JPS622598B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to benzo[ij]quinolidine-2-carboxylic acid derivatives and methods for producing the same. The benzo[ij]quinolidine-2-carboxylic acid derivatives and salts thereof of the present invention are novel compounds that have not been described in any literature, and have the general formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenylalkyl group, or a group

[Formula], R ³ represents a hydrogen atom or a halogen atom, respectively. ]. In the above general formula (1), examples of the lower alkyl group represented by R ¹ and R ² include straight chain or branched alkyl groups having 1 to 4 carbon atoms, specifically methyl, Examples include ethyl, propyl, isopropyl, butyl, and tert-butyl groups. ^R2
The lower alkanoyl group represented by has 1 carbon number
-4 linear or branched alkanoyl groups, and specific examples include formyl, acetyl, propionyl, butyryl, and isobutyryl groups. Examples of the lower alkanesulfonyl group represented by R ² include groups in which the above-mentioned lower alkyl group and sulfonyl group are bonded, and specifically, methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, tert -Butanesulfonyl group, etc. can be exemplified. Examples of the phenyl alkyl group represented by R ² include phenyl alkyl groups in which a linear or branched alkylene group having 1 to 4 carbon atoms and a phenyl group are bonded, and specifically, benzyl, 2 -phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl,
Examples include 1,1-dimethyl-2-phenylethyl group. Examples of the halogen atom represented by R ³ include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom. In the above general formula (1), R ² is a group

When the formula is shown, the enol form (A) (i.e. 4-hydroxy-1,5-naphthyridine-3-carbonyl) and the keto form (B) (i.e. 4-oxo-1,4-dihydro-1,5 -Naphthyridine-
3-carbonyl). Representative compounds of the present invention are listed below. Γ8-(1-piperazinyl)-6,7-dihydro-
1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ10-chloro-8-(1-piperazinyl)-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ9-chloro-8-(1-piperazinyl)-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ9-fluoro8-(1-piperazinyl)-6,
7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(1-piperazinyl)-5-methyl-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(1-piperazinyl)-5-ethyl-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(1-piperazinyl)-5-butyl-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-methyl-1-piperazinyl)-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-butyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H
-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-acetyl-1-piperazinyl)-6,
7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-isobutyryl-1-piperazinyl)-
5-methyl-6,7-dihydro-1-oxo-
1H,5H-Benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-formyl-1-piperazinyl)-9-
Fluoro-5-methyl-6,7-dihydro-1-
Oxo-1H,5H-benzo[ij]quinolidine-2
-Carboxylic acid Γ8-(4-benzoyl-1-piperazinyl)-
6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-benzoyl-1-piperazinyl)-5
-Methyl-6,7-dihydro-1-oxo-
1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H
-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-tert-butanesulfonyl-1-piperazinyl)-5-methyl-6,7-dihydro-1
-Oxo-1H,5H-benzo[ij]quinolidine-
2-carboxylic acid Γ8-(4-benzyl-1-piperazinyl)-6,
7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-[4-(2-phenylethyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-
Oxo-1H,5H-benzo[ij]quinolidine-2
-Carboxylic acid Γ8-[4-(4-phenylbutyl)-1-piperazinyl]-10-chloro-6,7-dihydro-1-
Oxo-1H,5H-benzo[ij]quinolidine-2
-Carboxylic acid Γ8-(1-piperazinyl)-10-fluoro-5-
Methyl-6,7-dihydro-1-oxo-1H,
5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-[4-(4-hydroxy-1,5-naphthyridine-3-carbonyl)-1-piperazinyl]-
6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-[4-(4-hydroxy-1,5-naphthyridine-3-carbonyl)-1-piperazinyl]- 5
-Methyl-6,7-dihydro-1-oxo-
1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-[4-(4-oxo1,4-dihydro-
1,5-naphthyridine-3-carbonyl)-1-
Piperazinyl]-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-ethyl-1-piperazinyl)-10-fluoro6,7-dihydro-1- Oxo-1H,
5H-benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-propionyl-1-piperazinyl)-
9-bromo-5-methyl-6,7-dihydro-1
-Oxo-1H,5H-benzo[ij]quinolidine-
2-Carboxylic acid Γ8-(1-piperazinyl)-10-fluoro-5-
Methyl-6,7-dihydro-1-oxo-1H,
5H-Benzo[ij]quinolidine-2-carboxylic acid Γ8-(4-benzoyl-1-piperazinyl)-7
-Fluoro-5-methyl-6,7-dihydro-1
-Oxo-1H,5H-benzo[ij]quinolidine-
2-carboxylic acid Γ8-[4-(P-toluenesulfonyl)1-piperazinyl]-5-methyl-6,7-dihydro-1
-Oxo-1H,5H-benzo[ij]quinolidine-
2-Carboxylic acid The compound of the present invention can be produced by various methods, but preferably, for example, by the general formula [In the formula, R ⁴ represents a halogen atom, a lower alkanesulfonyloxy group, or an allenesulfonyloxy group. R ¹ and R ³ are the same as above. ] The benzo[ij]quinolidine-2-carboxylic acid derivative represented by the general formula [In the formula, R ² is the same as above. ] is produced by reacting piperazines represented by Among the compounds of general formula (2) which are the starting materials of the present invention, compounds in which R ⁴ represents a halogen atom are known compounds or can be easily produced according to known methods. [Special Publication No. 51-6156, USP No. 4014877
Please refer to the specification]. Among the compounds of general formula (2), the compound in which R ⁴ represents a lower alkanesulfonyloxy group or an allenesulfonyloxy group (represented by general formula (2a)) is a new compound, and is shown, for example, in the following reaction scheme-1. manufactured by the method. The lower alkanesulfonyloxy group represented by R ⁴ includes methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, and the like. Furthermore, the allenesulfonyloxy group represented by R ⁴ includes benzenesulfonyloxy, naphthalenesulfonyloxy, and the like. A halogen atom, lower alkyl group, lower alkoxy group, hydroxyl group, nitro group, etc. may be substituted on the arene ring constituting the arenesulfonyloxy group. [In the formula, R ⁵ is a lower alkanesulfonyl group or allenesulfonyl group, R ⁶ is a lower alkyl group,
Each X represents a halogen atom. R ¹ and R ³ are the same as above. ] That is, the compound of general formula (2a) is obtained by reacting the compound of general formula (4) with the compound of general formula (6), and then reacting the obtained compound of general formula (8) with the compound of general formula (9). , further cyclizing the obtained compound of general formula (10),
It is produced by hydrolyzing the compound of general formula (11) obtained next. Among the compounds of general formula (8)
A compound in which R ¹ represents a hydrogen atom can also be produced by reacting a compound of general formula (5) with a compound of general formula (6) and then reducing the resulting compound of general formula (7). . In the reaction between the compound of general formula (4) and the compound of general formula (6), the ratio of the latter to the former is usually equal to or more, preferably equimolar to twice the molar amount of the latter. It is better. The reaction is usually carried out in an inert solvent in the presence of an acid scavenger. Specific examples of deoxidizing agents include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, inorganic carbonate compounds such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, pyridine, quinoline,
Examples include tertiary amines such as triethylamine. Such a deoxidizing agent is usually used in an amount equal to or more than equimolar, preferably equimolar to twice the molar amount of the compound of general formula (4). The fugitive solvents used include lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diglyme, aromatic hydrocarbons such as benzene and toluene, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric acid. Examples include triamide and pyridine. The reaction is usually carried out at 0 to 100°C, preferably around room temperature, and is usually completed in about 0.5 to 6 hours.
In this way, a compound of general formula (8) is produced. The reaction between the compound of general formula (8) and the compound of general formula (9) can be carried out without a solvent or in a solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid amide, etc., preferably without a solvent. It will be held in The ratio of compound (9) to compound (8) to be used is usually at least equimolar, preferably equimolar in the reaction without a solvent, and preferably in an equimolar amount in the reaction in a solvent.
The molar amount is preferably 1.1 to 1.5 times. The reaction temperature is usually about room temperature to 150°C, preferably 100 to 130°C, the reaction is usually completed in 0.5 to 6 hours, and the compound represented by general formula (10) can be easily obtained. The cyclization reaction of the compound (10) 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 a cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetraphosphoric acid diphenyl ether and diethylene glycol dimethyl ether is used, and usually 100 to 250
Heating conditions of 150-200°C can be employed. 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 (10), and usually at 100 to 150°C, it is used in an amount of 0.5 to 6
It is sufficient to allow the reaction to take place for about an hour. In this way, a compound of general formula (11) is produced. The hydrolysis reaction of compound (11) obtained by the above cyclization reaction can be carried out according to a conventional method, for example, using a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide, a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid, or acetic acid. , in the presence of conventional catalysts such as organic acids such as aromatic sulfonic acids. The reaction is generally carried out using water, methanol, ethanol, isopropanol, acetone,
It is carried out in common solvents such as methyl ethyl ketone, dioxane, ethylene glycol, acetic acid, etc. The reaction temperature is usually room temperature to 200℃, preferably 50 to 150℃
It is. In this way, the compound of general formula (2a) is easily obtained. The reaction between the compound of general formula (5) and the compound of general formula (6) may be carried out in the same manner as the reaction between the compound of general formula (4) and the compound of general formula (6). Thus the general formula
Compound (7) is produced. A catalytic reduction method, a reduction method using a hydrogenating agent, etc. can be applied to the reduction of the compound of general formula (7). 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 (7). The ring reaction using 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 (8) in which R ¹ represents a hydrogen atom can be obtained. Also, among the compounds of general formula (2), general formula [In the formula, X ¹ and X ² represent a halogen atom. R ¹ is the same as above. The compound represented by ] can also be produced by the method shown in the following reaction scheme-2. [In the formula, R ¹ , R ⁶ , X ^{1 and} The nitration reaction is carried out under nitration reaction conditions, for example, without a solvent or in a suitable inert solvent using a nitration agent. Examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of nitrating agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum, phosphoric acid, or acetic anhydride and nitric acid), potassium nitrate, sodium nitrate, etc. Examples include alkali metal nitrates and sulfuric acid, respectively. The amount of the above-mentioned nitrating agent used may be at least equimolar to the starting compound, usually in excess, and the reaction is advantageously carried out at 0 to 15°C for 1 to 4 mol.
Implemented in hours. The reduction reaction of the nitro group of the compound represented by the general formula (13) obtained above can be carried out, for example, by combining iron, zinc, tin or stannous chloride with an acid (e.g. hydrochloric acid, sulfuric acid, etc.) in a suitable inert solvent, or iron, ferrous sulfate, zinc or tin and alkali metal hydroxides, sulfides,
This is carried out by using a mixture with sulfite or the like as a reducing agent or by catalytic reduction using a catalytic reduction catalyst such as palladium on carbon. Examples of the inert solvent include water, acetic acid, methanol, ethanol, and dioxane.
The conditions for the above-mentioned reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as reducing agents, it is advantageous to
The reaction is preferably carried out at 100°C for about 0.5 to 1 hour, and in the case of catalytic reduction reaction, the reaction is preferably carried out at room temperature for about 0.5 to several hours. The amount of the reducing agent to be used is at least equimolar, usually equimolar to twice the molar amount of the raw material compound. The halogen substitution reaction of the amino group of the compound of general formula (14) obtained above can be carried out by applying Sandmeyer reaction via diazotization reaction. Diazotization of the compound of general formula (14) can be carried out using, for example, water,
The reaction is advantageously carried out using, for example, sodium nitrite or potassium nitrite and hydrochloric acid or sulfuric acid as a diazotizing agent in a solvent such as hydrochloric acid or sulfuric acid at a temperature of -30 DEG C. to room temperature for about 0.5 to 2 hours. The diazonium salt of the general formula (14) thus produced is usually isolated or not isolated, and a halogenating agent such as cuprous chloride or cuprous bromide is added to it for 0.5 to 20 minutes at 0 to 50°C. A compound represented by general formula (15) is obtained by reacting for about a period of time. The amounts of the diazotizing agent and halogenating agent to be used are at least equimolar, usually equimolar to twice the molar amount, relative to the raw material compound. The reduction of the pyridine ring of the compound of general formula (15) obtained above is carried out by catalytic reduction of the compound of general formula (15) in an appropriate inert solvent under acidic conditions. As the acid used here, a wide range of acids that can form an acid with quinoline can be used, and examples thereof include acetic acid, hydrochloric acid, and sulfuric acid. Examples of the inert solvent include dioxane, tetrahydrofuran, acetic acid, and water. Examples of the catalytic reduction catalyst include platinum-carbon, palladium-carbon, radium-carbon, and ruthenium-carbon. The above reduction reaction is advantageously carried out at room temperature ~50°C.
It is carried out for about 1 to 10 hours at ℃. In this way, a compound represented by general formula (16) is obtained. Further, the compound of general formula (16) is obtained by reducing the pyridine ring of the compound of general formula (14) to produce a compound of general formula (17), and then substituting the amino group of this compound of general formula (17) with halogen. It is also manufactured by The reduction of the pyridine ring of the compound of general formula (14) can be carried out in the same manner as the reduction of the pyridine ring of the compound of general formula (15) above. Further, the halogen substitution of the amino group of the compound of general formula (17) can be carried out in the same manner as the halogen substitution of the amino group of the compound of general formula (14). Furthermore, the compound of general formula (17) can also be produced by reducing the compound of general formula (13). general formula
The reduction of the compound (13) can be carried out in the same manner as the reduction of the pyridine ring of the compound of general formula (15) above. The compound of general formula (16) obtained in this way and the general formula
The reaction with the compound (18) may be carried out in the same manner as with the compound of the general formula (8) and the compound of the general formula (9). The cyclization of the compound of general formula (19) may be carried out in the same manner as the cyclization of the compound of general formula (10) above. Further, the compound of general formula (20) may be hydrolyzed in the same manner as the hydrolysis of the compound of general formula (11) above. The compound of general formula (2') is obtained by the various reactions described above. The compound of general formula (3), which is the other starting material of the present invention, 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 used relative to the former. 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. Specifically, such solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as tetrahydrofuran, dioxane, diglyme,
dimethyl sulfoxide, dimethyl formamide,
Examples include hexamethylphosphoric triamide.
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. Specific examples of such deoxidizing agents include inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, and tertiary amines such as pyridine, quinoline, and triethylamine. The reaction is usually carried out under a pressure of 1 to 20 atm (preferably 1 to 10 atm) and at 100 to 250°C (preferably 140 to 200°C), and 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. Among the compounds of the present invention, R ² is a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenylalkyl group, or a group

[Formula] A compound (general formula (1b)) is a compound in which R ² is a hydrogen atom (general formula (1a)) in the presence of a deoxidizing agent.
It can also be produced by reacting a compound of general formula (12) with [In the formula, R ⁷ is a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenylalkyl group, or a group

[Formula] is shown. R ¹ , R ³ and X are the same as above. ] The compound of the present invention represented by the general formula (1) thus obtained can be made into a pharmacologically acceptable acid addition salt, and the present invention also includes this acid addition salt.
The acid used to form the acid addition salt may be any pharmacologically acceptable organic or inorganic acid, including, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and acetic acid; Oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid,
Examples include organic acids such as ethanesulfonic acid and P-tosylic acid. Further, the compound represented by the general formula (1) of the present invention is
This can be treated with a pharmaceutically acceptable basic compound to form a carboxylic acid salt. Examples of the basic compounds used include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, and sodium bicarbonate, as well as morpholine, piperazine, pyridine, piperidine, ethylamine, dimethylamine, triethylamine, Examples include organic basic compounds such as aniline. The benzo[ij]quinolidine-2-carboxylic acid derivative represented by the general formula (1) and its salt thus obtained can be easily isolated and purified by conventional separation means after the above-mentioned reaction steps are completed. Examples of the separation means include solvent extraction, dilution, precipitation, recrystallization, column chromatography, and preparative thin layer chromatography. The benzo[ij]quinolidine-2-carboxylic acid derivatives represented by the above general formula (1) and their salts have excellent antibacterial activity against Gram-positive and Gram-negative bacteria and are useful as antibacterial agents, as shown below. It is. The compounds of the present invention exhibit remarkable antibacterial activity particularly against Pseudomonas aeruginosa and Streptococcus. In addition, the compound of the present invention has excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, as shown in the following reaction scheme-2.
In particular, it can be derived into a penicillanic acid derivative represented by the general formula (13) which has a remarkable antibacterial effect against Pseudomonas aeruginosa and Streptococcus. [In the formula, R ⁸ represents a lower alkyl group, X represents a halogen atom, R ⁹ represents a hydrogen atom or a hydroxyl group, and M represents a hydrogen atom or an alkali metal atom. R ¹ , R ² and
R ³ is the same as above. ] For example, 6-{2
[8-(1-piperazinyl)-6,7-dihydro-
1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxamide]-2-phenylacetamide}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0] heptane
2-carboxylic acid can be obtained [see Reference Example 7]. When the benzo[ij]quinolidine-2-carboxylic acid derivative 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 adjust 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, dried starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, twine, Disintegrants such as sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil;
Absorption enhancers such as quaternary ammonium bases 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, cocoa 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, including 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; when forming these solutions, emulsions and suspensions, diluents used in the art are used. All those commonly used in the field can be used, such as water, ethylene alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, and the like. 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, buffering agents, soothing agents,
In addition, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., 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 is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it is administered rectally; and in the case of an ointment, it is 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 about 10 mg to 5 g/body-day of the compound of the present invention is administered in 3 to 4 divided doses. do it. <Antibacterial action> 8-(1-piperazinyl)-6,7-dihydro-
1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (compound of the present invention) and 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthylidene-3- The antibacterial activity of carboxylic acid (nalidixic acid, control compound) against various bacteria was determined by the agar dilution plate method. The minimum inhibitory concentration for Gram-positive bacteria is shown in Table 1 below.
The minimum growth-inhibiting concentrations of Gram-negative bacteria are shown in Table 2 below. In addition, the number of various bacteria is 1× ¹⁰⁸ bacteria/ml (OD660
mμ, 0.13 to 0.14) and the number of bacteria was adjusted to 1×10 ⁶ bacteria/ml.

【table】

【table】

【table】

[Table] Reference examples, examples, and formulation examples are listed below. Reference Example 1 10 g of 5-hydroxy-3,4-dihydrocarbostyryl was added to a solution of 3.8 g of potassium hydroxide dissolved in 100 ml of methanol, and after stirring at room temperature for 30 minutes, the methanol was distilled off under reduced pressure. Benzene is added to the residue, and after crystallization, the benzene is distilled off. The residue was suspended in 50 ml of dimethylformamide, and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension while stirring on ice. After dropping, add 3.5 ml of methanesulfonyl chloride.
g was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [Silica gel; Wako C-
200 (manufactured by Wako Pure Chemical Industries, Ltd.), eluent: chloroform], and then recrystallized from aqueous ethanol to obtain colorless columnar crystals of 5-methanesulfonyloxy-3,
4-dihydrocarbostyryl is obtained. Yield 5.7g mp227-231°C Reference Example 2 5-(p-Toluenesulfonyloxy)-3,4-dihydrocarbostyryl is obtained in the same manner as in Reference Example 1. mp215-216°C Reference Example 3 4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyryl is suspended in 90 ml of dioxane, 35 g of NaBH ₄ is added, and 5.3 ml of acetic acid is added dropwise. After the dropwise addition, the mixture was heated under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. Add saturated sodium bicarbonate solution to the residue, filter the precipitate, wash with chloroform, and extract the liquid with chloroform. chloroform layer with Na ₂ SO ₄
After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Silica gel;
(manufactured by Wako Pure Chemical Industries, Ltd.) Eluate: Chloroform] After isolation and purification, crystallize with petroleum ether. The obtained crystals were recrystallized from methanol to give colorless prismatic crystals of 5-methanesulfonyloxy-1,2,3,4.
- Tetrahydroquinoline is obtained. Yield 1.9g mp74-76°C Reference Example 4 5-(p-Toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline is obtained in the same manner as in Reference Example 3. mp112-113℃ Reference example 5 5-methanesulfonyloxy-1,2,3,4
- Add 21.6 g of ethyl ethoxymethylene malonate to 22.4 g of tetrahydroquinoline and place on an oil bath while stirring.
Heat at 110°C for 30 minutes. Distillation of ethanol is observed. 120g of phosphoric acid and 120g of phosphorus pentoxide after heating
Add 240g of polyphosphoric acid adjusted from
Incubate at 140°C for 45 minutes. After the reaction, the mixture is cooled to room temperature, poured into 400 ml of water, cooled on ice again, and neutralized with a 40% aqueous solution of caustic soda to precipitate crystals. Add 150 ml of 10% caustic soda aqueous solution to the obtained crystals and reflux for 40 minutes. Filter after hot activated carbon treatment.
After cooling the liquid and adjusting the pH to 2 with concentrated hydrochloric acid, the precipitated crystals were collected. The crude crystals were recrystallized from dimethylformamide to give white needle-like crystals of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H,5H.
-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 21.3g mp270-275℃ Reference example 6 5-(p-toluenesulfonyloxy)-1,
Add 21.6 g of ethyl ethoxymethylene malonate to 30.0 g of 2,3,4-tetrahydroquinoline and heat on an oil bath at 110° C. for 30 minutes while stirring. 240g of polyphosphoric acid after heating (120g of phosphoric acid and 120g of phosphorus pentoxide)
(adjusted) and react for 40 minutes at 140℃ on an oil bath. After the reaction, cool to room temperature, pour into 400 ml of water, neutralize with 40% caustic soda aqueous solution, and collect precipitated crystals. Add 150 ml of 10% caustic soda aqueous solution to the obtained crystals and reflux for 40 minutes. Filter after hot activated carbon treatment. Cool the liquid and adjust the pH with concentrated hydrochloric acid.
2 and then collect the precipitated crystals. The crude crystals were recrystallized from dimethylformamide to give white needle-like crystals of 8-
(p-Toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 27.4g mp300℃ or higherReference Example 7 Dissolve 11g of 6-chloroquinaldine in 15ml of concentrated sulfuric acid and cool on ice. Next, a solution of 7.1 g of potassium nitrate dissolved in 20 ml of concentrated sulfuric acid is added dropwise. At this time, keep the reaction temperature below 10°C. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour and then poured into 200 g of ice. Then, when the mixture is made alkaline with 10% caustic soda, taking care not to exceed the internal temperature of 20°C, a pale yellow precipitate is deposited. The precipitate was collected, washed with water, and recrystallized with ethanol to obtain 5-
12.3 g of nitro-6-chloroquinaldine are obtained. Pale yellow edge-like crystals, mp123-124℃ Reference example 8 Dissolve 25g of stannous chloride in 50ml of concentrated hydrochloric acid, add 6.7g of 5-nitro-6-chloroquinaldine, and place on a water bath.
React for 30 minutes at 80-90°C. Cool the reaction solution with water for 30 minutes.
% caustic soda to make alkaline (PH10), filter and extract using 500 ml of chloroform and Celite. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from benzene-hexane.
-4.5 g of amino-6-chloroquinaldine are obtained. Colorless plate crystals, mp 196-197°C Reference Example 9 4 g of 5-amino-6-chloroquinaldine was dissolved in 40 ml of concentrated hydrochloric acid and cooled on ice. Next, under ice-cooling, a solution of 2.1 g of sodium nitrite dissolved in 5 ml of water is added dropwise. After reacting for 1 hour at the same temperature, add 7 g of cuprous chloride to 15 g of concentrated hydrochloric acid.
ml of the solution and react for 1 hour at 50°C on a water bath. At this time, intense nitrogen gas generation can be seen. The mixture is then cooled, made alkaline with 30% caustic soda, filtered and extracted using 300 ml of chloroform and Celite. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from isopropanol-water to give 5,6-dichloroquinaldine 3.5
get g. White needle crystals, mp84-85°C Reference Example 10 In the same manner as in Reference Example 9, 6-fluoro-5-chloro-1,2,3,4-tetrahydroquinaldine was obtained as a pale yellow oil. NMR spectrum δ ^{CDC 3} _ppn = 1.88 (d, 3H, J = 6Hz) 1.72 (m, 2H) 2.68 (m, 3H) 3.19 (m, 1H) 3.43 (s, 1H) 6.37 (m, 2H) Reference example 11 5.5g of 5,6-dichloroquinaldine and 50ml of acetic acid
0.1 g of 5% platinum on carbon was added and catalytic reduction was carried out using the Parr method under a hydrogen pressure of 4 kg/cm ² . After absorbing the theoretical amount of hydrogen, the filtrate is concentrated under reduced pressure. The residue is made alkaline with 20% caustic soda solution and 50 ml of water, and then extracted with 100 ml of chloroform.
Anhydrous potassium carbonate was added to the extract, dried and concentrated to obtain 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine as an oil. NMR spectrum δ ^{CDC 3} _ppn = 1.23 (d, 3H, J = 6Hz) 1.7 (m, 2H) 2.72 (m, 2H) 3.28 (m, 1H) 3.75 (m, 1H) 6.62 (q, 2H, J = 9Hz ) Reference Example 12 In the same manner as Reference Example 11, 6-fluoro-
5-amino-1,2,3,4-tetrahydroquinaldine is obtained. Confirm that the compound obtained from the NMR spectrum and mass spectrum is the above compound. Reference Example 13 3.2 g of diethyl ethoxymethylene malonate is added to 3.2 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine and reacted by heating at 160°C for 30 minutes. Next, polyphosphoric acid prepared from 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid was added and reacted by heating at 140 to 150° C. for 1 hour. After the reaction, put it in 100g of ice,
Adjust the pH to 4-5 with 10N caustic soda solution. After removing the precipitate, dry it and add 10% caustic soda to the crystals.
ml and react at 100-110°C for 1 hour. After cooling, acidify with concentrated hydrochloric acid to precipitate crystals. Recrystallization from ethanol gives 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid. mp269-271°C Reference Example 14 0.2 g of 5% platinum carbon was added to 8 g of 6-fluoro-5-acetylaminoquinaldine, dissolved in 80 ml of acetic acid, and catalytically reduced using the Parr method at a hydrogen pressure of 4 Kg/cm ² . After absorbing a theoretical amount of hydrogen, the solution was filtered and concentrated under reduced pressure to obtain 8 g of 6-fluoro-5-acetylamino-1,2,3,4-tetrahydroquinaldine as an oil. Confirm that the compound obtained from the NMR spectrum and mass spectrum is the above compound. Reference example 15 6-fluoro-5-acetylamino-1,2,
8 g of 3,4-tetrahydroquinaldine and 35 g of concentrated hydrochloric acid
ml and 20ml of water to dissolve. After refluxing for 1 hour, a solution of 5 g of sodium nitrite dissolved in 10 ml of water was added dropwise under ice-cooling, taking care not to let the reaction temperature exceed 5°C. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then poured into a solution of 10 g of cuprous chloride dissolved in 12 ml of concentrated hydrochloric acid. After reacting at 80°C for 1 hour, cool on ice, make alkaline with 28% aqueous ammonia, and extract using 300ml of chloroform and Celite. The chloroform layer is dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to silica gel column chromatography [Silica gel:
Isolated and purified using Wako C200, manufactured by Wako Pure Chemical Industries, Ltd.
3.2 g of 6-fluoro-5-chloro-1,2,3,4-tetrahydroquinaldine are obtained. Light orange oil Confirm that the compound obtained from NMR spectrum and mass spectrum is the above compound. NMR spectrum δ ^{CC 4} _ppn = 1.88 (d, 3H, J = 6Hz) 1.72 (m, 2H) 2.68 (m, 3H) 3.19 (m, 1H) 3.43 (s, 1H) 6.37 (m, 2H) Reference example 16 6-fluoro-5-chloro-1,2,3,4-
Add 1.8 g of diethyl ethoxymethylene malonate to 1.5 g of tetrahydroquinaldine and heat at 160℃ for 30 minutes.
Heat for a minute. Next, 7g of phosphorus pentoxide and 7g of phosphoric acid.
Add polyphosphoric acid prepared from
React by heating for a period of time. After the reaction, pour into 100g of ice,
Adjust pH to 6-7 with 10N caustic soda solution. After collecting the precipitate, it was added to 30 ml of concentrated hydrochloric acid and heated under reflux for 1 hour. After heating, add 50 ml of water, collect the precipitated crystals, wash with water, and dry. Recrystallized from ethanol to obtain 9-fluoro-8-chloro-5-methyl-6,
1.2 g of 7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid are obtained. mp 297-298℃, white edge-shaped crystals Reference example 17 8-(1-piperazinyl)-6,7-dihydro-
0.78 g of 1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is suspended in 25 ml of dry dimethylformamide, 0.42 ml of triethylamine is added, and the mixture is stirred for 15 minutes under ice cooling. Next, add 0.4 ml of isobutyl chlorocarbonate and continue stirring at the same temperature for 45 minutes. Separately, 1.3 g of ampicillin was suspended in 15 ml of dry dimethylformamide, 0.7 ml of triethylamine and 0.5 g of anhydrous magnesium sulfate were added under ice cooling, and after stirring at the same temperature for 30 minutes, insoluble materials were removed. Add to the reaction solution and stir for 2 hours under ice cooling. After the reaction, insoluble matter was removed, and 2.5 ml of a 20% n-butanol solution of potassium 2-ethylhexanoate was added to the solution, followed by 300 ml of ethyl ether to obtain the desired 6-{2-[8
-(1-piperazinyl)-6,7-dihydro-1-
Oxo-1H,5H-benzo[ij]quinolidine-2
-carboxamide]-2-phenylacetamide}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2
- Obtain 0.97 g of carboxylic acid potassium salt. Pale yellow amorphous crystals mp218-225℃ (red change) 245-250℃ (decomposition) Reference example 18 6-chloro-5-acetylaminoquinaldine 8
0.2 g of 5% platinum carbon was added to the solution, dissolved in 80 ml of acetic acid, and catalytically reduced using the Parr method at a hydrogen pressure of 4 kg/cm ² . After absorbing the theoretical amount of hydrogen, it was filtered and the liquid was concentrated under reduced pressure to obtain an oily product of 6-chloro-5-acetylamino-1,2,3,4-tetrahydroquinaldine.
Obtain 7.1g. The compound obtained from the NMR spectrum and elemental analysis values is confirmed to be the above compound. Reference example 19 6-chloro-5-acetylamino-1,2,
Add 100 ml of 47% hydrobromic acid and 60 ml of water to 25 g of 3,4-tetrahydroquinaldine and dissolve. After refluxing for 1 hour, a solution of 12 g of sodium nitrite dissolved in 24 ml of water was added dropwise under ice-cooling, taking care not to allow the reaction temperature to exceed 5°C. After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then poured into a solution of 45 g of cuprous bromide dissolved in 50 ml of 47% hydrobromic acid. After reacting at 80°C for 1 hour, cool on ice, make alkaline with 28% aqueous ammonia, and extract using 300ml of chloroform and Celite. The chloroform layer is dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to silica gel column chromatography [Silica gel: Wako C200, manufactured by Wako Pure Chemical Industries, Ltd.]
6-chloro-5-bromo-1,
4.5 g of 2,3,4-tetrahydroquinaldine are obtained. Light orange oil Confirm that the compound obtained from the NMR spectrum and elemental analysis is the above compound. Reference example 20 6-fluoro-5-bromo-1,2,3,4-
Add 3.0 g of diethyl ethoxymethylene malonate to 3.1 g of tetrahydroquinaldine and heat at 160℃.
Heat and react for 30 minutes. Next, add polyphosphoric acid prepared from 12 g of phosphorus pentoxide and 12 g of phosphoric acid, and add
Heat the reaction at 160°C for 1 hour. 100g of ice water after reaction
The precipitate was removed, washed with water, and dried. 50 ml of 10% caustic soda was added to the crystals and reacted at 100 to 110°C for 1 hour. After cooling, acidify with concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected, washed with water, and recrystallized from dimethylformamide to give 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid. Obtain 3.2g. White edge-like crystals, mp288-289℃ Reference example 21 Add 1.8g of diethyl ethoxymethylene malonate to 1.5g of 6-chloro-5-bromo-1,2,3,4-tetrahydroquinaldine and heat at 160℃ for 30 minutes. do. Next, polyphosphoric acid prepared from 7 g of phosphorus pentoxide and 7 g of phosphoric acid was added, and 1
React by heating for a period of time. After the reaction, pour into 100g of ice,
Adjust pH to 6-7 with 10N caustic soda solution. After removing the precipitate, it was added to 30 ml of concentrated hydrochloric acid and heated under reflux for 1 hour. After heating, add 50 ml of water and collect the precipitated crystals, wash with water and dry. Recrystallize with ethanol9
1.1 g of -chloro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid are obtained. White crystal Elemental analysis value (as C ₁₄ H ₁₁ NO ₃ BrC) C H N Theoretical value (%) 47.15 3.11 3.93 Actual value (%) 47.43 3.35 4.21 Example 1 8-chloro-6,7-dihydro-1-oxo −
19.2 g of 1H,5H-benzo[ij]quinolidine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl sulfoxide, and the mixture was heated and stirred at 170-180°C for 6 hours. After the reaction, the solvent was distilled off under reduced pressure, 500 ml of water was added to the resulting residue, the pH was adjusted to 2 with concentrated hydrochloric acid, the insoluble materials were removed, the liquid was concentrated to 100 ml under reduced pressure, and 10% sodium hydroxide was added. PH= in aqueous solution
9. After extracting the alkaline aqueous solution with chloroform and removing substances that dissolve in chloroform, the alkaline aqueous layer is left to stand, and precipitated crystals are collected.
The obtained crude crystals were dissolved in a 10% aqueous sodium hydroxide solution.
ml, treated with activated carbon, and adjusted to pH=8 with 10% aqueous hydrochloric acid solution. The precipitated crystals were collected, thoroughly washed with water, and then recrystallized from dimethylformamide to obtain white needle-like crystals of 8-(1-piperazinyl)-6,
7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 6.5g mp267-268℃ Obtained 8-(1-piperazinyl)-6,7-
Dihydro-1-oxo-1H,5H-benzo [ij]
6.4 g of quinolidine-2-carboxylic acid was suspended in 50 ml of water, 15 ml of 10% aqueous hydrochloric acid was added to remove insoluble matter, and the water was distilled off under reduced pressure to obtain white amorphous crystals.
-(1-piperazinyl)-6,7-dihydro-1-
Oxo-1H,5H-benzo[ij]quinolidine-2
- Obtain the carboxylic hydrochloride. Yield 5.7g mp300℃ or higherExample 2 8-chloro-5-methyl-6,7-dihydro-
Add 19.5 g of 1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid and 35.5 g of piperazine to 350 ml of anhydrous dimethyl sulfoxide to give 170-180 ml of anhydrous dimethyl sulfoxide.
Heat and stir at ℃ for 6 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain white amorphous crystals of 8-(1-piperazinyl)-5-methyl-6,7-
Dihydro-1-oxo-1H,5H-benzo [ij]
Quinolidine-2-carboxylic hydrochloride is obtained. Yield: 5.3g Add 100ml of water to the obtained 3.8g of hydrochloride, and add 1N-
Add sodium hydroxide and heat to dissolve. Next, when the pH is set to 8 with an aqueous hydrochloric acid solution, 8-
(1-Piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 3.1g mp264-265℃ Example 3 8-chloro-6,7-dihydro-1-oxo-
10 ml of anhydrous dimethyl sulfoxide was added to 4.0 g of 1H,5H-benzo[ij]quinolidine-2-carboxylic acid and 4.6 g of N-methylpiperazine, and the mixture was heated and stirred at 150 to 160°C for 8 hours. After the reaction is completed, the solvent and excess N-methylpiperazine are distilled off under reduced pressure, methanol-ether is added to the residue, and the precipitate is collected and washed with ether. The obtained crystals were suspended in 20 ml of 10% aqueous hydrochloric acid solution to remove insoluble matter, the liquid was neutralized with saturated sodium bicarbonate solution, and this solution was mixed with Amberlite.
After isolation and purification using column chromatography (eluent, water, ethanol) packed with LH-20 (manufactured by Tokyo Organic Chemical Industry Co., Ltd.), the 8- (4-methyl-1-piperazinyl)-6,7-dihydro-1-
Oxo-1H,5H-benzo[ij]quinolidine-2
- Obtain carboxylic acid. Yield 1.0g mp278-280.5℃ Example 4 8,10-dichloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-
Add 10 ml of anhydrous dimethyl sulfoxide to 4.4 g of carboxylic acid and 4.5 g of piperazine, and heat and stir at 160-170°C for 7 hours. Thereafter, the compound obtained after the treatment was treated with concentrated hydrochloric acid in the same manner as in Example 3 to obtain white amorphous crystals of 8-(1-piperazinyl)-10-chloro-6,7-dihydro-1.
-Oxo-1H,5H-benzo[ij]quinolidine-
2-carboxylic hydrochloride is obtained. Yield: 0.9g mp: 300°C or higher The compounds shown in Table 3 were obtained in the same manner as in Examples 1 to 4 using appropriate starting materials.

【table】

[Table] Example 14 8-(p-toluenesulfonyloxy)-6,7
-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (19.1 g) and piperazine (12.9 g) in anhydrous dimethyl sulfoxide (200 ml)
In addition, heat and stir in an autoclave at 150 to 160°C under a nitrogen stream at 10 atm for 18 hours. After the reaction is complete,
The solvent and excess piperazine are distilled off under reduced pressure, and even when methanol-ethanol is added to the residue, the precipitate that precipitates is collected and washed with ether. The obtained crystals were suspended in 200 ml of water and 40 ml of 10% aqueous hydrochloric acid solution, impurities were removed, and the liquid was neutralized with saturated sodium bicarbonate solution.
This solution was isolated and purified using column chromatography (eluent, water, ethanol) packed with Amberlite LH-20 (manufactured by Tokyo Organic Chemical Industry Co., Ltd.), and then recrystallized from dimethylformamide to form white needle-shaped crystals. 8-(1-piperazinyl)-6,7-dihydro-1
-Oxo-1H,5H-benzo[ij]quinolidine-
2-carboxylic acid is obtained. Yield 2.7g mp267-268℃ Example 15 8-(p-nitrobenzenesulfonyloxy)-
20.0 g of 6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid and 12.9 g of piperazine were dissolved in anhydrous dimethyl sulfoxide.
Add to 200 ml and heat and stir in an autoclave at 150-160°C under a nitrogen stream at 10 atm for 17 hours. Thereafter, the process was carried out in the same manner as in Example 14 to obtain 8-(1) white needle crystals.
-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 2.1g mp267-268℃ Example 16 8-methanesulfonyloxy-5-methyl-
15.4 g of 6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid and 12.9 g of piperazine were dissolved in anhydrous dimethyl sulfoxide.
Add to 200 ml and heat and stir in an autoclave at 8 atm and 170-180°C under nitrogen flow for 20 hours. Examples below
After treatment in the same manner as in 14, the obtained compound was treated with concentrated hydrochloric acid to obtain 8-(1-piperazinyl)- as a white amorphous crystal.
5-methyl-6,7-dihydro-1-oxo-
1H,5H-benzo[ij]quinolidine-2-carboxylic hydrochloride is obtained. Yield 1.7g mp300℃ or higher Example 17 8-benzenesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid 18.5g and piperazine
Add 12.9 g to 200 ml of anhydrous dimethyl sulfoxide, and heat and stir in an autoclave at 10 atm and 160 to 170° C. for 20 hours under a nitrogen stream. After treatment in the same manner as in Example 14, white needle-like crystals of 8-(1-piperazinyl)-
6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 1.5g mp267-268℃ Example 18 8-(0-Methoxybenzelsulfonyloxy)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid 20.7 g and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl oxide and heated to 150 ml at 10 atm under a nitrogen stream.
Heat and stir in an autoclave at ~160°C for 18 hours. Thereafter, the same treatment as in Example 16 was carried out to obtain a white amorphous crystal of 8-(1-piperazinyl)-5-methyl-
6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic hydrochloride is obtained. Yield 2.5g mp300°C or higher The compounds shown in Table 4 were obtained in the same manner as in Examples 14 to 18 using appropriate starting materials.

[Table] Example 26 8-(1-piperazinyl)-6,7-dihydro-
2.0 g of 1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid and sodium hydrogen carbonate
Add 1.2 g to 30 ml of water, stir at room temperature for 30 minutes, dropwise add 5 ml of an acetone solution of 1.0 g of benzoyl chloride under ice cooling, and stir for another 30 minutes at the same temperature.
Then stir at room temperature for 1.5 hours. The precipitated crystals were collected, washed with water, and then recrystallized from dimethylformamide to obtain white needle-like crystals of 8-(4-benzoyl-1).
-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 2.4g mp300℃ or higher Example 27 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine was added to a solution of 0.8g of potassium hydroxide dissolved in 20ml of water. After adding and dissolving 2.0 g of -2-carboxylic acid, methanesulfonyl chloride was added under stirring at room temperature.
After dropping 0.8 g, stir overnight at the same temperature. The precipitated crystals are collected, washed with water, dissolved in a 1N aqueous sodium hydroxide solution, treated with activated carbon, and neutralized with a 10% aqueous hydrochloric acid solution. The precipitated crystals were collected, washed with water, and recrystallized from dimethylformamide to give white needle-like crystals of 8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-
1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 1.0g mp300℃ or higherExample 28 8-(1-piperazinyl)-6,7-dihydro-
Add 2.0 g of potassium carbonate to 2.0 g of 1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid and water.
Add 20 ml of the solution and stir at room temperature for 30 minutes. Remove insoluble matter with 3 ml of 1N sodium hydroxide aqueous solution.
After adding and completely dissolving, 10 ml of a methanol solution of 0.9 g of benzyl chloride was added dropwise under ice cooling. After the completion of the dropwise addition, the reaction solution was heated under reflux for 3 hours, then treated with activated carbon, the solution was neutralized with a 10% aqueous hydrochloric acid solution, the precipitated crystals were collected, washed with water, and recrystallized from dimethylformamide to give pale yellow scale-like crystals. 8-
(4-Benzyl-1-piperazinyl)6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 0.25g mp274-278℃ Example 29 8,9-dichloro-5-
Methyl-6,7-dihydro-1-oxo-1H,
The following compound is obtained by reacting 5H-benzo[ij]quinolidine-2-carboxylic acid with piperazine, 4-methylpiperazine, 4-ethylpiperazine or 4-formylpiperazine. Γ8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H
-Benzo[ij]quinolidine-2-carboxylic acid White ridge-like crystals mp246-247℃ Γ 8-(1-piperazinyl)-9-chloro-5-
Methyl-6,7-dihydro-1-oxo-1H,
5H-Benzo[ij]quinolidine-2-carboxylic acid.
Monohydrochloride/monohydrate White amorphous crystal mp306-307℃ (blackening decomposition) Γ8-(4-methyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo -1H,5H-benzo[ij]quinolidine-2-carboxylic acid White ridge-like crystals mp292-293℃ Γ8-(4-ethyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -Oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid monohydriodide monohydrate White ridge-like crystals mp271-272℃ Γ8-(4-formyl-1-piperazinyl)-9 −
Chlor-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-
Carboxylic acid White edge-like crystals mp262-265℃ Example 30 -8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H- in the same manner as in Example 1
benzo[ij]quinolidine-2-carboxylic acid with 4-
8-(4-formyl-1-piperazinyl)-5-methyl-6,
7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. White ridge-like crystals mp300℃ or higher Example 31 9-Fluoro-8-chloro-5-methyl-6,
1.8 g of 7-dihydro-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid and N-
Add 15 ml of hexamethyltriamide phosphate to 36 ml of methylpiperazine, and heat and stir at 150-160°C for 4 hours. After the reaction, the solvent is distilled off under reduced pressure and the residue is washed with 10 ml of ethyl acetate. Add 100 ml of water to the resulting crystals, and then add acetic acid to adjust the pH to 4. Insoluble matters are filtered out, the liquid is treated with activated carbon, and then concentrated under reduced pressure.
Add 20 ml of water to the residue, adjust the pH to 9 with 10% caustic soda, and extract with 80 ml of chloroform. The extract was dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography [Silica gel: Wako C
8-(4-
Methyl-1-piperazinyl)-9-fluoro-5
-Methyl-6,7-dihydro-1-oxo-
0.8 g of 1H,5H-benzo[ij]quinolidine-2-carboxylic acid is obtained. mp276-278℃, white edge-like crystals Example 32 9-fluoro-8-bromo-5-methyl-6,
Anhydrous piperazine to 3 g of 7-dihydro-1-oxo-benzo[ij]quinolidine-2-carboxylic acid
Add 3.8g of hexamethyltriamide phosphate 30
ml and reacted for 5 hours under an argon stream at a bath temperature of 150-160°C. After the reaction, the solvent was removed under reduced pressure and the residue
Add 20 ml of ethyl acetate and collect the precipitated crystals. Next, dissolve the crystals in 300ml of water, add acetic acid, and adjust the pH.
Set it to 4. Activated carbon is added to the solution, and after filtering, the liquid is concentrated under reduced pressure. The obtained crystals were recrystallized from isopropanol-water (2:1) to obtain the desired 8-(1-piperazinyl)-9-fluoro-5-methyl-6,7.
2.7 g of -dihydro-1-oxo-benzo[ij]quinolidine-2-carboxylic acid hydrobromide are obtained. mp300℃ or higher White edge-shaped crystal Elemental analysis value (as C ₁₈ H ₂₀ N ₃ O ₃ F・HBr・H ₂ O) C H N Theoretical value (%) 48.65 5.18 9.46 Actual value (%) 48.53 5.11 9.32 Example 33 8-(4-methyl-1 obtained in Example 31 above)
-piperazinyl)-9-fluoro-5-methyl-
6,7-dihydro-1-oxo-benzo[ij]quinolidine-2-carboxylic acid was added to 48% hydrobromic acid, the solvent was distilled off under reduced pressure, and the residue was diluted with isopropanol:water (V/V) 2:1. Recrystallization gives white edge-like crystals of 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-benzo[ij]quinolidine-2-carboxylic acid. Hydrobromide monohydrate is obtained. mp298-299℃ (decomposition) Formulation example 1 8-(1-piperazinyl)-6,7 200mg -dihydro-1-oxo-1H,5H -benzo[ij]quinolidine-2-carboxylic hydrochloride Glucose 250mg distilled for injection Water Appropriate amount Total volume 5 ml Dissolve the compound of the present invention and glucose in distilled water for injection, inject into a 5 ml ampoule, purify with nitrogen, sterilize under pressure at 121°C for 15 minutes, and prepare an injection with the above composition. obtain. Formulation example 2 8-(1-piperazinyl)-6,7 100 g -dihydro-1-oxo-1H,5H -benzo[ij]quinolidine-2-carboxylic hydrochloride Aviciel (trade name, manufactured by Asahi Kasei Corporation) 40 g Cornstarch 30g Magnesium stearate 2g TC-5 10g (trade name: Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) Macrogol-6000 3g Castor oil 40g Methanol 40g The compound of the present invention, Abysiel, cornstarch, and magnesium stearate were mixed and polished. Post-glazing
Compress the tablets with an R10mm kine. The obtained tablet is 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. Formulation example 3 8-(1-piperazinyl)6,7 2g -dihydro-1-oxo-1H,5H -benzo[ij]quinolidine-2-carboxylic acid Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax The mixture is heated to a liquid state, and then the compound of the present invention, purified lanolin, and white petrolatum are added, heated until the mixture becomes a liquid state, and then stirred until it begins to solidify to obtain an ointment having the above composition.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenylalkyl group, or a group [Formula], and R ³ represents a hydrogen atom or a halogen atom, respectively. . ] A benzo[ij]quinolidine-2-carboxylic acid derivative and a salt thereof. 2 General formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ³ represents a hydrogen atom or a halogen atom, and R ⁴ represents a halogen atom, a lower alkanesulfonyloxy group, or an allenesulfonyloxy group, respectively. ] The benzo[ij]quinolidine-2-carboxylic acid derivative represented by the general formula [In the formula, R ² represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenylalkyl group, or a group [Formula]. ] By reacting piperazines represented by the general formula [In the formula, R ¹ , R ² and R ³ are the same as above] A benzo[ij]quinolidine-2-carboxylic acid derivative and its Salt manufacturing method. 3. The production method according to claim 2, wherein a compound in which R ⁴ represents a lower alkanesulfonyloxy group or an allenesulfonyloxy group is used as the compound of general formula (2).