JPS6344156B2 - - 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. According to Special Publication No. 51-6156, the general formula [In the formula, Y is lower alkyl, lower alkoxy, halogen, hydroxy, nitro, cyano, trifluoromethyl, amino, lower alkanamide, trifluoroacetylamide, or N,N-lower dialkylamino, and R is methyl, ethyl, or trifluoro. methyl, n is an integer from 0 to 2, when n is 2, Y is methylenedioxy or ethylenedioxy bonded to the adjacent ring position, m is an integer from 0 to 2, and R is a trifluoromethyl group; When m
is 1. ] It is already a known fact that the compound represented by is a known compound and that this compound has a wide range of activities against Gram-positive bacteria and Gram-negative bacteria. As a result of further research on the compounds represented by the above general formula (1), the present inventors found that among the compounds belonging to the above general formula (1), the general formula is not specifically described at all in the above publication. [In the formula, R ¹ represents a chlorine atom, and R ² represents a fluorine atom. ] benzo[ij]quinolidine-2
- It has been found that carboxylic acid derivatives and salts thereof have extremely significant antibacterial activity compared to the compounds specifically disclosed in the above publications. That is, benzo[ij]quinolidine-2-carboxylic acid represented by general formula (2) and its salts have a remarkable effect on Gram-positive bacteria and Gram-negative bacteria when compared with the compounds specifically disclosed in the above publication. Demonstrates antibacterial activity. In particular, the compound represented by the general formula (2) and its salt can be used against Streptococcus, Pseudomonas, and Enterobacter, for which the compounds specifically disclosed in the above publication have no antibacterial activity or only show weak antibacterial activity. It exhibits extremely remarkable antibacterial activity against , Proteus, etc. In addition, the compound represented by general formula (2) and its salts exhibit excellent antibacterial activity against Escherichia coli, Staphylococcus, etc., which account for a large proportion of the causes of infectious diseases. It also shows excellent antibacterial activity against Klebsiella and is a clinically useful compound. Also, the oral toxic dose of the compound of general formula (2) and its salts is much lower than the effective oral dose of the compound. Further, the compounds include penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin,
It also has antibacterial activity against bacteria resistant to commonly used antibiotics such as nalidixic acid. Furthermore, general formula (2)
The compound and its salt can be derived into the compound represented by the general formula (3) and its salt useful as an antibacterial agent as shown in the following reaction scheme-1.
Therefore, the compound of general formula (2) and its salt are useful as intermediates for synthesizing the compound of general formula (3) and its salt. Reaction formula-1 [In the formula, R ³ represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group. R ¹ and R ² are the same as above. ] The compound of general formula (3) and its salts exhibit antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria at low concentrations. The compound exhibits particularly strong antibacterial activity against Streptococcus, Pseudomonas, Enterobacter, Proteus, etc., on which conventional antibacterial agents have no or only weak antibacterial activity. In addition, this compound shows strong activity against Escherichia coli and Staphylococcus, which account for a large proportion of the causes of infectious diseases, and also shows sufficient activity against Serratia and Klebscilla, whose infectious diseases have become a problem in recent years. It is a clinically useful compound. As described above, the compound represented by the general formula (3) and its salts have significant characteristics in terms of the antibacterial spectrum and the fact that they exhibit strong antibacterial activity. Furthermore, in the case of conventional compounds with antibacterial activity, their antibacterial activity decreases due to binding with serum, whereas in the case of the compound of general formula (3) and its salts, the antibacterial activity surprisingly decreases. However, the activity tends to be enhanced. This means that the general formula
This means that when the compound (3) and its salts are administered to the human body, they exert a strong antibacterial effect in the blood. Moreover, the oral toxic dose of the compound of general formula (3) and its salts is much lower than the effective oral dose of the compound. Further, the compounds include penicillin, cephalosporin, ampicillin, streptomycin,
It also has antibacterial activity against bacteria resistant to commonly used antibiotics such as erythromycin, kanamycin, and nalidixic acid. The present invention was completed based on such surprising findings that no one could have predicted in the past. The compound of the present invention can be produced by various methods, and a preferred example thereof is, for example, by the method shown in Reaction Scheme-2 below. The compound of the present invention can also be produced according to the method described in Japanese Patent Publication No. 51-6156. Reaction formula-2 [In the formula, R ⁴ and R ⁵ represent a lower alkyl group. Also
R ¹ and R ² are the same as above. ] In the above reaction scheme-2, the nitration reaction of the compound represented by the general formula (4) is carried out under the usual nitration reaction conditions for aromatic compounds, for example, without a solvent or in a suitable inert solvent. This is done using a curing agent. Examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of nitration agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, fuming sulfuric acid, 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, usually in excess, relative to the raw material compound, and the reaction is preferably 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 (5) 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 (6) obtained above can be carried out by applying Sandmeyer reaction via diazotization reaction. Diazotization of the compound of general formula (6) is 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 water, hydrochloric acid, or sulfuric acid at -30°C to room temperature for 0.5 to 2 hours. It is carried out to an advantageous extent. The diazonium salt of general formula (6) thus produced is usually isolated or not isolated, and is treated with a halogenating agent such as cuprous chloride or tetrafluoroboron hydride at 0 to 50°C for 0.5 to 2 hours. A compound represented by the general formula (7) is obtained by a certain degree of reaction. 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 (7) obtained above is carried out by catalytic reduction of the compound of general formula (7) in an appropriate inert solvent under acidic conditions. As the acid used here, a wide variety of acids that can form salts 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 rhdenium-carbon. The above reduction reaction is advantageously carried out at room temperature to 50°C for about 1 to 10 hours. Thus, the general formula (8)
A compound represented by is obtained. Further, the compound of general formula (8) is produced by reducing the pyridine ring of the compound of general formula (6) to produce a compound of general formula (9), and then substituting the amino group of this compound of general formula (9) with halogen. It is also manufactured by The reduction of the pyridine ring of the compound of general formula (6) is given by the above general formula (7).
can be carried out in a similar manner to the reduction of the pyridine ring of the compound. Further, the halogen substitution of the amino group of the compound of general formula (9) can be carried out in the same manner as the halogen substitution of the amino group of the compound of general formula (6). Furthermore, the compound of general formula (9) can also be produced by reducing the compound of general formula (5). The reduction of the compound of general formula (5) can be carried out in the same manner as the reduction of the pyridine ring of the compound of general formula (7) above. The reaction between the compound of general formula (8) and the compound of general formula (10) can be carried out without a solvent or in a solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc., preferably without a solvent. It will be held in The ratio of compound (10) to compound (8) to be used is usually equal to or more than the same molar amount, preferably an equimolar amount in the reaction without a solvent, and preferably 1.1 to 1.5 times the molar amount in the reaction in a solvent. Good. The reaction temperature is usually about room temperature to 150℃, preferably 100 to 130℃
The reaction is usually completed in 0.5 to 6 hours, and the compound represented by the general formula (11) can be easily obtained. The cyclization reaction of the compound (11) 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. For example, when employing a cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, diethylene glycol, and dimethyl ether is used, and
Heating conditions of 100 to 250°C, preferably 150 to 200°C can be employed. In addition, when an oxidation method using an acidic substance is employed, it is used in an equimolar amount to a large excess amount, preferably 10 to 20 times the amount of compound (11), and is usually heated at 100 to 150°C.
The reaction may be carried out for about 0.5 to 6 hours. In this way, a compound of general formula (12) is produced. The hydrolysis reaction of compound (12) obtained by the above cyclization reaction can be carried out using a basic compound such as sodium hydroxide, potassium hydroxide, or barium hydroxide, a mineral acid such as sulfuric acid, hydrochloric acid, or nitric acid, or acetic acid. , in the presence of a conventional decomposition solvent such as an organic acid such as an aromatic sulfonic acid. 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 (2) is easily obtained. Further, the compound represented by general formula (2) can be treated with a pharmaceutically acceptable basic compound to form a carboxylate salt, and the present invention also includes such salts. 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 compound of general formula (2) and its salt thus obtained can be easily isolated and purified by conventional separation means after the above-described reaction steps are completed. Examples of separation means include solvent extraction, dilution, precipitation, and recrystallization. When using the compound represented by general formula (2) and its salt as an antibacterial agent, fillers, extenders, binders, wetting agents, disintegrants, surface It is formulated into a pharmaceutical composition by a conventional method together with a diluent or excipient such as an active agent and a lubricant. 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, pill solutions, suspensions, emulsions, granules, and capsules, they are administered orally; in the case of injections, they are administered alone or intravenously in a mixture with normal replacement fluids such as glucose and amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it can be administered rectally; and in the case of an ointment, it can be applied. The dosage of the compound of the present invention as an antibacterial agent is appropriately selected depending on the purpose of use, symptoms, etc., and usually a pharmaceutical composition containing about 10 mg/5 g/body of the compound of the present invention per day is administered in 3 to 4 divided doses. good. <Antibacterial activity> Antibacterial test In order to investigate the antibacterial activity of the test compounds shown below against various bacteria, the minimum growth-inhibiting concentration was determined by the agar dilution plate method [CHEMOTHERAPY, 22 , 1126-1128 (1974)]
reference〕. The results obtained are shown in Table 1. The number of various bacteria is 1× ¹⁰⁸ bacteria/ml (OD660mμ, 0.07-0.16)
and 1×10 ⁶ bacteria/ml (100-fold dilution). (Test bacteria) No.1 Esherichia coli NIHJ JC-2
(IFO12734) No.2 Klebsiella pneumoniae No.3 Proteus rettgeri NIH96 No.4 Pseudomonas aeruginosa E-2 No.5 Pseudomonas aeruginosa NCTC 10490 No.6 Pseudomonas aeruginosa ATCC 10145 No.7 Salmonella tyypphi O-901
(NCTC8393) No.8 Shigella sonnei EW33 No.9 Serratia marcescens IFO12648 No.10 Staphyrococcus aureus FDA 209 P No.11 Streptococcus pyogenes IID S-23 (Test compound) Compound A 9-fluoro-8-chloro-5-methyl -6,7-dihydro-1-oxo-1H,5H
-Benzo[ij]quinolidine-2-carboxylic acid (compound of the present invention) Compound B 9-fluoro-5-methyl-6,7-
Dihydro-1-oxo-1H,5H-benzo [ij]
Quinolidine-2-carboxylic acid (flumequin)
(Compound described in Example 2 of Japanese Patent Publication No. 51-6156) Compound C 8-chloro-6,7-dihydro-5,
9-dimethyl-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid
Compound described in Example 6 of Publication No.-6156) Compound D 8-chloro-6,7-dihydro-5-
Methyl-1-oxo-1H,5H-benzo [ij]
Quinolidine-2-carboxylic acid (Special Publication No. 51-6156
Compound described in Example 63 of the publication) Compound E 8-(4-methyl-1-piperazinyl)
-9-Fluoro-5-methyl-6,7-dihydro-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (compound of Reference Example 9 derived from the compound of the present invention) Compound F 1-ethyl -1,4-dihydro-7-
Methyl-4-oxo-1,8-naphthylidene-
3-carboxylic acid (nalidixic acid) (control compound)

[Table] Reference examples and examples are listed below. Reference Example 1 Dissolve 11 g of 6-chloroquinaldine in 15 ml of concentrated sulfuric acid and cool on ice. Next, add 7.1g of potassium nitrate to concentrated sulfuric acid.
Drop the solution dissolved in 20 ml. 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, mpi 23-124℃ Reference example 2 Dissolve 25g of stannous chloride in 50ml of concentrated hydrochloric acid, add 6.7g of 5-nitro-6-chloroquinaldine, and dissolve on a water bath.
React for 30 minutes at 80-90°C. Cool the reaction solution on ice 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 3 4 g of 5-amino-6-chloroquinaldine was dissolved in 40 ml of concentrated hydrochloric acid and cooled on ice. Next, a solution of 2.1 g of sodium nitrite dissolved in 5 ml of water was added dropwise under ice. 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 4 In the same manner as in Reference Example 3, 6-fluoro-5-chloro-1,2,3,4-tetrahydroquinaldine was obtained as a pale yellow oil. NMR spectrum δ ^CDCl3 _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 5 5 , 5.5 g of 6-dichloroquinaldine and 50 ml 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 ^CDCl3 _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 6 In the same manner as in Reference Example 5, 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 7 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 large amount of hydrogen, it was filtered and the liquid was 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 8 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 ^CCl4 _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 9 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 3.6 ml of methylpiperazine, and heat and stir at 150 to 160°C for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with 10 ml of ethyl acetate. 100ml of water to the resulting crystals
and then 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 20ml of water to the residue and pH it with 10% caustic soda.
9 and extracted with 80 ml of chloroform. The extract was dried over anhydrous sodium sulfate, concentrated, and isolated using silica gel column chromatography [Silica gel: Wako-C200, manufactured by Wako Pure Chemical Industries, Ltd., eluent chloroform:methanol = 9:1]. 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-shaped crystals Example 1 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, polyphosphoric acid prepared from 7 g of phosphorus pentoxide is added, and the mixture is heated and reacted at 140 to 150°C for 1 hour. After the reaction, pour into 100 g of ice and adjust the 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. Recrystallized from ethanol to give 9-fluoro-8-chloro-5-methyl-6,7-dihydro-
1.2 g of 1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid are obtained. mp297-298℃, white edge-shaped crystal preparation example 1 9-fluoro-8-chloro-5-methyl-6,7
-dihydro-1-oxo-1H,5H-benzo [ij]
Quinolidine-2-carboxylic acid 100g Avicel [trade name, Asahi Kasei Corporation] 40g Cornstarch 30g Magnesium stearate 2g TC-5 [trade name Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose] 10g Macrogol-6000 3g Castor Oil: 40g Methanol: 40g The compound of the present invention, Avicel, cornstarch and magnesium stearate are mixed, polished and sugar-coated.
Compress the tablets with an R10mm kine. The obtained tablets were TC-
5. Coat with a film coating agent consisting of Macrogol-6000, castor oil and methanol to produce film-coated tablets having the above composition.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a chlorine atom, and R ² represents a fluorine atom. ] A benzo[ij]quinolidine-2-carboxylic acid derivative and a salt thereof. 2 General formula [In the formula, R ¹ represents a chlorine atom, and R ² represents a fluorine atom. ] Compounds and general formulas represented by (In the formula, R ⁴ and R ⁵ represent lower alkyl groups.) [In the formula, R ¹ , R ² and R ⁴ are the same as above. ] A general formula produced by cyclizing the compound represented by [In the formula, R ¹ , R ² and R ⁴ are the same as above. ] The compound represented by is hydrolyzed to form the general formula [In the formula, R ¹ and R ² are the same as above. ] A method for producing benzo[ij]quinolidine-2-carboxylic acid derivatives and salts thereof, which comprises obtaining benzo[ij]quinolidine-2-carboxylic acid represented by: