JPS63239270A - 1-acyl-2,3-dihydro-4(1h)-quinoline-4-oxime derivative, its production and diuretic, hypotensor, antihydropic and ascites remover therefrom - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is 1-8C alkyl, 3-6C cycloalkyl, alkoxy, methoxymethyl, benzyl, naphthyl, unsubstituted or substituted phenyl; R<2>, R<3> are H, methyl; R<4> is carboxymethyl, sulfo, methanesulfonyl; R<5>, R<6> are H, halogen, OH, methylthio, methylsulfinyl, methyl; wave line is syn or anti type], its salt or solvate. EXAMPLE:Potassium 7-chloro-1-(2, 4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinoline-4- oxime-O-sulfonate. USE:Diuretic, hypotensor, antihydropic, ascites remover. PREPARATION:A compound of formula II is converted with hydroxylamine into 4-oxime and the product is allowed to react with sulfur trioxide complex or halogenated phosphoric acid ester, when desired, followed by hydrolysis, to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Field of Application j The present invention relates to 1-acyl-2,8-dihydro-4 (IH)
- Quinolinone-4-oxime derivatives, their production methods, and therapeutic agents containing them, more specifically, general formula (■) -R4 (wherein R1 is a straight chain or branched chain having 1 to 8 carbon atoms). Branched alkyl groups, straight-chain or branched halogenated alkyl groups having 1 to 4 carbon atoms, 3 to 6 carbon atoms
cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, chenyl group, pyrazinyl group, phenyl group, straight chain having 1 to 4 carbon atoms or substituted at any position with 1 to 5 substituents of the same or different type selected from the group consisting of branched alkyl groups, hydroxyl groups, nitro groups, lower alkoxy groups, trifluoromethyl groups, and halogen atoms. represents a phenyl group, R2 and R3 are the same or different and represent a hydrogen atom or a methyl group, R4 is a carboxymethyl group,
Represents a sulfo group, methanesulfonyl group, or methoxyphosphoryl group, and R5 and R6 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group, a methylsulfinyl group, a methanesulfonyl group, an N,N-dimethylamino group, a nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group, or methoxy group, and the wavy line represents syn type or anti(a
ntll) type of connection. ) 1-acyl-
2,3-dihydro-4(IH)-quinolinone-4-oxime derivatives, salts, solvates, and solvates of salts thereof, or methods for producing these compounds; The present invention relates to an agent for removing edema and ascites, and also to a synthetic intermediate thereof.

``Prior Art'' and ``Problems to be Solved by the Invention'' Conventionally, hypertension has been treated by increasing the excretion of electrolytes and water by acting on the distal tubule of the kidney, the loop of Henle, etc. , thiazide diuretics and loop diuretics that lower blood pressure have been frequently used. However, many of these antihypertensive diuretics are known to have common side effects such as hypokalemia, hyperuricemia, decreased glucose tolerance, and abnormalities in lipid metabolism.

Diuretics have also been used to remove edema caused by water and electrolyte retention due to decreased kidney and heart function and impaired substance metabolism, but these diuretics are also used to treat abdominal tumors, liver cirrhosis, etc. At present, we cannot expect much of a therapeutic effect on the ascites accumulation that occurs.

It is well known that many of these thiazide diuretics and loop diuretics have similar chemical structures. believed that a completely new chemical compound was needed, and selected among the newly synthesized compounds that would be effective in the treatment of hypertension, as well as in the treatment of edema and removal of ascites. We have been conducting research for many years to find out.

"Means for Solving the Problems" The present inventors have discovered that 1-acyl-2,3-dihydro-4 (1
8) -quinolinone-4-oxime derivatives, especially 1-
Acyl-2,8-dihydro-4(IH)-quinolinone-
It has been found that 4-oxime-O-sulfonic acid derivatives, salts, solvates, and solvates of salts have strong antihypertensive, antiedema, diuretic, and ascites removal effects. The present invention was completed based on the above findings.

1-acyl-2,3-dihydro-4(IH)- of the present invention
Quinolinone-4-oxime derivatives are new compounds,
Generally, it can be synthesized by the following steps. That is, 2,3-dihydro-4, which is a compound known per se.
(IH)-quinolinone derivatives, such as 7-chloro-2,
8-dihydro-4(IH)-quinolinone, 5-chloro-
2,3-dihydro-4(IH)-quinolinone (French Patent No. 1°514.280), 6-chloro-2,3-dihydro-4(IH)-quinolinone (The Journal of American Chemical Society Volume 71, 19
01-1904, 1949 and U.S. Pat. No. 2,558°211), 8-chloro-2,3-dihydro-4(IH)-quinolinone (French Patent No. 1.51)
4.280), etc., or by reacting a known mono- or di-substituted aniline with γ-butyrolactone or acrylic acid according to a conventional method, and then converting the resulting N-carboxyethyl form of the mono- or di-substituted aniline into a free delta raft. The novel 2,3-dihydro-
4(IH)-quinolinone derivatives, such as 6-chloro-7
-Fluoro-2,3-dihydro-4(IH)-quinolinone, 7-chloro-6-fluoro-2,3-dihydro-4
(IH)-quinolinone, 6,7-difluoro-2,3-
By reacting dihydro-4(IH)-quinolinone etc. with a reactive derivative of the carboxylic acid to be introduced as an acyl group, especially an acid chloride, in an organic solvent in the presence of a base as a deoxidizing agent if desired, An intermediate 1-acyl-2,3-dihydro-4(IH)-quinolinone derivative is obtained. Organic solvents that can be used in this reaction include chloroform, methylene chloride, ether, tetrahydrofuran,
Dioxane, benzene, ethyl acetate, etc., and bases used as deoxidizing agents include pyridine, triethylamine,
Organic bases such as N,N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate can be used. As the acid chloride, R1 of general formula (1)
Acid chlorides corresponding to, for example 2-methylbenzoyl chloride, 2゜4-dichlorobenzoyl chloride,
2-bromobenzoyl chloride, 4-chlorobenzoyl chloride, 2,2-dimethylpropionyl chloride, propionyl chloride, etc. can be used.

The intermediate thus obtained, 1-acyl-2,3-
The corresponding 1-acyl-2,3-dihydro-4(IH)-quinolinone-4- is obtained by reacting a dihydro-4(IH)-quinolinone derivative with hydroxylamine in a solvent such as methanol, ethanol, tetrahydrofuran, or dimethylformamide. By obtaining an oxime and reacting it with a sulfonating reagent such as a sulfur trioxide/pyridine complex or a sulfur trioxide/dimethylformamide complex, or in the presence of a base such as n-butyllithium, sodium hydride, phenyllithium, etc. by reacting with a halogenated phosphoric acid ester such as dichlorophosphoric acid methyl ester, or by reacting with a halogenated acetic acid such as bromoacetic acid or its ester in the presence of a base such as 40% potassium hydroxide, or by reacting with triethylamine, etc. By reacting a methanesulfonyl halide such as methanesulfonyl chloride in the presence of a base, or by hydrolysis after the reaction if desired, the corresponding 1-acyl-2,3-dihydro-4(IH)-quinolinone-4 -oxime-O-
Sulfonic acid derivatives, or 1-acyl-2,8-dihydro-4(IH)-quinolinone-4-oxime-〇-phosphate monomethyl ester derivatives, or 1-acyl-
2,8-dihydro-4(IH)-quinolinone-4-oxime-〇-acetic acid derivative, or 1-acyl-2,8-
A dihydro-4(IH)-quinolinone-4-oxime-〇-methanesulfonyl derivative is obtained.

In addition, 1-acyl-2,3-dihydro-4(IH)-quinolinone derivatives can be prepared in organic solvents such as methanol, ethanol, tetrahydrofuran, dimethylformamide, etc., for example, using pyridine, N,N-dimethylaniline, potassium acetate, etc. 1-acyl-2,3-dihydro-4(IH)- by reacting with hydroxylamine-O-sulfonic acid in the presence of an organic base, an inorganic base such as potassium carbonate, sodium carbonate, etc.
A quinolinone-4-oxime-〇-sulfonic acid derivative can be obtained.

Representative examples of the 1-acyl-2°3-dihydro-4(IH)-quinolinone-4-oxime derivatives prepared in this manner are shown in Table 1.

Second, we will discuss the efficacy, toxicity, and toxicity of representative compounds included in the present invention.
The usage, dosage, etc. will be explained using experimental examples.

Experimental example 1. Diuresis in dogs A mongrel dog weighing 7 to 15 kg was fasted for one day, fixed in the anterior position under artificial respiration and anesthesia with intravenous injection of 30 mg/kg pendoparbital, and 0,
Physiological saline was continuously infused at a rate of 15 ml/kg/min. After laparotomy, a catheter was inserted into the left ureter and 10
Urine was collected every minute and the urine volume was measured. The test compound was administered intravenously, and the rate of increase in urine volume was calculated using the following formula.

Increase in urine volume = [Urine volume for 90 minutes after administration - (Urine volume for 30 minutes before administration x 8)] Urine volume increase rate (%) = (Increase in urine volume due to test compound) ÷ (
The results are shown in Table 2.

Table 2 Diuretic effect in dogs A significant diuretic effect was observed in all compounds.

Experimental Example 2 Rat carrageenan paw edema suppressive effect Body weight approx. 12
0 g Wistar rats were used in groups of 3 to 5 rats. One hour after the oral administration of the test compound and phenylbutacin, 0.1 ml of a 1% carrageenan saline solution as an inflammatory agent was subcutaneously injected into the right hind paw mark of the rat, which had been previously dehaired. The volume of the right hind paw was measured before and 8 hours after administration of the inflammatory agent, and the difference was divided by the paw volume before administration to determine the edema rate. Further, the inhibition rate of each compound administration group was determined by setting the edema rate of the control group as 100, and the dose showing the inhibition rate of 30% was calculated and expressed as ED3o (mg/kg). The results are shown in Table 3.

Table 3 Rat carrageenan paw edema inhibitory effect All compounds were found to have a significant anti-edema effect.

Experimental Example 3 Antihypertensive effect in spontaneously hypertensive rats (SHR) Body weight 250-300g, blood pressure 170-19QmmHg
A group of 8 to 5 male SHRs were used. The test compound was administered on different days for 7 days, and blood pressure before and after the start of administration was measured using a plethysmograph. The results are shown in Table 4.

Table 4: Antihypertensive effect in SHR A significant hypotensive effect was observed in all compounds.

Experimental example 4. Ascites removal effect in tumor-bearing mice 6-7 week old BDF, mouse leukemia cells P3
106 pieces of 88 per animal were implanted intraperitoneally, and 2 days later, 1
The test compound was administered intravenously to a group of 6 animals, the amount of ascites was measured 5 hours later, and the ascites removal rate was calculated in comparison with the control group. The results are shown in Table 5.

Table 5: Ascites removal activity in tumor-bearing mice All compounds were found to have a stronger ascites removal activity than furosemide.

Experimental example 5. Acute toxicity experiment A test compound was administered intraperitoneally to a group of 5 ICR mice weighing 20 g, and the mortality rate was measured 7 days later. The results are shown in Table 6.

Table 6: Acute Toxicity The doses in the above experiments were all sufficiently large compared to the values showing pharmacological effects, so these compounds are highly safe.

As is clear from the above experimental examples, these compounds are
All have remarkable diuretic, anti-edema, antihypertensive, and ascites-removing effects, and are also extremely safe, and are sufficiently safe at doses that produce these pharmacological effects. Therefore,
These compounds are very useful in treating conditions such as liver and renal dysfunction, edema, congestive heart failure, hypertension, and cancerous ascites.

The compound of the present invention represented by general formula (1) can be made into a pharmaceutically acceptable salt form. In the form of salt,
For example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, salts with organic bases such as ammonium salts, benzylamine salts, diethylamine salts, and salts with amino acids such as arginine salts and lysine salts. I can give you salt.

These compounds are typically administered orally or intravenously, but can also be administered subcutaneously, intravenously or intramuscularly;
It can also be in the form of an inhalant, external preparation or suppository. The therapeutic dose for adults is 1-5,000 mg/day, preferably 10-5,000 mg/day.
The dosage is 1 r OOOmg/day, but it can be increased or decreased as appropriate depending on the symptoms or route of administration.

The compounds of the present invention can be prepared into pharmaceutical formulations in a conventional manner with any optional conventional pharmaceutical carriers, bases, or excipients.

For oral administration, capsules, tablets, granules, fine granules, powders, or oral liquid preparations; for intrarectal administration, rectal suppositories; for injections, aqueous solutions and pharmaceutically acceptable dispersion aids; For example, it is preferable to use a suspension using Tween 80 or Bum arabicum solution, an ointment for external use, and a spray for inhalation.

Next, examples of the present invention will be shown, but the present invention is not limited to the following examples.

Example 1 6-chloro-1-(2,4-dichlorobenzoyl)-2
Synthesis of ,3-dihydro-4(IH)-quinolinone 20 g of 6-chloro-2,3-dihydro-4(IH)-
Mix quinolinone, 26g of pyridine, and 200ml of dioxane, and heat to 30°C while stirring at 060 to 56C.
g of 2,4-dichlorobenzoyl chloride was added dropwise. After completion of the dropwise addition, the mixture was allowed to react at room temperature for 3 hours.

The reaction product was poured into 500 ml of water, and 11 dichloromethane was added to separate the layers. The organic layer was washed once with 100 ml of 1N hydrochloric acid, twice with 200 ml of water, and once with saturated brine, and after washing, dried over anhydrous sodium sulfate.

The solvent dichloromethane was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of dichloromethane-n-hexane to give white crystals 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro. -4(IH)-quinolinone 35
I got gt'.

Melting point: 176.8-177.8°C IR (KBr, cm-1): 1700+167
0, 1480. 139O NMR (CDCI3.I)I)m)'2,
87 (2H, t) 4, 22 (2H, t) 7, 07-8. 04 (6H.

m, aromatic) Example 2 8-chloro-1-(2,4-dichlorobenzoyl)-2
, 3-dihydro-4(IH)-quinolinone a) 30 g of 8-chloro-2,8-dihydro-4(IH)
)-quinolinone, 52 g of pyridine and 400 ml of dioxane were mixed, and 100 g of 2,4-dichlorobenzoyl chloride was added dropwise at room temperature while stirring. After the dripping is finished,
The reaction was carried out under reflux for 5 hours. After cooling, the same treatment as in Example 1 was performed to obtain 61 g of white crystals of 8-chloro-1-(2°4-dichlorobenzoyl)-4-[(2,4-dichlorobenzoyl)oxy]-1,2-dihydroquinoline. @Obtained.

b) 61 g of the above compound was dissolved in 400 ml of ethanol, and 4.5 g of sodium hydroxide was added over about 30 minutes while stirring and maintaining the temperature at 09°C to 5°C. After the addition was completed, the reaction was allowed to proceed at room temperature for 1 hour. The reaction product was poured into 11 portions of water, and 21 portions of dichloromethane were added to separate the layers. The organic layer was washed twice with 3,00 ml of water and once with saturated brine, and then dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of dichloromethane-n-hexane to obtain white crystals 8-
Chloro-1-(2,4-dichlorobenzoyl)-2゜8
32 g of -dihydro-4(IH)-quinolinone were obtained.

Melting point: 157.0-159.46CIR(KBr, am-1)'170C)
+1680.1440,128O NMR (CDCI3.ppm): 2.73 (2
H, t) 3.97 (2H, t) 6.73 7.84 (6H, m) Example 3 6-chloro-1-(2,4-dichlorobenzoyl)-2
Synthesis of ,3-dihydro-3-methyl-4(IH)-quinolinone 4.7 g of diisopropylamine and 100 ml of anhydrous tetrahydrofuran were mixed, and under stirring in a nitrogen stream, -
A 1.6N n-butyllithium hexane solution of 29:1 was added dropwise over 30 minutes while maintaining the temperature at 20°C to -15°C.

After the dropwise addition was completed, the temperature was raised to 0°C, and after stirring at the same temperature for 30 minutes, the reaction solution was cooled to -75°C with acetone-dry ice, and the same temperature was maintained to obtain the 6 -chloro-1-(2,4-dichlorobenzoyl)-2
, 15 g of 3-dihydro-4(IH)-quinolinone
A solution dissolved in 0 ml of anhydrous tetrahydrofuran was added dropwise over about 1 hour. After the completion of the dropwise addition, the reaction was carried out at -750C for 1 hour, and then 18g of methyl iodide was added dropwise over about 30 minutes while maintaining the same temperature.

After the dropwise addition was completed, the temperature was raised to Q'C over about 2 hours, and 2N hydrochloric acid was added under cooling to make it weakly acidic.
The mixture was poured into 1111ml of water, and 500ml of ethyl acetate was added to separate the liquids. The organic layer was washed with saturated saline, and after washing,
It was dried with anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel/hexane:ethyl acetate (4:1) to give white crystals of 6-chloro-1-(2,4-dichlorobenzoyl). -2,3-dihydro-3-methyl-4(IH)
- 7.8 g of quinolinone were obtained.

Melting point: 156.7-159,4°C IR (KBr, cm-”): 1690+1650.1
470.1385 NMR (CDCI3.ppm): 1.35 (3
H, d) 3, 61 (IH, m) 4, 38 (2H, d) 6.89-7.95 (6H, m) Example 4 7-chloro-1-(2,4-dichlorobenzoyl') −
Synthesis of 2,3-dihydro-4(IH)-quinolinone 25 g of 7-chloro-2,3-dihydro-4(IH)-
Quinolinone, 32 g of lysine, and 200 ml of dioxane were mixed, and 37 g of 2,4-dichlorobenzoyl chloride was added dropwise while stirring while maintaining the temperature at 0°C to 5°C. After the completion of the dropwise addition, the mixture was allowed to react at room temperature for 3 hours. The mixture was treated in the same manner as in Example 1 to obtain 43 g of white crystalline 7-chloro-1-(2,4-dichlorobenzoyl)-2°3-dihydro-4(IH)-quinolinone.

Melting point: 159.0-162.9°C 1660, 1395. 1195 NMR (CDCI3.pI)m):2
, 78 (2H, t) 4, 08 (2H, t) 7, 03-7. 95 (6H, m) Example 5 7-chloro-1-(2,4-dichlorobenzoyl)-2
,3-dihydro-4(IH)-quinolinone-4-dioxime-〇-potassium sulfonate (Compound 11) 7-chloro-1-(2,4-dichlorobenzoyl')- obtained in Example 4 14.5 g of 2,3-dihydro-4(IH)-quinolinone, 200 ml of methanol and 200 ml of
4. Mix ml of dichloromethane and stir at room temperature.
6g of hydroxylamine-〇-sulfonic acid was added.

After reacting for 30 minutes at room temperature, an aqueous solution of 5.6 g of potassium carbonate in 10 ml of water was added at once.

After stirring at room temperature for 2 hours, the precipitated crystals were removed by filtration, the solvent methanol and dichloromethane were distilled off from the filtrate under reduced pressure, and the residue was subjected to column chromatography using silica gel/dichloromethane:methanol (10:1). and then recrystallized from a mixed solvent of methanol and carbon tetrachloride to give white crystals of 7-chloro-1-(2,″4-dichlorobenzoyl)-2°3-dihydro-4(IH)-quinolinone-4- Potassium oxime-〇-sulfonate 10.
Obtained 0g.

Melting point: 217.56C (decomposition) IR (KB r, cm-''): 1660°1395.
124O NMR (DMSO-d6.ppm): 2.80
(2H, t) 3.59 (2H, t ) 7.12-7.93 (6H.

m, aromat lc) Example 6 Two-chloro-1-(2,4-dichlorobenzoyl)-2
, 7-chloro-1-(2,4-dichlorobenzoyl)-2 obtained in Synthesis Example 4 of sodium 3-dihydro-4(IH)-quinolinone-4-oxime-〇-sulfonate (compound 11), 14.5 g of 3-dihydro-4(IH)-quinolinone, 200 ml of methanol and 200 ml of
1 with dichloromethane and stirred at room temperature, 4.6
g of hydroxylamine-〇-sulfonic acid was added.

After reacting for 30 minutes at room temperature, an aqueous solution of 4.3 g of sodium carbonate in IQ ml of water was added at once.

After stirring at room temperature for 2 hours, the precipitated crystals were removed by filtration, the solvent methanol and dichloromethane were distilled off from the filtrate under reduced pressure, and the remaining liquid was mixed with silica gel/dichloromethane:methanol (10:1). Column chromatography was performed, followed by recrystallization with a mixed solvent of methanol and carbon tetrachloride to give white crystals of 7-chloro-1-(2,4-dichlorobenzoyl)-2°3-dihydro-4(IH)-quinolinone- Sodium 4-oxime-〇-sulfonate8.
Obtained 0g.

Melting point: 176.5°C (decomposed) IR (KBr, cm-'): 1670+1395.1
235 NMR (DMSO-ds, ppm): 3,'0
5 (2H, t) 3.90 (2H, t) 7.25-8.15 (6H.

ml aromatic) Example 7 Two-chloro-1-(2,4-dichlorobenzoyl)-2
, 3-dihydro-4(IH)-quinolinone-4-oxime-O-potassium sulfonate (compound 11) synthesis step 1) 7-chloro-1-(2,4-dichlorobenzoyl) obtained in Example 4 -2,3-dihydro-4(IH)-
Dissolve 17.5 g of quinolinone in 250 ml of ethanol, add 7 g of hydroxylamine hydrochloride and 8.5 g
of pyridine was added, and the mixture was reacted under reflux for 1.5 hours. The reaction product was poured into water in Step 11, filtered, washed with water, dried, and then recrystallized with ethanol to give white crystals 7-chloro-1-(2
, j-dichlorobenzoyl)-2,3-dihydro-4(
16 g of IH)-quinolinone-4-oxime were obtained.

Melting point: 230.7-232.8 °C IR (KBr, cm-1): 3250 1635.1420.945 NMR (DMSOda, I) pm): 2.7
2('2H,t) 3,'57(2H,t) 7.05 7.94(6H,m) Step 2) Dissolve 16g of the above compound in 250ml of dichloromethane, and add 7g of sulfur trioxide pyridine to this. After adding the complex salt and reacting at room temperature for 24 hours, about 15 Qml of the solvent dichloromethane was distilled off under reduced pressure. 200m for residual liquid
1 of methanol was added thereto, and an aqueous solution of 6 g of potassium carbonate dissolved in 1 Q ml of water was added thereto at once, followed by treatment in the same manner as in Example 5 to give white crystals of 7-chloro-1-(2,
4-dichlorobenzoyl)-2,3-dihydro-4(I
13 g of potassium H)-quinolinone-4-oxime-〇-sulfonate was obtained. The obtained product is! The R1 NMR spectrum and melting point completely matched the product obtained in Example 5.

Example 8 6-chloro-2,3-dihydro-1=(1-oxopropyl)-4(IH)-quinolinone-4-oxime-〇-
Synthesis of acetic acid (compound 14) 7.7 g of bromoacetic acid, 6.5 g of potassium hydroxide and 5 Q ml of water were mixed, and 6-chloro-2,3-dihydro-1-oxopropyl-4(IH)- was prepared under water cooling. Quinolinone
12.7 g of 4-year-old Kisim was added little by little. 24 at room temperature
After reacting for a period of time, the pH was adjusted to 3 with 2N hydrochloric acid under water cooling. The reaction product was poured into 150 ml of water, and 500 ml of ethyl acetate was added to separate the layers. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel/dichloromethane:methanol (9:1) to give white crystals of 6-chloro-2,8-
Dihydro-1-(1-oxopropyl)-4(IH)-
10.5 g of quinolinone-4-oxime-○-acetic acid was obtained.

Melting point: 142.8-144.0°C IR (KB r, cm-1): 3300-2800.1740°1650.1480,139O NMR (DMSOd6+ ppm): 1.03
('3H, t) 2, 52 (2H, q) 2, 84 (2H, t) 3, 79 (2H, t) 4, 69 (2H, s) 7, 26-7, 75 (3H.

m, aromat lc) Example 9 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(IH)-quinolinone-4-oxime-〇-
Synthesis of phosphoric acid monomethyl ester (compound 15) - 7,5 g of 6-chloro-2,3-dihydro-1-(1
-oxopropyl')-4(IH)-quinolinone-4-
To a solution of oxime dissolved in 1.50 ml of anhydrous tetrahydrofuran, 21 ml of a 1.6N n-butyllithium hexane solution was added dropwise over 30 minutes while stirring and maintaining the temperature at -75°C in a nitrogen stream. After the addition was completed, the mixture was stirred at the same temperature for 80 minutes, and then 4.9 g of methyl dichlorophosphate was added dropwise over 30 minutes.

After completion of the dropwise addition, the mixture was reacted at -70 to -6060 for 2 hours, and then the temperature was raised, and the pH was adjusted to 2 with 1N hydrochloric acid water while cooling with water.

After reacting at room temperature for 5 hours, the reaction product was poured into 200 ml of water, and 50 Q ml of ethyl acetate was added to separate the layers.

The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure.
The residue was dissolved in silica gel/dichloromethane:methanol (19
: 1) to obtain white crystals 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(IH)-quinolinone-4-oxime-〇-phosphate monomethyl ester 7゜2g was obtained.

Melting point near 1,0-75.0'C IR (KBr, cm"): 3420°2950.1680,1395°NMR (DMSO-d6.ppm): 1,0
1 (3H, t) 2. 50(21(,q) 2, 88(2H,t) 3, 62(3H,d) 3, 78(2H,t) 7, 22-7. 85(3M.

m, aromatic) Example 10 6-chloro-1-(2,4-dichlorobenzoyl)-2
,3-dihydro-4(1)J)-quinolinone-4-oxime mesylate 10 g of 6-chloro-1-(2,
4-dichlorobenzoyl)-2,3-dihydro-4(I
H)-quinolinone-4-dioxime and 4.1 g of triethylamine and 150 ml of dichloromethane were mixed;
While stirring and maintaining the temperature at -20°C, 3.5 g of methanesulfonyl chloride was added dropwise. After dropping, react at the same temperature for 30 minutes, add 300ml of dichloromethane,
It was washed successively with normal hydrochloric acid, saturated sodium bicarbonate, and then saturated brine, and then dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the residue was dissolved in ether-n-
Recrystallize with a mixed solvent of hexane to produce white crystals of 6-chloro-
11 g of 1-(2,4-dichlorobenzoyl)-2<3-dihydro-4(IH)-quinolinone-4-oxime mesylate was obtained.

Melting point=197.4-198.1°C IR(KB l"lam-')' 166()+
1365.118O NMR (DMSO-d6.ppm): 3.03
(2H, t) 3.38 (3H, s) 3.72 (2H, t") 7.12-7.92 (6H.

Example 11 Synthesis of 7-chloro-2,8-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone 20 g of 7-chloro-2,3-dihydro-4(IH)
-Quinolinone and 26 g of pyridine were mixed in 200 ml of dichloromethane, and 26 g of 2-methylbenzoyl chloride was added dropwise at room temperature while stirring. After the dropwise addition was completed, the mixture was heated under reflux for 4 hours. Pour the reaction mixture into 50'Oml of water,
11 of dichloromethane was added to separate the layers. organic layer t'l
Once with ooml of 1N hydrochloric acid, twice with 200ml of water,
The mixture was washed with saturated brine once and then dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the remaining liquid was crystallized with diethyl ether to give white crystals 7-
28 g of chloro-2,9-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone was obtained.

Melting point: 106.5-108.1°C IR (KBr, cm-'): 1695+1655.1
405.138O NMR (CDCI3 1 1) pm)'2,
34 (3H, s) 2, 80 (2H, t) 4, 16 (2H, t) 7, 00 8. 00(7H,m) Example 12 Potassium 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4-oxime-〇-sulfonate (compound 6) 7-chloro-2,3-dihydro-1 obtained in Synthesis Example 11
-(2methylbenzoyl)-4(IH)-quinolinone 1
0 g, 150 ml of methanol and 100 ml of dichloromethane were mixed, and 11 g of hydroxylamine-O-sulfonic acid was added under stirring at room temperature.

After reacting for 80 minutes at room temperature, an aqueous solution of 14 g of potassium carbonate in 20 ml of water was added at once. After stirring at room temperature for 2 hours, the solvents methanol and dichloromethane were distilled off under reduced pressure, and the residual liquid was subjected to column chromatography using silica gel/dichloromethane:methanol (5:1), and then column chromatography using methanol-carbon tetrachloride. Recrystallize from a mixed solvent to obtain white crystals of potassium 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4-oxime-〇-sulfonate12.
Obtained 0g.

Melting point: 189,0°C (decomposed) IR (KBr, cm-1): 1660°1380.12
4O NMR (DMSOds, Plum): 2.22 (
3H,s) 2.81(2H,trs 3.73(2H,t) 6.90-7.95 (7H,m) Example 13 7-chloro-2,3-dihydro-1-(2-methyl benzoyl)-4(IH')-quinolinone-4-oxime-
〇-Potassium sulfonate (compound 6) synthesis step 1) 14.9 g of 7-chloro-2゜3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone obtained in Example 11 was added to 250 ml. dissolved in ethanol,
To this, 7 g of hydroxylamine hydrochloride and 8.5 g of pyridine were added, and the mixture was reacted under reflux for 1.5 hours. The reactant Th1+ was poured into water, filtered, washed with water, dried, and then recrystallized with ethanol to give white crystals of 7-chloro-2,3-
Dihydro-1-(2-methylbenzoyl)-4(LH)
-quinolinone-4-oxime 13.6. I got g.

Melting point: 166.0-16f3.4°C IR (KBr, cm""): 3330 1635.140O NMR (DMSOda, I) pm): 2, 20
(3H,""s) 2.81 (2H, t) 3, 77 (2H, t) 7, . 05-7. 98 (7H, m) Step 2) Dissolve 13.6 g of the above compound in 250 ml of dichloromethane, add 7 g of sulfur trioxide pyridine complex salt, and react at room temperature for 24 hours. It was distilled off under reduced pressure. Add 200ml of methanol to the residual liquid, and add 6g of potassium carbonate to this for 10 minutes.
After adding at once an aqueous solution dissolved in ml of water, Example 1
2, white crystals 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4-oxime-〇-sulfonate potassium 1
3g was obtained. The obtained product had completely identical R, NMR spectra and melting point to the product obtained in Example 12.

Example 14 7'-chloro-6-fluoro-2,3-dihydro-1-
(2-methylbenzoyl)-4(1H)-quinolinone-
Potassium 4-oxime-〇-sulfonate (compound 18)
Synthesis step 1) Using 3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate as raw materials, W. Nis-Johnson et al. (Journal of the American Chemical Society, Vol. 71, p. 1901, 1949 38 g of 3-(3-chloro-4-fluorophenylamino)propionic acid synthesized according to the method of
was added to 600 g of polyphosphoric acid and heated at 110°C for 70
Stir for a minute.

The reaction mixture was poured into 1.5 liters of ice water, and 1.5 liters of dichloromethane was added thereto for separation. The organic layer was washed twice with 300 ml of saturated brine, and then dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel/hexane:ether (4:1) to obtain pale yellow crystals 7-
Chloro-6-fluoro-2°3-dihydro-4 (IH)
-20gt of quinolinone- was obtained.

Melting point: 192.0-194.0°C IR (KBr, cm-'): 3350°1645.12
50,116O NMR (DMS Ode + CD CI
3ppm): 2.61 (2H, t) 3.52 (2H, t) 6.83 (IH, d) 7.43 (IH, d) Step 2) 15 g of the compound obtained in Step 1, 2-methyl A reaction was performed in the same manner as in Example 11 using 17 g of benzoyl chloride, 12 g of pyridine, and 200 ml of dichloromethane to obtain 7-chloro-6-fluoro-2,3''-dihydro-1-(2-methylbenzoyl)-4 (IH). -21 g of quinolinone were obtained.

Melting point: 84.9-88.7°C IR (KBr, cm''): 1700+1665.1
480.137O NMR (CD CI3 1 ppm) ”2
．． 38 (3H, s) 2, 81 (2H, t) 4, 16 (2H, t) 7, 16 7.78 (6H, m) Step 3) 10 g of the compound obtained in Step 2, hydroxylamine-〇- Sulfonic acid 3.6g, potassium carbonate 4.4
The reaction was carried out in the same manner as in Example 12 using g and 1°Oml of methanol to give 7-chloro-6-fluoro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4- Potassium oxime-〇-sulfonate 4g
I got it.

Melting point: 204.16C (decomposed) IR (KBr, cm-1): 1650°1375.12
1O NMR (DMSO-d6.ppm): 2.23
(3H,' s ) 2.82 (2H, t ) 3.75 (2H, t ) 7, 16 7. 79 (6H, m) The compounds of Examples 15 to 266 are shown in Table 3 with their melting points or IR and NMR data (data marked with * were measured at 60 MHz, other data were measured at 90 MHz). The results are summarized in Table 18.

Synthesis methods for these compounds are classified into five types shown in Table 7.

Kodan bag! NMR smooth data marked with * was measured at 60MHz.

NMR spectrum data marked with * were measured at 60 MHz.

凰LQL 1st place. n OR1 Thinking 1 and OR1 1st lantern ORl 1U Kokodan table Star! Thoughts 11 Next, examples of formulations containing the compounds of the present invention will be shown.

Example A Capsule Compound 6 40g Lactose 645g Magnesium stearate 15g The above components were each weighed on a weighing plate and mixed uniformly. The mixed powder is filled into N091 hard capsules in an amount of 350 mg each to form capsules.

Example B Tablet Compound 11 50g Lactose 800g Potato starch 120g Polyvinyl alcohol 15g Magnesium stearate 15g After weighing the above ingredients, Compound 11, lactose, and potato starch are mixed uniformly. An aqueous solution of polyvinyl alcohol is added to this mixture, and granules are prepared by wet granulation. The granules are dried, mixed with magnesium stearate, and compressed into tablets weighing 200 mg.

Example C Powder Compound 7 100g Lactose 890g
Magnesium stearate 10g After weighing each of the above ingredients, mix them uniformly and add 10g of magnesium stearate.
% defeating agent.

Example D Suppositories Compound 4 100 g Polyethylene glycol 1500 180 g Polyethylene glycol 4000 720 g Compound 4 was ground well in a mortar to form a fine powder, and then made into a rectal suppository by a melting method.

Compound 7 1g Sterile distilled water for injection 200ml After weighing Compound 7, dissolve it in sterile distilled water for injection,
After sterilization by filtration, dispense 2 ml into 5 ml ampoules and seal them to prepare an injection.

Claims (57)

[Claims] (1) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is a straight or branched alkyl group having 1 to 8 carbon atoms, a carbon atom A linear or branched halogenated alkyl group having numbers 1 to 4, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkoxy group, a methoxymethyl group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, pyridyl group, thienyl group, pyrazinyl group, phenyl group, or straight or branched chain alkyl group having 1 to 4 carbon atoms, hydroxyl group, nitro group,
Represents a phenyl group substituted at any position with 1 to 5 substituents of the same type or different types selected from the group consisting of a lower alkoxy group, a trifluoromethyl group, and a halogen atom, and R^2 and R^3 are same or different;
Represents a hydrogen atom or a methyl group, R^4 represents a carboxymethyl group, sulfo group, methanesulfonyl group or methoxyphosphoryl group, R^5 and R^6 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, Methylthio group, methylsulfinyl group, methanesulfonyl group, N
, N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group, and the wavy line represents a syn-type or anti-type bond. ) 1−
Acyl-2,3-dihydro-4(1H)-quinolinone-
4-oxime derivatives, salts, solvates and solvates of salts thereof. (2) The compound according to claim 1, wherein R^4 is a sulfo group. (3) The compound according to claim 2, wherein at least one of R^5 and R^6 is a halogen atom at the 7-position. (4) The compound according to claim 3, wherein R^1 is a phenyl group. (5) The compound according to claim 3, wherein R^1 is a 2-halophenyl group. (6) The compound according to claim 3, wherein R^1 is a 2-methylphenyl group. (7) The compound according to claim 3, wherein R^1 is a 2-ethylphenyl group. (8) The compound according to claim 3, wherein R^1 is a 2-trifluoromethylphenyl group. (9) The compound according to claim 3, wherein R^1 is a 2-methoxyphenyl group. (10) The compound according to claim 3, wherein R^1 is a 2-nitrophenyl group. (11) The compound according to claim 3, wherein R^1 is a 4-chlorophenyl group. (12) The compound according to claim 3, wherein R^1 is a 2,4-dichlorophenyl group. (13) The compound according to claim 3, wherein R^1 is a 2,4-dimethylphenyl group. (14) The compound according to claim 3, wherein R^1 is a 2,6-difluorophenyl group. (15) The compound according to claim 3, wherein R^1 is a 2,3-dimethoxyphenyl group. (16) The compound according to claim 3, wherein R^1 is a 4-chloro-2-methylphenyl group. (17) The compound according to claim 3, wherein R^1 is a 1,1-dimethylethyl group. (18) The compound according to claim 3, wherein R^1 is a 2-chloro-1,1-dimethylethyl group. (19) The compound according to any one of claims 1 to 18, wherein the bond indicated by the wavy line is of the syn type. (20) General formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is a straight or branched alkyl group having 1 to 8 carbon atoms, a carbon atom A linear or branched halogenated alkyl group having numbers 1 to 4, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkoxy group, a methoxymethyl group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, pyridyl group, thienyl group, pyrazinyl group, phenyl group, or straight or branched chain alkyl group having 1 to 4 carbon atoms, hydroxyl group, nitro group,
Represents a phenyl group substituted at any position with 1 to 5 substituents of the same type or different types selected from the group consisting of a lower alkoxy group, a trifluoromethyl group, and a halogen atom, and R^2 and R^3 are same or different;
Represents a hydrogen atom or a methyl group, and R^5 and R^6 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group, a methylsulfinyl group, a methanesulfonyl group, an N,N-dimethylamino group, a nitro group , represents an acetyl group, a methyl group, a trifluoromethyl group, a methoxycarbonyl group or a methoxy group. ) is reacted with hydroxylamine to form the corresponding 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-
The general formula ( I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is a straight or branched alkyl group having 1 to 8 carbon atoms, or a straight chain having 1 to 4 carbon atoms. Chain or branched halogenated alkyl groups, C3-C6 cycloalkyl groups, lower alkoxy groups, methoxymethyl groups, methoxycarbonylethyl groups, benzyl groups, styryl groups, naphthyl groups, pyridyl groups, thienyl groups, pyrazinyl group, phenyl group, or straight or branched chain alkyl group having 1 to 4 carbon atoms, hydroxyl group, nitro group,
Represents a phenyl group substituted at any position with 1 to 5 substituents of the same type or different types selected from the group consisting of a lower alkoxy group, a trifluoromethyl group, and a halogen atom, and R^2 and R^3 are same or different;
Represents a hydrogen atom or a methyl group, R^4 represents a carboxymethyl group, sulfo group, methanesulfonyl group or methoxyphosphoryl group, R^5 and R^6 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, Methylthio group, methylsulfinyl group, methanesulfonyl group, N
, N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group, and the wavy line represents a syn-type or anti-type bond. ) 1−
Acyl-2,3-dihydro-4(1H)-quinolinone-
A method for producing a 4-oxime derivative, a salt, a solvate thereof, and a solvate of the salt. (21) General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1, R^2, R^3, R^5 and R^6
has the same meaning as above. ) in the presence of an organic base such as pyridine, N,N-dimethylaniline, or potassium acetate, or an inorganic base such as potassium carbonate or sodium carbonate in the 1-acyl-2,3-dihydro-4(1H)-quinolinone derivative represented by General formula (III) characterized by reacting hydroxylamine-O-sulfonic acid below: ▲Mathematical formula, chemical formula, table, etc.▼(III) (In the formula, R^1 is a carbon atom number of 1 or 8 straight-chain or branched alkyl group, straight-chain or branched halogenated alkyl group having 1 to 4 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group, pyrazinyl group, phenyl group, or straight or branched chain alkyl group having 1 to 4 carbon atoms, hydroxyl group, nitro group,
Represents a phenyl group substituted at any position with 1 to 5 substituents of the same type or different types selected from the group consisting of a lower alkoxy group, a trifluoromethyl group, and a halogen atom, and R^2 and R^3 are same or different;
Represents a hydrogen atom or a methyl group, and R^5 and R^6 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group, a methylsulfinyl group, a methanesulfonyl group, an N,N-dimethylamino group, a nitro group , represents an acetyl group, a methyl group, a trifluoromethyl group, a methoxycarbonyl group, or a methoxy group, and the wavy line represents a syn
) type or anti type bond. ), a method for producing a 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acid derivative, a salt, a solvate thereof, and a solvate of the salt. (22) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is a straight or branched alkyl group having 1 to 8 carbon atoms, a carbon atom A linear or branched halogenated alkyl group having numbers 1 to 4, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkoxy group, a methoxymethyl group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, pyridyl group, thienyl group, pyrazinyl group, phenyl group, or straight or branched chain alkyl group having 1 to 4 carbon atoms, hydroxyl group, nitro group,
Represents a phenyl group substituted at any position with 1 to 5 substituents of the same type or different types selected from the group consisting of a lower alkoxy group, a trifluoromethyl group, and a halogen atom, and R^2 and R^3 are same or different;
Represents a hydrogen atom or a methyl group, R^4 represents a carboxymethyl group, sulfo group, methanesulfonyl group or methoxyphosphoryl group, R^5 and R^6 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, Methylthio group, methylsulfinyl group, methanesulfonyl group, N
, N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group, and the wavy line represents a syn-type or anti-type bond. ) 1−
Acyl-2,3-dihydro-4(1H)-quinolinone-
1. A diuretic, antihypertensive, antiedema and ascites removing agent, which contains as an active ingredient at least one of a 4-oxime derivative, a salt, a solvate, and a solvate of the salt. (23) Claim 22 in which R^4 is a sulfo group
Diuretic, antihypertensive, anti-edema and ascites-removing agents as described in Section 1. (24) At least one of R^5 and R^6 is 7
The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 23, which is a halogen atom. (25) Claim 2 in which R^1 is a phenyl group
The diuretic, antihypertensive, antiedema and ascites removing agent according to item 4. (26) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2-halophenyl group. (27) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2-methylphenyl group. (28) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is 2-ethylphenyl group. (29) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2-trifluoromethylphenyl group. (30) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2-methoxyphenyl group. (31) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2-nitrophenyl group. (32) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 4-chlorophenyl group. (33) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2,4-dichlorophenyl group. (34) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2,4-dimethylphenyl group. (35) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2,6-difluorophenyl group. (36) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2,3-dimethoxyphenyl group. (37) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 4-chloro-2-methylphenyl group. (38) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 1,1-dimethylethyl group. (39) The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R^1 is a 2-chloro-1,1-dimethylethyl group. (40) The diuretic, antihypertensive, antiedema and ascites removing agent according to any one of claims 22 to 39, wherein the bond indicated by the wavy line is syn type. (41) General formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is a straight or branched alkyl group having 1 to 8 carbon atoms, a carbon atom A linear or branched halogenated alkyl group having numbers 1 to 4, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkoxy group, a methoxymethyl group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, pyridyl group, thienyl group, pyrazinyl group, phenyl group, or straight or branched chain alkyl group having 1 to 4 carbon atoms, hydroxyl group, nitro group,
Represents a phenyl group substituted at any position with 1 to 5 substituents of the same type or different types selected from the group consisting of a lower alkoxy group, a trifluoromethyl group, and a halogen atom, and R^2 and R^3 are same or different;
Represents a hydrogen atom or a methyl group, and R^5 and R^6 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group, a methylsulfinyl group, a methanesulfonyl group, an N,N-dimethylamino group, a nitro group , represents an acetyl group, a methyl group, a trifluoromethyl group, a methoxycarbonyl group or a methoxy group. ), 1-
Acyl-2,3-dihydro-4(1H)-quinolinone-
1- which is an intermediate compound in the synthesis of 4-oxime derivatives
Acyl-2,3-dihydro-4(1H)-quinolinone derivative. (42) At least one of R^5 and R^6 is 7
42. The compound according to claim 41, which is a halogen atom. (43) Claim 4 in which R^1 is a phenyl group
Compound according to item 2. (44) The compound according to claim 42, wherein R^1 is a 2-halophenyl group. (45) The compound according to claim 42, wherein R^1 is a 2-methylphenyl group. (46) The compound according to claim 42, wherein R^1 is a 2-ethylphenyl group. (47) The compound according to claim 42, wherein R^1 is a 2-trifluoromethylphenyl group. (48) The compound according to claim 42, wherein R^1 is a 2-methoxyphenyl group. (49) The compound according to claim 42, wherein R^1 is a 2-nitrophenyl group. (50) The compound according to claim 42, wherein R^1 is a 4-chlorophenyl group. (51) The compound according to claim 42, wherein R^1 is a 2,4-dichlorophenyl group. (52) The compound according to claim 42, wherein R^1 is a 2,4-dimethylphenyl group. (53) The compound according to claim 42, wherein R^1 is a 2,6-difluorophenyl group. (54) The compound according to claim 42, wherein R^1 is a 2,3-dimethoxyphenyl group. (55) The compound according to claim 42, wherein R^1 is a 4-chloro-2-methylphenyl group. (56) The compound according to claim 42, wherein R^1 is a 1,1-dimethylethyl group. (57) The compound according to claim 42, wherein R^1 is a 2-chloro-1,1-dimethylethyl group.