JPS61161252A - N-methyl-n-phenylureidoethylamine derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is phenyl or naphthyl which may have 1-2 substituent groups selected from halogen, cyano, 1-6C alkanoyl, 1-6C alkanoylamino, etc.). EXAMPLE:3-[2-(3-Methyl-3-phenylureido)ethyl]amino-1-phenoxy-2-propanol. USE:The compound is effective to block the cardiac beta1-receptor selectively without blocking the beta2-receptor in peripheral vessel and bronchial muscule, and is useful as a remedy for stenocardia, arrhythmia and hypertension complicated with respiratory diseases such as asthma or diabetes. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II with 2-(3-methyl-3-phenylureido-ethylamine in an organic solvent (e.g. methanol) at a temperature between room temperature and the boiling point of the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel compound having excellent adrenergic β receptor blocking action and a method for producing the same.

[Conventional technology]

It is well known that 3-alkylamino-1-7enyl-2-propatol derivatives have β-blocking activity.

As a phenylureido derivative similar to the compound of the present invention, a compound represented by the general formula is described in Japanese Patent Publication No. 59-19090 (Japanese Patent Publication No. 49-94638), and its analogue is represented by the general formula % Formula % It has been shown that the compound has a β-traversing action in JP-A-50-89334 and JP-A-52-77020. However, X -Y-R, is -NHCONR'
Examples include compounds in which R'' is a phenyl group and R' is a hydrogen atom.

[Problem to be solved by the invention]

The purpose of the present invention is to discover a new compound that is more effective than the above-mentioned known compounds and has fewer side effects, and to provide an industrially advantageous manufacturing method for the compound, thereby providing a therapeutic agent for various circulatory system diseases in humans. The goal is to provide drugs that can be used safely.

[Failure to solve the problem]

The present inventors focused on N-phenylureidoethylamine derivatives and conducted extensive research (wherein R is a halogen atom, a cyano group, a C1-6 alkanoyl group, a 01-6 alkanoylamino group, a cycloalkylureido group). and a phenyl group or a naphthyl group which may be substituted with one or two of the same or different substituents selected from phenylureido groups. It was also discovered that it has an adrenergic β-receptor blocking effect. In addition, the compound of the present invention selectively blocks β1-receptors in the heart without blocking β2-receptors in peripheral blood vessels and bronchial muscles, thereby treating airway diseases such as asthma or angina pectoris complicated by diabetes.・Can be used as a therapeutic agent for patients with arrhythmia and hypertension.

The compound of the present invention is produced by reacting a compound represented by the general formula (in which R1 has the same meaning as above) and 2-(3-methyl-3-phenylureido)ethylamine in an organic solvent. can do.

As the organic solvent, common inert solvents such as methanol, ethanol, propatool, benzene, toluene, N-methyl-2-pyrrolidone, and DMF can be used. The reaction can be carried out at a temperature from room temperature to the boiling point of the solvent.

Furthermore, the compound of the present invention has an asymmetric carbon in the globanol moiety, and an optically active form can be obtained by performing optical resolution from a racemic form by a conventional method. It is not a moat to say that it also includes.

7.79 g of 2.3-epoxy-1-phenoxypropane and 10 g of 2-(3-methyl-3-phenylureido)ethylamine were added to 70 ml of ethanol and stirred under reflux for 6 hours. After the reaction, the solvent was distilled off under reduced pressure and the resulting residue was purified on a silica gel plate (methanol) to give 3-C2-(3-methyl-3-phenylureido)ethyl]amino-1-phenoxy-2. 5.0 g of -propatol (compound 1) (mp67-70°C) was obtained. In the same manner, 2-(3-methyl-3-phenyl used in the production of the present invention) Ureido)ethylamine is a new compound described at the end of the literature.An example of its production is shown below.

A mixture of 10.79 grams of N-methylaniline, 25 grams of water, and 75 grams of chloroform was stirred while maintaining the temperature at 0°C. After the reaction, the mixture was separated into layers, the chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain N-methyl-N-phenoxycarbonylaniline 219.

N-methyl-N-phenoxycarbonylaniline 669
The mixture of ethylenediamine 40- was stirred at 45° C. overnight and then concentrated under reduced pressure. The residue was dissolved in dilute hydrochloric acid and washed with chloroform (3 times). The aqueous layer was made strongly alkaline with a 10% caustic soda aqueous solution and extracted with chloroform (3 times) [7
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.39 ml of 2-(3-methyl-3-phenylureido)ethylamine (n2o-71,5598).

〔Effect of the invention〕

The compound of the present invention represented by the general formula (I) and its salts inhibit the increase in heart rate caused by isoproterenol and the relaxation of histamine-induced constricted tracheal smooth muscle, and block β receptors. It has an effect.

In addition, the compound of the present invention has excellent β1 receptor selectivity, and is useful for the treatment and prevention of airway diseases such as asthma, or cardiovascular diseases such as angina pectoris, arrhythmia, and hypertension, which are accompanied by diabetes. It can also be used for many purposes. The effect of the N-methyl-substituted compound of the present invention is 5 to 20 times stronger than that of known phenylureido derivatives.

Test Example Experimental Method: Hartley weighing 250-500 minutes
A male guinea pig I. was hit on the head, the carotid artery was severed, and the animal was exsanguinated to death.The atrium and trachea were immediately removed and excess tissue was carefully removed.

Test I) β1 receptor blocking effect in isolated atrium The isolated atrium was placed in a Krebs-Hens slide at 30±1°C.
Hen5eleit) 02 in a tank containing 50 nutrient liquids
Suspend with a resting tension of ~0.79. 9 for equal rights
A gas mixture of 5% oxygen and 5% carbon dioxide is constantly bubbled through.

The atrium's pulsation was detected using a tension transducer (Nihon Kohden 1.
TB-612T) and strain pressure preamplifier (Nihon Kohden,
AP-620G) to a heart rate tachometer (Nihon Kohden, AT-600G), and the beat rate 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 at a dose ratio of approximately 5, and an increase in heart rate was observed. The atrium was then washed several times and allowed to stand for 30-60 minutes before being pretreated with increasing doses of the test compound and 30 minutes later, isoproterenol was administered cumulatively according to each dose. The beat rate was observed.

A dose-response curve of isoproterenol was obtained by such operations, and the ratio of the β1 receptor blocking effect to that of the standard drug propranolol was determined.

Test ■) β2 receptor blocking effect in the 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 31 m1.
Krebs-Henslide (Krebs-H) at 7 ± 1°C.
en5eleit) 05~ in the tank containing the nutrient solution 10-
Suspend with a tension of 1g. Similar to I) 9
A gas mixture of 5% oxygen and 5% carbon dioxide is constantly bubbled through.

Changes in tension of the excised trachea specimen were recorded on a hot writing oscillograph (Nihon Kohden, WT-585G) via a Zhang Kadorande user (Nihon Kohden, TB-612T) and a preamplifier for strain pressure (Nihon Kohden, A, P-620G). recorded.

Wait for the condition of the specimen to stabilize, and after the contraction of the specimen reaches its maximum by applying 10-5 moles of histamine, isoproterenol is administered cumulatively at a dose ratio of approximately 5" to induce a relaxation response of the specimen. The specimen was then washed several times and
After being left for ~60 minutes [7], the test compound was pretreated by increasing the dose stepwise, and after 30 minutes, the contraction due to histamine and the relaxation response due to isoproterenol were observed according to each dose, and a dose-response curve was established. and the ratio of the β2 receptor blocking effect to that of the standard drug glopranolol was determined.

These results and β! Receptor selectivity is shown in Table 1. As control drugs, atenolol, acebutolol, and a known compound described in Japanese Patent Publication No. 59-1.9090 were used.

The compound of the present invention can be administered orally or parenterally, and can be formulated into various dosage forms depending on the administration method. For example, it can be used as tablets, capsules, granules, solutions, emulsifiers, etc.

During formulation, commonly used phase substances or excipients such as lactose, sucrose, starch, cellulose, Merck, magnesium stearate, magnesium oxide, calcium sulfate, gum arabic powder, gelatin, sodium alginate,
Sodium benzoate, stearic acid, etc. are used.

Injectables are prepared using distilled water, physiological saline, Ringer's solution, etc.

When administered orally, the compound of the present invention has a dosage of about 3 to 300 m9 per day;
In the case of intravenous injection, about 01 to 50 m9 is administered.

Table 1

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a halogen atom, a cyano group, C_1_～_6
one or the same or different two substituents selected from the alkanoyl group, the alkanoylamino group, the cycloalkylureido group, and the phenylureido group of C_1_ to_6
represents a phenyl group or naphthyl group which may be substituted with ). (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a halogen atom, a cyano group, C_1_～_6
one or the same or different two substituents selected from the alkanoyl group, the alkanoylamino group, the cycloalkylureido group, and the phenylureido group of C_1_ to_6
represents a phenyl group or naphthyl group which may be substituted with ) A general formula characterized by reacting a compound represented by 2-(3-methyl-3-phenylureido)ethylamine ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R has the same meaning as above. A method for producing a compound represented by