JPH0578326A - Benzoheterocyclic compound - Google Patents

Abstract

PURPOSE:To obtain a new benzohetero ring compound useful as a germicide for external use and a disinfectant of medical tools, etc., besides a therapeutic agent for diseases caused by various pathogenic germs, widely showing excellent antibacterial activity against Gram-positive and Gram-negative bacteria. CONSTITUTION:A compound of formula I [R<1> is lower alkyl capable of containing substituent group such as halogen at the 1-position; X is halogen; R<2> is NH2, halogen, amino group-substituted lower alkylamino capable of containing substituent group such as OH group on the amino group or group of formula IV; R<3> is COOH, lower alkyl, etc.; R<4> is H or SO2OH; R is H, lower alkyl or group of formula V) or its salt such as 1-cyclopropyl-5-methyl-6- fluoro-7-(3-hydroxycarbonyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid. A compound of formula Ia (R<2>' is group of formula VI, R<2>, etc.; R<8> is lower alkoxycarbonyl, etc.; R<5> is H or group of formula VII; R<6> and R<7> are alkyl) among the compounds of formula I is produced from a compound of formula II (X<4> is halogen) and a compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel benzoheterocyclic compound.

[0002]

BACKGROUND OF THE INVENTION The benzoheterocyclic compound of the present invention is a novel compound which has not been described in the literature, and the present invention aims to provide the above-mentioned compounds useful as pharmaceuticals and the like as described later.

[0003]

According to the present invention, the general formula (1)

[0004]

[Chemical 5]

[Wherein R ¹ is a halogen atom as a substituent,
A lower alkyl group which may have a hydroxyl group or a lower alkanoyloxy group at the 1-position of alkyl is shown. X represents a halogen atom. R ² is an amino group, a halogen atom, an amino group-substituted lower alkylamino group or group which may have a hydroxyl group, a lower alkoxycarbonyl group or a lower alkanoyl group as a substituent of the amino group.

[0006]

[Chemical 6]

(R ³ represents a carboxyl group, a lower alkyl group or a hydroxy lower alkyl group, and R ⁴ represents a hydrogen atom or a hydroxysulfonyl group). R is a hydrogen atom, a lower alkyl group or a group

[0008]

[Chemical 7]

Is shown. Provided that when R represents a hydrogen atom or a lower alkyl group and R ¹ represents a lower alkyl group, R ² represents a halogen atom or R ³ represents a lower alkyl group and R ⁴ represents a hydrogen atom.

[0010]

[Chemical 8]

Must not be ] The benzoheterocyclic compound represented by these or its salt is provided.

The benzoheterocyclic compound of the above-mentioned general formula (1) and its salt exhibit a wide range of excellent antibacterial activity against Gram-positive and Gram-negative bacteria, and are effective for humans, animals, fishes and the like caused by various pathogenic bacteria. It is useful as a remedy for diseases and also as an external germicide or disinfectant for medical instruments and the like.

More specifically, each group represented by the above general formula (1) is as follows.

As the halogen atom, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

As the lower alkyl group, for example, methyl,
Ethyl, propyl, isopropyl, butyl, tert-
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl and hexyl groups.

The lower alkanoyloxy group is, for example, a straight or branched chain alkanoyloxy group having 1 to 6 carbon atoms such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy and hexanoyloxy groups. Is mentioned.

As the lower alkyl group which may have a halogen atom, a hydroxyl group or a lower alkanoyloxy group as the substituent at the 1-position of the alkyl, in addition to the above lower lower alkyl group, 3-chloropropyl, bromomethyl, 2-
Fluoroethyl, 4-chlorobutyl, 3-fluoropentyl, hydroxymethyl, 2-hydroxyethyl, 1-
Hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, acetyloxymethyl, 2-propanoyloxyethyl, 3-butyryloxypropyl, 4-pentanoyloxybutyl, 5- As a substituent such as hexanoyloxypentyl, 6-acetyloxyhexyl, propanoyloxymethyl, 1-acetyloxyethyl, 2-acetyloxyethyl, 2-hexanoyloxyethyl group, a halogen atom, a hydroxyl group or a carbon number of 1 to 6 And a linear or branched alkyl group having 1 to 6 carbon atoms which may have the linear or branched alkanoyloxy group at 1-position of alkyl.

The lower alkoxycarbonyl group is, for example, a straight chain having 2 to 7 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups. Alternatively, a branched alkoxycarbonyl group may be mentioned.

Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl groups.

The amino group-substituted lower alkylamino group which may have a hydroxyl group, a lower alkoxycarbonyl group or a lower alkanoyl group as a substituent of the amino group includes aminomethylamino, (2-aminoethyl) amino and (1-amino Ethyl) amino, (3-aminopropyl) amino, (4-aminobutyl) amino, (5-aminopentyl) amino, (6-aminohexyl) amino,
Hydroxyaminomethylamino, (2-hydroxyaminoethyl) amino, (1-hydroxyaminoethyl) amino, (3-hydroxyaminopropyl) amino, (4
-Hydroxyaminobutyl) amino, (5-hydroxyaminopentyl) amino, (6-hydroxyaminohexyl) amino, methoxycarbonylaminomethylamino, (2-ethoxycarbonylaminoethyl) amino,
(3-propoxycarbonylaminopropyl) amino,
(4-tert-Butoxycarbonylaminobutyl) amino, (5-pentyloxycarbonylaminopentyl) amino, (6-hexyloxycarbonylaminohexyl) amino, tert-butoxycarbonylaminomethylamino, (2-tert-butoxycarbonylamino) Ethyl) amino, (1-tert-butoxycarbonylaminoethyl) amino, formylaminomethylamino, acetylaminomethylamino, (2-propanoylaminoethyl) amino, (3-butyrylaminopropyl) amino, (4-penta Noylaminobutyl) amino, (5-hexanoylaminopentyl) amino, (6
-Acetylaminohexyl) amino, propanoylaminomethylamino, (1-acetylaminoethyl) amino, (2-hexanoylaminoethyl) amino group, and the like, as a substituent of an amino group, a hydroxyl group, a straight chain having 2 to 7 carbon atoms. Or a branched chain alkoxycarbonyl group or 1 to 6 carbon atoms
And an amino group having a linear or branched alkanoyl group which may have an amino group-substituted linear or branched alkyl group having 1 to 6 carbon atoms.

The hydroxy lower alkyl group includes, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like. Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms having a group.

The compound of the present invention can be produced by various methods.

[Reaction Formula-1]

[0024]

[Chemical 9]

[Wherein R ¹ and X are the same as defined above. X ⁴ represents a halogen atom. R ⁵ is a hydrogen atom or a group —B (OCO
R ⁶⁾ shows a (OCOR ⁷⁾ (R ⁶ and R ⁷ are alkyl groups). R ^2'is a group

[0026]

[Chemical 10]

(R ⁸ is a lower alkoxycarbonyl group, a hydroxy lower alkyl group or a lower alkyl group), a group

[0028]

[Chemical 11]

(R ⁹ is a hydrogen atom or a lower alkyl group, R 9
¹⁰ represents a lower alkanoyl group or a lower alkyloxycarbonyl group) or R ² (R ² is the same as defined above). In the reaction of the compound of the general formula (2) and the compound of the general formula (3), the use ratio of both is not particularly limited and can be appropriately selected from a wide range, but usually the latter is at least about equimolar to the former, It is preferable to use an equimolar to 5-fold molar amount. The reaction is carried out in an inert solvent, specifically water, methanol, ethanol, isopropanol, butanol,
Amyl alcohol, alcohols such as isoamyl alcohol, benzene, toluene, aromatic hydrocarbons such as xylene, dioxane, tetrahydrofuran, ethers such as diglyme, dimethylacetamide, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, It is carried out in N-methylpyrrolidone, methyl cyanide or the like or a mixed solvent thereof. Of these solvents, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, N-methylpyrrolidone and methyl cyanide are preferred. The reaction is carried out by using a deoxidizing agent, specifically, inorganic carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, pyridine,
It can also be carried out in the presence of organic bases such as quinoline and triethylamine. Also, an alkali metal halide such as potassium fluoride may be added. The above reaction is carried out usually under a pressure of 1 to 20 atm, preferably 1 to 10 at room temperature to about 250 ° C, preferably room temperature to 200 ° C, and is generally completed in about 10 minutes to 30 hours. ..

In the general formula (1a), R ⁵ is a group -B.
When (OCOR ⁶ ) or (OCOR ⁷ ) is shown, the chelate can be decomposed by treating with an acid or a basic compound to give a compound (1a) in which the corresponding R ⁵ is a hydrogen atom. Examples of the acid used here include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate and potassium carbonate, and organic bases such as triethylamine. The reaction normally proceeds at 0 to 150 ° C., preferably at about 0 to 100 ° C. The amount of the acid or basic compound used is usually at least an equimolar amount, preferably about 1 to 10 times the amount of the raw material compound.

In the compound of the general formula (1a) obtained above, R ^{2'is a} group

[0032]

[Chemical formula 12]

[In the formula, R ⁸ is the same as above. By hydrolyzing the compound represented by the above formula, the corresponding compound of the present invention in which R ⁸ is a carboxyl group can be derived. Further, in the compound of the general formula (1a), R ^{2 ′} is a group

[0034]

[Chemical 13]

[In the formula, R ⁹ is the same as above. Compounds showing], the compound R 2 ^'is a group represented by the chemical formula 11 (1
It is produced by hydrolyzing a).

Any ordinary reaction conditions for hydrolysis can be applied to these hydrolysis reactions. Specifically, for example, basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate and sulfuric acid. Water, in the presence of mineral acids such as hydrochloric acid and nitric acid, organic acids such as acetic acid and aromatic sulfonic acid,
Alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone,
It is carried out in a solvent such as dioxane, ethers such as ethylene glycol diethyl ether, acetic acid, or a mixed solvent thereof. The reaction usually proceeds at room temperature to 200 ° C., preferably at room temperature to about 150 ° C., and generally 0.1 to 30.
It will finish in about time.

Among the compounds of the present invention represented by the above general formula (1), the compounds in which R ² is an amino group-substituted lower alkylamino group which may have a lower alkoxycarbonyl group or a lower alkanoyl group as a substituent correspond to It can also be produced by acylating a compound wherein R ² is a lower alkylamino group substituted with an amino group.

This acylation is carried out using a usual acylating agent. Examples of the acylating agent include lower alkanoyl halides such as acetyl chloride and propionyl chloride, lower alkanoic acids such as acetic acid and propionic acid, and lower alkanoic acid anhydrides such as acetic anhydride.

When a lower alkanoyl halide is used as the acylating agent, the reaction between the starting compound and the lower alkanoyl halide is carried out in a suitable solvent, preferably in the presence of a basic compound. Examples of the basic compound used include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,
5-diazabicyclo [4.3.0] nonene-5,1,8
-Diazabicyclo [5.4.0] undecene-7,1,
Examples include organic bases such as 4-diazabicyclo [2.2.2] octane, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like. it can. These basic compounds are used in at least equimolar amounts, usually equimolar to 3-fold molar amounts with respect to the raw material compounds. Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, tetrahydrofuran, diethyl ether,
Ethers such as dimethoxyethane, ethyl acetate, esters such as methyl acetate, dimethylformamide, dimethylsulfoxide, aprotic polar solvents such as hexamethylphosphoric triamide, methanol, ethanol, propanol, butanol, 3-methoxy-butanol, Examples thereof include alcohols such as ethyl cellosolve and methyl cellosolve, pyridine, acetone and the like. The use ratio of the raw material compound and the lower alkanoyl halide is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least about equimolar amount, preferably equimolar to the former.
It is preferable to use a 5-fold molar amount. The reaction is usually -20 to 1
The reaction is carried out at about 80 ° C., preferably 0 to 150 ° C., and generally the reaction is completed in about 5 minutes to 30 hours.

When a lower alkanoic acid anhydride is used as the acylating agent, the acylation is preferably carried out in the presence of a basic compound. Examples of the basic compound used include alkali metals such as metal sodium and metal potassium, and hydroxides, carbonates, bicarbonates of these alkali metals, and aromatic amine compounds such as pyridine and piperidine. The reaction proceeds either in the absence of a solvent or in a solvent, but is usually performed using a suitable solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, water and pyridine. The acylating agent is used in at least an equimolar amount with respect to the raw material compound, but it is generally preferable to use an equimolar amount to a large excess amount. The reaction proceeds at 0 to 150 ° C, but generally 0 to 80 ° C.
It is better to carry out at ℃. The reaction time is usually about 0.5 to 10 hours.

When a lower alkanoic acid is used as the acylating agent, a mineral acid such as sulfuric acid or hydrochloric acid or a sulfonic acid such as paratoluenesulfonic acid or ethanesulfonic acid is added to the reaction system, preferably 50 By maintaining the reaction temperature at 120 ° C, the acylation reaction proceeds advantageously.

General formula

[0043]

[Chemical 14]

[0044] [wherein R ^{1 'is} halogen atom as a substituent,
A lower alkyl group which may have a hydroxyl group or a lower alkanoyloxy group at the 1-position of alkyl is shown. R ^{2 ″} represents an amino group, a halogen atom, an amino group-substituted lower alkylamino group which may have a hydroxyl group, a lower alkoxycarbonyl group or a lower alkanoyl group as a substituent of the amino group, or a group represented by Chemical formula 2. R'is a hydrogen atom,
A lower alkyl group or a group represented by Chemical formula 3 is shown. X is the same as above. ] Among the compounds of the present invention represented by the above, the compound in which R'is a lower alkyl group is produced by esterifying the corresponding compound in which R'is a hydrogen atom.

This esterification reaction is carried out by using an acid such as hydrochloric acid or sulfuric acid, thionyl chloride, phosphorus oxychloride, or the like in a lower alcohol such as methanol, ethanol or isopropanol.
In the presence of halogenating agents such as phosphorus pentachloride and phosphorus trichloride, organic acids such as aromatic sulfonic acids, Lewis acids such as boron fluoride ether, mixtures of peroxoboric acid and sulfuric acid, polyphosphoric acid, polyphosphoric acid esters, etc. Done. The reaction is usually 0
˜150 ° C., preferably around 50 to 100 ° C., and is generally completed in about 1 to 10 hours.

The esterification reaction is also carried out by using a large excess of alcohols and aromatic hydrocarbons such as benzene and toluene and azeotropically distilling the produced water using a Dean-Stark separator. it can.

The esterification reaction can also be carried out using a condensing agent such as dicyclohexylcarbodiimide.
At this time, methylene chloride, with alcohol in the reaction system,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride,
Ethers such as tetrahydrofuran, aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, etc. may be added. The reaction is usually carried out at room temperature to around reflux temperature, preferably 50 to 120 ° C., and generally 2
It will be finished in about 24 hours.

Further, the above esterification reaction can also be carried out by using hexamethylphosphoric triamide as a solvent in the presence of an alkali such as sodium hydroxide or potassium hydroxide and reacting the starting compound with alcohol. The reaction temperature of the reaction is suitably around 50 ° C., and the reaction is completed in about 1 hour.

The compound of the present invention represented by the above chemical formula 14 in which R ^{1 ′} is a lower alkyl group having a halogen atom as a substituent has the same structure as the compound represented by the chemical formula 14 in which R ^{1 ′} is a lower alkyl group.
It is produced by reacting a halogenating agent such as N-halogenated succinimide such as -bromosuccinimide and N-chlorosuccinimide, and benzoyl peroxide and 2,2'-azobis (isobutyronitrile). The amount of the halogenating agent used is usually at least equimolar, preferably 0.1 to 10 times the molar amount of the starting compound. As the reaction solvent, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride are preferable, and carbon tetrachloride is particularly preferable. The reaction is usually room temperature to around reflux temperature, preferably 50 to 150.
It is carried out at 0 ° C and is generally completed in about 2 to 24 hours.
Further, the fluorinated compound or iodide compound of the above compounds can be easily obtained by fluorinating or iodizing the chlorinated compound or brominated compound obtained above by the method described below. That is, the fluorination is carried out in a solvent such as dimethylformamide, sulfolane, dimethyl sulfone, acetonitrile, etc.
It is carried out by reacting the starting compound with an alkali fluoride such as potassium fluoride, cesium fluoride or sodium fluoride in the presence of 8-crown-6. The fluorination is usually 1
It is carried out at a temperature of 00 ° C or higher, preferably about 100 to 250 ° C, and is generally completed in 2 to 10 hours. Also, iodination is
It is carried out by reacting the starting compound with an alkali iodide such as potassium iodide, cesium iodide or sodium iodide in a solvent such as acetone, acetonitrile, dimethylformamide or dioxane, preferably acetone or acetonitrile. The iodination is usually performed at room temperature to 200 ° C., preferably about 50 to 100 ° C., and is generally completed in 2 to 3 hours.

[0050] Also, R 1 ^'present invention compound of the above Formula 14 is a lower alkyl group having a halogen atom as a substituent, the corresponding R ^1' under the the compound of Formula 14 a lower alkyl group ultraviolet radiation It can also be produced by warming the solution and reacting it with Br ₂ , Cl ₂ or the like. The reaction temperature of the reaction is suitably around 100 to 180 ° C., and the reaction is completed in about 1 to 5 hours.

[0051] R ^{1 'present} invention are compounds of the chemical formula 14 is a lower alkyl group having a lower alkanoyloxy group as a substituent, the corresponding R ^1' is a lower alkyl group having a halogen atom as a substituent of 14 It is produced by reacting the compound of (1) with a lower fatty acid salt in a suitable solvent. Examples of the solvent include dimethylformamide, N-
Methyl-2-pyrrolidone, dioxane, tetrahydrofuran and the like are preferable, and dimethylformamide is preferable. Examples of the lower fatty acid salt include sodium acetate, potassium acetate, silver acetate, cesium acetate and the like. The reaction temperature of the reaction is suitably around 80 ° C., and the reaction is completed in about 1 to 4 hours.

The compound of the present invention represented by the above chemical formula 14 in which R ^{1 ′} is a lower alkyl group having a hydroxyl group as a substituent has the corresponding chemical formula 14 in which the corresponding R ^{1 ′} is a lower alkyl group having a lower alkanoyloxy group as a substituent. It is produced by acid hydrolysis of a compound. Examples of the acid used include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, acetic acid and the like.
Ethers such as tetrahydrofuran, dioxane and diglyme, and solvents such as dimethylformamide may be added to the reaction system. The reaction is usually at room temperature to
It is carried out near the reflux temperature, preferably at 50 to 150 ° C., and is generally completed in about 1 to 10 hours.

The compound of the present invention represented by Chemical formula 14 in which R ^{2 ″} is an amino group is reacted with ammonia gas in an autoclave by using an appropriate solvent for the corresponding compound represented by Chemical formula 14 in which R ^{2 ″} is a halogen atom. It is manufactured by Examples of the solvent include N-methyl-2-pyrrolidone, dimethylformamide, dioxane, tetrahydrofuran and the like. The reaction temperature of the reaction is suitably around 100 ° C., and the reaction is completed in about 6 to 24 hours.

[0054] The present invention compounds of R ² is of 2 represents a group represented by and R ⁴ is of a hydroxy sulfonyl group 14 represents a group represented by the corresponding R ² is of 2 and R ⁴ is a hydrogen atom Is prepared by sulfonation of the compound of formula 14 The sulfonation is carried out by using a raw material compound in a suitable solvent, such as a pyridine / sulfur trioxide complex, a trimethylamine / sulfur trioxide complex, a triethylamine / sulfur trioxide complex, a dioxane / sulfur trioxide complex or the like, preferably a sulfur trioxide complex. It is carried out by reacting a pyridine / sulfur trioxide complex. Such sulfur trioxide complex is preferably used in an amount of 1 to 10 times equivalent to the raw material compound. As the solvent, in addition to the corresponding amine and the corresponding dioxane, various amines other than the above amines are used. The reaction temperature of the reaction is appropriately from room temperature to about 120 ° C., and the reaction is completed in about 2 to 12 hours. Chlorsulfone / pyridine may be used instead of the sulfur trioxide complex, and in this case, pyridine is preferably used as a solvent. The amount of chlorosulfone / pyridine used is preferably about 1 to 4 times the equivalent of the starting compound. The reaction temperature of the reaction is suitably from room temperature to around 120 ° C.

[0055] The present invention compounds of R ² is of 2 represents a group represented by and R ⁴ is of a hydroxy sulfonyl group 14 represents a group represented by the corresponding R ² is of 2 and R ⁴ is a hydrogen atom First, the compound represented by the formula (14) is reacted with sulfuryl chloride to give the corresponding compound represented by the formula (2) in which R ² represents the group represented by the formula ( ₂₎ and R ⁴ represents the SO ₂ Cl group, and then the compound is hydrolyzed. It is manufactured by The reaction between the raw material compound and sulfuryl chloride is carried out in the presence of a basic compound in a suitable solvent. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Examples of the basic compound include various amines such as trimethylamine, triethylamine and pyridine. Such amine and sulfuryl chloride are each 1 to 5 relative to the raw material compound.
It is used in a double equivalent amount. The reaction temperature of the reaction is suitably 0 ° C. to room temperature, preferably about 0 to 5 ° C., and the reaction is completed in about 1 to 5 hours. The subsequent hydrolysis can be carried out under the same reaction conditions as the hydrolysis of the compound (1a), but a 5% hydrochloric acid aqueous solution is used in a large excess, or sodium hydroxide, potassium hydroxide, sodium carbonate is used. It is preferable that the raw material compound is converted into the form of an alkali salt by using an alkaline aqueous solution such as the above, and then a hydrochloric acid aqueous solution of about 5% is applied. The reaction temperature at this time may be around room temperature.

Among the compounds of the present invention represented by the above general formula (1), compounds in which R is a group represented by the above chemical formula 7 are:
Administering to the rat a compound in which the corresponding R is a hydrogen atom,
It can be collected as its metabolite. Further, among the compounds of the present invention represented by the general formula (1), compounds in which R ⁴ is a hydroxysulfonyl group are also available, and the corresponding compounds in which R is a hydrogen atom can be administered to rats and collected as metabolites thereof.

The compound represented by the general formula (1) of the present invention can easily form a salt by reacting with a pharmaceutically acceptable acid or basic 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, lactic acid, methanesulfonic acid,
Organic acids such as propionic acid can be exemplified, and examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The compounds of the present invention naturally include stereoisomers and optical isomers.

The desired compound obtained by the method shown in each of the above reaction schemes can be separated from the reaction system by a conventional separation means and further purified. As the separation and purification means, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction method and the like can be adopted.

The compounds of the present invention are usually used in the form of general pharmaceutical preparations. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose,
Typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions,
Suspension agents etc.) and the like. When molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, sucrose, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl Binders such as pyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, sucrose , Stearin,
Decay inhibitor for cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoter for sodium lauryl sulfate, humectant for glycerin, starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Agents, refined talc, stearates, boric acid powder, lubricants such as polyethylene glycol and the like can be used. Further, the tablet may be a tablet coated with an ordinary coating, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet or a double-layered tablet, or a multi-layered tablet. In the case of molding in the form of pills, various carriers conventionally known in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, binders such as ethanol, laminaran,
A disintegrating agent such as agar can be used. In the case of molding in the form of suppositories, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. Capsules are usually prepared by mixing active ingredient compounds with the various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood, and when molded into these forms, those commonly used in the art as diluents Can be used, such as water, ethyl alcohol, macrogol, propylene glycol,
Ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. Furthermore, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained in the pharmaceutical preparation. When forming into a paste, cream or gel form, for example, white petrolatum, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite and the like can be used as a diluent. When the active ingredient compound is precipitated in the injection solution, the injection solution is stabilized by adding an acid such as methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid, lactic acid, etc., if necessary. It can be kept in the form of a solution.

Further, the pharmaceutical preparation of the present invention can also be in the form of an injection solution or injection solution containing the compound of the above-mentioned general formula (1) or a salt thereof (eg lactate) and an acid which does not cause precipitation. Examples of the acid that does not cause precipitation include lactic acid, methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid and the like, preferably lactic acid.

When the lactic acid is used as the acid, the amount of the acid which does not cause the precipitation to be contained in the infusion solution or the injection solution is usually about 0.1 to 10% by weight, preferably about 10% by weight in the solution. It is preferable to set it to about 0.5 to 2% by weight, and when an acid other than lactic acid is used as the acid,
It is usually about 0.05 to 4% by weight, preferably about 0.3 to 2% by weight in the solution. The above-mentioned injectable solution or injectable solution may be mixed with a usual auxiliary agent, if necessary. Examples of such auxiliary agents include thickeners,
Examples include absorption promoters, absorption inhibitors, crystallization inhibitors, complexing agents, antioxidants, isotonic agents, normal hydrating agents and the like. The pH of the solution can be appropriately adjusted by adding an alkali such as sodium hydroxide, and the pH of the solution is usually 2.5 to
It is adjusted within the range of 7. The injectable solution or the injectable solution is excellent in stability and can be stored and stored in the solution state for a long period of time.

The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected from a wide range, but it is usually about 1 to 70% by weight in the pharmaceutical composition.
It is good to say

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and various preparation forms, patient age, sex and other conditions,
It is administered by a method depending on the degree of disease and the like. For example tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, it is orally administered. Further, in the case of an injection, it is administered alone or mixed with an ordinary replenisher such as glucose and amino acid, and then intravenously administered. Further, if necessary, it is intramuscularly, intradermally, subcutaneously or intraperitoneally administered alone. In the case of suppositories, it will be administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected according to the usage, age of the patient, sex and other conditions, degree of disease and the like. Usually, the amount of the active ingredient compound is about 1 kg / day body weight. It is preferable that the amount is about 0.2 to 100 mg. In addition, the active ingredient compound is contained in a dosage unit form of about 10
It is preferably contained in the range of 1000 mg.

[0066]

EXAMPLES The present invention will be further clarified with reference to the following Reference Examples and Examples.

Reference Example 1 1-Cyclopropyl-5-methyl-6-fluoro-7-
(3-ethoxycarbonyl-1-piperazinyl) -1,
Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid 2-ethoxycarbonylpiperazine hydrochloride 0.69 g
Was suspended in 20 ml of acetonitrile, and under ice cooling, 0.97 ml of triethylamine and 1-cyclopropyl-5-
Methyl-6-fluoro-7-bromo-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.B (OCOC
H ₃ ) ₂ chelate (hereinafter this chelate is simply referred to as “B (O
COCH ₃ ) ₂ chelate ”) 0.47 g,
The reaction was carried out by stirring at 70 ° C. The solvent was distilled off under reduced pressure, extracted with methylene chloride, dried over magnesium sulfate and evaporated,
0.68 g of brown powder was obtained. This was purified by silica gel column chromatography (silica gel × 70 = 48 g, methylene chloride: methanol = 15: 1),
30 g of yellow oil was obtained. This oil was dissolved in 3 ml of acetonitrile, 3 ml of 1N-hydrochloric acid aqueous solution and 5 ml of water, reacted at 60 ° C. for 20 minutes, and then acetonitrile was distilled off under reduced pressure. Chloroform was added to the residue, the pH was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate, chloroform was extracted, and 0.21 g (50.0
%) Was obtained.

NMR (CDCl ₃ ) δ ppm; 1.10.
-1.50 (m, 5H), 1.33 (t, 3H, J =
7.14 Hz), 2.77 (d, 3H, J = 3.22H)
z), 3.00-3.85 (m, 8H), 4.26.
(Q, 2H, J = 7.14 Hz), 7.34 (d, 1
H, J = 7.60 Hz), 8.68 (s, 1H), 1
5.51 (broad, 1H).

Example 1 1-Cyclopropyl-5-methyl-6-fluoro-7-
(3-Hydroxycarbonyl-1-piperazinyl)-
Production of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5-methyl-6-fluoro-7- (3-ethoxycarbonyl-1 obtained in Reference Example 1 above.
-Piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (83 mg) was dissolved in ethanol (3 ml) and 1N-sodium hydroxide aqueous solution (1 ml) at 50 ° C.
It was stirred for 1 hour. Ethanol was distilled off under reduced pressure, pH was adjusted to 4 with a 10% aqueous citric acid solution, and crystals were collected by filtration. Recrystallized from methanol to obtain 70 mg of the above target compound as a white powder.
(89.7%) was obtained.

Melting point: 271-273 ° C. (decomposition) NMR (DMSO) δ ppm; 1.05-1.50
(M, 4H), 2.76 (d, 3H, J = 3.22H)
z), 2.60-4.00 (m, 8H), 7.46.
(D, 1H, J = 7.96 Hz), 8.61 (s, 1
H).

Example 2 1-Cyclopropyl-5-methyl-6-fluoro-7-
Production of [(2-acetylaminoethyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 88 mg of (N-acetylamino) ethylenediamine was dissolved in 2 ml of pyridine, and 1-cyclopropyl-5- Methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (60 mg) was added, and the temperature was 110 ° C.
And reacted for 20 hours. Pyridine was distilled off under reduced pressure, 20%
An aqueous citric acid solution was added to acidify the mixture, and the mixture was extracted with chloroform. It was dried over magnesium sulfate to obtain 80 mg of a yellow powder, which was purified by preparative thin layer chromatography (methylene chloride: methanol = 10: 1) to obtain 51 mg (65.4%) of a white powder. Recrystallized from methylene chloride-methanol to give the target compound 43 as colorless needles.
mg was obtained.

Melting point: 255-256 ° C. NMR (DMSO) δ ppm; 1.00-1.20
(M, 2H), 1.30-1.50 (m, 2H), 1.
83 (s, 3H), 2.72 (d, 3H, J = 2.75)
Hz), 3.10-3.25 (m, 3H), 3.60-
3.80 (m, 1H), 4.05-4.20 (m, 1
H), 7.07 (broad, 1H), 7.21 (d,
1H, J = 7.75 Hz, 8.12 (broad, 1
H), 8.54 (s, 1H), 16.14 (s, 1
H).

Example 3 1-Cyclopropyl-5-methyl-6-fluoro-7-
Amino-1,4-dihydro-4-oxoquinoline-3-
Production of Carboxylic Acid 1-Cyclopropyl-5-methyl-
6,7-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.28 g, N-methyl-2-
Pyrrolidone 4 ml and ammonia gas saturated 10
The reaction was carried out at 0 ° C for 20 hours. Pour the reaction mixture into ice water,
The crystals were collected by filtration and dried to give 0.24 g (85.7%).
Was obtained as a pale yellow powder. Recrystallization from chloroform-methanol gave the target compound as a pale yellow powder.

Melting point: 300 ° C. or higher NMR (DMSO) δ ppm; 1.05-1.35
(M, 4H), 2.72 (d, 3H, J = 2.96H
z), 3.50-3.75 (m, 1H), 6.66 (b
road, 2H), 7.29 (d, 1H, J = 8.12)
Hz), 8.52 (s, 1H), 16.13 (s, 1
H).

Reference Example 2 Preparation of 1-mesyloxy-2-tert-butoxycarbonylaminopropane 16.65 g of 1-hydroxy-2-tert-butoxycarbonylaminopropane was dissolved in 30 ml of methylene chloride, and 10.8 ml of pyridine was added, Mesyl chloride was added under ice cooling, and the mixture was reacted at room temperature for 38 hours. The solvent was distilled off, and the mixture was extracted with ethyl acetate. The solution was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over magnesium sulfate and evaporated to give 18.97 g of a black oil. This was purified by silica gel column chromatography (silica gel × 10 = 190 g, n-hexane: ethyl acetate = 2: 1), and 15.96 g
(66.3%) of the target compound was obtained as soft colorless needle crystals.

NMR (DMSO) δ ppm; 1.24
(D, 3H, J = 6.84 Hz), 1.45 (s, 9
H), 3.04 (s, 3H), 3.85-4.10.
(M, 1H), 4.10-4.35 (m, 2H), 4.
60 (broad, 1H).

Reference Example 3 Preparation of 1-azido-2-tert-butoxycarbonylaminopropane 1-Mesyloxy-2-ter obtained in Reference Example 2 above.
15.71 g of t-butoxycarbonylaminopropane was dissolved in dimethylformamide, and sodium azide was added.
24 g was added and reacted at 50 ° C. for 5 hours, further 2.02 g of sodium azide and 30 ml of dimethylformamide.
Was added and reacted at 50 ° C. for 18 hours. The reaction mixture was poured into water, extracted with ethyl acetate-toluene, dried over magnesium sulfate, and evaporated to give a yellow oil as the above target compound 7.25.
g (58.4%) was obtained.

NMR (CDCl ₃ ) δppm; 1.29
(D, 3H, J = 6.76 Hz), 1.45 (s, 9
H), 3.20-3.50 (m, 2H), 3.70-
4.00 (m, 1H), 4.53 (broad, 1
H).

Reference Example 4 2- (tert-Butoxycarbonylaminopropyl)
Production of amine 7.21 g of 1-azido-2-tert-butoxycarbonylaminopropane obtained in Reference Example 3 above was dissolved in 150 ml of ethanol, and 10% palladium-carbon 0.5
5 g was added, and hydrogenated at 3.5 atm and room temperature using a glass autoclave. 10% Palladium-carbon was filtered off, and ethanol was distilled off under reduced pressure to obtain 6.30 g of the above target compound as a soft white powder.

NMR (CDCl ₃ ) δ ppm; 1.13
(D, 3H, J = 6.70 Hz), 1.45 (s, 9
H), 2.21 (s, 2H), 2.55-2.85.
(M, 2H), 3.50-3.80 (m, 1H), 4.
74 (broad, 1H).

Example 4 1-Cyclopropyl-5-methyl-6-fluoro-7-
Preparation of [2- (tert-Butoxycarbonylaminopropyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-Cyclopropyl-5-methyl-in an autoclave
A yellow color was obtained in the same manner as in Example 2 except that 84 mg of 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 209 mg of 2- (tert-butoxycarbonylaminopropyl) amine and 2 ml of pyridine were used. 130 mg of the above target compound as a powder was obtained.

NMR (CDCl ₃ ) δ ppm; 1.00
-1.70 (m, 4H), 1.29 (d, 3H, J =
6.76 Hz), 2.81 (d, 3H, J = 3.06H
z), 3.00-3.70 (m, 3H), 3.90-
4.15 (m, 1H), 4.53 (broad, 1
H), 5.44 (broad, 1H), 7.26 (br
oad, 1H), 8.71 (s, 1H), 16.08
(S, 1H).

Example 5 1-Cyclopropyl-5-methyl-6-fluoro-7-
Production of [(2-aminopropyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 1-Cyclopropyl-5-methyl-6-fluoro obtained in Example 4 above 130 mg of -7- [2- (tert-butoxycarbonylaminopropyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 6 ml of dioxane and 0.7 ml of 6N hydrochloric acid aqueous solution, and the mixture was heated at 50 ° C. The reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure and recrystallized from methanol-diethyl ether to obtain 110 mg (99.1%) of the above target compound as a yellow powder.

Melting point: 300 ° C. or higher.

Example 6 1-Cyclopropyl-5-methyl-6-fluoro-7-
[2- (formylaminopropyl) amino] -1,4-
Preparation of dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5-methyl-6-fluoro-7-[(2-aminopropyl) amino] -1,4-obtained in Example 5 above Dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 50 mg was added to dimethylformamide 3 m.
1 and ethyl formate (6 ml) were dissolved, and then triethylamine (0.056 ml) was added and the reaction was carried out at 70 ° C. for 7 hours. The solvent was distilled off under reduced pressure, acidified with 20% citric acid solution, extracted with chloroform, dried over magnesium sulfate, and purified by preparative thin layer chromatography (methylene chloride: methanol = 20: 1) to give 47 mg of a white powder ( 97.1%). Recrystallization from methanol-diethyl ether gave the target compound as a white powder.

Melting point: 229-230.5 ° C. NMR (CDCl ₃ ) δ ppm; 1.00-1.25
(M, 2H), 1.35 (d, 3H, J = 6.70H
z), 1.45 to 1.60 (m, 2H), 2.81.
(D, 3H, J = 3.00 Hz), 3.10-3.75
(M, 3H), 4.20-4.55 (m, 1H), 5.
30 (broad, 1H), 5.70 (broad, 1
H), 7.27 (d, 1H, J = 7.66 Hz), 8.
23 (s, 1H), 8.69 (s, 1H), 16.05
(S, 1H).

Example 7 1-Cyclopropyl-5-methyl-6-fluoro-7-
[(2-Acetylaminopropyl) amino] -1,4-
Preparation of dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5-methyl-6-fluoro-7-[(2-aminopropyl) amino] -1,4-obtained in Example 5 above Dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 60 mg was dissolved in 0.5 ml of water, 0.49 ml of 1N-sodium hydroxide aqueous solution and 2 ml of acetone, and 0.023 ml of acetyl chloride was added under ice-cooling. The reaction was carried out under cold conditions for 0.5 hours and at room temperature for 3 hours. The solvent was distilled off under reduced pressure, acidified with a 1N-hydrochloric acid aqueous solution, extracted with chloroform, and then distilled off with magnesium sulfate,
70 mg of white powder was obtained. Further, it was recrystallized from methanol-diethyl ether to give the target compound 4 as colorless needle crystals.
Obtained 3 mg (70.5%).

Melting point: 237-238 ° C NMR (CDCl ₃ ) δppm; 1.00-1.20
(M, 2H), 1.31 (d, 3H, J = 6.76H
z), 1.40-1.55 (m, 2H), 2.03
(S, 3H), 2.81 (d, 3H, J = 3.06H
z), 3.05-3.30 (m, 1H), 3.40-
3.65 (m, 2H), 4.20-4.40 (m, 1
H), 5.42 (broad, 1H), 5.56 (br
oad, 1H), 7.23 (d, 1H, J = 7.66H
z), 8.68 (s, 1H), 16.07 (s, 1)
H).

Example 8 1-Cyclopropyl-5-methyl-6-fluoro-7-
[2- (tert-butoxycarbonylaminoethyl)
Amino] -1,4-dihydro-4-oxoquinoline-3
-Preparation of carboxylic acid 1-Cyclopropyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 112 mg, pyridine 3 ml and [N- (tert.
-Butoxycarbonyl) amino] ethyleneamine 256
Using mg, and in the same manner as in Example 4, 152 mg (90.5%) of the above target compound was obtained as a white powder.

Melting point: 237-240.5 ° C. NMR (CDCl ₃ ) δ ppm; 1.10-1.65
(M, 4H), 1.46 (s, 9H), 2.82 (d,
3H, J = 3.00 Hz), 3.30-3.70 (m,
4H), 4.88 (broad, 1H), 5.39 (b
road, 1H), 7.12 (d, 1H, J = 7.66)
Hz), 8.71 (s, 1H), 16.05 (s, 1)
H).

Example 9 1-Cyclopropyl-5-methyl-6-fluoro-7-
[(2-Aminoethyl) amino] -1,4-dihydro-
Preparation of 4-oxoquinoline-3-carboxylic acid / hydrochloride 1-Cyclopropyl-5-methyl-6-fluoro-7- [2- (tert-butoxycarbonylaminoethyl) amino] obtained in Example 8 above -1,4-dihydro-
210 mg of 4-oxoquinoline-3-carboxylic acid was dissolved in 8 ml of dioxane and 1 ml of 6N hydrochloric acid aqueous solution, and 55
The reaction was carried out at 0 ° C for 1 hour. The solvent was distilled off under reduced pressure and recrystallized from methanol-diethyl ether to obtain 150 mg (84.3%) of the target compound as a white powder.

Melting point: 294-297 ° C. (decomposition) NMR (DMSO) δ ppm; 1.00-1.20
(M, 2H), 1.30-1.50 (m, 2H), 2.
74 (d, 3H, J = 3.04 Hz), 3.00-3.
25 (m, 2H), 3.50-3.70 (m, 2H),
3.70-3.85 (m, 1H), 7.08 (broa
d, 1H), 7.10 (d, 1H, J = 7.52H
z), 8.00 (broad, 3H), 8.57 (s,
1H), 16.06 (s, 1H).

Example 10 1-Cyclopropyl-5-methyl-6-fluoro-7-
Preparation of [(2-formylaminoethyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5-methyl-6-fluoro-7 obtained in Example 9 above -[(2-Aminoethyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 50 mg, dimethylformamide 3 m
1, ethyl formate 6 ml and triethylamine 0.059
mg was used and treated in the same manner as in Example 6, and recrystallized from dimethylformamide-water to obtain 35 mg (71.4%) of the above target compound as pale yellow needle crystals.

Melting point: 286-289.5 ° C. (decomposition) NMR (DMSO) δ ppm; 1.05-1.25
(M, 2H), 1.25-1.50 (m, 2H), 2.
73 (d, 3H, J = 3.04 Hz), 3.00-3.
50 (m, 4H), 3.60-3.85 (m, 1H),
7.09 (broad, 1H), 7.21 (d, 1H,
J = 7.92 Hz), 7.95 (s, 1H), 8.26
(Broad, 1H), 8.55 (s, 1H), 16.
14 (s, 1H).

Example 11 1-Cyclopropyl-5-methyl-6-fluoro-7-
(3-Hydroxymethyl-1-piperazinyl) -1,4
- the production of dihydro-4-oxoquinoline-3-carboxylic acid 2-hydroxymethyl piperazine hydrochloride 1.51g was suspended in acetonitrile 20 ml, triethylamine 3.1ml added, further B (OCOCH _{3) 2} chelate 0. 94 g was added and the mixture was refluxed for 6 hours. The solvent was evaporated under reduced pressure, acidified with 1N hydrochloric acid, and extracted with methylene chloride. Make the aqueous layer alkaline with saturated aqueous sodium hydrogen carbonate solution,
It was extracted with methylene chloride. 10m acetonitrile on the residue
1 and 0.7 ml of 1N hydrochloric acid were added, and the mixture was reacted at 80 ° C. for 1 hour, the solvent was distilled off, the mixture was made weakly alkaline with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off to obtain 0.17 g of a yellow powder, which was then recrystallized from methanol to obtain 80 mg (10.7%) of the above target compound as a yellow powder.

Melting point: 219-221 ° C. NMR (DMSO) δ ppm; 1.00-1.45
(M, 4H), 2.55-3.15 (m, 5H), 3.
30-3.90 (m, 5H), 4.72 (t, 1H, J
= 5.70 Hz), 7.44 (d, 1H, J = 8.10)
Hz), 8.62 (s, 1H).

Example 12 Preparation of 1-Cyclopropyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester 1-Cyclopropyl-5-methyl-6 0.34 g of 7,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 16 ml of methanol, 0.26 ml of thionyl chloride was added, and the mixture was refluxed for 6 hours. Methanol was distilled off under reduced pressure, 5% aqueous sodium hydroxide solution was added,
Extraction with methylene chloride gives a white powder of the target compound 0.
36 g (almost theoretical) was obtained.

NMR (CDCl ₃ ) δ ppm; 1.05
-1.20 (m, 2H), 1.30-1.45 (m, 2
H), 2.88 (d, 3H, J = 3.00 Hz), 3.
92 (s, 3H), 7.50-7.70 (m, 1H),
8.53 (s, 1H).

Example 13 1-Cyclopropyl-5-bromomethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-
Production of Carboxylic Acid Methyl Ester 0.35 g of 1-cyclopropyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester was suspended in 20 ml of carbon tetrachloride, After adding 29 mg of benzoyl peroxide and 0.26 g of N-bromosuccinimide and refluxing for 2.5 hours,
Extracted with methylene chloride. It was dried over magnesium sulfate and evaporated to obtain 0.44 g of yellow powder. This was subjected to silica gel column chromatography (silica gel × 60 = 27 g,
Purify with methylene chloride: methanol = 40: 1),
0.30 g (66.7%) of the above target compound as a pale yellow powder.
Got

NMR (CDCl ₃ ) δ ppm; 1.10.
-1.23 (m, 2H), 1.30-1.50 (m, 2)
H), 3.35-3.50 (m, 1H), 3.93.
(S, 3H), 5.50 (d, 3H, J = 2.80H
z), 7.70-7.85 (m, 1H), 8.57
(S, 1H).

Example 14 1-Cyclopropyl-5-acetoxymethyl-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-
Preparation of 3-Carboxylic Acid Methyl Ester 1-Cyclopropyl-5-bromomethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-
0.30 g of carboxylic acid methyl ester was dissolved in 6 ml of N, N-dimethylformamide, and sodium acetate 0.1
7 g was added and reacted at 80 ° C. for 1.5 hours. N, N-
Dimethylformamide was distilled off under reduced pressure and extracted with chloroform. It was dried over magnesium sulfate and evaporated to obtain 0.40 g of a black oily substance. This was purified by silica gel column chromatography (silica gel × 75 = 27 g, methylene chloride: methanol = 40: 1) to obtain 0.17 g (almost theoretical amount) of the above target compound as a light brown powder.

NMR (CDCl ₃ ) δ ppm; 1.10.
-1.25 (m, 2H), 1.30-1.50 (m, 2)
H), 2.06 (s, 3H), 3.35-3.50.
(M, 1H), 3.92 (s, 3H), 5.92 (d,
2H, J = 2.90 Hz), 7.75-7.90 (m,
1H), 8.56 (s, 1H).

Example 15 1-Cyclopropyl-5-hydroxymethyl-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-
Preparation of 3-carboxylic acid 1-cyclopropyl-5-acetoxymethyl-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-
35 mg of 3-carboxylic acid methyl ester was added to concentrated hydrochloric acid 0.5
ml, acetic acid 0.5 ml and water 0.1 ml, and the mixture was gently refluxed for 5 hours. Ice was added to this solution, which was extracted with methylene chloride. Dried over magnesium sulfate, distilled off, 30 mg
Of white powder was obtained. This was purified by preparative thin layer chromatography (methylene chloride: methanol = 20: 1), and 4 mg (13.
3%) was obtained.

NMR (CDCl ₃ ) δ ppm; 1.20
-1.30 (m, 2H), 1.40-1.55 (m, 2)
H), 3.50-3.70 (m, 1H), 5.10.
(T, 1H, J = 8.18 Hz), 5.10-5.20
(M, 2H), 7.90-8.00 (m, 1H), 8.
96 (s, 1H), 14.44 (s, 1H).

Example 16 Preparation of 1-Cyclopropyl-5-hydroxymethyl-6-fluoro-7-amino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-Cyclopropyl-5 in an autoclave Hydroxymethyl-6,7-difluoro-1,4-dihydro-4-
4 mg of oxoquinoline-3-carboxylic acid and 2 ml of N-methyl-2-pyrrolidone were added, and further saturated with ammonia gas, and reacted at 100 ° C. for 20 hours. The reaction mixture was poured into ice water, and the crystals were collected by filtration and dried to obtain 1.5 mg (37.5%) of the above target compound as a pale yellow powder.

NMR (CDCl ₃ ) δ ppm; 1.10.
-1.20 (m, 2H), 1.25-1.40 (m, 2
H), 3.60-3.75 (m, 1H), 4.85.
(T, 1H, J = 6.20 Hz), 4.90-5.05
(M, 2H), 6.82 (s, 2H), 7.40 (d,
1H, J = 7.96Hz), 8.59 (s, 1H), 1
5.66 (s, 1H).

Example 17 1-Cyclopropyl-5-hydroxymethyl-6-fluoro-7- (3-methyl-1-piperazyl) -1,4-
Preparation of dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5-hydroxymethyl-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid (11 mg) was suspended in acetonitrile (3 ml), 2-methylpiperazine (15 mg) was added, the mixture was refluxed for 18 hours, and acetonitrile was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography (methylene chloride:
Purified by methanol = 10: 1, 13 mg (9
(2.9%) of a pale yellow powder was obtained, which was then recrystallized from methanol to obtain 6.6 mg of the above objective compound as pale yellow needle crystals.

Melting point: 212-214 ° C. NMR (CDCl ₃ ) δ ppm; 1.05 (d, 3H,
J = 6.20 Hz), 1.10-1.45 (m, 4
H), 2.70-3.10 (m, 5H), 3.40-
3.70 (m, 2H), 3.75-3.90 (m, 1
H), 4.82 (t, 1H, J = 6.60 Hz), 4.
95-5.10 (m, 2H), 7.55 (d, 1H, J
= 7.98 Hz), 8.70 (s, 1H).

Example 18 1-Cyclopropyl-5-methyl-6-fluoro-7-
(3-Methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added to S. D. Orally administered to male rats (body weight: 135-150 g, age 5 weeks, static cooperative, n = 5) at a dose of 40 mg / kg, placed in a metabolic cage immediately after administration, and excreted spontaneously by 24 hours after administration. Collected urine. In addition, 1-cyclopropyl-5-methyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4- was added to rats in which the common bile duct was cannulated under ether anesthesia in advance. After oxoquinoline-3-carboxylic acid was orally administered at a dose of 40 mg / kg, the oxoquinoline-3-carboxylic acid was fixed in a Ballman cage, and bile excreted by 24 hours after the administration was collected. The administration liquid was distilled for injection into 1-cyclopropyl-5-methyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid bulk powder. Water was added and dissolved to give an aqueous solution having a concentration of 8 mg / ml, which was forcibly orally administered using a rat sonde. Fast before administration 1
From 6 hours to 4 hours after administration, during the other period, the rats were allowed to freely ingest the rat solid diet (MF, oriental yeast). Also, water was freely available during all periods.

Urine collected was Amberlite XAD-2.
After charging the column packed with (200 g), washed with distilled water (400 ml), 50% methanol (400 m
It was eluted with l). The 50% methanol fraction was concentrated under reduced pressure, redissolved in 50 ml of water, and washed twice with ethyl acetate (50 ml) under neutral conditions. The aqueous layer was adjusted to pH 7.0 with 1N-sodium hydroxide aqueous solution and then concentrated to give acetonitrile-water-acetic acid (35: 65: 1, as a mobile phase).
retention time 1 by HPLC using v / v / v)
6.5 to 17.5 minutes (fraction I) were separated and purified. HPL
510 type pump (manufactured by Waters) as a device of C,
Using a U6K type injector (manufactured by Waters),
For detection, a SPD-6A type UV detector (280 nm, manufactured by Shimadzu Corporation) and an RF-535 fluorescence detector (Ex28) are used.
5 nm, Em 448 nm, manufactured by Shimadzu Corporation. As a column, TSKgel ODS-80T
M (inner diameter 7.8 mm × 30 cm, manufactured by Tosoh Corporation) was used. Fraction I obtained above was concentrated under reduced pressure to give a 4'-sulfate compound (ie, 1-cyclopropyl-5-methyl-6-fluoro-7- (4-sulfo-3) as a colorless oil. -Methyl-1-piperazyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid) was obtained.

The bile was diluted 10 times with distilled water, charged with Amberlite XAD-2 (200 g), washed with distilled water (400 ml), and then washed with 50% methanol (40 g).
0 ml). The 50% methanol fraction was concentrated under reduced pressure, redissolved in 50 ml of water, and washed twice with ethyl acetate (50 ml) under neutral conditions. After the aqueous layer was concentrated under reduced pressure, acetonitrile-water-acetic acid (4
HPLC (H: 0: 60: 0.2, v / v / v)
PLC conditions are the same as above) and retention time is 1
0.0 to 10.5 minutes (fraction II) were separated and purified. Fraction II was concentrated under reduced pressure to give a 3-glucuronide compound as a colorless oil (ie, 1- [1-cyclopropyl-5-methyl-6-fluoro-7- (3-methyl-1-piperazyl)). -1,4-Dihydro-4-oxoquinolin-3-yl] carbonyl-β-D-glucopyranosideuronic acid)
Got

Antibacterial Test In order to investigate the antibacterial activity of the test compounds shown below against various bacteria, the minimum growth inhibitory concentration was determined by the agar dilution plate method [Chemotherapy, 22 , 11].
26-1128 (1974)]. The results obtained are shown in Table 1. The various bacteria were 1 × 10 6 bacteria / ml (O.
D. 660 mμ, diluted 0.07 to 0.16 100 times).

[Test compound] 1.1-Cyclopropyl-5-methyl-6-fluoro-
7-amino-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 2.1-cyclopropyl-5-methyl-6-fluoro-
7-[(2-aminopropyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 3.1-Cyclopropyl-5-methyl-6-fluoro-
7-[(2-aminoethyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 4.1-Cyclopropyl-5-methyl-6-fluoro-
7-[(2-formylaminoethyl) amino] -1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid 5.1-Cyclopropyl-5-methyl-6-fluoro-
7- (3-Methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester [Strain name] A: S. aureus FDA 209P B: P. aeruginosa E-2

[0114]

[Table 1]

Formulation Example 1 1-Cyclopropyl-5-methyl-6-fluoro-7-amino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 mg Glucose 250 mg Distilled water for injection Total amount 5 ml 1-Cyclopropyl-5-methyl-6- in distilled water for injection
After dissolving fluoro-7-amino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and glucose, the mixture was poured into a 5 ml ampoule, and after nitrogen substitution, heat sterilization was performed at 121 ° C. for 15 minutes, An injection having the above composition was obtained.

Formulation Example 2 1-Cyclopropyl-5-methyl-6-fluoro-7-[(2-aminopropyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride 100 g Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.) 40 g Konstarch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose (TC-5, manufactured by Shin-Etsu Chemical Co., Ltd.) 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 40 g 1-Cyclopropyl- 5-methyl-6-fluoro-7-
[(2-Aminopropyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride, Avicel, corn starch and magnesium stearate were taken, and after mixed polishing, tableted with a sugar coated R10 mm kine. . The obtained tablets are TC-5, polyethylene glycol-600.
A film-coated tablet having the above composition was produced by coating with a film-coating agent consisting of 0, castor oil and ethanol.

Formulation Example 3 1-Cyclopropyl-5-methyl-6-fluoro-7-[(2-aminoethyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 2 g Purified lanolin 5 g Sarah beeswax 5 g White petrolatum 88 g Total amount 100 g Sarah beeswax is heated to form a liquid, and then 1-cyclopropyl-5-methyl-6-fluoro-7-[(2-
Aminoethyl) amino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloride, purified lanolin and white petrolatum are added, and the mixture is heated until it becomes liquid and then stirred until it begins to solidify. An ointment having the composition was obtained.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display area C07D 215: 00 7019-4C 309: 00) 6701-4C

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents a lower alkyl group which may have a halogen atom, a hydroxyl group or a lower alkanoyloxy group at the 1-position of alkyl as a substituent. X represents a halogen atom. R ² is an amino group, a halogen atom, an amino group-substituted lower alkylamino group or a group which may have a hydroxyl group, a lower alkoxycarbonyl group or a lower alkanoyl group as a substituent of the amino group. (R ³ represents a carboxyl group, a lower alkyl group or a hydroxy lower alkyl group, and R ⁴ represents a hydrogen atom or a hydroxysulfonyl group). R is a hydrogen atom, a lower alkyl group or a group Indicates. However, R represents a hydrogen atom or a lower alkyl group,
When R ¹ represents a lower alkyl group, R ² is a halogen atom or a group in which R ³ is a lower alkyl group and R ⁴ is a hydrogen atom. Must not be ] The benzoheterocyclic compound represented by these, or its salt.