JPS6043341B2 - carbostyril derivatives - Google Patents

Description

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

The compound of the present invention is a new compound, and has the general formula: [
I] [In the formula, R represents a hydrogen atom, a lower alkyl group, or a pyridyl alkyl group, and the bond at the 3.4-position of the carbostyryl skeleton represents a single bond or a double bond, respectively.

]. The compound has anti-inflammatory effects, platelet aggregation inhibitory effects, anti-bacterial effects, and the effect of lowering the lipid content in the blood, especially cholesterol, phospholipids, triglycerides, etc., and is effective as an anti-inflammatory agent, antithrombotic agent, antibacterial agent, and arteriosclerosis agent. It is useful as a treatment and prophylaxis for diseases. In the above general formula [I], the lower alkyl group represented by R may be a straight chain or branched alkyl group having 1 to 4 carbon atoms, specifically methyl, ethyl, propyl, isopropyl. , butyl, sec-butyl groups, etc.
Examples of the pyridyl alkyl group include groups in which a linear or branched alkylene group having 1 to 4 carbon atoms is bonded to a pyridyl group, specifically 3-pyridylmethyl, 2-(pyridine-3- yl)ethyl, 3-(pyridin-4-yl)propyl, 1,1-dimethyl-2-(pyridin-3-yl)ethyl, 2-methyl-3-(pyridin-2-yl)propyl, 4-(pyridin-2-yl) An example is a butyl group.

Representative compounds of the present invention are listed below.

06-carboxy 3.4-dihydrocarbostyryl 06-carboxycarbostyryl○6-ethoxycarbonyl-3●4-dihydrocarbostyryl○6-ethoxycarbonylcarbostyryl06-(3-pyridylmethoxycarbonyl)-3,4-dihydro Calbostyril 06
-(3-pyridylmethoxycarbonyl)carbostyryl 06-(Sec-butoxycarbonyl)-3●4-dihydrocarbostyryl○6-isopropoxycarbonylcarbostyryl○6-butoxycarbonyl-3●4-dihydrocarbostyryl06-[ 2 (pyridin-3-yl)
Ethoxycarbonyl]-3●4-dihydrocarbostyryl 06-[2-methyl-3-(pyridin-2-yl)propoxycarbonyl]carbostyryl 06-[3-(pyridin-4-yl)propoxycarbonyl]-3●4-
Dihydrocarbostyrinore 06-[1●1-dimethyl-2-(pyridin-3-yl)ethoxycarbonyl]-carbostyrinore Z The compound of the present invention represented by the above general formula [1] can be produced by various methods, For example, it is manufactured as shown in the following formula.

(In the above, X represents a halogen atom.

) That is, a known acetylcarbostyryl derivative represented by the general formula [■] and a halogen are reacted to form the general formula [■]
An α-dihalogenoacetylcarbostyryl derivative represented by is obtained, and then a basic compound is reacted with the α-dihalogenoacetylcarbostyryl derivative to produce a carbostyryl derivative represented by the general formula [1-1] of the present invention.

Further, a carbostyryl derivative represented by the following general formula [1-2] is produced by esterifying the compound of general formula [1-1]. [In the formula, R'' is a lower alkyl group or a pyridyl alkyl group] The compounding ratio of the compound of the general formula [■] and the halogen is not particularly limited and is appropriately selected within a wide range, but usually the latter is 2 to 2 of the former. ~5 times molar, preferably 2-3
It is better to use twice the molar amount.

The reaction between the compound of general formula [■] and a halogen is usually carried out in a solvent. Examples of the solvent used include ethers such as tetrahydrofuran and dioxane, carboxylic acids such as acetic acid and propionic acid, aromatic hydrocarbons such as benzene, dimethylformamide, and dimethylsulfoxide. In this reaction, calcium carbonate or the like may be added as a deoxidizing agent to remove by-produced hydrogen halide. The reaction is usually carried out at a temperature of 0 to 50°C, and is usually completed within several hours to about 2 minutes. The reaction for obtaining the compound of general formula [1-1] from the compound of general formula [■] is preferably carried out in an aqueous solution in the presence of a basic compound.

As the basic compound, a wide variety of known compounds can be used, such as alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The amount of the basic compound used is not particularly limited and can be selected within a wide range,
Generally, it is preferable to use the compound in an amount ranging from 2 times the mole to a large excess amount relative to the compound of the general formula [■]. The reaction is usually carried out at 50 to 150°C,
Preferably, the temperature is 70 to 120°C, and usually 1 to 120°C.
The reaction completes in about 1 full hour. The esterification reaction between the compound represented by the general formula [1-1] and the alcohol represented by the general formula [in the formula, R'' is the same as above] is carried out under normal esterification reaction conditions.The above reaction This is usually carried out in the presence of a catalyst. Any catalyst commonly used for esterification reactions can be used. Specific examples include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, Inorganic acids such as chloric acid, trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfonic acid, p-
Examples include organic acids such as tosylic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride, acetone, and dimethyl acetal. Acidic ion exchange resins are also used. Further, the above reaction is carried out without a solvent or in the presence of a solvent. As the solvent, a solvent commonly used in esterification reactions is used. Specific examples include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, dichloroethane,
Examples include halogenated hydrocarbons such as chloroform and carbon tetrachloride, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. Further, the above reaction is advantageously carried out using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, oil-water calcium sulfate, or phosphorus pentoxide. In the above esterification reaction, the proportions of the compounds represented by the general formulas [1-1] and [■] are not particularly limited and can be selected as appropriate; When using a solvent, the latter should be equimolar to the former.
It is desirable to use about 5 times the molar amount, preferably about the same molar to 2 times the molar amount. The reaction temperature is not particularly limited, but is usually -20
A temperature of about 0 to 200°C, preferably about 0 to 150°C can be adopted. The compound of the present invention represented by the general formula [1-2] is produced as described above.

After completion of the reaction, the compound of the present invention thus obtained is isolated from the reaction mixture according to a conventional method. For example, when a solvent is used, it can be obtained by distilling it off, or by diluting or extracting with water, petroleum ether, ether, n-hexane, etc. The obtained compound can be further purified, if necessary, by conventional methods such as recrystallization, solvent extraction, column chromatography, and thin layer chromatography. The present invention will be clearly explained by reference examples and examples below.

Reference Example 15.1y of 6-acetyl-3,4-dihydrocarbostyryl was added to 100mt of acetic acid and dissolved, and the internal temperature was 35-40.
While keeping at ℃, Br2ll. 10ml of acetic acid containing 2ml
Add the solution to 3. It takes a while to be added dropwise while stirring.

After leaving the reaction solution overnight, the precipitated crystals are filtered out and washed with a small amount of acetic acid. The obtained crystals were treated with activated carbon in an ethanol solvent and recrystallized from ethanol to obtain 6-dibromoacetyl-3●4-dihydrocarbostyryl as flame yellow needle-like crystals.19.
Get 5y. Melting point 168-169.5 Obtained C Example 1 Dissolve 26f NaOH in 250 mL of water and
While stirring at °C, 35f of 6-dibromoacetyl-3,4-dihydrocarbostyryl was added and reacted for 3 hours.

After cooling, insoluble matter is filtered off, the mother liquor is acidified with concentrated hydrochloric acid, and the precipitated crystals are collected and washed with water. The obtained crystals were recrystallized twice from ethanol to give pale yellow amorphous crystals of 6-carboxy 3.4.
-dihydrocarbostyril 10.5f is obtained. Melting point 32
4.5-32rC (decomposition) Example 2 A reaction is carried out in the same manner as in Example 1 to obtain colorless needle-like 6-carboxycarbostyryl from 6-dibromoacetylcarbostyryl.

Melting point: 353-35rC Example 3 To 300 mt of ethanol, 3.8 y of 6-carboxy 3●4-dihydrocarbostyryl and 0.5 ml of concentrated acid were added and refluxed for 5 hours.

After the reaction, concentrate the reaction solution and add 300ml of chloroform to the residue.
The chloroform layer is washed with dilute NaHCO3 water and water, and concentrated. The residue was recrystallized from chloroform-petroleum ether to obtain 3.1 g of 6-ethoxycarbonyl-3,4-dihydrocarbostyryl in the form of colorless needles.
Melting point: 178-179.5sC Example 4 A reaction is carried out in the same manner as in Example 3 to obtain colorless needle-like 6-ethoxycarbonylcarbostyryl from 6-carboxycarbostyryl.

Melting point 230.5-23rC Example 5 6-carboxy 3●4-dihydrocarbostyryl 2.0y. ．． p-Toluenesulfonic acid monohydrate 4.5y
13-pyridine methanol 1.3y and benzene 200
Take Tn1 and stir under reflux for 8 hours.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. Double bonds are shown respectively. ] A carbostyryl derivative represented by