JPS61106576A - Triazolopyridazin-3-one derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is 1-12C alkyl, or hydroxy-substituted lower alkyl; R2 and R3 are lower alkyl, or phenyl) and its salt. EXAMPLE:8-Methyl-6-phenyl-2-sec-butyltriazolo[4,3-b]pyridazin-3-one. USE:A cardiac, or a drug for bronchiectasis. PREPARATION:A compound shown by the formula II is reacted with an alkyl halide in an inert solvent such as DMF, benzene, etc., in the presence of an alkali (e.g., sodium carbonate, NaOH, or pyridine) at room temperature - the boiling point of the solvent to give a compound shown by the formula I where R1 is alkyl, or a compound shown by the formula II is reacted with an alkylene carbonate in an inert solvent such as DMF, benzene, etc., in the presence of a catalytic amount of an alkali at 100-130 deg.C, to give a compound shown by the formula I where R1 is hydroxy-substituted lower alkyl.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel compound having excellent cardiotonic and bronchodilatory effects and useful as a pharmaceutical, and a method for producing the same.

(Prior art) A method for producing 8-)riazolo(4,3-b) pyridazin-3-one is described in J. Heterocycle, Chem.
.

197613 f3) 639-40 (CA 85:
143052j) or Khim, Geterotsi
ki, 5oadin, 1972 (911292
~3 (CA 77: 164612g) etc.

1,j Also, 8-) Riazolo(4,3-b
) Regarding the pharmacological effects of pyridazine derivatives, see Japanese Patent Publication No. 40-17,076, Takeda Research Institute Report 197332 (
It has been described that S-)riazolo(43-b)pyridazin-3-one derivatives having a 21118-24C, C-dialkylaminoalkyl group at the 2-position have antihypertensive and antiarrhythmic effects.

(Problems to be Solved by the Invention) The purpose of the present invention is to search for a new substance that has excellent pharmacological action, is safe, and has no side effects, and to provide an industrially advantageous manufacturing method thereof. .

(Means for Solving the Problems) The present inventors have conducted various studies using S-triazolo(4,3-b)pyridazin-3-one derivatives (R% in the general formula (in the formula, gourd is CI The compound represented by = ctt (lower alkyl group substituted with an alkyl group or hydroquine group; for birds and horses, a lower alkyl group or phenyl group) has excellent cardiotonic and bronchodilatory effects, and is also non-toxic. The compound of the present invention is produced by reacting a compound represented by the general formula (in the formula, "R" and "Tori" have the same meanings as above) with an alkyl halide or an alkylene carbonate. I can do something.

The reaction between the compound represented by the general formula (IF) and the alkyl haquid is carried out in the presence of an alkali in an inert solvent such as dimethylformamide, acetone, or benzene at room temperature to the boiling point of the solvent. Alkali include sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride,
Examples of alkylparites for which inorganic and organic bases such as triethylamine and pyridine can be used include chloride, bromide,
Iodite etc. can be used.

The reaction with alkylene carbonate is carried out at 100-130° C. in an inert solvent such as dimethylformamide, benzene, acetone, etc. with the addition of a catalytic amount of alkali. Potassium hydroxide is usually used as the alkali.

(Example) The following (two examples will be given to explain the manufacturing method of the present invention).
:explain in detail.

Example 1 8-Mesol-6-phenyltriazolo[:4.3-b]
Pyridazin-3-one 0.651 (2.9m mol
e) with 20 ml of N,N-dimethylformamide and 1.2.9 ml of acetone (8,8 m onole
) and stirred for 1 hour under heating (inner temperature: 80-85°). After the reaction is complete, the solvent is distilled off and the residue is poured into 9fn1 of water.
1: Suspended. After making C2 liquid and neutral by dropping 2N hydrochloric acid, insoluble matter was removed. The obtained crystals were purified by silica gel column chromatography (developing solvent: ethyl acetate) (=680Q (2.4m mol
e) The target product was obtained.

Melting point 152-153°C (yield 83.7%) Example 2 6-methyl-8-phenyltriazolo(4,3-b]pyridazin-3-oy 1.6JF (7,1m mol
e) was dissolved in a mixed solvent of 10ml of N,N-dimethylformamide and 5ml of acetone.
(21 mmole) of potassium carbonate, followed by 2.6 g (21 mmole) of propyl bromide were added and stirred for 1.5 hours under heating (inner temperature 70-80''). After the reaction was completed, the solvent was distilled off and the residue was suspended in 50 ttttt of water. 2N-hydrochloric acid was added dropwise (after neutral C2, which is more liquid), the insoluble matter was removed.

The obtained crystals were purified by recrystallization with a mixed solvent of benzene and n-hexitine to give 1.611 (6.0 m m
ole) was obtained.

(Yield 84.5%) Melting point 137-138. '55 Implementation 3 8-Methyl-6-phenylated triazolo(4,3-b)pyridazin-3-oy 3.6g (15,9mmole
) and 111 (80 mmole) of propylene carbonate were dissolved in 40 mj of N,N-dimethylformamide.
It was heated for 2 hours (inner temperature 120-130°). After the reaction was completed, the solvent was distilled off and the residue was diluted with 50 mL of water. 2N-
After adding hydrochloric acid dropwise to make the mixture more liquid and neutral, remove the insoluble matter. The obtained crystals were subjected to silica gel column chromatography (developing solvent: ethyl acetate), and further recrystallized with ethyl acetate (purified in step 2, 2.61 (
9.1 mmole) of the target product was obtained.

(Yield 57.2%) Melting point 175.5-176.5 Example 4 6-methyl-8-phenyltriazolo(4,3-bl pyridazin-3-one 1.31 (5,8m mole
) and 2.0 g (19.6 mmole) of propylene carbonate were dissolved in 3Qmj of N,N-dimethylformamide (2). Three grains of caustic potash were added and heated for 1 hour (inner temperature 120-130°). After the reaction, the solvent was distilled off and the residue was suspended in water. 2N-hydrochloric acid was added dropwise to make the liquid neutral (after stirring, the insoluble matter was removed). The resulting crystals was purified by recrystallizing it from a mixed solvent of ethyl acetate and n-hexitine to give 950μ (3,
3 mmole) of the target product was obtained.

(Yield 57.7%) m, p, 190 = 19I
Representative compounds of the present invention and their physical constants are shown in Table 1.

Table 1 (Effects of the Invention) As shown in Test Example L below, the compounds of the present invention exhibit excellent inotropic and bronchodilatory effects and are useful as pharmaceuticals.

Test Example 1, Bronchodilation Arch, Int, Pharmacodyn, 11
Volume 1, pp. 392-400, 1957 (F, P,
The method of Luduena et al.
After killing the guinea pig, the lungs were removed together with the trachea, and a cannula was inserted into the trachea, and Tyrode's solution was perfused through the cannula.

Methacol ine
) Q, Q 5 Tyrode's solution of 5 r/41v was flowed forward to constrict the trachea, and then Tyrode's solution containing a constant concentration of the test compound was perfused, and an increase or decrease in the amount of perfusion was measured. As a result, the lowest concentration of compound l that increases the irrigation rate by 50% is 10 r/
It was m. Incidentally, in the case of aminophylline used as the C2 control drug, it was ioo r74nl.

2 Cardiac action Arch, Int, Pharmacodyn, 1
Written in Vol. 55, p. 251, 965 Q) Erjavek
, F., Adamic, S. et al.'s method C: was followed. Namely, after killing a guinea pig by cutting the condylar artery and exsanguinating the heart, the heart was removed, oxygen was aerated, the blood was washed out in Rockringer's solution maintained at 30'Cl2, the left atrium was cut, and the left atrium was removed! = The attached adipose tissue was removed and a specimen was created.

One end of the prepared specimen was fixed with a thread to the Rockringer solution reaction tank, and the other end was connected with a thread to a tension transducer to record contractions. In addition, electrodes were set on the specimen (2) using an electrical stimulation device, and electrical stimulation was applied so that the contraction tension was constant C2.The test compound was suspended in Tween 80 in advance, and then diluted with Tsukringer's solution at a constant concentration [1]. Then, a certain amount of liquid was added to the Rockringer solution reaction tank and the change in contractile force was measured.As a result, the lowest concentration of Compound 1 that enhanced the contractile force of Compound 1 was determined.
．． 0 r/ml, and the increase in contractile force at that concentration (2) was 47%.

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is a lower alkyl group substituted with an alkyl group or hydroxy group of C_1_ to_1_2, and R_2 and R_3 are lower alkyl groups or phenyl groups. ) and its pharmaceutically acceptable salts. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_2 and R_3 represent lower alkyl groups or phenyl groups.) Compounds and general formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(I) (In the formula, R_1' represents an alkyl group of C_1 to C_1_2.) A general formula characterized by reacting with a compound represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1', R_2 and R_3 have the same meanings as above.) A method for producing a compound represented by the formula. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 represent a lower alkyl group or a phenyl group.) Characterized by reacting a compound represented by the alkylene carbonate with an alkylene carbonate. Method for producing a compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ .