JPS58183687A - Pyridazinone derivative or its salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H, 1-6C alkyl, alkenyl, amino, etc.; R<2> is H, halogen, 1-6C alkoxy; dotted part represents single or double bond) or its salt. EXAMPLE:4,5-Dihydro-6-(2'-methyl-2',3'-dihydrobenzofuryl)-3-(2H)-pyrid azinone. USE:A cardiac stimulant having high activity and exhibiting the effect for a long period. PROCESS:The objective compound of formula I ' can be prepared by (1) adding 4,5-dihydro-6-(2',3'-dihydrobenzofuryl)-3-(2H)-pyridazinone dihydrobenzofuran derivative and succinic anhydride to a viscous liquid derived from anhydrous aluminum chloride and DMF, (2) stirring the mixture at about 50-100 deg.C for several tens minutes - several hours, and (3) reacting the resultant ketocarboxylic acid of formula III with hydrazine hydrate in a solvent such as ethanol by heating at 50-100 deg.C for 2-10hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to h-pyridazinone derivatives or salts thereof useful as cardiotonic agents. Cardiac inotropes have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure.

However, many of these inotropic agents have disadvantages such as extremely narrow safety ranges that cause arrhythmia, or their inotropic effects are transient and unsuitable for oral administration.

The present inventors have searched for a compound that is highly active as a cardiotonic agent and has a sufficiently long-lasting effect, and has thus arrived at the present invention.

That is, the gist of the present invention is the general formula (I) where R1 is a hydrogen atom, an alkyl group or alkenyl group having 1 to 6 carbon atoms, an amino group, or a monoalkylamino group or dialkylamino group having 1 to Z carbon atoms. and R2 and water 5 represent an atom, a halogen atom, an alkoxy group or thioalkoxy group having 7 to 2 carbon atoms, a nitro group, a halogenoalkyl group or a carboxamido group having 7 to 7 carbon atoms.) Pyridazinone derivatives represented by or its salts.

The present invention will be explained in detail below.

The pyridazinone derivative in the present invention can be synthesized, for example, by the following method.

1) ri,j-dihydro-6-(2'13I-dihydrobenzo71))v)-3-(,2H)-pyridazinones I
NH, NH! @H,0 Dihydrobenzofuran derivative (It) and succinic anhydride are added to a viscous liquid produced from anhydrous aluminum chloride and dimethylformamide, and stirred at a temperature of about jθ0 to lθθC for several tens of minutes to several hours. Ketocarboxylic acid (1) is obtained. (1) with colored water hydrazine in a solvent such as water, ethanol, methanol, etc. and jθ0~/θ
(1') can be obtained by heating at θC for 2 to 70 hours.

+I) t-C2',3'-dihydrobenzofuryl)
-3(2H)-Viridazinones 2 (1v) ↓MeOH/BOOI.

↓NH, NH1++ H! 0 ↓aqHOt ” (1 “) (1) and maleic anhydride are added to the viscous liquid formed from anhydrous aluminum chloride and dimethylformamide, and! 00
Ketocarboxylic acid (IV) can be obtained by stirring at a temperature of ~/θθC for several tens of minutes to several hours.

(1v) with thionyl chloride in methanol (Otake ethanol) and θ0~riOc at 7~! Stir for 5 hours and remove the solvent under reduced pressure. The residue is heated and stirred with colored water hydrazine in water-methanol (ethanol) at 5θ0-10OC for 7-3 hours, then hydrochloric acid is added to make it acidic, and the mixture is further heated at 500-10θC for 7-3 hours. By doing this, (I") can be obtained.

Examples of such pyridazinone derivatives include compounds such as Uchi.

91j-dihydro-t-(,2'-methel-co'I3
'-dihydro □benzofuryl')-3-(,2H)
-pyridazinone, j-dihydro-4-(2'-methylamino-2', 3'-dihydrobenzofuryl)-3-
(2H)-pyridazinone hydrobenzofuryl)-3-(
,2H)-Viridazinone F3 Ri,! -Resihydro-6 (21-methyl-3'-trifluoromethyl-9-λ', 3'-dihydrobenzofuryl)
-3-(,2H)-Viridazinone F tag! -dihydro-4-(,2'-methyl,3'-fluoro,-2',3'-dihydrobenzofuryl)-3-(2
H)-pyridazinone NO.

aq-dihydro-(λ'-methyl, 3'-nitro,
-J'.

3'-Dihydrobenzofuryl)-J-(2H)-pyridazinone Furthermore, the above-mentioned pyridazinone derivatives include pharmaceutically acceptable salts, such as inorganic acid salts such as hydrochloric acid and phosphoric acid, and organic acid salts such as citric acid and oxalic acid. Acid salts, etc. are exposed.

When the compound according to the present invention is used as a cardiotonic agent, it can be administered by an appropriate oral or parenteral administration method.

In this case, the forms provided include, for example, powders, granules, tablets, dragees, pills, capsules, solutions, etc. for oral administration, and e.g. suppositories, suspensions, solutions, emulsions, ampoules, etc. for parenteral administration. and injection solutions. Of course, a combination of these can also be provided.

For formulation, conventional methods in this field can be used.

In addition, the amount of the compound of the present invention to be administered as a cardiotonic drug should be determined based on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, severity of disease, physical condition, nature/preparation/type of pharmaceutical preparation, and active ingredients. Determined by the doctor, taking into account the size of the cat.

For example, in the case of oral administration, body weight 7/7 days, θ, /~
/θIV/kya degree is selected, but is of course not limited to this.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example/ Kai 5-dihydro-6-(,2'-me fk
-λ′,3′-dihydrobenzofuryl)-J-(,2H
) - Synthesis of pyridazinone While stirring anhydrous aluminum chloride θt, ♂m
/ When dimethylformamide is added, it generates heat and becomes liquid. here 2-methyl-13 dihydrobenzofuran r
Add a mixture of t and 3.732 succinic anhydride. The reaction mixture is heated and stirred at 7θC for 7 hours. When hot, add to ice water while stirring, and then add concentrated hydrochloric acid to precipitate a red oil. Extract with ethyl acetate and then extract the ethyl acetate layer with sodium bicarbonate solution. The aqueous layer was brought to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, ethyl acetate is distilled off under reduced pressure to obtain an oil.

4tt of this oily substance is suspended in 7d of water, colored water hydrazine (/θ0俤)θ,/comml is added, and the mixture is heated under reflux for 5 hours. The precipitated solid is washed with water by decantation, and ethanol is added to suspend it. 8- Washing is performed.

The solid is separated, washed with ethanol, and dried to obtain a pale yellow solid θ,/917ff.

IR (KBr): 32θθ, /, <Kθ, /Otsu ri, /j9 evening.

1 night lθ, /ta/ta, /3riθl/22 night, /ηke.

//7 cm-' Reference Example 1 The usefulness of the pyridazinone derivative of the present invention as a cardiotonic agent was tested by a method using a canine isolated papillary muscle cross perfusion specimen.

Canine isolated papillary muscle cross perfusion specimens were prepared using the method of Endo and Hashimoto [American Journal of Physiology (Amer)].
ican J, Physiol, ) 2/J
Vol. 1, p. 63, p. 63, p. 97θ]. The compounds obtained in Example// were dissolved in a solvent, and these were moved close to the specimen, and the effect on the contractile force of the breast muscle was recorded. The results are shown in Table 1.

to the saw Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase-yo - 7 others 11-

Claims (1)

[Claims] (1) General formula CI) R (in the formula, R1 represents a hydrogen atom, an alkyl group or alkenyl group with a carbon number of ~2, an amino group, or a common monoalkylamino group or dialkylamino group with a carbon number of ~2), and R2 is a hydrogen atom, a halogen atom, an alkoxy group or thioalkoxy group having 1 to 2 carbon atoms, a nitro group, and a carbon number 7
- Represents a halogenoalkyl group or a carboxamide group t-. The dotted line represents saturation or unsaturation. ) Pyridazinone derivatives or salts thereof.