JPS5953479A - Pyridazinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula 1 (R<1> is H, formyl, alkanoyl, etc.; R<2> is H, or alkyl). EXAMPLE:5-Methyl-6-(4-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro -3(2H)-pyr idazinone. USE:Useful as a drug for a circulatory organ system such as hypotensor, antithrombosis, cardiac, etc. Having increasing action on contraction ability of cardiac muscle, inhibitory action on blood platelet aggregation, etc. PROCESS:A compound shown by the formula 2 (Z is OH, etc.) is reacted with a compound shown by the formula 3 in a solvent such as benzene, etc. at room temperature -200 deg.C to give a compound shown by the formula 4. The prepared reaction product is reacted in polyphosphoric acid or sulfuric acid at room temperature -250 deg.C to give a compound shown by the formula 5, which is reacted with acetic acid, acetic anhydride, etc. in a solvent such as benzene, etc. at room temperature, and, if necessary, cooled or heated, to give a compound shown by the formula 1.

Description

DETAILED DESCRIPTION OF THE INVENTION In the formula, R1 is hydrogen, formyl, alkanoyl, benzoyl, furoyl, thenoyl, pyridinecarbonyl or R″NHCO-, R2 is hydrogen-spanning alkyl, or R
3 represents hydrogen or alkyl).

The present inventors have discovered that the compound of general formula (1) is a new compound and has excellent pharmacological action. That is, the compound of general formula (1) has a strong antihypertensive action, an action to inhibit platelet aggregation, and an action to increase myocardial contractility, and is useful as a pharmaceutical for the cardiovascular system, such as an antihypertensive agent, an antithrombotic agent, and a cardiotonic agent.

To explain more specifically the definitions of the symbols used in the general formula (1) of the present invention, alkyl means methyl, ethyl, isopropyl, proyl, butyl, isobutyl, sec-
Butyl, t-butyl, etc., alkanoyl means acetyl, gropanoyl, butanoyl, furoyl means 2-furoyl, roufuroyl, and thenoyl means 2-thenoyl, 6
-Thenoyl and pyridinecarbonyl mean 2-pyridinecarbonyl, 6-pyridinecarbol, and 4-pyridinecarbonyl.

The compound of general formula (1) of the present invention can be produced, for example, by the following method.

R' (2) (3) (5) (1) (However, in formulas (2), (3), (4) and (5), R2 has the same meaning as above, and Z is OH, methoxy or ethoxy ) The compound of formula (4) can be obtained by adding acrylic acid or acrylic ester to the known compound (b). This reaction is carried out with a compound of formula (b) without a solvent or in an inert organic solvent, such as evaporate, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, di-l-robenzene, dimethylformamide, etc. The compound of formula (4) can be obtained by reacting the compound of formula (2) at room temperature to 200°C, preferably around the boiling point of the reaction mixture, for 1 to 7 hours.

Separately, the compound (z
= OH) can be produced.

The compound of formula (4) is then added to polyhydric acid or sulfuric acid at room temperature to 250°C, preferably from 50°C to 15°C.
The compound of formula (5) can be obtained by reacting in a temperature range of 0° C. for 1 to 5 hours. The compound of formula (4) in which Z=OH is replaced with another reactive derivative such as acid chloride, and the Friedel-Crafts reaction conditions are changed, such as dichloromethane, carbon tetrachloride, carbon disulfide,
The ring-closing reaction can also be carried out in a solvent such as benzene or nitrobenzene in the presence of a suitable acid catalyst such as aluminum chloride or stannic chloride. Equation (4) vs. Equation (5)
In the reaction to obtain the compound of formula (4), after replacing the >NH group of the quinoline skeleton of formula (4) with a group represented by the general formula (R1 (however, R1 excludes hydrogen)), The reaction to formula (5) may also be carried out.

Although a compound of general formula (1) can be produced when producing a compound of formula (5), it can also be produced using the compound of formula (5) as a raw material. The compound of formula (5) is treated with an alkanoic acid, such as acid-resistant propionic acid, propionic acid, butanoic acid, benzoic acid, 2-thiophene, in a suitable solvent such as benzene, toluene, dimethylformamide, dimethyl sulfoxide, etc., or without a solvent. Carphonic acid, 2-furancarboxylic acid, --y-offenecarboxylic acid,
, 2-pyridinecarboxylic acid, pyridinecarboxylic acid, 4-pyridinecarboxylic acid, etc., such as acid anhydrides, acid chlorides, at room temperature or by cooling or heating as necessary, the general formula ( 1
) is produced.

During this reaction, a base such as triethylamine, pyridine, sodium carbonate, hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, etc. may be allowed to coexist as required. The compound in which Bl is formyl in general formula (1) can be obtained by a known method, for example, by reacting the compound of formula (5) with acid-resistant anhydride in formic acid at a temperature range of 0°C to 150°C.

In the compound of general formula (1), R1 is R3NHCO-(
R" represents hydrogen or alkyl), the compound of formula (5) can be prepared by dissolving the corresponding inanate, e.g. isocyanate, ethyl inocyanate, propyl isocyanate, butyl isone anate, etc. at room temperature (with cooling if necessary) or by heating. /Reactive derivatives of cumic acid, for example, alkylcarbamic acid chlorides, are added to the compound of formula (5), benzene, toluene, dimethylformamide, dimethyls/l-
The reaction is carried out in the presence of a suitable base such as pyridine, triethylamine, sodium carbonate, potassium carbonate, etc. for 1 to 5 hours at a temperature range of room temperature to 150°C in a solvent of 4, such as phosphatide or tetrahydrofuran. However, a compound included in general formula (1) can be obtained. A compound in which R1 is R''NHOO- in the general formula,
A compound in which R3 is hydrogen can also be obtained by reacting the compound of formula (5) with sia/sodium acid in acetic acid.

For example, the following compounds can be produced using such a method.

5-Methyl-6-(4-oxo-1,2,5,4-tetrahydroquinolin-6-yl)-4,5-dihydro-
3(2H)-pyridazinone, 6-(4-oxo-1,2,5,4-tetrahydroquinolin-6-yl)-4,5-dihydro-3(2H)-pyridazino/, 5-methyl-6- (1-formyl-4-oxo-1,2
,5,4-tetrahydroquinolin-6-yl)4.5-
Dihydro-3(2)T)-pyridazinone, 5-methyl-
6-(1-acetyl-4-okino1.2.6.4-tetrahydroquinolin-6-yl)-4,5-dihydro-
6(2H)-pyridazinone, 5-methyl-6-(1-butanoyl-4-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5(2H)
-pyridazinone, 5-methyl-6-(1-benzoyl-
4-oxo-1,2,5,4-tetrahydroquinoline-
6-yl)-4,5-dihydro-3(2H)-pyridazinone, 5-methyl-6-(1-70yl-4-oxo-
1,2,3,4-tetrahydroquinolin-6-yl)-
4,5-dihydro-3(2H)-pyridazinone, 5-methyl-6-(1-thenoyl-1,2,3,4-3(2H)
) -1,2,ro,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5(2T()-pyridazinone, 5-methyl-6-(1-carbamoyl-1,2,3゜4)
-tetrahydroquinolin-6-yl) -4,5-dihydro-3(2H)-pyridazinone, 5-methyl-6-(
1-methylcarbamoyl-1,2,3,4-tetrahydroquinolin-6-yl)-4,5-dihydro-3(2H
)-pyridazinone, 5-methyl-6-(1-7'ropylcarbamoyl-1,2,ro,4-tetrahydroquinolin-6-yl)-4,5-dihydro-5(2H)-pyridanone, 5-methyl -6-1:1-(2-pyridinecarbonyl) -1,2,3,4-tetrahydroquinoline-
6-yl) -4,5-dihydro-3(2H)-pyridazinone, 5-methyl-6-1:1-(3-pyridinecarbonyl)
-1,2,ro,4-tetrahydroquinolin-6-yl)
-4,5-dihydro-5(2H)-pyridazinone, 5-methyl-6-(1-(4-pyridinecarbonyl)-
1,2,5,4-tetrahydroquinol/-6-yl)
-4,5-dihydro-3(2H)-pyridazinone, 6-1:1-(ro-pyridinecarbonyl) -1,2゜6.4-tetrahydroquinolin-6-yl) -4,5
-dihydro-lo(2H)-pyridazinone The compound of general formula (1) thus obtained exhibits antihypertensive action, platelet aggregation inhibiting action, and myocardial contractile force increasing action, and is an antihypertensive agent, an antithrombotic agent, and an antithrombotic agent.
It is useful as a cardiovascular drug such as a cardiotonic agent.

Hereinafter, the present invention will be specifically described by way of example.

Example 1 5-Methyl-6-(4-oxo-1,2,5,4-tetrahydroquinolin-6-yl)-4,s-di1nidolo(2H)-pyridazinone (a) 6-(p -aminophel)-5-methyl-4,
5-dihydro-5(2H)-pyridazinone 152 and acrylic acid 505iI were added to O-dichlorobenzene and stirred at 140 to 145°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by 7 silica gel column chromatography (solvent: chloroform, methanol, acetic acid = 200
: 2.5 : 2.5) Concentrate both desired fractions to obtain 6-(4-(2-carboxyethyl)aminophenyl)-5-methyl-4,5-dihydro-3(2rq)
- Pyridazinone is di'tJ ((12 crystals as 1171
Obtained. mp, 183-185℃ (decomposition) (1)>
(a> -C44t The leaked Compound 22 was added to BoIJ IJ acid 237 at 80 °C K and stirred for 30 minutes. After cooling, the reaction mixture was poured into ice water 500+NE, chloroporm 50ME was added, and sodium hydrogen carbonate was added. was added to adjust the pH to 63. Several layers were separated, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain yellow crystals 197. This was purified by silica gel column chromatography (solvent;
o Ho,,qzmu1. ' evening/ -/l/, rv'l
acid=11]1]:1:1) to obtain yellow crystals. This was further recrystallized from methanol-chloroform (1:1) to obtain 5-methyl-6-(4-oquinol-1,2-4-tetrahydroquinolin-6-yl).
-4,5-dihydro-3(2H)-pyridazinone o1
I got 57. mp 25-255°C Example 2 6-(1-acetyl-4-oxo-1,2,ro,4-tetrahydroquinolin-6-yl)-5-methyl-4,5
-dihydro-6(2H)-pyridazinone Example 1 (+
)) Compound 057 obtained in 50 me K of acetic anhydride
W? ! ii3L, Bill) Thin 0.1me was taken from the right eye, heated to 60°C to dissolve it, and then left in the room τ for 4 hours. The solvent was distilled off under reduced pressure to obtain a yellow oil.

This was subjected to silica gel column chromatography;
Chloroform, methanol-100: 1') f
H color crystal and 1 to 0.29 objective. mp, 22 filter - 226°C Example filter 6-(1-formyl-4-okino 1.2. filter, 4-tetrahydroquinolin-6-yl)-5 to methyl-4,5
-7hydro6(2H)-pyridazinone Example 1(b)
The obtained compound 10 Roa was dissolved in 98 group formic acid 2°1 TLe, and while keeping the inner Y crystal at 4 to 6°C under water cooling, it was dissolved in anhydrous acid resistance 6.
me was added dropwise for 30 minutes. same? , 1 item IW for 1
Time 1 month? After adding 40ml of water, the mixture was left in a room at 7°C overnight. The solvent was distilled off under reduced pressure to obtain an amorphous powder 1.17. This was purified by silica gel column chromatography (solvent: chloroform, methanol, 150:1
:1) to obtain pale yellow crystal 057. This was recrystallized from methanol-chloroform to obtain the desired product 0.257. 1ηp, 220-221°C Example 4 6-(1-carbamoyl-4-oxo-1,2,3°4
-tetrahydroquinol-7-6-yl)-5-methyl-4
, 5-dihydro-6(2H) ~ Pyridazinone Example 1 (b)-c was obtained.
0ml of the solution, 40ml of water was added, and then 25ml of an aqueous solution containing sodium cyanate filter 7 was added over a period of 15 hours at room temperature. Furthermore, add a small amount of sodium cyanate 257
0 hours were added at 1~. The solvent was distilled off under reduced pressure and 100ml of water was added to the residue. He and 100 le of chloroporum were added and the product was transferred to the organic layer. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated. The crude product obtained was purified by silica gel column chromatography (solvent: chloroform, methanol, acetic acid = 10:1:1) to obtain pale yellow crystals. Ta. This was recrystallized from methanol-chloroform to obtain 150m9 of the desired product. mp, 223-224℃
(Decomposition) Example 5 6-(1-nicotinoyl-4-okino 1.2.3°4
-tetrahydroquinolin-6-yl)-5-methyl-4
, 5-dihydropyridazinone dimethylformamide 40me to Example 1 (h)
in? Compound 1.28 f! Dissolved, added 1.38 fi' of anhydrous potassium carbonate, and further added 09 g of nicotinic acid chloride 1'M salt, and filtered at room temperature for 1 hour.
1'l strike/ζ. Next, the solvent was distilled off under reduced pressure, and the residue was dissolved in water.
0me was added, and one crystal was collected. The target product was recrystallized from water-ethanol at 0.6 f! Obtained. rnp
, 225-226℃ Patent issued (Continued from Tojin Mitsui Toatsu Chemical Co., Ltd., page 1 [Phase] Inventor Ryo Matsubara 1541 Yabe-cho, Totsuka-ku, Yokohama [Phase] Inventor Takashi Nishina 3-58 Hagiwara, Mobara City Address: 0 Author: Joji Kamiya 2143 Togo, Mobara City 0 Author: Yasuhito Tanaka 2143 Togo, Mobara City 0 Author: Akira Awaya 1541 Yabe-cho, Totsuka-ku, Yokohama City

Claims (1)

[Claims] (1) General formula (wherein R1 is hydrogen, formyl, alkyl, benzyl, furoyl, thenoyl, pyridinecarbonyl, and R
3 represents hydrogen or alkyl).