JPS5914024B2 - 3,4-dihydrocarbostyryl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 3,4-dihydrocarbostyryl derivatives.

The compound of the present invention is a new substance and has the general formula [In the formula, R1 and R2 each represent a lower alkyl group.

] It is a 3,4-dihydrocarbostyryl derivative represented by. In the above general formula, the lower alkyl group is a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group,
Examples include butyl group, sec-butyl group, tert-butyl group, pentyl group, and hexyl group.

The compound of the present invention has a β-adrenergic inhibitory effect and is useful as a therapeutic agent for arrhythmia, angina pectoris, hypertension, and the like.

The fact that the compound of the present invention has the above-mentioned β-adrenergic inhibitory effect will be explained in detail in the pharmacological tests described later. Typical compounds of the present invention include, for example, 5-(1-
hydroxy-2-ethylamino)butyl-3-4-dihydrocarbostyryl, 5-(1-hydroxy-2-
propylamino)hexyl-3,4-dihydrocarbostyryl, 5-(1-hydroxy-2-iso-propylamino)buna-3,4-dihydrocarbostyryl,
5-(1-hydroxy-2-butylamino)butyl-3,4-dihydrocarbostyryl, 5-(1-hydroxy-2-butylamino-3-methyl)butyl-3,4-dihydrocarbostyryl, 5-(1 -Hydroxy-2-sec-butylamino)butyl 3
- 4-dihydrocarbostyryl, 5-(1-hydroxy-2-pentylamino)butyl-3,4-dihydrocarbostyryl, etc., and further in the present invention,
Also included are pharmaceutically acceptable inorganic or organic acid addition salts of these compounds.

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 compound of the present invention has, for example, the general formula [wherein R and R2 are the same as above].

] It is produced by hydrogenating a carbostyryl derivative represented by: The compound of the general formula [] is a new compound, for example, an 8-hydroxycarbostyryl derivative represented by the general formula [wherein R1 and R2 are the same as above] and a compound represented by the general formula [wherein X represents a halogen atom].

] is produced by reacting with 2-halogenobenzoxazole. Compounds of formula [] and formula [
] The reaction with a compound of formula [] is, for example, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal amide such as sodium amide or potassium amide, an alkali metal such as metallic potassium or metallic sodium, By reacting with an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium ethoxide, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, a metal alkyl compound such as n-butyllithium, etc. The 8-position hydroxyl group of the carbostyryl group is introduced into 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, 1,2- dimethoxyethane, dioxane, tetrahydrofuran, etc.), aprotic polar solvents (dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc.) from 0 to 200
The process proceeds at a temperature of preferably room temperature to 10°C for 30 minutes to 5 hours. Next, 2-halogenobenzoxazole of the general formula [] was added to the obtained alkali metal salt of the 8-hydroxycarbostyryl derivative, and the reaction temperature was 0 to 200°C.
The reaction proceeds preferably at 50 to 100° C. for 1 to 5 hours, and the compound of formula [] is obtained. The amount of the alkali metal or its compound to be used is usually 1 to 5 times the mole of the compound of formula [], preferably 1 to 1.5 moles. The amount of the compound of formula [] to be used is usually 1 to 5 times the mole, preferably 1 to 2 times the mole of the compound of formula []. In the present invention, the hydrogenation reaction of the compound of formula [] can be carried out using, for example, water,
It is carried out in a solvent such as acetic acid, methanol, ethanol, isopropanol, ether, dioxane, etc.

At this time, the catalyst is preferably 10 to 20%, such as palladium black, palladium carbon, platinum black, Raney nickel, etc.
Using a hydrogenation catalyst such as palladium on carbon, the reaction temperature is 0 in a hydrogen stream at normal pressure to 100 atm, preferably 10 to 50 atm.
The reaction is carried out at ~200°C, preferably 30-100°C, for 5-20 hours with thorough shaking or stirring.
The amount of catalyst used is 0 for the compound of general formula []
．． It progresses suitably when it is used in an amount of 1 to 30%, preferably 10 to 20%, and palladium on carbon is used in an amount of 10 to 20%. After completion of the reaction, the compound of this step is isolated from the reaction mixture according to a conventional method.

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 methods such as fractional recrystallization, column chromatography, thin layer chromatography, etc. Incidentally, the present invention naturally includes optical isomers of the 3,4 dihydrocarbostyryl derivative of the general formula []. Furthermore, a true carbostyryl derivative in which hydrogen at the 3 and 4-positions of the 3,4-dihydrocarbostyryl group of the 3,4-dihydrocarbostyryl derivative of the general formula [1] is dehydrogenated is a compound of the general formula []. It can be easily obtained by controlling the reduction reaction or by dehydrogenating the 3,4-dihydrocarbostyryl derivative of general formula [I]. 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 8-hydroxy-5-(1-hydroxy-2isopropylamino)butylcarbostyryl 4.57 to 100ml
(:I) Add THF and heat for 30 minutes, then cool to room temperature.

Sodium hydride 1,11 is added in small portions. At this time, after adding sodium hydride to form a homogeneous solution with vigorous hydrogen generation, the mixture was refluxed for 30 minutes, and then a solution of 2-chlorobenzoxazole 3y dissolved in 20 ml of TlIF' was added dropwise under reflux. After refluxing for 2 hours, cool
Separation is performed using a water-mono-salt system, and the TllF layer is dried using K2CO3, concentrated under reduced pressure, and crystallized from ether to obtain yellowish brown crystals 6.07.

Column chromatography (CHCl3:MeOH3:
1) to give pale yellow crystals 5-(1-
Hydroxy-2-isopropylamino)butyl-8-(
2-Benzoxazolyl)oxycarbostyryl 5.0
Get 7.

Example 1 Compound 47 obtained in Reference Example 1 was added to 99.5% ethanol 25
When the solution is dissolved in 0ml, 20% N-Cl7 is added, and reacted in an autoclave at 30 atmospheres and 60°C for 12 hours, the raw material is completely eliminated and new spots appear on the TLG.

Column chromatography (CHCl3:MeOH2:
1) When purified and added with hydrochloric acid, Mpl73-174℃
2.77 of pale yellow crystals of 5-(t)-hydroxy-isopropylamino)butyl-3,4-dihydrocarbostyryl hydrochloride are obtained. Hereinafter, pharmacological tests of the compounds of the present invention will be described.

[Pharmacological test] An adult male dog (body weight 10-16 kg) is anesthetized by intravenously administering 30η/K9 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, 20m1/Kg, 18r. p.
m. Artificial respiration was performed at a rate of

Blood pressure is measured by Pressu
retranducers MDU-0.5 type, Ni
ppOnKOdenCO. The heart rate was measured using an instantaneous heart rate tachometer (2130 type, SaI
leiSOkkiCO. Blood pressure was determined from the pulse wave using a commercially available product. Air resistance (AR) is determined by the KOnzett-R6ssler method (K6 Ett).
H. &R6sslerR. ,”VersuchsanO
rdnugzuUntersuchungenande
rBrOnchialMOskOlatur7ARch
．． Exp. Path. ,Pharmak,. L ship, 7
1-74, 27-40 (1940), low pressure type Pledger 1 Transuser 1 (LPU-0.1,
NippOnKOdenCO. (manufactured by).
His blood pressure and heart rate were recorded on a polygraph (8
S28 type, manufactured by SaneiSOkki). During the experiment, in order to avoid air resistance fluctuations, gallamine was applied 3 times a day every hour.
K9 was administered intravenously. The β-adrenergic blocking effect of the test compound was due to the sphinctive effect (inhibition %) on the suppression of diastolic blood pressure and increase in heart rate induced by intravenous administration of isoprenaline 1 μy/K9 and histamine (5 μy/K9).
g) Antagonistic effect (inhibition %) against isoprenaline, which suppresses the increase in air resistance induced by intravenous administration. In this case, histamine was administered 45 seconds after isoprenaline administration. The test compound was 300μy/I
<g was administered intravenously, and the β-adrenergic blocking effect was measured 10 minutes later. The results are shown in Table 1 below. In the table, HRl is heart rate, DBP2 is diastolic blood pressure, and AR3 is
indicates air resistance.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 each represent a lower alkyl group. ] A 3,4-dihydrocarbostyryl derivative and its acid addition salt.