JPH01110687A - 2-oxa-isocephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents amino group having protecting group; R<2> represents cycloalkyl, etc.; R<3> represents group expressed by formula II (n is 1 or 2); R<4> represents carboxyl, carboxylate, etc.]. EXAMPLE:Diphenylmethyl (6S,7S)-7-[2-(2-tritylaminothiazol-4-yl)-2- methoxyiminoacetamido]-3-(1-pyrrolidinyl)methyl-DELTA<3>-0-2-isocephem -4-carboxylate. USE:The compound exhibits superior antibacterial activity against Gram-positive and Gram-negative bacteria, and dextrose-non-fermenting bacteria such as Pseudomonas aeruginosa, etc. PREPARATION:A compound expressed by formula III is reacted with a thioacetamide compound expressed by formula IV at -10-50 deg.C for 1-10hr to afford the aimed derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field of the Invention The present invention relates to 2-oxa-isocephem derivatives having antibacterial activity.

DISCLOSURE OF THE INVENTION As a 2-oxa-isocephem derivative having an antibacterial effect, for example, the compound described in JP-A-57-192387 is known, but the isosephem derivative of the present invention is a novel compound not described in the literature. , and the following general formula (1
).

(In the formula, R1 is an amino group that may have a protecting group; R2 is a lower alkyl group, a cycloalkyl group optionally substituted with a carboxy group, a cycloalkyl (lower) alkyl group, a lower alkenyl group, a lower alkynyl group, or Group: A-R5 (in the formula, A is a lower alkylene group, R5 is a cyano group, carboxy group or carbamoyl group); R3 is a group: (in the formula, n represents 1 or 2) [in the formula , n is the same as above, R6 is a lower alkyl group, a lower alkenyl group, or a group: B-R7 (wherein, B is a lower alkylene group, and R7 is a hydroxyl group, a carbamoyl group, a cycloalkyl group, or a lower alkanoyl group). ] The group: and the group: form a fused ring with a benzene ring that may have 1 to 2 groups selected from the group consisting of hydroxyl group, lower alkoxy group, and lower alkanoyloxy group as substituents on the benzene ring. (R4 represents a carboxy group, a carboxylate group, or an esterified carboxy group.) The compound of the present invention represented by the above general formula (1) is
It exhibits excellent antibacterial activity against a wide range of Durham-positive bacteria and Durham-negative bacteria.
cus aureus PDA-209-P), Streptococcus e pneumonia
us pneumoniae) and Corynebacterium diphtheriae (Corynebacterium diphtheriae).
dfphtherfae). Furthermore, it exhibits excellent antibacterial activity against non-glucose fermenters such as Pseudomonas aeruginosa. Furthermore, the compound of the present invention has the characteristics of good absorption into the body, long duration of medicinal efficacy, and low toxicity, and exhibits excellent effects against resistant bacteria and clinically isolated bacteria. Furthermore, the compound of the present invention has high stability and excellent absorption and excretion properties. i.e., renal excretion is high;
Bile transit is also good. It is also highly distributed in various organs including the lungs. There is little difference between the minimum inhibitory concentration and the minimum bactericidal concentration,
It has few side effects such as immunosuppressive effects and allergic effects.

Therefore, the compounds of the present invention are useful as therapeutic agents for diseases of humans, animals, and fish caused by various pathogenic bacteria, and are also useful as external disinfectants and disinfectants for medical instruments and the like.

More specifically, each group shown in this specification is as follows.

As protecting groups for amino groups that may have protecting groups, common protecting groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
A lower alkanoyl group having 1 to 6 carbon atoms such as hexanoyl;
Monochloroacetyl, monofluoroacetyl, monobromoacetyl, monoiodoacetyl, dichloroacetyl,
Trichloroacetyl, trifluoroacetyl, 3-gelolopropionyl, 2,3-dichloropropionyl, 3
．． 3. A compound having 2 to 6 carbon atoms substituted with 1 to 3 halogen atoms, such as 3-trichloropropionyl, 4-chlorobutyryl, 5-chloropentanoyl, 6-chlorohexanoyl, 3-fluoropropionyl, 4-fluorobutyryl, etc. Lower alkanoyl group; phenyl (lower) alkyl group having 1 to 3 phenyl groups and having 1 to 6 carbon atoms in the alkyl moiety, such as benzyl, α-phenethyl, β-phenethyl, 3-phenylpropyl, benzhydryl, trityl, etc. ; Carbon number of alkoxy moiety such as phenylmethoxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, etc. is 1 to 6 phenyl (lower) alkoxycarbonyl group; carbon number of alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl Examples include 1 to 6 lower alkoxycarbonyl groups.

Examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

Examples of the cycloalkyl group which may be substituted with a carboxy group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, cyclooctyl, 1-carboxycyclopropyl, 1-carboxycyclobutyl, 1-carboxycyclopentyl,
Examples include cycloalkyl groups having 1 to 3 carbon atoms that may be substituted with a carboxy group such as 2-carboxycyclopentyl, 3-carboxycyclopentyl, 1-carboxycyclohexyl, 1-carboxycyclohebutyl, and 1-carboxycyclooctyl. .

Examples of the cycloalkyl (lower) alkyl group include:
Cyclohexylmethyl, 2-cyclohexylethyl, 3
- Cycloalkyl such as cyclohexylpropyl, 4-cyclohexylbutyl, 5-cyclohexylpentyl, 6-cyclohexylhexyl, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclohebutylethyl, cyclooctylmethyl, etc. Examples include cycloalkyl-alkyl groups in which the moiety has 3 to 8 carbon atoms and the alkyl portion has 1 to 6 carbon atoms.

Examples of lower alkenyl groups include vinyl, allyl,
2-butenyl, 3-butenyl, 1-methylallyl, 2-
Examples include alkenyl groups having 2 to 6 carbon atoms such as pentenyl and 2-hexenyl.

Examples of lower alkynyl groups include alkynyl groups having 2 to 6 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, and 2-hexynyl. can.

Examples of the lower alkylene group include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene,
Examples include alkylene groups having 1 to 6 carbon atoms such as 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of the heterocyclic moiety in the heterocyclic group represented by R3 include 1-pyrrolidinyl, piperidino, 1-indolinyl, 2-isoindolinyl, 1.2.3.4-tetrahydroquinolin-1-yl, 1,2, 3.4-Tetrahydroisoquinolin-2-yl, 4-hydroxyindolin-1-yl, 5-hydroxyindolin-1-yl, 6-hydroxyindolin-1-yl, 7-hydroxyindolin-1-yl, 5 .6-dihydroxyindolin-1-yl, 4,5-dihydroxyindoline-1
-yl, 4-methoxyindolin-1-yl, 5-ethoxyindolin-1-yl, 6-bropoxyindolin-1-yl, 7-hexyloxyindolin-1-yl, 6,7-cymethoxyindolin-1-yl 1-yl, 5,6-
Cymethoxyindolin-1-yl, 4-acetoxyindolin-1-yl, 5-propionyloxyindolin-1-yl, 6-hexatsuyloxyindolin-1-yl
yl, 4,5-diacetoxyindolin-1-yl, 5
．． 6-diacedoxyindolin-1-yl, 5-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 6-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 7 -Hydroxy-1,2,3,4-
Tetrahydroquinolin-1-yl, 8-hydroxy-1
, 2,3,4-tetrahydroquinolin-1-yl, 5.
6-cyhydroxyl, 1.2,3.4-tetrahydroquinolin-1-yl, 6,7-cyhydroxyl, 1.2,3.
4-tetrahydroquinolin-1-yl, 5,8-dihydroxy-1,2,3°4-tetrahydroquinolin-1-
yl, 5-methoxy-1,2,3,4-tetrahydroquinolin-1-yl, 6-bropoxy 1.2,3.4-yl
Tetrahydroquinolin-1-yl, 7-hexyloxy-1,2,3,4-tetrahydroquinolin-1-yl,
8-ethoxy-1,2,3,4-tetrahydroquinolin-1-yl, 5.8-dimethoxy-1,2,3,4-tetrahydroquinolin-1-yl, 6.7-simethoxy1.2,3 .4-tetrahydroquinolin-1-yl, 7
, 8-dimethoxy-1,2,3,4-tetrahydroquinolin-1-yl, 5-acetoxy-1,2,3,4-tetrahydroquinolin-1-yl, 6-hexatsuyloxy-1.2,3. 4-tetrahydroquinolin-1-yl, 7-butyryloxy-1.2゜3.4-tetrahydroquinolin-1-yl, 8-acetoxy-1,2,3,4
-tetrahydroquinolin-1-yl, 5,6-diacedoxy1.2゜3.4-tetrahydroquinolin-1-yl, 6゜7-diacedoxy1.2.3.4-tetrahydroquinolin-1-yl, 6, 8-diacetoxy-1,
2,3,4-tetrahydroquinolin-1-yl, 4-hydroxyisoindolin-2-yl, 5-hydroxyisoindolin-2-yl, 4゜5-dihydroxyisoindolin-2-yl, 5゜6-yl Hydroxyisoindolin-2-yl, 4゜6-hydroxyisoindolin-2-'yl, 4-methoxyisoindolin-2-yl, 5-butoxyisoindolin-2-yl, 4,7-simethoxyisoindolin-2-yl -2-yl, 5', 6-jethoxyisoindolin-2-yl, 4-hexanoyloxyisoindolin-2-yl, 5-acetoxyisoindolin-2-yl, 5,6-diacedoxyiso Indolin-2-yl, 4,6-diacedoxyisoindolin-2-yl, 5-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl, 6-hydroxy-
1,2,3,4=tetrahydroisoquinolin-2-yl, 7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl, 8-hydroxy-1,2,3゜4
-Tetrahydroisoquinolin-2-yl, 5°8-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl, 5.6-dihydroxy-1.2,3.4-
Tetrahydroisoquinolin-2-yl, 5-methoxy-
1,2,3,4-tetrahydroisoquinolin-2-yl, 6-pentyloxy-1,2,3,4-tetrahydroisoquinolin-2-yl, 7-nitoxy1.2,3°4-tetrahydroisoquinolin-2 -yl, 7゜8-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl, 5,6-simethoxy1.2,3.4-tetrahydroisoquinolin-2-yl, 5-acetoxy-
1,2,3,4-tetrahydroisoquinolin-2-yl, 6-butyryloxy-1.2.3.4-tetrahydroisoquinolin-2-yl, 7-hexatsuyloxy-1
゜2.3.4-tetrahydroisoquinolin-2-yl,
8-acetoxy-1,2,3,4-tetrahydroisoquinolin-2-yl, 5,6-diacedoxy1.2,3
．． 4-tetrahydroisoquinolin-2-yl, 6.7-
Diacetoxy 1.2゜3.4-tetrahydroisoquinolin-2-yl, 7.8-diacetoxy-1,2,3,
1 to 2 groups selected from the group consisting of hydroxyl group, alkoxy group having 1 to 6 carbon atoms, and alkanoyloxy group having 1 to 6 carbon atoms as a substituent on the benzene ring, such as 4-tetrahydroisoquinolin-2-yl. 1-pyrrolidinyl, which may form a fused ring with a benzene ring,
piperidino, 1-indolinyl, 2-isoindolinyl, 1,2.3.4-tetrahydroquinolin-1-yl,
Examples include 1,2,3°4-tetrahydroisoquinolin-2-yl.

Examples of lower alkoxy groups include those having 1 carbon number, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, and hexyloxy.
-6 alkoxy groups can be exemplified.

Examples of the lower alkanoyloxy group include alkanoyloxy groups having 1 to 6 carbon atoms such as formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, and hexanoyloxy.

The ester residue in the esterified carboxy group is a common ester residue, for example, an alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc. Group: benzyl, benzhydryl, α-phenethyl,
(Mono or di) phenyl lower alkyl having 1 to 6 carbon atoms in the alkyl moiety such as β-phenethyl, α, β-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, etc. Base;
Alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, crotyl, 2-pentenyl, 2-hexenyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloalkyl groups having 3 to 8 carbon atoms such as cycloheptyl and cyclooctyl; cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 5-cyclohexylpentyl, 6-
cyclohexylhexyl, cyclopropylmethyl, 2-
Examples of cycloalkyl (lower) alkyl groups in which the cycloalkyl part has 3 to 8 carbon atoms and the alkyl part has 1 to 6 carbon atoms, such as cyclobutylethyl, cyclopentylmethyl, 2-cyclohebutylethyl, and cyclooctylmethyl can do.

The phenyl moiety in the (mono- or di)phenyl lower alkyl group of the ester residue has, as a substituent, a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom, an iodine atom; methyl, ethyl, propyl, isopropyl. , butyl, isobutyl, tertiary butyl, pentyl,
Lower alkyl groups having 1 to 6 carbon atoms such as hexyl; methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Lower alkoxy groups having 1 to 6 carbon atoms such as tertiary butoxy, pentyloxy, hexy, and ruoxy; nitro group; cyano group; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl , pentyloxycarbonyl, hexyloxycarbonyl and other lower alkoxycarbonyl groups having 1 to 6 carbon atoms in the alkoxy moiety; and acetyloxy, propionyloxy, butyryloxy, imbutyryloxy, pentanoyloxy,
The number of carbon atoms in the alkanoyl moiety such as hexanoyloxy is 1
1 to 3 substituents selected from the group consisting of 6 lower alkanoyloxy groups, or lower alkyl groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy. It may have a dioxy group.

Furthermore, the lower alkyl group of the ester residue has, for example, 1 to 3 of the above halogen atoms' as a substituent,
The above-mentioned lower alkoxy group, the above-mentioned lower alkanoyloxy group, cyano group, nitro group, amino group, the above-mentioned lower alkanoylamino group, or lower alkylthio group such as methylthio, ethylthio, propylthio, and butylthio may be substituted.

Next, typical examples of the compounds of the present invention represented by the following general formula are shown in the following table.

(Left below) The compound and raw material compound of the present invention can be produced by various methods, and for example, can be produced by the methods shown in Reaction Scheme-1 to Reaction Scheme-8 below.

Reaction scheme-1 (1-al (wherein R', R2, n and the group: are the same as above, R8 is a halogen atom, a cl-6 flucanesulfonyloxy group optionally substituted with a halogen atom, or An arylsulfonyloxy group optionally having 1 to 3 groups selected from the group consisting of a C1-6 alkyl group, a halogen atom, and a nitro group, and 1l (4a
represents a carboxy group or an esterified carboxy group.

Further, the compound may form a fused ring with a benzene ring that may have 1 to 3 groups selected from the group consisting of hydroxyl group, lower alkoxy group, and lower alkanoyloxy group as substituents on the benzene ring. . ) The compound represented by the general formula (1-a), which is a compound of the present invention, is prepared in a suitable inert solvent,
It is obtained by reacting a compound represented by general formula (2) with a compound represented by general formula (3-a).

In the compound represented by the general formula (■), examples of the halogen atom represented by R8 include chlorine, bromine, iodine, fluorine, etc., and C1- which may be substituted with a halogen atom.
Examples of the 6-flukanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, and C alkyl group, halogen atom, if substituted with 1.-6 or nitro group. Examples of suitable arylsulfonyloxy groups include benzenesulfonyloxy, toluenesulfonyloxy, p-chlorobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, and the like.

As the solvent, any solvent can be used as long as it does not adversely affect this reaction; for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as hexane and heptane, and alcohols such as methanol, ethanol, and propatool. , dimethylformamide (D
MF), hexamethylphosphate triamide (HMPA)
, aprotic polar solvents such as dimethyl sulfoxide (DMSO), and carbon disulfide.

General formula (3-a) for the compound represented by general formula (2)
The proportion of the compound represented by ) is preferably at least an equimolar amount, preferably 1 to 2 times the molar amount. The reaction temperature is preferably -10°C to 100°C, preferably 0 to 50°C.

In this way, a compound represented by the formula (1-a) is obtained.

In the obtained compound represented by general formula (1-a),
When R1 represents a protected amino group, the compound is subjected to a reaction for removing the amino protecting group (hereinafter referred to as amino protecting group elimination reaction) to derive a corresponding compound in which R1 represents an amino group. be able to. Also - murderous (1
- In the compound represented by a), when R4a represents an esterified carboxy group, a reaction of removing the ester residue from the compound (hereinafter referred to as deesterification reaction)
A compound in which the corresponding Raa represents a carboxyl group can be derived. Furthermore, - slaying (
In the compound represented by 1-a), when R1 represents a protected amino group and R4a represents an esterified carboxy group, the corresponding R1 can be derived into a compound in which R4a is an amino group and R4a is a carboxy group.

The above amino-protecting group elimination reaction can be carried out by reacting a compound represented by -Salt (1-a) with an acidic compound or a basic compound in a solvent-free or inert solvent; ) is subjected to a catalytic reduction reaction.

Examples of the inert solvent used in the above reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, and anisole, and nitromethane and nitrobenzene. Nitro compounds, alcohols such as methanol and ethanol, acetate esters such as ethyl acetate and methyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, aromatic hydrocarbons such as benzene, toluene and xylene, pyridine, Amines such as piperidine, dimethylformamide (DMF), hexamethylphosphoric triamide (
HMPA), aprotic polar solvents such as dimethyl sulfoxide (DMSO), carbon disulfide, water or a mixed solvent of water and the above-mentioned organic solvents. When water is added to the reaction system, the amount of water added is preferably about 10 to 80 v/v% relative to the acidic compound or basic compound, and it is further preferable to add 10 to 20 times the amount after the reaction is completed. .

Acidic compounds used include anhydrous aluminum chloride, stannic chloride, titanium tetrachloride, boron trichloride, boron trifluoride-diethyl ether complex, Lewis acids such as zinc chloride, hydrochloric acid, hydrobromic acid, nitric acid, Examples include inorganic acids such as sulfuric acid, organic acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid, and formic acid, and acids such as acid type ion exchange resins. Basic compounds include triethylamine,
Trialkylamines such as tributylamine, pyridine,
Organic bases such as picoline, 1,5-diazabicyclo[4,3,0]nonene-5,1,4-diazabicyclo[2,2゜2]octane, 1,8-diazabicyclo[5,4゜0oundecene-7 , alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate,
Examples include bases such as inorganic bases such as alkali metal hydrogen carbonates such as potassium hydrogen carbonate.

When the above reaction is carried out by a catalytic reduction method, the catalytic reduction catalyst used is, for example, a platinum catalyst (e.g., platinum oxide, platinum black, platinum wire, platinum plate, sponge platinum, colloidal platinum, etc.), palladium catalyst (For example, palladium black, palladium chloride, palladium oxide, palladium-
carbon, palladium-barium sulfate, palladium-barium carbonate, spongy palladium, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. , reduced iron, Raney iron, etc.), copper catalysts (for example, reduced copper, Raney copper, etc.), and the like.

In the above reaction, when using an acidic compound or a basic compound, the ratio of the acidic compound or basic compound to the compound represented by -killing (1-a) is:
The amount is preferably 1 to 100 times the molar amount, preferably 1 to 20 times the molar amount. Further, the reaction is carried out at a temperature of -20°C to 80°C, preferably -10°C to 50°C, and 30°C to 80°C.
It takes about 1 minute to 48 hours, preferably 1 to 24 hours.

In addition, when applying the contact reduction method, -killing (1-a
) The ratio of the catalytic reduction catalyst to be used is 0.1 to 10 times the molar amount, preferably 0.1 to 1 times the molar amount. The reaction is carried out at a temperature of 0 to 200°C, preferably 0 to 100°C, for 30 minutes to 40 minutes.
The process is completed in about 8 hours, preferably about 30 minutes to 6 hours.

The deesterification reaction of the compound represented by (1-a) is carried out without a solvent or in a suitable inert solvent in the presence of a hydrolysis catalyst. Examples of the inert solvent and hydrolysis catalyst used include the inert solvents, acidic compounds, and basic compounds exemplified in the above amino-protecting group elimination reaction.

The deesterification reaction can also be carried out by a catalytic reduction method when the ester residue of R4a is an ester residue such as benzyl that is easily eliminated by a catalytic reduction method. Examples of the catalyst used in the catalytic reduction method include the catalysts exemplified in the above-mentioned amino-protecting group elimination reaction.

When an acid or base is used in the above reaction, the molar ratio of the acid or base to the compound represented by (1-a) is 1 to 100 times, preferably 1 to 20 times the molar amount.
It is better to double the molar amount. Moreover, the reaction is carried out at -20°C to 8°C.
3 at a temperature of 0°C, preferably -10°C to 50°C.
It may be carried out for about 0 minutes to 48 hours, preferably about 1 to 24 hours.

In addition, when applying the contact reduction method, -killing (1-a
) The ratio of the catalytic reduction catalyst to be used is 0.1 to 10 times the molar amount, preferably 0.1 to 1 times the molar amount. The reaction may be carried out at a temperature of 0 to 200°C, preferably 0 to 100°C, for about 30 minutes to 48 hours, preferably about 30 minutes to 6 hours.

(1-bl (1-cl (wherein R1, R2, R4a, R6, R8, n and the group: are the same as above, R4b represents a carboxy group or a carboxylate group, and g represents 0 or 1.

Further, the compound may form a fused ring with a benzene ring that may have 1 to 3 groups selected from the group consisting of hydroxyl group, lower alkoxy group, and lower alkanoyloxy group as substituents on the benzene ring. .

However, when R4b represents a carboxy group, g represents 1, and when R4b represents a carboxylate group, g represents 0. ) In the above reaction scheme, the reaction between the compound represented by -Sakura ■ and the compound represented by general formula (3-b) is represented by general formula (2) in the above reaction scheme-1. The reaction can be carried out under the same conditions as the reaction between the compound and the compound represented by general formula (3-a).

In addition, in the obtained compound represented by the general formula (1-b), when R4a represents an esterified carboxy group, by subjecting the compound to a deesterification reaction, -killing (1-c) can be performed. The represented compounds can be obtained. The deesterification reaction can be carried out under the same conditions as the deesterification reaction conditions shown in the reaction step-1.

In addition, after the completion of the deesterification reaction, Diaion HP-2
0 (manufactured by Mitsubishi Chemical Corporation), Amberlight XAD-2 (
By purifying the product by column chromatography using a column chromatography (manufactured by Rohm & Hass Co., Ltd.), anions can be removed and an inner salt can be formed. After deesterification,
When the anionic group is not removed, a compound represented by -saccharide (1-c) in which R4b represents a carboxy group is produced.

In addition, in the compound represented by -Kakeru (1-b) or -Kakeru (1-c), when R1 represents a protected amino group, the removal of the amino protecting group shown in Reaction Scheme-1 By subjecting the amino protecting group to an elimination reaction under the same conditions as the elimination reaction, a compound in which the corresponding R1 represents an amino group is derived.

Furthermore, in the compound represented by -Sakobatsu (1-b) or -Kabatsu (1-c), the anionic group represented by (R8)- can be exchanged with other anions by subjecting it to an anion exchange reaction. It can be converted into a group.

The above exchange reaction is -killing (t-b) or -killing (1
The compound represented by -c) and the anion donating reagent are combined in a suitable solvent, such as ethers such as diethyl ether, tetrahydrofuran, and dioxane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, 0 in inert solvents such as aromatic hydrocarbons such as benzene, toluene, xylene, etc. at -10℃ to 50℃
．． This is carried out by reacting for about 5 to 5 hours.

Examples of the anion donating reagent used in this reaction include sulfuric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, hydrobromic acid, hydroiodic acid, and hydrofluoric acid.

Reaction scheme-3 (1-al (1-d) ' (wherein, R1, R2, R4a, R4, R6, R8, f
l s n s group; and group; are the same as above.

However, when R4 represents a carboxylate group, g represents 0, and when R4 represents a carboxy group or an esterified carboxy group, Ω represents 1. ) The compound represented by general formula (1-d) is prepared in an inert solvent,
- Manufactured by reacting a compound represented by saccharide (1-a) and a halide compound represented by general formula (4).

Examples of inert solvents used in this reaction include dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene,
Examples include aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, and dioxane. The reaction is completed by reacting at room temperature to 100°C, preferably about 50 to 80°C, for about 2 to 8 hours. The amount of the halide compound represented by the above-mentioned -salting (4) is preferably about 1 to 1.5 times the molar amount of the compound represented by -salting (1-a).

In the compound represented by the general formula (1-d) thus obtained, when R1 represents a protected amino group, the corresponding It is derived from a compound in which R1 represents an amino group. Further, the anion group represented by (R8)'' can be converted into another anion by the above-mentioned anion exchange reaction.

Furthermore, in the compound represented by -killing (1-d),
Compounds in which R4 represents a carboxyl group are purified by column chromatography using Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), Amberlite XAD-2 (manufactured by Rohm and Hass), etc. after the above reaction is completed. By doing so, it is possible to remove the anion and obtain a compound in which R4 represents a carboxylate group and g represents 0, forming an inner salt. When anionic groups are not removed, -killing (1
A compound represented by -d) in which R4 represents a carboxy group is produced.

In addition, when R4 of the compound represented by -Sakuhatsu (1-d) represents an esterified carboxy group, a compound in which R4 is a carboxy group can be obtained by subjecting the compound to the above-mentioned deesterification reaction, Further, after the deesterification reaction, by removing anions by a column method using the above-mentioned resin, an inner salt in which R4 represents a carboxylate group can be formed.

Reaction Scheme-4 (In the formula, R' 8% R8% ns group and compound are the same as above, R9 is an azide group, a phthalimide group that may have a nitro group as a substituent on the phenyl ring, phenylacetic acid (Indicates an amide group or an amino group that may have a protective group.) - The reaction between the compound represented by saccharide (5) and the compound represented by general formula (3-a) is carried out according to the reaction scheme-1 described above. The reaction can be carried out under the same conditions as the reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3-a).

(Left space below) Reaction process formula-5 (In the formula, R4, R4a, R4b, R6, R8
, R9, Ω, ns group: and the compounds are the same as above. However, when R4 represents a carboxy group or an esterified carboxy group, or R4b represents a carboxy group, Ω represents 1, and when R4 or R4b represents a carboxylate group, g represents 0. ) The reaction between the compound represented by the general formula (5) and the compound represented by the general formula (3-b) is performed by reacting the compound represented by the general formula (2) in the reaction process scheme-1 with the general formula ( The reaction can be carried out under the same conditions as the reaction with the compound represented by 3-a).

In addition, in the generated compound represented by general formula (7),
When R4 represents an esterified carboxy group, general formula (8) can be obtained by subjecting the compound to a deesterification reaction.
A compound represented by can be obtained. The deesterification reaction can be carried out under the same conditions as the deesterification reaction shown in Reaction Scheme-1 above.

Reaction Scheme-6 (In the formula, R3, R4, and R9 are the same as above.) The above Reaction Scheme-6 shows that the compound represented by -Sakatsu (9),
A method for producing a compound represented by the general formula 00), which includes some new compounds, by subjecting it to a reduction reaction, a hydrolysis reaction, or a hydrazine decomposition reaction depending on the type of R9, which is a substituent thereof. .

In the above reaction scheme, when group R9 is an azido group,
- The compound represented by (9) is treated with a reducing agent in the absence of a solvent or in the presence of an appropriate inert solvent;
An amine compound represented by is obtained.

Examples of the solvent used in this reaction include dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene,
Examples include aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and amines such as triethylamine and pyridine.

Examples of the reducing agent include hydrogen sulfide. When hydrogen sulfide or the like is used, amines such as triethylamine and pyridine may be added.

- The ratio of the reducing agent used to the compound represented by (9) is preferably equal to 100 times the molar amount, preferably 3 to 50 times the molar amount. The reaction is usually carried out at -30°C to 50°C.
, preferably at -10°C to 10°C for 30 minutes to
It will be completed in about 10 hours.

In addition, when the group R9 is a phenylacetic acid amide group, the amine represented by the general formula (10) can be prepared by subjecting the compound represented by -salt (9) to a hydrolysis reaction without a solvent or in an inert solvent. A compound is obtained.

This reaction can be carried out in substantially the same manner as the deesterification reaction shown in reaction scheme-1 above, and the reaction method and reaction conditions (e.g., hydrolysis catalyst, solvent, reaction temperature, reaction time, etc.) are , the explanation of the deesterification reaction in the reaction scheme-1 above can be referred to.

When the group R9 is a phthalimide group which may have a nitro group as a substituent on the phenyl ring, a compound represented by -salt (9) is reacted with hydrazine or a hydrazine derivative without a solvent or in an inert solvent. The amine compound represented by the general formula (10) is obtained by subjecting it to a hydrazine decomposition reaction.

Examples of the inert solvent used in this reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and alcohols such as methanol and ethanol. Examples of hydrazine derivatives include lower alkyl-substituted hydrazines such as methylhydrazine and ethylhydrazine, and aryl-substituted hydrazines such as phenylhydrazine.

- The ratio of hydrazine or hydrazine derivative used to the compound represented by (9) is at least an equimolar amount, preferably 1 to 2 times the molar amount, and the reaction is usually carried out at 0 to 100°C, preferably 0 to 100°C. carried out at 80°C,
The reaction is completed in about 1 to 40 hours.

When the group R9 is an amino group with a protecting group, this reaction is
The reaction can be carried out under the same reaction conditions as the above-mentioned amino-protecting group elimination reaction.

Reaction scheme-7 (In the formula, R', R2, R3 and R4 are the same as above.

) In the above reaction scheme-7, the compound represented by -Sakuburu (1) is an amine compound represented by -Kaburu00), and -
It can be produced by reacting a carboxylic acid compound represented by Sakuhatsu (11) or a compound whose carboxy group has been activated in a normal amide bond forming reaction.

As the amide bond forming reaction, any known amide bond forming reaction conditions can be applied. For example, a) a method using a condensing agent: that is, a method of reacting a carboxylic acid compound represented by -killing (11) with an amine compound represented by general formula (10) in the presence of a condensing agent; b) Mixed acid anhydride method: In other words, a carboxylic acid compound represented by -Sakuburu (11) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and an amine compound represented by -Kaburu00) is reacted with this. Method; C) Active esterification method: That is, the carboxylic acid compound treated in -killing (11) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. To this - murderous (1
A method of reacting an amine compound represented by 0); d) A carboxylic acid compound represented by (11) is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and then -
A method of reacting an amine compound represented by the formula 00); e) - A lower alcohol ester of a carboxylic acid compound represented by the formula 00) is reacted with an amine compound represented by the general formula 00) at high temperature and under high pressure. How to make it react; f) - Killing (
The carboxylic acid compound represented by 11) is an acid halide,
That is, carboxylic acid halide, and this - 00)
Examples include a method of reacting an amine compound represented by:

Next, an example of the amide bond forming reaction will be explained in more detail.

The compound of the present invention represented by the general formula (1) is added to the amine compound represented by the general formula (1) in the presence of a condensing agent.
It can be obtained by reacting the carboxylic acid compound represented by 1) in the absence of a solvent or in the presence of an inert solvent.

Examples of the condensing agent used in the reaction include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and (chloromethylene)dimethylammonium chloride synthesized by the reaction of dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene, etc. Vilsmeier (V
Illsmeier's reagent, dicyclohexylcarbodiimide (DCC), and 2°2-1pyridinyl disulfide triphenylphosphine.

As the solvent, any solvent can be used as long as it does not adversely affect this reaction. For example, ethers such as diethyl ether, tetrahydrofuran, and dioxane, halogenated solvents such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. Hydrocarbons, aromatic hydrocarbons such as benzene, toluene, xylene, amines such as pyridine, piperidine, triethylamine, aliphatic hydrocarbons such as hexane, heptane, methanol, ethanol,
Alcohols such as propatool, dimethylformamide (DMF), hexamethylphosphate triamide (HMP)
A), aprotic polar solvents such as dimethyl sulfoxide (DMSO), carbon disulfide, etc. can be exemplified.

The above reaction is more preferably carried out in the presence of a basic compound. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine;
Pyridine, picoline, 1゜5-diazabicyclo[4,3
,0] nonene-5,1,4-diazabicyclo[2,2
, 21 octane, 1,8-diazabicyclo[5,4,0
] Organic bases such as undecene-7, monotrimethylsilylacetamide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Examples include inorganic bases such as alkali metal hydrogen carbonates.

In addition, in the above reaction, the ratio of the carboxylic acid compound represented by the general formula (11) to the amine compound represented by -Sakuburu00) is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount. It is better to - The ratio of basic compound to amine compound expressed as (10) is:
The amount is preferably equal to 40 times the molar amount, preferably 5 to 20 times the molar amount.

The above reaction is performed at -20°C to 100°C, preferably -20°C.
This is carried out at a temperature of .degree. C. to 50.degree. C. for 30 minutes to 24 hours, preferably for about 30 minutes to 10 hours.

In this way, the compound of the present invention represented by -Kakuburu (1) is obtained.

In addition, in the reaction between the amine compound represented by the above general formula (10) and the carboxylic acid compound represented by the general formula (11), when the group R4 is a carboxylate group, -
A compound may be obtained in which the carboxylate group of the compound of the present invention represented by the formula (1) is condensed with the carboxylate group of the amine compound represented by the general formula (10).

In this case, the condensation compound is hydrolyzed in the presence of an acid catalyst, for example, an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, etc. Inventive compounds can be obtained.

(In the formula, R1, R2, R3 and R4 are the same as above, X
indicates a halogen atom. ) In the above reaction process formula, the compound represented by -Sakuburu (13) is obtained by reacting the amine compound represented by -Kaburu00) with the carboxylic acid compound represented by General Formula (12). In the compound represented by general formula (12), the halogen atom represented by X is chlorine,
Examples include bromine, iodine, and fluorine. This reaction is
The reaction can be carried out in the same manner as the amide bond forming reaction between the amine compound represented by the general formula (10) and the carboxylic acid compound represented by the general formula (11) in Reaction Scheme-7 above.

The compound represented by the general formula (13) thus obtained is reacted with a thioacetamide compound represented by the general formula (14) in the presence or absence of an appropriate solvent,
The compound of the present invention represented by general formula (1) can be obtained.

In this reaction, the inert solvent used is not particularly limited, and the solvent used in the above reaction scheme-7 can be used.

In this reaction, the ratio of the thioacetamide compound represented by the general formula (14) to the compound represented by the general formula (13) is 1 to 10 times the molar amount, preferably 1 to 5 times the molar amount. Good. The reaction is usually carried out at -10°C to 10°C.
It is carried out at 0°C, preferably -10°C to 50°C, and is generally completed in 1 to 50 hours, preferably 1 to 10 hours.

The raw material compounds represented by the general formula (2) include some new compounds, and can be produced from known compounds by, for example, the method shown in the following reaction scheme-9.

Reaction Scheme-9 -0-R2 (In the formula, R2, R4a and In the above reaction, the reaction between the compound represented by the general formula (15) and the compound represented by the general formula (1B) is represented by the general formula 00) of the reaction scheme-7 above. Compounds and general formulas (
The reaction can be carried out under the same reaction conditions as the reaction with the compound represented by 11).

The halogenation reaction to obtain the compound represented by the general formula (18) from the compound represented by the general formula (17) is carried out using the general formula (17).
) This is a halogenation reaction in which the alcoholic hydroxyl group or lower alkanoyloxy group of the compound represented by formula (2) is replaced with a halogen atom, and a wide range of ordinary halogenation reaction conditions can be applied.

For example, when R10 is a hydrogen atom, the compound represented by the general formula (17) is reacted with a thionyl halide such as thionyl chloride, thionyl bromide, and thionyl iodide in the presence or absence of a solvent. A compound represented by formula (18) can be obtained.

Any solvent can be used as long as it does not affect the reaction, such as halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, and dioxane. Nitro compounds such as nitromethane and nitrobenzene, acetate ester compounds such as ethyl acetate and methyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
Examples include aprotic polar solvents such as hexamethylphosphoric acid triamide (HMPA), carbon disulfide, and the like. General formula (
The proportion of thionyl halide to be used in 17) is preferably at least an equimolar amount, preferably 1 to 2 times the molar amount, and the reaction is carried out at 0°C to room temperature, preferably under water cooling. It will finish in about 1 minute to 1 hour.

In this reaction, it is preferable to add a basic compound such as pyridine, dimethylaniline, or triethylamine to the reaction system as a deoxidizing agent.

In addition, when R10 is a lower alkanoyl group, the compound represented by the formula (17) can be reacted with a tri(lower alkyl)silylnolide in the absence of a solvent or in the presence of an inert solvent to form a compound of the general formula (18). A compound represented by is obtained.

Examples of the inert solvent used in this reaction include the same solvents as mentioned above. Examples of tri(lower alkyl)silyl halides include trimethylsilyl chloride and triethylsilyl chloride.

The ratio of tri(lower alkyl)silyl halide to the compound represented by general formula (17) is at least an equimolar amount, preferably 1 to 2 times the molar amount. The reaction is carried out at -20°C to 50°C, preferably at room temperature, and
It will finish in about 5 minutes to 5 hours.

The sulfonation reaction to obtain the compound represented by general formula (19) from the compound represented by general formula (17) is carried out in the presence or absence of an inert solvent. This is carried out by reacting a sulfonic acid compound corresponding to R9a or a reactive derivative thereof at the sulfo group.

Examples of the inert solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as dimethyl ether and diethyl ether, and aliphatic hydrocarbons such as hexane, heptane, and octane. .

Examples of the sulfonic acid compound include lower alkanesulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and propanesulfonic acid; 01-6 such as benzenesulfonic acid, toluenesulfonic acid, p-chlorobenzenesulfonic acid, and p-nitrobenzenesulfonic acid; Examples include arylsulfonic acids which may have 1 to 3 groups selected from the group consisting of alkyl groups, halogen atoms, and nitro groups.

Examples of reactive derivatives of sulfonic acid include sulfonic acid halides such as sulfonic acid chloride and sulfonic acid bromide, and sulfonic acid anhydrides.

The ratio of the sulfonic acid compound or its reactive derivative at the sulfo group used to the compound represented by general formula (17) is at least an equimolar amount, preferably 1 to 1.5
It is preferable to double the molar amount, and the reaction is carried out at 0° C. or under water cooling, and is completed in about 1 to 50 minutes. The reaction can be carried out in the presence of a deoxidizing agent such as pyridine or triethylamine, but preferably the deoxidizing agent is added after the above reaction is completed, and the reaction is continued for about 30 minutes to 3 hours, preferably about 1 hour. It is better to let The proportion of the deoxidizing agent to be used is preferably at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the reactive derivative of the sulfonic acid.

In addition, in the obtained compound represented by general formula (18) or (19), the amino-protecting group of R1a is subjected to an amino-protecting group elimination reaction under the same conditions as the above-mentioned amino-protecting group elimination reaction. By adding the amino protecting group, a corresponding amino compound can be derived from which the amino protecting group has been removed. - In the compound represented by (18) or (19),
When R4a is an esterified carboxy group, it can be induced into a corresponding carboxy compound from which the ester residue has been removed by subjecting it to a deesterification reaction under the same conditions as the deesterification reaction described above. can. Furthermore, in the compound represented by -Kakubatsu (18) or (19),
By performing both the deesterification reaction of R4a and the elimination reaction of the amino protecting group of R1a, compounds having the corresponding carboxyl group and amino group can be obtained.

Among the compounds represented by the general formula (1) of the present invention, compounds having a basic group can be treated with a pharmaceutically acceptable acid, and compounds having an acidic group can be treated with a pharmaceutically acceptable basic group. A salt may be formed on the container by acting on the compound. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, and p-)luenesulfone. Examples of the basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium carbonate, sodium hydrogen carbonate,
Examples include alkali metal carbonates or bicarbonates such as potassium hydrogen carbonate.

Furthermore, the salts of the compounds of the present invention naturally include inner salts and quaternary ammonium salts.

The compound of the present invention thus obtained can be easily isolated and purified by conventional separation means. As the separation means, for example, solvent extraction method, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. can be employed.

The compound represented by the general formula (1) of the present invention naturally includes optical isomers, syn isomers, and anti isomers. These isomers can be determined using conventional resolution methods, e.g.
Separation can be performed by methods using optical resolution agents, enzymes, etc.

The compounds of the present invention are usually used in the form of intramembrane pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, emulsions, powders, solutions, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.)
Examples include. When forming into tablet form,
As carriers, a wide variety of carriers conventionally known in this field can be used, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid, water, ethanol, and propylene chloride. Tools, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar, liminalan powder, sodium bicarbonate, calcium carbonate , polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, sucrose, stearin,
Disintegration inhibitors such as cocoa butter and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch,
Examples include adsorbents such as lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol.

Furthermore, the tablets can be made into tablets with conventional coatings, such as sugar-coated tablets, gelatin-packaged tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, gum arabic powder, etc. , tragacanth powder, gelatin, binders such as ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide range of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. .

When prepared as injectables, solutions, emulsions and suspensions are preferably sterile and isotonic with blood;
In forming these solutions, emulsions and suspensions, all diluents commonly used in this field can be used, such as water, ethyl alcohol,
Examples include propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotoxic solution may be included in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents, etc. may also be added. Coloring material if necessary,
Preservatives, fragrances, flavors, sweeteners, and other pharmaceutical agents may also be included in the therapeutic agent. When forming into a paste, cream or gel form, for example, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The amount of the compound represented by general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be selected from a wide range, but is usually 1 to 70% by weight of the total composition. It is better to do so.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and the method of administering the pharmaceutical preparation of the present invention is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids.
Administered subcutaneously or intraperitoneally. In case of skewering, it is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
Usually, the amount of the compound of the present invention is 1 to 1 per kg of body weight per day.
00mg, preferably 5-20II1g, and the formulation can be administered in 2-4 divided doses per day.

<Examples> The present invention will be described in detail below based on reference examples, examples, formulation examples, and pharmacological tests.

Reference example 1 diphenylmethyl (6S,7S)-7-azido-3-
2 g of iodomethyl-Δ3-0-2-isocephem-4-carboxylate was dissolved in 20 ml of methylene chloride, 0.39 ml of pyrrolidine was added, and the mixture was reacted at room temperature for 3 days. The reaction solution was washed with 0.5M citric acid, saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure. This is separated and purified using silica gel column chromatography (eluent: chloroform) to obtain 0.7 g of the title compound.

NMR (CDCII3) δ: 1.6-1.9 (4H, m), 2.3-2.7 (4
H, m), 3.6-4.2 (4H, m), 4, 6
3 (IH, dd), 5. 20 (IH, d
), 6, 84 (IH,s), 7. 0~
7. 6 (10H.

m) Reference example 2 diphenylmethyl (6S,7S)-7-azido-3-
Dissolve 1.90 g of iodomethyl-Δ3-0-2-isocephem-4-carboxylate in 60 ml of methylene chloride, add 1.20 g of 1,2,3,4-tetrahydroisoquinoline, and react at room temperature for 6 hours. . The reaction solution is then washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After concentrating the solvent, silica gel column chromatography (eluent; n-hexane:ethyl acetate-3
:2) to obtain 1.53 of the title compound as a white powder.
get g.

NMR (CDCN3) δ: 6, 90-7. 59 (15H, m), 5
．． 22 (IH, d, J=5Hz), 4. 6
3 (IH.

dd, J=12Hz, 4Hz), 3.
61-4, 07 (6H, m), 2. 78
(4H, bs) Example 1 0.7 g of the compound of Reference Example 1 was dissolved in 50 ml of methylene chloride, 0.3 ml of triethylamine was added, hydrogen sulfide gas was passed through the solution for 10 minutes under water cooling, and the mixture was reacted for 2 hours at room temperature.

Wash with aqueous sodium bicarbonate and brine, and dry with anhydrous magnesium sulfate.

After filtration, concentrate the filtrate. This was added in advance to 0.74. .

Dicyclohexylcarbodiimide (DCC) 0°35,
and 1-hydroxybenzotriazole (HOBT)
0.23 g was added to the mixture reacted in methylene chloride for 1 hour under ice cooling, and the mixture was reacted at room temperature for 17 hours. After filtration, concentrate the filtrate. This was carried out using silica gel column chromatography (
Separation and purification is performed using an eluent (chloroform:methanol (50:1)) to obtain 0.75 g of the title compound.

mp: 108-110°C NMR (CDCIIs) δ: 1.8-2.2 (4H, m), 3.0-4.6 (1
2H,m [including 3,75,3H,s]), 5.76
(IH, dd), 6.59 (IH, s), 6.7
0 (IH,s), 6.9-7.7 (25H.

m), 8.59 (LH, d) Example 2 4 ml of 60% acetic acid was added to 0.4 g of the compound of Example 1, reacted at 40°C for 1 hour, and then concentrated. Thoroughly dry under reduced pressure, add 0.4 ml of anisole and 4 ml of trifluoroacetic acid, and react for 10 minutes under water cooling. Diethyl ether is added, and the precipitated powder is filtered and dried to obtain 0.14 g of the title compound.

mp: 120°C (discoloration) NMR (DMSO-dB) δ: 1.7-2.2 (4H, m), 3.0-3.6 (4H, m), 3.8-5.0 (8
H,m [3,86,3H,s, included]), 5.76
(IHldd), 6.80 (LH,s), 9.1
9 (LH,d) Example 3 Diphenylmethyl (6S,7S)-7-[2-(2-
Tritylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methanesulfonyloxymethyl-4-carboxylate (syn isomer) Ig was dissolved in 5 ml of methylene chloride, and 0.5 ml of N-methylpyrrolidine was dissolved.
Add 35ml and react at room temperature for 2 days. After repeating reprecipitation three times with methylene chloride and diethyl ether (the supernatant was removed by decantation), it was dried.

Add 20 ml of 60% acetic acid to this, react at 40°C for 1 hour, and then concentrate. After drying, the mixture is reacted with 10 ml of trifluoroacetic acid in the presence of 1 ml of anisole for 10 minutes under water cooling, diethyl ether is added, and the precipitated powder is collected by filtration. Dissolve this in water again and use nonionic adsorption resin (HP).
-20) Add 25g and adjust the pH to 4 with sodium hydrogen carbonate for adsorption.

The column is filled, washed with water, and then eluted with a 5% aqueous isopropanol solution. The effluent was concentrated, precipitated with methanol-diethyl ether, and the precipitate was collected by filtration to obtain 0.22 g of the title compound.

mp: 160°C (discoloration) NMR (DMSO-dB) δ: 1, 8-2. 3 (4H, m), 3. 03
(3H.

s), 3. 2-4. 8 (12H, m [
3,85° (including 3H, s), 5.59 (IH,
dd), 6, 78 (IH, s), 7° 1
8 (2H, bs), 9, 23 (IH, d
) Example 4 1.08 g of the compound obtained in Reference Example 2 was added to 1 part of methylene chloride.
00 ml, add 0.35 ml of triethylamine, and pass hydrogen sulfide gas under water cooling. After confirming the disappearance of the raw material and the formation of the amine compound on TCL, the mixture is washed with a 1% aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered. Add 2-(2
-) dithylaminothiazol-4-yl) -2-methoxyiminoacetic acid (synisomer) 1.95 g was added, and after cooling in a water bath, 0.93 g of dicyclodicarbodiimide was added.
Add 0.20 g of 1-hydroxybenzotriazole and stir overnight at room temperature. After removing the precipitate by filtration, concentrate
The residue was dissolved in ethyl acetate and the insoluble matter was filtered off. The filtrate is washed successively with water, saturated aqueous carbonate/sodium solution, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is separated and purified by silica gel column chromatography (eluent: chloroform) to obtain 1.85 g of the title compound as a pale yellow powder.

mp: Gradual discoloration from around 152°C NMR (CDCN3) δ: 6.72 to 7.56 (32H, m), 6.58 (I
H, s), 5.49 (IH, dd, J-5Hz, 4
Hz), 4.66 (2H, dd, J-13Hz, 8
Hz), 3.76-4.07 and 4.01 (m and S1 total 6H), 3.64 (2H, bs), 2
．． 78 (4H, bs) Example 5 (6S, 7S)-7-C2-(2-aminothia Example 4
Dissolve 0.70 g of the compound obtained in 20 ml of acetic acid, and add 1 ml of water.
Add 0ml of the mixture and stir at 40°C for 2 hours. Next, the solvent was distilled off under reduced pressure, 20 ml of methanol was added to the residue, and the solvent was distilled off under reduced pressure. After adding 20 ml of methanol to the residue again and distilling off the solvent under reduced pressure, the residue is reacted in the presence of 1 ml of anisole in 7 ml of trifluoroacetic acid under ice cooling for 7 minutes. Add 50 ml of diethyl ether, isolate the solidified product, wash with diethyl ether and dry, and the trifluoroacetate of the target product is 0.32. can get.

Dissolve this in a 5% aqueous sodium hydrogen carbonate solution, add nonionic adsorption resin (HP-20), and ply with IN hydrochloric acid.
Adjust to H3.5. When the resin is packed in a column and developed with a mixed solvent of water and ituburobanol, the target product is eluted with a 10% aqueous solution of isopropanol. The eluate was distilled off under reduced pressure and lyophilized to obtain 0.09 g of the title compound as a light brown powder.

mp: Discoloration at 173-178°C NMR (DMSO-dB') δ: 9.07 (IH, d, J = 9 Hz, ), 7.11 (
6H, bs), 6.79 (IH, s), 5.66
(IH, dd, J=9Hz, 4Hz), 4.53 (2
H, dd, J=14Hz, 8Hz), 3.83 and 3
．． 25-3.96 (s and m.

Total 8H), 2.85 (4H, bs) Example 6 0.85g of the compound obtained in Example 4 was added to 10m of methyl iodide.
1 and methanol (10 ml) overnight. After distilling off the solvent, diethyl ether is added to solidify to obtain a yellow solid quaternary salt. This is treated in the same manner as in Example 5 with acetic acid-water and then anisole-trifluoroacetic acid to obtain the desired trifluoroacetate. Further, the mixture is adsorbed on a nonionic adsorption resin (HP-20) at pH 2.5, the resin is packed into a column, and eluted with a 10% aqueous isopropanol solution. The eluate is concentrated and then freeze-dried to obtain 0.14 g of the title compound as a light brown powder.

mp: Discoloration near 177°C NMR (DMSO-dB) δ: 9.12 (IH, d, J-9Hz), 7.02-7
．． 26 (6H, m), 6.76 (IH, s), 5
．． 56 (LH, dd, J=9Hz, 4Hz), 4.6
0-4.94 (2H, m), 3.83 and 3.6
5-3.94 (s and m1 total 8H), 3.09
(4H, bs), 2.37 (3H, s) Examples of formulations are shown below.

Formulation Example 1 (6S, 7S)-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-pyrrolidinyl)methyl-Δ3-0-2-isocephem-4 -Carboxylic acid (syn isomer) 2001g
Glucose 250 a
+G Injection Water Reservoir (appropriate amount)
amount
511i distilled water for injection, (6S, 7S)-7-[
2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide] -3-(1-pyrrolidinyl)
After dissolving methyl-Δ3-0-2-isocephem-4-carboxylic acid (syn isomer) and glucose, 51!
The mixture is injected into an ampoule, replaced with nitrogen, and then autoclaved at 121° C. for 15 minutes to obtain an injection having the above composition.

Formulation Example 2 (6S, 7S) -7-[2- (2-Aminoanazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1-pyrrolidinio)methyl-Δ3-0 -2-Isosephem-4-carboxylate (syn isomer) 100g Avicel (trade name, manufactured by Asahi Kasei ■) 40g corn starch
30g magnesium stearate 2gTC-5 (trade name, Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) 1
0g polyethylene glycol - 800003g castor oil
40g ethanol
40g (6S, 7S)-
7-[2-(2-aminoanazol-4-yl)-2-
methoxyiminoacetamide] -3-(1-methyl-
1-pyrrolidinio)methyl-Δ3-0-2-isocephem-4-carboxylate (syn isomer), Avicel,
After mixing and polishing the cornstarch and magnesium stearate, the mixture is tableted using a kinematic machine with a sugar coating radius of 10 mm. The obtained tablets were treated with TC-5, polyethylene glycol-Boooo,
A film-coated tablet consisting of castor oil and ethanol is applied to produce a film-coated tablet having the above composition.

Formulation Example 3 (6S, 7S)-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1,2,3,4-tetrahydroisoquinolin-2-yl) Methyl-83-0-2-isocephem-4-carboxylic acid (syn isomer) 2g purified lanolin 5g white beeswax 5g white petrolatum
88゜full amount
Too much beeswax is heated to make it liquid, and then (63,7S)-7-[2-(2-
aminothiazol-4-yl)-2-methoxyiminoacetamidoco-3-(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-Δ3-0-2-isocephem-4-carboxylic acid (synisomer After adding purified lanolin and white petrolatum, and heating until it becomes liquid,
Stir until it begins to solidify to obtain an ointment having the above composition.

[Antibacterial Test] In order to investigate the antibacterial effects of the following test compounds against various bacteria, the minimum inhibitory concentration (MIC) was determined by the agar dilution plate method.

[CHEMOTHERAPY, 22.1126-112
8 (1974)] The results obtained are shown in Table 1.

In addition, the number of various bacteria is IX 106 bacteria, /vf(0,D.

600 mμ, 0.07 to 0.16).

Test compound No. 1 (6S, 7S) -7-[2-(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide] -3-(1-pyrrolidinyl)methyl-
Δ3-0-2-Isosephem-4-carboxylic acid (syn isomer) N to 2 (6S, 7S)-7-[2-(2-aminoanazol-4-yl)-2-methoxyiminoacetamide] - 3-(1-Methyl-1-pyrrolidinio)methyl-Δ3-'0-2-isocephemu 4-carboxylate (syn isomer) No. 3 (6S, 7S)
-7-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide] -3-(1,2
,3,4-tetrahydroisoquinolin-2-yl)methyl-Δ3-0-2-isocephem-4-carboxylic acid (syn isomer) No. 4 (6S, 7S) -7-[2-(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2-methyl-2-1°2.3.
4-tetrahydroisoquinolinio)methyl-Δ3-0-
2-isocephem-4-carboxylate (syn isomer) (blank below)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ {In the formula, R^1 is an amino group that may have a protecting group; R^2 is substituted with a lower alkyl group or a carboxy group -A-R^5 (wherein, A is a lower alkylene group, R^5 is a cyano group, (represents a carboxy group or carbamoyl group); R^3 is a group; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n represents 1 or 2); ▼ [In the formula, n is the same as above, R^6 is a lower alkyl group, lower alkenyl group, or group; -B-R^7 (In the formula, B is a lower alkylene group, R^7 is a hydroxyl group, a carbamoyl group , indicates a cycloalkyl group or a lower alkanoyl group.)] The group: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and groups; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is a hydroxyl group, as a substituent on the benzene ring, It may form a condensed ring with a benzene ring that may have one or two groups selected from the group consisting of lower alkoxy groups and lower alkanoyloxy groups; R^4 is a carboxy group, a carboxylate group, or an ester represents a converted carboxy group. } A 2-oxa-isocephem derivative or a pharmaceutically acceptable salt thereof.