JPS5919540B2 - carbostyril derivatives - Google Patents

Description

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

The compound of the present invention is a new substance, and is a carbostyryl derivative represented by the general formula [wherein R_ and R_2 are the same or different and represent a hydrogen atom or a lower alkyl group].

The compound has a β-adrenergic inhibitory effect and is useful as a therapeutic agent for arrhythmia, angina pectoris, hypertension, and the like. In the above general formula (I), examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a probyl group, an isopropyl group, a butyl group, sec-9 Butyl group, tert
Examples include -butyl group, pentyl group, hexyl group, etc.

Representative compounds of the present invention are listed below.

5-(1-Hydroxy-2-amino)butylcarbostyryl 55-(l-hydroxy-2-ethylamino)butylcarbostyryl 5-(1-hydroxy-2-amino)0
pylamino)hexylcarbostyryl 5-(1-hydroxy- 2-iso-propyla0 mino)butylcarbostyryl 5-(1-hydroxy- 2-butylamino)butylcarbostyryl 5-(1-hydroxy-
2-butylamino-3-methyl)butylcarbostyryl 55-(1-hydroxy-2-sec-butylamino)butylcarbostyryl 5-(l-hydroxy-
2-pentylamino)butylcarbostyryl 5-(l-
Hydroxy-2-hexylamino)"0 Ethylcarbostyryl The compound of the present invention can be synthesized by various methods, for example, the general formula OHR_, CH-CH-NHR_2 '゜ □O(■) [In the formula, R is a lower alkyl group or represents an aryl group, and is produced by hydrogenating a carbostyril derivative represented by the following formula.

The compound of the general formula () is a new compound, for example, an 8-hydroxycarbostyryl derivative represented by the general formula [wherein R and R2 are the same as above] and a general formula [wherein X represents a halogen atom and R3 is produced by reacting with an alkyl or arylsulfonyl halide represented by the same formula as above].

The reaction between the compound of formula (9) and the compound of formula (IV) is expressed by formula (1
11), for example, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal amides such as sodium amide and potassium amide, metallic potassium,
Alkali metals such as sodium metal, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, n
- Reacting butyllithium with a metal alkyl compound or the like to lead the hydroxyl group at the 8-position of the carbostyryl group to an alkali metal salt.

The reaction leading to the alkali metal salt is carried out by using the alkali metal or its compound in a suitable solvent, such as aromatic solvents (benzene, toluene, xylene, etc.), n-hexane, cyclohexane, ether solvents (diethyl ether,
2-dimethoxyethane, dioxane, tetrahydrofuran, etc.), in an aprotic polar solvent (dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc.) at 0 to 200°C, preferably at room temperature.
Progresses from 0 minutes to 5 hours. Then, an alkyl or arylsulfonyl halide of general formula (IV) (e.g., methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, para-toluenesulfonyl chloride, etc.) is added to the obtained alkali metal salt of the 8-hydroxycarbostyryl derivative. Reaction temperature 0~
The reaction proceeds suitably at 200° C., preferably at 0° C. to room temperature for 1 to 5 hours to obtain a compound of formula (). The amount of alkali metal hydroxide or its compound to be used is determined by the formula (
The amount is usually 1.0 to 5.0 times the mole, preferably 1.0 to 1.2 times the mole of the ID compound. Further, the amount of the compound of formula () to be used is usually 1.0 to 1.0 to that of the compound of formula (nl).
It is 5.0 times the mole, preferably 1.0 to 1.2 times the mole.

The hydrogenation reaction of the compound of formula (H) is carried out in a solvent such as water, 10% aqueous metal hydroxide solution, methanol, ethanol, isopropanol, ether, dioxane, or the like.

At this time, a hydrogenation catalyst such as palladium black, palladium carbon, platinum black, Raney nickel, etc., preferably 5 to 20% palladium carbon, is used as a catalyst, and at normal pressure to 10 atm.
The reaction is preferably carried out in a hydrogen stream at normal pressure at a reaction temperature of 0°C to 40°C, preferably at room temperature, for 5 to 20 hours with thorough shaking or stirring. The amount of catalyst used is 0.1 to 30%, preferably 5% to the compound of general formula ().
~20%, and palladium on carbon preferably proceeds when used at 10 to 20%. The compounds of the invention are isolated from the reaction mixture in conventional manner after the reaction has ended. For example, it can be obtained by distilling off the solvent from the reaction mixture. The obtained compound can be further purified, if necessary, using general conventional methods such as fractional recrystallization, column chromatography, thin layer chromatography, etc. The compounds of the present invention can be easily converted into acid addition salts by reacting with pharmacologically acceptable inorganic or organic acids.

Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and examples of organic acids include oxalic acid, maleic acid, succinic acid, malonic acid, acetic acid, salicylic acid, citric acid, and benzoic acid. The present invention naturally includes optical isomers of the carbostyril derivative of general formula (1). Reference Examples and Examples will be described below to explain the present invention in more detail, but the present invention is not limited thereto. Reference Example 1 To 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxy-carbostyryl 159, an aqueous solution in which 3.69 of potassium hydroxide was dissolved in 40-proof water was added.

After stirring for 30 minutes, the water was concentrated under reduced pressure, and then 20 ml of dimethylformamide was added, and after cooling to 0°C, methanesulfonylchloride 69 was added little by little.

Once the addition is complete, the inside of the reaction will solidify, so 50T of ether! 11
After stirring for 30 minutes, filter through P. The white crystals on F3 paper are washed with acetone and dried. Yield 159NMR. IR
It was confirmed from elemental analysis that it was 5-(1-hydroxy-2-isoprobylamino)butyl-8-(methanesulfonyl)oxycarbostyryl. Reference Example 2 An aqueous solution of 3.69 potassium hydroxide dissolved in 40 ml of water is added to 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxycarbostyryl 159.

After stirring for 30 minutes, the water was concentrated under reduced pressure, followed by adding 20 ml of dimethylformamide and cooling to 0°C.
Add the dissolved mZ.

After stirring for 1 hour, water was added to precipitate crystals, which were filtered with P and washed with ether-acetone to give 5-(1-hydroxy-2-
Isopropylamino)butyl-8-(p-toluenesulfonyl)oxycarbostyryl 209 is obtained.

Identification was based on NMR and IRl elemental analysis values. Example 1 Compound 109 obtained in Reference Example 1 and potassium hydroxide 109 were added to a solution in 150 WLI of water.

Subsequently, 5% palladium on carbon 19 was added and reacted at 1Kf/Clll for 4 hours at 20°C using a Parr hydrogenation apparatus.
The raw material disappears completely and a new spot appears on the TLC. When the solution is filtered with P and neutralized with concentrated hydrochloric acid, crystals are obtained. After filtering with P again, the crystals are dissolved in chloroform, washed with 0.1% potassium hydroxide solution, and the chloroform layer is dried with magnesium sulfate. Subsequently, after filtration, hydrogen chloride gas is introduced into the 0-form layer to obtain white crystals. Recrystallized from ethanol-methanol-ether, melting point 23
White crystalline 5-(1-hydroxy-2-isopropylamino)butylcarbostyryl hydrochloride 69 with a temperature of 7-239°C is obtained. Example 2 Compound 109 obtained in Reference Example 2 was subjected to the same reaction conditions and operations as in Example 1 to give white crystals of 5-(1-hydroxy-2-isopropylamino)butylcarbohydrate with a melting point of 237 to 239°C. 4 g of styryl hydrochloride are obtained.

Example 3 5-(1-hydroxy-2-ethylamino)ethyl carbostyril hydrochloride is obtained in the same manner as in Example 2.

Melting point: 238,0-239.5°C Example 4 In the same manner as in Example 2, 5-(1-hydroxy-2-isopropylamino)pentylcarbostyryl dihydrate was obtained.

Pharmacological tests of the compound of the present invention, which has a melting point of 176.5 to 179.0°C or lower, will be described.

[Pharmacological test] An adult male dog (body weight 10 to 16 K') is anesthetized by intravenously administering 30 K/K' of pentobarbital sodium salt, and a cannula is inserted into the trachea.

Heparin is administered intravenously at a level of 1000 units to avoid blood clotting. A cannula is then inserted into the right femoral artery. During the experiment, 20111/K', 18r. p
．． m. Artificial respiration was performed at a rate of

Blood pressure is measured by Pressu
retranducer,. MDU-0.5 type, N
ippOnKOdenCO. The heart rate was measured using an instantaneous heart rate tachometer (2130 type, Sa
neiSOkkiCO. Blood pressure was determined from the pulse wave using a commercially available product. Air resistance (AR) is calculated using the Konzett-Rfu Ssler method (Kdnzet).
tH. &RtomiSslerR. l Versu Chsan
OrdnugznUntersuchungenand
erBrOnchialMOskOlatur7ArC
h. E)q). Path. ,Pharmak,l95,
7l-74, 27-40 (1940), low pressure type Pledger 1 Transuser 1 (LPU-0.1
, NippOnKOdenCO. (manufactured by). The blood pressure and heart rate mentioned above were recorded on a polygraph (
8S28 type, manufactured by SaneiSOkki). During the experiment,
Apply 3η of galamin every hour to avoid air resistance fluctuations.
/Kp was administered intravenously.

The β-adrenergic blocking effect of the test compound was an antagonistic effect on the suppression of diastolic pressure and increase in heart rate induced by intravenous administration of isoprenaline 1 μ9/KP (inhibition 01)) and histamine (5 μ9/KO intravenous administration). It was expressed by the antagonistic effect (inhibition %) against isoprenaline, which suppresses the increase in air resistance induced by administration. In this case, histamine was administered 45 seconds after isoprenaline administration. The test compound was administered intravenously at 300μ9/KP. death,
After 10 minutes, the β-adrenergic blocking effect was measured.
The results are shown in Table 1 below. The following test compounds were used. Test compound boiled 15-(1-hydroxy-2-isopropylamino)butyl carbostyril hydrochloride (Example 1) 25-(1-hydroxy-2-ethylamino)ethyl carbostyryl hydrochloride (Example 3) 35- (1-hydroxy-2-isopropylamino)pentylcarbostyryl dihydrate (Example 4) 4 (comparison) 6-(2-methylamino-1-hydroxy)ethyl-3,4-dihydrocarbostyryl hydrochloride (In the example table of JP-A-51-68575, HR! indicates heart rate, DBP2 indicates diastolic blood pressure, and AR3 indicates air resistance.

From Table 1 above, the compounds of the present invention, compared to the comparative compounds,
It is found that it has an excellent β-adrenergic action inhibiting effect.

Claims (1)

[Claims] 1 Carbostyryl derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a lower alkyl group] and their acid additions salt.