JPS628114B2 - - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel quinoline derivatives.

The quinoline derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula [].

[In the formula, R is a hydrogen atom or a lower alkyl group,
represents a halogen atom, and Y represents a lower alkylene group. ] The compound of the present invention has an antihistamine effect and a central nervous system depressant effect, and therefore can be used as an antihistamine agent for allergic symptoms of the respiratory respiratory tract such as combing, nasal discharge, itching of the eyes, nose, and throat, hay fever, hay fever, acute It is useful as a therapeutic and preventive agent for hives, angioedema, pruritus, allergic rhinitis, etc., and as a central nervous system depressant, such as a central muscle relaxant,
It is useful as a sleep-inducing drug, a pre-surgery drug, an anti-schizophrenic drug, a drug for treating neurosis and psychosomatic disorders, an antipyretic analgesic, a sedative, an anti-manic drug, etc. The compounds of the present invention are also useful as intermediates for synthesizing thiocarbostyryl derivatives useful as antihistamines and central nervous system depressants, as described below.

In this specification, examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl groups.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of lower alkylene groups include methylene, ethylene, trimethylene, 2-methyltrimethylene, 1
-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethylethylene, 2,2-dimethyltrimethylene groups, and the like.

Representative compounds of the present invention are listed below.

Γ 2-chloro-7-[3-(4-phenyl-1-
piperazinyl)propoxy]quinolineΓ 2-chloro-5-[3-(4-phenyl-1-
piperazinyl)propoxy]quinolineΓ 2-chloro-6-[3-(4-phenyl-1-
piperazinyl)propoxy]quinolineΓ 2-chloro-8-[3-(4-phenyl-1-
Piperazinyl)propoxy]quinoline Γ 2-chloro-4-methyl-7-[3-(4-phenyl-1-piperazinyl)propoxy]quinoline Γ 2-chloro-4-methyl-5-[3-(4-phenyl- 1-piperazinyl)propoxy]quinoline Γ 2-chloro-4-ethyl-6-[3-(4-phenyl-1-piperazinyl)propoxy]quinoline Γ 2-fluoro-5-[3-(4-phenyl-1
-piperazinyl)propoxy]quinolineΓ 2-bromo-7-[3-(4-phenyl-1-
piperazinyl)propoxy]quinolineΓ 2-chloro-5-[2-(4-phenyl-1-
piperazinyl)propoxy]quinolineΓ 2-chloro-7-[4-(4-phenyl-1-
2-chloro-7-[2-methyl-3-(4-phenyl-1-piperazinyl)propoxy]quinoline Γ 2-chloro-5-[6-(4-phenyl-1-
Piperazinyl)hexyloxy]quinoline The compound of the present invention can be produced by various methods, and one preferred example thereof is produced by the method shown in Reaction Scheme-1 below.

[In the above formula, X ¹ and X ² represent halogen atoms. R, X and Y are the same as above. ] In Reaction Scheme-1, the reaction between the compound represented by the general formula [2] and the compound represented by the general formula [3] is carried out using a basic compound as a dehydrohalogenation agent in an appropriate solvent at room temperature to 200°C. Preferably 50-150
It is carried out within a few hours to 15 hours at ℃. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, diethylene glycol, and dimethyl ether, and aromatic hydrocarbons such as benzene, toluene, and xylene. , dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. Basic compounds that can be used as dehydrohalogenation agents include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metallic potassium, sodium Examples include tertiary amines such as amide, pyridine, quinoline, triethylamine, and tripropylamine. In the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can also be used as a reaction promoter. The ratio of the compound represented by the general formula [2] and the compound represented by the general formula [3] is not particularly limited, but the latter is usually 1 to 5 moles or more per 1 mole of the former, preferably 1 to 1.2 moles. It is best to use a molar amount.

The reaction between the compound represented by the general formula [4] and the compound represented by the formula [5] is carried out in the absence of a solvent or in a common inert solvent at room temperature to 200°C, preferably at 60 to 120°C.
The process is completed within several hours to 24 hours at a temperature of ℃. As the inert solvent, the lower alcohols mentioned above,
Any of the above-mentioned ethers, the above-mentioned aromatic hydrocarbons, polar solvents such as dimethylformamide, dimethyl sulfoxide, etc. can be used. The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. As the basic compound, for example, tertiary amines such as calcium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, and quinoline can be used. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula [4] and the compound represented by the formula [5] in the above reaction is usually at least 1 mole of the former, preferably 1 to 5 times the mole of the latter, more preferably 1 mole or more of the latter.
It should be ~1.2 times the mole.

The reaction between the compound represented by the general formula [6] and the compound represented by the general formula [7] is carried out in the absence of a solvent or in a suitable inert solvent, usually at a temperature of 50 to 150°C, preferably 80 to 110°C. It will be completed in about 3 to 8 hours. Examples of the inert solvent include the above-mentioned ethers, the above-mentioned aromatic hydrocarbons, dimethyl sulfoxide, and dimethylformamide. Regarding the ratio of the compound of general formula [6] and the compound of general formula [7], when the reaction is carried out without a solvent, it is usually best to use a large excess of the latter relative to the former; When the reaction is carried out, the latter is usually used in an equimolar amount or more, preferably 1 to 3 times the molar amount of the former. In this way, a compound represented by the above general formula [1] is obtained.

The quinoline derivative represented by the general formula [1] obtained above can be easily converted into an acid addition salt by acting with a pharmaceutically acceptable acid,
Such salts are also included in the compounds of the present invention. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid,
Organic acids such as malonic acid, methanesulfonic acid and benzoic acid can be mentioned.

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like.

Note that the present invention naturally includes optical isomers of the compound of general formula [1].

The quinoline derivative represented by the above general formula [1] and its salt are induced into the thiocarbostyryl derivative represented by the general formula [8], which is useful as an antihistamine and a central nervous system depressant, as shown in the following reaction scheme-2. obtain.

[In the formula, R, X and Y are the same as above. ] Reference examples and examples are listed below.

Reference Example 1 16.1 g of 7-hydroxycarbostyryl and 9 g of potassium hydroxide are mixed in 150 ml of isopropanol, stirred at 70-80°C for 30 minutes, then 25 g of 1,3-bromochloropropane is added and heated under reflux for 6 hours. After the reaction is complete, pour the reaction solution into 200 ml of 2N aqueous sodium hydroxide solution, remove insoluble matter, wash with water and dry. The crude crystals were recrystallized from ethanol to obtain 18.2 g of 7-(3-chloropropoxy) carbostyril in the form of yellow needles.

Melting point: 130-133°C Reference Example 2 In the same manner as in Reference Example 1, colorless needle-like crystals of 4-methyl-7-(3-chloropropoxy)carbostyryl are obtained. Melting point 169-170℃ Reference example 3 7-(3-chloropropoxy)carbostyryl
4.8g and 4g of phenylpiperazine in toluene 40g
ml and heated under reflux for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in 80 ml of chloroform.
The chloroform layer is washed twice with a 5.0% aqueous sodium bicarbonate solution and then twice with water, dried over anhydrous sodium sulfate, and then the chloroform is distilled off. The residue was recrystallized from methanol to give yellow needles of 7-
3.2 g of [3-(4-phenyl-1-piperazinyl)propoxy]carbostyryl are obtained.

Melting point: 237-238°C Reference Example 4 Colorless powdery crystals of 4-methyl-7-[3-(4-phenyl-1-piperazinyl)propoxy]carbostyril were obtained in the same manner as in Reference Example 3.

Melting point 253-254℃ Reference example 5 2-chloro-7-[3-(4-phenyl-1-piperazinyl)propoxy]quinoline under a nitrogen stream
1.5 g and 2.0 g of thiourea in dimethylformamide
After stirring for 5 hours at 60-70℃, add 5% to the residue after distilling off dimethylformamide under reduced pressure.
Add 50 ml of % sodium bicarbonate aqueous solution and extract the organic matter with chloroform. Wash the chloroform layer with water,
After dehydration, the residue after chloroform distillation is recrystallized from benzene-chloroform to yield yellow needle-like crystals of 7-[3-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl 1/2 hydrate. 0.8g is obtained.

Melting point 213-215°C Example 1 7-[3-(4-phenyl-1-piperazinyl)
Propoxy] carbostyril 2g with phosphorus oxychloride
The mixture was mixed with 30 ml of water, heated under reflux for 7 hours, concentrated under reduced pressure, and 80 ml of water was added to the residue, which was left overnight. When the precipitate was washed with water and recrystallized from ethanol, yellow needle-like crystals of 2-chloro-7-[3-(4-phenyl-1-piperazinyl)propoxy]-quinoline were obtained.
1.5g is obtained. Melting point: 206-208°C Example 2 3 g of 4-methyl-7-[3-(4-phenyl-1-piperazinyl)propoxy] carbostyril was mixed with 30 ml of phosphorus oxychloride, and heated under reflux for 5 hours.
Concentrate under reduced pressure, add 50 ml of 5% sodium hydrogen carbonate to the residue under ice cooling, and extract the organic layer with chloroform. After washing the chloroform layer with water and dehydrating it, the chloroform was distilled off and the residue was recrystallized from ligroin to give pale yellow needle-like crystals of 4-methyl-2-chloro-7-[3-(4-phenyl-1-piperazinyl). ) Obtain 2.2 g of propoxy]quinoline.

Melting point 81-83°C Example 3 2-chloro-6-[3-(4-phenyl-1
-piperazinyl)propoxy]carbostyryl is obtained.

Pale yellow needle crystals (recrystallization solvent: ethanol) Melting point 193-195℃.

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom or a lower alkyl group,
represents a halogen atom, and Y represents a lower alkylene group. ] A quinoline derivative represented by these and its salt.