by Q2 are a carbamoyl group, a linear or branched alkyl-substituted rubamoyl group having 1 to 6 carbon atoms.

R! is preferably a formula E in which R3 is a cyano group or a nitro group. tri/1 logenomethyl group, or formula 1000Q, -COQ, -S (0
). Q. -0-Q. -OCO-Q or one CONQ,Q
The group represented by x is R4 is R3, a hydrogen atom. A halogen atom, a group represented by the formula -NHQ or NHCOQ, or a hydrocarbon group, Q. Ql. Q* is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, m is O. It is a group represented by j representing I or 2.

More preferably, R3 is a straight chain or branched alkylcarbonyl group having 1 to 6 carbon atoms, or a straight chain or branched alkylsulfonyl group having 1 to 6 carbon atoms. Carbon number 6 to 1
The aryl carbonyl group of 4. Straight chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms. cyano group
R4 is a group represented by 1 representing a hydrogen atom or a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, respectively.

Here, as the straight chain or branched alkyl-carbonyl group having 1 to 6 carbon atoms, for example, acetyl or gropionyl is used, and as the straight chain or branched alkyl sulfonyl group having 1 to 6 carbon atoms, for example, Methylsulfonyl or ethylsulfonyl is used, the aryl carbonyl group having 6 to 14 carbon atoms is, for example, benzoyl, and the linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms is, for example, methoxy. Carbonyl or ethoxyluponyl is used. Compound (1) may be used as a pharmacologically acceptable salt.

When compound (1) has a basic group (eg, amino group) in its molecule, it may form an addition salt with an acid. Examples of acids that can form these acid addition salts include inorganic acids such as hydrochloric acid and VL acid, succinic acid, and maleic acid. Organic acids such as p-toluenesulfonic acid are used.

When compound (1) contains an acidic group (carboxyl group, sulfo group, etc.) in its molecule, it may form a salt with a base. As the base capable of forming these base salts, inorganic bases or organic bases are used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), and examples of organic bases include trimethylamine, triethylamine, tributynoleamine, diisopropylene, etc. Organic tertiary amines such as raremine, pyridine, picoline, and dicyclohexylamine are used.

Compound (1) or a salt thereof is a valuable antibiotic that exhibits excellent antibacterial activity against Durham-positive and Durham-negative bacteria, including clinical isolates, and is used as a medicine for humans and livestock. It is safely used as an antibacterial agent to treat and prevent infections caused by it.

Furthermore, the compound (1) of the present invention or a salt thereof can also be added to animal feed as a bactericide, for example, to preserve the feed. It can also be used as a disinfectant to eliminate harmful bacteria on medical and dental equipment.

Compound (I) of the present invention or a salt thereof may be used alone or in combination with other active ingredients and optionally with a stabilizer. By adding an auxiliary agent such as a dispersant, the composition can be used as a preparation such as a capsule, tablet, solution, suspension, or liquid preparation such as an emulsion. They can be administered parenterally (eg, by intravenous or intramuscular injection) or orally.

Formulations for injection may be presented in the form of ampoules or containers with an added preservative. The formulation may be a suspension, solution or emulsion in an oily or aqueous solvent, and may optionally contain auxiliary agents such as known suspending agents, stabilizing agents and/or dispersing agents. Good too. Compound (I) or a salt thereof can also be prepared as a powder. Immediately before use, the powder can be dissolved in a suitable solvent, such as sterilized pyrogen-free water, and then used.

Compound (I) or a salt thereof may be used as a binder such as syrup, gum arabic. Fillers such as gelatin, sonolevitol, gum tragacanth, polyvinylpyrrolidone, etc.; fillers such as lactose, sugars, corn starch, calcium phosphate, sorbitol, glycine; and thickening agents such as magnesium stearate, talc. After suitably mixing polyethylene glycol, silica, etc. with a disintegrant such as potato starch, or a wetting agent such as sodium lauryl sulfate, tablets for oral administration are prepared. Capsules, powders. It can be made into powder. tablet. Powders and the like can also be coated with a film by a method known per se. Oral formulations may be used as liquid formulations such as aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, and the like.

Further, components such as known antioxidants, preservatives, binders, wetting agents, thickening agents, thickening agents, or flavoring agents may be mixed with these preparations. Furthermore, other active ingredients (eg, β-lactam antibiotics) can be mixed with the formulation to provide a formulation that exhibits a broader spectrum of antibacterial activity.

Compound (I) or a salt thereof can be used as a therapeutic agent for bacterial infections, such as respiratory infections in humans and other mammals, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetrics and gynecology. It can be used for the treatment and prevention of medical infections, otorhinolaryngological infections, surgical infections, etc.

The daily dosage of Compound (I) or its salt varies depending on the condition and weight of the patient, the method of administration, etc., but in parenteral administration, the amount of active ingredient (Compound (1) or its salt) per 1 kg of adult body weight is approximately 0.5 to 80 mg, preferably about 1-
to 40 mg, and is suitably administered by intravenous or intramuscular injection in 1 to 4 divided doses daily. The oral dosage is 1 kg of adult body weight per day divided into 4 doses.
About 5 to 1 active ingredient (compound (I) or its salt) per
00mg is appropriate.

Compound (1) or a salt thereof can be produced by the following method.

Production method 1 Compound (1) or a salt thereof is prepared by formula (II) [wherein,
R! ' represents a methylene group substituted with 1 or 2 electron-withdrawing groups; RF represents a hydrogen atom or a protecting group for a carboxyl group that can be removed under acidic conditions; and other symbols represent 1 having the same meanings as above. It is produced by subjecting a compound or its salt to a lactonization reaction under acidic conditions.

R! The methylene group substituted with l or 2 electron-withdrawing groups represented by ゛ is one hydrogen atom removed from the methyl group of the methyl group substituted with l or 2 electron-withdrawing groups represented by R2. Groups formed by this method are used.

The carboxyl protecting group that can be removed under acidic conditions is β-
It has been well established in the field of lactam compounds, and those skilled in the art can arbitrarily select and use it. Preferable examples of the carboxyl protecting group that can be removed under acidic conditions include p-me:xypenzyl, penzhydryl.
Aralkyl groups such as trityl, methoxymethyl, methylthiomethyl, tertiary butyl, and the like are used.

In the structural formula of compound (III) or a salt thereof, an amino group,
When a reactive group such as a hydroxyl group or a carboxyl group is included, these groups may be protected with a protecting group as described below.

As the salt of compound (I[[), a salt with a base is used. As these base salts, those similar to the salt of compound (1) can be used.

This reaction is usually carried out in a solvent that does not adversely affect the reaction. Examples of solvents that do not adversely affect the reaction include formamide. Amides such as dimethylformamide and dimethylacetamide, dichloromethane. Chlorophonolem, 1.2-
Halogenated hydrocarbons such as dichloroethane, diethyl ether, tetrahydro7ran. Ethers such as dioxane, methyl acetate, ethyl acetate, isobutyl acetate. Esters such as methyl propionate, acetonitrile. Nitriles such as probionitrile, nitromethane. Nitro compounds such as nitroethane, ketones such as acetone and methyl ethyl ketone, benzene. Aromatic hydrocarbons such as toluene, alcohols such as methanol, ethanol, and propanol, water, and the like are used, and these may be used alone or in combination of two or more in an appropriate ratio.

When performing in water or a mixed solvent of organic solvent and water,
It is advantageous to work at a pH below 5. When the reaction is carried out in an organic solvent, the acid is used in a catalytic amount to a large excess amount relative to compound (III) or its salt.

Acids used in the reaction include hydrochloric acid and hydrobromic acid. [No acid, nitric acid, phosphoric acid, etc.! Acid, formic acid, acetic acid, trichloroacetic acid, trichloroacetic acid. Methanesulfonic acid. Examples include organic acids such as p-toluenesulfonic acid, acidic ion exchange resins, and the like.

The reaction temperature varies depending on the amount and type of the raw material compound Cm) or its salt, solvent, acid, etc., but is usually about -70 to 100°C. Reaction time is 1 minute to 24f? It is about between 1 and 2.

The raw material compound (I[[) or its salt is disclosed in, for example, British Patent No. 134224, Journal of Medicinal
Chemistry (Journal of Medici)
nal Chemistry) 18. 986 (
1975) or a method similar thereto.

Compound (1) or a salt thereof has the general formula (IV) [wherein,
Rl represents a hydrogen atom or an ester residue, and other symbols have the same meanings as above] or a salt thereof, and is produced by subjecting a compound represented by the formula or a salt thereof to a ring-closing reaction.

The ester residue represented by Ra includes, for example, methyl,
Butyl. Lower alkyl groups such as tertiary butyl, methoxymethyl. Ethoxymethyl. Lower alkoxy-lower alkyl groups such as l-ethoxyethyl, lower alkyl-lower alkyl groups such as methylthiomethyl and ethylthioethyl, mono (di or tri) such as 2-iodoethyl, 2,2.2-1-lycroethyl, etc. Halogeno lower alkyl group, lower alkanoyloxy mono-lower alkyl group such as acetoxymethyl, pivaloyloxymethyl, benzyl, p-methoxybenzyl. Mono(di or tri)phenyl-lower alkyl groups which may have substituents such as p-nitrobenzyl and penzhydryl are used.

In the structural formula of the compound (!V) or a salt thereof, an amino group. When a reactive group such as a hydroxyl group or a carpoxyl group is included, these groups may be protected by a protecting group as described below.

When the raw material compound (IV) is a basic salt, it may be subjected to the reaction after being neutralized by adding an acid.

This reaction is usually carried out in a solvent that does not adversely affect the reaction.

Examples of solvents that do not adversely affect the reaction include the above-mentioned ethers,
Esters, halogenated hydrocarbons, amides, ketones, nitriles, alcohols, water, etc. are used. .

An acid or a condensing agent may be added to accelerate the reaction. As the acid, the inorganic acid and organic acid used in production method 1 are used. Examples of condensing agents include tlfN,N-dicyclohexyllupodiimide, N-cyclohexyl-N-
Morpholinoethyllupodiimide, N-ethyl-N-(
3-dimethylaminopropyl)carposiimide, etc. are used.

The reaction is carried out at a temperature range of about -lθ to 150°C. The reaction time varies depending on the reaction temperature, but is usually 10 minutes to 7 minutes.
It is 0 hours.

Starting compound (IV) or a salt thereof is produced by a method known per se. For example, the 3-formylcetem compound [Helvetica
Chimica Acta)57. 2044
(1974)] and the general formula
(V) MR” (V) [where M is Li, Na, K or MgX, ZnX (X
is a halogen) and an organometallic compound represented by 1.

The halogen represented by X includes chlorine. bromine. Iodine etc. are used.

This reaction is carried out in an inert solvent. Examples of inert solvents include diethyl ether, diisopropyl ether,
Ethers such as ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, dimethoxymethane,
benzene. Hydrocarbons such as hexane are used.

The reaction is carried out at about -100 to 30°C, preferably about -80 to θ°C.
It is carried out over a temperature range of The reaction time varies depending on the type of 3-formyl cephem compound and organometallic compound used as raw materials and the reaction temperature, but is usually from 1 minute to 3 hours. The organometallic compound is used in an amount of about 1 to 10 equivalents per equivalent of the 3-formylcephem compound.

Production method 3 In addition, compound (1) or a salt thereof, a compound represented by the general formula (Vl) [1 in which the symbols have the same meanings as above, or a salt thereof, and a compound of the general formula (■) R'OH
(■) [Symbols in the formula have the same meanings as above]
It can be produced by reacting a compound represented by or a reactive derivative thereof in the carboxyl group.

When an amino group is present in the substituent represented by Rl in the general formula (■), this amino group is preferably protected with a protecting group. Examples of the protecting group for this amino group include β-lactam and Those used in the field of peptides can be suitably employed, among which formyl. Chloroacetyl. Phenylacetyl, phenoxyacetyl. Tertiary butoxycarponyl, penzyloxycarponyl. p-Methoxybenzyloxyluponyl, p-nitropenzyloxyluponyl, 2-trimethylsilylethoxyluponyl. 2,2.2-1-IJ Chloroethoxyluponyl, trityl, etc. are preferred.

Furthermore, when a hydroxyl group is present, it is preferable that this hydroxyl group is protected, and examples of protecting groups for this hydroxyl group include, for example, chloroacetyl. Benzyl, p-nitrobenzyl. Methylthiomethyl, trimethylsilyl, tertiary butyldimethylsilyl. 2-Tetrahydropyranyl. 4-methoxy-4-tetrahydropyranyl and the like are used.

Furthermore, when a carpoxyl group is present, it is preferable that this rupoxyl group is protected, and examples of protecting groups for this carpoxyl group include benzyl. Benzhydryl, trityl. p-methoxybenzyl, p-nitrobenzyl, tertiary butyl, etc. are used.

Examples of reactive derivatives at the carboxyl group of compound (■) include acid halides, which can be produced according to conventional methods. Acid anhydrides, active amides, active esters, active thioesters, etc. are used, and specific examples of such reactive derivatives are as follows.

l) Acid halide: For example, acid chloride, acid bromide, etc. are used.

2) Acid anhydride: For example, a mono-lower alkyl carbonic acid mixed anhydride is used.

3) Active amides: e.g. pyrazole. Amides with imidazole, 4-monosubstituted imidazole, dimethylpyrazole, penzotriazole, etc. are used.

4) Active ester: For example, methoxymethyl ester. Penzotriazole ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester. Trichlorophenyl ester. In addition to esters such as pentacrophenyl ester, l-
Esters with hydroxy-IH-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, etc. are used.

5) Active thioester: For example 2-pyridylthiol. Thioesters with heterocyclic thiols such as 2-penzothiazolylthiol are used.

As the salt of the raw material compound (Vl+), the same salt as the salt of compound (1) is used.

In this reaction, the compound (■) or its reactive derivative at the carboxyl group is used in an amount of 1 mol or more, preferably about 1 to 4 mol, per 1 mol of the compound (Vl) or its salt.

This reaction is usually carried out in a solvent that does not adversely affect the reaction. Examples of solvents include water, ketones such as acetone, ethers such as tetrahydrofuran and dioxane,
Nitriles such as acetonitrile, cyclomethane, chloroform. Halogenated hydrocarbons such as l,2-dichloroethane, esters such as ethyl acetate, amides such as dimethylformamide and dimethylacetamide, etc. are used, and one or more of these are mixed in an appropriate ratio. May be used.

When compound (■) or a salt thereof is used in its free form or as a salt thereof, the reaction is preferably carried out in the presence of a condensing agent. Examples of condensing agents include N,N-dicyclohexylcanoleposiimide, N-cyclohexyl-N-
Morpholinoethylcarbodiimide, N-cyclohexyl-N-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N-(3-dimethylaminopropyl)carbodiimide, and the like are used. Also, for example, sodium carbonate. Potassium carbonate. Alkali metal carbonates such as sodium bicarbonate and potassium bicarbonate, such as triethylamine and tributylamine. N-methylmorpholine. N
- tertiary amines such as methylpiperidine, N,N-dimethylaniline, e.g. pyridine. Picoline, lutidine. The reaction can also be carried out in the presence of a base such as pyridines such as collidine. These bases have the effect of accelerating the reaction or neutralizing the acid produced in the reaction, and usually have an effect of about 0.0% relative to compound (Vl) or its salt. It is used in an amount of 0 to 10 times the mole, preferably about 0.1 to 5 times the mole. The reaction temperature is not particularly limited, but is usually about -30 to 50°C.
It is often done in The reaction time is about several minutes to several tens of hours (for example, 5 minutes to 30 hours).

In the above production method 3, the raw material compound (Vl
) or a salt thereof, for example, in the general formula (■) c, R9 represents a protecting group for the amino group, and other symbols have the same meanings as above]
It can be produced by removing the protecting group of the amino group of the compound represented by or a salt thereof. This deprotecting group reaction is carried out by hydrolysis; reduction; method using Lewis acid; compound (■) or its salt is reacted with an iminohalogenating agent and then an iminoetherifying agent; if necessary, This is carried out by a method known per se, such as a method of subjecting the resulting compound to hydrolysis.

Further, the starting compound (■) and its reactive derivatives can be produced by methods known per se or by known methods.

Production method 4 Compound (I) or a salt thereof has the general formula (II) [wherein,
A compound represented by the general formula (V) M-R'' (V) [wherein the symbols have the same meanings as above] It is obtained by reaction and then treatment with acid.

This reaction is carried out in an inert solvent. Examples of inert solvents include diethyl ether, diisopropyl ether,
Ethylene glycol dimethyl ether, dioxane,
Ethers such as tetrahydride, dimethoxymethane, and hydrocarbons such as benzene and hexane are used.

The reaction is carried out at a temperature range of about -100 to 30°C, preferably about -80 to 0°C. The reaction time is the starting material compound (I
! ) and the type of organometallic compound and reaction temperature, but it is usually 1 minute to 3 hours. Organometallic compounds are
About 1 to 10 equivalents are used per 1 equivalent of compound (If).

Acids used in the reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, and p-}luenesulfonic acid. Examples include acids.

The raw material compound (II) or its salt is disclosed in, for example, JP-A-49
-124091 or a method similar thereto.

The reaction products obtained by the above production methods 1, 2.3 and 4 can be prepared by means known per se, such as solvent extraction, liquid conversion,
It can be isolated and purified by dissolution, salting out, crystallization, recrystallization, chromatography, etc.

Further, when the reaction product contains a protecting group, the protecting group can be removed by a method well known in the art to obtain compound (I) or a salt thereof. In other words, β-lactam. Amino, hydroxyl or carboxyl protecting groups have been well studied in the field of peptide synthesis, and methods of protection and deprotection have been established. For example, methods for removing the protecting group include a method using an acid, a method using a base, and a method using hydrazine. Method by reduction, N-
Known means such as a method using sodium methyldithiocarbamate can be appropriately selected and used.

Further, the reaction product (1) obtained by the above production methods 1.2.3 and 4 is usually obtained as a diastereoisomer mixture. These mixtures can be sorted by fractional recrystallization or column chromatography.

Hereinafter, when referring to compound (I) in this specification, it means a diastereomer mixture unless otherwise specified.

In the above production methods 1.2.38 and 4, compound (I)
(syn[2] monoisomer) may be obtained as a mixture with its anti[E] monoisomer. In order to separate the desired syn isomer (ie, compound (I) or a salt thereof) from the mixture, a method known per se or a method analogous thereto can be applied. Examples of such methods include fractionation methods that utilize differences in solubility and crystallinity, separation methods using chromatography, and the like.

Further, when the obtained compound is a 1-oxide, that is, when n is 1 in the general formula (I), it can be converted to the sul7ide compound [n is 0 in the general formula (1)] by reduction. Examples of reducing agents used here include reducing inorganic salts (thiosulfates, iodides, divalent tin salts, iron salts, etc.),
Examples include phosphorus compounds (phosphorus trihalide, phosphorus pentasulfide, phosphine, etc.) and hydrides (sodium borohydride, etc.).

? Effects of the Invention) Compound (I) of the present invention or a salt thereof has broad-spectrum antibacterial activity, and is effective against humans and... It can be used for the prevention and treatment of various diseases caused by pathogenic bacteria in animals and animals.

The present invention will be explained in more detail below using reference examples, working examples, and test examples. However, these are merely examples and do not limit the invention in any way.

Elution in column chromatography in the following Reference Examples and Examples was performed under observation by TLC (thin layer chromatography). In TLC observation, a TLC plate manufactured by Merck (7) 60F■.
The solvent used as the elution solvent in column chromatography 7E was used as the developing solvent, and a UV detector was used as the detection method. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh), also manufactured by Merck, was used.

“Se7 Addex” is manufactured by Pharmacia Fine Chemicals.
icals).

XAD-II resin is manufactured by Rohm and Haas (R
ohm & Hass Co. ). HP-20
The resin is made by Mitsubishi Kasei. NMR spectra were analyzed using EM3 using tetramethylsilane as internal or external reference.
90 (90MHz) type and GEMINI 20
0 (200MHz) type spectrometer,
All δ values are shown in ppm. For mixed solvents used in chromatography, the numbers shown in parentheses are the volumetric mixing ratios of each solvent. % indicates weight percent unless otherwise specified.

Symbols in Reference Examples and Examples have the following meanings.

S: singlet, d: doublet, t: triplet q: quartet, ABQeAB type quartet dd nidapu nore doublet, m: manoret triplet b'. J: Coupling constant sh: Shoulder reference example l 4-Methoxybenzyl 7β-phenylacetamide F-
3-(Triphenylphosphonio)methyl-3-cephem-4-carpoxylate Dissolve 41.4 g of iodide in a mixture of 300 mQ of dichloromethane and 150 d of water, and while stirring, dissolve 40'% pyruvaldehyde aqueous solution 2.
After adding 00g, adjust the pH with 20% sodium carbonate aqueous solution.
It was adjusted to 9.0 to 9.5. The reaction solution was stirred at room temperature for 2 hours, and then adjusted to pH 7 with IN hydrochloric acid. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Pour the residue into silica gel (800g
) The product was subjected to column chromatography and eluted with a mixture of ethyl acetate and dichloromethane (1:9). The eluate was concentrated to dryness under reduced pressure, and the obtained solid was recrystallized from ethyl acetate-hexane, resulting in a ratio of 1 to 1 of the cis and trans forms of the target product.
4.87 g of a mixture was obtained as a colorless solid. The mother liquor was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of ethyl acetate and dichloromethane (1:9). The eluate was concentrated under reduced pressure and the residue was treated with ether to yield 4-methoxybenzyl 3-[(Z)-3oxo l-butenyl l-7β.
-7 Phenylacetate? 3.07 g of mido 3-ce7m-4-carpoxylate was obtained as a pale yellow solid. Melting point II9-121'O (decomposition) Summer R (KBr) cm-': 3270.3
030.2960. l775. l? 10. NMR
(CDCIs) δ: 2.19 (3H, s). 3.3
3 (IH, d, J48Hz), 3.62 (IH, d,
J=18Hz). 3.64 (2H, ABq.J=
16Hz). 3.80 (3H, s). 5.01 (I
H, d, J=5Hz), 5.14 (2H.ABq.
J=12Hz). 5.85 (IH, dd, J=5&9
Hz). 6.16 (IH, d, J=9Hz). 6.1
9 (IH, d, J=12Hz). 6-74 (IH,
J■1 2Hz) ,6.87(IH,d, J■9H
z)． 7. 31 (2H, d, J = 9Hz
)． 7.2-7.4 (5H, 01) Elemental analysis value: C,,H,. N. O. S-0.4H! O
Calculated value (%): C, 63.12; H, 5
．． 26; N, 5.45 Actual value (%): c, fl:
3. o6;H. 5.11;N. 5.23 On the other hand, 4.8 g of the above mixture of cis and trans isomers (l:1) was dissolved in 25 mα of chloroform, and 1 ml of a chloroform solution saturated with hydrogen chloride was added while cooling with water, followed by stirring for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate and hexane to give 4-methoxybenzyl 3-[(
E) 3.4 g of -3-oxo l-butenyl 1-7β-phenylacetamide 3-cephem-4-carpoxylate was obtained as a pale yellow solid. Melting point 179-182
°C (decomposition) I R (KBr) cm-': 3270.3030
．． 2960. l780. l710,1670.1610 N M R (CDC13) δ: 2.22 (3H, s
), 3-45 (IH, d, J=18Hz). 3.59
(IH, d, J=18Hz). 3-65 (2H, ABq
．． J=17Hz). 3.81 (3H.s), 4.97
(IH, d.J=5Hz), 5.25 (2H, ABq
．． J=12Hz), 5.88(IH, dd, J=5&
9Hz), fi. 23 (IH, d, J=16Hz).
6.24 (lH.d, J=9Hz). 6.90 (2H
, d, J=9Hz). 7.2-7.4 (7H, m),
7.75 (IH, d, J=16Hz) Elemental analysis value 'Cz
Calculated value as tHtsNzOsS (%): C, 64
．． 02;H. 5. l7; N. 5.53 Actual value (%)
: C, 63.71; H. 5. ll;N. 5.3
6 Reference Example 2 4-methoxybenzyl 7β-7phenylacetamide-
8.29 g of 3-(triphenylphosphonio)methyl-3-se7emu-4-carpoxylate iodide was dissolved in a mixture of 60 ml of dichloromethane and 30 ml of water, and 10.0 g of 7-enylglyoxal-hydrate was added. The pH was then adjusted to 9.0 to 9.5 with a 20% aqueous sodium carbonate solution, and the mixture was stirred at room temperature for 30 minutes. After neutralizing with IN hydrochloric acid, the organic layer was separated, washed with brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (250 g) and eluted with a mixture of dichloromethane and ethyl acetate (9:l). The eluate was concentrated to dryness and the residue was washed with ether to give 4-methoxybenzyl 3-(2-benzoylvinyl)-7β-7phenylacetamide-3-cephem-4.
Mixture of cis and trans isomers of monocanoleboxylate (
2.50 g of about 3:I) were obtained as a pale yellow solid.

Melting point 177-179°C (decomposition) I R (KBr) cm-': 3430.3260
．． l780. l715.1655.1540.1515 Cis NMR (CDCI.) δ: 3.48
(2H.ABq, J=18Hz). 3.64 (2H, A
Bq. J=4Hz). 3.79 (3H, s). 4.97
(IH, d, J=5Hz), 5.12 (2H.ABq
．． J-12Hz). 5.84 (IH, dd, C5&9
Hz), 6.14 (IH, d, J=9Hz). 6.
82 (lH.d, J=12Hz). 6.84 (2H, d
, J=91{z). 7.04 (IH, d, J42Hz
). 7.2-7.9 (12H, m) Elemental analysis value: Calculated value (%) as C 32H zaN to as: C. 67.59; H, 4.96;
N, 4.93 Actual value (%): C. 67.40; H
．． 4.93;N. 4.76 Reference Example 3 4-Methoxybenzyl 7β-7enylacetamide-
Dissolve 4.76 g of 3-(triphenylphosphonio)methyl-3-cephem-4-carpoxylate iodide in a mixture of 70 raQ of chloroform and 80 d of ethyl acetate, add 20.5 aQ of IN sodium hydroxide aqueous solution, and stir for 10 minutes. Ta. The organic layer was separated and dried over anhydrous magnesium sulfate. 10 g of diethyl ketomalonate was added to the resulting solution, and after stirring for 30 minutes, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (200 g) and eluted with a mixture of dichloromethane and ethyl acetate (9:1). Good? The resulting crude product was reprecipitated with dichloromethane and ether to give 4-methoxybenzyl 3-[2,2-bis(ethoxylponyl)hinyl]-7β-7enylacetamido-3-cepheme-4-carpoxylate. 2. as a colorless solid. lO
g was obtained. Melting point 164-168°C IR (KBr) cm-': 3430.3270
．． 2970. l780,1730.1710.1655
, 1615.1535.1520N M R (CDC
I. ) δ: 1.29 (6H, t, J■7Hz), 3
．． 45 (2H, ABq. J48Hz) . 3.64
(2H, ABq, J=15Hz). 3.80 (
3H, s). 4.25 (2H.q, J=7Hz).
4.26 (2H.q.J=7Hz). 4.80 (IH,
d, J=5Hz). 5.20 (2H, s). 5.86
(IH, dd, J=5&9Hz). 6.08 (IH,
d, J=9Hz). 6.88 (2H, a, J=9Hz)
．． 7.2-7.4 (7H, m). 7.71 (IH, s) Elemental analysis value: C s r H s z N ! O
* S・0.3H, o calculated value (%): C, 61.1
7;H. 5.30;N. 4.60 Actual value (%):
C, 60.78; H. 5.25i N. 4.63 Reference Example 4 In a mixture of 3.6 g of zinc granules (washed sequentially with 2% hydrochloric acid, water, ethanol, acetone, and dry ether and dried at 100° C. under vacuum) and 50 d of dry dimethoxymethane,
Add a small amount of iodine and 5.6 m<1 of ethyl bromoacetate,
The mixture was heated to reflux for an hour. The resulting pale yellow solution was ice-cooled, and 2.56 g of di7enylmethyl 3-formyl-7β-phenylacetamide 2-cephem-4-carpoxylate was added while stirring, followed by stirring at the same temperature for 10 minutes. 200+nQ of ice-cooled 0.5N hydrochloric acid was added, stirred, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel (long) column chromatography and eluted with a mixture of dichloromethane and ethyl acetate (4:l). The eluate was concentrated under reduced pressure, 5 mQ of diethyl ether was added to the residue, and hexane lowQ was added with stirring. A candy-like substance was formed, so the upper groove was removed by decantation and dried under vacuum to yield diphenylmethyl 3-(2-ethoxylponyl=1
-Hydroxyethyl)-7β-7enylacetamide-
2-Cefem-41 Carbo? 2-18 g of sylate (diastereomeric mixture, approx. l=1) as a pale yellow solid
Obtained.

Melting point 98-102℃ IR (KBr) am-'2 3420.3
060.3030.2980.2930,1780. l
740. l670. l530N M R (CDCIs
) δ: 1.23 (3H.t, J=7Hz), 2.4
1 (0.5H, dd, J■4&l6Hz). 2.4
2 (0.5H, dd, J■9&l6Hz). 2.55
(0.5H, dd, J=9&l6Hz). 2.55
(0.5H, dd, J=4&16Hz). 3.20 (
IH, br. s), 3.63 (2H, s). 4.
12 (2B, q.J=7 Hz). 4.5-4.6(
IH, a+). 5.02 (0.5H, s), 5.1
1 (0.5H, d, J=4Hz), 5.13 (0.
5H, d, J=4Hz), 5.21 (0.5H, s).
5.55 (0.5H, dd, J=4&7Hz), 5
．． 59 (0.5H, dd, J=4&7Hz). 6.2
3 (0.5H, s). 6.2=6.3(IH, m),
6.38 (0.5H, s). 6.87 (IH,s)
．． 7.2-7.4 (15H, m) Elemental analysis value: CssHsxNzOtS ・0.8Hx
Calculated value as O (%'): C, 64.44; H.
5.51;N. 4.55 Actual value (%): C. 64.
47;H. 5.23;N. 4.44 Reference Example 5 Anhydrous tetrahydrofuran (hereinafter abbreviated as THF) 6ml2
was cooled to -78°C, and n-butyllithium (1.6M
Hexane solution) 6 mff was added, and while stirring, a THF solution of 0.6 mQ of acetonitrile was added dropwise over 5 minutes.
The mixture was stirred at the same temperature for 30 minutes. The resulting suspension was mixed with 1.64 g of diphenylmethyl 3-formyl-7β-7phenylacetamido-2-cephem-4-carpoxylate.
It was added dropwise to a HF (15 m4) solution at -78°C, and 1
Stir for 5 minutes. After adding 2N hydrochloric acid and stirring,
water! Pour into 50ml2. Extraction was performed with dichloromethane, the extract was washed with brine, and after drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel (100 g) column chromatography 7E, and a mixture of ethyl acetate and dichloromethane (1
:4), diphenylmethyl 3-(2-cyano-1-hydroxyethyl)-7β-phenylacetamide F-2-cephem-4-carpoxylate (diastereomer mixture, approximately 2=1) is pale yellow. 882 as a solid
mg was obtained. Melting point 75-78°C IR (KBr) cod-': 3410.303
0.2930.2250. l775.1745. 16
65. 1530 N M R (CDCI.) δ of main isomer: 2.49
(2H.d, J=6Hz). 2.68 (IH, d, J=
5Hz). 3. fi4(2H,s). 4.44 (lH.
dd, J=5&6Hz). 5.02 (IH, s), 5.
15 (IH, d, J=4Hz), 5.58IH, dd
, J・4&9Hz). 6.30 (IH, d, J=9Hz
). 6.48 (IH, s) 6.90 (l}1, s). 7
．． 2-7.4 (15H, m) Elemental analysis value: C s l
Calculated value as H x v N s O a S (%)
:C, 67.25; H. 4.92;N. 7.59 Actual value (%): C, 67.58; H. 5.22;
N. 7.34 Reference Example 6 Dimethylsulfone l. 92 g was dissolved in 60 mQ of THF, 12 ounces of n-butyllithium (1.6 M hexane solution) was added at -78°C, and the mixture was stirred at the same temperature for 2 hours. This solution was added dropwise to a solution of 1.97 g of diphenylmethyl 3-formyl-7β-7phenylacetamide-2cephem-4-carpoxylate in THF (18 m<2) at -78°C, and the mixture was stirred at the same temperature for 10 minutes. . After adding 2N hydrochloric acid (11) and stirring, the mixture was poured into ice water (150) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel).
．． Eluent: Diphenylmethyl 3(1-hydroxy-2-
1.41 diastereomeric mixture (approximately 1:l) of (methylsulfonylethyl)-7β-7enylacetamido-2-cephem-4-carpoxylate as a pale yellow solid.
g was obtained. Melting point 63-67°C IR (KBr) cm-': 3440.3060
．． 3030.2930. l775.1745.1665
．． 1535. N M R (CDCIs) δ: 2.82 (3H, s
). 2-8-3.3 (2H, m). 3.63(2H,s
). 4.7-4.8 (IH, m). 5.08 (0.5H
, d, J=4Hz). 5.09 (0.5H, s). 5.
12 (0.5H, d, J = 4Hz), 5-20 (0.5
H,s). 5.56 (LH, dd, J=4&9Hz).
6.37 (IH, d, J=9Hz). 6.37 (0.5
H. s). 6.41 (0.5H.s). 6.87 (0.
5H,s). 6.88 (0.5H, s). 7.2=7.
5 (15H, m) elemental analysis value. 'CssHsoNxOt
S*・l. 5H. 0 Calculated value (%): C, 5B. 75;
H. 5.25i N. 4.42 Actual value (%): C,
58.45; H, 5.1B. N. 4.12 Reference Example 7 (9R.l OR)-10-amino-4-oxa-3.
11-Dioxo-5-(2-oxopropyl)-8-thia ■-Azatricyclo[7.2,0.08.6]undec-2(6) monoene hydrochloride HC7 4.5 g of phosphorus pentachloride was dissolved in 40 m of dichloromethane. (1.8 m<2 of pyridine was added while stirring under water cooling. After stirring for 60 minutes under water cooling, (9R.IOR)
-4-Oxer3.11-dioxo-5-(2-oxoprobyl)-1O-phenylacetamido8-thia1-azatricyclo[7.2.0.0'・6J undec-2(6)-ene2 .7 g was added, and the mixture was further stirred at the same temperature for 2 hours.

After adding methanol 26- at -50°C and stirring at -10°C for 75 minutes, 0.7 mQ of water was added and the mixture was stirred for 30 minutes under water cooling. 300 ml2 of ether was added and the mixture was cooled to -40°C, and the precipitated syrupy substance was collected by decantation and then dissolved in 10 ml2 methanol. 400 mff of chloroform and Koichitel 1O- were added and stirred. The precipitate was collected by filtration and washed with Koichitel to obtain 1.30 g of the title compound as a pale yellow powder.

Melting point 150-164°0 (decomposition) I R (KBr) cm-': 3430,2900
．． l795. l715. l675, l630 N M R (d,-DMSO) δ: 2.17 (3H
, s), 2.79 (0.5H, dd, J=9&18Hz
). 2.83 (0.5H, dd, J=9&l8Hz)
．． 3.15 (0.5H, dd, J=4&l8Hz),
3.30 (0.5H, dd, J=4&18Hz). 3
．． 87 (IH, s). 3.90 (1B, s). 5.
16 (0.5H, J=5Hz). 5.21 (0.5H
, d, J=5Hz). 5.31 (IH, d, J=5H
z). 5.56 (0.5H, dd, J=4&9Hz
). 5.60 (0.5H, dd, J=4&9Hz) Elemental analysis value: C,,Hl3N,0,S-HCQ-1.4
Calculated value (%) as H, 0: C, 40.04i H. 4.83;
N. 8.49 Actual value (%): C. 40.24;H.
4.78; N, 8.42 Reference Example 8 Diphenylmethyl 3-[2-(
N,N-diethylrubamoyl)-1-hydroxyethyl]-7β-phenylacetamide 2-cephem-4
-carpoxylate (diastereomeric mixture, 7:3
)was gotten.

Melting point 60-65℃ IR (KBr) cm-': 3200.1780
．． l745. l680. l620. l540 NMR of main isomer (d,-CDCQ3)δ: 1
．． 03 (3H, t, J=7Hz). 1.09 (3H, t
, J=7Hz). 2.33 (2H, d, J・6Hz).
3.04 (2H, q, J=7Hz). 3.29 (2
H. q, J=7Hz). 3.63 (2H, s). 4
．． ! r4.6 (IH, m). 4.75 (IH, d,
J=3Hz), 5-10(lH.d, J=4Hz).
5.16 (IH, s). 5.53 (IH, dd, J=
4 & 9Hz). 6.33 (lH.s). 6.37 (
18, d, J=9Hz). 6.85 (IH, s)
．． 7.2=7.4 (15H, m) Elemental analysis value: C3
*HsrNsO*S ・0.3H! Calculated value as O (%
): C. 66.39;H. 5.98;N. 6.6
3 Actual measurement value (%): C, 66.44; H, 6.22
; N, 6.64 [Example] Example l (9R.1 0R)-4-oxer3.11-dioxo-5-(2-year-old -Azatricyclo[7,2. O,
O”・1] undec-2(6)ene 4-methoxybenzyl 3-(3-oxo!-butenyl)-7β-7enylacetamide-3=cephem-4
-carboxylene}4.2g in dichloromethane 12ml
2 and 12 d of anisole and trifluoroacetic acid were added thereto while cooling with water, and the mixture was stirred for 1 hour. While cooling with water, 120 mff of ether was added and stirred for 5 minutes. The precipitate was collected by filtration and washed with ether to give a diastereomeric mixture (approximately 1:1) of the title compound as a pale yellow powder.
7g was obtained. Melting point 190-195℃ (decomposition)? R
(KBr) cm-': 3270.3030.29
20. l795. l715. l665 N M R (CDCls) a: 2.24 (1.
5H. s). 2.26 (1.5H, s). 2.81 (0
．． 5H, dd, J■7&l8Hz). 2.82 (0.
5}1, dd, J=6&l8Hz). 3.03 (0.
5H, dd, J=6&l8Hz). 3.05 (0.5H
, dd, J=6&l8Hz). 3.30 (0.5H, d
, J=19Hz). 3-53 (IH, s). 3.66(
2H, ABq, J=16Hz), 3.67 (0.
5H. dd, J = 2&l 9Hz). 4.96
(0.5H, d, J■5Hz), 4.99 (0.5H,
d, J■5Hz), 5.42 (0.5H, dd, J=6
&7Hz). 5.47 (0.5H, dt, J=2&6H
z). 5.93 (LH, dd, J=5&9Hz). 6.
31 (IH, d, J=9Hz). 7.4-7.8 (5H
．． ■) Example 2 (9R.l OR)-10-[2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetamide]-4-oxer3.11-dioxo-
5-(2-oxobyl)-8-thia l-azatricyclo[7.2. O. O''・'] undec-2(6)-ena) 2- (2-tritylaminothiazol-4yl)
6.88 g of -(Z)-2-trityloxyiminoacetic acid was suspended in 50IIl12 of dichloromethane, and triethylamine was added under water cooling. ．． 7 mff and 2.27 g of phosphorus pentachloride were added and stirred for 60 minutes.

On the other hand, (9R.IOR)-10-amino-4-oxer3.
-Thia1-azatricyclo[7,2.0.0'・6]
2.60 g of undec-2(6) monoene hydrochloride was suspended in 50 llff of dichloromethane, and while stirring at room temperature,
N,O-bis(trimethylsilyl)acetamide 6.3
1III2 was added. The obtained solution was cooled to -15°C, and the acid chloride solution prepared earlier was added dropwise while stirring. What about the reaction solution? After stirring for 1 hour at 20~-5°C,
Washed sequentially with water and saline. After drying, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (30 g).
:2) eluted with (9R,l OR)-4-oxer3.11-dioxo5-(2-year-old
-Thia10- [2- (2-tritylaminothiazol-4-yl)- (Z)-2-trityloxyiminoacetamide]-1=azatricyclo[7.2.0.
3.89 g of a diastereomeric mixture (about tel) of undeca-2(6)monene was obtained as an orange solid.

JR (KBr) cm-': 3380,3050
．． 3020. l800. l690.1600. l520
．． l495 N M R (CDCI 3) δ: 2.23 (3H,
s), 2.7-3.2 (2H, m). 3.4-3.7(
2H, m), 5.06 (0.5H, d, J=5Hz).
5.08 (0.5H, d, J=5Hz). 5.3-5.
5 (IH, o+). 6.16 (IH, dd, J■5&9
Hz). 6.45 (0.5H, s). 6.46 (0
．． 5H,s). 6.86 (LH, br.s). 7.
1=7.4(30H,m)b) Product 3.6 of a) above
9 g of formic acid was dissolved in 40 m (1?) of formic acid and stirred at room temperature for 1 hour. The formic acid was distilled off under reduced pressure, and the residue was diluted with 100 m of ether.
ff was added and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with Koichitel to obtain 1.93 g of the title compound formate as a brown solid. Of this, 244 mg was added to a mixed solvent of methanol and THF, IQm (2), insoluble matter was filtered off, and ether 40- was added to the filtrate and stirred. Stereomeric mixture (approximately 1:1) as a brown solid at 127
mg was obtained. Melting point 2lO~220°C (decomposition) I R (KBr) cm-': 3420.2920
．． 1?90. l670. l620. l530 NMR (ds-DMSO) δ: 2.16 (3H
, s). 2.7-3-3 (2H, m), 3.5-3.9
(2H, m). 5. 10 (0.5H, d, J■5H
z), 5.15 (0.5H, d, J-5Hz), 5.5
~5.6 (IH, m). 5.94 (0.5H, dd, J
=5&8}1z). 5.97 (0.5H, dd, J=5
&8Hz). 6.66 CIH, s). 7.14 (2H,
br. s). 9.55 (LH, d, J=8Hz). 11
．． 34(lH.s) Example 3 (9R.IOR)-4-oxer3.11-dioxo5-7enacyl-10-7phenylacetamide 8-thia l-azatricyclo[7,2.0.02.6 ] undeca-2(6)-ene-4-methoxybenzyl 3-(2
-benzoylvinyl)-7β-7phenylacetamide-
569 mg of 3-ce7emu-4-carpoxylate was suspended in 1.5 ml of dichloromethane, and while stirring under ice-cooling, 0-15 ml of anisole and 1.5 ml of trifluoroacetic acid were added.
5- was added. After stirring for 40 minutes under water cooling, it was concentrated under reduced pressure and the residue was treated with ether.

The precipitate was collected by filtration and washed with ether to obtain 404 IIlg of a diastereomeric mixture (approximately 1:1) of the title compound as a pale yellow solid. Melting point 200-204°C (decomposition) I R (KBr) am-': 1795.1680
,1600.1530N M R (CDCI3+d1
DMSO) δ: 3.4-3.9 (6H, m).
5.02?0.5H, d, J■5Hz). 5.05 (
0.5H, d, J■5Hz), 5.7~5.8(LH
, m). 5.87 (LH, dd, J=5&8Hz).
7.2-8.1 (IOH, m), 8.95 (Q.5
H, d, J=8Hz), 9.00 (0.5H, d, J=
8Hz) Elemental analysis value: C! aH*-NzOsS・0.
5H,0 calculated value (%): C. 63.01;H. 4.6
3. N, 6.12 Actual value (%): C. 63.29
．． H. 4.34. N. 5.72 Example 4 (9R.IOR)-5-[bis(ethoxycarponyl)methyl]-4-oxer3.11-dioxole 1O-
7-enylacetamido-8-thia-1-azatricyclo[7,2.0.0''-undec-2(6)-1ene-4-methoxybenzinole 3-[2.2-bis(ethoxycarbonyl)hinyl]- 1.22 g of 7β-7 enylacetamido-3-cephem-4-carpoxylate was dissolved in dichloromethane, and 0.0 g of anisole was added under cooling.
Add 3mQ and 3ml2 of tri7fluoroacetic acid and mix at the same temperature.
Stirred for an hour. After concentrating under reduced pressure and washing the residue with ether, it was dissolved in dichloromethane and the solvent was distilled off under reduced pressure to obtain a diastereomer mixture of the title compound (approximately 1:
627 mg of 1) was obtained as a pale yellow solid.

I R (KBr) cm-': 3426.2930
．． l800. l735.1670. NMR (CD
C l s ) δ: 1.21 (1.5H, t, J=7
Hz). 1.25 (1.5H, J=7Hz). 1.28
(1.5H, t, J=7Hz). 1.29 (1.5H,
t, J=7Hz). 3.60 (2H.ABq, J=19
Hz). 3.61 (IH.s). 3.64(LH,s)
．． 3.96 (0.5H, d, J=5Hz). 3.99
(0.5H, d, J=5Hz). 4.17 (lLq.
J=7Hz>. 4-19CIH. q, J=7Hz).
4.22 CIH, q. J■7Hz). 4.26 (l
H. q, J=7Hz). 4.96 (18. d,
J=5Hz) ,5.58(0.5H,d,J=5Hz
). 5.61 (0.5H, d, J=5Hz). 5.93
(0.5H, dd, J=5&9Hz). 5.95 (0.
5H, dd, J=5 & 9Hz), 6.33 (0.5H,
d, J■9Hz). 6.46 (0.5H, d, J=9H
z). 7.2-7.4(58,+a) Example 5 (9R.1 0R)-10- [2- (2-aminothiazol-4-yl)- (Z)-2-methoxyiminoacetamide 1-4 -oxer3.11-dioxo-5
-(2-oxopropyl)-8-thia l-azatricyclo[7.2.0.0''.1]undec-2(6)monene (9R.IOR)-10-amino-4-oxa-3. 1
1-dioxo-5-(2-year-old xopupil)-8-thia l-azatricyclo[7.2.0,02.@]undec-2(6)-1-dioxohydrochloride (1.22 g) was mixed with water and THF. 2.0 g of sodium hydrogen carbonate was dissolved in a 50-liter mixture (1:l) and stirred under cooling with water. Then 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-
1.33 g of methoxyiminoacetyl chloride hydrochloride was added. After stirring the reaction solution for 30 minutes under water cooling,
The pH was adjusted to 3-4 with hydrochloric acid and then saturated with sodium chloride. The reaction solution was extracted with a mixture of ethyl acetate and THF (5:l),
The extract was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 50 m4 of a mixture of water and THF (1:l), 1.04 g of sodium N-methyldithiocarbamate was added, and the mixture was diluted with 1.0 g of sodium N-methyldithiocarbamate.
．． Stir for 5 hours. After adjusting the pH to 4 with IN hydrochloric acid, the mixture was saturated with sodium chloride. The organic layer was separated, and the aqueous layer was extracted with THF.

The organic layers were collected and concentrated under reduced pressure. The residue was dissolved in water and THF.
Dissolved in a mixture of XAD-II (300mf
f) It was subjected to column chromatography and eluted with a 40% by volume ethanol aqueous solution. The eluate was concentrated under reduced pressure and lyophilized to obtain 0.5 g of pale yellow powder.

This powder was dissolved in a mixture of 50 m of THF (2) and methanol IO-, and 0.1 m of a methanol solution of hydrogen chloride (1) was added and stirred. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Purification by chromatography (silica gel 200 gs eluent: acetonitrile:ethyl acetate - 1:10) gave 60 mg of a diastereomeric mixture (approximately 4:1) of the title compound as a yellow solid.

I R (KBr) cm'': 3430.2940
．． 1?90. l670. l620. l535 NMR (d,-DMSO)δ of main isomer: 2.
16 (3H.s). 3.36 (2H, ABq, J=16
Hz), 3.7-4.0 (2H, m). 3.85 (3H
, s). 5.11 (In, d, J=5Hz). 5.5-
5.6 (lH.m). 5.95 (18, dd, J=5&
8Hz), 6.74 (lH.s). 7.27 (2H,b
r. s). 9.70 (IH, d, J = 8 Hz) Example 6 (9R.IOR) -5-ethoxylponylmethyl-
4-Oxor3.11-dioxo-10'-7phenylacetamido-8-thia1-azatricyclo[7.2.
O,O''-'lundec-2(6)-ene 8-oxidodiphenylmethyl 3-(2-ethoxylponyl-l
-Hydroxyethyl)-7β-7enylacetamide-
Dissolve 2.40 g of 2-se7m-4-carpoxylate in 8 ml of ethyl acetate, add a solution of 863 mg of m-chloroperbenzoic acid in ethyl acetate (4 + n(2)) under water cooling,
The mixture was stirred at the same temperature for 1 hour.

Add 50 mρ of water and adjust the pH to 7 with aqueous sodium hydrogen carbonate solution.
After adjusting to the following conditions, the mixture was extracted with dichloromethane.

The extract was washed with brine, dried, and concentrated under reduced pressure.

Dissolve the residue in 6 m+2 dichloromethane, add 0.6 ml of anisole and 6-trifluoroacetic acid while cooling with water,
The mixture was stirred at the same temperature for 1 hour. It was concentrated under reduced pressure, ether was added to the residue and stirred, and the precipitate was collected by filtration and washed with ether to obtain 1.52 g of the title compound as a yellow solid.

J R (KBr)c+m-': 3430,2
930,1805. l735. l675,NMR
(CDCIs) δ: 1.26 (1.5H, t, J=7
Hz). 1.28 (1.5H, t, J=7Hz). 2
．． 7=2.9(2H,m). 3.3=4.0(4H,
01). 4.16 (lH.q.J=7Hz). 4.
18 (IH, q.J=7Hz). 4.5? (0.5H,
d, J=5Hz). 4.60 (0.5H, d, J■5
Hz), 5-4-5.5 (IH, +w). 6. 1
2 (lH.dd, J■5&lOHz). 6.89 (
0.5H, d, J=lOHz). 6.94 (0.5H
．． d, J 10Hz), 7.2 = 7.4 (5H, m) Example 7 (9R, IOR)-5-ethoxylponylmethyl-4
-oxer3.11-dioxo-lO-7enylacetamido-8-thia l-azatricyclo[7.2.0.
0''.61 undeca-2(6) 1.52 g of the compound obtained in Example 6 was dissolved in DMF3.5+aQ and heated at -30°C.
Then 0.7 mm of phosphorus trichloride was added and stirred at the same temperature for 30 minutes. After diluting with 150 ml of water, the mixture was extracted with ethyl acetate. After washing the extract with water, 300 mQ of water was added, and the pH was adjusted to 6 with an aqueous sodium hydrogen carbonate solution. Separate the organic layer and ? After washing with brine, it was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was dissolved in silica gel (15 g).
The column was subjected to chromatograph 7E and eluted with ethyl acetate. The eluate was concentrated to dryness under reduced pressure, the residue was dissolved in dichloromethane, 10 times the amount of methane was added, the precipitate was collected by filtration, and washed with ether to give a diastereomer mixture of the title compound ( 3:2) as a pale yellow solid.
68g was obtained. Melting point 85-87°C ER (KBr) am-': 3420,1795
．． l735. l675,1525. N M of the main isomer
R (CDCII) δ: 1.27 (3H, t, J=7
Hz), 2.79 (l}f, d, J=8Hz), 3.3
9 (IH, d, J=19Hz). 3.66 (2H, s)
．． 3.67 (IH, d.J=19Hz). 4.20 (2
H. q, J■7Hz). 4.99 (IH, d, J=5H
z), 5.42 (IH, t, J=8Hz). 5.95 (
IH, dd, J=5&9Hz). 6.29 (IH, d,
J=9Hz). 7.2-7.4 (5H, m) Elemental analysis value: C2. H! . N! O, S.o. Calculated value (%) as sH,o: C, 56.46; H. 4.97;N.
6.58 Calculated value (%): C. 56.64;H. 4
．． 59; N, 6.77 Example 8 (9R, IOR)-5-cyanomethyl-4-oxer 3
．． 11-dioxo-IO-7phenylacetamide-8-
Thia l-azatricyclo[7,2. O, O”・6] undeca-2(6)-ene 8-oxide Elemental analysis value: C+sH+iNxOsS-0.6HzO
Calculated value (%): C. 54.57;H. 4.
l2. N, 10.61 Actual value (%): C. 54.
69; ■. 3.86i N, 10.32 Example 9 (9R.1 0R)-5-cyanomethyl-4-oxer3.11-dioxo-10-yenylacetamide-
8-thia l-azatricyclo[7.2,0,O”#●
] Undeka-2 (6) 1en? When reacted in the same manner as in Example 6, a diastereomeric mixture (approximately 1:t) of the title compound was obtained.
was obtained as a pale yellow solid. Melting point 134-144℃I
R (KBr) cm-': 3430.2930,
2260.1805,1675. N M R (d, -
DMSO) δ:3. θ~4.4 (6H, m). 4.88
(0.5H, d, J=5Hz). 4.90 (0.5H,
d, J=5Hz). 5.53 (0.5H, t, J=5H
z). 5.59 (0.5H, t, J-5Hz). 5.9
7 (0.5H, dd, J=5&8Hz). 6.02 (0
．． 5H, dd, J■5&8Hz). 7.2-7.4 (5
H, +m). 8.58 (0.5H, d, J=8Hz).
8.66 (0.5H, d, J=8Hz) When reacted in the same manner as in Example 7, a diastereomer mixture of the title compound (
1:1) was obtained as a pale yellow solid. Melting point 212~
213°C (decomposition) I R (KBr) Cal-':
3440.3360.2970.2940.2250
,1800.1765,1680.1520N M R
(CDCI s) δ: 3.15 (0.5H, dd,
J=6&l7Hz), 3.31(0.5H, dd, J=
4&18Hz). 3.43 (0.5H, dd, J=6&
l7Hz). 3.53 (0.5H, dd.J=4&18
Hz). 3.54 (2H, ABq.J=14Hz). 3
．． 77 (lH.s). 3.84 (IH, ABq, J=1
9Hz). 5.09 (0.5H.d, J=5Hz). 5
．． ll (0.5H, d, J=5Hz). 5.55 (0.
5H, t, J=4Hz). 5.59 (0.5H, t, J
=6Hz). 5.90 (IH, dd, J=5&8Hz)
．． 7.2=7.4 (5H, m). 9.20 (0.5H,
d, J = 8Hz), 9.33 (0.5H, d, J = 8H
z) Elemental analysis value: C. aH,,N. 04s-0.38,O
Calculated value (%): C. 57.68. H. 4.
20; N, 11.21 Actual value (%): C, 57.
57;H. 4.20; N, 11.09 Example lO (9R,IOR)-5-methylsulfonylmethyl-4-
Oxer 3,l1-dioxo-lO-7phenylacetamido-8-thia l-azatricyclo[7.2.0,O
"=@l Undec-2(6)-ene 8-oxide Reaction was carried out in the same manner as in Example 6 to obtain a diastereomeric mixture (approximately 1:1) of the title compound as a pale yellow solid. Melting point 143-148°. C (decomposition) summer R (KBr
) am-': 3430.2930. l805.
l675. l515N M R (di-DMSO) δ
: 3.08 (3H, s). 3.4-4. 5 (6H
, m) ,4.86 (0.5H, d, J=5Hz). 4
-89 (0.5H.d, J=5Hz). 5.58 (0.
5H, d, J=8Hz). 5.68 (0.5H.d, J
=16Hz). 5.99 (0.5H, dd, J=4&8
Hz), 6.01 (0.5H, dd, J=4&8Hz)
．． 7.2=7.4(5H,+a). 8.48 (0.5H
, d, J=8Hz). 8.57 (0.5H, d, J=8
Hz) Elemental analysis value: C+sH+sN*ChSt・0-IHz
Calculated value (%) as o: C. 49. lO;H. 4.17; N
, 6.36 Actual value (%): C. 49.06; H,
4.16; N, 6.06 Example 11 (9R, IOR)-5-methylsulfonylmethyl-4-
Oxer3.11-dioxoIO-7phenylacetamido-8-thia l-azatricyclo[7.2.0.0
``-'l undec-2(6)monene Example 1 614 mg of the compound obtained in O was mixed with DMFl4I
0.28 m of phosphorus trichloride dissolved in Tl12 at -30°C
12 was added and stirred at the same temperature for 30 minutes. water 70m
Q was added and extracted with ethyl acetate. The extract was washed successively with water and brine, dried, and concentrated under reduced pressure to a concentration of about 50%.

The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 117n+g of the title compound as colorless crystals. Melting point 234~
236°C (decomposition) I R (KBr) cm-':
3270,1800. l655. l530N M R
(d,-DMSO)δ: 3.08 (3B,s). 3.
54 (2H, ABq.J=14Hz). 3.61 (IH
, ad, J=9&l5Hz). 3.79 (2H.s),
3.87 (IH, dd, J=2&l5Hz). 5.05
(IH, d, J=5Hz). 5.68 (IH, dd,
J = 2&9Hz). 5.88 (IH, dd
, J = 5&8Hz). 7.2-7.4 (5H
, m). 9.21 (IH, d, J=8Hz) Elemental analysis value: Calculated value (%) as C'+aH+aN*OsS*
: C, 51.17i H. 4.29. N, 6.6
3 Actual measurement value (%): C. 51.38;H. 4.28
; N, 6.61 Example 12 (9R.IOR)-5-penzyl-4-oxa-3.1
1-Dioxo IO-7phenylacetamido-8-thia -azatricic CI [7. 2.0,02・“]
undeca-2(6)-ene(9R.l OR)-5-hydroxy-4-oxer 3.11-dioxo-10-phenylacetamide 8-thia l-azatrisic[
7.2.0.0!・6] Undeka-2 (6) 1-en 34
6 mg was dissolved in a mixture of 517+ THF and 11 hexamethylphosphoric triamide, and benzylmagnesium chloride (2.0M THF solution, 2-) was added at -78°C, followed by stirring at the same temperature for 5 minutes. 4 parts of 2N hydrochloric acid and 50 m of water
was added and extracted with ethyl acetate. The extract was washed successively with water and brine, dried, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel (10 g) column chromatography 7E and eluted with a mixture of ethyl acetate and dichloromethane (1:4) to obtain 104 mg of the title compound as a colorless solid.

Melting point 96-104°C r R (KBr) cm-': 1790.1665
,1525.1495N M R (CDC123)δ
: 3.02 (IH, dd, J'7 & l5Hz).
3.12 (18, dd, J-5&l5Hz). 3
．． 27 (IH, d, J=18Hz). 3.55 (IH.
dd, J=2&18Hz). 3.65 (2H, AB
q. J=16Hz). 4.94 (IH, d, J=5Hz
). 5.23 (lH.ddd, J=2.5&7Hz)
．． 5.90 (IH, aa, J=5&9Hz). 6.
12 (IH, d, J=9Hz), 7.2-7.5 (
IOH, m) Elemental analysis value: CzsHz. NxO*S-
Calculated value (%) as 0.2HxO: C. 65. l4;
H. 4.85. N. 6.60 Actual value (%): C
．． 65.08;H. 5. l2;N. 6.39 Examples 13 to 17 The following compounds were obtained in the same manner as in Example 2 or Example 6.7.

HonjiasderemanmaruflJ('ノ礪δ, Tokyosha dedicated T-Kurinow τ crystal C tension lko.

Test Examples Escherichia coli O of the compounds obtained in Examples 2 and 5
- The MIC (minimum inhibitory concentration in an in vitro antibacterial test) value for 111 is shown below.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is an acyl group, R^2 is a methyl group substituted with an electron-withdrawing group, and n is 0 or 1. A cephalosporin lactone compound or a salt thereof.