JPH0514713B2 - - Google Patents

Description

[Detailed description of the invention]

(Field of Industrial Application) The present invention relates to a novel compound that has β-adrenergic receptor blocking action and is useful for the treatment and prevention of hypertension and cardiac disorders such as angina pectoris and arrhythmia, and a method for producing the same. . (Prior art) British Patent No. 1058822 (Japanese Patent Publication No. 41-20343)
42−3626, 45−25284, 45−32697) It has been reported that the compound represented by has β-adrenergic receptor blocking effect, and as a dihydrohenzofuran derivative similar to the present invention, 2,3-dihydro-6-[2-hydroxy-3-(isopropylamino)propoxy ]-Benzofuran is exemplified. However, the β ₁ receptor blocking effect of the known compound was weak and about 1/60th that of the standard drug propranolol. (Problems to be Solved by the Invention) The present inventors focused on dihydrobenzofuran derivatives and found a compound that has a stronger β ₁ receptor blocking effect and a smaller β ₂ receptor blocking effect compared to known compounds. The present invention was made for the purpose. (Means for solving the problem) The present invention is based on the general formula [In the formula, R is a hydrogen atom, R ₁ is a lower alkoxy group, and mononu is a lower alkyl group substituted with a di-substituted phenyl group, a carbamoyl phenoxy group, or an acetylaminophenyl group, or
CH ₂ CH ₂ NHCONR ₃ R ₄ (R ₃ represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ₄ represents a phenyl group or a phenyl group mono- or di-substituted with a halogen atom, methyl group, or methoxy group.) This shows a ureidoethyl group represented by ], its acid addition salt, and its production method. The compound of the present invention has the general formula (In the formula, R has the same meaning as above.) A compound represented by the general formula R ₁ NH ₂ () (In the formula, R ₁ has the same meaning as above.) can be produced by heating under reflux for 30 minutes to several hours to react in an organic solvent. As the organic solvent, common inert solvents such as methanol, ethanol, propanol, benzene, toluene, N-methyl-2-pyrrolidone, and DMF can be used. The compound represented by the above general formula () is the general formula It can be produced by reacting a compound represented by (wherein R has the same meaning as above) with epihahypidrine. The reaction is carried out in an aqueous alkaline solution with stirring at room temperature for 10 to 24 hours. Sodium hydroxide or potassium hydroxide can be used as the alkali. Acid addition salts of the compounds of the present invention include inorganic acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as oxalate, succinate, malate, maleate, and tannate. . These can be easily produced by conventional methods, for example, by reacting the free base of the compound of the present invention with a desired acid in a suitable organic solvent if necessary. Furthermore, the compound of the present invention has an asymmetric carbon in the propanol moiety, and an optically active band can be obtained by performing optical resolution from a racemic pair using a conventional method. Needless to say, it also includes. (Example) Example 1 4-(2,3-epoxypropoxy)-2-methyl-2,3-dihydrobenzofuran 0.66 g, 2-
(4-methylphenylureido)ethylamine
0.74 g and 10 ml of ethanol were combined and heated under reflux for 4 hours. After the reaction is completed, the solvent is concentrated under reduced pressure,
The residue was subjected to silica gel thin layer chromatography (developing solvent: chloroform: water: methanol = 65:4:
25) to obtain 0.35 g of the target product. Melting point 136-138℃ Example 2 4-(2,3-epoxypropoxy)-2-methyl-2,3-dihydrobenzofuran 0.7g, 2-
0.98 g of (3-methyl-3-phenylwade) ethylamine and 10 ml of ethanol were combined and heated under reflux for 4 hours. Thereafter, in the same manner as in Example 1, the target object 0.23
I got g. n ^31.5 _D 1.5594 Table 1 shows the structures and physical constants of representative examples of compounds of the present invention produced in the same manner.

【table】

[Table] ｜
*Substitution position: Shows the substitution position of OCH ₂ CHCH ₂ NHR ₁ .
(Effects of the Invention) As shown in the test examples below, the compound of the present invention represented by the above general formula () and its acid addition salt have an effect on the increase in heart rate caused by isoproterenol and the relaxation of histamine-induced constricted tracheal smooth muscle. β-
It has a receptor blocking effect. In addition, some of the compounds of the present invention have _β1 receptor selectivity and can be used to treat airway diseases such as asthma or cardiovascular diseases such as hypertension, angina pectoris, and arrhythmia, which are accompanied by diabetes. and can be used for prevention. Test Example Experimental Method: A male Hartley guinea pig weighing 250 to 500 g is hit on the head, the carotid artery is severed, and the animal is exsanguinated to death.The atrium and trachea are immediately removed and excess tissue is thoroughly removed. Test (i) _β1 receptor blocking effect in isolated atrium The isolated atrium was placed in a bath containing 50 ml of Krebs-Hanseleit nutrient solution at 30 ± 1°C.
Suspend by applying a static tension of 0.2 to 0.7 g. A gas mixture of 95% oxygen and 5% carbon dioxide is constantly vented into the tank. The atrial pulsation is input to a heart rate tachometer (Nihon Kohden, AT-600G) via a tension transducer (Nihon Kohden, TB-612T) and a strain pressure preamplifier (Nihon Kohden, AD-620G), and the beat rate is measured. It was recorded on a hot writing oscillograph (Nihon Kohden, WT-685G). After the atrial suspension was left for 30 to 60 minutes, the following operations were performed after the heart rate stabilized. That is, isoproterenol, which is a β-agonist, was administered cumulatively so that the good dose ratio was approximately √10, and an increase in the beat rate was observed. The atrium is then washed several times, 30~
After standing for 60 minutes, the test compound was pre-stimulated by increasing the dose in steps, and 30 minutes later, isoproterenol was administered cumulatively according to each dose, and the beat rate was observed. Through this procedure, a dose-response curve of isoproterenol was obtained, and the ratio of the _β1 receptor blocking effect to that of the standard drug propranol was determined. Test (ii) _β2 receptor blocking effect on isolated trachea The isolated trachea was made into a spiral specimen with a length of 3 to 4 cm and a width of 2 to 3 mm, and 10 ml of Krebs-Henselit nutrient solution was added at 37 ± 1°C. Inside the ivy tank 0.5
Suspend with a tension of ~1 g. As in (i), a mixed gas consisting of 95% oxygen and 5% carbon dioxide is constantly aerated into the tank. Tension changes in the isolated trachea specimen were recorded on a hot writing oscillograph (Nihon Kohden, WT-685G) via a tension transducer (Nihon Kohden, TB-612T) and a strain pressure melt amplifier (Nihon Kohden, AP-620G). did. Wait for the condition of the specimen to stabilize, then test with histamine 10 ^-5
After the maximum contraction of the specimen due to the application of molar
Isoproterenol was administered cumulatively at a dose ratio of approximately √10, and the contraction response of the specimen was observed. The specimens were then washed several times and allowed to stand for 30-60 minutes before being pretreated with increasing doses of the test compound.
After 30 minutes, the histamine-induced contraction and isoproterenol-induced relaxation responses were observed according to each dose to obtain a dose-response curve, and the ratio to the _β2 receptor blocking effect of the standard drug propranolol was determined. These results as well as β ₁ receptor selectivity are shown in Table 2. Note that atenolol, acebutolol, and a known compound described in British Patent No. 1058822 were used as control drugs. The compound of the present invention can be administered orally or parenterally, and can be formulated into various dosage forms depending on the method of administration. For example, it can be made into tablets, capsules, granules, solutions, emulsifiers, etc. During formulation, commonly used carriers or excipients such as lactose, sucrose, starch, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulfate, powdered gum arabic, gelatin, sodium alginate, sodium benzoate, Stearic acid is used. Injectables are prepared using distilled water, physiological saline, Ringer's solution, etc. The compound of the present invention is administered orally at a dose of about 3 to 300 mg per day.
Approximately 0.1 to 50 mg is administered by intravenous injection.

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Claims (1)

[Claims] 1. General formula [Wherein, R is a hydrogen atom, R ₁ is a phenyl group mono- or di-substituted with a lower alkoxy group, a lower alkyl group substituted with a carbamoylphenoxy group or an acetylaminophenoxy group, or a lower alkyl group substituted with a carbamoylphenoxy group or an acetylaminophenoxy group, or
CH ₂ CH ₂ NHCONR ₃ R ₄ (R ₃ represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ₄ represents a phenyl group or a phenyl group mono- or di-substituted with a halogen atom, a methyl group, or a methoxy group. )
This shows a ureidoethyl group represented by ] and its acid addition salts. 2 General formula (In the formula, R represents a hydrogen atom.) A compound represented by the general formula R ₁ NH ₂ [In the formula, R ₁ is a phenyl group mono- or di-substituted with a lower alkoxy group, a carbamoyl phenoxy group, or Lower alkyl group substituted with acetylaminophenoxy group, or formula
CH ₂ CH ₂ NHCONR ₃ R ₄ (R ₃ represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ₄ represents a phenyl group or a phenyl group mono- or di-substituted with a halogen atom, a methyl group, or a methoxy group. )
This shows a ureidoethyl group represented by ] A general formula characterized by reacting a compound represented by A method for producing a compound represented by the formula (wherein R and R ₁ have the same meanings as above).