JPS61100568A - Benzohetero-ring compound - Google Patents

Abstract

NEW MATERIAL:The benzo-heterocyclic compound of formula I [R is halogen or group of formula II (R<2> is H or lower alkyl); R<1> is OH or lower alkoxy; X is halogen] or its salt. EXAMPLE:6,7-Difluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxo-qui-noline- 3-carboxy-lic acid. USE:It has remarkable antibacterial activity against Gram-negative bacteria and Gram- positive bacteria such as Pseudomonas aeruginosa, anaerobic bacteria, etc., and is useful as a remedy for diseases caused by the above bacteria. It can be used also as an antibacterial agent having low toxicity and weak side effect and usable also as an external disinfectant and sterilizer for medical tools. etc. PREPARATION:The compound of formula Ia which is one of the compound of formula I can be prepared by hydrolyzing the compound of formula III (X<1> is halogen; R<4> is lower alkyl) by conventional method. If necessary, the product is converted to the compound of formula Ib which is another form of the compound of formula I by reacting with the compound of formula 11 in an inert solvent.

Description

[Detailed Description of the Invention] Ll””S L1 degree! The present invention relates to a novel benzoheterocyclic compound or a salt thereof.

The benzoheterocyclic compound of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). .

(R2 is a hydrogen atom or a lower alkyl group), R1 is a hydroxyl group or a lower alkoxy group, and X is a halogen atom. ] The benzoheterocyclic compound represented by the above general formula (1) and its salt exhibit excellent antibacterial activity against a wide range of Gram-negative bacteria and bacteria, and are effective against various diseases caused by bacteria such as humans, animals, and fish. It is useful as a therapeutic agent for diseases such as, and is also useful as an external disinfectant or disinfectant for medical instruments.

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

Lower alkyl groups include methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
An example is a straight or branched alkoxy group in No. 6.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

The compound of the present invention represented by the above general formula (1) can be produced by various methods, and one preferred example thereof is produced by the method shown below.

[Reaction Scheme-1] t) (lO) (1&) [In the formula, R3, RA, R5, Re, R7 and R8 each represent a lower alkyl group. XI, X2 and x3 each represent a halogen atom. R1 and X are the same as above.

] The halogenation reaction of the compound of general formula (2) is carried out by reacting it with a halogenating agent in the presence or absence of a suitable solvent. Solvents used here include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran, and diethyl ether, and dimethylformamide. (DM
F), dimethyl sulfoxide (DMSO), and the like. As the halogenating agent, a usual halogenating agent that can convert the hydroxyl group of a carboxyl group into a halogen can be used. Ru. The ratio of compound (2) and halogenating agent to be used is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out without a solvent, the latter is usually used in a large excess of the former. In addition, when the reaction is carried out in a solvent, the latter is usually used in an amount equal to at least 1 molar amount of the former, preferably 2 to 4 times the molar amount of the latter. The reaction temperature and reaction time are also not particularly limited, but are usually carried out at room temperature to about 100°C for about 30 minutes to 6 hours.

The reaction between the compound of general formula (3) and the compound of general formula (4) is carried out in a suitable solvent in the presence of a basic compound.

Any solvent can be used as long as it does not affect the reaction, but examples include water, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, benzene, toluene, xylene, etc. Aromatic hydrocarbons, aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane, and ligroin, amines such as pyridine, N,N-dimethylaniline, and halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride. ,DMF.

DMSO, hexamethylphosphate triamide (HMPA)
or a mixed solvent thereof. Basic compounds that can be used include sodium metal, potassium metal, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc., non-sodium bases, sodium methylate, Examples include metal alcoholades such as sodium ethylate, and aqueous bases such as pyridine, helidine, quinoline, triethylamine, and N,N-dimethylaniline. The reaction temperature is usually O~1
The temperature is preferably 50°C, preferably around V temperature to 120°C, and the reaction is generally completed in about 0.5 to 15 hours. Regarding the usage of the compound of general formula (4) relative to the compound of general formula (3), it is generally preferable to use at least an equimolar amount of the latter with respect to the former, preferably twice the molar amount to equimolar. The amount of the basic compound to be used is preferably at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (5).

The CORG removal reaction of the compound of general formula (5) is carried out in an appropriate solvent in the presence of a basic compound.

Examples of the solvent used here include diethyl ether, dioxane, tetrahydrofuran, monoglyme,
Ethers such as diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, n-hexane, heptane,
Aliphatic hydrocarbons such as cyclohexane, OMF, DMS
Examples include aprotic polar solvents such as Oll-IMPA. Examples of m-based compounds include ammonia (gas), ammonium salts such as ammonium chloride, and primary or secondary amines such as ethylamine, diethylamine, and piperidine. The reaction temperature is usually 0 to 150°C, preferably room temperature to around 100°C, and the reaction is generally 1 to 20°C.
It will finish in about an hour.

Then, the resulting C0Ra-depleted compound and the general formula (6
) with the compound is carried out by reacting both in an appropriate solvent. As the solvent used here, any solvent used in the above-mentioned CORG removal reaction can be used. The reaction temperature is usually around 0 to 150'C1, preferably around 0 to 100'C, and the reaction is generally 0 to 150'C1.
It will be completed in about 5 to 10 hours. The compound of general formula (6) is used in a large excess, usually equimolar to the amount of the compound of general formula (5), preferably equimolar to 2 times the molar amount.

The reaction between the compound of general formula (7) and the compound of general formula (8) is carried out by reacting the two in a suitable solvent. As the solvent used here, any solvent can be used as long as it does not affect the reaction, such as ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, zig'lime, n-
Aliphatic hydrocarbons such as hexane, heptane, cyclohexane, ligroin, halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, DMF, DMSOl
Examples include aprotic polar solvents such as HMPA.

The reaction concentration is usually 0 to 150°C, preferably room temperature to 100°C.
The temperature is preferably around 0°C, and the reaction is generally completed in about 0.5 to 5 hours. The amount of the compound of general formula (8) to be used is at least equimolar, preferably twice the molar equivalent of the compound of general formula (7).

The ring reaction of the compound of general formula (9) is carried out in a suitable solvent in the presence of a basic compound. As the solvent used here, any solvent can be used as long as it does not affect the reaction, such as ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, and fatty acids such as n-hexane, heptane, and ligroin. Group hydrocarbons, halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, DMF, DMSOlHMP
Examples include aprotic polar solvents such as A and the like. Basic compounds that can be used include radio bases such as sodium metal, potassium metal, sodium hydride, sodium amide, sodium hydroxide, and potassium hydroxide; metal alcoholades such as sodium methylate and sodium ethylate; Examples include organic bases such as 8-diazabicyclo(5,4,O)undecene-7 (DBU), N-benzyltrimethylammonium hydroxide, and tetrabutylammonium hydroxide.

The reaction temperature is usually 0 to 150°C, preferably air temperature to 12°C.
The temperature is preferably around 0°C, and the reaction is generally completed in about 0.5 to 5 hours. The amount of basic compound used is based on the general formula (
The amount is usually at least equimolar, preferably twice equimolar, relative to the compound (9).

For the hydrolysis reaction of the compound of general formula (10), any usual hydrolysis reaction conditions can be applied, and specifically, for example, basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, sulfuric acid, etc. , mineral acids such as hydrochloric acid and nitric acid, alcohols such as acetic acid and aromatic sulfonic acids, water, alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, dioxane, and ethylene glycol. The reaction is carried out in an ether such as fur, a solvent such as acetic acid, or a mixed solvent thereof. The reaction usually proceeds in a room at a temperature of 1 to 200°C, preferably around 50 to 150°C, and is generally completed in about 0.5 to 6 hours. In this way, a compound of general formula (1a) is produced.

[Reaction Scheme-2] <IL) [In the formula, R1, R2, X and Xl are the same as above. ] In the reaction between the compound of general formula (1a) and the compound of general formula (11), the ratio of the two used is not particularly limited and can be appropriately selected from a wide range, but usually the latter is at least equimolar to the former, Preferably, it is used in an equimolar amount to about 5 times the molar amount. The reaction is carried out using an inert solvent, specifically water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, and isoamyl alcohol, aromatic hydrocarbons such as benzene, toluene, and xylene, tetrahydrofuran, and dioxane. , ethers such as diglyme,
This is carried out in a solvent such as DMF, DMSO, H, MPA, or N-methylpyrrolidone. Among these, DMF, DMS
O.

HMPA and N-methylpyrrolidone are preferred.

The reaction may also be carried out in the presence of a deoxidizing agent, specifically inorganic carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and tertiary amines such as pyridine, quinoline, and triethylamine. can. The reaction is usually carried out under a pressure of 1 to 20 atm, preferably 1 to 10 atm, at a temperature of about 100 to 250°C, preferably 100 to 200°C.
It is carried out at a temperature of 0.degree. C. and generally takes about 1 to 20 hours.

[Reaction Scheme-3] [In the formula, R and X are the same as above, and R1' represents a lower alkoxy group. ] The reaction for converting the compound of general formula (1C) into the compound of general formula (1d) is carried out without a solvent or by reacting with an acid in a suitable solvent. Examples of solvents include water, aromatic hydrocarbons such as nitrobenzene, toluene, and benzene, saturated hydrocarbons such as hexane and octane, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as dioxane and tetrahydrofuran. , ketones such as acetone, acetic acid, acetonitrile, and mixed solvents thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, carboxylic acids such as p-toluenesulfonic acid, pyridine p-toluenesulfonate, acetic acid, and propionic acid, aluminum chloride, tin chloride, and boron fluoride. , zinc chloride, boron tribromide, boron trichloride, and the like. The amount of such acid to be used is preferably at least equimolar or more, usually in large excess, relative to compound (1C). The reaction temperature is usually -30 to 200
℃, preferably about -30 to 150℃, and the reaction is generally completed in about 0.5 to 8 hours.

Furthermore, among the compounds of general formula (10) in Reaction Scheme-1, compounds in which R1 is a lower alkoxy group can be prepared under the same reaction conditions as above, where R1 is water Il! can be derived from a compound that is a group.

(Reaction Scheme-4) [In the formula, R1 and The reaction is carried out in a suitable solvent in the presence of a dehydrohalogenating agent.As a solvent, water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, and diethyl ether are used. , ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, etc. As dehydrohalogenating agents, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium, potassium carbonate, etc. and various bases such as pyridine and piperidine can be used respectively.The compound of general formula (1e) is usually used in equimolar to large excess, preferably about 1 molar excess, relative to the compound of general formula (12). ~
3 times molar amount is used. The reaction is usually completed at room temperature to 150°C, preferably around 50 to 120°C, in about 1 to 12 hours.

[Reaction Scheme-5] (II) [In the formula, R1 and X are the same as above. R9 and RIIl each represent a hydrogen atom or a lower alkyl group. ] General formula (
The reaction between the compound of 1e) and the compound of general formula (13) is
It is carried out without a solvent or in a suitable solvent in the presence of a reducing agent.

Examples of the solvent used here include water, alcohols such as methanol, ethanol, and isopropanol, ethers such as acetic acid, dioxane, diethyl ether, diglyme, and tetrahydrofuran, benzene, xylene,
Examples include aromatic hydrocarbons such as toluene.

Examples of reducing agents include hydroxide reducing agents such as formic acid, sodium boron hydroxide, sodium cyanoborohydride, lithium aluminum hydroxide, and catalytic reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel. can. When formic acid is used as a reducing agent, the reaction temperature is usually room temperature to 200°C, preferably around 50 to 150°C, and the reaction is completed in about 1 to 10 hours.

It is preferable to use formic acid in a large excess amount relative to the compound of general formula (1e). Further, when a hydrogenation reducing agent is used, the reaction temperature is usually -30 to 100°C, preferably about 0 to 70'C, and the reaction is completed in about 30 minutes to 12 hours. The reducing agent is preferably used in an amount equivalent to 20 times, preferably 1 to 5 times the amount of the compound of general formula (1e). Particularly when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme, and aromatic hydrocarbons such as benzene, toluene, and xylene as the solvent. When using a catalytic reducing agent, the normal straightening time is ~20
The reaction is preferably carried out in a hydrogen atmosphere at atmospheric pressure, preferably normal pressure to 10 atm, at a temperature of usually -30 to 100C, preferably 0 to 60C, and the reaction is usually completed in 1 to 12 hours.

The amount of the catalyst to be used is usually 0.1 to 40% by weight, preferably 1 to 20% by weight, based on the compound of general formula (1e). The amount of the compound of general formula (13) to be used is usually a small amount (equimolar, preferably equimolar to large excess) relative to the compound of general formula (1e).

The compound represented by the general formula (1) of the present invention can be easily formed into 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, and acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. As a basic compound,
Examples include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium hydrogen carbonate.

The compound of the present invention thus obtained can be easily isolated by conventional separation means. [1! I can do 1m. As the separation means, for example, a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, a pre-variety Wi-layer chromatography, etc. can be employed.

Among the compounds of the present invention, the compound of general formula (1b) or a salt thereof is particularly suitable for Pseudomonas aeruginosa, anaerobes, 5taphVlococcus aureus and staph.
They have remarkable antibacterial activity against Gram-negative and Gram-positive bacteria such as Phytococcus pyogenes, and are useful as antibacterial agents against diseases caused by these bacteria.These compounds are also characterized by low toxicity and weak side effects. It also has

Among the compounds of the present invention represented by general formula (1b), those in which the lower alkyl group represented by R2 is a methyl group or an ethyl group are preferred, and those in which the lower alkyl group represented by R2 is a methyl group are most preferred. Further, the halogen atom represented by X is preferably a chlorine atom or a fluorine atom, and most preferably a fluorine atom.

The compounds of the invention are normally used in the form of common pharmaceutical formulations. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, full-fill formulations, injections (liquids, suspending agents, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, grape mucilage, starch liquid, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone,
Dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cocoa butter, Disintegration inhibitor III such as hydrogenated oil, absorption enhancer such as quaternary ammonium base, sodium lauryl sulfate, humectant such as glycerin, starch, adsorbent such as starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Examples include purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multi-beta tablets. When forming into an emulsion, a wide variety of carriers conventionally known in this field can be used, such as glucose, lactose, starch, cocoa butter, etc. Examples include excipients such as hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminalan agar. When molding into a fully opened form, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When E1m is manufactured as an injection, liquid, emulsion and! ! ? ! The suspending agent is preferably sterilized and isotonic with blood, and when forming these into the form of solutions, emulsions and ff1i preparations, all diluents commonly used in this field can be used, such as water. , ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxydiethylene sorbitan fatty acid esters, and the like. In this case, sufficient amounts of salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, as well as common solubilizing agents. ! ! ! Agents, soothing agents, etc. may be added. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The amount of the compound of general formula (1) or its salt to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 701i% by weight based on the total composition. Good.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and the administration method is determined depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, gunpowder, liquid,
Suspensions, emulsions, granules and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and further, if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. If fully dilated, it is administered rectally.

The dosage m of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually determined per body weight per day. It is best to set it at about 0.2 to 1oon per kg.
The formulation can be administered in 2 to 4 divided doses per day.

9-English-1 Below are reference examples, examples, antibacterial test results, and formulation examples.

Reference Example 1 70 mIQ of thionyl chloride was added to 39.5Q of 2-promo-4,5-difluorobenzoic acid, left to stand at room temperature for 1 hour, and then heated under reflux for 1 hour. After completion of the reaction, excess thionyl chloride was distilled off under reduced pressure, and the residual oil was distilled under reduced pressure to obtain 37.80 of 2-promo-4,5-difluorobenzoyl chloride as a pale yellow oil with a bp of 121 to 123'C (32 mm H1). .

Reference example 2 Ethyl acetoacetate 13. Oa, ligroin 16-
While stirring a mixed solution of 32- and water under water cooling, 33%
Add 4.4 ml of aqueous sodium hydroxide solution. 2 more
-Promo 4,5-dihydrobenzoyl chloride 25.
A solution of 6G dissolved in ligroin 14- and a 33% aqueous sodium hydroxide solution 18- are added to the water-cooled and stirred bodies. After the addition is complete, stir at room temperature for 14 hours. The precipitated product is taken out, washed with water, and the furnace solution is made weakly acidic with ammonium chloride, followed by extraction with dichloromethane. The collected precipitated crystals are dissolved in methanol 200WIJ, ammonium chloride 20Q is added, and the mixture is stirred at room temperature for 1 hour, and then extracted with dichloromethane. Combine with the dichloromethane extract and dry over sodium sulfate. The solvent was distilled off to obtain 30.1 Gl of ethyl 2-acetyl-2-(2-promo-4,5-difluorobenzoyl)acetate as a yellow oil.

NMR (CDCQs) δ: 17.20 (bs, IH) 7.38 (dd, IH, J-9Hz, 7Hz)
7, 10 (dd, IH, J-9, 5Hz, 8
．． 5Hz) 3.97 (Q, 2H%J-6H2) 2.53 (s, 3H) 1.93 (t, 38%J-6Hz) Reference Example 3 and ethyl 2-7 cetyl 2-(2-promo 4 24.30% of 5-difluorobenzoyl)acetate was dissolved in 5019 anhydrous ether, and ammonia gas was slowly passed through the solution for 45 minutes while cooling with water. Then leave it at room temperature for 17 hours.
Dichloromethane and water are added to the reaction mixture, acidified with 1N hydrochloric acid, the dichloromethane layer is separated, the dichloromethane solution is washed with saturated sodium chloride solution, and then dried over sodium sulfate. After evaporation of the solvent, 65 ml of anhydrous benzene was added to the resulting residue, and then 1 ml of DMF dimethyl acetal was added to the resulting residue.
Add 1- and heat under reflux for 2 hours. The solvent was distilled off, and the resulting residue was separated using silica gel column chromatography (eluent: dichloromethane:methanol-80:1') to obtain 9.0 g of ethyl orange oil.
(2-promo-4,5-difluorobenzoyl)-3-
Dimethylaminoacrylate is obtained.

NMR (CDCQs) δ Near, 83 (s, IH) 7.33 (dd, 1H1J-9Hz, 8.5Hz - 7.19 (dd, IH, J-11Hz, 8.5Hz)
) 3.94 (Q, 2H, J-7H2) 3.30 (bs
, 3H) 3.02 (bs, 3H) 1.95 (t, 3H, J-7H2) Reference Example 4 Ethyl 2-(2-promo 4,5-difluorobenzoyl)-3-dimethylaminoacrylate 2.18a and 0.9a of p-anisidine is dissolved in 12m of anhydrous benzene and stirred at room temperature for 2 hours.

After the reaction is completed, the benzene layer is separated, washed with dilute hydrochloric acid and saturated saline in that order, and dried over sodium sulfate.

The solvent was distilled off, and the resulting residue was separated by silica gel column chromatography (eluent: dichloromethane) to yield a 2.09G yellow solid, mp.

Ethyl 2-(2-promo 4°5-
(difluorobenzoyl)-3-p-7 nisidinyl acrylate is obtained as a mixture of trans:cis (3:1).

Reference Example 5 Cis-trans mixture ethyl 2 obtained in Reference Example 4
-(2-promo4,5-difluorobenzoyl)-3
-p-7 Nisidinyl acrylate 2.040 was dissolved in anhydrous dioxane 4o-, 60% sodium hydride 0.2
40 and stirred at room temperature for 1 hour. Heat and reflux for an additional hour. After cooling, the reaction solution was poured into a saturated ammonium chloride aqueous solution under water cooling, and the precipitated crystals were collected, washed with water, and purified with silica gel column chromatography (eluent: dichloromethane:methanol-80:1).

Thereafter, it is recrystallized from ethanol to obtain ethyl 6°7-difluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate 1.40a.

mp, 212-214°C Colorless needles Example 1 Ethyl 6.7-difluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxo-quinoline-3
-carboxylate 0.61a, 90% vinegar, oa
T and Hi concentrated salt 1! ! 2. Heat and stir at 110°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was thoroughly washed with water to give 0,54Q(1)6.7-7/L+O0-1-(4-methoxyphenyl)-1, 4
-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained.

rrl, 256-258°C Colorless needles Example 2 Ethyl 6.7-difluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxo-quinoline-3
-carboxylene) -0,70c+ 148
Add 8% hydrochloric acid and stir at 100-110°C for 3 hours. After cooling, remove the precipitated product and wash with water.

Recrystallized from dichloromethane-ethanol to give 0.57
g of 6,7-difluoro-1-(4-hydroxyphenyl)-1,4-dihydro-4-oxo-quinoline-3-
Obtain carboxylic acid.

ff1.288-290°C Colorless needle crystal Example 3 6.7-difluoro-1-(4-hydroxyphenyl)
-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 0.220 was suspended in DMSO10, N-methylbiperazine 0.391112 was added, and the mixture was heated at 110°C for 3 hours.
．． Stir for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was washed with ethanol and recrystallized from DMF to give 0.2
3g 6-fluoro-1-(4-hydroxyphenyl)
-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-3-carboxylic acid is obtained.

ml), pale yellow prismatic crystals NMR (CF 3 COOH) δ: 9.22 (s
llH) 8.34 (d, 1H1J-12Hz) 7°48 (
d, 2H, J-9Hz) 7.32 (d, 2H, J-
9Hz >6.90 (d, IH, J-6H2) 4.20-3.26 (m, 8H) 3.16 (d, 3H, J-5Hz) Appropriate starting under conditions similar to Example 3 The following compounds are obtained using the raw materials.

Example 7 Rhofluoro 1-(4-methoxyphenyl)-7-(
1-piperazinyl)-1,4-dihydro-4-oxo-
20111111 of a DMF solution containing 7.7 g of methyl iodide is added to 4.14 g of 3-carboxylic acid and 29 ml of DMF. The mixture is heated in a stainless steel autoclave on an oil bath at 110-120°C for 5 hours. DM
F is distilled off under reduced pressure, and a 10% aqueous sodium hydroxide solution is added to the residue to adjust the pH to 13. After removing insoluble materials, acetic acid was added to adjust the pH to 8, the precipitated crystals were collected, washed with water,
Dry and recrystallize from ethanol to obtain 6-fluoro-1
-(4-methoxyphenyl)-7-(4-methyl-1-
piperazinyl)-1,4-dihydro-4-oxo-3-
1.80 I of carboxylic acid.

mp, 236-238° C. Colorless needle crystals The compound of Example 3 is obtained in the same manner as in Example 7 using appropriate starting materials.

Example 8 6-fluoro-1-(4-methoxyphenyl)-7-(
1-piperazinyl)-1,4-dihydro-4-oxo-
3-Carbon! Add 48% hydrogen bromide 18 to 10.770 and stir at 100 to 110°C for 3 hours. After cooling, filter out the precipitate, wash with water, and add 15 tl of saturated sodium hydrogen carbonate.
Suspend the mixture to 12 fl and stir at a steady temperature for 30 molar gJ. The precipitated crystals were washed at the bottom of the furnace, washed with water, and recrystallized from DMF to give 6-fluoro-1-(4- and droxyphenyl)-7-(1-piperazinyl)-124-dihydro-4-oxo-3-carvone. Obtain iu0.5a.

mp, 302-304°C Pale yellow prismatic crystals The compound of Example 3 is obtained in the same manner as in Example 8 using appropriate starting materials.

Example 9 6-fluoro-1-(4-methoxyphenyl)-7-(
1-piperazinyl)-1,4-dihydro-4-oxo-
3-carboxylic acid 0.79Q under water cooling at 90% of 4vA
The mixture was slowly added to a mixed solution of formic acid and 4 ml of 37% formalin, and after the addition was completed, the mixture was heated under reflux for 5 hours. The reaction solution was dried under reduced pressure, and saturated sodium hydrogen carbonate water was added to the residue. 1
The mixture was suspended at 115°C and stirred at air temperature at 309°C. The precipitated crystals are washed at the bottom of the furnace, washed with water, and then dried. Recrystallized from ethanol to give 6-fluoro-1-(4-methoxyphenyl)-7-
110.50 of (4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-3-carvone are obtained.

mp, 236-238° C. Colorless needle crystals The compound of Example 3 is obtained in the same manner as in Example 9 using appropriate starting materials.

[Antibacterial test]

CCHEMOTHERAPY, 22.1126-112 In order to investigate the antibacterial effects of the test compounds shown below against various bacteria, the minimum growth-inhibiting concentration was determined by the agar dilution plate method.
8 (1974)], the results obtained are shown in Table 1.

For each type of bacteria, the number of bacteria is 1 x 1011 bacteria/mfJ (0, D, 6
60mμ, 0.07-0.16) and lX10B bacterial count/
m (100-fold dilution).

(Test compound) No, 1 6-fluoro-1-(4-hydroxyphenyl)-7-(4-methyl-1-piperazinyl)-1,4
-Dihydro-4-oxo-3-carboxylic acid Formulation Example 1 Compound of Example 6 200111! Glucose 250mg injection, distilled water fit
51119 After dissolving the compound of Example 6 and glucose in distilled water for injection 51
Pour into a 11Q ampoule and heat at 121°C for 15 minutes after replacing with nitrogen.
Autoclave sterilization is performed for a minute to obtain an injection having the above composition.

Formulation Example 2 Compound of Example 3 100a Avicel (
Trade name: Asahi Kasei Corporation) 40Q Cornstarch
3 (1 stearin magnesium
2gTC-5 (trade name, Shin-Etsu Chemical 10Q
Co., Ltd., Hydroxypropyl Methyl Cellulose) Polyethylene Glycol-60003Q Castor Oil
40g ethanol
4C1 The compound of Example 3, Avicel, cornstarch, and stearic magnesium were mixed, polished, and then tableted using a sugar-coated R10wm+ machine. T
C-5, polyethylene glycol-6000, castor oil, and ethanol are coated with a film coating agent to produce film-coated tablets having the above composition.

Formulation Example 3 Compound of Example 5 2Q purified lanolin 5g white beeswax
5g Vaseline
88g total m 1
00CJ white beeswax is heated to make it liquid, and then - Add the compound of Example 5, purified lanolin, and white petrolatum, and after heating until it becomes liquid, stir until it starts to solidify to make an ointment with the above composition. obtain.

Formulation example 4 Compound of Example 3 (hydrochloride) 200m.

Glucose 250g.

Distilled water for injection 11
5II2 The compound of Example 3 and glucose are dissolved in distilled water for injection, then poured into a five-precept ampoule, and after nitrogen substitution, autoclaving is performed at 121° C. for 15 minutes to obtain an injection having the above composition.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is a halogen atom or R^2 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Group (R^2 is a hydrogen atom or a lower alkyl group) , R^1 represents a hydroxyl group or a lower alkoxy group, and X represents a halogen atom. ] A benzoheterocyclic compound or a salt thereof.