JPS60258152A - Hydrazinecarboxylic acid and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is phenyl substituted with lower alkoxy, or group of formula II (R4 is H or lower alkyl; X is halogen, lower alkyl, etc.; n is 0-2); R2 is H, halogen, lower alkyl or lower alkoxy; R3 is lower alkyl] and its salt. USE:It suppresses the increase of pulse rate caused by isoproterenol and the histamine-induced relaxation of the constricted smooth muscle of the trachea, and has beta-receptor blocking activity. Some of the compounds of formula I have excellent selectivity of beta1-receptor, and are useful for the remedy of tracheal diseases such as asthma and circulatory diseases such as stenocardia, arrhythmia, hypertension, etc. complicated by diabetes. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula III with the phenylureide of formula IV in an organic solvent 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 hydrazinecarboxylic acid derivative that has an excellent adrenergic β receptor blocking effect and is useful as a pharmaceutical, and a method for producing the same.

(Prior Art) JP-A No. 48-28441 describes that a compound represented by the general formula has a β rapid-acting action.

Among phenylmethylenehydrazinecarphonic acid derivatives similar to those of the present invention, 1-(4-ethoxycarbonylhydrazinomethyl-2-methoxyphthonoxy)-3-isopropylamino-2-propatool is exemplified, but β□ receptor Due to its low selectivity, it is difficult to use it as a therapeutic agent for patients with airway diseases such as asthma or patients with angina pectoris, arrhythmia, or hypertension who also have diabetes.

(Problems to be Solved by the Invention) The present inventors have discovered a compound that selectively blocks β1 receptors in the heart without rapidly blocking β2 receptors in peripheral blood vessels and bronchial muscles, and has high efficacy. The present invention was carried out for the purpose of providing a drug that can be safely used as a therapeutic drug for various circulatory system diseases.

(Means for Solving the Problems) The present inventors conducted research on a number of alkanolamine derivatives, and found that the general formula [wherein R1 is a phenyl group substituted with a lower alkoxy group, or /d formula NHCON]
In the ReXn C formula, R4tf represents a water IA K atom or a lower alkyl group, X represents a halogen atom, a lower alkyl group, or a lower alkoxy group, and n represents 0.1 or 2. ) represents a phenylureido group and R3 represents a lower alkyl group. The present inventors have discovered that the compound represented by the following and its pharmaceutically acceptable salts have an excellent β-receptor-blocking action and selectively rapidly block β□ receptors.

The compound of the present invention is a compound represented by the general formula % (in which R2 and R3 have the same meaning as above) and a compound represented by the general formula % (1) (in which R1 has the same meaning as above). ) in an organic solvent.

As the organic solvent, common inert solvents such as methanol, ethanol, propatool, benzene, toluene, N-methyl-2-pyrrolidone, and silica can be used. The reaction is at room temperature ~
This can be done at temperatures up to the boiling point of the solvent.

Mugaga salts of the compounds of the present invention include inorganic acid salts such as hydrochlorides, sulfates, nitrates, and oxalates; Among them, it can be easily produced by reacting with a desired acid.

In addition, the compound of the present invention has an asymmetric carbon in the propane moiety, and an optically active form can be obtained by optical resolution from a silamate by a conventional method. It goes without saying that optically active substances are also included.

(Example) Example 1 (Compound 2) ゛4-(2,3-epoxypropoxy)-3-fluorobenzaldehydemethoxycarbonylhydrazone 0.27
f, 3.4-dimethoxyphenylethylamine 0
．． 22 f and 5 liters of ethanol were combined and heated under reflux for 5 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: methanol) to obtain the target product 0.16 f.

Melting point 46-49°C Example 2 CH=NNHCOOCH3 (Compound 8) 4-(2,3-epoxypropoxy)-3-fluorobenzaldehydemethoxycarbonylhydrazone 0.27
f, phenylureidoethylamine 0°22f and ethanol 5- were combined and heated under reflux at 111° for 5 hours. After cooling, the precipitated crystals were collected in a furnace and recrystallized from ethanol to obtain the desired product with a weight of 0.25 f. Melting point 151-153.5°C Example 3 (Compound 1) 7.5f of 4-(2,3-epoxypropoxy)benzaldehydemethoxycarbonylhydrazone, 6.53f of 3°4-dimethoxyphenylethylamine and 75ml of ethanol were combined, The mixture was heated to reflux for an hour.

After evaporating the solvent under reduced pressure, the residue was separated by silica gel column chromatography (developing solvent: polyproform-methanol-water = 65:25:4) to obtain 7.17 t of the target product. Table 1 shows the structural formula and physical constants of the compound of the present invention prepared in the same manner with a melting point of 47 to 50°C.

(Effects of the Invention) The compound of the present invention represented by the above general formula (1) and its salt have an effect on the increase in heart rate caused by inproterenol and the relaxation of histamine-induced constricted tracheal smooth muscle, as shown in the test examples below. and has a β receptor blocking effect.

In addition, some of the compounds of the present invention have excellent β1 receptor selectivity and are effective for patients with airway diseases such as asthma or cardiovascular diseases such as angina pectoris, arrhythmia, hypertension, etc., who are also accompanied by diabetes. It can also be used for treatment and prevention.

Test Example Experimental Method: Hartley weighing 250-500f
After a male guinea pig 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 1) Rapid action of β□ receptors in isolated atrium.
-Hen5ele mouth) A static tension of 0.2 to 0.7 f is applied and suspended in a tank containing 59 ml of nutrient solution. The homogenate is constantly vented with a gas mixture consisting of 95% oxygen and 5% carbon dioxide.

The atrial pulsation is measured using a tension transducer (Nihon Kohden, TB
-6127) and positive pressure preamplifier (Nihon Kohden, AP
-620G) via a heart rate tachometer (Nihon Kohden,
AT-600G) and the number of beats was recorded on a hot writing oscillograph (Nihon Kohden, Wr-685G).

After the atrial suspension was left for 30 to 60 minutes, the following operations were performed after the heart rate stabilized. Specifically, isoproterenol, a β-agonist, was administered cumulatively at a dose ratio of approximately 5, and an increase in heart rate was observed.

did. 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. Through this procedure, a dose-response curve of isoproterenol was obtained, and the ratio of the standard drug propranolol to the β1 receptor fast-acting action was determined.

Test II) β2 receptor fast-acting action in the isolated trachea The isolated trachea was made into a spiral specimen with 3 to 4 wounds in length and 2 to 311II11 in width, and was heated in a Krebs-Hens slide (Krebs) at 37±1°C.
s-Hen5eleit) Suspend in a tank containing 10 ml of nutrient solution by applying a tension of 0.5 to 1 f. Similar to 1), a mixed gas consisting of 95% oxygen and 5% carbon dioxide is constantly aerated through the same type of gas.

Tension changes in the excised trachea specimen were recorded on a hot writing oscillograph (Nihon Kohden, WT-685G) via a strain pressure preamplifier (Nihon Kohden, AP-620G) and a strain pressure preamplifier (Nihon Kohden, TB-612T). .

Wait for the condition of the specimen to stabilize, and after the contraction of the specimen reaches its maximum due to the application of 10-5 mol of histamine, administer isoproterenol cumulatively at a dose ratio of about 100 to 3000 ml and observe the relaxation response of the specimen. did. The specimens were then washed several times, 30~
After being left for 60 minutes, 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 to obtain a dose-response curve. β2 of standard drug propranolol
The ratio to receptor fast-acting action was determined.

These results and β□ receptor selectivity are shown in Table 2. As control drugs, atenolol, acebutolol, and a known compound described in JP-A No. 48-28441 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 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, 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.

The compound of the present invention is administered at a dose of about 3 to 300 μl per day when administered orally, and about 0.1 to 50 μl per day when administered intravenously.

Table 2 Procedural Amendments Showa 5% J year? Manabu Shiga, Director General of the Tsukinobi Patent Office1, Identification of the case, Patent Application No. 114666, Year 1925,2, Title of the invention: Hydrazinecarboxylic acid derivatives and manufacturing method 3, Person making the amendment, Relationship with the case, Patent applicant: 100 Tokyo 2-2-1 Otemachi, Chiyoda-ku, Miyako (480
7 Nippon Soda Co., Ltd. Representative: Takeo Sannomiya 4, Agent Address: 2-2-1 Otemachi, Chiyoda-ku, Tokyo 100 Japan Telephone: 24576284 5, Specifications subject to amendment - persimmons within the scope of Eba's claims and Column 6 of Detailed Description of the Invention, the same content of the amendment (as per the appendix of Claims 49 of 11 Specification).

Claim 1: A general formula or a lower alkyl group, X is a halogen atom, a lower alkyl group or a lower alkoxy group Y, and n is 0, 1 or 21. ], R is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkyl group.
R3 represents an alkoxy group, and R3 represents a lower alkyl group. ] and its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein R1 is an 8,4-dimethoxyphenyl group or a 7-enylureido group.

3. General formula (in the formula, R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, and R3 represents a lower alkyl group)
, l and the general formula H, NCH2CH2R.

n represents an alkyl group or a lower alkoxy group; n represents 0, ■ or 2; ] indicates a phenylureido group represented by T,]
General formula (wherein R1, R, and R3 have the same meanings as above)
A method for producing a compound represented by

Claims (1)

[Claims] 1. General formula [wherein R1 is substituted with a lower alkoxy group] atom or lower alkyl group, Company X halogen atom, lower alkyl group or lower alkoxy group, n is 0.1 or 2 is shown. )
R2 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group,
R3 represents a lower alkyl group. ] and its pharmaceutically acceptable salts. 2. The compound according to claim 1, wherein R1 is a 3,4-dimethoxyphenyl group or a phenylureido group. 3. Compounds represented by the general formula (wherein R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, and R3 represents a lower alkyl group) and the general formula H2NCH2CH2R [wherein R1 represents a lower alkoxy group] X represents a halogen atom, a lower alkyl group, or a lower alkoxy group, and n represents 0°l or 2. ) represents a phenylureido group. ] (wherein R1, R2 and R8 have the same meanings as above)
A method for producing a compound represented by