JPS6232194B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel piperazinyl benzoheterocyclic derivatives. For more details, refer to the present invention or the general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. R ² represents a hydrogen atom or a halogen atom. -A- represents -CH ₂ -CHR ³ - (R ³ is a hydrogen atom or a lower alkyl group). ] or a salt thereof. The compound of the present invention has low toxicity and excellent antibacterial activity, and is particularly useful as a therapeutic agent for diseases caused by various bacteria in humans, animals, and fish, as well as as an external disinfectant for medical instruments, etc. It is also useful as a disinfectant. In this specification, lower alkyl groups include straight chain or branched alkyl groups having 1 to 4 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, tert-butyl. Examples include groups. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, and iodine atom. Representative compounds represented by general formula (1) are listed below. Γ9-(1-piperazinyl)-6-oxo-1,
2-dihydro-6H-pyrrolo [3,2,1-ij]
Quinoline-5-carboxylic acid Γ9-(1-piperazinyl)-2-methyl-6-
Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ9-(1-piperazinyl)-2-ethyl-6-
Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ9-(1-piperazinyl)-2-isopropyl-6-oxo-1,2-dihydro-6H- Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ9-(1-piperazinyl)-2-butyl-6-
Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ7-chloro-9-(1-piperazinyl)-6-
Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ8-fluoro-9-(1-piperazinyl)-6
-Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ9-(4-methyl-1-piperazinyl)-2-
Methyl-6-oxo-1,2-dihydro-6H
-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid Γ9-(4-isopropyl-1-piperazinyl)
-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid In the present invention, the compound of general formula (1) is a new compound that has not been described in any literature. , the compound has the general formula [wherein R ⁴ is a halogen atom, R ² and -A-
is the same as above. ] to the benzoheterocyclic derivative represented by the general formula [In the formula, R ⁴ represents a halogen atom. R ² and −
A- is the same as above. ] to the benzoheterocyclic derivative represented by the general formula [In the formula, R ₁ is the same as above. It is easily produced by reacting piperazyl compounds represented by the following formula. The compound of general formula (2) above is a known compound (USP No.
Specification No. 3917609, Specification No. 3896131, Specification No.
Specification No. 3985882, Specification No. 3969463, Specification No.
4001243 and 4014877), or a compound that can be easily produced by the method shown in Reaction Scheme-1 described below. Further, the compound of the above general formula (3) is a known compound or can be easily produced according to a known method. In the reaction between the compound of general formula (2) and the compound of general formula (3), the ratio of the two to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is Equimolar amount or more, preferably equimolar amount or more
It is preferable to use 5 times the molar amount. The reaction is carried out in an inert solvent. Specific examples of such solvents include water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, and isoamyl alcohol, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as tetrahydrofuran, dioxane, and diglyme. Examples include dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and the like. Among these, dimethyl sulfoxide, dimethyl formamide and hexamethyl phosphoric triamide are preferred. The reaction may be carried out in the presence of a deoxidizing agent. Specifically, such deoxidizing agents include sodium carbonate, potassium carbonate, potassium hydrogen carbonate,
Examples include inorganic carbonates such as sodium hydrogen carbonate, tertiary amines such as pyridine, quinoline, and triethylamine. The reaction is usually carried out at 100 to 250°C under a pressure of 1 to 20 atm (preferably 1 to 10 atm).
(preferably 140 to 200°C), and the reaction is generally completed in about 5 to 20 hours. In this way, the compound of the present invention represented by general formula (1) is synthesized. The compound of general formula (2) is, for example, the following reaction scheme-1
It is easily manufactured by the method shown in . Reaction equation 1 [In the formula, R ⁵ and R ₆ each represent a lower alkyl group. R ² , -A- and R ⁴ are the same as above. ] The compound of general formula (4) is a known compound. Further, among the compounds of general formula (4), the compound in which -A- represents -CH ₂ H ₂ - (compound of general formula (9)) can be easily produced by the method shown in the following reaction scheme-2. Reaction equation 2 [In the formula, X′ represents a halogen atom. R ₂ is the same as above. ] The compound of general formula (8) is a known compound or a compound easily obtained according to a known method. A catalytic reduction method, a reduction method using a hydrogenating agent, etc. can be applied to the reduction of the compound of general formula (8). Reduction with a hydrogenating agent is preferred. Examples of the hydrogenating agent include hydrogenating agents prepared by appropriately combining sodium borohydride or lithium aluminum hydride with lower fatty acids such as acetic acid, trifluoroacetic acid, and propionic acid. The amounts of sodium borohydride or lithium aluminum hydride and lower fatty acids to be used are preferably equimolar to excess, preferably 3 to 5 times the molar amount of the compound of general formula (8). The reduction reaction with a hydrogenating agent is carried out in an inert solvent. Specific examples of the inert solvent used include ethers such as dioxane, tetrahydrofuran and diglyme, aromatic hydrocarbons such as benzene and toluene, and lower fatty acids such as acetic acid, trifluoroacetic acid and propionic acid. The reaction is usually carried out at room temperature to 100°C, preferably 50 to 100°C, and is usually completed in about 1 to 6 hours. In this way, a compound of general formula (9) is produced. Further, the compound of general formula (5) is a known compound or a compound easily produced according to a known method. The reaction between the compound of general formula (4) and the compound of general formula (5) can be carried out without a solvent or in a solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc., preferably without a solvent. It will be held in The ratio of compound (5) to compound (4) to be used is usually at least equimolar, preferably equimolar in the reaction without a solvent, and preferably 1.1 to 1.5 times the molar amount in the reaction in a solvent. Good. The reaction temperature is usually about room temperature to 150℃, preferably 100 to 130℃
The reaction is usually completed in 0.5 to 6 hours, and the compound represented by the general formula (6) can be easily obtained. The cyclization reaction of the compound (6) thus obtained can be carried out according to various conventionally known cyclization reactions. Examples include a heating method, a cyclization method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, and polyphosphoric acid. When employing the cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc. is used, and usually 100 to 250
Heating conditions of 150-200°C can be employed. In addition, when an oxidation method using an acidic substance is employed, it is used in an equimolar amount to a large excess, preferably 10 to 20 times the amount of compound (6), and is usually 0.5 to 6 molar at 100 to 150°C.
It is enough to allow the reaction to take place for about an hour. In this way, a compound of general formula (7) is produced. The hydrolysis reaction of compound (7) obtained by the above cyclization reaction can be carried out using a basic compound such as sodium hydroxide, potassium hydroxide or barium hydroxide, a mineral acid such as sulfuric acid, hydrochloric acid or nitric acid, acetic acid, It is carried out in the presence of conventional catalysts such as organic acids such as aromatic sulfonic acids. The reaction generally involves water, methanol,
It is carried out in common solvents such as ethanol, isopropanol, acetone, methyl ethyl ketone, dioxane, ethylene glycol, acetic acid, etc. The reaction temperature is usually room temperature to 200°C, preferably 50 to 150°C. In this way, a compound represented by general formula (2) is easily obtained. Among the compounds of the present invention, compounds in which R ¹ represents a lower alkyl group (represented by the general formula (1b)) are generally combined with compounds in which R ¹ represents a hydrogen atom (represented by the general formula (1a)) in the presence of an oxygen absorber. It can also be produced by reacting a compound of formula (10). [In the formula, R ⁸ represents a lower alkyl group. X" represents a halogen atom. R ² and -A- are the same as above.] Among the compounds represented by the general formula (1) obtained in this way, those having basicity are The acid addition salts may be formed into addition salts, and the present invention also encompasses these acid addition salts.The acid used to form the acid addition salt may be a variety of pharmacologically acceptable organic or inorganic acids, including, for example, Inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and acetic acid, oxalic acid, malonic acid, succinic acid, mayic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, p-tosylic acid, etc. Examples include organic acids.Also, the compound represented by the general formula (1) can be treated with a pharmaceutically acceptable basic compound to form a carboxylic acid salt. Examples of the basic compound used include: Inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, and sodium bicarbonate, and organic basic compounds such as morpholine, piperazine, pyridine, piperidine, ethylamine, dimethylamine, triethylamine, and aniline. The thus obtained compound represented by the general formula (1) and its salt can be easily isolated and purified by a conventional separation method after the completion of the above reaction process. Examples of the separation method include a solvent extraction method. , dilution method, precipitation method,
Examples include recrystallization method, column chromatography, and preparative thin layer chromatography. The compound represented by general formula (1) and its salt exhibit antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria at low concentrations. The compound is effective against Streptococcus, Pseudomonas, etc., for which conventional antibacterial agents have no or only weak antibacterial activity.
It exhibits particularly strong antibacterial activity against Enterobacter, Proteus, etc. In addition, this compound shows strong activity against Escherichia coli and Staphylococcus, which account for a large proportion of the causes of infectious diseases, and also shows sufficient activity against Serratia and Klebscilla, whose infectious diseases have become a problem in recent years. It is a clinically useful compound. As described above, the compound represented by the general formula (1) and its salts have significant characteristics in terms of the antibacterial spectrum and the fact that they exhibit strong antibacterial activity. Furthermore, in the case of conventional compounds with antibacterial activity, their antibacterial activity decreases due to binding with serum, whereas in the case of the compound of general formula (1) and its salts, the antibacterial activity surprisingly decreases. However, the activity tends to be enhanced. This means that when the compound of general formula (1) and its salts are administered to the human body, they exert a strong antibacterial effect in the blood. Also, the oral toxic dose of the compound of general formula (1) and its salts is much lower than the effective oral dose of the compound. Furthermore, the compound has antibacterial activity against bacteria resistant to commonly used antibiotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin, and nalidixic acid. When the compound represented by the general formula (1) and its salt are used as an antibacterial agent, they are usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. I can give an example. Various dosage unit forms of antibacterial agents can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, Examples include injections (solutions, suspensions, etc.), ointments, and the like. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder , disintegrants such as sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as quaternary ammonium chloride and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc,
Examples include lubricants such as stearate, boric acid powder, macrogol, and solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar. Furthermore, tablets may be coated with conventional coatings as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-coated tablets.
It can be a multi-layered tablet. When forming into a suppository, 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 prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, diluents known in the art are used. All commonly used alcohols can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples include polyoxyethylene sorbitate and sorbitan ester. In this case, the antibacterial agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, preservatives, etc. Furthermore, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent, if necessary. When forming into a paste, cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. The amount of the compound of the present invention to be included in the antibacterial agent is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight based on the total composition. Furthermore, there are no particular restrictions on the use of the above-mentioned antibacterial agents, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it can be administered rectally; and in the case of an ointment, it can be applied. The dosage of the compound of the present invention as an antibacterial agent is appropriately selected depending on the purpose of use, symptoms, etc., and usually a pharmaceutical composition containing the compound of the present invention at about 10 mg to 5 g/boby-day is administered in 3 to 4 divided doses. do it. <Antibacterial activity> Antibacterial test In order to investigate the antibacterial activity of the test compounds shown below against various bacteria, the minimum growth-inhibiting concentration was determined by the agar dilution plate method [CHEMOTHERAPY, 22 , 1126-1128 (1974)]
reference〕. The results obtained are shown in Table 1. The number of various bacteria is 1× ¹⁰⁸ bacteria/ml (0.D.660mμ, 0.07-0.16)
and 1×10 ⁶ bacteria/ml (100-fold dilution). (Test bacteria) No.1 Esherichia coli NIHJ No.2 Esherichia coli NIHJ JC-2
(IFO12734) No.3 Klebsiella pneumoniae No.4 Klebsiella pneumoniae ST-101 No.5 Proteus rettgeri NIH 96 No.6 Proteus morganii IID Kono No.7 Proteus vulgaris IID OX-19 No.8 Enterobacter aerogenes IFO 12979 No.9 Enterobacter cloacae No.10 Yersinia enterocolitica 0-3 No.11 Yersinia enterocolitica 0-5 No.12 Hafnia alvei IFO 3731 No.13 Pseudomonas aeruginosa E-2 No.14 Pseudomonas aeruginosa NCTC 10490 No.15 Pseudomonas aeruginosa ATCC 10145 No.16 P seudomonas maltophilia IFO 12692 No.17 Pseudomonas putida IFO 13696 No.18 Salmonella typhi 0-901 (NCTC
8393) No.19 Shigella sonnei EW33 No.20 Serratia marcescens IFO 12648 No.21 Bacillus subtilis PCI 219 No.22 Staphyrococcus aureus FDA 209 P No.23 Streptococcus pyogenes IID S-23 No.24 Streptococcus pyogenes IID Ccck No.25 Streptococ cus pneumoniae Type No.26 Streptococcus pneumoniae Type No.27 Streptococcus pneumoniae Type No.28 Corinebacterium diphteriae (Test compound) Compound A 9-(1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-
6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic hydrochloride compound B 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1- ij] Quinoline-5-carboxylic hydrochloride compound C 1-ethyl-1,4-dihydro-7-
Methyl-4-oxo-1,8-naphthylidene-3-carboxylic acid (nalidixic acid, control compound)

【table】

【table】

[Table] Effect of serum addition Agar medium [Heart infusion agar, manufactured by Difco]
horse serum at final concentrations of 0%, 10%, 20%, and 40%.
An agar plate was prepared by adding the following amounts. The inhibitory effect of the test compound on bacterial growth was measured by the agar plate method [CHEMOTHERAPY,
22 , 1126-1128 (1974)]. The results obtained are shown in Table 2. The number of bacteria is 1× ¹⁰⁸ bacteria/ml and 1
The number of bacteria was adjusted to ×10 ⁶ bacteria/ml.

[Table] Antibacterial activity against bacteria causing fish infectious diseases To investigate the antibacterial activity of the test compound against various bacteria, the minimum growth-inhibiting concentration was determined by the agar dilution plate method. The results obtained are shown in Table 4. Each type of bacteria was adjusted to 1 x 10 ⁸ bacteria/ml and 1 x 10 ⁶ bacteria/ml.

[Table] <Acute Toxicity> The LD ₅₀ values of Compound A and Compound B were determined by intravenous administration to mice and were both 500 mg/Kg or higher. Below, production examples of raw materials for synthesizing the compound of general formula (1) are listed as reference examples, production examples of the compound of general formula (1) are listed as examples, and further formulation examples are listed. Reference example 1 Dissolve 5.5 g of 4-chlorooxindole in 80 ml of dioxane and add 6.2 g of sodium borohydride.
was added to suspend, and then 12.7 ml of trifluoroacetic acid (d-1.48) was added dropwise while stirring at room temperature. After heating under reflux for 4.5 hours, the solvent was distilled off under reduced pressure. Water is added to the residue to remove insoluble matter, and the residue is washed with ether. The liquid was extracted with ether, the ether layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 4-chloroindoline. Yield 3.9g, bp 135℃/10mmHg, colorless oil Reference example 2 4.4g of 2-methyl-4-chloroindole was dissolved in 66ml of pyridine and 5g of sodium borohydride was added.
Add. Finely pulverize 10.6 g of aluminum chloride and add it little by little to this solution while stirring on ice. After addition, stir at room temperature. After reacting at room temperature for 27 hours, the solvent was distilled off under reduced pressure. Add water to the residue and add benzene
Extract with 100ml. After washing the benzene layer with saturated sodium chloride solution, the benzene layer is concentrated. Add 10% hydrochloric acid to the residue, and after foaming has finished, add sodium carbonate solution to neutralize, extract with 100 ml of benzene, and dry over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform) to obtain 3.4 g of 2-methyl-4-chloroindoline. Confirm by NMR. Reference example 3 Add 4.4 g of diethyl ethoxymethylene malonate to 3 g of 4-chloroindoline and heat on oil bath for 40 minutes at 110°C.
Heat at ~120°C. At this time, production of ethanol is observed. Next, 10g of phosphoric acid and 10g of phosphorus pentoxide
Add the polyphosphoric acid prepared by g and place on an oil bath.
Heat at 130-140°C for 40 minutes. After the reaction, cool to 60°C, put into ice water, and neutralize with 10% sodium hydroxide aqueous solution. After removing the precipitated crystals and washing with water 10
Add 50 ml of % sodium hydroxide aqueous solution and heat to reflux on an oil bath. After reacting for 1 hour, it is treated with activated carbon. 9 by making the solution acidic using concentrated hydrochloric acid.
-Chloro-6-oxo-1,2-dihydro-6H
-3.5 g of pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid is obtained. Recrystallized in dimethylformamide. White needle crystals mp307.5°C (decomposed) Reference Example 4 Add 4.4 g of dimethylethoxymethylene malonate to 3.4 g of 2-methyl-4-chloroindoline and heat at 110-120°C for 40 minutes on an oil bath. Next, polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide is added and heated on an oil bath at 130-140° C. for 1 hour. After the reaction, it was cooled to 60℃ and placed in ice water for 10 minutes.
Neutralize with % sodium hydroxide aqueous solution. Collect the precipitated crystals, wash with water, add 50 ml of a 10% aqueous sodium hydroxide solution, and heat to reflux on an oil bath. After reacting for 1 hour, it is treated with activated carbon. By acidifying the solution with concentrated hydrochloric acid, 9-chloro-2-methyl-6
-Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 3.8
get g. Recrystallized from dimethylformamide. White needle crystals mp288-290℃ Example 1 9-chloro-6-oxo-1,2-dihydro-
Add 20 ml of dimethyl sulfoxide to a mixture of 3 g of 6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid and 6 g of anhydrous piperazine, and heat on an oil bath for 140-150 min.
React at ℃ for 6 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of water and dissolved in chloroform.
Shake 100ml, separate the aqueous layer, and treat with activated carbon. Then, acidify with 10% hydrochloric acid. The liquid is treated with activated carbon again and concentrated. Crystals are precipitated by adding ethanol to the concentrate. Recrystallized from ethanol-water to give 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,
2,1-ij] Quinoline-5-carboxylic hydrochloride 1.5
get g. mp300℃ or more. Pale yellow needle-like crystals Example 2 9-chloro-2-methyl-6-oxo-1,2
-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 1.6g and anhydrous piperazine 3
Add 20ml of dimethyl sulfoxide to the mixture of
React for 6 hours at 140-150°C on an oil bath. After the reaction, the solvent is distilled off under reduced pressure, and the residue is dissolved in 50 ml of water, shaken with 100 ml of chloroform, and the aqueous layer is separated and treated with activated carbon. Then, acidify with 10% hydrochloric acid.
The filtrate is treated with activated carbon again and concentrated. Crystals are precipitated by adding ethanol to the concentrate. Recrystallized from ethanol-water to give 9-(1-piperazinyl)2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-
0.9 g of carboxylic hydrochloride is obtained. mp269~273℃
(Decomposition) Pale yellow needle-like crystals Example 3 8,9-dichloro-2-methyl-6-oxo-
1,2-dihydro-6H-pyrrolo[3,2,1-
ij] Using quinoline-5-carboxylic acid and piperazine, treatment was performed in the same manner as in Example 1 to obtain 8-chloro-9.
-(1-Piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,
1-ij] Quinoline-5-carboxylic acid is obtained. mp 258-260℃ Example 4 8,9-dichloro-2-methyl-6-oxo-
1,2-dihydro-6H-pyrrolo[3,2,1-
ij] Quinoline-5-carboxylic acid and 1-methyl-
8 treated in the same manner as in Example 1 using piperazine.
-Chloro-9-(4-methyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5
- Obtain carboxylic acid. mp 273-276℃ Example 5 8-fluoro-9-iodo-2-methyl-6-
Oxo-1,2-dihydro-6H-pyrrolo[3,
2,1-ij] quinoline-5-carboxylic acid and 1-
8-fluoro-9-(4-methyl-1-piperazinyl)-2-methyl-6-oxo-1,2 was treated in the same manner as in Example 1 using methyl-piperazine.
-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid is obtained. mp 242-244℃ Formulation example 1 8-chloro-9-(1-piperazinyl-2-methyl-6-oxo-1,2-dihydro-6H-
Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax is heated to make it liquid, and then the compound of the present invention, purified lanolin and white petrolatum are added. Formulation Example 2: 9-(1-piperazinyl)-6-oxo-1, which is added and heated until it becomes liquid, and then stirred until it begins to solidify to obtain an ointment having the above composition.
2-dihydro-6H-pyrrolo [3,2,1-ij]
Quinoline-5-carboxylic acid hydrochloride 200mg Glucose 250mg Distilled water for injection Appropriate total volume 5ml Dissolve the compound of the present invention and glucose in distilled water for injection, inject into a 5ml ampoule, and inject at 121℃ for 15 minutes after purging with nitrogen. Autoclave sterilization is performed for a minute to obtain an injection having the above composition. Formulation example 3 9-(1-piperazinyl)-2-methyl-6-
Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic hydrochloride 100g Abysiel [trade name, manufactured by Asahi Kasei Corporation] 40g Cornstarch 30g Magnesium stearate 2g TC-5 (Trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) 10g Macrogol-6000 3g Castor oil 40g Methanol 40g The compound of the present invention, Abysiel, cornstarch and magnesium stearate were mixed and coated with sugar after polishing.
Compress the tablets with an R10mm kine. TC-
5. Coat with a film coating agent consisting of polyethylene glycol-6000, castor oil, and methanol to produce film-coated tablets having the above composition.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. R ² represents a hydrogen atom or a halogen atom. -A- represents -CH ₂ -CHR ³ - (R ³ is a hydrogen atom or a lower alkyl group). ] A piperazinyl benzoheterocyclic derivative or a salt thereof. 2 General formula [In the formula, R ² represents a hydrogen atom or a halogen atom. R ₄ represents a halogen atom. -A- is-CH _2-
CHR ³ - (R ³ is a hydrogen atom or lower alkyl group)
shows. ] The benzoheterocyclic derivative represented by the general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. ] A general formula characterized by reacting piperazines represented by [In the formula, R ₁ , R ² and -A- are the same as above. ] A method for producing a piperazinyl benzoheterocyclic derivative represented by