JPS60161987A - Benzoheterocyclic ring derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {R<1> is lower alkyl; R<2> is halogen or formula II [R<4> and R<5> may link mutually through O or N to form (lower alkyl- or OH-substituted) saturated heterocyclic ring]; R<3> is amino or nitro; X is halogen; n is 0 or 1}. EXAMPLE:8-Fluoro-2-methyl-9-( 4-methyl-1-piperazinyl )-7-amino-6-oxo-1, 2-dihydropyrrolo(3,2,1-ij)quinoline-5-carboxylic acid. USE:An antimicrobial agent having low toxicity with little side effect. PREPARATION:For example, a compound expressed by formula III (X<1> is halogen, lower alkanesulfonyloxy, etc.) is nitrated to give a compound expressed by formula IV, which is then reacted with a compound expressed by the formula R<2>H to afford the compound expressed by formula I (R<3> is NO2). The resultant compound expressed by formula I (R<3> is NO2) is then reduced to give the compound expressed by formula I (R<3> is NH2).

Description

[Detailed description of the invention] 1! The present invention relates to a novel benzoheterocyclic derivative, a salt thereof, and an antibacterial agent containing the same.

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

General formula t [In the formula, R1 represents a lower alkyl group, and R2 represents a nitro group. In the above group, R and R5 are bonded to each other with or without an oxygen atom or a nitrogen atom, and together with the nitrogen atom to which they bond, R and R5 are 5- or 6-membered.
represents a group forming a saturated heterocyclic group, and the heterocyclic group may have a lower alkyl group or a hydroxyl group as a substituent. X represents a halogen atom, and n represents 0 or 1. ] The compound of the present invention represented by the above general formula (1) and its salt have the characteristics of exhibiting excellent antibacterial activity against a wide range of Gram-negative bacteria and Gram-negative bacteria, as well as having low toxicity and weak side effects. It is useful as a therapeutic agent for diseases of humans, animals, fish, etc. caused by various pathogenic bacteria, and is also useful as an external disinfectant and disinfectant for medical instruments. In particular, the compounds of the present invention and their salts have remarkable antibacterial activity against Pseudomonas aeruginosa, non-glucose-fermenting bacteria, anaerobic bacteria, fresh clinical isolates, etc., and can be used as antibacterial agents against diseases caused by these. Useful. In particular, the compounds of the present invention and their salts have excellent absorbability and exhibit excellent antibacterial activity in vivo.
In addition, because of its high urinary excretion rate, it is useful as a therapeutic agent for urinary tract infections, and because it is excellently excreted from bile, it is useful as a therapeutic agent for intestinal infections.

Furthermore, the compound in which R2 in the general formula (1) represents a halogen atom is also useful as a synthetic intermediate for a compound in which R2 represents a group other than a halogen atom.

2 More specifically, each group represented by R, R, R3, R4, R5 and X in the above general formula (1) is as follows.

Examples of lower alkyl groups include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

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

Examples of the 5- or 6-membered saturated heterocyclic group which may have a lower alkyl group or a hydroxyl group as a substituent include piperazinyl, 4-methyl-1-piperazinyl, 3-ethyl-1-piperazinyl, 2- Brovyl-1-piperazinyl, 4-butyl-1-piperazinyl, 4-pentyl-1
-piperazinyl, 3-hexyl-1-piperazinyl, 4
-Hydroxy-1-piperazinyl, 3-hydroxy-1
-piperazinyl, 2-hy, droxy-1-piperazinyl, piperidinyl, 4-methyl-1-piperidinyl, 3-
Ethyl-1-piperidinyl, 2-propyl-1-piperidinyl, 4-butyl-1-piperidinyl, 4-pentyl-1-piperidinyl, 3-hexyl-1-piperidinyl, 4-hydroxy-1-piperidinyl, 3-hydroxy- 1-piperidinyl, 2-hydroxy-1-piperidinyl, morpholinyl, 3-methyl-1-morpholinyl, 2
-ethyl-1-morpholinyl, 3-propyl-1-morpholinyl, 3-butyl-1-morpholinyl, 3-hexyl-1-morpholinyl, 3-hydroxy-1-morpholinyl, 2-hydroxy-1-morpholinyl, pyrrolidinyl, 3-methyl-1-pyrrolidinyl, 2-ethyl-1-
pyrrolidinyl, 3-propyl-1-pyrrolidinyl, 2-
Number of carbon atoms as a substituent on a cyclic amino group such as butyl-1-pyrrolidinyl, 3-benzene-1-pyrrolidinyl, 3-hexyl-1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, 2-hydroxy-1-pyrrolidinyl group, etc. 1~
Examples include cyclic amines having 5 to 6 carbon atoms, which may have a group selected from the group consisting of 6 straight-chain or branched alkyl groups and hydroxyl groups.

The compound represented by the above general formula (1) can be manufactured by various methods, and one preferred example thereof is the following method.

Reaction Scheme-1 (2) (6) (3) (1a) (4) (Ib) [In the formula, Xl represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an arylalkanesulfonyloxy group.

2 R1R, X and n are the same as above. ] The nitration reaction of the compound of general formula (2) is carried out under usual nitration reaction conditions for aromatic compounds, for example, without a solvent or in a suitable inert solvent, using a nitration agent.

Examples of the inert solvent include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of the nitrating agent include fuming nitric acid, concentrated nitric acid, and mixed acids (sulfuric acid, fuming sulfuric acid, phosphoric acid, or acetic anhydride and nitric acid).
Examples include alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid. The amount of the above nitrating agent used is at least equimolar to the raw material compound (usually an excess amount).
The reaction is more advantageously carried out at around 0 to 100°C for 1 to 4 hours.

The compound of general formula (2) used as a starting material is a known compound. In the general formula (2), examples of the halogen atom represented by x1 include fluorine, chlorine, bromine, and iodine atoms, and examples of the lower alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy,
Examples include propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy, and arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2 -methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4
Examples include substituted or unsubstituted arylsulfonyloxy groups such as -methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and examples of arylalkanesulfonyloxy groups include benzylsulfonyloxy and 2-phenylethyl groups. Sulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy,
Examples include substituted or unsubstituted aryl alkanesulfonyloxy groups such as 3-chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy groups.

The reduction reaction of the compound of general formula (3) can be carried out, for example, by using a catalytic reduction catalyst in an appropriate solvent, or by using a metal or metal salt and an acid or a metal or metal salt and alkali metal water in an appropriate inert solvent. This is carried out by using a mixture with an oxide, sulfide, ammonium salt, etc. as a reducing agent. In the case of (2) above, the solvents include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, and ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran (THF), and diethyl ether. ,
Esters such as ethyl acetate and methyl acetate, aprotic polar solvents such as N,N-dimethylformamide (DMF), etc. can be used. As a catalytic reduction catalyst, palladium,
Palladium-black, palladium-carbon, platinum, platinum oxide,
Copper chromite, Raney nickel, etc. can be used.

The amount of catalyst used is usually 0 for the compound of general formula (3).
．． It is preferable to set it as 02 to 1.00 times the weight.

The reaction temperature is usually around -20 to 150°C, preferably 0°C.
- Near room temperature, hydrogen pressure is 1 to 10 atm, and reaction is 0.
It will be completed in about 5 to 10 hours. In the case of (■) above, a mixture of iron, zinc, tin or stannous chloride with a mineral acid such as hydrochloric acid or sulfuric acid, or an alkali metal hydroxide such as iron, ferrous sulfate, zinc or tin and sodium hydroxide, A mixture of a sulfide such as ammonium sulfide, aqueous ammonia, and an ammonium salt such as ammonium chloride is used as the reducing agent. As the inert solvent, water, acetic acid, methanol, ethanol, dioxane, etc. can be used. The conditions for the above-mentioned reduction reaction are appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as reducing agents, the temperature is preferably 0°C to 100°C.
It is preferable to carry out the reaction for about 0.5 to 10 hours. The amount of the reducing agent used is at least equimolar, usually equimolar to 5 times the molar amount of the raw material compound.

In the reaction between the compound of general formula (3) or the compound of general formula (4) and the compound of general formula (5), the proportion of both to be used is not particularly limited and can be appropriately selected from a wide range, but the former is usually used. On the other hand, it is preferable to use the latter in at least an equimolar amount, preferably an equimolar amount to about 5 times the molar amount. The reaction is performed 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, and THF.

It is carried out in a solvent such as ethers such as dioxane and diglyme, DMF, dimethyl sulfoxide (DMSO), hexamethylphosphoric acid triamide (HMPA), and N-methylpyrrolidone. Among these, DMF, DMSO,
HMPA and N-methylpyrrolidone are preferred. The reaction is also carried out using deoxidizing agents, specifically inorganic carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and tertiary carbonates such as pyridine, quinoline, and triethylamine.
It can also be carried out in the presence of grade amines and the like. The reaction is usually carried out under a pressure of 1 to 20 atm, preferably 1 to 10 atm.
The process is carried out at a temperature of about 00 to 250°C, preferably 100 to 200°C, and is generally completed in about 1 to 20 hours. In this way, the compound of the present invention represented by general formula (1a) or (1b) is produced.

The compound of general formula (1a) can also be produced by nitration of the compound of general formula (6). This nitration reaction can be carried out under the same conditions as for the nitration of the compound of general formula (2) above.

Furthermore, the compound of general formula (1b) can also be produced by reducing the compound of general formula (1a).

This reduction reaction may be carried out under the same conditions as in the case of reduction of the compound of general formula (3) above.

Reaction Scheme-2 (7) (1c) [In the formula, R1, R3, x and n are the same as above. R4 represents a lower alkyl group, and x2 represents a halogen atom. ] The reaction between the compound of general formula (7) and the compound of general formula (8) is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. As the dehydrohalogenating agent, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, alkali metals such as sodium and potassium, and organic bases such as pyridine and piperidine can be used, respectively. The compound of general formula (8) has the general formula (
It is usually used in an equimolar to large excess amount, preferably about 1 to 3 times the molar amount of the compound 7). The reaction is usually carried out in a room m~15
The process is completed in about 1 to 12 hours at 0°C, preferably around 50 to 120°C.

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 nucleic acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid; Examples of compounds include sodium hydroxide, potassium hydroxide,
Examples include calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

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

Among the compounds of the present invention of general formula (1) thus produced, those in which the lower alkyl group represented by R1 is a methyl group or an ethyl group are preferred, and those in which the lower alkyl group represented by R1 is a methyl group are most preferred.

The halogen atom represented by Most preferably. Further, the group represented by R3 is preferably an amino group. Therefore, particularly preferred compounds of the present invention have the general formula (
1) R is a methyl group, R2 is 4-lower alkyl substitution-1
-piperazinyl group, R3 is an amino group, X is a fluorine atom, and n is 1.

The compound of the present invention is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders, binders,
It is prepared using diluents or excipients such as 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, suspensions, etc.), ointments, etc. When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry 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, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as grade ammonium bases and sodium lauryl sulfate, moisturizing agents such as glycerin and starch, starch,
Adsorbents such as lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming into an emulsion, carriers such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin,
Excipients such as talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminalan agar can be used. When molding into a fully opened form, carriers such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols,
Gelatin, semi-synthetic glyceride, etc. can be used. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, diluents such as water, ethyl alcohol, propylene glycol, etc. , ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to prepare an iso-strength solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary.

When molding into bases, creams, and gels, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, and bentonite can be used.

The amount of the compound of general formula (1) or its salt to be contained in the pharmaceutical formulation of the present invention is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the pharmaceutical formulation. Good.

The administration method of the above pharmaceutical preparation is not particularly limited, and is determined depending on various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, are administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Full dilatation is administered rectally.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the compound of general formula (1), which is the active ingredient, is 1 kQ of body weight per day. The dosage is preferably about 0.2 to 100 mg, and the preparation can be administered in divided doses 3 to 4 times a day.

1 凰1 Examples, antibacterial test results, and formulation examples are listed below.

Example 1 8.9-difluoro-2-methyl-6-oxo-1,2
-dihydro-pyrrolo(3,2,1-IJ)quinoline-5
- Dissolve 11.5 oz of carboxylic acid in 12 oz of concentrated sulfuric acid, then add 17 oz of potassium nitrate and react at 170°C for 2 hours. After the reaction, pour into ice water 1Q, filter the precipitated crystals,
Recrystallize from DMF to obtain 8,9-difluoro-2-methyl-
7-nitro-6-oxo-1,2-dihydro-pyrrolo(
3,2,1-ij) quinoline-5-carboxylic acid 6.89
get.

Sono p, 265-268°C (decomposition), white edge-shaped crystals Example 2 8.9-difluoro-2-methyl-7-nitro-6-oxo 1,2-dihydro-pyrrolo [3°2.1-1j )
Dissolve 6 g of quinoline-5-carboxylic acid in DMF300-, add 0.5 g of 20% palladium-carbon catalyst, and add 5 kc
Catalytic reduction is carried out at +/c■2. After the reaction, the catalyst is removed, then DMF is distilled off under reduced pressure, and ethanol is added to the residue for crystallization.

The crystals were collected and recrystallized with DMF to give 8,9-difluoro-2-methyl-7-amino-6-oxo-1,2-dihydro-pyrrolo(3,2,1-iJ)quinoline-5- 2.7 g of carboxylic acid are obtained.

Yellow edge-like crystals, ■p, 270-274°C (decomposition) Example 3 8.9-difluoro-7-amino-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3°2.1- 1j)
Quinoline-5-carvone R2o and N-methylbiperazine 4m are suspended in N-methylpyrrolidone 201111!2 and reacted on an oil bath at 110°C to 120°C for 3 hours.

After the reaction, the solvent and excess N-methylbiperazine are distilled off under reduced pressure, and ethyl acetate is added to the residue for crystallization. The crystals are taken out and dissolved in 0.1N-80980m at 50°C. After removing insoluble matter, the filtrate was concentrated to dryness, and the residue was recrystallized from ethanol-water to obtain yellow edge-shaped crystals. This was resuspended in 10 ml of water, and plating with 10% sodium hydroxide aqueous solution
H12 and then adjusted to EIH8 with acetic acid. The precipitated crystals were collected, washed with water, and dried to give 8-fluoro-2-methyl-9-(4-methyl-1-piperazinyl)-7-amino-6-oxo-1,2-dihydro-pyrrolo(3,2
, 1-ij) 1.4 g of quinoline-5-carboxylic acid are obtained.

mp, 240-243°C, yellow edge-like crystals Example 4 8.9-difluoro-7-amino-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3°2.1-1j]
13 g of quinoline-5-carvone, anhydrous piperazine 4.
8-fluoro-
2-Methyl-9-(1-piperazinyl)-7-amino-
6-oxo-1,2-dihydro-pyrrolo(3,2,1-
ij) Quinoline-5-carvone i! Obtain 2.1 g.

Pale yellow edge-like crystals, II), 256-259°C (decomposition) Example 5 7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo [3°2.1 -IJ)
Quinoline-5-carboxylic acid 1. OQ and morpholine 1.5
g in N-methylpyrrolidone 101I2, and reacted in a sealed tube at 110 to 120°C for 5 hours. The reaction mixture was dried under reduced pressure, and ethyl acetate was added to the residue to crystallize it. The crystals were collected and recrystallized from DMF to give 7-amino-8.
-Fluoro-9-(4-morpholinyl)-2-methyl-
6-oxo-1,2-dihydro-pyrrolo (3,2゜1-
iJ) 0.6 g of quinoline-5-carboxylic acid is obtained.

11), above 300℃, yellow edge-like crystal elemental analysis value (C17H18N304F and shite) CHN calculated value m58.78 5.22 12.10 actual value (X
) 58.66 5.27 12.01 Example 6 Tsuamino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo [3°2.1-ij)
Quinoline-5-carboxylic acid 0.50 and piperidine 0.8
c+ and N-methylbiolidone are suspended in 10110 Gm and reacted in a sealed tube at 110 to 120°C for 5 hours. The reaction mixture was dried under reduced pressure, and ethyl acetate was added to the residue to crystallize it. The crystals were collected and recrystallized from DMF to give 7-amino-8-fluoro-2-methyl-6-oxo-9-(1-
0.3 g of quinoline-5-carboxylic acid is obtained.

Ill, 273-276°C (decomposition), yellow edge-like crystals Example 7 Tsuamino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo (3°2.1-1j)
0.5 g of quinoline-5-carboxylic acid and 1.0 g of 4-hydroxypiperidine are suspended in N-methylpyrrolidone 511G and reacted at 110 to 120°C for 5 hours. The reaction mixture is dried under reduced pressure, and ethanol is added to the residue for crystallization. The crystals were collected and recrystallized from DMF to give 7-amino-8-fluoro-9-(4-hydroxy-1-piperidinyl)-2-methyl-6-oxo-1,2-dihydropyrrolo(3,2, 1-ij) quinoline-5-powerbonne 1
We get 10.20.

mp, 287-292°C (decomposition), yellow edge-like crystals Example 8 7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3°2.1-ij )
Quinoline-5-carvone 1110.5g and pyrrolidine 0
．． 70 is suspended in N-methylpyrrolidone 10- and reacted in a sealed tube at 110 to 120°C for 5 hours. The reaction mixture was dried under reduced pressure, and ethyl acetate was added to the residue to crystallize it. The crystals were collected and recrystallized from DMF to give 7-amino-8.
-Fluoro-2-methyl-6-oxo-9-(1-pyrrolidinyl)-1,2-dihydro-pyrrolo(3,2゜1-
ij) 0.29 of quinoline-5-carboxylic acid is obtained.

Garden p, 296-299°C (decomposition), yellow edge-shaped crystals Example 9 8-bromo9-fluoro-5-methyl-6°7-sihydro-1-oxo-18,5H-benzo(i,j)quinolidine- 2-carboxylic acid 17.19 to concentrated sulfuric acid 18011
11, add potassium nitrate 25.30, 65~
Stir at 70°C for 3 hours. The reaction solution was transferred to 1 kg of ice, and the precipitated orange crystals were collected and washed with water to give 8-bromo-9-fluoro-5-methyl-6,7-cyhydro-1-oxy-IH.

5H-benzo(+,J)quinolidine-2-carboxylic acid 1
Get 0.50. This is recrystallized from glacial acetic acid.

u, 300℃ or higher, pale yellow needle crystal elemental analysis value (as C14H16N205 FBr)C
HN Total IDI (%) 43.66 2.62.7.27 Actual value (X) 43.59 2.55 7.34 Example 10 8-Bromo-9-fluoro-5-methyl-10-nitro6 .7-Sihydro-1-oxo-18°5-day-benzo(i,j)quinolidine-2-carvone l! 4.60 is dissolved in 300ml of glacial acetic acid, and at 110-120°C, a solution of 11.60ml of stannous chloride in 10ml of concentrated sulfuric acid is added while stirring. After stirring at the same temperature for 15 minutes, it was concentrated to dryness under reduced pressure, the residue was thoroughly washed with water, and 10-amino-8-bromo-9-
1.320 fluoro-5-methyl-6,7-cyhydro-1-oxo-IH,5H-benzo(i,j)quinolidine-2-carboxylic acid is obtained.

Peng p, above 300℃, yellow needle crystal elemental analysis value (as C14812N203 FBr)C
HN Calculated value (%) 47.34 3.41 7.89 Actual measurement II
(%) 47,45 3,47 7.82 Example 11 10-amino-8-bromo-9-fluoro-5-methyl-6,7-sihydro-1-oxo-18°5day-benzo (i, j ) HMPAIol to 1730g+g of quinolidine-2-carvone and 1.141Q of N-methylbiperazine.
llg and stirred at 150-160°C for 10 hours.

The solvent was distilled off under reduced pressure, and the residue was washed with 80% of ethyl acetate.
The obtained crystals were heated to 50°C of 0.2N hydrochloric acid (50°C).
After treating with activated carbon, insoluble matter is removed, and the solution is concentrated to dryness under reduced pressure. Dissolve the residue in 10 parts of water, adjust the pH to 8 to 9 by adding saturated aqueous sodium bicarbonate solution, and collect the precipitated crystals. This was recrystallized from ethanol and 10-amino-9-fluoro-5-methyl-8-(4
-methyl-1-piperazinyl)-〇,7-sihydro1
-Oxo IH,5H-benzo(i,J)quinolidine-
601 g of 2-carboxylic acid are obtained.

ip, 293-295°C, yellow needles Example 12 9-(1-piperazinyl)-8-fluoro-7-amino-2-methyl-1,2-dihydro-〇-oxopyrrolo(3,2,1- iJ) Quinoline-5-carboxylic acid 3.4
50 and DMF20IQ to 20 ml of a DMF solution of trifluoromethyl iodide containing 7.7 g of methyl iodide.

The mixture is heated in a stainless steel autoclave on an oil bath at 110-120°C for 5 hours. DMF was distilled off under reduced pressure, and a 10% aqueous sodium hydroxide solution was added to the residue to adjust the pH to 13. After removing insoluble matter, acetic acid was added to adjust the pH to 8, and the precipitated crystals were collected, washed with water, and dried to give 9-(4-methyl-1-piperazinyl)-8-fluoro-7-amino. -2-methyl-1,2-dihydro-6-
Oxitupyrrolo [3°2.1-iJ)quinoline-5-carvone I11.82Q is obtained.

19.240-243°C, yellow ridge-like crystals [Antibacterial test] 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 (CHEMOTHERAPY, Mu, 1126-1128
(1974)). The results obtained are shown in Table 1. In addition, each type of bacteria is 1 x 108 bacteria/11 fl (0, D, 660-
μ, 0.07-0.16) and 1 x 106 bacterial count/IIQ
(100-fold dilution).

(Test compounds) 1... Compound of Example 3 2... Compound 3 of Example 4... Compound 4 of Example 5... Compound 5 of Example 6... Compound of Example 7 6... Compound of Example 8 7... Compound of Example 11 (test bacteria) A.S. aureus FDA 209PB-8, pV
OQeneS IID S-23C...E, coll
NIHJ JC-2D...E, coli No.
, 29E・K, pneumoniae NCTC9
632F-P 9mlrabills 1287G-P
, 5oraanii II D K on.

H-8, marcescens I FO126481
・A, calcoaceticus A C-54
J-P, aeruginosa ATCC10145 -P, aeruginosa E-2 Table 1 [Measurement of blood and urine concentrations] The test compound was orally administered at 25-a/ka to male rats (body weight 190-24213). Urine and blood were collected over time.The test bacteria were Bacillus subtilis (B,
The concentration of the test compound in the collected blood and urine was measured by the thin layer plate cup method (6-medium/diameter 901 Shear) using Sensitivity Measurement Medium (manufactured by Eiken Kagaku Co., Ltd.) as the medium.

The urine concentration is shown in Table 2, and the blood concentration is shown in Table 3.

Table 2 Table 3 [Treatment efficacy test for urinary tract infections] Pseudomonas aeruginosa (p 5eudo■on
asaeruginosa E-Z) at 37°C, 1
Cultured in nutrient medium for 8 hours, diluted with the same medium,
A bacterial solution with a bacterial count of /- was prepared. MGM (glyceryl monomystate Nikko Chemicals) and SC8 (sodium cetyl sulfate Nikko Chemicals) were mixed at a ratio of 9:1 (weight ratio), and after assimilation, UV sterilized disks (diameter 2,011 mm,
A edible bacterial disk for inoculation was prepared by soaking a 3.011 mm long disk in the bacterial solution for 1.5 hours under water cooling.

The above disc was surgically inserted into the bladder of JCL: SD female rats (4 rats per group, Nippon Yura) under anesthesia using Ional sodium (cocebarbital: Yoshitomi Pharmaceutical). After the surgery was completed, sutures were made with Mitsel suture tacks. 1% oxamide-containing food and water were given 6 hours after the disk insertion. In addition, the feed containing 1% oxamide was given for 24 hours, and thereafter the feed was switched to normal feed. 6 hours of disc insertion,
16 Q/kQ, 8.0 mg/kg of the test compound suspended in 0.5% CMC after 24 and 48 hours, respectively.
, 4.0■(J/kQ, 2.0+a/ka and 1.0
112/kQ was orally administered.

Four days after infection, the presence or absence of bacteria in the urine and kidneys was determined by the following method. A rat was anesthetized with sodium ional and its abdomen was opened, urine was collected, and the urine was applied to a plate of NAC agar (manufactured by Eiken Kagaku Co., Ltd.) using a Conlage stick. After the kidney was removed, it was divided into two equal parts, the cut surface was stamped on the above-mentioned flat plate, and after culturing at 37°C for 18 hours, it was judged as + or -.

The criteria for judgment is that when 10 or more colonies are observed on the coated or stamped plate, it is considered + (valid), and 1
If the number is less than 0, it is set as - (invalid, no effect), and the effective number of strokes in each group is calculated, and the probit method (prob
lt), the ED5o value was measured.

In addition, in the control, the number of colonies above is 100.
It was more than one. The results are shown in Table 4. In Table 4, the following compounds were used as Comparative Compounds 1 and 2.

8-fluoro-2-methyl-6-oxo-9-(4-methyl-1-piperazinyl)-1,2-dihydro-pyrrolo(3,2,1-ij)quinoline-5-carboxylic acid (comparative compound 1 ) and 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-sihydro-1-oxo-IH,
5H-benzo[1j]quinolidine-2-carboxylic acid (comparative compound 2).

Table 4 [Acute Toxicity] The acute toxicity of the compounds of the present invention was determined by intraperitoneal administration (i, v, ) to mice that had been fasted for 12 hours before the test. The L Dso value (50% lethal dose) is shown in the fifth column.

Table 5 Formulation Example 1 Compound of Example 3 (Hydrochloride) 2001G Glucose 2
50 Garden a Total amount of water 5II2 Dissolve the compound of Example 3 and glucose in distilled water for injection, then inject into the ampoule of 5-, and after purging with nitrogen, autoclave at 121°C for 15 minutes to obtain the above composition. Obtain injections.

Formulation Example 2 Compound of Example 4 100g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Cornstarch 30g Magnesium stearate 2g TO-5 (trade name, Shin-Etsu Chemical Co., Ltd. 10g, manufactured by Hydroxypropyl methylcellulose) Polyethylene glycol- 600030 Castor oil 40
g Methanol 40g The compound of Example 4, Avicel, cornstarch, and magnesium stearate were mixed, polished, and then tableted using a sugar-coated R1011 machine. The obtained tablets are coated with a film coating agent consisting of TO-5, polyethylene glycol-6000, mustard oil, and methanol to produce film-coated tablets having the above composition.

Formulation Example 3 Compound of Example 5 2Q Purified lanolin 5g White beeswax 50 Colored petrolatum 88g Total amount 100g White beeswax was heated to make it liquid, and then Example 5
The compound, purified lanolin, and white petrolatum are added, heated until it becomes liquid, and then stirred until it begins to solidify to obtain an ointment having the above composition.

Production Example 4 Compound of Example 11 (hydrochloride) 200mg glucose
250mg Injection Water Total Volume 5m12 After dissolving the compound of Example 11 and glucose in distilled water for injection, inject it into a 5-ampule, and after replacing with nitrogen, 12
Autoclaving is performed at 1° C. for 15 minutes to obtain an injection having the above composition.

Claims (1)

[Claims] (1) General formula [In the formula, R1 represents a lower alkyl group, and R2 represents a nitro group. In the above group, R4 and R5 represent a group that is bonded to each other with or without an oxygen atom or a nitrogen atom to form a 5- or 6-membered saturated heterocyclic group together with the bonded nitrogen atom, and the heterocyclic group may have a lower alkyl group or a hydroxyl group as a substituent. X represents a halogen atom. n represents 0 or 1. ] A benzoheterocycle represented by l! Conductors and their salts. (2) General formula C In the formula, R1 represents a lower alkyl group, and R2 represents a halog represents a nitro group. In the above group, R4 and R5 represent a group that is bonded to each other with or without an oxygen atom or a nitrogen atom to form a 5- or 6-membered saturated heterocyclic group together with the bonded nitrogen atom, and the heterocyclic group 6x, which may have a lower alkyl group or a hydroxyl group as a substituent, represents a halogen atom. n represents O or 1. ] An antibacterial agent containing a benzoheterocyclic derivative represented by and its salt.